CA1183841A - Bicyclic prostaglandins and process for their preparation - Google Patents
Bicyclic prostaglandins and process for their preparationInfo
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- CA1183841A CA1183841A CA000366521A CA366521A CA1183841A CA 1183841 A CA1183841 A CA 1183841A CA 000366521 A CA000366521 A CA 000366521A CA 366521 A CA366521 A CA 366521A CA 1183841 A CA1183841 A CA 1183841A
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- methyl ester
- dihydroxy
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides a compound of formula I
(I)
The invention provides a compound of formula I
(I)
Description
The present invention relates to 2-oxa-bicyclic prosta-glandins, to a method for their preparation and to pharmaceutical and veterinary compositions containing them.
The compounds of the invention are 2 oxa~bicyclic prostaglandins of formula (I) H X ( 2)4 R
~, B~ I
~I
~ ~2 ~3 HO Y-C (CH2)n -~C-X (CH2)n2 6 ~4 wherein R is a free or esterified carboxy group; Y is -CH2CII2- or -CH=CH-trans; R2 is hydrogen; R5 is hydroxy; R3 is hydrogen or Cl-C6 alkyl; R4 is hydrogen or Cl-C6 alkyl; nl is zero or an integer of 1 to 6; n2 is zero, 1 or 2; X is -O- or -(CH2)m-, wherein m is zero or l; R6 is hydrogen, Cl-C4 alkyl or an unsub-stituted C3-C9 cycloaliphatic radical, provided that (a) when X
is -O- and n2 is zero R6 is Cl-C4 alkyl or an unsubstituted C3-Cg cycloaliphatic radical; (b) when X is -O- and n2 is 1 or 2 R6 is Cl-C4 alkyl, and (c) when X is -(CH2)m- R6 is hydrogen or Cl-C4 alkyl and nl is zero, 1 or 2, n2 is zero.
Also the pharmaceutically or veterinarily acceptable salts as well as the optical antipodes, i.e. the enantiomers, the racemic mix-tures of the optical antipodes, the geometric isomers and their mixtures and the mixtures of -the diastereoisomers of the compounds oE formula (I) are included in the scope of the present ~4 ,.1~1 ~3~
invention.
In the formulae of this specification the broken line (--..) indicates that a substituent bound to the cyclopentane ring is in the ~-configuration, i.e. below the plane of the ring, a substituent bound to the 2-oxa-bicyclic system is in the endo-configuration and a substituent bound to a chain is in the S-configuration; the heavy solid line ( _ ) indicates that a sub-stituent bound to the cyclopentane ring is in the ~-configuration, i.e. above the plane of the ring, a substituent bound to the 2-oxa-bicyclic system is in the exo-configuration and a substituent bound to a chain is in the R-configuration; the wavy line attach-ment (~) indicates that a substituent do~s not possess a definite stereochemical identity i.e. that a substituent bound to the cyclopentane ring may be both in the ~- and in the ~-configuration, a substituent bound to the 2-oxa-bIcyclic system may be both in the endo- or in the exo-configuration and a substituent bound to a chain may he both in the S- and in the R-configuration.
In the compounds of the above formula (I) the heterocyclic ring B is cis-fused with the cyclopentane ring A and the two bonds indicated by the dotted lines (...) are both in the ~-configuration with respect to the ring A.
The side chain ~-linked to the cyclopentane ring A is in trans-configuration with respect to the ~-fused heterocyclic ring B and consequently it is an exo substituent with respect to the 2-oxa-bicyclic system.
The ca;rbon atom of the heterocyclic ring B bearing the side chain ~(C~I2)~-~ bears also an hydrogen atom.
i` ;~~'~' When the side chain V~V~(CH2)4-R is in the endo-con~igura-tion with respect to the 2-oxa-bicyclic system, then said hydrogen atom is an exo-substituent and its absolute con~iguration is reported as ~ while when the chain ~V(CH2)~-R is in the exo-configuration, then said hydrogen atom is an endo-substituent and its absolute configuration is reported as ~.
The compounds of the invention wherein the chain ~ (CH2)~-R is in the exo-configuration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-Qxide prostanoic acid derivatives (prostaglandin numbering), while the compounds wherein the chain ~(CH2)4-R is in the endo-configuration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-oxide prostanoic acid derivatives (prostaglandin numbering).
Alternatively the 6~H-6,9~-oxide prostanoic acid derivatives are reported as (2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-alkanoic acid derivatives, and the 6~H-6,9~-oxide prostanoic acid derivatives as (2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-alkanoic acid derivatives.
The 6~H-6,9~-oxide prostanoic acid derivatives have a higher chro-matographic mobility (i.e. a higher Rf~ and a less positive : rotatory power ([~]D~ than the corresponding 6~H-6,9~-oxide derivatives.
All the above notations refer to the natural compounds;
the d,l-compounds are mixtures containing equimolar amounts oE
nat-compounds which possess the above reported absolute stereo-chemistry and of ent-compounds which are mirror-like images of the .'...,~, ~l83~
formers; in the ent-compounds the stereochemical configuration is the opposite at all the asymmetric centers with respect to the configuration of the natural compounds and the prefix ent indicates jus~ this.
The alkyl groups are branched or straight chain groups.
A Cl-C6 alkyl group is preferably methyl, ethyl or propyl.
When R is an esterified carboxy group it is preferably a -COORC group wherein Rc is a Cl-C12 alkyl radical, in particular methyl, ethyl, propyl and heptyl, or a C2-C12 alkenyl radical, in particular allyl.
nl is preferably zero or an integer of 1 to 3; n2 is preferably 1 or 3.
When R6 is a C3-Cg cycloaliphatic radical, it is prefer-ably a C3-Cg cycloalkyl radical e.g. cyclopentyl, cyclohexyl and ; cycloheptyl or a C3-C~ cycloalkenyl radical, e.g. cyclopentenyl, cyclohexenyl and cycloheptenyl.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) are e.g. those with pharmaceutically and veterinarily acceptable bases. Pharmaceutically and veterinarily acceptable bases are either inorganic bases such as, for example, alkaline hydroxides and alkaline-earth hydroxides as well as aluminium and zinc hydroxides or organic bases e.g. organic amines such as, for example, methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, N-methyl-N-hexylamine~ decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzyl~
amine, dibenzylamine, ~-phenyl-ethylamine, ~-phenyl-ethylamine, ethylenediamine, diethylenetriamine, morpholine, piperldine, ~38~
pyrrolidine, piperazine, as well as the alkyl derivatives of the latter four bases, mono-, di- and tri-ethanolamine, ethyl-diethanol-amine, N-methyl-ethanolamine, 2-amino-1-butanol, 2-amino-2-methyl-l-propanol, N-phenyl-ethanolamine, galactamine, N-methyl-glucamine r N-methyl-glucosamine, ephedrine, procaine, dehydroabietilamine, lysine, arginine and other ~ or ~ amino acids. Preferred salts of the invention are those of the compounds of ~ormula (I) wherein R is -COORd wherein Rd ls a pharmaceutically or veterinarily acceptable cation deriving from one of the above mentioned bases.
Particularly preferred compounds of the invention are 6~H-6t9~-oxide compounds of formula (I) wherein R is a free carboxy group and ~6 is Cl-C4 alkyl or C5-C7 cycloalkyl The prefixes nor, dinor, trinor, tetranor- etc., are used to identify the compounds of formula (I) wherein the side chain bound to the cyclopentane ring A is one, two, three, four, etc. carbon atoms shorter than the analogous chain in the natural prostaglandins.
Specific examples of preferred compounds of the invention are the following:
13t-6~H-6,9~-oxide~ ,15S-dihydroxy-prost-13-enoic acid;
13-6~H-6,9~-oxide-11~,15S-dihydroxy-prostanoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-20-methyl-prost-13-enoic acld;
13t-6~H-6,9~-oxide~ ,15S-dihydroxy-20-methyl-prostanoic acid;
13t-6~H 6,9~-oxide-11~,15S-dihydroxy-16,16-dimethyl-prost-13-enoic acidî
13t-6~H-6,~-oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-13-enoic acid;
.!~
3~
13t-6~H-6,9~-oxide 11~,15S-dihydroxy~20-ethyl-prost-13~enoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-16S methyl-prost-13-enoic acid;
13t-6~H-6,9~-oxide-lla,15S-dihydroxy-16R-methyl-prost-13-enoic acid; as well as the 15R-epimers and the 6~H-diastereo-isomers of all the compounds mentioned above.
The compounds of the invention are prepared by a process comprising: reacting a compound o:E formula (IV) H~,~(CH23~-R
~ 2 A (IV) Rl CHO
wherein R is as defined above and Rl is hydroxy or a protecting group bound to the ring by an ethereal oxygen atom, with a compound of formula (V) (_) 1 ~ 2 6 (V) (+) wherein E is a group (.C6H5)3P- or a group (ReO)2P- wherein each of the Re groups, which are the same or different, is alkyl or aryl and R3, R4, nl, n2, X and R6 are as defined above, so obtaining, a~ter the remova:L of the known protecting groups, if present, a compound corresponding to one of formula I wherein R2 and R5, taken f ~3 ~i33~
together, form an oxo group and Y is trans~CH=CH- and reducing the obtained compound to give a compound of formula I ~herein one of R2 and ~5 is hydrogen and the other is hydroxy and Y is trans-CH=
OEI-, and, if desired, hydrogenating the compound of formula I
wherein Y is trans-CH=CH- to give a compound of formula I wherein Y is -CX2CH2- or hydrogenating a compound corresponding to one of formula I wherein ~2 and R5~ taken together, form an oxo group and Y is trans-CH=C~-, to give a compolmd corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is -CH2CH2- and reducing the obtained compound to give a compound of formula ~ wherein Y is -CH2-CH2- and/or, if desired, converting a compound of formula I into another compound of formula I and/or, if desired, salifying a compound of formula I and/or, if desired, obtaining a free compound of formula I from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
The known protecting groups, i.e., other groups, are convertible to hydroxy groups under mild reaction conditions, e.g., acid hydrol~sis. Examples are acetal ethers, enol ethers and silyl ethers~ The preferred groups are (CH3)3-SiO- , ~ OAlk O \S i - O-O- , - O - ~ ~ , CH / ¦
OAlk 3 ¦ 3 -- 7 ~
38~
wherein W is -O- or -CH2- and Alk is a lower alkyl group.
The diastereoisomer wherein the chain ~(CH2)4-R is in the exo-configuration may be separated from the diastereoisomer wherein said chain is in the endo configuration by fractional crystallization e.g. from diethylether but preferably by thin layer preparative chromatography, by column chromatography or by high speed liquid chromatography.
The separation by thin layer preparative chromatography or by column chromatography is preferably carried out on a support of silica gel or magnesium silicate with methylene chloride, diethylether, isopropylether, ethylacetate, benzene, methyl acetate, cyclohexane or their mixtures as elution solvents.
When in the compound of formula (V~ E is (ReO)2 ~-, wherein Re is aryl, it is preferably phenyl; when Re is alkyl, it is preferably Cl-C6 alkyl. The reaction between an aldehyde of formula (IV) and a compound of formula (V) is carried out with an excess of the compound of formula (V), e.g., at least 1.01 molar equivalent of the compound of formula ~V) for each mole of the compound of formula ~IV).
2Q Any inert solvent can be used, such as linear and cyclic ethers, e.g. ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, aliphatic or aromatic hydrocarbons, e.g., n-heptane, n-hexane, benzene, toluene or halogenated hydrocarbons, e.g. methylene-chloride, tetrachloroethane and also mixtures of these solvents.
The reaction temperature may vary between the freezing and the boiling points o~ the solvent.
When the reaction is carried out with a compound of 3~
formula (V) wherein E is (ReO)2~ the preferred temperature is the room temperature i~e. from about 10C to about 25C, when the reaction is carried out with a compound of formula (V) wherein E
is (C6H5)3(~), the preferred temperature is the reflux temperature of the solvent.
The product of the reaction between a compound of formula (IV) and a compo~nd of formula (V) is a mixture of a compound of formula (I) wherein Y is trans-CH=CH- and a compound of formula (I) wherein Y is cis-CH=CH-, in a ratio varying between approxi-mately 90:10 and 95:5.
The compound of formula (I) wherein Y is trans-CH=CH-, may be separated from the mixture by crystallization with a suit-able solvent, while the compound of formula (I) wherein Y is cis-CH=CH-, may be obtained by concentration of the mother liquor and subsequent chromatographic separation of the residue, either by column or preparation TLC chromatography using silica gel or magnesium silicate as support and e.g. methylene chloride, diethyl-ether, isopropylether, ethylacetate, benzene, cyclohexane or their mixtures as elution solvents.
The removal of the known protecting groups bound to the ring or to the chain by an ethereal oxygen atom is, whenever required, performed under conditions of mild acid hydrolysis, for example with a mono~ or poly~carboxylic acid such as formic, acetic, oxalic, citric and tartaric acid, and in a solvent, which may be water, acetone, tetrahydrofuran, dimethoxyethane or a lower aliphatic alcohol, or with a sulphonic acid, e.g., p-toluenesulphonic _ g _ ~3~
acid in a solvent such as a lower aliphatic alcohol, dry methanol or dry ethanol, for example, or with a polystyrene-sulphonic resin.
For example, 0.1 to 0.25 N poly-carboxylic acid (e.g., oxalic or citric acid) is used in the presence of a convenient low-boiling co-sol~ent which is miscible with water and which can be easily removed in vacuo at the end of the reaction .
The reduction of a compound of formula (I) wherein R2 and R5, taken together form an oxo group, and Y is -CH=CH-, to give a compound of formula (I) wherein Y is -CH=CH-, and wherein one of R2 and R5 is hydrogen and the other is hydroxy, must be regarded as an application of a reaction which is a 1.2 polar addition to the carbonyl group. The reduction of an obtained compound of formula (I) wherein R2 and R5 taken together form an oxo group, and Y is -CH=CE-, to give a compound of formula (I) wherein Y is -CH~CH-, and wherein one of R2 and R5 is hydrogen and the other is hydroxy, is preferably carried out with alkaline or alkaline-earth metal borohydrides, preferably sodium, lithium, calcium, magnesium or zinc borohydride, using from 0.5 to 6 moles of the reducing agent for each mole of the compound of formula (I).
The reduction may ~e performed either in aqueous or anhydrous inert solvents such as linear or cyclic ethers, e.g., ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane or aliphatic or aromatic hydrocarbons, e.g., n-heptane or benzene, or halogenated hydro-carbons, e.g. methylene dichloride, or hydroxylated solvents, e.g., ethyl, methyl or isopropyl alcohol, or mixtures of these solvents.
The reaction temperature may vary between approximately -40C and the boiling point of the solvent used, but the preferred tempera-ture ranges from about -20C to about 25C.
!11 -- 1 0 ~ ,~..,~,) 33~
This reduction leads to a mixture of the two epimeric S(- ~H ~ and R(- ~H ) alcohols from which the sinyle epimers can be separated, if desired, by fractional crystallization, e.g. with diethylether, n-hexane, n-heotane, cyclohexane but preferably by chromatography either on silica gel or magnesium silicate columns or preparative TLC chromatography with, for example, silica gel, eluting, e.g., ~ith CH2C12, ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane or mixtures of these, or by high speed liquid chromatography.
lQ The optional hydrogenation of a compound of formula (I) wherein Y is -CH=CH-, to give a compound of formula (I) wherein Y is -CH2-CH2- is carried out, e.g., catalytically, preferably in an alcoholic solvent, in the presence of platinum or palladium on charcoal as catalyst at temperatures varying from about -40~C to the reflux temperature of the solvent.
The reduction of a compound of formula (I) wherein R2 and R5 taken together form an oxo group and Y is -CH2-CH2- to give a compound of formula (I) wherein one of R2 and R5 is hydrogen and the other is hydroxy and Y is -CH2-CH2- may be carried out as described above for the analogous reduction of a compound of formula (I) wherein R2 and R5 taken toge-ther form an oxo group and Y is -CH=CH-.
The optional conversion of a compound of formula (I) into another compound of ~ormula (I) as well as the salification of a compound of formula (I), the preparation of a free compound from a salt and the separation of the isomers from a mixture may be carxied out by known methods.
-- 11 ~
J !
3~
A compound of formula (I) wherein R is a free carboxy group may be converted into a compound of formula (I) wherein R is an es-terified carboxy group, e.g., a Cl-C12 carbalkoxy group, by known methods, e.g., by reac-tion wi-th the appropriate alcohol, e.g., a Cl-C12 aliphatic alcohol, in the presence of an acid catalyst, e.g., p-toluenesulphonic acid and also by treatment wi-th a diazoalkane.
The optional conversion of a compound of formula (I) wherein R is an esterified carboxy group into a compound of formula (I) wherein R is a free carboxy group, if desired, may be earried out by the usual methods of saponification, e.g., by treatment with an alkaline or alkaline-earth hydroxide in aqueous or aleoholie aqueous solu-tion followed by aeidifieation.
The optional salifiea-tion of a eompound of formula (I) may be performed in a eonventiona] manner.
Also the optional separation of the optieally aetive eompounds from a raeemie mixture as well as the optional separa-tion of the diastereoisomers or of the geometrieal isomers from their mixtures may be effeeted by eonventional methods.
The eompound of formula (IV) may be prepared by a proeess eomprising the cyelization of a eompound of formula (VI) ~ H2-D-(CH2)4-R
Ri G
wherein RL is hydroxy, Cl-C6 alkoxy, ar-Cl-C6 alkoxy, l - 12 -acyloxy or a protecting group bound to -the ring by an ethereal oxygen atom, D is cis or trans-CH=CH- and G is a protected aldehydic group or a protected -CH2-OH group, preferably a member selected Erom the group consisting of / 10 /SRlo -CH or -CH
wherein Rlo is Cl-C6 alkyl;
/0\ / \
-CH (CH2)n or -CH (CH2 n3 wherein n3 is an integer of 2 to 4, preferably 2 or 3;
-CH2--cH2-c6H5 or -CH2-O-CH2SCH3~ in the presence of a source of Hg( )ions and the subsequent reduction of the obtained com-pound. The reduction of the compound may be carried out by -treatment with mixed hydrides such as alkaline, e.g., sodium, potassium or lithium, borohydrides, with alkaline-earth, e.g., calcium or magnesium, borohydrides in an inert solvent, preferably a solvent miscible with water, such as tetrahydrofuran, dimethoxy-ethane or lower aliphatic alcohols, e.g. methanol or ethanol; or with tri~n-butyl)tin hydride in benzene or toluene, preferably benzene; or also by treatment with hydrazine hydra-te in a lower aliphatic alcohol, e.g. methanol or ethanol as solvent, at tempera-tures varying from room temperature to the reflux temperature of the solvent used. Suitable sources oE Hg( ) ions may be, e.g., either compounds of Eormula Hg(z)2 or compounds of formula Gh(OH)Z, wherein Z( ) is the anionic residue of an acid. Z( ) is prefer-ably selected Erom th~ group consisting of Cl( ), Br( ), I( ), i[,l`~
I ~ - 13 --R8-COO( ), wherein R8 is an optionally halo-substituted Cl-C12 alkyl group (preferably Cl-C6 alkyl or trifluoromethyl) and Rg ~ COO( ), wherein Rg is, e.g., hydrogen, Cl-C6 alkyl, halogen, e.g., bromine, or trifluoromethyl. Preferably Z( ) is Cl( ), Br( ), CH3COO( ), CF3COO( ) or ~ COO( ).
The above cyclization may be performed, e.g., using 1.01 to 1.5, preferably 1.2, equivalents of the mercuric compound for each mole of the cornpound of formula (VI), in an organic sol-vent miscible with water, e.g., tetrahydrofuran, methanol, ethanol or in a mixture of the organic solvent and water. The reaction temperature may vary between 0C and the boiling point of the reaction mixture and the reaction time ranges from about 5 minutes to about 2 hours.
The removal of the protecting group from -the aldehydic or alcoholic functions may be carried out by mild acid hydrolysis in the same conditions already described in this specification for the removal of the protecting groups (i.e. ether groups) of the hydroxylic functions. The selective oxidation of -CH2OH to -CHO
may be effected in a conventional manner, e.g. by treatment with an excess of at least 3 moles per mole of primary alcohol of dicyclohexylcarbodiimide in benzene-dimethylsulphoxide and in the presence of an acid catalyst, e.g., pyridine trifluoroacetate or phosphoric acid. O
The compound of formula (V) wherein E is (ReO)2P- may be prepared by treatment of a phosphonate of formula (VII) \ t I ~R3 P - C - CO - (C~12)n - ~C - X - (CH2)n2 6 (VII) R~O H R4 3~
wherein Re, nl, R3, R4, X, n2 and R6 are as defined above, with at least an equivalent of a base preferably selected from the group consisting of an alkaline or alkaline-earth hydride, e.g., sodium, potassium, lithium or calcium hydride; an alkaline alkoxide, e.g., sodium or potassium tert.butoxide; an alkaline or alkaline-earth metal amide, e.g., sodium amide; an alkaline or alkaline-earth derivative of a carboxy-amide, e.g., sodium acetamide or sodium succinimide.
(+) The compound of formula (V) wherein E is (C6H5)3P- may be prepared by reacting a compound of formula (VIII) H R
(VIII) ¦ 1 ~ 2 6 wherein nl, R3, R4, X, n2, R6 are as defined above and Hal is a halogen atom, with l-1.2 molar equivalent of triphenylphosphine in an inert organic solvent such as e.g. benzene, acetonitrile, diethylether, then treating the triphenylphosphonium halide so obtained with an equivalent amount of an inorganic base such as, for example, NaOH, KOH, Na2CO3, NaHCO3.
The compound of formula (VI) may be prepared, e.g., according to Tetrahedron Letters No. 42, 4307~4310 (1972).
The compounds of formula (VII) may be prepared by known methods, e.g. according to ~.J. Corey et al, J. ~m. Chem. Soc.
90, 3247 (1968) and E.J. Corey and G.K. Kwiatkowsky, J. Am. Chem.
Soc., _ , 565~ (1966).
The compounds of formula (VIII~ are known compounds or 33~
may be prepared by known methods.
The compounds of the invention can be used, in general, for the same therapeutic indications as the natural prostaglandins in either human or veterinary medicine. In particular, those having an acetylene bond in the 13,14-position instead of an ethylene and those with mono and di-substituents such as methyl and f luoxine groups have the advantages of superior resistance to degradation by the l~-PG-dehydrogenase enzymes, which quickly inactivate natural compounds, and, of a more selective therapeutic action, as indicated below.
In order to obtain a preliminary biological profile, i.e., to assess whether the compounds of the invention possess PG-like or thromboxane (TXA2)-like or PGX-like activity, they were at first tested by a superfusion cascade technique by the method of Piper and Vane, Nature 223, 28 tl969).
In order to increase the sensitivity of the bioassay, a mixture of antagonists [Gilmore et al. Nature 218, 1135 (1968)]
is added to the Krebs-Henseleit and indomethacin (4 ~g/ml) is also added to prevent the endogenous biosythesis of prostaglandins.
Contraction of rat colon (RC), rat stomach strip (RSS) and bovine coronary artery (BCA), and relaxation of rabbit mesentery artery (RbMA) are assumed to represent prostaglandin-like activity.
TXA2-like activity is indicated when RbMA is contracted and must be confirmed by in vitro platelet pro-aggregation activity, since PGF2~-like compounds also contract Rb~5A, as opposed to PGE.
Finally, PGX-like acti~it~ is indicated by the relaxation of BCA, and is con~irmed by `in` vitro platelet anti~aggregat:ion activity.
_ ~_ ~L~83~
Synthetic PGE2 and both the biosynthetic TXA2 and PGX are utilized as standard compounds.
They are active at a range of concentrations from 1-5 ~g/ml. The compounds o~ the invention were dissolved in a few drops of ethanol jus-t before testing; the stock solution was prepared in 0.1 M tris-buf~er, p~ 9.0, (1 mg/ml) and diluted with Krebs-Henseleit to the required concentration.
The compound 13-trans-11~,15S-dihydroxy-6~H-6,9~-oxide-prostenoic acid was taken as the parent compound and is called 6~H-6,9~-oxide; the diastereoisomer ]3-trans-11~,15S-dihydroxy 6~H-6,9~-oxide-prostenoic acid is then referred to as 6~H-6,9~-oxide. The chemical names of the other tested compounds are also referred to those of the parent compounds. The compounds, and the compounds which are the subject of related application Serial Nos.
329,306; 329,309 and 394,875, were tested at concentrations up to 100 ng/ml.
The results obtained showed that, in general, the 6~H-diastereoisomers, e.g., the compounds 6~H-6,9~-oxide, dl-6~H-5-bromo-6,9a-oxide, 6~H-6,9~-oxide-16-m-CF3-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor possess BCA-relaxing activity and therefore have PGX-like activity.
Among the 6~H-derivatives, only the compound dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor showed a BCA-contracting activity. The 6~H-derivatives, e.g. the compound 6~H-6,9~-oxide, dl-6~H-5-bromo-6,9~-oxide, dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor, 6~H-6,9~-oxide-16-m-CF3-phenoxy-~tetranor and 6~H-6, 9~-oxide-16-m-ch:Loro-phenoxy-~-tetranor also showed BCA-contracting _ ~_ :~83~
activity.
In general, the exo-configuration is associated with BCA
contraction. Furthermore, the compounds of the invention have hypotensive activity in mammals as does the natural compound PGX.
However, as compared to PG~, they have the great advantage of a higher chemical stability and can he used in pharmaceutical formulations.
The hypotensive activity was demonstrated by the limb perfusion test. During the perfusion of the ratls left leg, through the left femoral artery, with a constant perfusion pressure, both the 6~H~ and 6~H-6,9~-oxide compounds caused a lowering of the values of the mean perfusion pressure at all the doses, over the range from 0.05~1 ~g (to -42.5% for 6~H and -32% for 6~H). More-over, the systemic pressure, both systolic and diastolic, was depressed from 0.05 ~g/kg up to 5 ~g/kg ~about -45%).
Because of their hypotensive and vasodilatory activity, the compounds of the invention are useful or treatment of cases of gangrene of the lower limbs. For this therapeutic use they have been found to be more active than PGEl and PGE2. They are also useful in disturbances o~ the peripheral vasculature and, therefore, in the prevention and treatment of diseases such as phlebitis, hepato-renal syndrome, ductus arteriosus, non-obstruc-tive mesenteric ische~ia, arteritis and ischemic ulcerations of the leg.
Among the compounds of the invention, in particular, the 6~H-derivatives also have a high anti-aggregating activity.
Among the 6~H co~pounds, the more important ones are, in order oE increasing polency, compounds dl-6~H-5-bromo-6,9~-oxide, 5~H-~3~
6,9~-oxide-16-m-C~'3-phenoxy-~-tetranor, dl-6~H-6,9~-oxide, and 6~H-6,9~-oxide.
Using platelet-rich plasma (PRP) from healthy human donors who had not taken any drugs for at least one week, and monitoring platelet aggregation by continuous recording of light transmission in a Born aggregometer [sorn G.V.~., Nature (London) 194, 927 (1962)] there is evidence that the compounds 6~H-6 ,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-6,9r~-oxide-16-m-CF3-phenoxy--~-tetranor and 6~H-6,9~-oxide-16-m-chloro-phenoxy-~-tetranor mimic the biosynthetic PGX in its platelet-antiaggregating properties.
The compounds investigated were incubated for 2-3 minutes at 37C
in the PRP prior to the addition of the aggregating agents, arachidonic acid (0.4 mM), ADP (10 ~M), collagen (38 ~M) or adrenaline (15 ~M). The potency ratio for the compound is, e.g., 1:10 for arachidonic acid-induced aggregation and 1:100 for ADP--induced aggregation, as compared with biosynthetic PGX.
A very interesting increase in the anti-aggregating potency follows 20-methyl substitution in both the 6~H- and 6~H
6,9~-oxide parent compounds. Similarly, 6~H-5-bromo-20-methyl, 6~H-5,14-di~romo, 6~H-13,14-didehydro-20-methyl and finally 6~H-5-bromo-13,14-didehydro compounds and their 6~H-6-iodo (but not 6~H-5-iodo isomers) are very active compounds as anti-aggregating agents. The compounds of the invention are, therefore, particular-ly useful ln mammals for inhibiting platelet aggregation, for preventing and inhibiting thrombus formation and for decreasing the adhesiveness of platelets.
Therefore, they are useful in treatment and prevention .j,.~ ., :~: 3 i~: ~
33~
of thromboses and myocardial infarct, in treatment of atheroscler-osis, and in general in all syndromes etiologically based on or associated with lipid imbalance or hyperlipidemia, as well as in treatment of geriatric patients for prevention o cerebral ischemic episodes, and in long-term treatment a~ter myocardial infarct~
When the compounds of the invention are given as anti-aggregating agents, the routes of administration are the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary from 0.005 to about 10 mg/kg/day. The exact dose will depend on the condition of the patient, his weight, his age and the route of administration.
The compounds of the invention ~ere also studied for their uterine contractile activity, both in vitro and in vivo, against PGF2 as standard.
For example, in vitro, on the uterus of the estrogenized rat, compounds 6~H-6,9~-oxide-16-m-chloro-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-m-CF3-phenoxy-~-tetranor, were 1.3 and 3.1 times as active as PGF2 . In the in vivo assay, measuring the intrau-terine pressure of the ovariectomized rabbit, the same compoundswere 5.9 and 8025 times as active as PGF2 (see the following Table) ~7
The compounds of the invention are 2 oxa~bicyclic prostaglandins of formula (I) H X ( 2)4 R
~, B~ I
~I
~ ~2 ~3 HO Y-C (CH2)n -~C-X (CH2)n2 6 ~4 wherein R is a free or esterified carboxy group; Y is -CH2CII2- or -CH=CH-trans; R2 is hydrogen; R5 is hydroxy; R3 is hydrogen or Cl-C6 alkyl; R4 is hydrogen or Cl-C6 alkyl; nl is zero or an integer of 1 to 6; n2 is zero, 1 or 2; X is -O- or -(CH2)m-, wherein m is zero or l; R6 is hydrogen, Cl-C4 alkyl or an unsub-stituted C3-C9 cycloaliphatic radical, provided that (a) when X
is -O- and n2 is zero R6 is Cl-C4 alkyl or an unsubstituted C3-Cg cycloaliphatic radical; (b) when X is -O- and n2 is 1 or 2 R6 is Cl-C4 alkyl, and (c) when X is -(CH2)m- R6 is hydrogen or Cl-C4 alkyl and nl is zero, 1 or 2, n2 is zero.
Also the pharmaceutically or veterinarily acceptable salts as well as the optical antipodes, i.e. the enantiomers, the racemic mix-tures of the optical antipodes, the geometric isomers and their mixtures and the mixtures of -the diastereoisomers of the compounds oE formula (I) are included in the scope of the present ~4 ,.1~1 ~3~
invention.
In the formulae of this specification the broken line (--..) indicates that a substituent bound to the cyclopentane ring is in the ~-configuration, i.e. below the plane of the ring, a substituent bound to the 2-oxa-bicyclic system is in the endo-configuration and a substituent bound to a chain is in the S-configuration; the heavy solid line ( _ ) indicates that a sub-stituent bound to the cyclopentane ring is in the ~-configuration, i.e. above the plane of the ring, a substituent bound to the 2-oxa-bicyclic system is in the exo-configuration and a substituent bound to a chain is in the R-configuration; the wavy line attach-ment (~) indicates that a substituent do~s not possess a definite stereochemical identity i.e. that a substituent bound to the cyclopentane ring may be both in the ~- and in the ~-configuration, a substituent bound to the 2-oxa-bIcyclic system may be both in the endo- or in the exo-configuration and a substituent bound to a chain may he both in the S- and in the R-configuration.
In the compounds of the above formula (I) the heterocyclic ring B is cis-fused with the cyclopentane ring A and the two bonds indicated by the dotted lines (...) are both in the ~-configuration with respect to the ring A.
The side chain ~-linked to the cyclopentane ring A is in trans-configuration with respect to the ~-fused heterocyclic ring B and consequently it is an exo substituent with respect to the 2-oxa-bicyclic system.
The ca;rbon atom of the heterocyclic ring B bearing the side chain ~(C~I2)~-~ bears also an hydrogen atom.
i` ;~~'~' When the side chain V~V~(CH2)4-R is in the endo-con~igura-tion with respect to the 2-oxa-bicyclic system, then said hydrogen atom is an exo-substituent and its absolute con~iguration is reported as ~ while when the chain ~V(CH2)~-R is in the exo-configuration, then said hydrogen atom is an endo-substituent and its absolute configuration is reported as ~.
The compounds of the invention wherein the chain ~ (CH2)~-R is in the exo-configuration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-Qxide prostanoic acid derivatives (prostaglandin numbering), while the compounds wherein the chain ~(CH2)4-R is in the endo-configuration, the hydrogen atom linked to the same carbon atom of the ring B having necessarily the ~-absolute configuration, are reported as 6~H-6,9~-oxide prostanoic acid derivatives (prostaglandin numbering).
Alternatively the 6~H-6,9~-oxide prostanoic acid derivatives are reported as (2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-alkanoic acid derivatives, and the 6~H-6,9~-oxide prostanoic acid derivatives as (2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-alkanoic acid derivatives.
The 6~H-6,9~-oxide prostanoic acid derivatives have a higher chro-matographic mobility (i.e. a higher Rf~ and a less positive : rotatory power ([~]D~ than the corresponding 6~H-6,9~-oxide derivatives.
All the above notations refer to the natural compounds;
the d,l-compounds are mixtures containing equimolar amounts oE
nat-compounds which possess the above reported absolute stereo-chemistry and of ent-compounds which are mirror-like images of the .'...,~, ~l83~
formers; in the ent-compounds the stereochemical configuration is the opposite at all the asymmetric centers with respect to the configuration of the natural compounds and the prefix ent indicates jus~ this.
The alkyl groups are branched or straight chain groups.
A Cl-C6 alkyl group is preferably methyl, ethyl or propyl.
When R is an esterified carboxy group it is preferably a -COORC group wherein Rc is a Cl-C12 alkyl radical, in particular methyl, ethyl, propyl and heptyl, or a C2-C12 alkenyl radical, in particular allyl.
nl is preferably zero or an integer of 1 to 3; n2 is preferably 1 or 3.
When R6 is a C3-Cg cycloaliphatic radical, it is prefer-ably a C3-Cg cycloalkyl radical e.g. cyclopentyl, cyclohexyl and ; cycloheptyl or a C3-C~ cycloalkenyl radical, e.g. cyclopentenyl, cyclohexenyl and cycloheptenyl.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) are e.g. those with pharmaceutically and veterinarily acceptable bases. Pharmaceutically and veterinarily acceptable bases are either inorganic bases such as, for example, alkaline hydroxides and alkaline-earth hydroxides as well as aluminium and zinc hydroxides or organic bases e.g. organic amines such as, for example, methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, N-methyl-N-hexylamine~ decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzyl~
amine, dibenzylamine, ~-phenyl-ethylamine, ~-phenyl-ethylamine, ethylenediamine, diethylenetriamine, morpholine, piperldine, ~38~
pyrrolidine, piperazine, as well as the alkyl derivatives of the latter four bases, mono-, di- and tri-ethanolamine, ethyl-diethanol-amine, N-methyl-ethanolamine, 2-amino-1-butanol, 2-amino-2-methyl-l-propanol, N-phenyl-ethanolamine, galactamine, N-methyl-glucamine r N-methyl-glucosamine, ephedrine, procaine, dehydroabietilamine, lysine, arginine and other ~ or ~ amino acids. Preferred salts of the invention are those of the compounds of ~ormula (I) wherein R is -COORd wherein Rd ls a pharmaceutically or veterinarily acceptable cation deriving from one of the above mentioned bases.
Particularly preferred compounds of the invention are 6~H-6t9~-oxide compounds of formula (I) wherein R is a free carboxy group and ~6 is Cl-C4 alkyl or C5-C7 cycloalkyl The prefixes nor, dinor, trinor, tetranor- etc., are used to identify the compounds of formula (I) wherein the side chain bound to the cyclopentane ring A is one, two, three, four, etc. carbon atoms shorter than the analogous chain in the natural prostaglandins.
Specific examples of preferred compounds of the invention are the following:
13t-6~H-6,9~-oxide~ ,15S-dihydroxy-prost-13-enoic acid;
13-6~H-6,9~-oxide-11~,15S-dihydroxy-prostanoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-20-methyl-prost-13-enoic acld;
13t-6~H-6,9~-oxide~ ,15S-dihydroxy-20-methyl-prostanoic acid;
13t-6~H 6,9~-oxide-11~,15S-dihydroxy-16,16-dimethyl-prost-13-enoic acidî
13t-6~H-6,~-oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-prost-13-enoic acid;
.!~
3~
13t-6~H-6,9~-oxide 11~,15S-dihydroxy~20-ethyl-prost-13~enoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-16S methyl-prost-13-enoic acid;
13t-6~H-6,9~-oxide-lla,15S-dihydroxy-16R-methyl-prost-13-enoic acid; as well as the 15R-epimers and the 6~H-diastereo-isomers of all the compounds mentioned above.
The compounds of the invention are prepared by a process comprising: reacting a compound o:E formula (IV) H~,~(CH23~-R
~ 2 A (IV) Rl CHO
wherein R is as defined above and Rl is hydroxy or a protecting group bound to the ring by an ethereal oxygen atom, with a compound of formula (V) (_) 1 ~ 2 6 (V) (+) wherein E is a group (.C6H5)3P- or a group (ReO)2P- wherein each of the Re groups, which are the same or different, is alkyl or aryl and R3, R4, nl, n2, X and R6 are as defined above, so obtaining, a~ter the remova:L of the known protecting groups, if present, a compound corresponding to one of formula I wherein R2 and R5, taken f ~3 ~i33~
together, form an oxo group and Y is trans~CH=CH- and reducing the obtained compound to give a compound of formula I ~herein one of R2 and ~5 is hydrogen and the other is hydroxy and Y is trans-CH=
OEI-, and, if desired, hydrogenating the compound of formula I
wherein Y is trans-CH=CH- to give a compound of formula I wherein Y is -CX2CH2- or hydrogenating a compound corresponding to one of formula I wherein ~2 and R5~ taken together, form an oxo group and Y is trans-CH=C~-, to give a compolmd corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is -CH2CH2- and reducing the obtained compound to give a compound of formula ~ wherein Y is -CH2-CH2- and/or, if desired, converting a compound of formula I into another compound of formula I and/or, if desired, salifying a compound of formula I and/or, if desired, obtaining a free compound of formula I from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
The known protecting groups, i.e., other groups, are convertible to hydroxy groups under mild reaction conditions, e.g., acid hydrol~sis. Examples are acetal ethers, enol ethers and silyl ethers~ The preferred groups are (CH3)3-SiO- , ~ OAlk O \S i - O-O- , - O - ~ ~ , CH / ¦
OAlk 3 ¦ 3 -- 7 ~
38~
wherein W is -O- or -CH2- and Alk is a lower alkyl group.
The diastereoisomer wherein the chain ~(CH2)4-R is in the exo-configuration may be separated from the diastereoisomer wherein said chain is in the endo configuration by fractional crystallization e.g. from diethylether but preferably by thin layer preparative chromatography, by column chromatography or by high speed liquid chromatography.
The separation by thin layer preparative chromatography or by column chromatography is preferably carried out on a support of silica gel or magnesium silicate with methylene chloride, diethylether, isopropylether, ethylacetate, benzene, methyl acetate, cyclohexane or their mixtures as elution solvents.
When in the compound of formula (V~ E is (ReO)2 ~-, wherein Re is aryl, it is preferably phenyl; when Re is alkyl, it is preferably Cl-C6 alkyl. The reaction between an aldehyde of formula (IV) and a compound of formula (V) is carried out with an excess of the compound of formula (V), e.g., at least 1.01 molar equivalent of the compound of formula ~V) for each mole of the compound of formula ~IV).
2Q Any inert solvent can be used, such as linear and cyclic ethers, e.g. ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, aliphatic or aromatic hydrocarbons, e.g., n-heptane, n-hexane, benzene, toluene or halogenated hydrocarbons, e.g. methylene-chloride, tetrachloroethane and also mixtures of these solvents.
The reaction temperature may vary between the freezing and the boiling points o~ the solvent.
When the reaction is carried out with a compound of 3~
formula (V) wherein E is (ReO)2~ the preferred temperature is the room temperature i~e. from about 10C to about 25C, when the reaction is carried out with a compound of formula (V) wherein E
is (C6H5)3(~), the preferred temperature is the reflux temperature of the solvent.
The product of the reaction between a compound of formula (IV) and a compo~nd of formula (V) is a mixture of a compound of formula (I) wherein Y is trans-CH=CH- and a compound of formula (I) wherein Y is cis-CH=CH-, in a ratio varying between approxi-mately 90:10 and 95:5.
The compound of formula (I) wherein Y is trans-CH=CH-, may be separated from the mixture by crystallization with a suit-able solvent, while the compound of formula (I) wherein Y is cis-CH=CH-, may be obtained by concentration of the mother liquor and subsequent chromatographic separation of the residue, either by column or preparation TLC chromatography using silica gel or magnesium silicate as support and e.g. methylene chloride, diethyl-ether, isopropylether, ethylacetate, benzene, cyclohexane or their mixtures as elution solvents.
The removal of the known protecting groups bound to the ring or to the chain by an ethereal oxygen atom is, whenever required, performed under conditions of mild acid hydrolysis, for example with a mono~ or poly~carboxylic acid such as formic, acetic, oxalic, citric and tartaric acid, and in a solvent, which may be water, acetone, tetrahydrofuran, dimethoxyethane or a lower aliphatic alcohol, or with a sulphonic acid, e.g., p-toluenesulphonic _ g _ ~3~
acid in a solvent such as a lower aliphatic alcohol, dry methanol or dry ethanol, for example, or with a polystyrene-sulphonic resin.
For example, 0.1 to 0.25 N poly-carboxylic acid (e.g., oxalic or citric acid) is used in the presence of a convenient low-boiling co-sol~ent which is miscible with water and which can be easily removed in vacuo at the end of the reaction .
The reduction of a compound of formula (I) wherein R2 and R5, taken together form an oxo group, and Y is -CH=CH-, to give a compound of formula (I) wherein Y is -CH=CH-, and wherein one of R2 and R5 is hydrogen and the other is hydroxy, must be regarded as an application of a reaction which is a 1.2 polar addition to the carbonyl group. The reduction of an obtained compound of formula (I) wherein R2 and R5 taken together form an oxo group, and Y is -CH=CE-, to give a compound of formula (I) wherein Y is -CH~CH-, and wherein one of R2 and R5 is hydrogen and the other is hydroxy, is preferably carried out with alkaline or alkaline-earth metal borohydrides, preferably sodium, lithium, calcium, magnesium or zinc borohydride, using from 0.5 to 6 moles of the reducing agent for each mole of the compound of formula (I).
The reduction may ~e performed either in aqueous or anhydrous inert solvents such as linear or cyclic ethers, e.g., ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane or aliphatic or aromatic hydrocarbons, e.g., n-heptane or benzene, or halogenated hydro-carbons, e.g. methylene dichloride, or hydroxylated solvents, e.g., ethyl, methyl or isopropyl alcohol, or mixtures of these solvents.
The reaction temperature may vary between approximately -40C and the boiling point of the solvent used, but the preferred tempera-ture ranges from about -20C to about 25C.
!11 -- 1 0 ~ ,~..,~,) 33~
This reduction leads to a mixture of the two epimeric S(- ~H ~ and R(- ~H ) alcohols from which the sinyle epimers can be separated, if desired, by fractional crystallization, e.g. with diethylether, n-hexane, n-heotane, cyclohexane but preferably by chromatography either on silica gel or magnesium silicate columns or preparative TLC chromatography with, for example, silica gel, eluting, e.g., ~ith CH2C12, ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane or mixtures of these, or by high speed liquid chromatography.
lQ The optional hydrogenation of a compound of formula (I) wherein Y is -CH=CH-, to give a compound of formula (I) wherein Y is -CH2-CH2- is carried out, e.g., catalytically, preferably in an alcoholic solvent, in the presence of platinum or palladium on charcoal as catalyst at temperatures varying from about -40~C to the reflux temperature of the solvent.
The reduction of a compound of formula (I) wherein R2 and R5 taken together form an oxo group and Y is -CH2-CH2- to give a compound of formula (I) wherein one of R2 and R5 is hydrogen and the other is hydroxy and Y is -CH2-CH2- may be carried out as described above for the analogous reduction of a compound of formula (I) wherein R2 and R5 taken toge-ther form an oxo group and Y is -CH=CH-.
The optional conversion of a compound of formula (I) into another compound of ~ormula (I) as well as the salification of a compound of formula (I), the preparation of a free compound from a salt and the separation of the isomers from a mixture may be carxied out by known methods.
-- 11 ~
J !
3~
A compound of formula (I) wherein R is a free carboxy group may be converted into a compound of formula (I) wherein R is an es-terified carboxy group, e.g., a Cl-C12 carbalkoxy group, by known methods, e.g., by reac-tion wi-th the appropriate alcohol, e.g., a Cl-C12 aliphatic alcohol, in the presence of an acid catalyst, e.g., p-toluenesulphonic acid and also by treatment wi-th a diazoalkane.
The optional conversion of a compound of formula (I) wherein R is an esterified carboxy group into a compound of formula (I) wherein R is a free carboxy group, if desired, may be earried out by the usual methods of saponification, e.g., by treatment with an alkaline or alkaline-earth hydroxide in aqueous or aleoholie aqueous solu-tion followed by aeidifieation.
The optional salifiea-tion of a eompound of formula (I) may be performed in a eonventiona] manner.
Also the optional separation of the optieally aetive eompounds from a raeemie mixture as well as the optional separa-tion of the diastereoisomers or of the geometrieal isomers from their mixtures may be effeeted by eonventional methods.
The eompound of formula (IV) may be prepared by a proeess eomprising the cyelization of a eompound of formula (VI) ~ H2-D-(CH2)4-R
Ri G
wherein RL is hydroxy, Cl-C6 alkoxy, ar-Cl-C6 alkoxy, l - 12 -acyloxy or a protecting group bound to -the ring by an ethereal oxygen atom, D is cis or trans-CH=CH- and G is a protected aldehydic group or a protected -CH2-OH group, preferably a member selected Erom the group consisting of / 10 /SRlo -CH or -CH
wherein Rlo is Cl-C6 alkyl;
/0\ / \
-CH (CH2)n or -CH (CH2 n3 wherein n3 is an integer of 2 to 4, preferably 2 or 3;
-CH2--cH2-c6H5 or -CH2-O-CH2SCH3~ in the presence of a source of Hg( )ions and the subsequent reduction of the obtained com-pound. The reduction of the compound may be carried out by -treatment with mixed hydrides such as alkaline, e.g., sodium, potassium or lithium, borohydrides, with alkaline-earth, e.g., calcium or magnesium, borohydrides in an inert solvent, preferably a solvent miscible with water, such as tetrahydrofuran, dimethoxy-ethane or lower aliphatic alcohols, e.g. methanol or ethanol; or with tri~n-butyl)tin hydride in benzene or toluene, preferably benzene; or also by treatment with hydrazine hydra-te in a lower aliphatic alcohol, e.g. methanol or ethanol as solvent, at tempera-tures varying from room temperature to the reflux temperature of the solvent used. Suitable sources oE Hg( ) ions may be, e.g., either compounds of Eormula Hg(z)2 or compounds of formula Gh(OH)Z, wherein Z( ) is the anionic residue of an acid. Z( ) is prefer-ably selected Erom th~ group consisting of Cl( ), Br( ), I( ), i[,l`~
I ~ - 13 --R8-COO( ), wherein R8 is an optionally halo-substituted Cl-C12 alkyl group (preferably Cl-C6 alkyl or trifluoromethyl) and Rg ~ COO( ), wherein Rg is, e.g., hydrogen, Cl-C6 alkyl, halogen, e.g., bromine, or trifluoromethyl. Preferably Z( ) is Cl( ), Br( ), CH3COO( ), CF3COO( ) or ~ COO( ).
The above cyclization may be performed, e.g., using 1.01 to 1.5, preferably 1.2, equivalents of the mercuric compound for each mole of the cornpound of formula (VI), in an organic sol-vent miscible with water, e.g., tetrahydrofuran, methanol, ethanol or in a mixture of the organic solvent and water. The reaction temperature may vary between 0C and the boiling point of the reaction mixture and the reaction time ranges from about 5 minutes to about 2 hours.
The removal of the protecting group from -the aldehydic or alcoholic functions may be carried out by mild acid hydrolysis in the same conditions already described in this specification for the removal of the protecting groups (i.e. ether groups) of the hydroxylic functions. The selective oxidation of -CH2OH to -CHO
may be effected in a conventional manner, e.g. by treatment with an excess of at least 3 moles per mole of primary alcohol of dicyclohexylcarbodiimide in benzene-dimethylsulphoxide and in the presence of an acid catalyst, e.g., pyridine trifluoroacetate or phosphoric acid. O
The compound of formula (V) wherein E is (ReO)2P- may be prepared by treatment of a phosphonate of formula (VII) \ t I ~R3 P - C - CO - (C~12)n - ~C - X - (CH2)n2 6 (VII) R~O H R4 3~
wherein Re, nl, R3, R4, X, n2 and R6 are as defined above, with at least an equivalent of a base preferably selected from the group consisting of an alkaline or alkaline-earth hydride, e.g., sodium, potassium, lithium or calcium hydride; an alkaline alkoxide, e.g., sodium or potassium tert.butoxide; an alkaline or alkaline-earth metal amide, e.g., sodium amide; an alkaline or alkaline-earth derivative of a carboxy-amide, e.g., sodium acetamide or sodium succinimide.
(+) The compound of formula (V) wherein E is (C6H5)3P- may be prepared by reacting a compound of formula (VIII) H R
(VIII) ¦ 1 ~ 2 6 wherein nl, R3, R4, X, n2, R6 are as defined above and Hal is a halogen atom, with l-1.2 molar equivalent of triphenylphosphine in an inert organic solvent such as e.g. benzene, acetonitrile, diethylether, then treating the triphenylphosphonium halide so obtained with an equivalent amount of an inorganic base such as, for example, NaOH, KOH, Na2CO3, NaHCO3.
The compound of formula (VI) may be prepared, e.g., according to Tetrahedron Letters No. 42, 4307~4310 (1972).
The compounds of formula (VII) may be prepared by known methods, e.g. according to ~.J. Corey et al, J. ~m. Chem. Soc.
90, 3247 (1968) and E.J. Corey and G.K. Kwiatkowsky, J. Am. Chem.
Soc., _ , 565~ (1966).
The compounds of formula (VIII~ are known compounds or 33~
may be prepared by known methods.
The compounds of the invention can be used, in general, for the same therapeutic indications as the natural prostaglandins in either human or veterinary medicine. In particular, those having an acetylene bond in the 13,14-position instead of an ethylene and those with mono and di-substituents such as methyl and f luoxine groups have the advantages of superior resistance to degradation by the l~-PG-dehydrogenase enzymes, which quickly inactivate natural compounds, and, of a more selective therapeutic action, as indicated below.
In order to obtain a preliminary biological profile, i.e., to assess whether the compounds of the invention possess PG-like or thromboxane (TXA2)-like or PGX-like activity, they were at first tested by a superfusion cascade technique by the method of Piper and Vane, Nature 223, 28 tl969).
In order to increase the sensitivity of the bioassay, a mixture of antagonists [Gilmore et al. Nature 218, 1135 (1968)]
is added to the Krebs-Henseleit and indomethacin (4 ~g/ml) is also added to prevent the endogenous biosythesis of prostaglandins.
Contraction of rat colon (RC), rat stomach strip (RSS) and bovine coronary artery (BCA), and relaxation of rabbit mesentery artery (RbMA) are assumed to represent prostaglandin-like activity.
TXA2-like activity is indicated when RbMA is contracted and must be confirmed by in vitro platelet pro-aggregation activity, since PGF2~-like compounds also contract Rb~5A, as opposed to PGE.
Finally, PGX-like acti~it~ is indicated by the relaxation of BCA, and is con~irmed by `in` vitro platelet anti~aggregat:ion activity.
_ ~_ ~L~83~
Synthetic PGE2 and both the biosynthetic TXA2 and PGX are utilized as standard compounds.
They are active at a range of concentrations from 1-5 ~g/ml. The compounds o~ the invention were dissolved in a few drops of ethanol jus-t before testing; the stock solution was prepared in 0.1 M tris-buf~er, p~ 9.0, (1 mg/ml) and diluted with Krebs-Henseleit to the required concentration.
The compound 13-trans-11~,15S-dihydroxy-6~H-6,9~-oxide-prostenoic acid was taken as the parent compound and is called 6~H-6,9~-oxide; the diastereoisomer ]3-trans-11~,15S-dihydroxy 6~H-6,9~-oxide-prostenoic acid is then referred to as 6~H-6,9~-oxide. The chemical names of the other tested compounds are also referred to those of the parent compounds. The compounds, and the compounds which are the subject of related application Serial Nos.
329,306; 329,309 and 394,875, were tested at concentrations up to 100 ng/ml.
The results obtained showed that, in general, the 6~H-diastereoisomers, e.g., the compounds 6~H-6,9~-oxide, dl-6~H-5-bromo-6,9a-oxide, 6~H-6,9~-oxide-16-m-CF3-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor possess BCA-relaxing activity and therefore have PGX-like activity.
Among the 6~H-derivatives, only the compound dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor showed a BCA-contracting activity. The 6~H-derivatives, e.g. the compound 6~H-6,9~-oxide, dl-6~H-5-bromo-6,9~-oxide, dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor, 6~H-6,9~-oxide-16-m-CF3-phenoxy-~tetranor and 6~H-6, 9~-oxide-16-m-ch:Loro-phenoxy-~-tetranor also showed BCA-contracting _ ~_ :~83~
activity.
In general, the exo-configuration is associated with BCA
contraction. Furthermore, the compounds of the invention have hypotensive activity in mammals as does the natural compound PGX.
However, as compared to PG~, they have the great advantage of a higher chemical stability and can he used in pharmaceutical formulations.
The hypotensive activity was demonstrated by the limb perfusion test. During the perfusion of the ratls left leg, through the left femoral artery, with a constant perfusion pressure, both the 6~H~ and 6~H-6,9~-oxide compounds caused a lowering of the values of the mean perfusion pressure at all the doses, over the range from 0.05~1 ~g (to -42.5% for 6~H and -32% for 6~H). More-over, the systemic pressure, both systolic and diastolic, was depressed from 0.05 ~g/kg up to 5 ~g/kg ~about -45%).
Because of their hypotensive and vasodilatory activity, the compounds of the invention are useful or treatment of cases of gangrene of the lower limbs. For this therapeutic use they have been found to be more active than PGEl and PGE2. They are also useful in disturbances o~ the peripheral vasculature and, therefore, in the prevention and treatment of diseases such as phlebitis, hepato-renal syndrome, ductus arteriosus, non-obstruc-tive mesenteric ische~ia, arteritis and ischemic ulcerations of the leg.
Among the compounds of the invention, in particular, the 6~H-derivatives also have a high anti-aggregating activity.
Among the 6~H co~pounds, the more important ones are, in order oE increasing polency, compounds dl-6~H-5-bromo-6,9~-oxide, 5~H-~3~
6,9~-oxide-16-m-C~'3-phenoxy-~-tetranor, dl-6~H-6,9~-oxide, and 6~H-6,9~-oxide.
Using platelet-rich plasma (PRP) from healthy human donors who had not taken any drugs for at least one week, and monitoring platelet aggregation by continuous recording of light transmission in a Born aggregometer [sorn G.V.~., Nature (London) 194, 927 (1962)] there is evidence that the compounds 6~H-6 ,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-6,9r~-oxide-16-m-CF3-phenoxy--~-tetranor and 6~H-6,9~-oxide-16-m-chloro-phenoxy-~-tetranor mimic the biosynthetic PGX in its platelet-antiaggregating properties.
The compounds investigated were incubated for 2-3 minutes at 37C
in the PRP prior to the addition of the aggregating agents, arachidonic acid (0.4 mM), ADP (10 ~M), collagen (38 ~M) or adrenaline (15 ~M). The potency ratio for the compound is, e.g., 1:10 for arachidonic acid-induced aggregation and 1:100 for ADP--induced aggregation, as compared with biosynthetic PGX.
A very interesting increase in the anti-aggregating potency follows 20-methyl substitution in both the 6~H- and 6~H
6,9~-oxide parent compounds. Similarly, 6~H-5-bromo-20-methyl, 6~H-5,14-di~romo, 6~H-13,14-didehydro-20-methyl and finally 6~H-5-bromo-13,14-didehydro compounds and their 6~H-6-iodo (but not 6~H-5-iodo isomers) are very active compounds as anti-aggregating agents. The compounds of the invention are, therefore, particular-ly useful ln mammals for inhibiting platelet aggregation, for preventing and inhibiting thrombus formation and for decreasing the adhesiveness of platelets.
Therefore, they are useful in treatment and prevention .j,.~ ., :~: 3 i~: ~
33~
of thromboses and myocardial infarct, in treatment of atheroscler-osis, and in general in all syndromes etiologically based on or associated with lipid imbalance or hyperlipidemia, as well as in treatment of geriatric patients for prevention o cerebral ischemic episodes, and in long-term treatment a~ter myocardial infarct~
When the compounds of the invention are given as anti-aggregating agents, the routes of administration are the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary from 0.005 to about 10 mg/kg/day. The exact dose will depend on the condition of the patient, his weight, his age and the route of administration.
The compounds of the invention ~ere also studied for their uterine contractile activity, both in vitro and in vivo, against PGF2 as standard.
For example, in vitro, on the uterus of the estrogenized rat, compounds 6~H-6,9~-oxide-16-m-chloro-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-m-CF3-phenoxy-~-tetranor, were 1.3 and 3.1 times as active as PGF2 . In the in vivo assay, measuring the intrau-terine pressure of the ovariectomized rabbit, the same compoundswere 5.9 and 8025 times as active as PGF2 (see the following Table) ~7
- 2-~'--! ``l "~
3139!~
= __ in vitro in vivo U-terus Ileum 6~H-6,9~-oxide-16-m-chloro-phenoxy-~- 1.3 0.05 5.9 tetranor 6~H-6~9~-oxide-16-m-CP3-phonoxy-~-tetra- 3.1 0.1 8.25 The -table shows that the compounds have greater activity on the uterus -than on the gastrointestinal tract. These compounds, which are useful for induc-tion of labor, for expulsion of dead fetuses from the pregnant female, in either human or veterinary medicine, are without the undesirable side effects of the natural prostaglandins, such as vomiting and diarrhea.
For this purpose the compounds of the invention can be given by intravenous infusion, at a dose of about 0.01 ~g/kg/minute until the end of labor. At the same dosage, -the compounds of the invention dilate the uterine cervix, facilitating therapeutic abortion and, in that situation are given preferably in the form of vaginal tablets or suppositories.
The compounds of the inven-tion, in particular the compound dl-6~H-6,9~-oxide-16-m-chloro-phenoxy ~-tetranor also have luteo-lytic activi-ty and are therefore of use for con-trol of fertility.
The 6~H-6~9~-oxicLe and their 6~H-isomers were also investigated for their action on the gastrointestinal tract, in order to know:
,~1 -- 2~ --~33!3~
(a) cytoprotective activity against lesions induced by non-steroid anti-inflammatory drugs; (b) ability to prevent the ulcers induced by the method of Togagi-Okabe [(Japan J. Pharmac. vol. 18, 9 (1968)]
and (c) antisecretory activity, according to Shay et al Gastroenter.
26, 906 (1954).
The cytoprotective ability is a common feature of all the compounds. for example, given subcutaneously, the 6~H~6,9~-oxido is slightly more active (1.5-2 timesl than the standard PGE2 as a gastric antisecretory agent. In general, the cytoprotective activity of the 6~H compounds is doubled when an acetylene bond is present in the 13,14-position; it is quadrupled when a 16-alkyl group, usually a methyl/ is positioned in the 16(S)-configuration.
As an ulcer-preventing substance, the parent 6~H-6,9~-oxide analog is at least equipotent with PGE2 and the following substitutions, 13,14-acetylene bond; 16S, or R methyl; 16S, or R fluoro, highly increase (up to 30 times) the potency ratio. Furthermore, a significant oral antisecretory activity appears when a methyl group is in the C-15-position of the parent 6~H-6,9~-oxide or in the 16,16-dimethyl compounds, such as the 6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor derivative.
For this purpose the compounds are preferably given by intravenous injection or infusion, subcutaneously or intramuscular-ly. For intravenous infusion, the doses vary from about 0.1 ~g to about 500 ~g/kg body weight/minute. The total daily dose, either by injection or by infusion, is of the order of 0.1 to 20 mg/kg, the exact dose depending on the age, ~eight and condition of the patient or o~ the animal being treated and on the route of ~i `c
3139!~
= __ in vitro in vivo U-terus Ileum 6~H-6,9~-oxide-16-m-chloro-phenoxy-~- 1.3 0.05 5.9 tetranor 6~H-6~9~-oxide-16-m-CP3-phonoxy-~-tetra- 3.1 0.1 8.25 The -table shows that the compounds have greater activity on the uterus -than on the gastrointestinal tract. These compounds, which are useful for induc-tion of labor, for expulsion of dead fetuses from the pregnant female, in either human or veterinary medicine, are without the undesirable side effects of the natural prostaglandins, such as vomiting and diarrhea.
For this purpose the compounds of the invention can be given by intravenous infusion, at a dose of about 0.01 ~g/kg/minute until the end of labor. At the same dosage, -the compounds of the invention dilate the uterine cervix, facilitating therapeutic abortion and, in that situation are given preferably in the form of vaginal tablets or suppositories.
The compounds of the inven-tion, in particular the compound dl-6~H-6,9~-oxide-16-m-chloro-phenoxy ~-tetranor also have luteo-lytic activi-ty and are therefore of use for con-trol of fertility.
The 6~H-6~9~-oxicLe and their 6~H-isomers were also investigated for their action on the gastrointestinal tract, in order to know:
,~1 -- 2~ --~33!3~
(a) cytoprotective activity against lesions induced by non-steroid anti-inflammatory drugs; (b) ability to prevent the ulcers induced by the method of Togagi-Okabe [(Japan J. Pharmac. vol. 18, 9 (1968)]
and (c) antisecretory activity, according to Shay et al Gastroenter.
26, 906 (1954).
The cytoprotective ability is a common feature of all the compounds. for example, given subcutaneously, the 6~H~6,9~-oxido is slightly more active (1.5-2 timesl than the standard PGE2 as a gastric antisecretory agent. In general, the cytoprotective activity of the 6~H compounds is doubled when an acetylene bond is present in the 13,14-position; it is quadrupled when a 16-alkyl group, usually a methyl/ is positioned in the 16(S)-configuration.
As an ulcer-preventing substance, the parent 6~H-6,9~-oxide analog is at least equipotent with PGE2 and the following substitutions, 13,14-acetylene bond; 16S, or R methyl; 16S, or R fluoro, highly increase (up to 30 times) the potency ratio. Furthermore, a significant oral antisecretory activity appears when a methyl group is in the C-15-position of the parent 6~H-6,9~-oxide or in the 16,16-dimethyl compounds, such as the 6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor derivative.
For this purpose the compounds are preferably given by intravenous injection or infusion, subcutaneously or intramuscular-ly. For intravenous infusion, the doses vary from about 0.1 ~g to about 500 ~g/kg body weight/minute. The total daily dose, either by injection or by infusion, is of the order of 0.1 to 20 mg/kg, the exact dose depending on the age, ~eight and condition of the patient or o~ the animal being treated and on the route of ~i `c
3 ~
administration.
In addition, the compounds are also useful for treatment of obstructive pulmonary diseases such as bronchial asthma, since they have considerable bronchodilatory activity. For treatment of the obstructive pulmonary disorders, for example bronchial asthma, the compounds of the invention can be given by different routes; orally in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups; rectally in suppositories;
intravenously, intramuscularly or subcutaneously; 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, with the e~act dose depending on the age, weight and condition of the patient and on the route of administration.
For use as an antiasthmatic, the compounds of the invention can be combined with other antiasthmatic agents, such as sympathico-mimetic drugs ]ike isoproterenol, ephedrine, etc., xanthine derivatives, such as theophylline and aminophylline, or cortico-steroids.
The dosages when used as hyoptensive and vasodilatory agents are about the same as those used for the anti-aggregating effec-ts.
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 oE suppositories; parenterally, subcutaneous-ly or intramuscuLarly, with intravenous administration being ~3 - 2~4 -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 intravagir~ally in the form, e.g., of bougies. The pharmaceutical or veterinary compositions containing the compounds of the invention may be prepared in conventional ways and contain conventional carriers and/or diluents.
For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous 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, etc. For administration by nehulizer, 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 dichlorodifluoromethane or dichloro-tetrafluoroethane, 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 co-solvent, such as ethanol, dipropylene glycol and/or a surfactant to the pharmaceutical _ ~' :~83~
formulation.
The inven-tion is illustrated ~y the following examples, wherein the abbreviations "THF", 'IDME", "EMS0", "THP", "Et20"
refer to tetrahydrofuran, dimethoxyethane, dimethylsulphoxide, tetrahydropyranyl, and ethyl ether, respectively.
The following examples illustrate the preparation of compounds of the invention, the preparatlon of compounds which are the subject of related application serial Nos. 329.306;
329,309 and 394,875, and the preparation of intermediate compounds, but do not limit the present invention.
~,,, ~..
E ;amr)le -To a solution of 1.0 g of dl-53-hydroxymethyl-2~,4~-dihydroxy-cyclopentan-l~-acetic acid-r-lactone-4-_-phenylbenzoate in 8 ml of benzene/
DMSO ~75/25) is added with stirring O.S9 g of dicyclohexylcarbodiimide. At room temperature, 1.42 ml of a solution of pyridinium trifluoroacetate is added (prepared from 1 ml of trifluoroacetic acid and 2 ml of pyridine brought to 2S ml with 75/25 benzene/DMSO). After 3 hours 19 ml of benzene is added and the mixture is treated dropwise with an oxalic acid dihydrate solution, 0.3 g in 3.8 ml of water. After approximately 15 minutes of stirring, the mixture is filtered, and the organic phase is washed with water until neutral, concentrated to 2 ml, and then diluted with 5 ml of isopropyl ether. The product is isolated by filtration and crystallized from isopropyl ether to give 0.8 g of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone-4-_-phenylbenzoate, m.p. = 129 - 131 C. A solution of 800 mg of this in 2.8 ml of anhydrous methanol is treated with 0.62 ml of methyl orthoformate and 18 mg of _-toluenesulfonic acid monohydrate. After 1 hour, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate; it is washed with l.On NaOH and then saturated ~83~
NaCl until neutral. The solvent is removed at reduced pressure and the resi-due is crystalli7ed from methanol to give 800 mg of dl-5~-dimethoxymethyl-2~, 4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-_-phenylbenzoate, m. p. =
108 - 110C.
60 mg of K2C03 is added to a solution of this in 5.6 ml of anhydrous methanol. After 4 hours of stirring-at room temperature, the solution is filtered; it is then reduced to small volume and acidified with a saturated NaH2P04 solution. The methanol is removed and the residue taken up in ethyl acetate. This is washed with saturated NaCl until neutral, is dried over an-hydrous Na2S04, is filtered, and evaporated under reduced pressure to give 480 mg of dl-5~-dimethoxymethyl-2cY,4cY-dihydroxy-cyclopentan-l~-acetic acid-y-lactone.
A solution of this in 4 ml of CH2C12 is treated with 0.32 ml of 2,3-dihydropyran and 4.8 mg of ~-toluenesulfonic acid. After 4 hours at room temperature, pyridine is added and the solution is evaporated at reduced pres-sure. The crude reaction product is filtered on 5 g of silica gel, with cyc-lohexane:ethylether ~50:50) as eluent, to give 380 mg of dl-5~-dimethoxymethyl 2a,4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-tetrahydropyranyl ether.
Starting from a 4-ester of 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone (for example: 4-p-phenyloen~oate, m. p. 128 - 130C, ~CY]D = -85) or from a 4-ester of 5cy-hydroxymethyl-2~4~-dihydroxy-cyclopentan l~-acet~c-y-lactone (for example: the 4-_-phenylben~oate, m. p. = 127 - 129C, ~a~ = ~84.5), the same procedure was used to prepare the following compounds:
5~-dimethoxymethyl-2cY,4~-dihydroxy-cyclopentan-ly-acetic acid-y-lactone-4-tetrahydropyranyl ether and 5~-climethoxymethyl-2~,4~-dillydro~y-cyclopentan-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether. If 1,4-dio~c-2-ene is used instead of 2,3-dihydropyran, the corresponclin~ 4-dioxanyl ether derivatives ~lre o~tained.
389L~
Example 2 A solution of 216 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan-l~-acetic acid-y-lactone [~]D = -16 [~]365= -48 (C - 1-0 CHC13) in 1.6 ml of dimethylformamide is treated with 0.3 ml of trie~hylamine followed by 291 mg of dimethyl-tert-butylchlorosilane. After one hour, the mixture is diluted with 8.3 ml of water and extracted with hexane. The organic phase is washed with water and dried over Na2S04 to give 310 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether.
Example 3 To a solution of dl-5~-hydroxymethyl-2~4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-p-phenylbenzoate (1 g) in 8 ml of benzene:DMSO
C75:25) is added 0.86 g of dicyclohexylcarbodiimide followed by 1.37 ml of a freshly prepared pyridinium trifluoroacetate Isee example 1). After three hours, 18 ml of benzene is added; a solution of 0.29 g of oxalic acid dihydrate in 3.7 ml of water is then added dropwise. After 15 minutes of stirring~ the dicyclohe.xylurea is removed by filtration and the organic pl-ase is washed with water until neutral. This is then reduced to volume to approximately 2 ml and isopropyl ether is added. One obtains 0.793 g of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-l~-propionic acid-~-lactone-4-~-phenylbenzoate.
A solution of 780 mg of this in 2.7 ml of anhydrous methanol is treated wi-th 0.59 ml of methylorthoformate and 17.3 mg of p-toluenesulfonic acid. After approximately one hour, 0.01 ml of pyridine is added and the solu-tiOII is evaporated to dryness. The residue is taken up in ethyl acctate; the organic phase is ~ashed with lN NaOI-I and then saturated `NaCl until neutral.
Evaporation to dryness gives 769 mg of dl-5~-dimethoxymetllyl-2~,4~dillydroxy-cyclopcntan-l~-propionic acid-~-lactone-~-p-pllenylbenzoate. This is then dis-solved in 5.4 ml of anhydrolls methanol and 75 mg of ~2C03 is added. After 33~
four hours of stirring at room temperature and filtration, the solution is reduced in volume and acidified with a saturated solution of NaH2P04. The methanol is evaporated and the aqueous phase treated with ethyl acetate; the organic phase is then washed with a saturated NaCl solution until neutral, dried over Na2S04J and evaporated under vacuum to give crude dl-5~-dime-thoxy-methyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone. A solution of this in 4 ml of CH2C12 is treated with 0.3 ml of 2,3-dihydropyran and 4.5 mg of ~-toluenesulfonic acid. After four hours at room temperature, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The reaction product is purified on silica gel with cyclohexane: ethyl ether (50:50) as eluent to give 480 mg of dl-53-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether.
From a 4-ester of 5g-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone and from a 4-ester of 5~-hydroxymethyl-2~,43-dihy-droxycyclopentan-l~-propanoic acid-~-lactone (for examplc, the 4-~phenylbenzo-ate), using the same procedure, the following compounds were obtained:
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether;
5~-dimethoxymethyl~2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether.
If 1~4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives are obtained.
Example 4 A solution of 1 g of 5~-formyl-2~-hydroxycyclopontan-1~-acetic acid-y-lactone in 6.5 ml of anhydrous methanol is treated with 1.74 ml of methylorthoformate and 52 mg of p-tolueneslllfonic acid. Aftcr approximately ono ho~lr, 0.04 ml of pyridine is added and tlle solution is evaporated to dry-noss. rhe residue is ta~en ~Ip in ethyl acetate,and then washed with lN NaOil ~3~
and then saturatcd NaCl until neutral. Evaporation under vacuum gives 1 g of 5~-dimethoxymethyl-2cY-hydroxycyclopentan-l~-acetic acid-y-lactone, [~] = -16.
The same procedure gave 5~-dimethoxymethyl-2cY-hydroxycyclopentan-lcY-propionic acid-c)-lactone and its dl derivatives from 5~-formyl-2cY-hydroxy-cyclopentan-lcY-propionic acid-c)-lactone.
Example 5 To a solution of 960 mg of dl-5~-dimethoxymethyl-2~,4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-tetrahydropyranyl ether in 16 ml of toluene, cooled to -70C, is added S.5 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride, over a 30 minute period. After a further 30 minutes of stirring at -70C, 10 ml of a 2M toluene solution of iso-propanol is added dropwise. The solution is warmed to 0C and treated with 3 ml of a 30~ solu-tion of NaH2P04. After 1 hour of stirring, 12 g of anhydrous Na2S04 is added.
Filtration and evaporation of solvent gives 900 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-ethanal-y-lactol-4-tetrahydropyranyl ether.
Example 6 Following the yrocedure of e~ample 5, a solution of 400 mg of 5~-dimethoxymethyl-2a,4cY-dihydroxycyclopentan-lc~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether in 11 ml of toluene, cooled to -70 C, is treated drop-wise with 5.9 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride to give 0.43 g of 5~-dimethoxymethyl-2cY,4cY-dihydroxycyclopentan-lcY-ethanal-y- lactol-4-dimethyl-tert-butylsilyl ether.
Example 7 Under a nitrogen atmosphere, a solution of 62S mg of 5~-dimetho~y-metllyl-2cy~4cy-dillydro~;ycyclopentan-lcy-propalloic acid-c)-lactone-4-tetrahydro-pyrarlyl cther in 11 ml of toluenc, coolccl to -70 C, is treated dropwise with 5.9 ml of a 0.5hl toluene solution of di-iso-butylalwninum hydride. After 30 minutcs at -70 C, 10.~ ml of a 2~1 tolucne solution of isopropanol is added ~B3~
dropwise. The temperature is allo~Yed to rise to 0C and 2 ml of 30% NaH2P04 is added. After one hour of stirring, 8.3 g of anhydrous ~a2S04 is added and the mixture is filtered. Evaporation of the organic phase under vacuum gives 620 mg of 5~-dimethoxymethyl-2~,4~-dillydroxycyclopentan-1~-propanal-~-lactol-
administration.
In addition, the compounds are also useful for treatment of obstructive pulmonary diseases such as bronchial asthma, since they have considerable bronchodilatory activity. For treatment of the obstructive pulmonary disorders, for example bronchial asthma, the compounds of the invention can be given by different routes; orally in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups; rectally in suppositories;
intravenously, intramuscularly or subcutaneously; 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, with the e~act dose depending on the age, weight and condition of the patient and on the route of administration.
For use as an antiasthmatic, the compounds of the invention can be combined with other antiasthmatic agents, such as sympathico-mimetic drugs ]ike isoproterenol, ephedrine, etc., xanthine derivatives, such as theophylline and aminophylline, or cortico-steroids.
The dosages when used as hyoptensive and vasodilatory agents are about the same as those used for the anti-aggregating effec-ts.
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 oE suppositories; parenterally, subcutaneous-ly or intramuscuLarly, with intravenous administration being ~3 - 2~4 -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 intravagir~ally in the form, e.g., of bougies. The pharmaceutical or veterinary compositions containing the compounds of the invention may be prepared in conventional ways and contain conventional carriers and/or diluents.
For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous 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, etc. For administration by nehulizer, 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 dichlorodifluoromethane or dichloro-tetrafluoroethane, 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 co-solvent, such as ethanol, dipropylene glycol and/or a surfactant to the pharmaceutical _ ~' :~83~
formulation.
The inven-tion is illustrated ~y the following examples, wherein the abbreviations "THF", 'IDME", "EMS0", "THP", "Et20"
refer to tetrahydrofuran, dimethoxyethane, dimethylsulphoxide, tetrahydropyranyl, and ethyl ether, respectively.
The following examples illustrate the preparation of compounds of the invention, the preparatlon of compounds which are the subject of related application serial Nos. 329.306;
329,309 and 394,875, and the preparation of intermediate compounds, but do not limit the present invention.
~,,, ~..
E ;amr)le -To a solution of 1.0 g of dl-53-hydroxymethyl-2~,4~-dihydroxy-cyclopentan-l~-acetic acid-r-lactone-4-_-phenylbenzoate in 8 ml of benzene/
DMSO ~75/25) is added with stirring O.S9 g of dicyclohexylcarbodiimide. At room temperature, 1.42 ml of a solution of pyridinium trifluoroacetate is added (prepared from 1 ml of trifluoroacetic acid and 2 ml of pyridine brought to 2S ml with 75/25 benzene/DMSO). After 3 hours 19 ml of benzene is added and the mixture is treated dropwise with an oxalic acid dihydrate solution, 0.3 g in 3.8 ml of water. After approximately 15 minutes of stirring, the mixture is filtered, and the organic phase is washed with water until neutral, concentrated to 2 ml, and then diluted with 5 ml of isopropyl ether. The product is isolated by filtration and crystallized from isopropyl ether to give 0.8 g of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone-4-_-phenylbenzoate, m.p. = 129 - 131 C. A solution of 800 mg of this in 2.8 ml of anhydrous methanol is treated with 0.62 ml of methyl orthoformate and 18 mg of _-toluenesulfonic acid monohydrate. After 1 hour, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate; it is washed with l.On NaOH and then saturated ~83~
NaCl until neutral. The solvent is removed at reduced pressure and the resi-due is crystalli7ed from methanol to give 800 mg of dl-5~-dimethoxymethyl-2~, 4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-_-phenylbenzoate, m. p. =
108 - 110C.
60 mg of K2C03 is added to a solution of this in 5.6 ml of anhydrous methanol. After 4 hours of stirring-at room temperature, the solution is filtered; it is then reduced to small volume and acidified with a saturated NaH2P04 solution. The methanol is removed and the residue taken up in ethyl acetate. This is washed with saturated NaCl until neutral, is dried over an-hydrous Na2S04, is filtered, and evaporated under reduced pressure to give 480 mg of dl-5~-dimethoxymethyl-2cY,4cY-dihydroxy-cyclopentan-l~-acetic acid-y-lactone.
A solution of this in 4 ml of CH2C12 is treated with 0.32 ml of 2,3-dihydropyran and 4.8 mg of ~-toluenesulfonic acid. After 4 hours at room temperature, pyridine is added and the solution is evaporated at reduced pres-sure. The crude reaction product is filtered on 5 g of silica gel, with cyc-lohexane:ethylether ~50:50) as eluent, to give 380 mg of dl-5~-dimethoxymethyl 2a,4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-tetrahydropyranyl ether.
Starting from a 4-ester of 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone (for example: 4-p-phenyloen~oate, m. p. 128 - 130C, ~CY]D = -85) or from a 4-ester of 5cy-hydroxymethyl-2~4~-dihydroxy-cyclopentan l~-acet~c-y-lactone (for example: the 4-_-phenylben~oate, m. p. = 127 - 129C, ~a~ = ~84.5), the same procedure was used to prepare the following compounds:
5~-dimethoxymethyl-2cY,4~-dihydroxy-cyclopentan-ly-acetic acid-y-lactone-4-tetrahydropyranyl ether and 5~-climethoxymethyl-2~,4~-dillydro~y-cyclopentan-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether. If 1,4-dio~c-2-ene is used instead of 2,3-dihydropyran, the corresponclin~ 4-dioxanyl ether derivatives ~lre o~tained.
389L~
Example 2 A solution of 216 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan-l~-acetic acid-y-lactone [~]D = -16 [~]365= -48 (C - 1-0 CHC13) in 1.6 ml of dimethylformamide is treated with 0.3 ml of trie~hylamine followed by 291 mg of dimethyl-tert-butylchlorosilane. After one hour, the mixture is diluted with 8.3 ml of water and extracted with hexane. The organic phase is washed with water and dried over Na2S04 to give 310 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether.
Example 3 To a solution of dl-5~-hydroxymethyl-2~4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-p-phenylbenzoate (1 g) in 8 ml of benzene:DMSO
C75:25) is added 0.86 g of dicyclohexylcarbodiimide followed by 1.37 ml of a freshly prepared pyridinium trifluoroacetate Isee example 1). After three hours, 18 ml of benzene is added; a solution of 0.29 g of oxalic acid dihydrate in 3.7 ml of water is then added dropwise. After 15 minutes of stirring~ the dicyclohe.xylurea is removed by filtration and the organic pl-ase is washed with water until neutral. This is then reduced to volume to approximately 2 ml and isopropyl ether is added. One obtains 0.793 g of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-l~-propionic acid-~-lactone-4-~-phenylbenzoate.
A solution of 780 mg of this in 2.7 ml of anhydrous methanol is treated wi-th 0.59 ml of methylorthoformate and 17.3 mg of p-toluenesulfonic acid. After approximately one hour, 0.01 ml of pyridine is added and the solu-tiOII is evaporated to dryness. The residue is taken up in ethyl acctate; the organic phase is ~ashed with lN NaOI-I and then saturated `NaCl until neutral.
Evaporation to dryness gives 769 mg of dl-5~-dimethoxymetllyl-2~,4~dillydroxy-cyclopcntan-l~-propionic acid-~-lactone-~-p-pllenylbenzoate. This is then dis-solved in 5.4 ml of anhydrolls methanol and 75 mg of ~2C03 is added. After 33~
four hours of stirring at room temperature and filtration, the solution is reduced in volume and acidified with a saturated solution of NaH2P04. The methanol is evaporated and the aqueous phase treated with ethyl acetate; the organic phase is then washed with a saturated NaCl solution until neutral, dried over Na2S04J and evaporated under vacuum to give crude dl-5~-dime-thoxy-methyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone. A solution of this in 4 ml of CH2C12 is treated with 0.3 ml of 2,3-dihydropyran and 4.5 mg of ~-toluenesulfonic acid. After four hours at room temperature, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The reaction product is purified on silica gel with cyclohexane: ethyl ether (50:50) as eluent to give 480 mg of dl-53-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether.
From a 4-ester of 5g-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone and from a 4-ester of 5~-hydroxymethyl-2~,43-dihy-droxycyclopentan-l~-propanoic acid-~-lactone (for examplc, the 4-~phenylbenzo-ate), using the same procedure, the following compounds were obtained:
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether;
5~-dimethoxymethyl~2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-tetrahydropyranyl ether.
If 1~4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives are obtained.
Example 4 A solution of 1 g of 5~-formyl-2~-hydroxycyclopontan-1~-acetic acid-y-lactone in 6.5 ml of anhydrous methanol is treated with 1.74 ml of methylorthoformate and 52 mg of p-tolueneslllfonic acid. Aftcr approximately ono ho~lr, 0.04 ml of pyridine is added and tlle solution is evaporated to dry-noss. rhe residue is ta~en ~Ip in ethyl acetate,and then washed with lN NaOil ~3~
and then saturatcd NaCl until neutral. Evaporation under vacuum gives 1 g of 5~-dimethoxymethyl-2cY-hydroxycyclopentan-l~-acetic acid-y-lactone, [~] = -16.
The same procedure gave 5~-dimethoxymethyl-2cY-hydroxycyclopentan-lcY-propionic acid-c)-lactone and its dl derivatives from 5~-formyl-2cY-hydroxy-cyclopentan-lcY-propionic acid-c)-lactone.
Example 5 To a solution of 960 mg of dl-5~-dimethoxymethyl-2~,4cY-dihydroxy-cyclopentan-lcY-acetic acid-y-lactone-4-tetrahydropyranyl ether in 16 ml of toluene, cooled to -70C, is added S.5 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride, over a 30 minute period. After a further 30 minutes of stirring at -70C, 10 ml of a 2M toluene solution of iso-propanol is added dropwise. The solution is warmed to 0C and treated with 3 ml of a 30~ solu-tion of NaH2P04. After 1 hour of stirring, 12 g of anhydrous Na2S04 is added.
Filtration and evaporation of solvent gives 900 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-ethanal-y-lactol-4-tetrahydropyranyl ether.
Example 6 Following the yrocedure of e~ample 5, a solution of 400 mg of 5~-dimethoxymethyl-2a,4cY-dihydroxycyclopentan-lc~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl ether in 11 ml of toluene, cooled to -70 C, is treated drop-wise with 5.9 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride to give 0.43 g of 5~-dimethoxymethyl-2cY,4cY-dihydroxycyclopentan-lcY-ethanal-y- lactol-4-dimethyl-tert-butylsilyl ether.
Example 7 Under a nitrogen atmosphere, a solution of 62S mg of 5~-dimetho~y-metllyl-2cy~4cy-dillydro~;ycyclopentan-lcy-propalloic acid-c)-lactone-4-tetrahydro-pyrarlyl cther in 11 ml of toluenc, coolccl to -70 C, is treated dropwise with 5.9 ml of a 0.5hl toluene solution of di-iso-butylalwninum hydride. After 30 minutcs at -70 C, 10.~ ml of a 2~1 tolucne solution of isopropanol is added ~B3~
dropwise. The temperature is allo~Yed to rise to 0C and 2 ml of 30% NaH2P04 is added. After one hour of stirring, 8.3 g of anhydrous ~a2S04 is added and the mixture is filtered. Evaporation of the organic phase under vacuum gives 620 mg of 5~-dimethoxymethyl-2~,4~-dillydroxycyclopentan-1~-propanal-~-lactol-
4-tetrahydropyranyl ether.
Example 8 Using one of the procedures outlined in examples 5, 6 and 7, a 4-acetal t4-tetrahydropyranyl ether; 4-dioxanyl ether) and a 4-dimethylbutyl-silyl ether of the following compounds are prepared:
S~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-ethanal-y-lactol, in its dl and optically active form ~or nat-);
Example 8 Using one of the procedures outlined in examples 5, 6 and 7, a 4-acetal t4-tetrahydropyranyl ether; 4-dioxanyl ether) and a 4-dimethylbutyl-silyl ether of the following compounds are prepared:
S~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-ethanal-y-lactol, in its dl and optically active form ~or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-ethanal-~-lactol (or ent-form);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-propanal-~-lactol, in its dl and optically active form ~or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-propanal-~-lactol ~or ent-form).
Example 9 0.29 ml of absolute ethanol in 3.5 ml of toluene is added dropwise to a solution of 5 x lO mol of sodium (2-methoxyethoxy)aluminum hydride ~1.4 ml of a 70% benzene solution diluted with 5 ml of toluene) cooled to 0C.
8.2 ml of the alanate solution so prepared is added, at -30C, to 0.98 g of dl-5~-benzyloxymethyl-2~-hydroxYcyclopentan-l~-propionic acid-~-lactone in 22 ml of toluene. AEter 45 minutes, excess reagent is qucnchcd with 6 ml of a 0.5 ~I toluene solution of isopropanol. The mixture is warmed to 0 C, 4 ml of 30J Natt2P0~l is added, and the resulting mixture is stirred for 2 hours. The inorganic salts are removed by filtration and the solution is evaporated to dryness to give 0.94 g of dl-5~-benzyloxYmethyl-2~-hydroxycyclopentan-l~-propanal-~-lactol. 3/
~3~
Using the procedure reported above, or one of those from examples 4 to 7, the follo~Ying compounds were prepared :Erom their corresponding ~-lac-tones:
5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-ethanal-~-lactol;
5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-propanal-~-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-ethanal-y-lactol;
5~-dimethoxymethyl-2c~-hydroxycyclopentan-lc~-propanal-ô-lactol .
Exam~le 10 With stirring and external cooling to maintain a reaction tempera-ture of 20 - 22C3 a solution of 1.05 g of potassium tert-butylate in 10 ml of DMSO is added dropwise to a solution of 1.8 g of 4-carboxybutyl-triphenyl-phosphonium bromide and 0.38 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan~ ethanal-y-lactol-4-tetrahydropyranyl ether. After the addition, the mixture is held at room temperature for 1 hour and then diluted ~ith 16 ml of ice/~ater. Ihe aqueous phase is extracted Yith ether (5 x S ml) and ether:
benzene ~70:30~ 5 x 6 ml), the organic layers, after re-extraction with 0.5`I
NaOH (2 x 10 ml), are discarded. The combined al~aline aqueous phase is acid-ified to pH 4.8 with 30% NaH2PO4 and then extracted ~ith ethyl ether:pentane (1:1, 5 x 15 ml); from tlle combined organic phases, after drying over Na2SO4 and solvent removal, one obtains 0.45 g of 5-c -7-~2'~,4'~-dihydroxy-5'~-dimethoxymethylcyclopentan-l'~-yl)-hept-5-enoic acid-4l-tetrahydropyranyl ether. This in turn is converted to the corresponding methyl ester upon treat-ment with diazomethane in ether. An analytic sample is prepared by adsorbing 100 mg of the crucle product on 1 g of silica gel and eluting I~ith benzene:
ethyl ether ~S5:15). N.~I.R.: C=C~ 5.46 p.p.m. multiplet.
~f 1-l Example 11 In an an~hydrous nitrogerI atmosphere, a suspension of 0.39 g of a 75o oi.l dispersion of Na~I in D~ISO (13 . 5 ml) is heated to 60 - 65 C for 3 1/~
hours; after cooling to room temperature and while maintaining the reaction mixture at 20 - 22C, the follo~ing are added, in order: 2.66 g of 3-carboxy-propyltriphenylphosphonium bromide in 6 ml of DMSO and 0.6 g of 5~-dimethoxy-methyl-2cx,4~-dihydroxycyclopentan-1~-propanal-c,-lactol-4-tetrahydropyranyl ether in 3 ml of DMSO. The mixture is stirred for 3 hours, and then diluted ~ith 35 ml of water. The aqueous phase is extracted with ethyl ether (5 c 12 ml) and ethyl ether:benzene (70:30, 7 x 12 ml); the combined organic extract, after re-extraction with 0.5N NaO~ ~2 x 15 ml), is discarded. The combined alkaline aqueous extract is acidified to pH 4.3 with 30~ aqueous Na~l2PO4 and extracted ~ith ethyl ether:pentane (1:1) to give, after ~ashing until neutral, drying over Na2S04, and removal of the solvent, 0.71 g of 4-Cis-7-~2~,4~c~l-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acicl. Treatment ~ith diazomethane affords the corresponding methyl ester.
Example 12 The methyl esters of the following acids were prepared from lactols made according to the procedures in examples 4 to ~ by treatment ~ith a l~ittig reagent (prepared from 4-carboxybutyl-triphenylphosphonium bromide or 3-car-boxypropyltriphenylphosphonium bromide) and successive esterification ~ith diazomethane, in their optically active or dl forms:
4-cis-7-C2~cx-hydro~Yy-5~-benzyloxymethylcyclopent-l~c~-yl)-hept-4-enoici 4-cis-7-(2'cx-hydroxy-5'~-dimethoxymet}lyl-cyclopent-l~cx-yl)-hept-4-enoic;
5-cis-7--~2'cx-}1ydroxy-5'13-dimethoxymet}lyl-cyclopent-l'cx-yl)-}lept-5-enoic;
5-cis-7-~2'cY-hydroxy-5'~-ben7yloxymethyl-cyclopellt-l'cx-yl)-}lcpt-S-enoic;
5--is-7-~2'cx~4'cy-dlllydroxy-5~-dimetlloxynlethyl-cyclopent-l~ yl)-llept-5-enoic-and its 4'-dioxallyl, tetrahydropyranil ancl dimethyl-tert-butylsilyl)-ethers;
4-cis-7-~2'c~,4'cx-clillydroxy-5' ~-dimcthoxymc?thyl-cycloperlt-l'cx-yl) -hept-4-enoic and its 4'-(dioxanyl, tetrahydroyyranyl and dimethyl-tert-butylsilyl)-ethers;
J - ~ _ ~183~
4-cis-6-~2'c~,4'c~ dihydroxy-5'~-dimethoxymethyl-cyclopent-l'c~-yl)-hex-4-enoic and its 4'-~tetrahydropyranylether;
5-cis-8-~2'oL,4'c~-dihydroxy-5',~-dimethoxymethyl-cyclopent-l'c~-yl)oct-5-enoic and its 4'-tetrahydropyranylether.
Example 13 A solution of 1.06 g of the methyl ester of 5-cis-7-(2'c~,4'c~-dihy-droxy-5l~-dimethoxymethyl-cyclopent-l~c~-yl)-hept-5-enoic acid-4'-tetrahydro-pyranyl ether in 5 ml of methanol is adcled to O.S4 g of mercuric acetate in methanol. After 30 minutes at room temperature, a solution of 250 mg of sodi-um ~orohydride in 2 ml of water is added with stirring and external cooling.
After 20 minutes of stirring, the mixture is acidified to plI 6.5 ~ith aqueous monosodium phosphate, the methanol is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase, upon rcmoval of the solvent, affords 1.02 g of 5-~6'-exo-dimethoxymethyl-7'-endo-Ilydroxy-2'-oxa-oicyclo[3.3~0]octan-3'~-yl)-pentanoic acid methyl ester-7'-t~rahydropyranyl ether.
Example 14 A solution of 1.59 g of 4-cis-7-(2'c~,4'c~-dihydroxy-5'~-dimethoxy-methyl-cyclopent-l'c~-yl)-hept-4-enoiC methyl ester-4'-tetrahydropyranyl etiler in 6 ml of THF is added to a solution of 1.26 g of mercuric acetate in 4 ml of water diluted with 4 ml of THF. The mixture is stirred for 1 1/2 hours until precipitation is complete. lS0 mg of sodiwn borohydride ~in 2.5 ml of water) is then added and tlle resulting mixture is stirred for 30 minutes. The solution is decanted from the precipitate, wIlicll is theIl washed with TI-IF. The aqueous/organic decanted solution is concentratecI under reduced pressure and the resid-~e extracted tYith ethyl acetate. The combine(I organic extract, after wasI~ing witIl~Yater until neutral, affords upon removal of the solvent 0.98 g o /I t7'-e.co-dimetIlo~ymethyl-S'-endo-ilydroxy-2'-oxa-bicyclo~3.4.0]nonan-3~-yl) i ~ ~ butanoic acid methyl ester-S'-tetrahycIropyranyl ether.
~l83 51~.
Exam~le 15 _, ., ._ Starting from the esters prepared as described in examples 9 to 11, by reaction with a mercuric salt and subsequent reductive demercuration as described in the procedures in examples 13 and 14, the follo,~ing bicyclic derivatives are obtained:
5-(6'-exo-ben~yloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo~3.3.0]octan-3'~-yl~-pentanoic acid methyl ester;
4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo~3.4.0]nonan-3'S-yl)-butanoic acid methyl ester;
a 7'-acetal ether ~tetrahydropyranyl ether, dioxanyl ether), and a 7'-dimethyl-tert-butylsilyl ether of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
an 8'-acetal ether ~tetrahydropyranyl ether, dioxanyl cther) and an 8'-dimethyl-tert-butylsilyl ether of 4-~7'-exo-dimethyoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
4-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-butanoic acid methyl ester-7'-tetrahydropyranyl ether;
5-(7'-exo-dimethoxymethyl-8'-endo-llydroxy-2'-oxa-bicyclo[3.~1.0]nonan-3'~,-yl)-pentanoic acid methyl ~ster-8'-tetrahydropyranyl ether.
All these compo~mds are obtaincd in the d,l-, nat- and ent-forms.
Exam~le 16 ~ solution of 0.4S g of bromine in 5 ml of methylene chloride is added cIrop~ise, ~ith stirring, to a solution of 0.27 g of pyridine and 1.2 g of 5-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopcnt-1'~-yl)-hept-5-~t~it3~
enoic acid methyl ester-4'-tetrahydropyranyl ether in 6 ml of methylene chlo-ride, coo]ed to 0 C. Stirring is continued for ten minutes fol~owing ~he ad-dition. The organic phase is washed with 5 ml of a pH 7 buffer solution 10~
in sodium t}liO sulfate and then with water until neutral. After drying over Na2S04, removal of the solvent affords :L.38 g of 5-bromo-5-~6'-exo-dimethoxy-methyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 17 1.24 g of N-iodosuccinimide is added to a solution of 2 g of 5-cis-7-(2l~,4'~-dihydroxy-5'~-dimetkoxymethy:L-cyclopent-l'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in 15 ml of carbon tctrachloride. The mixture is stirred for 3 hours and 30 ml of ethyl ether is added. The organic phase is washed with lN Na2S203 and then with water until neutral. Removal of the solvent affords 2.48 g of 5-iodo-5'-(6'-exo-dimethoxymethyl-7'-endo-hy-droxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl cster-7'-tetra-hydropyranyl ether.
E~ample 18 422 mg of N-bromosuccinimide is added with stirring to a solution of 0.78 g of 4-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymet}lyl-cyclopent-1'~-yl)-hept-4-enoic acid methyl ester-4-tetrahydropyranyl ether in 11 ml of CC14.
After four hours of stirring, ethyl ether is added; the solution is then washed with water, lN Na2S203, and water until neutral. Evaporation to dry-ness gives 0.98 g of 4-bromo-4-(7'-exo-dimethox)~ethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid mcthyl estcr-s~-tetrahydropyra nyl ether.
Example 19 To a suspension of 0.25 g of dry CaC0 in a solution of 346 mg of 5-cls-7-~2'~-hydroxy-5'~-~en7yloxymetllyl-cyclopent-l'~-yl)-llept-5-enoic acid l .r3 l''i'~ ~
3~
methyl ester in 10 ml of CCl4 cooled to 0 - 5C is added with stirring a solu-tion of 75 mg of chlorine in 3 ml of CC14. After stirring for 2 hours, the inorganic salts are removed by filtration. The solution is l~ashed with a 7%
aqueous solution of KI and Na2S203 and then with water until neutral. The residue upon evaporation to dryness is adsorbed on silica gel and eluted with cyclohexane:ethyl ether (80:20) to give 0.27 g of 5-chloro-5-(6'-exo-benzyl-oxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.
Example 20 A solution of 0.39 g of 5-CiS-7- (2'Cl,4'c~-dihydroxy-5'~-dimethoxy-methyl-cyclopent-l' cs-yl) -hept-5-enoic acid methyl ester-4'-dioxanyl ether and 98 mg of pyridine in 10 ml of dichloromethane is cooled to -40C. A solution of 81 mg of chlorine in 6 ml of CH2C12 is then added over a period of 30 min-utes. After 10 minutes of stirring, the mixture is heated to room temperature.
The organic phase is washed with a 7% solution of KI and Na2S203 and then ~ith water until neutral. Removal of the solvent affords 0.39 g of 5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentan-oic acid methyl ester-4'-dioxanyl ether.
Exam~le 21 280 mg of iodine in CC14 is added to a solution of 0.39 g of 4-cis-7-(2'ct,4'c~-dihydroxy-5~-dimethoxymethyl-cyclopent-l'c~-yl)-hept-4-enoic acid methyl ester-4'-tetrahydropyranyl ether and 82 mg of pyridine in 10 ml of CC14. Stirring is continued until the color disappears; 30 ml o ethyl ether is then added. The organic phase is washed with l~ater, then a solution 7%
in KI and Na2S203, ancl then water until neutral. Removal of the.solvent af-fords 0.4S g of 4-iodo-4-~7'-exo-dilllethoxymethyl-S'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~llonarl-3'~-yl)-butanoic acicl methyl ester-S'-tetrahydropyranyl c ther .
Example 22 ~ o a solution of 0.34 g of 5-cis-7-(2'c~-hydroxy-5'~-benzyloxymethyl-cyclopent-l'c~-yl)-hept-5-enoic acid methyl ester in 6 ml of methanol is added with stirring a solution of 0.325 g of mercuric acetate in water:methanol ~1:9,6 ml). The mixture is stirred for 15 minutes, reduced to 3 ml under vacuum, and then added to 5 ml of a saturated solution of NaCl in water. The precipitate is then extracted with methylene chloride. The organic phase is washed with water and evaporated to dryness to give 0.52 g of crude 5-chloro-mercurio-5-(6'-exo-ben~yloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester. A solution of this in methylene chloride (10 ml) is treat-ed with 80 mg of pyridine in 2 ml of CH2C12 and then dropwise with stirring with a solution of 150 mg of Br2 in CH2C12. After 20 minutes of stirring at room temperature, the organic phase is washed with water, then 7% ~i and Na2S2O3, ~nd water until neutral. Evaporation to dryness gives 0.34 g of 5-bromo-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.
Mass spectrum ~I 424,426 m/e M -~IBr 344 m/e M -CHBr (C~I2)3C02(C~I3 = 231 m/e.
Example 23 10.5 mg of ~-toluenesulfonic acid monohydrate is added to a solution of 0.26 g of 5-iodo-5-(6'-exo-dimetho~ymethyl-7'-endo-hydroxy-2'-oxa-bicyclo r3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tctrahydropyranyl ether and the resulting mixture is left at room temperature for 30 minutes. 10 mg of pyridine is then added and the solution is evaporated to dryness. The residue is taken up in ethyl etIler/~ater. After drying over Na2S04, the organic phase gives upon solvent evaporation 0.23 g of crude 5-iodo-5-(6'-exo-dimetho,Yymet!lyl-7'-endo-hydroxy-?'-oYa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid metIlyl ester. Separation by chromatograpIly on silica gel I~ith methylene chloride: ethyl ether (75:25) as eluent afforcls S4 mg of 5-iodo-5-~3~
~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-elldoyl)-pentanoic acid methyl ester and 55 mg of the 3'-exo isomer.
Referring the spectrometric data, the prostaglandin numbering ~Jill be used;
thus the above diastereoisomers can be n~med as follows: the endo diastereo-isomer: 5-iodo-6~H-6,9~-oxide-11~-hydroxy-12~-dimethoxy-formylacetal-~20 -~ 13)heptanor-prostanoic acid methyl ester and the exo diastereoisomer 5-iodo-6~H-6, 9a-oxide~ -hydroxy-12~-dimethoxy-formylacetal-~(2O ~ 13)heptanor-prostanoic acid methyl ester.
Analytical data:
endo diastereoisomer: TLC more polar-one spot Mass spectrum ~m/e; % intensity fragment): 442 0.002 M ; 412 4 M -CH2O, 315/314 3 M -iodine/Hl 283 11 315-C~13OH, 75 100 CH 3 N.M.R. ~solvent CDC13, TMS internal standard) p.p.m.:
~OC~I~
3 49 and 3 52 s 3H/3H CH ; 3 64 s 3H CO CH
~ ~P 5~ 9~ 11); ' ' Cll-OCH ;
4.60 m, lH, 6~H
3C-MR ~at 201~1Z in C6D6 solution T~IS int. standard) p.p.m.
172.9, 36.5, 33.1, 25.6, 41.8, 81.0, 38.1, 55.5, 83.1, 41.5, 74.2, 44.6, 108.0, 54.2, 54.1, 51Ø
exo diastereoisomer: TLC less polar-one spot Mass spectrum: 442 0.01 M , 366 3 M CH2CH~OC113)2, 315 4 M -1; 283 10 M 1-C113011; 75 100 Cl-l~OCH3)2 ~OC~I"
N.~l.R.: p.p.m. 3.34 and 3.37 31-l/3H s C ~; 3.5 and 4.1 oc~l3 n 111 and 21-1 protons at C5, C9, C11 uncertain assignment, ~OCI-I ~
3.65, s 311, C02CI-13; 4.21, dlll, CH ~; 4.35 m, 111,6~H
- OCil3 CMR: p.p.m~ 173.0, 37.0, 33.1, 25.5, 40.1, 84.4, 39.7, 57.2, 83.7, 40.5, 75.9, 4~.0, 107.3, 54.03 53.8, 51.1.
Example 24 A solution of 980 mg of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3~-yl)-butanoic acid methyl ester-8'-tetrahydTopyranyl ether in 6 ml of anhydrous methanol is treated at room temperature for 30 minutes with 48 mg o:E _-toluenesulfonic acid. 2% aqueous NaHC03 is added and the mixture is extracted with ethyl ether. From the organic phase, after washing ~mtil neutral and evaporation of the solvent, one obtains 0.68 g of a crude product which after purification on silica gel with methylene chloride: ethyl ether (80:20) as eluent affords 0.30 g of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~nonan-3'-exo-yl)-butanoic acid methyl ester and 0.29 g of the 3l-endo isomer.
Example 25 Starting from acids prepared according to the procedure of example 11 and performing their halocyclization as described in one of the examples 16 to 22, the following halobicyclic compounds are prepared:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and 7'-di-oxanyl ether and 7'-dimethylbutylsilyl ether);
4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-chloro-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acicl methyl ester;
5-chloro-5-(6~-exo-bcnzyloxymethyl-2~-oxa-bicyclo[3.3.o]octan-3~-yl)-pen tanoic aclcl methyl ester;
4-chloro-4-~7l-e~o-dimethoxymcthyl-2l-oxa-bicyclo[3.4.o]nonan-3l~-yl) ~ ~ 3 ~
338~
butanoic acid methyl ester;
4-chloro-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
5-bromo-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-oxanyl and 7'-dimethylbutylsilyl ethers);
4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0[nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-dioxanyl and 8'-dimethylbutylsilyl ethers);
5-bromo-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-bromo-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
4-bromo-4-~7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
4-bromo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid-methyl ester;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-oxanyl and 7'-dimethylbutylsilyl esters);
4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hYdrOxy-2'-oxa-bicyclo[3~4~o]nonan 3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-iodo-5-~6~-exo-dimethoxymethyl-2l-o:;a-bicyclo[3~3.o]octan-3l~-yl)-pentanoic acid methyl ester;
5-iodo-5-~6'-exo-bellzyloxymethyl-2~-oxa-bicyclo[3.3~oloctan3~-yl)-pentanoic aci~ methyl ester;
4-:iodo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic ~831~
acid methyl ester;
4-iodo-4-(7'-exo-dimethoxyme~hyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
Example 26 Selective de-acetali~ation or de-silylization of the ethers de-scribed in example 25, according to the procedure in examples 23 and 24 af-fords the 3'~-oxiran-hydroxide-formyl acetal derivatives, ~lhich give the following upon separation of isomers:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan--3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3' ~-yl)-butanoic acid methyl ester, and its individual 3'exo and 3'-endo isomers;
5-bromo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclol3.3.0]octan-3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
endo isomer: Tl,C on SiO2 more polar one spot OCH_ N.M.R.: (CDC13) p.p.m. 3.4 d,6H,CH OCH ; 3.65, s,3H C02CH
~ OCll3 4.00 m,4H (protons at C4, C5, C9,Cll); 4-17 d,l, CI~ OC~I ;
4.5 m, lH, 6~H
3C~IR: 173,0, 35.0, 33.3. 23.6, 59.4, 80.G, 36.4, 55.6, 83.3, 41.6, 74.3, 44.5, 108.0, 54.4, 54.2, 51.1 exo isomer: TLC on SiO2 less polar isomer one spot ~ OCII~
N.~l.R. ~CDC13) p.p.m.: 3.37 d,611 -Cll OCII ; 3-66 s,31l,C02CI-I
--~' ~ OCI-I_ 4.00 m,4I-I, protons at C4, C5, C9, Cll; 4-2 d,l, -CH OCII
4.32 m~ , Gc~lI
33~
C~R: 173.0, 35.5, 33.3, 23.6, 57.7, 84.2, 38.2, 57.9, 83.6, 40.5, 76.0, 43.9, 107.2, 53.8~ 53.8, 51Ø
4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2l-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual isomers, 3'-exo and 3'-endo;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers;
4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers.
Exam~le 27 With stirring under nitrogen, a benzene solution (30 ml) of 2.8 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether is treated with a solution of 2.8 g of tributyltin hydride in 8 ml of benzcne. The mixture is held at 55C for 8 hours and then overnight at room temperature. The ben-zene layer is t~ashed with 2 x 10 ml of a 5~ Na~lC03 solution and then with t~ater until neutral. The residue upon solvent evaporation is adsorbed on 10 g of silica gel and eluted ~ith benzene and benzene:ethyl ether (85:15) to give 1.9~ g of 5-(6'-exo-dimethoxymethyl-7'-endo-]-ydroxy-2'-oxa-bicyclo[3 3 o]
octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 28 60 Ing of ~-toluenesulfonic acid is adclecl to a solution of 1.9S g of 5-(6'-e~co-dimethoxymethyl-7'-el)do-]1ydroxy-2'-ox;l-bicycloL3.3.0]octall-3'~-yl)-pent.moic acid methyl cster-7l-tetrallydropyranyl ether in 10 ml of anhydrous methanol. Aftcr 30 minutes at room temperature, this is added to 20 ml of 20i aqucous NallC0 ~ The mixture is extractecl wit}l etllyl ether; the combined ~3~ ~
~3~
ether extract, after drying over Na2SOI~ is evaporated to dryness. The resi-due is adsorbed on 100 g of silica gel and eluted with methylene chloride:
ethyl ether ~94:6) to give 0.64 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2~oxa-bicyclo[3.3.o]octan-3~-exo-yl)-pentanoic acid methyl ester~
0.52 g of the 3'-endo isomer and 0.12 g of the 3' -yl.
N.~l.R. ~CDC13) endo isomer 4.6 p.p.m. m,lH 6~H, T.L.C. more polar;
e~o isomer 4.3 p.p.m. m,l~l 6~H, T.L.C. less polar.
0.32 g of the 3'-endo isomer is dissolved in pyridine (0.8 ml) and treated for 8 hours at room temperature with 0.3 ml of acetic anhydride. The mixture is then poured into ice/water, and, after acidifying to pll 4.2, is extracted with ethyl ether. The combined extract, after washing until neutral, is evaporated to give 0.315 g of 5-~6'-exo-dimethoxymethyl-7'-endo-hydro.Yy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl estcr-7'-acetate.
Example 2g A solution of 1.32 g of 4-(7'-exo-dimethoYymcthyl-8'-endo-llydro.Yy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-but~noic acid methyl ester-8'-tert-butyl-methylsilyl ether in 10 ml of anhydrous methanol is treated ~ith 55 mg of p-toluenesulfonic acid for 2 hours at room temperature. 0.1 ml of pyridine is added, the solvent is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase gives, upon removal of the solvent, 1.1 g of t~e crude 8'-hydroxy-3'~-yl derivative. Chromatograp]ly of this on silica gel with benzene:ethyl ether (80:20) as eluent separates this into 4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oYa-bicyclo[3.4.0]nonan-3'-endo-yl)-bu-tanoic acid methyl ester (0.42 g) and the 3'--exo-yl isomer (0.34-g).
Example 30 Using the proccdure in e~Yamples 28 and 29, mcthanolysis of the cthcrs tacetal or silyl) clcscribed in examplc 15 gives the corresponding free ~llcollols .
31~
Example 31 Upon acetylation with pyridine (0.6 ml) and acetic anhydride (0.3 ml) 0.2 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7~-endo-hydroxy-2'-oxa-bicyclo [3.3.0~octan-3~-endo-yl)-pentanoic acid methyl ester gives 0.21 g of the cor-responding 7'-acetoxy derivative.
N.M.R. ~CDC13) p.p.m.: 2.03 s,3H OCOCH3; 3.36 - 3.40 s,s 3H/311 , OCH3 CH OCH ; 3.66 s 3H CO CH~ ; 4.00 m 2i-1 protons at ~ OCH3 C5, Cg; 4-27 d lH CH OCH; 4.6 m lH 6~H 5.0 m lH
proton at Cll ~The spectrometric data for the 6clH isomer acetate are respectively the following 2.03; 3.34 - 33S, 3.66 s+m 4il CO2CH3 and one of C5, C9 protons 4.1 m lH other of C5, C9 protons 4.2, 4.4 m 111 6c~H, 5.1]. 1\ solution of the 5-iodo-3'-endo-acetate in benzene (5 ml) is trcated witll 0.4 g of tributyltin hydride for 10 hours at 50 C. After the benzene phase is ~Yashed ~ith 5Q~
NaHC03 and water, evaporation of the solvent and purification on silica gel (10 g) with a benzene:ethyl ether (S0:20) eluent afford O.lOS g of 5-~6'-octan-3'-endo-yl)-pentanoic acid methyl ester-7'-acetate, identical in all respects with a sample prepared by the procedure in example 2S.
Example 32 Using the procedure of examples 27 and 31, the reduction wit}l tri-butyltin hydride of one of the halo-derivatives synthesi7ed in examples 16 -26 gives the corresponding derivative in h~hich halogen is replaced by hydrogen.
These are identical in every ~1ay ~itl- -the compounds prepared according to the procedures of examples 15, 28, 29 and 30.
Example 33 5.4 mg of hydroquinone and a solution of 1.63 g of oxalic acid in 4S ml of water are adclecl to a solution of 4 g of 5-(6'-exo-dimetlloxymethyl-q~
~333~
7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 180 ml of acetone. After 12 hours at 40C, the acetone is removed at reduced pressure and the mixture is extracted with ethyl acetate (3 x 25 ml). The combined organic extract is washed until neutral with a 10% ammonium sulfate solution and dried over Na2SO4. Removal of the solverlt a~fords 3.21 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid methyl ester. The 6'-exo-~ormyl-3'-endo and the 6'-exo-formyl-3'-exo derivatives are prepared from the corresponding individual isomers.
Example 34 Using the procedure of example 33, starting from the corresponding bicyclo[3.3.0]octan-6~-exo-dimethoxymethyl and bicyclo[3.4.0]nonan-7'-exo-dimethoxymethyl derivatives, the ~ollowing compounds are prcpared, either as individual 3'-exo and 3'-endo or 3'~ isomers:
5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-t6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-~7' exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic 2Q acid methyl ester;
5-chloro-5-(6'-exo-formyl-2'-oxa-bicycloi3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-chloro-4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl estcr;
S-chloro-5-tG'-exo-formyl-7'-entlt)-llydroxy-2'-oxa-bicyclo[3.3.0]oc-tan-3'-yl)-pcntano;c acid metl~yl ester;
4-cilloro-~l-(7~-c~to-formyl-s'-endo-llydroxy-2~-oxa-bicyclo[3~4~o]nonan-3~-yl) ~ltalloic acicl mcthyl ester;
~838~
5-bromo-5-(6l-exo-formyl-2t-oxa-bicyclo[3.3 0]octan-3~-yl)-pentanoic acid methyl ester;
4-bromo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-bromo-5-(6'-exo-formyl-7~-endo-hydroxy-2'-oxa-bicyclo[3.3,0~octan-3'-yl)-pentanoic acid met~yl ester;
4-bromo-4-(7~-exo-formyl-8'-endo-hydroxy-21-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-iodo-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-acetate;
5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl-pentanoic acid methyl ester-7'-acetate;
5-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-pentanoic acid methyl ester;
4-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-b-l-tanoic acid methyl ester.
E ~camp 1 e_ To a solution of 1.2 g of 5-~6'-exo-ben7yloxymetllyl-2~-oxa-bicyclo [3.3.0]octan-3'i-yl) pentalloic acid methyl ester in metllanolmllet}lyl aceta-te (10 ml:10 ml) is added 2 ml of a O;lN methanol solution of ll~l. Aftcr 0.15 g ~3~ 7~
~3~
of PtO2 is added, the mixture is hydrogenated at ambient temperature and pres-sure until l molar equivalent of hydrogen is abosrbed. After the removal of the gas under vacuum and washing with nitrogen, the suspension is filtered, neutralized, and evaporated to dryness. The residue is taken up in ~ater/
ethyl acetate, and the organic phase yields 0,84 g of 5-(6'-exo-hydroxymethyl-2'-oxa-~icyclo[3 3.0]octan-3'~-yl)-pentanoic acid methyl ester. This is then oxidized to the 6'-exo-formyl derivative by the procedure in example 1, using dicyclohexylcarbodiimide in DMSO:ben~ene (25:75).
Example 36 To a solution of 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4~-dihydroxy-cyclopent-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether in 150 ml of toluene cooled to -70C is added in 30 minutes 12~ ml of a 5M solution of di-iso-butylaluminum hydride (1.2M/M). After 30 minutes at -70 C, 12S ml of a 2M toluene solution of isopropanol is added and the solution is brought to 0C. Then 10 ml of a saturated aqueous solution of NaH2P04 is added and the mixture is stirred for four hours. Following the addition of 10 g of anhydrous Na2S04 and lO g of filtering earth, the solution is filtered and evaporated to dryness to give 18.1 g of 5~-tetrahydropyranyloxymethyl-2cY,4c~-dihydroxy-cyclopent-lc~-ethanal-y-lactol-4-tetrahydropyranyl ether. A solution of tbis in 24 ml of anhydrous DMSO is added drop~ise to a solution of the ylide prepared as follows: 9.6 g of ~0'O sodium hydride in ~00 ml of DMS0 is heated for four hours at 60 C. Then after the mixture is brought to 1~ - 20C, 67 g of 4-carhoxybutyltriphenyl phosphonium bromicle dissolved in S0 ml of an-hydrous DMS0 is added ~hile maintaining a temperature of 20 - 22 C to generate a bright red color. After four hours of stirring, 600 ml of ~ater is added and the mixture is extractecl~ith ethyl cther:bcn7ene ~70:~0) to remove the tripllellylpllospl~ oxide. The ben~ene organic phase is re-extracted with 4~
8~
O.lN NaO~I and then with water until neutral; it is then discarded. The alkaline aqueous phase is acidified to p~l 5 - 4.~ and then extracted Wit}l ethyl ether:pentane (1:1) to give 21.6 g of 5-cis-7-(2'c~,4'~-dihydroxy-5'~-tetrahydropyranyloxymethyl-cyclopent-l~-yl)-hept-5-enoic acid-4'-tetrahydro-pyranyl ether, which may be converted to its methyl ester by treatment with diazomethane in ether. 7.72 g of this ester in 28 ml of tetrahydrofuran is added dropwise to a yellow-bro~n suspension formed by adding 28 ml of THF to a solution of 6.13 g of mercuric acetate in 28 ml of water. After the mixture is stirred for 20 minutes at room temperature, it is cooled in an ice:water ~ath and 810 mg of NaBH4 in 14 ml of water is added drop~iise. Elemental mercury precipitates out, the suspension is decanted, the tetrahydrofuran is evaporated at reduced pressure and the residue is extracted with ethyl ether. Removal of the solvent affords 7.5 g of 5-(6'-exo-tetrahydropyranyloxymethyl-7'-hydro~y-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydro-pyranyl ether; 0.42 g of p-toluenesulfonic acid is then added to a solution of this in 30 ml of methanol. After 2 hours at room tem~erature, the solution is concentrated under vacuum and water is added. After extraction with ether and chromatography on silica gel with ethyl ether as eluent, one obtains 2.4 g of 5-~6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 2.6 g of the 3'-endo isomer.
E ple 37 2.5 g of N-iodosuccinimide is added to a solution of 4.26 g of 5-cis-7- (2'c~,4'c~-dihydroxy-5'~-tetra}lydropyranyloxymethyl-cyclopent-l'c~-yl)-hept-5-elloic aci&-4'-tetrahydropyr.myl ether in C1l2C12:CCl~ (10 ml:10 ml) and the resulting mixture is stirred Eor four hours. 30 ml of anhydro~ls methanol containing 130 mg of ~-toluenesulEonic acid is aclded and stirring is continued for another 2 hours. 0.2 ml of pyridine is adcled, the mixture is reduced to sm.lll volulllc~, and the residue is takell up in ~ater/ethyl acetate. After waslling witll N~l S203 and tllen water until neutral, the organic phase is e~ap-~83~
orated to dryness to give a residue that is adsorbed on silica gel and eluted with ethyl ether to give 2.2 g of 5-iodo-5-~6'-exo-hydro~ymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 1.85 g of the 3'-endo isomer.
Example 38 Following the procedure of example 37, but using the methy] ester instead of the acid and N-bromoacetamide instead of ~-iodosuccinimide, the 5-bromo-5--~6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester is prepared. Silica gel chromatography allows the separation into the 3'-exo and 3'-endo isomers.
Example 39 A solution of 0.86 g of pyridine and 2.2 g of 5-cis-7-~2',4'~A-di-hydroxy-5'3-tetrahydropyranyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in dichloromethane (20 ml) is cooled to -30C and 0.38 g of chlorine in 10 ml of CC14:CI-I2C12 (1:1) is added. The mixture is stirred for 2 hours, warmed to room temperature, and ~ashed with 2N H2SO4 and then water until neutral. After evaporation of tl-e solvent, ~he residue is dissolved in methanol (10 ml) and treated wit}l 0.1 g of p-toluene-sulfonic acid. The solution is then concentrated, diluted ~ith water, and extracted with ethyl acetate. Removal of the solvent and purification of the residue on silica gel afford 0.6 g of 5-chloro-5-(6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid and 0.71 g of tha 3'-endo isomer.
Example 40 .
To a solution of 0.356 g of 5-iodo-5-(6'-e~o-hydroxymetllyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-~'-exo-yl)-pentanoic acid methyl ester in .8 ml of benzene:D~IS0 ~15:25) are added, in order, 0.28 g of dicyclohcxyl-carbodiimide and 0.4 ml of a pyridinium trifluoroacetate solution (see example l). After 3 hours of stirring, 8 ml of benzene and then aqueous oxalic acid (94 mg in l.2 ml) are added. The precipitate is removed by filtration and the benzene solution is washed with water until neutral. Removal of the sol-vent affords 0.32 g of 5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0]octan-3'-exo yl)-pentanoic acid methyl ester.
Example 41 Upon oxidation of the 6'-exo-hydroxymethyl-7'-endo-hydroxy deriva-tives prepared according to examples 36 - 39, following the procedure of ex-ample 40, the corresponding 6'-exo-formyl derivatives are prepared.
Exmple 42 -~ solution of 3.4 g of (2-oxo-heptyl)dimethoxyphosphonate in 50 ml of dimethoxyethane is added dropwise to a suspension of 0.45 g of 80% NaH
~mineral oil dispersion). After stirring for l hour, a solution of 2.7 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 40 ml of dimethoxyethane is added. In l0 minutes this is diluted with 50 ml of a 30% aqueous solution of monobasic sodium phosphate.
The organic phase is separated, the aqueous phase is re-extracted, and the combined organic extract is evaporated. Purification of the crude product on 50 g of silica gel ~cyclohexane:ethyl ether, 50:50) gives l.lg of 5-[6'-exo-~3"-oxo-oct-l"-trans-en-l"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl]-pentanoic acid methyl ester or l3t-6~H-6~9~)-oxide-llcY-hydroxy-l5-oxo-prost-13-enoic acid methyl ester and 0.9S g of 5-[6'-exo-(3"-oxo-oct-l"-trans-en-l"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pen-tanoic acid methyl ester or l3t-6c~i1-6(9c~)-oxido-llc~-hydroxy-l5-oxo-prost-l3-onoic acid met1lyl estor, plus 0.9 g of a l:l mixture of tlle t~o isomers (3'-exo and 3'-enc1O, or 6CY~ and 6~11). This last mixture is separated into its t~o i~o1neric con1pollents by thin layer chromatography ~ith ethyl ether. They s11o~Y t1~e ~ollo~in~ absorptions, respectively:
q ,,~
3~
~ MeOH = 230 m~, e = 13,070; ~ = 228 m~, E = 12,200.
N-M-R- (CDC13) 0-9 t 3H C20~CH3, 3.68 s 3H CO2CH3, 6.16 d lH vinylic proton at C14 (JH14-H15
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-propanal-~-lactol, in its dl and optically active form ~or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-l~-propanal-~-lactol ~or ent-form).
Example 9 0.29 ml of absolute ethanol in 3.5 ml of toluene is added dropwise to a solution of 5 x lO mol of sodium (2-methoxyethoxy)aluminum hydride ~1.4 ml of a 70% benzene solution diluted with 5 ml of toluene) cooled to 0C.
8.2 ml of the alanate solution so prepared is added, at -30C, to 0.98 g of dl-5~-benzyloxymethyl-2~-hydroxYcyclopentan-l~-propionic acid-~-lactone in 22 ml of toluene. AEter 45 minutes, excess reagent is qucnchcd with 6 ml of a 0.5 ~I toluene solution of isopropanol. The mixture is warmed to 0 C, 4 ml of 30J Natt2P0~l is added, and the resulting mixture is stirred for 2 hours. The inorganic salts are removed by filtration and the solution is evaporated to dryness to give 0.94 g of dl-5~-benzyloxYmethyl-2~-hydroxycyclopentan-l~-propanal-~-lactol. 3/
~3~
Using the procedure reported above, or one of those from examples 4 to 7, the follo~Ying compounds were prepared :Erom their corresponding ~-lac-tones:
5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-ethanal-~-lactol;
5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-propanal-~-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-ethanal-y-lactol;
5~-dimethoxymethyl-2c~-hydroxycyclopentan-lc~-propanal-ô-lactol .
Exam~le 10 With stirring and external cooling to maintain a reaction tempera-ture of 20 - 22C3 a solution of 1.05 g of potassium tert-butylate in 10 ml of DMSO is added dropwise to a solution of 1.8 g of 4-carboxybutyl-triphenyl-phosphonium bromide and 0.38 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-tan~ ethanal-y-lactol-4-tetrahydropyranyl ether. After the addition, the mixture is held at room temperature for 1 hour and then diluted ~ith 16 ml of ice/~ater. Ihe aqueous phase is extracted Yith ether (5 x S ml) and ether:
benzene ~70:30~ 5 x 6 ml), the organic layers, after re-extraction with 0.5`I
NaOH (2 x 10 ml), are discarded. The combined al~aline aqueous phase is acid-ified to pH 4.8 with 30% NaH2PO4 and then extracted ~ith ethyl ether:pentane (1:1, 5 x 15 ml); from tlle combined organic phases, after drying over Na2SO4 and solvent removal, one obtains 0.45 g of 5-c -7-~2'~,4'~-dihydroxy-5'~-dimethoxymethylcyclopentan-l'~-yl)-hept-5-enoic acid-4l-tetrahydropyranyl ether. This in turn is converted to the corresponding methyl ester upon treat-ment with diazomethane in ether. An analytic sample is prepared by adsorbing 100 mg of the crucle product on 1 g of silica gel and eluting I~ith benzene:
ethyl ether ~S5:15). N.~I.R.: C=C~ 5.46 p.p.m. multiplet.
~f 1-l Example 11 In an an~hydrous nitrogerI atmosphere, a suspension of 0.39 g of a 75o oi.l dispersion of Na~I in D~ISO (13 . 5 ml) is heated to 60 - 65 C for 3 1/~
hours; after cooling to room temperature and while maintaining the reaction mixture at 20 - 22C, the follo~ing are added, in order: 2.66 g of 3-carboxy-propyltriphenylphosphonium bromide in 6 ml of DMSO and 0.6 g of 5~-dimethoxy-methyl-2cx,4~-dihydroxycyclopentan-1~-propanal-c,-lactol-4-tetrahydropyranyl ether in 3 ml of DMSO. The mixture is stirred for 3 hours, and then diluted ~ith 35 ml of water. The aqueous phase is extracted with ethyl ether (5 c 12 ml) and ethyl ether:benzene (70:30, 7 x 12 ml); the combined organic extract, after re-extraction with 0.5N NaO~ ~2 x 15 ml), is discarded. The combined alkaline aqueous extract is acidified to pH 4.3 with 30~ aqueous Na~l2PO4 and extracted ~ith ethyl ether:pentane (1:1) to give, after ~ashing until neutral, drying over Na2S04, and removal of the solvent, 0.71 g of 4-Cis-7-~2~,4~c~l-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acicl. Treatment ~ith diazomethane affords the corresponding methyl ester.
Example 12 The methyl esters of the following acids were prepared from lactols made according to the procedures in examples 4 to ~ by treatment ~ith a l~ittig reagent (prepared from 4-carboxybutyl-triphenylphosphonium bromide or 3-car-boxypropyltriphenylphosphonium bromide) and successive esterification ~ith diazomethane, in their optically active or dl forms:
4-cis-7-C2~cx-hydro~Yy-5~-benzyloxymethylcyclopent-l~c~-yl)-hept-4-enoici 4-cis-7-(2'cx-hydroxy-5'~-dimethoxymet}lyl-cyclopent-l~cx-yl)-hept-4-enoic;
5-cis-7--~2'cx-}1ydroxy-5'13-dimethoxymet}lyl-cyclopent-l'cx-yl)-}lept-5-enoic;
5-cis-7-~2'cY-hydroxy-5'~-ben7yloxymethyl-cyclopellt-l'cx-yl)-}lcpt-S-enoic;
5--is-7-~2'cx~4'cy-dlllydroxy-5~-dimetlloxynlethyl-cyclopent-l~ yl)-llept-5-enoic-and its 4'-dioxallyl, tetrahydropyranil ancl dimethyl-tert-butylsilyl)-ethers;
4-cis-7-~2'c~,4'cx-clillydroxy-5' ~-dimcthoxymc?thyl-cycloperlt-l'cx-yl) -hept-4-enoic and its 4'-(dioxanyl, tetrahydroyyranyl and dimethyl-tert-butylsilyl)-ethers;
J - ~ _ ~183~
4-cis-6-~2'c~,4'c~ dihydroxy-5'~-dimethoxymethyl-cyclopent-l'c~-yl)-hex-4-enoic and its 4'-~tetrahydropyranylether;
5-cis-8-~2'oL,4'c~-dihydroxy-5',~-dimethoxymethyl-cyclopent-l'c~-yl)oct-5-enoic and its 4'-tetrahydropyranylether.
Example 13 A solution of 1.06 g of the methyl ester of 5-cis-7-(2'c~,4'c~-dihy-droxy-5l~-dimethoxymethyl-cyclopent-l~c~-yl)-hept-5-enoic acid-4'-tetrahydro-pyranyl ether in 5 ml of methanol is adcled to O.S4 g of mercuric acetate in methanol. After 30 minutes at room temperature, a solution of 250 mg of sodi-um ~orohydride in 2 ml of water is added with stirring and external cooling.
After 20 minutes of stirring, the mixture is acidified to plI 6.5 ~ith aqueous monosodium phosphate, the methanol is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase, upon rcmoval of the solvent, affords 1.02 g of 5-~6'-exo-dimethoxymethyl-7'-endo-Ilydroxy-2'-oxa-oicyclo[3.3~0]octan-3'~-yl)-pentanoic acid methyl ester-7'-t~rahydropyranyl ether.
Example 14 A solution of 1.59 g of 4-cis-7-(2'c~,4'c~-dihydroxy-5'~-dimethoxy-methyl-cyclopent-l'c~-yl)-hept-4-enoiC methyl ester-4'-tetrahydropyranyl etiler in 6 ml of THF is added to a solution of 1.26 g of mercuric acetate in 4 ml of water diluted with 4 ml of THF. The mixture is stirred for 1 1/2 hours until precipitation is complete. lS0 mg of sodiwn borohydride ~in 2.5 ml of water) is then added and tlle resulting mixture is stirred for 30 minutes. The solution is decanted from the precipitate, wIlicll is theIl washed with TI-IF. The aqueous/organic decanted solution is concentratecI under reduced pressure and the resid-~e extracted tYith ethyl acetate. The combine(I organic extract, after wasI~ing witIl~Yater until neutral, affords upon removal of the solvent 0.98 g o /I t7'-e.co-dimetIlo~ymethyl-S'-endo-ilydroxy-2'-oxa-bicyclo~3.4.0]nonan-3~-yl) i ~ ~ butanoic acid methyl ester-S'-tetrahycIropyranyl ether.
~l83 51~.
Exam~le 15 _, ., ._ Starting from the esters prepared as described in examples 9 to 11, by reaction with a mercuric salt and subsequent reductive demercuration as described in the procedures in examples 13 and 14, the follo,~ing bicyclic derivatives are obtained:
5-(6'-exo-ben~yloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo~3.3.0]octan-3'~-yl~-pentanoic acid methyl ester;
4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo~3.4.0]nonan-3'S-yl)-butanoic acid methyl ester;
a 7'-acetal ether ~tetrahydropyranyl ether, dioxanyl ether), and a 7'-dimethyl-tert-butylsilyl ether of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
an 8'-acetal ether ~tetrahydropyranyl ether, dioxanyl cther) and an 8'-dimethyl-tert-butylsilyl ether of 4-~7'-exo-dimethyoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
4-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-butanoic acid methyl ester-7'-tetrahydropyranyl ether;
5-(7'-exo-dimethoxymethyl-8'-endo-llydroxy-2'-oxa-bicyclo[3.~1.0]nonan-3'~,-yl)-pentanoic acid methyl ~ster-8'-tetrahydropyranyl ether.
All these compo~mds are obtaincd in the d,l-, nat- and ent-forms.
Exam~le 16 ~ solution of 0.4S g of bromine in 5 ml of methylene chloride is added cIrop~ise, ~ith stirring, to a solution of 0.27 g of pyridine and 1.2 g of 5-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopcnt-1'~-yl)-hept-5-~t~it3~
enoic acid methyl ester-4'-tetrahydropyranyl ether in 6 ml of methylene chlo-ride, coo]ed to 0 C. Stirring is continued for ten minutes fol~owing ~he ad-dition. The organic phase is washed with 5 ml of a pH 7 buffer solution 10~
in sodium t}liO sulfate and then with water until neutral. After drying over Na2S04, removal of the solvent affords :L.38 g of 5-bromo-5-~6'-exo-dimethoxy-methyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 17 1.24 g of N-iodosuccinimide is added to a solution of 2 g of 5-cis-7-(2l~,4'~-dihydroxy-5'~-dimetkoxymethy:L-cyclopent-l'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in 15 ml of carbon tctrachloride. The mixture is stirred for 3 hours and 30 ml of ethyl ether is added. The organic phase is washed with lN Na2S203 and then with water until neutral. Removal of the solvent affords 2.48 g of 5-iodo-5'-(6'-exo-dimethoxymethyl-7'-endo-hy-droxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl cster-7'-tetra-hydropyranyl ether.
E~ample 18 422 mg of N-bromosuccinimide is added with stirring to a solution of 0.78 g of 4-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymet}lyl-cyclopent-1'~-yl)-hept-4-enoic acid methyl ester-4-tetrahydropyranyl ether in 11 ml of CC14.
After four hours of stirring, ethyl ether is added; the solution is then washed with water, lN Na2S203, and water until neutral. Evaporation to dry-ness gives 0.98 g of 4-bromo-4-(7'-exo-dimethox)~ethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid mcthyl estcr-s~-tetrahydropyra nyl ether.
Example 19 To a suspension of 0.25 g of dry CaC0 in a solution of 346 mg of 5-cls-7-~2'~-hydroxy-5'~-~en7yloxymetllyl-cyclopent-l'~-yl)-llept-5-enoic acid l .r3 l''i'~ ~
3~
methyl ester in 10 ml of CCl4 cooled to 0 - 5C is added with stirring a solu-tion of 75 mg of chlorine in 3 ml of CC14. After stirring for 2 hours, the inorganic salts are removed by filtration. The solution is l~ashed with a 7%
aqueous solution of KI and Na2S203 and then with water until neutral. The residue upon evaporation to dryness is adsorbed on silica gel and eluted with cyclohexane:ethyl ether (80:20) to give 0.27 g of 5-chloro-5-(6'-exo-benzyl-oxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.
Example 20 A solution of 0.39 g of 5-CiS-7- (2'Cl,4'c~-dihydroxy-5'~-dimethoxy-methyl-cyclopent-l' cs-yl) -hept-5-enoic acid methyl ester-4'-dioxanyl ether and 98 mg of pyridine in 10 ml of dichloromethane is cooled to -40C. A solution of 81 mg of chlorine in 6 ml of CH2C12 is then added over a period of 30 min-utes. After 10 minutes of stirring, the mixture is heated to room temperature.
The organic phase is washed with a 7% solution of KI and Na2S203 and then ~ith water until neutral. Removal of the solvent affords 0.39 g of 5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentan-oic acid methyl ester-4'-dioxanyl ether.
Exam~le 21 280 mg of iodine in CC14 is added to a solution of 0.39 g of 4-cis-7-(2'ct,4'c~-dihydroxy-5~-dimethoxymethyl-cyclopent-l'c~-yl)-hept-4-enoic acid methyl ester-4'-tetrahydropyranyl ether and 82 mg of pyridine in 10 ml of CC14. Stirring is continued until the color disappears; 30 ml o ethyl ether is then added. The organic phase is washed with l~ater, then a solution 7%
in KI and Na2S203, ancl then water until neutral. Removal of the.solvent af-fords 0.4S g of 4-iodo-4-~7'-exo-dilllethoxymethyl-S'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~llonarl-3'~-yl)-butanoic acicl methyl ester-S'-tetrahydropyranyl c ther .
Example 22 ~ o a solution of 0.34 g of 5-cis-7-(2'c~-hydroxy-5'~-benzyloxymethyl-cyclopent-l'c~-yl)-hept-5-enoic acid methyl ester in 6 ml of methanol is added with stirring a solution of 0.325 g of mercuric acetate in water:methanol ~1:9,6 ml). The mixture is stirred for 15 minutes, reduced to 3 ml under vacuum, and then added to 5 ml of a saturated solution of NaCl in water. The precipitate is then extracted with methylene chloride. The organic phase is washed with water and evaporated to dryness to give 0.52 g of crude 5-chloro-mercurio-5-(6'-exo-ben~yloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester. A solution of this in methylene chloride (10 ml) is treat-ed with 80 mg of pyridine in 2 ml of CH2C12 and then dropwise with stirring with a solution of 150 mg of Br2 in CH2C12. After 20 minutes of stirring at room temperature, the organic phase is washed with water, then 7% ~i and Na2S2O3, ~nd water until neutral. Evaporation to dryness gives 0.34 g of 5-bromo-5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.
Mass spectrum ~I 424,426 m/e M -~IBr 344 m/e M -CHBr (C~I2)3C02(C~I3 = 231 m/e.
Example 23 10.5 mg of ~-toluenesulfonic acid monohydrate is added to a solution of 0.26 g of 5-iodo-5-(6'-exo-dimetho~ymethyl-7'-endo-hydroxy-2'-oxa-bicyclo r3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tctrahydropyranyl ether and the resulting mixture is left at room temperature for 30 minutes. 10 mg of pyridine is then added and the solution is evaporated to dryness. The residue is taken up in ethyl etIler/~ater. After drying over Na2S04, the organic phase gives upon solvent evaporation 0.23 g of crude 5-iodo-5-(6'-exo-dimetho,Yymet!lyl-7'-endo-hydroxy-?'-oYa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid metIlyl ester. Separation by chromatograpIly on silica gel I~ith methylene chloride: ethyl ether (75:25) as eluent afforcls S4 mg of 5-iodo-5-~3~
~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-elldoyl)-pentanoic acid methyl ester and 55 mg of the 3'-exo isomer.
Referring the spectrometric data, the prostaglandin numbering ~Jill be used;
thus the above diastereoisomers can be n~med as follows: the endo diastereo-isomer: 5-iodo-6~H-6,9~-oxide-11~-hydroxy-12~-dimethoxy-formylacetal-~20 -~ 13)heptanor-prostanoic acid methyl ester and the exo diastereoisomer 5-iodo-6~H-6, 9a-oxide~ -hydroxy-12~-dimethoxy-formylacetal-~(2O ~ 13)heptanor-prostanoic acid methyl ester.
Analytical data:
endo diastereoisomer: TLC more polar-one spot Mass spectrum ~m/e; % intensity fragment): 442 0.002 M ; 412 4 M -CH2O, 315/314 3 M -iodine/Hl 283 11 315-C~13OH, 75 100 CH 3 N.M.R. ~solvent CDC13, TMS internal standard) p.p.m.:
~OC~I~
3 49 and 3 52 s 3H/3H CH ; 3 64 s 3H CO CH
~ ~P 5~ 9~ 11); ' ' Cll-OCH ;
4.60 m, lH, 6~H
3C-MR ~at 201~1Z in C6D6 solution T~IS int. standard) p.p.m.
172.9, 36.5, 33.1, 25.6, 41.8, 81.0, 38.1, 55.5, 83.1, 41.5, 74.2, 44.6, 108.0, 54.2, 54.1, 51Ø
exo diastereoisomer: TLC less polar-one spot Mass spectrum: 442 0.01 M , 366 3 M CH2CH~OC113)2, 315 4 M -1; 283 10 M 1-C113011; 75 100 Cl-l~OCH3)2 ~OC~I"
N.~l.R.: p.p.m. 3.34 and 3.37 31-l/3H s C ~; 3.5 and 4.1 oc~l3 n 111 and 21-1 protons at C5, C9, C11 uncertain assignment, ~OCI-I ~
3.65, s 311, C02CI-13; 4.21, dlll, CH ~; 4.35 m, 111,6~H
- OCil3 CMR: p.p.m~ 173.0, 37.0, 33.1, 25.5, 40.1, 84.4, 39.7, 57.2, 83.7, 40.5, 75.9, 4~.0, 107.3, 54.03 53.8, 51.1.
Example 24 A solution of 980 mg of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3~-yl)-butanoic acid methyl ester-8'-tetrahydTopyranyl ether in 6 ml of anhydrous methanol is treated at room temperature for 30 minutes with 48 mg o:E _-toluenesulfonic acid. 2% aqueous NaHC03 is added and the mixture is extracted with ethyl ether. From the organic phase, after washing ~mtil neutral and evaporation of the solvent, one obtains 0.68 g of a crude product which after purification on silica gel with methylene chloride: ethyl ether (80:20) as eluent affords 0.30 g of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~nonan-3'-exo-yl)-butanoic acid methyl ester and 0.29 g of the 3l-endo isomer.
Example 25 Starting from acids prepared according to the procedure of example 11 and performing their halocyclization as described in one of the examples 16 to 22, the following halobicyclic compounds are prepared:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether (and 7'-di-oxanyl ether and 7'-dimethylbutylsilyl ether);
4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-chloro-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acicl methyl ester;
5-chloro-5-(6~-exo-bcnzyloxymethyl-2~-oxa-bicyclo[3.3.o]octan-3~-yl)-pen tanoic aclcl methyl ester;
4-chloro-4-~7l-e~o-dimethoxymcthyl-2l-oxa-bicyclo[3.4.o]nonan-3l~-yl) ~ ~ 3 ~
338~
butanoic acid methyl ester;
4-chloro-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
5-bromo-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-oxanyl and 7'-dimethylbutylsilyl ethers);
4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0[nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-dioxanyl and 8'-dimethylbutylsilyl ethers);
5-bromo-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
5-bromo-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester;
4-bromo-4-~7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester;
4-bromo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid-methyl ester;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-oxanyl and 7'-dimethylbutylsilyl esters);
4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hYdrOxy-2'-oxa-bicyclo[3~4~o]nonan 3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-di-oxanyl and 8'-dimethylbutylsilyl ethers);
5-iodo-5-~6~-exo-dimethoxymethyl-2l-o:;a-bicyclo[3~3.o]octan-3l~-yl)-pentanoic acid methyl ester;
5-iodo-5-~6'-exo-bellzyloxymethyl-2~-oxa-bicyclo[3.3~oloctan3~-yl)-pentanoic aci~ methyl ester;
4-:iodo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic ~831~
acid methyl ester;
4-iodo-4-(7'-exo-dimethoxyme~hyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
Example 26 Selective de-acetali~ation or de-silylization of the ethers de-scribed in example 25, according to the procedure in examples 23 and 24 af-fords the 3'~-oxiran-hydroxide-formyl acetal derivatives, ~lhich give the following upon separation of isomers:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan--3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
4-chloro-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3' ~-yl)-butanoic acid methyl ester, and its individual 3'exo and 3'-endo isomers;
5-bromo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclol3.3.0]octan-3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo isomers;
endo isomer: Tl,C on SiO2 more polar one spot OCH_ N.M.R.: (CDC13) p.p.m. 3.4 d,6H,CH OCH ; 3.65, s,3H C02CH
~ OCll3 4.00 m,4H (protons at C4, C5, C9,Cll); 4-17 d,l, CI~ OC~I ;
4.5 m, lH, 6~H
3C~IR: 173,0, 35.0, 33.3. 23.6, 59.4, 80.G, 36.4, 55.6, 83.3, 41.6, 74.3, 44.5, 108.0, 54.4, 54.2, 51.1 exo isomer: TLC on SiO2 less polar isomer one spot ~ OCII~
N.~l.R. ~CDC13) p.p.m.: 3.37 d,611 -Cll OCII ; 3-66 s,31l,C02CI-I
--~' ~ OCI-I_ 4.00 m,4I-I, protons at C4, C5, C9, Cll; 4-2 d,l, -CH OCII
4.32 m~ , Gc~lI
33~
C~R: 173.0, 35.5, 33.3, 23.6, 57.7, 84.2, 38.2, 57.9, 83.6, 40.5, 76.0, 43.9, 107.2, 53.8~ 53.8, 51Ø
4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2l-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual isomers, 3'-exo and 3'-endo;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers;
4-iodo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and its individual 3'-exo and 3'-endo isomers.
Exam~le 27 With stirring under nitrogen, a benzene solution (30 ml) of 2.8 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether is treated with a solution of 2.8 g of tributyltin hydride in 8 ml of benzcne. The mixture is held at 55C for 8 hours and then overnight at room temperature. The ben-zene layer is t~ashed with 2 x 10 ml of a 5~ Na~lC03 solution and then with t~ater until neutral. The residue upon solvent evaporation is adsorbed on 10 g of silica gel and eluted ~ith benzene and benzene:ethyl ether (85:15) to give 1.9~ g of 5-(6'-exo-dimethoxymethyl-7'-endo-]-ydroxy-2'-oxa-bicyclo[3 3 o]
octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether.
Example 28 60 Ing of ~-toluenesulfonic acid is adclecl to a solution of 1.9S g of 5-(6'-e~co-dimethoxymethyl-7'-el)do-]1ydroxy-2'-ox;l-bicycloL3.3.0]octall-3'~-yl)-pent.moic acid methyl cster-7l-tetrallydropyranyl ether in 10 ml of anhydrous methanol. Aftcr 30 minutes at room temperature, this is added to 20 ml of 20i aqucous NallC0 ~ The mixture is extractecl wit}l etllyl ether; the combined ~3~ ~
~3~
ether extract, after drying over Na2SOI~ is evaporated to dryness. The resi-due is adsorbed on 100 g of silica gel and eluted with methylene chloride:
ethyl ether ~94:6) to give 0.64 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2~oxa-bicyclo[3.3.o]octan-3~-exo-yl)-pentanoic acid methyl ester~
0.52 g of the 3'-endo isomer and 0.12 g of the 3' -yl.
N.~l.R. ~CDC13) endo isomer 4.6 p.p.m. m,lH 6~H, T.L.C. more polar;
e~o isomer 4.3 p.p.m. m,l~l 6~H, T.L.C. less polar.
0.32 g of the 3'-endo isomer is dissolved in pyridine (0.8 ml) and treated for 8 hours at room temperature with 0.3 ml of acetic anhydride. The mixture is then poured into ice/water, and, after acidifying to pll 4.2, is extracted with ethyl ether. The combined extract, after washing until neutral, is evaporated to give 0.315 g of 5-~6'-exo-dimethoxymethyl-7'-endo-hydro.Yy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl estcr-7'-acetate.
Example 2g A solution of 1.32 g of 4-(7'-exo-dimethoYymcthyl-8'-endo-llydro.Yy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-but~noic acid methyl ester-8'-tert-butyl-methylsilyl ether in 10 ml of anhydrous methanol is treated ~ith 55 mg of p-toluenesulfonic acid for 2 hours at room temperature. 0.1 ml of pyridine is added, the solvent is removed under vacuum, and the residue is taken up in water/ethyl ether. The organic phase gives, upon removal of the solvent, 1.1 g of t~e crude 8'-hydroxy-3'~-yl derivative. Chromatograp]ly of this on silica gel with benzene:ethyl ether (80:20) as eluent separates this into 4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oYa-bicyclo[3.4.0]nonan-3'-endo-yl)-bu-tanoic acid methyl ester (0.42 g) and the 3'--exo-yl isomer (0.34-g).
Example 30 Using the proccdure in e~Yamples 28 and 29, mcthanolysis of the cthcrs tacetal or silyl) clcscribed in examplc 15 gives the corresponding free ~llcollols .
31~
Example 31 Upon acetylation with pyridine (0.6 ml) and acetic anhydride (0.3 ml) 0.2 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7~-endo-hydroxy-2'-oxa-bicyclo [3.3.0~octan-3~-endo-yl)-pentanoic acid methyl ester gives 0.21 g of the cor-responding 7'-acetoxy derivative.
N.M.R. ~CDC13) p.p.m.: 2.03 s,3H OCOCH3; 3.36 - 3.40 s,s 3H/311 , OCH3 CH OCH ; 3.66 s 3H CO CH~ ; 4.00 m 2i-1 protons at ~ OCH3 C5, Cg; 4-27 d lH CH OCH; 4.6 m lH 6~H 5.0 m lH
proton at Cll ~The spectrometric data for the 6clH isomer acetate are respectively the following 2.03; 3.34 - 33S, 3.66 s+m 4il CO2CH3 and one of C5, C9 protons 4.1 m lH other of C5, C9 protons 4.2, 4.4 m 111 6c~H, 5.1]. 1\ solution of the 5-iodo-3'-endo-acetate in benzene (5 ml) is trcated witll 0.4 g of tributyltin hydride for 10 hours at 50 C. After the benzene phase is ~Yashed ~ith 5Q~
NaHC03 and water, evaporation of the solvent and purification on silica gel (10 g) with a benzene:ethyl ether (S0:20) eluent afford O.lOS g of 5-~6'-octan-3'-endo-yl)-pentanoic acid methyl ester-7'-acetate, identical in all respects with a sample prepared by the procedure in example 2S.
Example 32 Using the procedure of examples 27 and 31, the reduction wit}l tri-butyltin hydride of one of the halo-derivatives synthesi7ed in examples 16 -26 gives the corresponding derivative in h~hich halogen is replaced by hydrogen.
These are identical in every ~1ay ~itl- -the compounds prepared according to the procedures of examples 15, 28, 29 and 30.
Example 33 5.4 mg of hydroquinone and a solution of 1.63 g of oxalic acid in 4S ml of water are adclecl to a solution of 4 g of 5-(6'-exo-dimetlloxymethyl-q~
~333~
7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 180 ml of acetone. After 12 hours at 40C, the acetone is removed at reduced pressure and the mixture is extracted with ethyl acetate (3 x 25 ml). The combined organic extract is washed until neutral with a 10% ammonium sulfate solution and dried over Na2SO4. Removal of the solverlt a~fords 3.21 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-tanoic acid methyl ester. The 6'-exo-~ormyl-3'-endo and the 6'-exo-formyl-3'-exo derivatives are prepared from the corresponding individual isomers.
Example 34 Using the procedure of example 33, starting from the corresponding bicyclo[3.3.0]octan-6~-exo-dimethoxymethyl and bicyclo[3.4.0]nonan-7'-exo-dimethoxymethyl derivatives, the ~ollowing compounds are prcpared, either as individual 3'-exo and 3'-endo or 3'~ isomers:
5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-t6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-~7' exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic 2Q acid methyl ester;
5-chloro-5-(6'-exo-formyl-2'-oxa-bicycloi3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-chloro-4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl estcr;
S-chloro-5-tG'-exo-formyl-7'-entlt)-llydroxy-2'-oxa-bicyclo[3.3.0]oc-tan-3'-yl)-pcntano;c acid metl~yl ester;
4-cilloro-~l-(7~-c~to-formyl-s'-endo-llydroxy-2~-oxa-bicyclo[3~4~o]nonan-3~-yl) ~ltalloic acicl mcthyl ester;
~838~
5-bromo-5-(6l-exo-formyl-2t-oxa-bicyclo[3.3 0]octan-3~-yl)-pentanoic acid methyl ester;
4-bromo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-bromo-5-(6'-exo-formyl-7~-endo-hydroxy-2'-oxa-bicyclo[3.3,0~octan-3'-yl)-pentanoic acid met~yl ester;
4-bromo-4-(7~-exo-formyl-8'-endo-hydroxy-21-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-iodo-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester;
4-iodo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester-7'-acetate;
5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl-pentanoic acid methyl ester-7'-acetate;
5-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-pentanoic acid methyl ester;
4-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-b-l-tanoic acid methyl ester.
E ~camp 1 e_ To a solution of 1.2 g of 5-~6'-exo-ben7yloxymetllyl-2~-oxa-bicyclo [3.3.0]octan-3'i-yl) pentalloic acid methyl ester in metllanolmllet}lyl aceta-te (10 ml:10 ml) is added 2 ml of a O;lN methanol solution of ll~l. Aftcr 0.15 g ~3~ 7~
~3~
of PtO2 is added, the mixture is hydrogenated at ambient temperature and pres-sure until l molar equivalent of hydrogen is abosrbed. After the removal of the gas under vacuum and washing with nitrogen, the suspension is filtered, neutralized, and evaporated to dryness. The residue is taken up in ~ater/
ethyl acetate, and the organic phase yields 0,84 g of 5-(6'-exo-hydroxymethyl-2'-oxa-~icyclo[3 3.0]octan-3'~-yl)-pentanoic acid methyl ester. This is then oxidized to the 6'-exo-formyl derivative by the procedure in example 1, using dicyclohexylcarbodiimide in DMSO:ben~ene (25:75).
Example 36 To a solution of 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4~-dihydroxy-cyclopent-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether in 150 ml of toluene cooled to -70C is added in 30 minutes 12~ ml of a 5M solution of di-iso-butylaluminum hydride (1.2M/M). After 30 minutes at -70 C, 12S ml of a 2M toluene solution of isopropanol is added and the solution is brought to 0C. Then 10 ml of a saturated aqueous solution of NaH2P04 is added and the mixture is stirred for four hours. Following the addition of 10 g of anhydrous Na2S04 and lO g of filtering earth, the solution is filtered and evaporated to dryness to give 18.1 g of 5~-tetrahydropyranyloxymethyl-2cY,4c~-dihydroxy-cyclopent-lc~-ethanal-y-lactol-4-tetrahydropyranyl ether. A solution of tbis in 24 ml of anhydrous DMSO is added drop~ise to a solution of the ylide prepared as follows: 9.6 g of ~0'O sodium hydride in ~00 ml of DMS0 is heated for four hours at 60 C. Then after the mixture is brought to 1~ - 20C, 67 g of 4-carhoxybutyltriphenyl phosphonium bromicle dissolved in S0 ml of an-hydrous DMS0 is added ~hile maintaining a temperature of 20 - 22 C to generate a bright red color. After four hours of stirring, 600 ml of ~ater is added and the mixture is extractecl~ith ethyl cther:bcn7ene ~70:~0) to remove the tripllellylpllospl~ oxide. The ben~ene organic phase is re-extracted with 4~
8~
O.lN NaO~I and then with water until neutral; it is then discarded. The alkaline aqueous phase is acidified to p~l 5 - 4.~ and then extracted Wit}l ethyl ether:pentane (1:1) to give 21.6 g of 5-cis-7-(2'c~,4'~-dihydroxy-5'~-tetrahydropyranyloxymethyl-cyclopent-l~-yl)-hept-5-enoic acid-4'-tetrahydro-pyranyl ether, which may be converted to its methyl ester by treatment with diazomethane in ether. 7.72 g of this ester in 28 ml of tetrahydrofuran is added dropwise to a yellow-bro~n suspension formed by adding 28 ml of THF to a solution of 6.13 g of mercuric acetate in 28 ml of water. After the mixture is stirred for 20 minutes at room temperature, it is cooled in an ice:water ~ath and 810 mg of NaBH4 in 14 ml of water is added drop~iise. Elemental mercury precipitates out, the suspension is decanted, the tetrahydrofuran is evaporated at reduced pressure and the residue is extracted with ethyl ether. Removal of the solvent affords 7.5 g of 5-(6'-exo-tetrahydropyranyloxymethyl-7'-hydro~y-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydro-pyranyl ether; 0.42 g of p-toluenesulfonic acid is then added to a solution of this in 30 ml of methanol. After 2 hours at room tem~erature, the solution is concentrated under vacuum and water is added. After extraction with ether and chromatography on silica gel with ethyl ether as eluent, one obtains 2.4 g of 5-~6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 2.6 g of the 3'-endo isomer.
E ple 37 2.5 g of N-iodosuccinimide is added to a solution of 4.26 g of 5-cis-7- (2'c~,4'c~-dihydroxy-5'~-tetra}lydropyranyloxymethyl-cyclopent-l'c~-yl)-hept-5-elloic aci&-4'-tetrahydropyr.myl ether in C1l2C12:CCl~ (10 ml:10 ml) and the resulting mixture is stirred Eor four hours. 30 ml of anhydro~ls methanol containing 130 mg of ~-toluenesulEonic acid is aclded and stirring is continued for another 2 hours. 0.2 ml of pyridine is adcled, the mixture is reduced to sm.lll volulllc~, and the residue is takell up in ~ater/ethyl acetate. After waslling witll N~l S203 and tllen water until neutral, the organic phase is e~ap-~83~
orated to dryness to give a residue that is adsorbed on silica gel and eluted with ethyl ether to give 2.2 g of 5-iodo-5-~6'-exo-hydro~ymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 1.85 g of the 3'-endo isomer.
Example 38 Following the procedure of example 37, but using the methy] ester instead of the acid and N-bromoacetamide instead of ~-iodosuccinimide, the 5-bromo-5--~6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl ester is prepared. Silica gel chromatography allows the separation into the 3'-exo and 3'-endo isomers.
Example 39 A solution of 0.86 g of pyridine and 2.2 g of 5-cis-7-~2',4'~A-di-hydroxy-5'3-tetrahydropyranyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-tetrahydropyranyl ether in dichloromethane (20 ml) is cooled to -30C and 0.38 g of chlorine in 10 ml of CC14:CI-I2C12 (1:1) is added. The mixture is stirred for 2 hours, warmed to room temperature, and ~ashed with 2N H2SO4 and then water until neutral. After evaporation of tl-e solvent, ~he residue is dissolved in methanol (10 ml) and treated wit}l 0.1 g of p-toluene-sulfonic acid. The solution is then concentrated, diluted ~ith water, and extracted with ethyl acetate. Removal of the solvent and purification of the residue on silica gel afford 0.6 g of 5-chloro-5-(6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid and 0.71 g of tha 3'-endo isomer.
Example 40 .
To a solution of 0.356 g of 5-iodo-5-(6'-e~o-hydroxymetllyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-~'-exo-yl)-pentanoic acid methyl ester in .8 ml of benzene:D~IS0 ~15:25) are added, in order, 0.28 g of dicyclohcxyl-carbodiimide and 0.4 ml of a pyridinium trifluoroacetate solution (see example l). After 3 hours of stirring, 8 ml of benzene and then aqueous oxalic acid (94 mg in l.2 ml) are added. The precipitate is removed by filtration and the benzene solution is washed with water until neutral. Removal of the sol-vent affords 0.32 g of 5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0]octan-3'-exo yl)-pentanoic acid methyl ester.
Example 41 Upon oxidation of the 6'-exo-hydroxymethyl-7'-endo-hydroxy deriva-tives prepared according to examples 36 - 39, following the procedure of ex-ample 40, the corresponding 6'-exo-formyl derivatives are prepared.
Exmple 42 -~ solution of 3.4 g of (2-oxo-heptyl)dimethoxyphosphonate in 50 ml of dimethoxyethane is added dropwise to a suspension of 0.45 g of 80% NaH
~mineral oil dispersion). After stirring for l hour, a solution of 2.7 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 40 ml of dimethoxyethane is added. In l0 minutes this is diluted with 50 ml of a 30% aqueous solution of monobasic sodium phosphate.
The organic phase is separated, the aqueous phase is re-extracted, and the combined organic extract is evaporated. Purification of the crude product on 50 g of silica gel ~cyclohexane:ethyl ether, 50:50) gives l.lg of 5-[6'-exo-~3"-oxo-oct-l"-trans-en-l"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl]-pentanoic acid methyl ester or l3t-6~H-6~9~)-oxide-llcY-hydroxy-l5-oxo-prost-13-enoic acid methyl ester and 0.9S g of 5-[6'-exo-(3"-oxo-oct-l"-trans-en-l"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pen-tanoic acid methyl ester or l3t-6c~i1-6(9c~)-oxido-llc~-hydroxy-l5-oxo-prost-l3-onoic acid met1lyl estor, plus 0.9 g of a l:l mixture of tlle t~o isomers (3'-exo and 3'-enc1O, or 6CY~ and 6~11). This last mixture is separated into its t~o i~o1neric con1pollents by thin layer chromatography ~ith ethyl ether. They s11o~Y t1~e ~ollo~in~ absorptions, respectively:
q ,,~
3~
~ MeOH = 230 m~, e = 13,070; ~ = 228 m~, E = 12,200.
N-M-R- (CDC13) 0-9 t 3H C20~CH3, 3.68 s 3H CO2CH3, 6.16 d lH vinylic proton at C14 (JH14-H15
6.71 q lH vinylic proton at C13 ( H13 z B~ the same procedure, from the corresponding 5-H and 5-halo com-pounds, the following prostenoic acid derivatives are prepared:
13t-6~H-6(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~-oxide-5-chloro-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-bromo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R. = 3.67 s 3~1 CO2CH3; 3.95 m 4H C5, C9, Cll protons and llx/Hy proton at C4; 4.3 m lH 6~H; 6.15 d lH C14 proton; 6.63 q lH C13 proton;
13t-6~H-6~9~)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R. 0.9 s 3H C20CH3, 3.53 m lH proton at C5, 3.6 s 3H CO2CH3 3.9 m H
proton at C4, 4.1 m 211 proton at Cg, Cll; 4.4.m 1l-1 6~H; 6.2 d lH proton at C14 6.75 q lH proton at C13;
13t-6~1-l-6C9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6~9~j-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~-1-6(9~)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~ 6~9~-oxide-5-iodo-15-oxo-prost-13-er.oic acid methyl ester;
13t-63~ 6(9~)-oxide-5-chloro-11~-hydroxy-15-oxo-prost-13-enoic acid methyl estcr;
a, :~83~
13t-6~H-6~9~)-oxide-5-bTomo-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R.: 3.65 s 31I C02CH3; 4.00 m 3H proton at C5, Cg, Cll, 4-6 m lH 6~H;
6.2 d lH proton at C14; 6.64 q lH proton at C13;
l3t-6~H-6~9~)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
N.M.R. 3.66 s 3H C02CH3, 3.9~ m 311 protons at Cg, Cll and C5, 4.6 m lH 6~H, 6.21 d lH proton at C14 6.75 q lH proton at C13.
Exam~le 43 A solution of 2.16 g of ~2-oxo-octyl)dimethylphosphonate in 20 ml of benzene is added dropwise to a suspension of 292 mg of NaH ~75o mineral oil dispersion) in 30 ml of benzene. After 30 minutes of stirring, a solu-tion of 2.6 g of 4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.
0]nonan-3'?-yl)-butanoic acid methyl ester in 20 ml of benzcnc is added drop by drop. Stirring is continued for another 30 minutes, and 24 ml of a 300 aqueous solution of NaH2P04 is added. The organic phase is separated, and the aqueous phase is re-extracted with benzene. The organic layers are com-bined and evaporated to dryness. The residue is purified on silica gel ~50 g) with CH2Cl2:ethyl ether ~120:40) as eluent to give 0.52 g of 4-bromo-4-[7'-exo-~3''-oxo-oct-l~-trans-l~-enyl)-sl-endo-hydroxy-2~-oxa-bic~clo[3.4.o~nonan 3'-endo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~1-5~9~)-oxide-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester and 1.45 g of 4-bromo-4-.[7'-exo-(3'1-oxo-oct-l"-trans-l"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]
nonan-3'-exo-yl]-butanoic acid methyl cster or 13-trans-4-bromo-5~i-1-5(9~)-oxide-ll~ yclroxy-15-oxo-prost-13-enoic acid methyl csteT. ~lethanolic solu-tions of these two compounds absorb in the UV at A ma~ = 230 m~, ~ = 10,640, and ~ axII = 229 m~, ~ = 11,600, respectively.
~jl 53 The same procedure, starting from the 4-H and 4-halo bicyclo deriva-tives, gives the following prostenoic acids:
13-trans-5~H-5~9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-S~H-5(9~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5 ~9C4) -oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9cY)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-5cYH-5(9a)-oxide-15-oxo-prost-13-enoic acid metllyl ester;
13-trans-5c~H-5(9c~)-oxide-llcY-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5cYH-5(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester.
13-trans-4-chloro-5c~H-5(9c~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-~romo-5H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-_rans-4-bromo-5cYH-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5cYH-5(9c~)-oxide-15-oco-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9~)-oxide-111-llydroxy-15-oYo-prost-13-enoic acid methyl ester.
Example 44 By thc procedure of e~ample 42, the reaction of 620 mg of (2-o.xo-3-metllyl-4-~utoxyblltyl) yhosphonate ~ith 74 mg of Na~-l (75O) and 0.43 g of 5-(6'-exo-~`ormyl-7'-cnclo~ yclroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid , S~C~
~1i5 3~
methyl ester in dimethoxyethane gives, after chromatography on silica gel (25 g) with 1:1 ethyl ether:hexane as eluent, 0.15 g of 13t-6uH-6(9~)-oxide ~ hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20--trinor-prost-l3-enoic acid methyl ester ~ = 238 m~, = 14,500) and 300 mg of the 6~H-isomer (- max 237 m~, e = 12,2so) Mass spectrum: m/e 410 M , m/e 392 M -H2O;
m/e 379 M -OCH3; m/e 295 M -115, m/e 115 ~O-C4~9 .
The two isomers present similar spectra with minimal differences at level of secondary fragmentation.
Using the same procedure the 5-chloro, 5-bromo and 5-iodo 13t-6 il-6C9c~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester.
Exam~le 45 __ By the procedure of example 44, from 4-~7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3' ~yl)-butanoic acid methyl ester and the 4-iodo bicyclic derivati~e the following are obtained:
lst-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-lS,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5c~H-5(9c~)-oxide-llc!-llydro~cy-15-o~;o-16-met}lyl-16-buto:;y-18,19,20-trinor-prost-13-enoic acid methyl ester.
Example 46 _ 'rO ~ s~lspcllsion of 45 mg of S0O Nall in 10 ml of benzene is addcd a I ~ 3 ~ ss-.
33~
solution of 375 mg of (2-oxo-3,3-dimethyl-heptyl)-dimethylphosphonate in 10 ml of benzene, followed 30 minutes later by a solution of 0.305 g of 5-iodo-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester. After stirring for 45 minutes, the mixture is diluted with 10% aqueous NaEI2P04. The organic phase is washed until neutral, dried and concentrated to small volume. Adsorption on silica gel and elution ~Yith cyclohexane:ethyl ether ~90:10) give O.l2 g of 13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester and 0.095 g of 13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-13-enoic acid methyl ester.
Example 47 By substituting in the procedure of example 46 the formyl derivatives prepared according to example 34, the follo~Ying 16,16-dimethyl derivatives are prepared:
13t-6~H-6(9~)-oxide-lS-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6~l-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid nmethyl ester;
13t-S~H-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-S-chloro-6~H-6~9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6~H-6(9~)-oxide-11~-hydrOXy-15-Oxo-l6~l6-dimethyl-prost-l3-enoic acid methyl ester;
13t-4-chloro-5~ll-5(9~)-oxidc-l5-oxo-l6~l6-dimcthyl-prost-l3-cnoic acid methyl estcr;
13t-~-c~lloro-5~l-l-s (9c~) -oxi~!c-~ -hydro:cy-l5-oxo-l6 ~ l6-dimetllyl-prost-l3 onoic acid mctllyl ester;
13t-5-l~romo-G~I-6(9~)-oxide-15-o.Yo-16,16-dimetllyl-prost-13 enoic acid methyl ~8~
ester;
13t-5-bromo-6~H-6(9cl) -oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5~9cY)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5~9cY)-oxide-llc~-hydroxy-15-oxo-16,16-dimethyl prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9cY)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9cY)-oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9c~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9cY)-oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6c~H-6(9cY)-oxide-l5~oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6cYH-6~9a)-oxide-llcY-hydroxy-15-oxo-16~16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9cY)-oxide-15-oxo -16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9cy)-oxide-llcy-hydroxy-l5-oxo-l6~l6-dimethyl-prost-l3-enoic acid methyl ester;
13t-5-chloro-6cyH-6(9cy)-oxide-ls-oxo-l6~l6-dimetllyl-prost-l3-enoic acid methyl ester;
13t-s-chloro-6c~ -6~9cy)-oxide-llcy-~lydro~cy-ls-o~;o-l6~l6-dimetl~yl-prost-l3-enoic acicl methyl ester;
13t-4-chloro-Sc~tl-5(9N)-o.Yide-15-oxo-16,16-climetll~'l-prost-13-c?noic acid me-thyl cstcr;
13t-4-cilloro-5c~tl-5(?c~)-oxi(lc-llc~-llyclroYy-15-o.Yo-16,16-dimethyl-prost-13-enoic ~3 ~
31~
acid methyl ester;
13t-5-bromo-6~H-6~9~)-oxide-15-oxo-16,16-dimethyl-pros-t-13-enoic acid methyl ester;
13t-5-bromo-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bTomo-5~H-5~9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5(9~-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9x)-oxide-15-oxo-16,16-dimethyl-prost-13-e~oic acid methyl ester;
13t-5-iodo-6aH-6~9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~l-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimetl-yl-prost-13-enoic acid methyl ester;
Example 48 To a suspension of 178 mg of Na~l (75O mineral oil dispersion) in 15 ml of benzene is added dropl~ise a solution of 1.55 g of [2-oxo-3(S,R)-fluoro-4-cyclohexyl-butyl~-dimethylphosphonate in 10 ml of anhydrous benzene.
After 30 minutes of stirring, a solution of 1 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-o~a-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continucd for another hour. Tile mixt~lre is neutralized with 30O aqueous Nc~l2PO~, ancl the organic phase is separate~, concentrated and adsorbcd on si.lica gel. Elution liith C~l2C12:Et20 (90:10) gives, 0.62 g of 13t-6c~ 6(9c~)-ox.i(le-llc~ ydroxy-15-oxo-16(S,R)-fluoro-17-cycloilexyl-ls~ 'O-trinor-prost-13-enoic acid methyl ester 3~
MeO~ = 238 mll, e = 12,765) and 0.31 g of the 6~11 isomer (~ = 238 m~l, ~ = 9,870).
The N.M.R. data for the former compound are the followin~ (CDC13) p.p.m.
3.64 s 3H CO2CH3, 3.8 m lH Cg proton, 4.03 q lH pro~on at Cll, 4.3 m lH 6C~H, 5.00 and 5.55 t,t 1/2 }1, l/2 H proton at C16 JHF 55 Hz, 6.54 q lH proton at Cl4 6.9 q lH proton at Cl3 JH H 3~5 Hz, JH H 7-5 H~? JH H 15.5 Hz.
Treating this compound with pyridine and acetic anhydride it is converted into the ll-~cetoxy derivative, for which N.hl.R. data are: (CHCl3) p.p.m. 2.02 s 3H OCOCH3, 3.64 s 3H C02CH3, 3.8 proton at Cg, 4.25 m lH 6dH; 4.6S, 5.22 t.t. l/2 H, l/2 H proton at Cl6; 4.97 q lH proton at Cll; 6.51 proton at Cl4, 6.90 proton at Cl 3;
For the diastereoisomeric hydroxy ketones the mass spectrum shows the follow-ing masses:
M 424 m/e and then M -H20, M -HF, M -C1130H/CH20 M -CH2=CHOH (basis ion) M 115 M -44-59 and M -~CHF-CH2-C6Hll).
In mass spectrum of exo-diastereoisomer the following masses are predominant:
M -CH30H and M -44-28; in that of endo-diastereoisomer the predominant ones are M -C}130 and M -44-l8.
From the S-bromo derivative, l3t-5-bromo-6~H-6(9~)-oxide-ll~-hydr l5-oxo-l6(sJR)-fluoro-l7-cyclohexyl-l8Jl9>2o-trinor-prost-l3-enoic acid methyl ester is prepared.
Exal~le 49 Substituting in the procedurc of example 48 a phosphonate chosen rom (2-oxo-4-cyclohexyl-butyl)-dimet}1ylphosphonate and (2-oxo-4-phenyl-butyl)-dimethylphosphonat~ thc following were prcpared:
3~
13t-6~H-6(9~)-oxide-11~-hydro~-lS-oxo-17-c~clohexyl-18,19,20-trinor-prost-13-enoic acid meth~l ester, 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid me-thyl ester and their 6~H lsomers.
Example_50 To a suspension of 178 mg of NaH (75% mineral oil dispersion) in anhydrous tetrahydrofuran at 0C is adcled dropwise with stirring a solution of 1.63 g of 2-oxo-3-~m-chlorophenoxy)-propyl-dimetnylphosphonate in 10 ml of anhydrousTHF. After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continued for another hour. The mixture is acidlfied with aqueous NaH2PO4, the organic phase is separated, and tlle aque-ous phase is re-extracted with benzene. From the combined organic extract, after chromatography on silica gel with CH2C12:Et2O (95:5) as eluent, one obtains of 0.43 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16-_-chloro-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester (~ MeyH = 227 m~, = 16,800) and 0.11 g of the 6~H isomer (~ma~ = 224 m~, = 16,900).
Both the diastereoisomers show the mass peak m/e 436 according to C23H2~ClO6. This ion is involved in the following fragmentation:
M -H2O, M -OCH3/CH3OH, M -44, M -(O-C6H4Cl), M -~12O-(O-C6H4Cl) and M -(CH2)4-C02CH3, so furthermore confirming the proposed structure.
The following differences are between the two diastereoisomcrs: the e~o 6~H
isomer sho~s a pea~ at M -32 and a little intense pea~ at M -44 on the other hand the endo 6~11 isomer shows a pea~ at M -31 and an intcnse pea~ M -44.
E,Y;ImP10 51 The substitution of a phosphonate chosen from 2-o~o-3-(_-trifluoro-- ~r-389~
methylphenoxy)-propyl-dimethylphosphonate and 2-oxo-3-~p-fluorophenoxy)-propyl-dimethylphosphonate in the procedure of example 50 leads to the fol low-ing compounds, respectively:
13t-6~H-6~9cY)-oxide-llc~-hydroxy-15-oxo-16-m-trifluoromethylphenoxy-17,18, 19,20-tetranor-prost-13-enoic acid methyl ester, 13t-6~H-6(9c~)-oxide-llc~-hydro~cy-15-oxo-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, and their 6~1 isomers.
The mass spectra of all the compounds agree with the proposed structure for example showing the mass peak M -115; an interesting difference between the endo- and exo- trifluoromethyl analogous is that the mass peaks M -CH30H and ~1 -CF3-C6H4-OH are in the exo-isomer and the mass peak M -C1130 and ~l-cF3-C6H~-O
are in the endo-isomer.
Example 5~
The substitution of (2-oxo-3S-methyl-butyl)-climethylp1losphonate for the phosphonate in the procedure of example 4g gave 13t-6Q11-6~9~)-oxide-llr~-hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and its 6ciH isomer.
To a solution of 2.2 g of the 6~1 isomer in 2.6 ml of pyricline, cooled to O C, is added 1.05 ml of acetic anhydride. The solution is held at O C overnight and then added to an excess of cold 0.05~ sulfuric acicl. E~traction with ethyl ether and evaporation to dryness give 2.3 g of 13t-G~1-1-6~9c~)-oxide-'1 hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester-ll-acetate MeOII = 229 m~, ~ = 12,050) max 875 mg of bromine in glacial acetic acid is added drop~ise to a solution of the latter compo~md in 10 ml of glacial acetic acid, until a llght orange color appears. 1.52 g of anhyclrous potassium carbonate is then adcled and the resulting mixt~lre is held at 80 C for ~1 - 5 hours to complete the precipit~tion oE potassium bromide. E~cess acetic acid is removed under vacuum, water is added, and the pH is brought to pH 6.8 with alkaline hydrate.
This is then extracted with ethyl ether and the organic phase is reduced in volume. Adsorption on silica gel and elution with methylene chloride:ethyl ether (70:30) gives 2.01 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-14-bromo-15 oxo 16S-methyl-prost-13-enoic acid methyl ester-ll-acetate, m x = 249 m~, ~ = 11,450.
The 6~H isomer is similarly prepared.
Example 53 A solution of 2.06 g of (2-oxo-3S-methylheptyl~-dimethylphosphonate in 20 ml of dimethoxyethane is added dropwise to a suspensi.on of 0.265 g of NaH (80% mineral oil dispersion) in DM~ (10 ml~. After stirring for 30 mi-nutes, 1.6 g of N-bromosuccinimide is added and vigorous stirring is continued for 10 minutes. 1.35 g of 5-(6 -exo-formyl-7t-endo-hydroxy-2 -oxa-bicyclo [3.3.0]octan-3 ~-yl)-pentanoic acid methyl ester in 5 ml of dimethoxyethane is then added. The mixture is stirred for 1 hour and 20 ml of 30% Nall2P04 is added. After the usual wor~-up, crude 14-bromo-enone is obtained.
Separation on silica gel with methylene chloride:ethyl ether (85:15) gives 0.9 g of 13t-6~H-6~9~)-oxide-llN-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and 0.92 g of the 6~1~ isomer. Upon treatment with n. 4 ml of pyridine and 0.2 ml of acetic anhydride, 0.2 g of the 6~H isomer gives 0.205 g of the ll-acetoxy derivative, identical in all respects with that made by the procedure of example 52.
Example 54 ~ solution of 0.43 g of ~2-oxo-octyl)-dimet]lylp]losp11onate in 10 ml of benzclle is added drop~lse to a suspension of 54 mg of Na~-l (80Uu mineral oil dispersion) in S ml o~ benzelle. ~ftcr 1 hour, l~hen the evolution of ll2 has cc~scl, 0.32 g of n-bromosuccinimide is addcd all at oncc. To the carbanion thus prcpared, of (l-bromo-2-o~o-octyl)-1imetllylpllosp1Onate is added a solution ~33~
of Z70 mg of 5-c6~-exo-formyl-7~-endo-hydroxy-2~-oxa-bicyclo[3.3~o]octan-37 yl)-pentanoic acid methyl ester in 8 ml of benzene. After 30 minutes, the reaction is quenched by the addition of 20 ml of a 10% solu~ion of N ~12P04.
The organic phase, after being washed until neutral, gives 0.31 g of 13t-6~H-6t9u)-oxide-lla-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester; this is then separated into the 6~H and 6BH isomers.
Example 55 Upon substitution of the ~2-oxo-octyl)-dimethylphosphonate in the procedure of example 54 with (2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and ~2-oxo-4-phenyl-butyl)-dimethylphosphonate> the following compounds were prepared:
13t-6~H-6(9a)-oxide-lla-hydToxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-lla-hydroxy-14-bromo-15-oxo-17-phenyl-18,1g,20-trinor-prost-13-enoic acid methyl ester.
Example 56 By substituting the formyl derivatives in examples 53, 54 and 55 with 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester, 4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy_2~_ oxa-Dicyclo[3.4.0]nonan-3'~-yl)-bUtanic acid methyl ester, and the correspond-ing 4-H derivative, the ~ollowing compounds were prepared:
13t-5-iodo-6~H-6(9a)-oxide-lla-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3 enoic acid methyl ester;
13t-4-ido-5~H-5(9a)-oxide-lla-hydroxY-l4-bromo-l5-oxo-l6s-oethyl-prost-l3 enoic acid methyl ester;
13t-5~1 5C9~1_oxide-lla-hydroxy~14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester;
3~
13t-5-iodo-6~H-6(9)-oxide-11~-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-4-iodo-S~H-5(9~)-oxide-lla-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide~ -hydro~-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9c!.)-oxide-11-hydro.Yy-:14-bromo-15-oxo-17-cyclohexyl-i~,l9, 20-trinor-~rost-13-enoic acid methyl es~ter;
13t-S~H-5~9~)-oxide-lla-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6(9a)-oxide-lla-hydroxy-14-bro -15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5~9)-oxide~ -hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-triJIor-prost-13 enoic acid methyl ester.
Example 57 A solution of 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide in 6 ml of DMS0 is added to a solution of 0.15 g of potassium t-butylate in 3 ml of DM50 while keeping the reaction temperature at 16 - 19C. 0.27 g of S-; ~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 8 ml of anhydrous tetrahydrofuran is then added. After 30 minutes of stirring, an equal volume of water is ~dded and the mixture is extracted with ethyl ether. The combined organic extract is washed until neutral and the solvent is evaporated. Chromatography on silica gel (cyclo-hexane:ethyl ether, 40:60) gives 0.21 g of 13t-6~ 6(9)-oxide-11~-hydroxy-15-oxo-20-methyl-prost-13-enoic acid methyl ester.
~ ~ 3~
~ai5 3~
Subsequent preparative thin layer chromatography ~SiO2-Et20) allows separation of the 6cYII and 6~H isomers.
Example 58 A solution of d,l-13t-6cYH-6(9cY)-oxide-llcY-hydroxy-15-oxo-13-enoic acid methyl ester (exo-isomer at greatest Rf), (0.9 g), in dry ethyl ether (30 ml) is dripped on to a stirred 0.1 M solution of Zn(BH4)2 in dry ethyl ether (30 ml), over 15 minutes. AFter 2 hours, the excess reagent is decomposed by cautious addition of saturated NaCl solution and aqueous 2N sulfuric acid.
The organic layer is separated, washed to neutral and evaporated to dryness affording a residue which is adsorbed on silica gel, eluted with ethyl ether to yield 0.3~ g of 13t-6CYH-6(9CY)-oxide-llc~l5R-dihydroxy-prostenoic acid methyl ester, as an oil, and 0.42 g of d,l-13t-6cYH-6(9cY)-oxide-llcY,15S-di-hydroxy-prostenoic acid methyl ester, m.p. 69 - 71C (mass spectrum m/e 350 M -18, 319 ~I -18 -CH30; 318 M -18-CH30H). A solution in methanol (4 ml) of this ester is treated with 60 mg of lithium hydroxide and water (O.S ml) for 8 hours at room temperature. The methanol is removed in vacuum, the residue is diluted with water and extracted with ethyl ether to remove neutral impurities. The alkaline phase is treated with aqueous saturated NaH2P04 solution until to pH 5 and then extracted with ethyl ether. The later organic phases are collected to yield after evaporation of the solvents the free acid d~ 3t-6cyH-6(9cy)-oxide-llcy~l5s-dihydroxy-prostenoic acid, m.p.
105 - 106C. The 15R-hydroxy compound is a non-crystallizable oil.
In the same way using nat-keto compound in the reduction reaction with Zn(B~ )2 we obtained besidcs the 15-epi alcohol, the nat-13t-6cYH-6(9~)-oxide-llcY,15S-dihydroxy-prostenoic acid methyl ester, m.p. 71 - 72 C [cY]D =
~ 10.2 ~ [~]365 a ~ 32.2 (CIIC13) ancl aftcr saponification the free acid m.p. 101 - 102C [CY]D a ~ 6.3'1 , [~]~65 = ~~ 33-2 (CIICl_).
''' `1 1 ~83~
Starting from the endo-diastereoisomers (more polar compounds), the following esters were obtained:
13t-6~H-6~9~)-oxide-ll~,lSR-dihydroxy-prostenoic acid methyl ester (d~l, nat-3 ent- oils);
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-prostenoic acid methyl ester ~d, 1, nat-, [~]D = + 24-5 . [~]365 = + 52-9 (CHC13) oil; ent- [~]D = -22 , oil), and after saponification the following free acids:
13t-6~H-6~9~)-oxide-11~,15R-dihydroxy-pros~enoic acid (d,l, nat-, ent- oils);
13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-prostenoic acid ~d,l oil, nat-, Dl.p.
78 - 80 C [u]D = I 32-5 ~ [~]365 = + 11-6 (EtOI-I), ent- m-p- 78 - 79 C, [~]D = ~ 31 (EtOH)).
Example 59 .
With the temperature of the reaction mixture kept at around -5 to -8 C, a solution of 159 mg of NaBH4 in 7 ml of propan-Z-ol, is gradually added to a solution of 0.332 g of anhydrous CaC12 in propan-2-ol (7 ml); then, under stirring, a solution of 0.38 g of 13t-6~H-6(9Q)-oxide-ll~ ydroxy-15-oxo-16(S~R)-fluoro-17-cyclohexyl-18,19,20--trinor-prost-13-enoic acid methyl ester in 3 ml of propan-2-ol is added to the above prepared Ca(BHI)2 in a period of 40 minutes. The reaction mixture is ~ept under stirring at a temperature ranging at -~ 5C, then the excess reagent is destroyed by addition of 5 ml of acetone and 2 ml of water. The solvent is evaporated under vacuum and the residue is partitioned among water, O.lN H2S04 and ethyl acetate. The organic extracts are collected, washed until ncu-tral and after evaporation of solvent the rcsidue chromatographed on silica gel (30 g~ using CH2C12-ethyl otller 70:30 as eluont. The eluate yields 0.21 g of l~t-6~H-6(9(~)-oxide-11~,15R-dihydroxy-16(S~)-fluoro-l7-cyclo]lexyl-ls~l9~2o-trinor-prost-l3-enoic acid methyl ester, and 0.1~ g of the 15S-epimer, m.p. 83C - 84 C (frorn ethyl etller) .
:~33315 ~
In the same way, reduction of the 6~H-isomer (220 mg) yields 0.1 g of 13t-6~ 6(9~)-oxide-11~,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19, 20-trinor-prost-13-enoic acid methyl ester, m.p. 63 - 64 C (from isopropylic ether), and 60 mg of 15S-alcohol.
Example 60 -A solution of 0.15 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-keto-16-methyl^l6-butoxy-18,19,20-trinor-prostenoic acid methyl ester in methanol (5 ml) is cooled at -5 . - 10C and reduced by addition of a solution of NaBH4 ~30 mg) in water (0.5 ml).
The reaction mixture is neutralized by addition of 15% aqueous NaH2P04 solution after 15 minutes and then evaporated in vacuum. The aqueous residue is extracted with ethyl ether to yield a crude mixture of epimeric 15R,15S-alcohols. Chromatographic separation on silica gel ~Crl2C12-ethyl ether 70:30 as eluent) affords respectively 13t-6~H-6(9~)-o~ide-11~,15R-di-hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester (~5 mg) and 15S-hydroxy-epimer (62 mg).
Example 61 By reduction of 13t-5~H-5~9u)-oxide-11~ ydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester, under the same trial conditions as in the procedure of example 60 follo-~ed by chromatographic separation of the epimeric alcohols ~300 mg) on silica gel (12 g) with methylene chloride-ethyl ether 75:25 eluent, we respectively obtained 100 mg of 13t-5~H-5(9~)-oxide-ll~-l5R-dihydroxy-l6-metllyl-l6-buto~y-ls~l9~2o-trinor prostenoic acid methyl ester, and 110 mg of 15S-epimer. Tllese are then saponifled to yield the corresponding ~ree acids.
Example 6~
~ro~ ise, to a stirred 0.12 ~I solution of zincborohydride in ethyl ether (8 ml) a solution of 0.135 g of 13t-5-bromo-6~ll-6~9~)-oxide-11~-hydro~y-~,~i 6~
~13~
15-oxo-prostenoic acid methyl ester in 2 ml of anhydrous Et2O is added. The mixture is stirred for 2 hours and the excess reagent is decomposed with water--2N H2SO4. The organic phase is separated, washed to neutral and evaporated to dryness. After TLC on silica gel with ethyl ether-ethyl acetate 90:10, 38 mg of 13t-5-bromo-6c~ll-6~9c~)-oxide-llc~,15R-dihydroxy-prostenoic acid methyl ester and 46 mg of 15S-epimer were ob~ained.
Exam~le 63 Starting from 13t-5,14-dibromo-6~H-6(9cY)-oxide-llc~-hydroxy-15-oxo-prostenoic acid methyl ester (0.2 g) and using a mixture of CH2C12-ethyl ether 60:40J during the chromatographic separation on silica gel, we obtained 0.056 g of 13t-5,14-dibromo-6~H-6~9a)-oxide-llcY,15R-dihydroxy-prostenoic acid methyl ester and 0.098 g of 15S-isomer.
A solution of this product in methanol is then hydrolized ~ith aqueous LiOH to yield 72 mg of 13t-5,14-dibromo-6c~11-6(9c~)-oxide-11~,15S-dihydroxy-prostenoic acid.
Example 64 -Using, in the procedure of example 60, isopropanol as solvent and NaBH4 (45 mg), the reduction of 13t-6~H-6(9cY)-oxide-llc~-hydroxy-15-oxo-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester (0.47 g~ yields 0.20 g of 13t-6~H-6(9c~)-oxide-llce,15S-dihydroxy-16-~m-tri-fluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, [C~]D = ~ 33.3 (~eOII) and 0.18 g of 15R-epimer. The 6c~H-15S-alcohol epimer is an oil witll [c~]D ~ -I 12 (MeOII).
Example_65 A solution in dry ethyl ether ~20 ml) of 13t-16S-methyl-6c~ll-6~9c~)-oxide-Llc~-hydro.~y-15-o.yo-prost-13-enoic acicl methyl ester (0.002 ~I, 0.72 g) is added to a stirred etheral solution of ~inc borohydride t0.01 M, 100 ml).
Tllo e~coss reagon~ is destroyed, after 30 - 45 minutes, by addition of 2N-3~
sulphuric acid in NaCl saturated aqueous solution. The organic phase is washed until neutral and evaporated to dryness. The residue is chromatog-raphed on silica gel (25 g) using methylene-chloride:ethyl ether (80:20) as eluent affording (7.5.10 ~ M, 0.27 g) of the 15R-hydroxy-isomer and (1.1.10 4 M; 0.38 g) of the 15S-alcollol: 13t-16S-methyl-6~-6(9c~)-oxide-11~, 15S-dihydroxy-prost-13-enoic acid methyl ester. Using this procedure, the following methyl esters were obtained:
13t-6~H-6(9a)-oxide-l6s-methy~ l5s-dihydroxy-prost-l3-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-6c~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
57 - 59 C [cl]D = +14 ~ [a]365o = +47 (CHC13);
13t-6~H-6(9~)-oxide-20S-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
38 - 39C, [~]D = -~21-7, [~]365 = +77 (CHC13);
13t-5-bromo-6~H-6(9~)-oxide-16S-methyl-lla,15S-di}lydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-16R-methyl-11~,15S-di}lydroxy-prost-13-enoic acid;
13t-5-bron~o-6~1I-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-llc~,15S-dihydroxy-20-methyl-prost-13-enoic acid, ~'~]D = + 38 ;
13t-5-iodo-6~H-6(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9c~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~I-6(9a)-oxide-16R-methyl~ ,15S-dihydroxy-prost-13-enoic acid;
13t-5~iodo-6~H-6(9c~)-oxide-16,16-dimet}lyl-llc~,15S-dihyclroxy-prost-13-enoic acid;
13t-5-iocIo-6~I-6(9~)-oxi(Ie-llc~,15S-~ ydro~y-20-methyl-prost-13-enoic acid, [a]D = ~ 23 ~ [~365 = ~ 78 (CIICl~);
13t-5-cllloro--6~II-6~9~)-oxide-lGS-mc?t}lyl-11~,15S-diIlydro~y-prost-l3-enoic acid;
~3384~L
13t-5~EI-5(9~)-oxide-16S-methyl-lla,15s-dihydroxy-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
lat-4-bromo-5~H-5(9a~-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~H-5(9ci)-oxide-16R-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~H-5~9c~)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-iodo-5~H-5(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-chloro-5~H-5(9c~)-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-16S-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-16R-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-20-methyl-lla,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9cv)-oxide-15(S,R)-20-dimethyl-lla,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-16S-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-S(9c~)-oxide-16R-methyl-lla,15S-dillYdroxy-14-bromo-prost-13-enoic acid;
13t-5~EI-5~9a)-oxide-20-methyl-11~,15S-diElYdrOXy-l4-bromo-prost-l3-enoic acid;
13t-S~EI-5(9a)-oxide-16(S,R)-20-methyl-lla,15S-clillyclroxy-14-bromo-prost-13-enoic acid;
13t-5-bromo-6311-6~9a)-oxide-16S-methyl-lla,15S-dihydroxy-14-bromo-prost-13-cnoic acid;
lat-S-brolllo-6~11-6(9a) -o.~cide-16R-methyl-lla,15S-dihydro.~cy-14-bromo-prost-la-.
3~
enoic acid;
13t-5-bromo-6~ 6~9c~)-oxide-20-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c~)-oxide-16~S,R)-20-dimethyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9a)-oxide-16S-methyl--llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5(9c~)-o,cide-16R-methyl-llcl,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9c~)-oxide-20-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H- 5~9c~)-oxide-16~S,R)-20-dimethyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction follo~ed by chromatographic separation.
Starting from 6c~l and 5c~l diastereoisomeric 15-~eto compounds we prepare the corresponding 15S- and 15R-alcohols. All these compounds are then saponified to yield the corresponding free acids.
Example 66 A solution of 13t-5-iodo-6~l-6~9cY)-oxide-16R-methyl-15-oxo-prost-13-enoic acid methyl ester ~0.32 g) in ethyl ether ~S ml) is added to a stirred solution of ~inc borohydride in ethyl ether ~25 ml). After 30 minutes, the excess reagent ~as destroyed by addition of a saturated solution of NaCl and N ~l2S04. After the usual wor~ up the organic phase is separated and the crude residue is chromatograplled on SiO2 ~eluent ~Cil2C12-ethyi ether) to yield O.lG g of 13t-5-ioclo-6~ 6(9ct)-oxide-16R-methyl-15S-hyclroxy-prost-13-enoic-~cid metilyl ester ancl 0.095 g of 15R-epimer. Usin~ this procedure the follo~-ing metllyl esters ~ere obtainecl:
13t-6~H-6(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~-oxide-5-chloro-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-5-bromo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R. = 3.67 s 3~1 CO2CH3; 3.95 m 4H C5, C9, Cll protons and llx/Hy proton at C4; 4.3 m lH 6~H; 6.15 d lH C14 proton; 6.63 q lH C13 proton;
13t-6~H-6~9~)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R. 0.9 s 3H C20CH3, 3.53 m lH proton at C5, 3.6 s 3H CO2CH3 3.9 m H
proton at C4, 4.1 m 211 proton at Cg, Cll; 4.4.m 1l-1 6~H; 6.2 d lH proton at C14 6.75 q lH proton at C13;
13t-6~1-l-6C9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6~9~j-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~-1-6(9~)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~ 6~9~-oxide-5-iodo-15-oxo-prost-13-er.oic acid methyl ester;
13t-63~ 6(9~)-oxide-5-chloro-11~-hydroxy-15-oxo-prost-13-enoic acid methyl estcr;
a, :~83~
13t-6~H-6~9~)-oxide-5-bTomo-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester, N.M.R.: 3.65 s 31I C02CH3; 4.00 m 3H proton at C5, Cg, Cll, 4-6 m lH 6~H;
6.2 d lH proton at C14; 6.64 q lH proton at C13;
l3t-6~H-6~9~)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
N.M.R. 3.66 s 3H C02CH3, 3.9~ m 311 protons at Cg, Cll and C5, 4.6 m lH 6~H, 6.21 d lH proton at C14 6.75 q lH proton at C13.
Exam~le 43 A solution of 2.16 g of ~2-oxo-octyl)dimethylphosphonate in 20 ml of benzene is added dropwise to a suspension of 292 mg of NaH ~75o mineral oil dispersion) in 30 ml of benzene. After 30 minutes of stirring, a solu-tion of 2.6 g of 4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.
0]nonan-3'?-yl)-butanoic acid methyl ester in 20 ml of benzcnc is added drop by drop. Stirring is continued for another 30 minutes, and 24 ml of a 300 aqueous solution of NaH2P04 is added. The organic phase is separated, and the aqueous phase is re-extracted with benzene. The organic layers are com-bined and evaporated to dryness. The residue is purified on silica gel ~50 g) with CH2Cl2:ethyl ether ~120:40) as eluent to give 0.52 g of 4-bromo-4-[7'-exo-~3''-oxo-oct-l~-trans-l~-enyl)-sl-endo-hydroxy-2~-oxa-bic~clo[3.4.o~nonan 3'-endo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~1-5~9~)-oxide-ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester and 1.45 g of 4-bromo-4-.[7'-exo-(3'1-oxo-oct-l"-trans-l"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]
nonan-3'-exo-yl]-butanoic acid methyl cster or 13-trans-4-bromo-5~i-1-5(9~)-oxide-ll~ yclroxy-15-oxo-prost-13-enoic acid methyl csteT. ~lethanolic solu-tions of these two compounds absorb in the UV at A ma~ = 230 m~, ~ = 10,640, and ~ axII = 229 m~, ~ = 11,600, respectively.
~jl 53 The same procedure, starting from the 4-H and 4-halo bicyclo deriva-tives, gives the following prostenoic acids:
13-trans-5~H-5~9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-S~H-5(9~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5 ~9C4) -oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9cY)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-5cYH-5(9a)-oxide-15-oxo-prost-13-enoic acid metllyl ester;
13-trans-5c~H-5(9c~)-oxide-llcY-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5cYH-5(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester.
13-trans-4-chloro-5c~H-5(9c~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-~romo-5H-5(9~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-_rans-4-bromo-5cYH-5(9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5cYH-5(9c~)-oxide-15-oco-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9~)-oxide-111-llydroxy-15-oYo-prost-13-enoic acid methyl ester.
Example 44 By thc procedure of e~ample 42, the reaction of 620 mg of (2-o.xo-3-metllyl-4-~utoxyblltyl) yhosphonate ~ith 74 mg of Na~-l (75O) and 0.43 g of 5-(6'-exo-~`ormyl-7'-cnclo~ yclroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid , S~C~
~1i5 3~
methyl ester in dimethoxyethane gives, after chromatography on silica gel (25 g) with 1:1 ethyl ether:hexane as eluent, 0.15 g of 13t-6uH-6(9~)-oxide ~ hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20--trinor-prost-l3-enoic acid methyl ester ~ = 238 m~, = 14,500) and 300 mg of the 6~H-isomer (- max 237 m~, e = 12,2so) Mass spectrum: m/e 410 M , m/e 392 M -H2O;
m/e 379 M -OCH3; m/e 295 M -115, m/e 115 ~O-C4~9 .
The two isomers present similar spectra with minimal differences at level of secondary fragmentation.
Using the same procedure the 5-chloro, 5-bromo and 5-iodo 13t-6 il-6C9c~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester.
Exam~le 45 __ By the procedure of example 44, from 4-~7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3' ~yl)-butanoic acid methyl ester and the 4-iodo bicyclic derivati~e the following are obtained:
lst-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-lS,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-4-iodo-5c~H-5(9c~)-oxide-llc!-llydro~cy-15-o~;o-16-met}lyl-16-buto:;y-18,19,20-trinor-prost-13-enoic acid methyl ester.
Example 46 _ 'rO ~ s~lspcllsion of 45 mg of S0O Nall in 10 ml of benzene is addcd a I ~ 3 ~ ss-.
33~
solution of 375 mg of (2-oxo-3,3-dimethyl-heptyl)-dimethylphosphonate in 10 ml of benzene, followed 30 minutes later by a solution of 0.305 g of 5-iodo-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester. After stirring for 45 minutes, the mixture is diluted with 10% aqueous NaEI2P04. The organic phase is washed until neutral, dried and concentrated to small volume. Adsorption on silica gel and elution ~Yith cyclohexane:ethyl ether ~90:10) give O.l2 g of 13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester and 0.095 g of 13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-13-enoic acid methyl ester.
Example 47 By substituting in the procedure of example 46 the formyl derivatives prepared according to example 34, the follo~Ying 16,16-dimethyl derivatives are prepared:
13t-6~H-6(9~)-oxide-lS-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6~l-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid nmethyl ester;
13t-S~H-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-S-chloro-6~H-6~9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-chloro-6~H-6(9~)-oxide-11~-hydrOXy-15-Oxo-l6~l6-dimethyl-prost-l3-enoic acid methyl ester;
13t-4-chloro-5~ll-5(9~)-oxidc-l5-oxo-l6~l6-dimcthyl-prost-l3-cnoic acid methyl estcr;
13t-~-c~lloro-5~l-l-s (9c~) -oxi~!c-~ -hydro:cy-l5-oxo-l6 ~ l6-dimetllyl-prost-l3 onoic acid mctllyl ester;
13t-5-l~romo-G~I-6(9~)-oxide-15-o.Yo-16,16-dimetllyl-prost-13 enoic acid methyl ~8~
ester;
13t-5-bromo-6~H-6(9cl) -oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5~9cY)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5~9cY)-oxide-llc~-hydroxy-15-oxo-16,16-dimethyl prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9cY)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9cY)-oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9c~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9cY)-oxide-llcY-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6c~H-6(9cY)-oxide-l5~oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6cYH-6~9a)-oxide-llcY-hydroxy-15-oxo-16~16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9cY)-oxide-15-oxo -16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9cy)-oxide-llcy-hydroxy-l5-oxo-l6~l6-dimethyl-prost-l3-enoic acid methyl ester;
13t-5-chloro-6cyH-6(9cy)-oxide-ls-oxo-l6~l6-dimetllyl-prost-l3-enoic acid methyl ester;
13t-s-chloro-6c~ -6~9cy)-oxide-llcy-~lydro~cy-ls-o~;o-l6~l6-dimetl~yl-prost-l3-enoic acicl methyl ester;
13t-4-chloro-Sc~tl-5(9N)-o.Yide-15-oxo-16,16-climetll~'l-prost-13-c?noic acid me-thyl cstcr;
13t-4-cilloro-5c~tl-5(?c~)-oxi(lc-llc~-llyclroYy-15-o.Yo-16,16-dimethyl-prost-13-enoic ~3 ~
31~
acid methyl ester;
13t-5-bromo-6~H-6~9~)-oxide-15-oxo-16,16-dimethyl-pros-t-13-enoic acid methyl ester;
13t-5-bromo-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bTomo-5~H-5~9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-bromo-5~H-5(9~-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9x)-oxide-15-oxo-16,16-dimethyl-prost-13-e~oic acid methyl ester;
13t-5-iodo-6aH-6~9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-4-iodo-5~l-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimetl-yl-prost-13-enoic acid methyl ester;
Example 48 To a suspension of 178 mg of Na~l (75O mineral oil dispersion) in 15 ml of benzene is added dropl~ise a solution of 1.55 g of [2-oxo-3(S,R)-fluoro-4-cyclohexyl-butyl~-dimethylphosphonate in 10 ml of anhydrous benzene.
After 30 minutes of stirring, a solution of 1 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-o~a-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continucd for another hour. Tile mixt~lre is neutralized with 30O aqueous Nc~l2PO~, ancl the organic phase is separate~, concentrated and adsorbcd on si.lica gel. Elution liith C~l2C12:Et20 (90:10) gives, 0.62 g of 13t-6c~ 6(9c~)-ox.i(le-llc~ ydroxy-15-oxo-16(S,R)-fluoro-17-cycloilexyl-ls~ 'O-trinor-prost-13-enoic acid methyl ester 3~
MeO~ = 238 mll, e = 12,765) and 0.31 g of the 6~11 isomer (~ = 238 m~l, ~ = 9,870).
The N.M.R. data for the former compound are the followin~ (CDC13) p.p.m.
3.64 s 3H CO2CH3, 3.8 m lH Cg proton, 4.03 q lH pro~on at Cll, 4.3 m lH 6C~H, 5.00 and 5.55 t,t 1/2 }1, l/2 H proton at C16 JHF 55 Hz, 6.54 q lH proton at Cl4 6.9 q lH proton at Cl3 JH H 3~5 Hz, JH H 7-5 H~? JH H 15.5 Hz.
Treating this compound with pyridine and acetic anhydride it is converted into the ll-~cetoxy derivative, for which N.hl.R. data are: (CHCl3) p.p.m. 2.02 s 3H OCOCH3, 3.64 s 3H C02CH3, 3.8 proton at Cg, 4.25 m lH 6dH; 4.6S, 5.22 t.t. l/2 H, l/2 H proton at Cl6; 4.97 q lH proton at Cll; 6.51 proton at Cl4, 6.90 proton at Cl 3;
For the diastereoisomeric hydroxy ketones the mass spectrum shows the follow-ing masses:
M 424 m/e and then M -H20, M -HF, M -C1130H/CH20 M -CH2=CHOH (basis ion) M 115 M -44-59 and M -~CHF-CH2-C6Hll).
In mass spectrum of exo-diastereoisomer the following masses are predominant:
M -CH30H and M -44-28; in that of endo-diastereoisomer the predominant ones are M -C}130 and M -44-l8.
From the S-bromo derivative, l3t-5-bromo-6~H-6(9~)-oxide-ll~-hydr l5-oxo-l6(sJR)-fluoro-l7-cyclohexyl-l8Jl9>2o-trinor-prost-l3-enoic acid methyl ester is prepared.
Exal~le 49 Substituting in the procedurc of example 48 a phosphonate chosen rom (2-oxo-4-cyclohexyl-butyl)-dimet}1ylphosphonate and (2-oxo-4-phenyl-butyl)-dimethylphosphonat~ thc following were prcpared:
3~
13t-6~H-6(9~)-oxide-11~-hydro~-lS-oxo-17-c~clohexyl-18,19,20-trinor-prost-13-enoic acid meth~l ester, 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid me-thyl ester and their 6~H lsomers.
Example_50 To a suspension of 178 mg of NaH (75% mineral oil dispersion) in anhydrous tetrahydrofuran at 0C is adcled dropwise with stirring a solution of 1.63 g of 2-oxo-3-~m-chlorophenoxy)-propyl-dimetnylphosphonate in 10 ml of anhydrousTHF. After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is added and stirring is continued for another hour. The mixture is acidlfied with aqueous NaH2PO4, the organic phase is separated, and tlle aque-ous phase is re-extracted with benzene. From the combined organic extract, after chromatography on silica gel with CH2C12:Et2O (95:5) as eluent, one obtains of 0.43 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16-_-chloro-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester (~ MeyH = 227 m~, = 16,800) and 0.11 g of the 6~H isomer (~ma~ = 224 m~, = 16,900).
Both the diastereoisomers show the mass peak m/e 436 according to C23H2~ClO6. This ion is involved in the following fragmentation:
M -H2O, M -OCH3/CH3OH, M -44, M -(O-C6H4Cl), M -~12O-(O-C6H4Cl) and M -(CH2)4-C02CH3, so furthermore confirming the proposed structure.
The following differences are between the two diastereoisomcrs: the e~o 6~H
isomer sho~s a pea~ at M -32 and a little intense pea~ at M -44 on the other hand the endo 6~11 isomer shows a pea~ at M -31 and an intcnse pea~ M -44.
E,Y;ImP10 51 The substitution of a phosphonate chosen from 2-o~o-3-(_-trifluoro-- ~r-389~
methylphenoxy)-propyl-dimethylphosphonate and 2-oxo-3-~p-fluorophenoxy)-propyl-dimethylphosphonate in the procedure of example 50 leads to the fol low-ing compounds, respectively:
13t-6~H-6~9cY)-oxide-llc~-hydroxy-15-oxo-16-m-trifluoromethylphenoxy-17,18, 19,20-tetranor-prost-13-enoic acid methyl ester, 13t-6~H-6(9c~)-oxide-llc~-hydro~cy-15-oxo-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, and their 6~1 isomers.
The mass spectra of all the compounds agree with the proposed structure for example showing the mass peak M -115; an interesting difference between the endo- and exo- trifluoromethyl analogous is that the mass peaks M -CH30H and ~1 -CF3-C6H4-OH are in the exo-isomer and the mass peak M -C1130 and ~l-cF3-C6H~-O
are in the endo-isomer.
Example 5~
The substitution of (2-oxo-3S-methyl-butyl)-climethylp1losphonate for the phosphonate in the procedure of example 4g gave 13t-6Q11-6~9~)-oxide-llr~-hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and its 6ciH isomer.
To a solution of 2.2 g of the 6~1 isomer in 2.6 ml of pyricline, cooled to O C, is added 1.05 ml of acetic anhydride. The solution is held at O C overnight and then added to an excess of cold 0.05~ sulfuric acicl. E~traction with ethyl ether and evaporation to dryness give 2.3 g of 13t-G~1-1-6~9c~)-oxide-'1 hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester-ll-acetate MeOII = 229 m~, ~ = 12,050) max 875 mg of bromine in glacial acetic acid is added drop~ise to a solution of the latter compo~md in 10 ml of glacial acetic acid, until a llght orange color appears. 1.52 g of anhyclrous potassium carbonate is then adcled and the resulting mixt~lre is held at 80 C for ~1 - 5 hours to complete the precipit~tion oE potassium bromide. E~cess acetic acid is removed under vacuum, water is added, and the pH is brought to pH 6.8 with alkaline hydrate.
This is then extracted with ethyl ether and the organic phase is reduced in volume. Adsorption on silica gel and elution with methylene chloride:ethyl ether (70:30) gives 2.01 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-14-bromo-15 oxo 16S-methyl-prost-13-enoic acid methyl ester-ll-acetate, m x = 249 m~, ~ = 11,450.
The 6~H isomer is similarly prepared.
Example 53 A solution of 2.06 g of (2-oxo-3S-methylheptyl~-dimethylphosphonate in 20 ml of dimethoxyethane is added dropwise to a suspensi.on of 0.265 g of NaH (80% mineral oil dispersion) in DM~ (10 ml~. After stirring for 30 mi-nutes, 1.6 g of N-bromosuccinimide is added and vigorous stirring is continued for 10 minutes. 1.35 g of 5-(6 -exo-formyl-7t-endo-hydroxy-2 -oxa-bicyclo [3.3.0]octan-3 ~-yl)-pentanoic acid methyl ester in 5 ml of dimethoxyethane is then added. The mixture is stirred for 1 hour and 20 ml of 30% Nall2P04 is added. After the usual wor~-up, crude 14-bromo-enone is obtained.
Separation on silica gel with methylene chloride:ethyl ether (85:15) gives 0.9 g of 13t-6~H-6~9~)-oxide-llN-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester and 0.92 g of the 6~1~ isomer. Upon treatment with n. 4 ml of pyridine and 0.2 ml of acetic anhydride, 0.2 g of the 6~H isomer gives 0.205 g of the ll-acetoxy derivative, identical in all respects with that made by the procedure of example 52.
Example 54 ~ solution of 0.43 g of ~2-oxo-octyl)-dimet]lylp]losp11onate in 10 ml of benzclle is added drop~lse to a suspension of 54 mg of Na~-l (80Uu mineral oil dispersion) in S ml o~ benzelle. ~ftcr 1 hour, l~hen the evolution of ll2 has cc~scl, 0.32 g of n-bromosuccinimide is addcd all at oncc. To the carbanion thus prcpared, of (l-bromo-2-o~o-octyl)-1imetllylpllosp1Onate is added a solution ~33~
of Z70 mg of 5-c6~-exo-formyl-7~-endo-hydroxy-2~-oxa-bicyclo[3.3~o]octan-37 yl)-pentanoic acid methyl ester in 8 ml of benzene. After 30 minutes, the reaction is quenched by the addition of 20 ml of a 10% solu~ion of N ~12P04.
The organic phase, after being washed until neutral, gives 0.31 g of 13t-6~H-6t9u)-oxide-lla-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester; this is then separated into the 6~H and 6BH isomers.
Example 55 Upon substitution of the ~2-oxo-octyl)-dimethylphosphonate in the procedure of example 54 with (2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and ~2-oxo-4-phenyl-butyl)-dimethylphosphonate> the following compounds were prepared:
13t-6~H-6(9a)-oxide-lla-hydToxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-lla-hydroxy-14-bromo-15-oxo-17-phenyl-18,1g,20-trinor-prost-13-enoic acid methyl ester.
Example 56 By substituting the formyl derivatives in examples 53, 54 and 55 with 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester, 4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy_2~_ oxa-Dicyclo[3.4.0]nonan-3'~-yl)-bUtanic acid methyl ester, and the correspond-ing 4-H derivative, the ~ollowing compounds were prepared:
13t-5-iodo-6~H-6(9a)-oxide-lla-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3 enoic acid methyl ester;
13t-4-ido-5~H-5(9a)-oxide-lla-hydroxY-l4-bromo-l5-oxo-l6s-oethyl-prost-l3 enoic acid methyl ester;
13t-5~1 5C9~1_oxide-lla-hydroxy~14-bromo-15-oxo-16S-methyl-prost-13-enoic acid methyl ester;
3~
13t-5-iodo-6~H-6(9)-oxide-11~-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-4-iodo-S~H-5(9~)-oxide-lla-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide~ -hydro~-14-bromo-15-oxo-20-methyl-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6~9c!.)-oxide-11-hydro.Yy-:14-bromo-15-oxo-17-cyclohexyl-i~,l9, 20-trinor-~rost-13-enoic acid methyl es~ter;
13t-S~H-5~9~)-oxide-lla-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5-iodo-6~H-6(9a)-oxide-lla-hydroxy-14-bro -15-oxo-17-phenyl-18,19,20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5~9)-oxide~ -hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-triJIor-prost-13 enoic acid methyl ester.
Example 57 A solution of 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide in 6 ml of DMS0 is added to a solution of 0.15 g of potassium t-butylate in 3 ml of DM50 while keeping the reaction temperature at 16 - 19C. 0.27 g of S-; ~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 8 ml of anhydrous tetrahydrofuran is then added. After 30 minutes of stirring, an equal volume of water is ~dded and the mixture is extracted with ethyl ether. The combined organic extract is washed until neutral and the solvent is evaporated. Chromatography on silica gel (cyclo-hexane:ethyl ether, 40:60) gives 0.21 g of 13t-6~ 6(9)-oxide-11~-hydroxy-15-oxo-20-methyl-prost-13-enoic acid methyl ester.
~ ~ 3~
~ai5 3~
Subsequent preparative thin layer chromatography ~SiO2-Et20) allows separation of the 6cYII and 6~H isomers.
Example 58 A solution of d,l-13t-6cYH-6(9cY)-oxide-llcY-hydroxy-15-oxo-13-enoic acid methyl ester (exo-isomer at greatest Rf), (0.9 g), in dry ethyl ether (30 ml) is dripped on to a stirred 0.1 M solution of Zn(BH4)2 in dry ethyl ether (30 ml), over 15 minutes. AFter 2 hours, the excess reagent is decomposed by cautious addition of saturated NaCl solution and aqueous 2N sulfuric acid.
The organic layer is separated, washed to neutral and evaporated to dryness affording a residue which is adsorbed on silica gel, eluted with ethyl ether to yield 0.3~ g of 13t-6CYH-6(9CY)-oxide-llc~l5R-dihydroxy-prostenoic acid methyl ester, as an oil, and 0.42 g of d,l-13t-6cYH-6(9cY)-oxide-llcY,15S-di-hydroxy-prostenoic acid methyl ester, m.p. 69 - 71C (mass spectrum m/e 350 M -18, 319 ~I -18 -CH30; 318 M -18-CH30H). A solution in methanol (4 ml) of this ester is treated with 60 mg of lithium hydroxide and water (O.S ml) for 8 hours at room temperature. The methanol is removed in vacuum, the residue is diluted with water and extracted with ethyl ether to remove neutral impurities. The alkaline phase is treated with aqueous saturated NaH2P04 solution until to pH 5 and then extracted with ethyl ether. The later organic phases are collected to yield after evaporation of the solvents the free acid d~ 3t-6cyH-6(9cy)-oxide-llcy~l5s-dihydroxy-prostenoic acid, m.p.
105 - 106C. The 15R-hydroxy compound is a non-crystallizable oil.
In the same way using nat-keto compound in the reduction reaction with Zn(B~ )2 we obtained besidcs the 15-epi alcohol, the nat-13t-6cYH-6(9~)-oxide-llcY,15S-dihydroxy-prostenoic acid methyl ester, m.p. 71 - 72 C [cY]D =
~ 10.2 ~ [~]365 a ~ 32.2 (CIIC13) ancl aftcr saponification the free acid m.p. 101 - 102C [CY]D a ~ 6.3'1 , [~]~65 = ~~ 33-2 (CIICl_).
''' `1 1 ~83~
Starting from the endo-diastereoisomers (more polar compounds), the following esters were obtained:
13t-6~H-6~9~)-oxide-ll~,lSR-dihydroxy-prostenoic acid methyl ester (d~l, nat-3 ent- oils);
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-prostenoic acid methyl ester ~d, 1, nat-, [~]D = + 24-5 . [~]365 = + 52-9 (CHC13) oil; ent- [~]D = -22 , oil), and after saponification the following free acids:
13t-6~H-6~9~)-oxide-11~,15R-dihydroxy-pros~enoic acid (d,l, nat-, ent- oils);
13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-prostenoic acid ~d,l oil, nat-, Dl.p.
78 - 80 C [u]D = I 32-5 ~ [~]365 = + 11-6 (EtOI-I), ent- m-p- 78 - 79 C, [~]D = ~ 31 (EtOH)).
Example 59 .
With the temperature of the reaction mixture kept at around -5 to -8 C, a solution of 159 mg of NaBH4 in 7 ml of propan-Z-ol, is gradually added to a solution of 0.332 g of anhydrous CaC12 in propan-2-ol (7 ml); then, under stirring, a solution of 0.38 g of 13t-6~H-6(9Q)-oxide-ll~ ydroxy-15-oxo-16(S~R)-fluoro-17-cyclohexyl-18,19,20--trinor-prost-13-enoic acid methyl ester in 3 ml of propan-2-ol is added to the above prepared Ca(BHI)2 in a period of 40 minutes. The reaction mixture is ~ept under stirring at a temperature ranging at -~ 5C, then the excess reagent is destroyed by addition of 5 ml of acetone and 2 ml of water. The solvent is evaporated under vacuum and the residue is partitioned among water, O.lN H2S04 and ethyl acetate. The organic extracts are collected, washed until ncu-tral and after evaporation of solvent the rcsidue chromatographed on silica gel (30 g~ using CH2C12-ethyl otller 70:30 as eluont. The eluate yields 0.21 g of l~t-6~H-6(9(~)-oxide-11~,15R-dihydroxy-16(S~)-fluoro-l7-cyclo]lexyl-ls~l9~2o-trinor-prost-l3-enoic acid methyl ester, and 0.1~ g of the 15S-epimer, m.p. 83C - 84 C (frorn ethyl etller) .
:~33315 ~
In the same way, reduction of the 6~H-isomer (220 mg) yields 0.1 g of 13t-6~ 6(9~)-oxide-11~,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19, 20-trinor-prost-13-enoic acid methyl ester, m.p. 63 - 64 C (from isopropylic ether), and 60 mg of 15S-alcohol.
Example 60 -A solution of 0.15 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-keto-16-methyl^l6-butoxy-18,19,20-trinor-prostenoic acid methyl ester in methanol (5 ml) is cooled at -5 . - 10C and reduced by addition of a solution of NaBH4 ~30 mg) in water (0.5 ml).
The reaction mixture is neutralized by addition of 15% aqueous NaH2P04 solution after 15 minutes and then evaporated in vacuum. The aqueous residue is extracted with ethyl ether to yield a crude mixture of epimeric 15R,15S-alcohols. Chromatographic separation on silica gel ~Crl2C12-ethyl ether 70:30 as eluent) affords respectively 13t-6~H-6(9~)-o~ide-11~,15R-di-hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester (~5 mg) and 15S-hydroxy-epimer (62 mg).
Example 61 By reduction of 13t-5~H-5~9u)-oxide-11~ ydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester, under the same trial conditions as in the procedure of example 60 follo-~ed by chromatographic separation of the epimeric alcohols ~300 mg) on silica gel (12 g) with methylene chloride-ethyl ether 75:25 eluent, we respectively obtained 100 mg of 13t-5~H-5(9~)-oxide-ll~-l5R-dihydroxy-l6-metllyl-l6-buto~y-ls~l9~2o-trinor prostenoic acid methyl ester, and 110 mg of 15S-epimer. Tllese are then saponifled to yield the corresponding ~ree acids.
Example 6~
~ro~ ise, to a stirred 0.12 ~I solution of zincborohydride in ethyl ether (8 ml) a solution of 0.135 g of 13t-5-bromo-6~ll-6~9~)-oxide-11~-hydro~y-~,~i 6~
~13~
15-oxo-prostenoic acid methyl ester in 2 ml of anhydrous Et2O is added. The mixture is stirred for 2 hours and the excess reagent is decomposed with water--2N H2SO4. The organic phase is separated, washed to neutral and evaporated to dryness. After TLC on silica gel with ethyl ether-ethyl acetate 90:10, 38 mg of 13t-5-bromo-6c~ll-6~9c~)-oxide-llc~,15R-dihydroxy-prostenoic acid methyl ester and 46 mg of 15S-epimer were ob~ained.
Exam~le 63 Starting from 13t-5,14-dibromo-6~H-6(9cY)-oxide-llc~-hydroxy-15-oxo-prostenoic acid methyl ester (0.2 g) and using a mixture of CH2C12-ethyl ether 60:40J during the chromatographic separation on silica gel, we obtained 0.056 g of 13t-5,14-dibromo-6~H-6~9a)-oxide-llcY,15R-dihydroxy-prostenoic acid methyl ester and 0.098 g of 15S-isomer.
A solution of this product in methanol is then hydrolized ~ith aqueous LiOH to yield 72 mg of 13t-5,14-dibromo-6c~11-6(9c~)-oxide-11~,15S-dihydroxy-prostenoic acid.
Example 64 -Using, in the procedure of example 60, isopropanol as solvent and NaBH4 (45 mg), the reduction of 13t-6~H-6(9cY)-oxide-llc~-hydroxy-15-oxo-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester (0.47 g~ yields 0.20 g of 13t-6~H-6(9c~)-oxide-llce,15S-dihydroxy-16-~m-tri-fluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester, [C~]D = ~ 33.3 (~eOII) and 0.18 g of 15R-epimer. The 6c~H-15S-alcohol epimer is an oil witll [c~]D ~ -I 12 (MeOII).
Example_65 A solution in dry ethyl ether ~20 ml) of 13t-16S-methyl-6c~ll-6~9c~)-oxide-Llc~-hydro.~y-15-o.yo-prost-13-enoic acicl methyl ester (0.002 ~I, 0.72 g) is added to a stirred etheral solution of ~inc borohydride t0.01 M, 100 ml).
Tllo e~coss reagon~ is destroyed, after 30 - 45 minutes, by addition of 2N-3~
sulphuric acid in NaCl saturated aqueous solution. The organic phase is washed until neutral and evaporated to dryness. The residue is chromatog-raphed on silica gel (25 g) using methylene-chloride:ethyl ether (80:20) as eluent affording (7.5.10 ~ M, 0.27 g) of the 15R-hydroxy-isomer and (1.1.10 4 M; 0.38 g) of the 15S-alcollol: 13t-16S-methyl-6~-6(9c~)-oxide-11~, 15S-dihydroxy-prost-13-enoic acid methyl ester. Using this procedure, the following methyl esters were obtained:
13t-6~H-6(9a)-oxide-l6s-methy~ l5s-dihydroxy-prost-l3-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-6c~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
57 - 59 C [cl]D = +14 ~ [a]365o = +47 (CHC13);
13t-6~H-6(9~)-oxide-20S-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
38 - 39C, [~]D = -~21-7, [~]365 = +77 (CHC13);
13t-5-bromo-6~H-6(9~)-oxide-16S-methyl-lla,15S-di}lydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-16R-methyl-11~,15S-di}lydroxy-prost-13-enoic acid;
13t-5-bron~o-6~1I-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-llc~,15S-dihydroxy-20-methyl-prost-13-enoic acid, ~'~]D = + 38 ;
13t-5-iodo-6~H-6(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9c~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~I-6(9a)-oxide-16R-methyl~ ,15S-dihydroxy-prost-13-enoic acid;
13t-5~iodo-6~H-6(9c~)-oxide-16,16-dimet}lyl-llc~,15S-dihyclroxy-prost-13-enoic acid;
13t-5-iocIo-6~I-6(9~)-oxi(Ie-llc~,15S-~ ydro~y-20-methyl-prost-13-enoic acid, [a]D = ~ 23 ~ [~365 = ~ 78 (CIICl~);
13t-5-cllloro--6~II-6~9~)-oxide-lGS-mc?t}lyl-11~,15S-diIlydro~y-prost-l3-enoic acid;
~3384~L
13t-5~EI-5(9~)-oxide-16S-methyl-lla,15s-dihydroxy-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
lat-4-bromo-5~H-5(9a~-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~H-5(9ci)-oxide-16R-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~H-5~9c~)-oxide-16,16-dimethyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-iodo-5~H-5(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-enoic acid;
13t-4-chloro-5~H-5(9c~)-oxide-16S-methyl-llc~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-16S-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-16R-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-20-methyl-lla,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9cv)-oxide-15(S,R)-20-dimethyl-lla,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-16S-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-S(9c~)-oxide-16R-methyl-lla,15S-dillYdroxy-14-bromo-prost-13-enoic acid;
13t-5~EI-5~9a)-oxide-20-methyl-11~,15S-diElYdrOXy-l4-bromo-prost-l3-enoic acid;
13t-S~EI-5(9a)-oxide-16(S,R)-20-methyl-lla,15S-clillyclroxy-14-bromo-prost-13-enoic acid;
13t-5-bromo-6311-6~9a)-oxide-16S-methyl-lla,15S-dihydroxy-14-bromo-prost-13-cnoic acid;
lat-S-brolllo-6~11-6(9a) -o.~cide-16R-methyl-lla,15S-dihydro.~cy-14-bromo-prost-la-.
3~
enoic acid;
13t-5-bromo-6~ 6~9c~)-oxide-20-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c~)-oxide-16~S,R)-20-dimethyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9a)-oxide-16S-methyl--llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5(9c~)-o,cide-16R-methyl-llcl,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H-5~9c~)-oxide-20-methyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-4-bromo-5~H- 5~9c~)-oxide-16~S,R)-20-dimethyl-llc~,15S-dihydroxy-14-bromo-prost-13-enoic acid;
together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction follo~ed by chromatographic separation.
Starting from 6c~l and 5c~l diastereoisomeric 15-~eto compounds we prepare the corresponding 15S- and 15R-alcohols. All these compounds are then saponified to yield the corresponding free acids.
Example 66 A solution of 13t-5-iodo-6~l-6~9cY)-oxide-16R-methyl-15-oxo-prost-13-enoic acid methyl ester ~0.32 g) in ethyl ether ~S ml) is added to a stirred solution of ~inc borohydride in ethyl ether ~25 ml). After 30 minutes, the excess reagent ~as destroyed by addition of a saturated solution of NaCl and N ~l2S04. After the usual wor~ up the organic phase is separated and the crude residue is chromatograplled on SiO2 ~eluent ~Cil2C12-ethyi ether) to yield O.lG g of 13t-5-ioclo-6~ 6(9ct)-oxide-16R-methyl-15S-hyclroxy-prost-13-enoic-~cid metilyl ester ancl 0.095 g of 15R-epimer. Usin~ this procedure the follo~-ing metllyl esters ~ere obtainecl:
7/
~33~
13t-6~ 6(9c~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-6~H-6(9c~)-oxide-15S-hydroxy-16316-dimethyl-prost-13-enoic acid;
13t-5~H-5(9~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5~H-5(9c~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5~H-5(9cl)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cl)-oxide-15S-hydroxy-16S-methyl-prost-13-encic acid;
13t-5-bromo-6~H-6(9c~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9c~)-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c~)-oxide-15S-hydroxy-16S,20-dimethyl-prost-13-enoic acid, together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction follo~ed by chromatographic separation.
Starting from 6c~H and 5c~H diastereoisomeric 15-keto compouncls we prepare the corresponding 15S- and 15R-alcohols.
Example 67 The following 15S-hydroxy-9c~-oxide prostanoic acids methyl esters together with their 15R-epimeric alcohols are obtained after reduction of the corresponding 15-keto compounds using one of the procedures described in examples 58 to 66;
13t-6~H-6(9c~)-oxide-llc,15S-dihydroxy-13-prostanoic acid;
13t-14-bromo-6~H-6(9c~)-oxide-llc~,15S-diilydroxy-13-prostenoic acid;
13t-14-chloro-6~1l-6(9ct)-oxide-11~,15S-dihydroxy-13-prostenoic acid;
13t-5~l4-dibromo-6~3ll-6~9cl)-oxlde-llc~l5s-dihydroxy-l3-prostcnoic acid;
13t-6~l-6t9~)-o~ide-llc~,15S-dihydroxy-20-1netllyl-13-prostelloic acid;
13~-14-~romo-6~ 6t9~)-oxide-llc~,15S-~ yclro.~y-20-met}lyl-13-prostenoic acid;
13t-5,14-dibromo-6~H-6t9c~)-oxide-llc~,15S-(li}lydro.~;y-20-methyl-13-prostenoic .lcicl;
~' ~IL83134~L
13t-5-iodo-6~H-6(9a)-oxide-llaJl5s-dihydroxy~2o-methyl-l3-prostenoic acid;
13t-5-iodo-l4-hronlo-6~l-6(9a)-oxide-ll ,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a~-oxide-lla,15S-dihydroxy-16(S~R)-fluoro-17-cyclo-hexyl-18,19,20-trinor-prost-13-enoic acid, 13t-5-bromo-6~H-6(9a~-oxide-11~,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18jl9,20-trinor-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19s20-trinor-prost-13-enoic acid;
13t-14-bromo-6BH-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-l8 19,20-trinor-prost-13-enoic acid;
13t-6BH-6(9a)-oxide-lla~l5s-dihydroxy-l7-cyclopentyl-l8~l9~2o-trinor-prost 13-enoic acid;
13t-6~H-6~9a)-oxide-lla~l5s-dihydroxy-l7-cyclohexyl-l8~l9~2o-trinor-prost 13-enoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxY-l7-cyclohexyl-l8~l9~2o-trinor prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a) -oxide-lla,lSS-dihydroxy-l7-cyclohexyl-l8~l9~2 trinor-p~st-13-enoic acid;
13t-5-bromo-68H-6(9a)-oxide-llagl5S dihydroxy-17-cyclohexyl-18,19,20-tri.nor-prost-13-enoic acid;
13t-5-chloro-6~H-6~9a)-oxide-lla,15S-dihydToxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-11,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-lla,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl~16-amyloxy-18,19,20-lQ trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-17-cycloheptyl-18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6c9a)-oxide lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-6@H-6(9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla~l5s-dihydroxy-l6-cyclohexyloxy-l7~l8~l9J2o-tetranor 13-prostenoic acid, 13t-6~H-6(9a)-oxide-lla~l5s-dihydroxy-l6-(m-chlolo)-phenoxy-l7~l8~l9~2 tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla~l5s-dih~droxy-l6-(m-trifluoromethyl)-phenoxy-l7~l8 19,20-tetranor-13-prostenoic acid;
13t-l4-bromo-6BH-6(9a)-oxide-ll~l5s-dihydroxy-l6-(p-fluoro)-phenoxy-l7~l8 19,20-tetranor-13-prostenoic acicl;
13t~l4~b~omo~6~l~-6~9~)-oxide-lla~l5s-dihydroxy-l6-phenoxy~l7Jl8~l9~2o-tetranor 13-prostenoic acid;
13t-14-bromo-6~1-6(9a)-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18, .. 19,20-te~ranor-13-prostenoic acid;
~:18384~ lL
13t-14-bromo-6~H-6(9a).oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranoT 13-prostenoic acid;
13t-5-iodo-6~H-6(9~-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-11,15S-dihyclroxy-16-phenoxy~17,18,19,20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6~9)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoic acid;
13t~5-iodo-6~H-6~9a~-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-5~H-5(9)-oxide-11,15S-dihydroxy-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-14-chloro-5~H-5(9a)-oxide-lla,lSS-dihydroxy-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-5~H-5(9~)-oxide-lla,15S~dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-5eH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-11,15S-dihydroxy-20-methyl-13-prostenoic acid;13t-4-iodo-5~H-5(9~)-oxide-lla,lSS-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-l4-bromo-s~H-5(9)-oxide-lla~l5s-dihydroxy-2o-methyl-l3-prostenoic acid;
13t-14-bro -5~H-5(9aj-oxide-lla,lSS-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibro ~5~H~5(9)-oxide-11,15S-dihydroxy-16(S,R)-fluoro-17-cyclo-hexyl~l8J19,20~t~inor~prost-13 enoic acid;
13t-4-bromo-5~H-5~9)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-3~9~
18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-ll,lSS-dihydroxy-16(S,R)-fluoro-17~phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-5~H-5(9a~-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-56H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-1~,19,20-trinor-prost-13-enoic acid;
lQ 13t-14-bro~.o-5~H-5(9a)-oxide-11,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,1S,19,20 tetranor_ 13-prostenoic acid;
13t-4-iodo-5@H-5(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(m-chloro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid.
In similar way, we prepare the diastercoisomeric aH-9a-oxide-15S-and aH-~a-oxide-15R-alcohols when we use all-9a-oxide-15-~eto diastereoisomer starting material~
All these esters arc then saponified to obt~in the free acids.
313~L~
Example 6S
0.46 g of 13t-5~ -5(9~)-oxide-16S-methyl-llcl-hydroxy-15-oxo-prost-13-enoic acid methyl ester are treated IYith pyridine ~2 ml) and acetic an-hydride (1 ml). After 6 hours at room temperature the mixture is diluted with brine, acidified to pH 4.5 - 4.8 and extracted with ethyl ether. The combined organic phases are then evaporated to dryness yielding 0.48 g of ll-acetoxy-derivative (~ ~laH = 229 m~, ~ = 11.058). A solution of this compound in ethyl ether is then added dropwise to a solution of Zn(BH4)2 in ethyl ether.
After 30 minutes the excess reagent is decomposed with a N solution of ~2SO4 and after the usual work -up, 0.47 g of 13t-5~l-5(9c~)-oxide-16S-methyl-llcl, 15(S,R)-dihydroxy-13-prostenoic acid methyl ester ll-acetate are obtained.
A solution of this mixture in CH2C12 (5 ml) cooled to about -5C, -10C, is treated ~ith a solution of BF3 etherate (1.2 x 10 4 ~I) in Cll2C12 and then ~Yith a 5% solution of diazomethane in C112C12 until a persistent yellow coloration.
The reaction mixture ls evaporated to half volume undcr vacuum, washed ~Yith a 5% aqueous NaHCO3 solution and water to neutral, and evaporated to dryness to yield 0.47 g of 13t-5~l-5(9u)-oxide-16S-methyl-llc~-hydroxy-15(S,R)-methoxy-prost-13-enoic acid-ll-acetate which is separated in the individual isomers by chromatography on SiO2 using benzene-ethyl ether (S5:15) as eluent. On Ihe other hand, 0.21 g of the mixture of 15(S,R)-methoxy-clerivatives is dissolved in dry methanol (4 ml) and selectively deacetilated by trcatment ~Yith 20 mg of K2CO3 ~or 4 hours at room temperature. After neutralization by dilution ith a~ueous Nal~l2PO4, the methanol evaporated under vacuum and the residue is extracted with ethyl ether ~2 x 5) ethyl acetate (2 x 6 ml). The combincd organic phases are evaporated to dryness to yield lS0 mg of the crude 13t-5~ $~9~)-oxido-16S-metllyl~ ydroxy-15~S,R)-methoxy-prostenoic acid methyl estor, wllicll is then readily soparated by means of a silica gel column chroma-togrnphy using C~l2C12-ethyl et}-er S0:20 as eluent to yield the t~o pure ~L3 ~ ~
~8389~
isomers: 15S-methoxy and 15R-methoxy. Using the same procedure the following methyl esters were obtained:
13t-6~1-6(9cx)-oxide-16S-methyl-llcx-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9cx)-oxide-16R-methyl~ -hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9cx)-oxide-20-methyl-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide-20-methyl-llcY-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide-llcx-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide~16S-methyl-llcx-hydroxy-15S-methoxy-prost-13-enoic acid 9 and their epimeric 15R-methoxy compounds are obtained starting from the cor-responding ll-acetoxy-15-keto compounds.
Using in this procedure the ~H-diastereoisomer instead of the ~H, the corresponding cxH-15-methoxy compounds are also obtained.
The same procedure can be also utilized for any 15-keto compound, previously described and analogously an other diazo al~ane can be used inside of diazomethane.
Example 69 To a solution of 0.26 g of 13t-6~H-6(9cx)-oxide-15~S,R)-hydroxy-16S-methyl-prost-13-enoic acid rnethyl ester in methylene chloride, treated with 0.3 ml of a solution of BF3 etherate in methylene chloride, cooled at -10 . -8 C, a solution of diazoethane in methylene chloride is added until a persistent yello~ coloration is formed. The solvent is evaporated under vacuum and the residue chrolllatogr;lplled on silica gel using ethyl ether-methylene chloricle 10:90 as elucnt to yield 0.115 g of 13t-6~H-6~9~)-oxide-15S-ethoxy-16S-Inethyl-prostenoic acicl metllylcster, and 0.1 g of 15R-ethoxy isomer .
~ ell a nlixt-lre of 15S,15R-alcollols, for example 13-t-6~H-6~9cx)-oxide-3i3~L
llc~,15(S,R)-dihydroxy-16S-methyl-prostenoic acid, containing a free 11-hydroxy group is submitted to the procedure of the examples 68 and 69, the simultaneous alkoxylation of the ll-alcoholic function also occurs yielding ~ith diazomethane for example after chromatographic separation the 13t-6~H-6~9cY)-oxide llc~,15S-dimethoxy-16S-methyl-prostenoic acid methyl ester beside the 15R-epimeric derivative.
In a similar way the following 15S-alkoxy prostenoic derivatives were obtained:
13t-5~H-5~9c~)~oxide-lla,15S-dimethoxy-prostenoic acid;
13t-6~H-6~9c~)-oxide-llc~,15S-dimethoxy-prostenoic acid;
13t-6~H-6~9c~)-oxide-5-bromo-llc~,15S-dimethoxy-prostenoic acid;
13t-6~H-6~gcl)-oxide-5-iodo-llc~,15S-dimethoxy-prostenoic acid;
13t-5~H-5~9c~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16R-methyl-prostenoic acid;
13t-6~H-6~9c~)-oxide-15S-methoxy-16-methyl-16-butox~ ,19,20-trinor-prostanoic acid, and their 15R epimers are obtained and when they are saponified with LiOH in methanol the free acids are prepared. The same proceclure can be used to ob-tain diastereoisomeric c~-9c~-oxide derivatives.
Example 70 To a stirred solution of 1.33 g of 13-t-6CYII-6 (9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 6 ml of toluene and 54 ml of benzene, cooled at +4 C, a solution of 1.67 g of methylmagnesium iodicle in ethyl ether is a~cled. ~fter 20 minutes, the excoss reagent is decomposed with an icod 20o solution of ammonium chlori(lo in water. After dilution with one vol-mle of ethyl etho:r the organic phase is washecl with l~ater, sodium bi-carbona~e and water, dried over magnosium sulphate, treated with 0.1 ml of . I
~L~83~
pyridine and evaporated to dryness to yield 1.2 g of 13t-6~H-6(9~)-oxide~
15~S,R)-dihydroxy-15-methyl-prostenoic acid-methylcster-ll-acetate, of which 0.2 g are separated into the pure component by thin layer chromatography on silica gel, with benzene-ether 60:40 eluent. 1 g of the mixture of the two alcohols is dissolved in anhydrous methanol (20 ml) and stirred for 4 hours with 0.25 g of K2C03. The mixture is evaporated to dryness, the residue is partitioned between ethyl ether and aqueous 15% NaH2P04. The organic ph~se is evaporated in vacuum and the residue is absorbed on silica gel (200 g).
Elution with ethyl ether-isopropylic ether 80:20 affords 0.20 g of 13t-6~H-one 6(9~)-oxide-11~,15R-dihydroxy-15-methyl-prost-13-enoic acid methyl ester, and 0.36 g of 15S-epimer. 0.16 g of this compound are dissolved in 12 ml of methanol and treated with 0.8 ml of water and 0.2 g of K2CO3. After 5 hours at room temperature the methanol is evaporated under vacuum, the rcsidue is treated with 20% NaH2P04 and ethyl acetate. The organic phase yiei~s 0.14 g of 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prost-13-enoic acid. The corresponding 6~H-isomers are prepared in the same way.
Example 71 To 1.79 g of 13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 20 ml of anhydrous tetrahydrofurane, 50 ml of 0.3 M ethynylmagnesium bromide in anhydrous tetrahydrofurane is added.
Keep shaking for one hour, eliminate the excess rcagent by treating with a saturated NH4Cl solution, concentrate the organic phase under vacuum, and take up with ethyl ether to yicld 1.62 g of 13t-5~l-5(9~)-oxide-11~,15(S,R)-dihydroxy-15-et}lynyl-prost-13-enoic acid methyl estcr-ll-acctatc, which is dissolvod in anhydrous metllanol and treated l~ith 250 mg of ~nhydrous potassium carbonato for 3 llours under shaking. Evaporatcd ull(lcr vacuum and dilute with 20o a~ueo~s Nall2PO~ and ethyl cther. AEter cvaporating the solvent, the org~nlc phase yields 1.~1 g of 13t-5~l-5~9~)-oxide-11~,15(S,R)-dihydroxy-15-~83~
ethynyl-prostanoic acid methyl ester, which is separated into the two pure 15S-hydrox~ and 15R-hydroxy epimer by silica gel chromatography with benzene-ethyl ether 1:1 as eluent, and after saponification of the 15S-hydroxy epimer with K2C03 in methanol, there is yield of the 13t-5c~1-5(9c~)-oxide-llc~,15S-dihydroxy-15-ethynyl-prostenoic acid.
Example 72 To a solution in tetrahydrofuran anhydrous (25 ml) of 1.41 g or 13t-5-bromo-6~H-6(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester, a 0.5 ~1 solution of magnesium vinyl bromide in tetrahydrofurane (25 ml) is adcled at 0 - 5 C and let stand for 4 hours at room temperature. Decompose the excess reagent with a saturated solution of ammonium chloride, distil the tetrahydro-furane under vacuum and take up with ethyl ether. The organic phase is ad-sorbed on silica gel and eluted with methylene chloride-etllyl ether to yield 0.41 g of 13t-5-bromo-6~H-6(9~)-oxide-15R-hydroxy-15-vinyl-prostenoic acid methyl ester, and 0.62 g of 15S-isomer, which after saponification with LiOH
in methanol yields 0.49 g of pure 13t-5-bromo-6~1~-6(9c~)-oxide-15S-hydroxy-15-vinyl-prostenoic acid.
Example 73 A solution of 0.98 g of 13t-5-bromo-6~1l-6(9c~)-oxide-llc~-hydroxy-15-oxo-20-methyl-prostenoic acid methyl ester-ll-acetate in aO ml of benzene-toluene (85:15) is cooled at 3 - 4 C and to this a solution of 0.92 g of phenylmagnesium bromide in ethyl ether-benzene 1:1 is added. Let stand for 5 hours at room temperature, then decompose the e~cess rea~ent with an iced solution of 15% ~114Cl, wasll the organic pllase repeatedly Wit]l water to neutral thcn evayorate. The crude 15-phenyl-15~S,R)-llydroxy clelivative is dissolved ln n~ y(lrous metllanol to l~hiCIl 0. 25 g. of ~2C03 is adde(l, ~ept shaking for 2 hours. ~vaporatc to dryness, dilute witll aqueous 20% Na~l2P04 and ethyl ether, ancl from the org~nic phase after evaporation of the solvent, there is ~3~
a yield of 0.81 g of 13t-5-bromo-6~H-6(9c~)-oxide-llcY,15(S,R)-dihydroxy-15-phenyl-20-methyl-prostenoic acid methyl ester, which after separation on silica gel with ethyl ether elution yields the individual 15S and 15R isomers.
Exam~le 74 By reaction of the corresponding 15-oxo-derivative with a reagent selected from the group of an halogenide of methyl magnesium, vinyl magnesium, ethynyl magnesium and phenyl magnesium, ~orking to one of the procedures given in example 70 to 73, the folloliing methylesters were prepared:
13t-6~H-6(9c~)-oxide-15S-hydroxy-15-methyl-prostenoic acid;
13t-6~H-6~9a)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9cY)-oxide-15S-hyciroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llcY,15S-dihydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llc-~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9cY)-oxide-llcY,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-llcY,15S-dihydroxy-15-eth~yl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llcY,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-llcY~15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-5-bromo-6~H-6~9cY)-oxide-llcY,15S-dillydroxy-15-methyl-prostenoic acid;
13t-5-bromo-6~H-6~9c~)-oxide-llcY,15S-dihydroxy-15-vinyl-pros-tenoic acid;
13t-5-bromo-6~H-6(9cY)-oxide-11~,15S-dillydroxy-15-ethynyl-prostenoic acid;
13t-5-bromo-63ll-6~9c~)-oxide-llcY,15S-dillydroxy-15-ethyl-prostenoic acid;
13t-5-bromo-6~il-6(9c~)-oxicle-llc~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-4-bromo-5~ll-5(9cY)-oxide-llc~,15S-dillyclroxy-15-metllyl-prostenoic acid;
13t-4-bromo-5~i-l-5(9c~)-oxide-llcY,15S-dillydroxy-15,20-climetllyl-prostenoic acii;
13t-4-~romo-5~il-5~9~)-ocicie-].lc~,15S-ciillyciroxy-15-ethynyl-prostenoic acid;
13t-5~H-5(9cY)-oxide-llc~,15S-dillyciroxy-15-metllyl-prostenoic acid;
13t-5~i-l-5(9c~)-oxide-llcY,15S-dihydroxy-15,20-dimet}lyl-prostenoic acid;
æ
831~4~
13t-5~H-5(9~)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-5~1-5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid, and their 15R-hydroxy epimers.
Analogously starting from the ~H-~9~)-oxide-15-keto-compounds we obtained the corresponding ~H-~9~)-oxide-15-substituted alcohols.
Exam~le 75 To a solution of 0.5 g of 13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid-methyl ester-ll-acetate in 2 ml of di-methylformamide, dimethyl-t-butyl silane chloride ~0.21 g) and triethylamine (0.16 g) are added. Keep shaking for 2 hours, then dilute ~ith 4 volumes of water and extract with ethyl ether. The organic phase, after the usual washings, evaporation of the solvent, and filtration through silica gel with cyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of 13t-6~H-6~9~)-oxide 11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid methyl ester-ll-acetate-15-dimethyl-t.butylsilylether, from which, by transesterification in anhydrous methanol and 0.5 molar equivalents of K2CO3, the corrcsponding ll-hydroxy-derivative is yielded.
Example 76 To 0.52 g of 13t-5,14-dibromo-6~1-6~9~)-oxide-11~,15S-dihydroxy-prostenoic acid methyl ester in 10 ml of dichloromethane, 2,3-dillydro-pyrane (0.27 g) and p-toluensulphonic acid (4 m~) are added. Keep at room tempera-ture for 3 hours, then wasll ~ith a 5O sol~ltion of ~I-IC03 and water to ne~ltral, and evaporate to dryncss. Filter througll silica gel with c~clohexane-ethyl ethcr 90:10 as eluent, ~hicll yie'ds 0.59 g of 13t-5,1~1-dibromo-6~l-l-6~9~)-oYide-11~,15S-di}lydro.Yy-prostenolc acid methyl ester-11,15-bis-tetrallydropyranyl-ethcr.
,` c~;~Y
384~
Example 77 The l~-bromo-alcohols yielded by the foregoing examples, when treat-ed ~ith dimethyl-t.butylchlorosilane in dimethylformamide while, working to the procedures as in example 75,or ~ith an acetalic ether such as 2,3-dihydro-pyrane-1,4-diox-2-ene, l-ethoxy-ethylene, and ~orking to the procedure of example 76, are then converted into the corresponding silyloxy or the corres-ponding acetalic ethers.
Exam~le 78 Under an atmosphere of inert gas, to a stirred solution of 0.46 g of 13t-1"-bromo-6~H-6~9c-~-oxide-15S-methoxy-16S-methyl-prost-13-enoic acid methyl ester in anhydrous dimethy]sulfoxide ~5 ml), potassium tert-butylate ~0.15 g) is added and the stirring is continued for 30 minutes. The reaction mixture is diluted with 2 volumes of water and stirred for 15 minutes, then extracted with ethyl ether. The organic phases are re-extracted ~ith 2 x 5 ml of 0.2N NaOH and then with ~ater until neutral and evaporated to dryness to give 30 mg of 6~H-6~9c~)-oxide-lss-methoxy-l6s-methyl-prost-l3-ynoic acid methyl ester. The combined aqueous phase are acidified -to p~ 5.1 and extracted ~ith ethyl ether. After evaporation of the solvent, 0.28 g of 6~1-6~9c~)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid is obtained.
Example 79 Under an atmosphere of inert gas, with stirring and rigorous ex-clusion o humidity, 0.84 g of trimethylsilylimidazole is adcled to an anhydrous dimethylsulfoxlde solution of 0.445 g of 13t-5c~ll-5(9ci)-oxicle-14-bromo-16R-methyl-prost-13-enoic acicl. Stirring is continuecl ~or 30 minutes ~md then a solution of 0.]9 g of ~ tert-butylate is addc?d. ~fter 30 minutes stirring, the mixture is diluted with 3 volumes of water ancl stirred for 2 more hours.
~ter acidific.tion to p~l 5.2, it is extracted ~ith ethyl ether:hexane 80:20 an(l the org;mic e~tracts are dried and evaporated to dryness to give 0.31 g ~83~
of 5c~ 5(9cY)-oxide-16R-methyl-prost-13-ynoic acid.
Example 80 To a solution of sodium methylsulfinylcarbanion, obtained by heating at 60C for 3 hours and 30 minutes a suspension of 50 mg of 80% Na~l in 8 ml of anhydrous dimethylsulfoxide, a solution of 13t-6 ~1-6(9~)-oxide-llc~,15S-dimethoxy-14-bromo-16~S,R)-fluoro-20-methyl-prost-13-enoic acid methyl ester ~0.86 g) in 5 ml of dimethyl sulfoxide is added with stirring under an at-mosphere of inert gas, at a temperature of 18 - 20 C. After ~0 minutes of stirring an excess of 25% NaH2P04 ls poured in and the mixture extracted with ethyl ether to give 0.51 g of 6~H-6~9cY)-oxide-llcY,15S-dimethoxy-16~S,R)-fluoro-20-methyl-prost-13-ynoic acid methyl ester.
Example 81 . . _ To a solution of 80 mg of sodium amide in 10 ml of dimethyl-sulfoxide a solution of 13t-14-bromo-5cYH-5~9cY)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenoxy-l7~l8~l9~2o-tetranor-prost-l3-enoic acid-11,15-bis-tetrahydropyranyl-ether ~0.65 g) in 5 ml of dimethylsulfoxide is added.
It is stirred for 2 hours and then diluted with water and extracted with ethyl ether. The ether extracts, after re-extraction w1th alkali are dis-carded. The aqueous alkaline extracts are acidified to pll ~.5 and extracted with ethyl ether to give 0.54 g of 5~H-5(9~)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,1S,19,20-tetranor-prost-13-ynoic acid-11,15-bis-tetrahydropyranyl ether. A solution of this compound ~0.23 g) in anhydrous ethanol ~5 ml) and 2,2-diethoxypropane ~3 ml) is treated Wit]l 20 mg of p-tolucnesulfonic acid. ~fter 5 hours at room temperature it is neutralized ~Yi th aqueous NallCO_, evaporatcd under vacuum and the residue pnrtitioned ~etwcen IYater and etllyl ether. Tlle organic phnse is evaporated nnd after passin~ the resid~le througll silica gel 0.1 g of 5~l-1-5~9~)-oxide-llcY,15S-dihyclroxy-16-ill-tri:fluorollletilylphenoxy-17~18~19~20-tetranor-prost-13-ynoic ~;>
'I'l''-' i ,~
.~ e~
~3~
acid ethyl ester is obtained~ Deacetalizatioll carried out on another 0.2 g of product dissolved in 5 ml of acetone and treated with 3.5 ml of 0.2N oxalic acid for 8 hours at 40C, after evaporation of the acetone under vacuum, ex-traction of the aqueous phase with ethyl ether and chromatography on silica gel with ethyl ether:ethyl acetate 95:5 the free acid (95 mg) is obtained.
In the same way, starting from 13t-14-chloro-6~H-6~9a)-oxide-11~, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid-11,15-bis-dioxanylether the 6~H-6(9~)-oxide~11~,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor prost-13-ynoic acid is obtained.
Example 82 To a solution of 0.48 g of~l3t-1~ bromo-6~H-6(9~)-oxide~ ,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester in 3 ml of anhydrous dimethylsulfoxide is added after 30 minutes a solu-tion of 1,5-diazabicyclo[5.4.01undec-5-ene (0.25 g) in 2 ml of anhydrous di-methylformamide and the reaction mixture maintained for 6 hours at 65C. It is diluted with water acidified to pH 4.5, extracted ~ith ethyl ether. From the organic phase, after evaporation of the solvent and purification on silica gel ~eluted ~ith ben~ene-ethyl ether S0:20), 6~H-6(5~)-oxide-11~,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-ynoic acid methyl ester (0.29 g) is obtained.
Example 83 Using one of the procedurcs described in examples 78 to 82 and `starting from the corresponding 13t-14-halo-prost-13-enoic acids, the follo~-ing prost-13-ynoic acids are prepared:
6~1-6(9~-oxide-llu,15S-dihydro~y-prost-13-ynoic acid;
6~ 6~9~)-oxide-11~,15R-dihydroxy-prost-13-ynoic acid;
6~l-6~9~)-oxide-15-methoxy-prost-13-ynoic acid;
6~ 6(9~)-o.~ide-11~,15S-diilydroxy-16S-methyl-prost-13-ynoic acid;
A.11 j ~3~
6~H-~(9~)-oxide~ ,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
6~H-6(9c~)-oxide-11~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
68H-6~9~)-oxide-llc~,15S-dihydroxy-l~S-fluoro-prost-13-ynoic acid;
6~H-6~9~)-oxide-11~,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;
6~H-6(9~)-oxide-llcY,15S-dihydroxy-20-methyl-prost-13-ynoic acid;
6~H-6(9c~)-oxide-11~,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
? 6~H-6~9~)-oxide-11~,15S-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
6~H-6(9~-oxide-11~,15S~dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic acld;
5~H-5(9~)-oxide-11~,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;
5~l-5(9~)-oxide-11~,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
5~H-5(9~)-oxide~ ,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
5~H-5(9~)-oxide-llc~,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
5~H-5(9c~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
5~H-5~9~)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid.
Starting from c~H-(9u)-oxide compounds and using the same procedure, the epimeric ~H-(9~)-oxide~13-ynoic compounds are prepared.
Exam~le 84 .
A solution of 0.35 g of mercuric acetate in methanol is added at room temperature, with stirring, to a solution o 0.54 g of 5c,13t-9~ ,15S-trihydroxy-prosta~ienoic acid methyl ester-11,15-bis-TIIP-etller ~PGE2 -bis-Tl-lP-ether-methyl ester). After stirring for 15 minutes, 50 mg of sodiwn borohydricle is adcled in small portions, the elemental mercury generated is romoved ~y Eiltratioll and the methanol is evaporated under vacuum. The resi-due is partitioned bet~een dichloromethane/~ater; the organic phase, after ~38~
washing with sodium bicarbonate and water until neutral, is evapora-ted to give 0.51 g of crude 13t-llc~,15S-dihydroxy-6~H-6(9~)-o,cide-prostenoic acid methyl ester-11,15-bis-T~lP-ether. A solution of this in 10 ml of acetone added to 8 ml of 0.2N oxalic acid is heated to 40 - 45C for 6 hours. After the removal of the acetone under vacuum, the aqueous suspension is extracted with ethyl acetate (3 x 15 ml). The organic phase is washed until neutral and evaporated to dryness. The residue (approximately 0.45 g) is adsorbed on silica gel ~50 g) and eluted with ethyl ether collecting fractions of 20 ml.
From fractions 11 to 50, 13t-llc~,15S-dihydroxy-6c~1-1-6(9cY)-oxide-prostenoic acid methyl ester (0.11 g; m.p. 67 - 69C) is obtained. Then, after a mixture of diastereoisomers as 5 - 10% of ethyl acetate is added to ethyl ether, 13t-llc~,15~-dihydroxy-6~1-1-6(9c~)-oxide-prostenoic acid methyl ester (0.16 g;
~a]D = + 19.62 (CHC13)) is collected.
A sample of the later compound, after crystallization, shows m.p.
40 - 41 C, [cl]D = +25-2 ~ ['~365 = +S3.8 (CIIC13).
The crude free acid has [~]D = +18.3 ~EtOH).
A sample i.s crystallized from pentane-ethyl ether affording pure crystalline 13t-6~H-6(9c~)-oxide-llc~15S-dihydroxy-prost-l3-enoic acid, m.p.
80 - 81 C, [c~]D = +32.5 ~ [~]365 = +111.6 (EtOII). The mass spectrum of the compound shows the follo~-ing peaks (m/e, intensity, structure):
336 7% [M-H20] , 318 3% [hI-2I-I20] ; 292 100% [M-H20-44] ;
264 30% [M-H O-C~I2CHC02Il] ; 235 4% [M H2 ( 2 ~ 2 The mass spectrum of the 6c~1-I-diastereoisomer is substantially similar.
Examt~le 85 .
A solution of 0.19 g of 5c,13t-9c~,11c~15S-trillycIroxy-15-metilyl_ PGE2~-metIlyl ester in 2.5 ml of TIIF is addecl to 0.3 g of mercuric acetate in l . 5 ml water/3.0 ml TiIF. After 30 Ininutc?s of stirring, 60 Itlg of sodium ~83~
borohydride in 1.2 ml of ~ater is added -to the deep yellow suspension. After the mercury is separated, the TIIF is removed under vacuum and the aqueous sus-pension is extracted repeatedly with ethyl acetate. The organic phase, when ~ashed until neutral and evaporated to dryness, yie]ds 0.16 g of product which is purified by ~hin layer chromatography to give 0.04 g of 13t~ ,15S-di-hydroxy~6~I-6(9~)-oxide-15-methyl-PGF2 -methyl ester, [~]D = ~6.2 (CHC13) and 0.034 g of the 6BH-6(9~)-oxide-isomer, [~]D = ~19.62 (CIIC13).
E~ample 86 0.43 g of 5c,13t-9~,15S-dihydroxy-16R-methyl-prostadienoic acid methyl ester-15-dioxanyl ether in methanol (2.5 ml) is reacted with a solution of 0.38 g of mercuric bromide in methanol. The reaction mixture is held at room temperature for 15 minutes and overnight at 0 C. The crystalline pre-cipitate which forms is isola~ed by filtration to give 0.36 g of 13t-15~-hydroxy-16R-methyl-6~H-6(9~)-oxide-5-bromomercuric prostenoic acid methyl ester, from which the mercury is removed upon treatment with sodium borohydride to give 0.12 g of 13t-15S-hydroxy-16R-methyl-6~H-6(9~)-oxide-prostenoic acid methyl ester. Column chromatography on silica gel affects the separation into the 6~H-6(9~)-oxide and 6~H-6(9~)-oxide diastereoisomers.
Example 87 A solution of 0.55 g of 5c-9~ ,15S-trihydroxy-prostenoic acid methyl ester in 2.5 ml of D~iE is added to a solution of 0.5 g of mercuric acetate in 2 ml of water/ 4 ml of D~IE. After 15 minutes, the reaction mixture is treated with a solution of 0.08 g of sodium borollydride in 1.2 ml of ~aterJ
the mercury is separatocl, the D~IE is removed under vacuum, and the residue is extracted sevcral times with dichlorometIlane. The organic phase is evap-orate(I to dryness, adsorbed on silica gel and eluted ~ith ethyl ether/ethyl acctate to give 0.21 g of 11~,15S-dihydroxy-6~I-6(9~)-oxide-prostenoic acid methyl estcr and 0.18 g of the 6~H-6(9~)-oxide isomer.
,,d~3~`` . , ~
3~
Example 88 A solution of 116 mg of 5c-9N,llcl,15S-trihydroxy-17-cyclohe.Yyl-20, 19,18-trinor-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether in 1.5 ml of methanol is treated with 6~ mg of mercuric acetate~ in 1.5 ml of methanol. After 10 minutes, 25 mg of xodium borohydride is added. ~letIlanol is removed under vacuum, the mercury is separated and the product is dissolved in ~ater/ethyl acetate. Evaporation of the organic phase to dryness affords crude llc~,15S-dihydroxy-6~H-6(9N)-oxide-17-cyclohexyl-20,19,18-trinor-prost-13-ynoic acid methyl ester-11,15-bis-THP-ether (100 mg); this is treated in acetone (4 ml) with 2.5 ml of 0.2N oxalic acid overnight at 40 C. After re-moval of the acetone under vacuum, the mixture is extractcd lith ethyl acetate.
Evaporation of solvent gives a residue which is purified on silica gel (elu-ent, ethyl ether) to give 28 mg of llN,15S-dihydroxy-17-cyclohe.~cyl-20,19,1S-trinor-6NH-6~9N)-oxide-prost-13-ynoic acid methyl ester, [N]D = + 17.2, [N]365O = +54, and 12.5 mg of the 6~H-6(9N)-oxide-isomer, [u]D = + 26.5, [N] -65 = + 84 ~EtOH); M 406, ~1-H2O 388.
Under the same conditions, 5c-9N,llc~,15S-triIIydroxy-16S-metllyl-prost-5-en-13-ynoic acid methyl ester~ l5-bis-THp-ether gives llc~,15S-dihydroxy-16S-methyl-6NH-619c~)-oxide-prost-13-ynoic acid methyl ester and its 6~H-6(9N)-oxide isomer.
Example 89 0.2~ g of 13t-llN,15S-dihydroxy-6NH,6(9N)-o-Yide-16-metlIyl-16-butoxy-20,19,18-trinor-prostenoic acid methyl ester ancl 0.13 g of the 6~H-6(9N)-o~yide isomer are obtained from the reaction of 1.01 molar equiv.llent of mercuric acetate (636 mg) in 10 ml of methanol and l.l g of 5c,l3t-9c~,11N,15S-trihy-droxy-16-Inetllyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-ll, 15-bis-TIlP-ether in 5 ml of methanol. The mercury compound so prepared is roduced in situ l)y the cautious addition of 85 mg of sodium boroilydride in '~ ~ 5i'C) 33~
small portions. The methanolic solution is then decanted frcm the solid resi-due and reduced in ~olume. 10 ml of 0.2N aqueous oxalic acid and 20 ml of acetone are added, and the resulting mixture is held at 50C for 12 hours.
The organic solvents are removed under vacuum, and the resulting solution is saturated ~ith sodium sulfate and extracted with ethyl acetate. The organic phase is washed with 30% ammonium sul~ate (2 x 5 ml) and 2.5 ml of water;
after drying over NaS04, it is evaporated to give a crude residue which is purified on silica gel using an eluent containing an increasing ~raction o~
~enzene-methyl acetate, to give the isomeric 6~1-6(9~)-oxide and 6~H-6(9~)-oxide.
From the above reaction with 16-_-chloro-phenoxy,16-~-fluoro-phenoxy, and 16-m=trifluoromethyl-phenoxy-5c,13t-9~ ,15S-trihydroxy-20, 19,18,17-tetranor-prost-5,13-dienoic acid methyl ester-11,15-bis-TllP-ether and the analogous 17-phenyl-18,19,20-trinor-derivative were obtained respec-tively:
13t-11~,15S-dihydroxy-6~I-6(9~)-oxide-17-phenyl-20,19,18-trinor-prostenoic acid methyl ester, [~]D = + 28;
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-16-m-chloro-phenoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = + 31 ;
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-16-p-fluoro-phelIoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = + 30C;
13t-11~,15S-dihydroxy-6~I-I-6(9~)-oxide-16-m-trifluoromethyl-phenoxy-20,19,18, 17-tetranor-prostenoic acid methyl ester, [~]D = ~ 33;
and their 6~ll-6~9~)-oxide isomcrs t~hiCIl sho~ ]D ranging bet~een +8 and 12 in CIIC13.
E~alnplc 90 Using the lGS-Eluoro-17-cyclohe,~yl-5c,13t-9~ ,15S-trihydro~y-20,19,1S-trinor-prosta-5,13-dienoic acid mctlIyl ester-11,15-bis-THP-ether, in ~1~3~
the procedure of example 89~ the 13t~ ,15S-dihydroxy-6aH-6~9a)-oxide-16S-fluoro-17-cyclohexyl-20,19,18-trinor-prost-13-enoic acid methyl ester, and its 6~H-6(g~)-oxide diastereoisomer are obtained.
Example 91 0~12 g of 13t-lla,15S-dihydroxy-6~H-6(Sa)-oxide-prost-13-enoic acid methyl ester in 6 ml of methanol is reacted with a 0.5 N aqueous solution of lithium hydrate (2 ml). After six hours, the methanol is removed under vacuum.
The residue is diluted with water (2 ml) and extracted with ethyl ether to ~emove neutral impurities. The alkaline aqueous phase is acidified by treat-ment ~Yith 4 ml of 30% aqueous NaH2PO4 and extracted several times with ethyl ether. The later combined ether extracts are washed with wa~er (2 x 1 ml) and dried; removal of the solvent affords 91 mg of 13t-11~,15S-dihydroxy-6~H-6(9a)-oxide-prost-13-enoic acid, m.p. 78 - 80C, ~a]D = ~ 31 (EtOH). This procedure is used for saponification of the esters from the preceding examples to the corresponding free acids.
Example 92 11~,15S-dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost-13-ynoic acid ~0.11 g) in methylene chloride is treated with 1.5 molar equivalent of di-azomethane in methylene chloride. After 15 minutes, solvent is removed under ~acuum and the residue adsorbed on silica gel. Elution with ethyl ether/
benzene (70:30) gives, in the following order, 12 mg of 11-hydroxy-15S_ methoxy-6~H-6(9a)-oxide-16s-methYl-prost-l3-ynoic acid methyl ester and 78 mg of 11~,15S-dihydrox~r-6~H-6~9a)-oxide-16S-metilyl-prost-13-~noic acid methyl ester. Using in this procedure diazoethane instead of thc diazomethane, lla-hydroxy-15S-ethoxY-6~H-6(9a)-oxide-l6s-methyl-prost-l~-ynoic acid ethyl ester is obtained.
9~
31~
Example 93 A solution Of 12 ~0-33 g) in methylene chloride is added to a sus-pension of finely divided calcium carbonate in 6 ml of methylene chloride con-taining 0.5~ g of 5c,13t-9cY,llcY,15S-trihydroxy-prostadienoic acid methyl ester-11,15-bis-tetrahydropyranyl ether (PGF2 -bis-tetrahydropyranyl ether methyl ester). The reaction mixture is cooled in an ice/water bath and kept in darkness.~ After three hours of stirring~ inorganic compounds are removed by filtration and the organic phase is washed wi~h 0.25 N sodium thiosulfate and water. Removal of the solvent affords 0.66 g of crude 13t-5-iodo-6~H-6 (9c~)-oxide-llcy~l5s-dihydroxy-prost-l3-enoic acid methyl ester-11,15-bis-tetra--hydropyranyl ether. A solution of this in 10 ml of acetone is added to 8 ml of 0.lN oxalic acid and heated to 45 - 46C for 4 hours. The acetone is then removed at reduced pressure and the aqueous suspension is extracted with ethyl acetate (3 x 12 ml); the organic phase is washed ~mtil neutral and evaporated to dryness. The residue ~0.42 g) is separated on silica gel with ethyl ether el~lent. Elution of the high Rf fraction with acetone gives 0.14 g o~ 13t-5-iodo-6c~l-6(9c~)-oxide-llc~,15S-dihydroxy-prost-13-enoic acid methyl ester, t~hile the low Rf portion is 0.20 g of 13t-5-ioclo-6~-6(9cY)-oxide-llcy, ! 15S-dihydroxy-prost-13-enoic acid methyl ester.
The methyl ester of the following acids were prepared analogously:
i 13t-l6s-methyl-5-iodo-6~H-6~9a)-oxide-llc~l5s-dihyclroxy-prost-l3-enoic acid;
13t-20-methyl-5-iodo-6~1-6~9c~)-oxide-llcY,15S-dihydroxy-prost-13-enoic acid, [~D ~ + 23 , ~cY~365O = ~ 78 ~Cl-lC13);
13t-5-ioclo-6~1t-6~9cY) -oxide-llcY,15S-dihydro~y-lS,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-iodo-6c~ll-6(9c~)-oxide-llc~,15S-dihydroxy-lS,19,20-trinor-17-cyclohexyl-prost-13-clloic acicl;
~ 3 ~ 3~
3~
13t-5-iodo-6~I-6~9a)-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid;
13t-5-iodo-6a~1-6(9a)-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6c~-6~9a)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
13t-5-iodo-6c~-6(9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9a)-oxide-20-methyl-lla,15S-dihydroxy-prost-13-ynoic acid, [a]D = ~ 20 (C~IC13).
Example 9~
To a solution of 0.22 g of 5c,13t-9a,11a,15S-trihydroxy-15-metIlyl-PGF2 -methyl ester in 10 ml of C~I2C12 and 0.1 ml of pyridine is added drop-wise to a solution of 180 mg of iodine in methylene chloride. The resulting mixture is stirred for 1 hour. After dilution with water and washing of the organic phase with O.lN sodium thiosulfate and water until neutral, the solu-tion is evaporated in vacuum to a small volume and adsorbed on a silica gel plate 0.5 mm in thickness. After development with ethyl ether and elution with acetone, 0.052 g of 13t-15-methyl-5-iodo-6~H-6(9a)-oxicle-lla,15S-di-hydroxy-prost-l3-enoic acid methyl ester and 0.021 g of the isomeric 5-iodo-6a~1-6(9a)-oxide are obtained.
Example 95 0.2S~ g of 5c-l6~l6-dimethyl-9a~lla~l5s-tri~lydroxy-prost-s-cnoic acid methyl ester in a solution of 60 mg of pyricIiIle in me-th~leIle chloride ~ ml) is reactecl witII 115 ml of bromine in methylene chloride. After 30 minutes, starting material has completely clisapyearecI; tlIe organic yhase is ~asl~ccl liith I~ter, then 5o aqueous met~bisIllfite~ ancl then ~ater until neu-~d ~
3l5 ~
tral to give, after removal of the solvent and purification by TLC on silica gel with ethyl ether as eluent, 0.083 g of 16,16-dimethyl-5-bromo-6~H-6(9a)-oxide-prostanoic acid methyl ester and 0.04 g of 6aH-dias~ereoisomer.
The following compounds were prepared analogously:
13t-16,16-dimethyl-5-bromo-6~H-6(g~)-oxide-lla,15S-dihydroxy-prost-13-enoic acld;
13t-16,16-dimethyl-5-bromo-6aH-6~9a)-oxide-lla,lSS-dihydroxy-prost-13-enoic acid.
Example 96 To a solution of hydrotribromide pyrrolidone ~1.1 molar equivalents) in anhydrous tetrahydrofuran (6 ml) is added a solution of 5c,13t-9a,11a,15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5,13-dienoic acid methyl ester-11,15-bis-tetrahydropyranyl ether ~0.7 g) in 6 ml of tetrahydrofuran. The mixture is stirred for 12 hours, the precipitate which forms is removed by filtration, and the tetrahydrofuran solution is diluted with 2 ~-olumes of acetone and treated with 4 g of potassium iodide. After 4 hours at room temperature, the iodine liberated is decomposed with sodium metabisulfate.
1.5 volumes of O.lN aqueous oxalic acid is then added and the mixture heated to 48C for 4 hours. The mixture is reduced under vacuum and extracted with ethyl acetate, Separaticn on TLC gives 0.14 g of 13t-5-bromo-6aH-6~9a)-oxide_ lla~l5s-dihydroxy-l8~l9~zo-trinor-l7-cyclohexyl-prost-l3-enoic acid methyl ester and 0~11 g of the 5-bromo-6~H-6~9~)-oxide.
Using procedures of the examples 95 and 96, the following 6(9~)-oxides were obtained:
5-bromo 6~H~6~9al-oxide-lla,lSS-dihydroxy-18,19,20-trinor~17-cyclohexyl-prost-13~ynoic acid niethyl ester;
5-brolllo-6~1-6~9a)-oxide-lla~15S-dihydroxy-prostanoic acid;
.1[,~ ~I .Y~
~3~
13t-5-bromo-6~H-6(9a)-oxide~ ,lSS~dihydroxy-prost-13 enoic acid;
13t-20-methyl-5-bromo-6~H~6(9~)-oxide~ ,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6all-6~9)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-16S-methyl-5-bron~o-6~H-6(9~)-oxide-:Ll~,15S-dihydroxy-prost-13-enoic acid;
13t S-bromo-6~H-6(9~-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-bromo-S~H-6(9~)-oxide-11~,15S-dihydroxy-17,18,19,20-tetranor-16-m-tri-fluoromethyl-phenoxy-prost-13-enoic acid.
Example 97 A solution of 0.1 x 10 M of a methyl ester, prepared according to examples 93 to 96 in 2 ml of methanol is treated with 1 ml of an aqueous solution of lithium hydrate ~0.2 x 10 3 moles). The mixture is stirred for 3 hours, evaporated nearly to dryness, diluted with 5 ml of water, and extracted with ethyl ether.
The organic phase is washed with 0.lN LiOH ~2N) and water, and is then discarded. The aqueous phase is acidified to pH 4.8 with 30% aqueous NaH2PO4 and extracted with ethyl ether to give the free acid.
~33~
13t-6~ 6(9c~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-6~H-6(9c~)-oxide-15S-hydroxy-16316-dimethyl-prost-13-enoic acid;
13t-5~H-5(9~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5~H-5(9c~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5~H-5(9cl)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cl)-oxide-15S-hydroxy-16S-methyl-prost-13-encic acid;
13t-5-bromo-6~H-6(9c~)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9c~)-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9c~)-oxide-15S-hydroxy-16S,20-dimethyl-prost-13-enoic acid, together with their 15R-epimeric alcohols, when the corresponding 15-keto compounds are submitted to reduction follo~ed by chromatographic separation.
Starting from 6c~H and 5c~H diastereoisomeric 15-keto compouncls we prepare the corresponding 15S- and 15R-alcohols.
Example 67 The following 15S-hydroxy-9c~-oxide prostanoic acids methyl esters together with their 15R-epimeric alcohols are obtained after reduction of the corresponding 15-keto compounds using one of the procedures described in examples 58 to 66;
13t-6~H-6(9c~)-oxide-llc,15S-dihydroxy-13-prostanoic acid;
13t-14-bromo-6~H-6(9c~)-oxide-llc~,15S-diilydroxy-13-prostenoic acid;
13t-14-chloro-6~1l-6(9ct)-oxide-11~,15S-dihydroxy-13-prostenoic acid;
13t-5~l4-dibromo-6~3ll-6~9cl)-oxlde-llc~l5s-dihydroxy-l3-prostcnoic acid;
13t-6~l-6t9~)-o~ide-llc~,15S-dihydroxy-20-1netllyl-13-prostelloic acid;
13~-14-~romo-6~ 6t9~)-oxide-llc~,15S-~ yclro.~y-20-met}lyl-13-prostenoic acid;
13t-5,14-dibromo-6~H-6t9c~)-oxide-llc~,15S-(li}lydro.~;y-20-methyl-13-prostenoic .lcicl;
~' ~IL83134~L
13t-5-iodo-6~H-6(9a)-oxide-llaJl5s-dihydroxy~2o-methyl-l3-prostenoic acid;
13t-5-iodo-l4-hronlo-6~l-6(9a)-oxide-ll ,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a~-oxide-lla,15S-dihydroxy-16(S~R)-fluoro-17-cyclo-hexyl-18,19,20-trinor-prost-13-enoic acid, 13t-5-bromo-6~H-6(9a~-oxide-11~,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18jl9,20-trinor-prost-13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19s20-trinor-prost-13-enoic acid;
13t-14-bromo-6BH-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-l8 19,20-trinor-prost-13-enoic acid;
13t-6BH-6(9a)-oxide-lla~l5s-dihydroxy-l7-cyclopentyl-l8~l9~2o-trinor-prost 13-enoic acid;
13t-6~H-6~9a)-oxide-lla~l5s-dihydroxy-l7-cyclohexyl-l8~l9~2o-trinor-prost 13-enoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxY-l7-cyclohexyl-l8~l9~2o-trinor prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a) -oxide-lla,lSS-dihydroxy-l7-cyclohexyl-l8~l9~2 trinor-p~st-13-enoic acid;
13t-5-bromo-68H-6(9a)-oxide-llagl5S dihydroxy-17-cyclohexyl-18,19,20-tri.nor-prost-13-enoic acid;
13t-5-chloro-6~H-6~9a)-oxide-lla,15S-dihydToxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-11,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-lla,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl~16-amyloxy-18,19,20-lQ trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-17-cycloheptyl-18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6c9a)-oxide lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-6@H-6(9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla~l5s-dihydroxy-l6-cyclohexyloxy-l7~l8~l9J2o-tetranor 13-prostenoic acid, 13t-6~H-6(9a)-oxide-lla~l5s-dihydroxy-l6-(m-chlolo)-phenoxy-l7~l8~l9~2 tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla~l5s-dih~droxy-l6-(m-trifluoromethyl)-phenoxy-l7~l8 19,20-tetranor-13-prostenoic acid;
13t-l4-bromo-6BH-6(9a)-oxide-ll~l5s-dihydroxy-l6-(p-fluoro)-phenoxy-l7~l8 19,20-tetranor-13-prostenoic acicl;
13t~l4~b~omo~6~l~-6~9~)-oxide-lla~l5s-dihydroxy-l6-phenoxy~l7Jl8~l9~2o-tetranor 13-prostenoic acid;
13t-14-bromo-6~1-6(9a)-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18, .. 19,20-te~ranor-13-prostenoic acid;
~:18384~ lL
13t-14-bromo-6~H-6(9a).oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranoT 13-prostenoic acid;
13t-5-iodo-6~H-6(9~-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-11,15S-dihyclroxy-16-phenoxy~17,18,19,20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6~9)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoic acid;
13t~5-iodo-6~H-6~9a~-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-5~H-5(9)-oxide-11,15S-dihydroxy-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-14-chloro-5~H-5(9a)-oxide-lla,lSS-dihydroxy-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-5~H-5(9~)-oxide-lla,15S~dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-5eH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-11,15S-dihydroxy-20-methyl-13-prostenoic acid;13t-4-iodo-5~H-5(9~)-oxide-lla,lSS-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-l4-bromo-s~H-5(9)-oxide-lla~l5s-dihydroxy-2o-methyl-l3-prostenoic acid;
13t-14-bro -5~H-5(9aj-oxide-lla,lSS-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibro ~5~H~5(9)-oxide-11,15S-dihydroxy-16(S,R)-fluoro-17-cyclo-hexyl~l8J19,20~t~inor~prost-13 enoic acid;
13t-4-bromo-5~H-5~9)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-3~9~
18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-ll,lSS-dihydroxy-16(S,R)-fluoro-17~phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-14-bromo-5~H-5(9a~-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-phenyl-18,19,20-trinor-prost-13-enoic acid;
13t-56H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-1~,19,20-trinor-prost-13-enoic acid;
lQ 13t-14-bro~.o-5~H-5(9a)-oxide-11,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,1S,19,20 tetranor_ 13-prostenoic acid;
13t-4-iodo-5@H-5(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(m-chloro)-phenoxy-17,18,19, 20-tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,19,20-tetranor-13-prostenoic acid.
In similar way, we prepare the diastercoisomeric aH-9a-oxide-15S-and aH-~a-oxide-15R-alcohols when we use all-9a-oxide-15-~eto diastereoisomer starting material~
All these esters arc then saponified to obt~in the free acids.
313~L~
Example 6S
0.46 g of 13t-5~ -5(9~)-oxide-16S-methyl-llcl-hydroxy-15-oxo-prost-13-enoic acid methyl ester are treated IYith pyridine ~2 ml) and acetic an-hydride (1 ml). After 6 hours at room temperature the mixture is diluted with brine, acidified to pH 4.5 - 4.8 and extracted with ethyl ether. The combined organic phases are then evaporated to dryness yielding 0.48 g of ll-acetoxy-derivative (~ ~laH = 229 m~, ~ = 11.058). A solution of this compound in ethyl ether is then added dropwise to a solution of Zn(BH4)2 in ethyl ether.
After 30 minutes the excess reagent is decomposed with a N solution of ~2SO4 and after the usual work -up, 0.47 g of 13t-5~l-5(9c~)-oxide-16S-methyl-llcl, 15(S,R)-dihydroxy-13-prostenoic acid methyl ester ll-acetate are obtained.
A solution of this mixture in CH2C12 (5 ml) cooled to about -5C, -10C, is treated ~ith a solution of BF3 etherate (1.2 x 10 4 ~I) in Cll2C12 and then ~Yith a 5% solution of diazomethane in C112C12 until a persistent yellow coloration.
The reaction mixture ls evaporated to half volume undcr vacuum, washed ~Yith a 5% aqueous NaHCO3 solution and water to neutral, and evaporated to dryness to yield 0.47 g of 13t-5~l-5(9u)-oxide-16S-methyl-llc~-hydroxy-15(S,R)-methoxy-prost-13-enoic acid-ll-acetate which is separated in the individual isomers by chromatography on SiO2 using benzene-ethyl ether (S5:15) as eluent. On Ihe other hand, 0.21 g of the mixture of 15(S,R)-methoxy-clerivatives is dissolved in dry methanol (4 ml) and selectively deacetilated by trcatment ~Yith 20 mg of K2CO3 ~or 4 hours at room temperature. After neutralization by dilution ith a~ueous Nal~l2PO4, the methanol evaporated under vacuum and the residue is extracted with ethyl ether ~2 x 5) ethyl acetate (2 x 6 ml). The combincd organic phases are evaporated to dryness to yield lS0 mg of the crude 13t-5~ $~9~)-oxido-16S-metllyl~ ydroxy-15~S,R)-methoxy-prostenoic acid methyl estor, wllicll is then readily soparated by means of a silica gel column chroma-togrnphy using C~l2C12-ethyl et}-er S0:20 as eluent to yield the t~o pure ~L3 ~ ~
~8389~
isomers: 15S-methoxy and 15R-methoxy. Using the same procedure the following methyl esters were obtained:
13t-6~1-6(9cx)-oxide-16S-methyl-llcx-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9cx)-oxide-16R-methyl~ -hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6(9cx)-oxide-20-methyl-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide-20-methyl-llcY-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide-llcx-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9cx)-oxide~16S-methyl-llcx-hydroxy-15S-methoxy-prost-13-enoic acid 9 and their epimeric 15R-methoxy compounds are obtained starting from the cor-responding ll-acetoxy-15-keto compounds.
Using in this procedure the ~H-diastereoisomer instead of the ~H, the corresponding cxH-15-methoxy compounds are also obtained.
The same procedure can be also utilized for any 15-keto compound, previously described and analogously an other diazo al~ane can be used inside of diazomethane.
Example 69 To a solution of 0.26 g of 13t-6~H-6(9cx)-oxide-15~S,R)-hydroxy-16S-methyl-prost-13-enoic acid rnethyl ester in methylene chloride, treated with 0.3 ml of a solution of BF3 etherate in methylene chloride, cooled at -10 . -8 C, a solution of diazoethane in methylene chloride is added until a persistent yello~ coloration is formed. The solvent is evaporated under vacuum and the residue chrolllatogr;lplled on silica gel using ethyl ether-methylene chloricle 10:90 as elucnt to yield 0.115 g of 13t-6~H-6~9~)-oxide-15S-ethoxy-16S-Inethyl-prostenoic acicl metllylcster, and 0.1 g of 15R-ethoxy isomer .
~ ell a nlixt-lre of 15S,15R-alcollols, for example 13-t-6~H-6~9cx)-oxide-3i3~L
llc~,15(S,R)-dihydroxy-16S-methyl-prostenoic acid, containing a free 11-hydroxy group is submitted to the procedure of the examples 68 and 69, the simultaneous alkoxylation of the ll-alcoholic function also occurs yielding ~ith diazomethane for example after chromatographic separation the 13t-6~H-6~9cY)-oxide llc~,15S-dimethoxy-16S-methyl-prostenoic acid methyl ester beside the 15R-epimeric derivative.
In a similar way the following 15S-alkoxy prostenoic derivatives were obtained:
13t-5~H-5~9c~)~oxide-lla,15S-dimethoxy-prostenoic acid;
13t-6~H-6~9c~)-oxide-llc~,15S-dimethoxy-prostenoic acid;
13t-6~H-6~9c~)-oxide-5-bromo-llc~,15S-dimethoxy-prostenoic acid;
13t-6~H-6~gcl)-oxide-5-iodo-llc~,15S-dimethoxy-prostenoic acid;
13t-5~H-5~9c~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16R-methyl-prostenoic acid;
13t-6~H-6~9c~)-oxide-15S-methoxy-16-methyl-16-butox~ ,19,20-trinor-prostanoic acid, and their 15R epimers are obtained and when they are saponified with LiOH in methanol the free acids are prepared. The same proceclure can be used to ob-tain diastereoisomeric c~-9c~-oxide derivatives.
Example 70 To a stirred solution of 1.33 g of 13-t-6CYII-6 (9c~)-oxide-llc~-hydroxy-15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 6 ml of toluene and 54 ml of benzene, cooled at +4 C, a solution of 1.67 g of methylmagnesium iodicle in ethyl ether is a~cled. ~fter 20 minutes, the excoss reagent is decomposed with an icod 20o solution of ammonium chlori(lo in water. After dilution with one vol-mle of ethyl etho:r the organic phase is washecl with l~ater, sodium bi-carbona~e and water, dried over magnosium sulphate, treated with 0.1 ml of . I
~L~83~
pyridine and evaporated to dryness to yield 1.2 g of 13t-6~H-6(9~)-oxide~
15~S,R)-dihydroxy-15-methyl-prostenoic acid-methylcster-ll-acetate, of which 0.2 g are separated into the pure component by thin layer chromatography on silica gel, with benzene-ether 60:40 eluent. 1 g of the mixture of the two alcohols is dissolved in anhydrous methanol (20 ml) and stirred for 4 hours with 0.25 g of K2C03. The mixture is evaporated to dryness, the residue is partitioned between ethyl ether and aqueous 15% NaH2P04. The organic ph~se is evaporated in vacuum and the residue is absorbed on silica gel (200 g).
Elution with ethyl ether-isopropylic ether 80:20 affords 0.20 g of 13t-6~H-one 6(9~)-oxide-11~,15R-dihydroxy-15-methyl-prost-13-enoic acid methyl ester, and 0.36 g of 15S-epimer. 0.16 g of this compound are dissolved in 12 ml of methanol and treated with 0.8 ml of water and 0.2 g of K2CO3. After 5 hours at room temperature the methanol is evaporated under vacuum, the rcsidue is treated with 20% NaH2P04 and ethyl acetate. The organic phase yiei~s 0.14 g of 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prost-13-enoic acid. The corresponding 6~H-isomers are prepared in the same way.
Example 71 To 1.79 g of 13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-prost-13-enoic acid methyl ester-ll-acetate in 20 ml of anhydrous tetrahydrofurane, 50 ml of 0.3 M ethynylmagnesium bromide in anhydrous tetrahydrofurane is added.
Keep shaking for one hour, eliminate the excess rcagent by treating with a saturated NH4Cl solution, concentrate the organic phase under vacuum, and take up with ethyl ether to yicld 1.62 g of 13t-5~l-5(9~)-oxide-11~,15(S,R)-dihydroxy-15-et}lynyl-prost-13-enoic acid methyl estcr-ll-acctatc, which is dissolvod in anhydrous metllanol and treated l~ith 250 mg of ~nhydrous potassium carbonato for 3 llours under shaking. Evaporatcd ull(lcr vacuum and dilute with 20o a~ueo~s Nall2PO~ and ethyl cther. AEter cvaporating the solvent, the org~nlc phase yields 1.~1 g of 13t-5~l-5~9~)-oxide-11~,15(S,R)-dihydroxy-15-~83~
ethynyl-prostanoic acid methyl ester, which is separated into the two pure 15S-hydrox~ and 15R-hydroxy epimer by silica gel chromatography with benzene-ethyl ether 1:1 as eluent, and after saponification of the 15S-hydroxy epimer with K2C03 in methanol, there is yield of the 13t-5c~1-5(9c~)-oxide-llc~,15S-dihydroxy-15-ethynyl-prostenoic acid.
Example 72 To a solution in tetrahydrofuran anhydrous (25 ml) of 1.41 g or 13t-5-bromo-6~H-6(9c~)-oxide-15-oxo-prost-13-enoic acid methyl ester, a 0.5 ~1 solution of magnesium vinyl bromide in tetrahydrofurane (25 ml) is adcled at 0 - 5 C and let stand for 4 hours at room temperature. Decompose the excess reagent with a saturated solution of ammonium chloride, distil the tetrahydro-furane under vacuum and take up with ethyl ether. The organic phase is ad-sorbed on silica gel and eluted with methylene chloride-etllyl ether to yield 0.41 g of 13t-5-bromo-6~H-6(9~)-oxide-15R-hydroxy-15-vinyl-prostenoic acid methyl ester, and 0.62 g of 15S-isomer, which after saponification with LiOH
in methanol yields 0.49 g of pure 13t-5-bromo-6~1~-6(9c~)-oxide-15S-hydroxy-15-vinyl-prostenoic acid.
Example 73 A solution of 0.98 g of 13t-5-bromo-6~1l-6(9c~)-oxide-llc~-hydroxy-15-oxo-20-methyl-prostenoic acid methyl ester-ll-acetate in aO ml of benzene-toluene (85:15) is cooled at 3 - 4 C and to this a solution of 0.92 g of phenylmagnesium bromide in ethyl ether-benzene 1:1 is added. Let stand for 5 hours at room temperature, then decompose the e~cess rea~ent with an iced solution of 15% ~114Cl, wasll the organic pllase repeatedly Wit]l water to neutral thcn evayorate. The crude 15-phenyl-15~S,R)-llydroxy clelivative is dissolved ln n~ y(lrous metllanol to l~hiCIl 0. 25 g. of ~2C03 is adde(l, ~ept shaking for 2 hours. ~vaporatc to dryness, dilute witll aqueous 20% Na~l2P04 and ethyl ether, ancl from the org~nic phase after evaporation of the solvent, there is ~3~
a yield of 0.81 g of 13t-5-bromo-6~H-6(9c~)-oxide-llcY,15(S,R)-dihydroxy-15-phenyl-20-methyl-prostenoic acid methyl ester, which after separation on silica gel with ethyl ether elution yields the individual 15S and 15R isomers.
Exam~le 74 By reaction of the corresponding 15-oxo-derivative with a reagent selected from the group of an halogenide of methyl magnesium, vinyl magnesium, ethynyl magnesium and phenyl magnesium, ~orking to one of the procedures given in example 70 to 73, the folloliing methylesters were prepared:
13t-6~H-6(9c~)-oxide-15S-hydroxy-15-methyl-prostenoic acid;
13t-6~H-6~9a)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9cY)-oxide-15S-hyciroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llcY,15S-dihydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llc-~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9cY)-oxide-llcY,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-llcY,15S-dihydroxy-15-eth~yl-prostenoic acid;
13t-6~H-6(9c~)-oxide-llcY,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-6~H-6(9cY)-oxide-llcY~15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-5-bromo-6~H-6~9cY)-oxide-llcY,15S-dillydroxy-15-methyl-prostenoic acid;
13t-5-bromo-6~H-6~9c~)-oxide-llcY,15S-dihydroxy-15-vinyl-pros-tenoic acid;
13t-5-bromo-6~H-6(9cY)-oxide-11~,15S-dillydroxy-15-ethynyl-prostenoic acid;
13t-5-bromo-63ll-6~9c~)-oxide-llcY,15S-dillydroxy-15-ethyl-prostenoic acid;
13t-5-bromo-6~il-6(9c~)-oxicle-llc~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-4-bromo-5~ll-5(9cY)-oxide-llc~,15S-dillyclroxy-15-metllyl-prostenoic acid;
13t-4-bromo-5~i-l-5(9c~)-oxide-llcY,15S-dillydroxy-15,20-climetllyl-prostenoic acii;
13t-4-~romo-5~il-5~9~)-ocicie-].lc~,15S-ciillyciroxy-15-ethynyl-prostenoic acid;
13t-5~H-5(9cY)-oxide-llc~,15S-dillyciroxy-15-metllyl-prostenoic acid;
13t-5~i-l-5(9c~)-oxide-llcY,15S-dihydroxy-15,20-dimet}lyl-prostenoic acid;
æ
831~4~
13t-5~H-5(9~)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-5~1-5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid, and their 15R-hydroxy epimers.
Analogously starting from the ~H-~9~)-oxide-15-keto-compounds we obtained the corresponding ~H-~9~)-oxide-15-substituted alcohols.
Exam~le 75 To a solution of 0.5 g of 13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid-methyl ester-ll-acetate in 2 ml of di-methylformamide, dimethyl-t-butyl silane chloride ~0.21 g) and triethylamine (0.16 g) are added. Keep shaking for 2 hours, then dilute ~ith 4 volumes of water and extract with ethyl ether. The organic phase, after the usual washings, evaporation of the solvent, and filtration through silica gel with cyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of 13t-6~H-6~9~)-oxide 11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid methyl ester-ll-acetate-15-dimethyl-t.butylsilylether, from which, by transesterification in anhydrous methanol and 0.5 molar equivalents of K2CO3, the corrcsponding ll-hydroxy-derivative is yielded.
Example 76 To 0.52 g of 13t-5,14-dibromo-6~1-6~9~)-oxide-11~,15S-dihydroxy-prostenoic acid methyl ester in 10 ml of dichloromethane, 2,3-dillydro-pyrane (0.27 g) and p-toluensulphonic acid (4 m~) are added. Keep at room tempera-ture for 3 hours, then wasll ~ith a 5O sol~ltion of ~I-IC03 and water to ne~ltral, and evaporate to dryncss. Filter througll silica gel with c~clohexane-ethyl ethcr 90:10 as eluent, ~hicll yie'ds 0.59 g of 13t-5,1~1-dibromo-6~l-l-6~9~)-oYide-11~,15S-di}lydro.Yy-prostenolc acid methyl ester-11,15-bis-tetrallydropyranyl-ethcr.
,` c~;~Y
384~
Example 77 The l~-bromo-alcohols yielded by the foregoing examples, when treat-ed ~ith dimethyl-t.butylchlorosilane in dimethylformamide while, working to the procedures as in example 75,or ~ith an acetalic ether such as 2,3-dihydro-pyrane-1,4-diox-2-ene, l-ethoxy-ethylene, and ~orking to the procedure of example 76, are then converted into the corresponding silyloxy or the corres-ponding acetalic ethers.
Exam~le 78 Under an atmosphere of inert gas, to a stirred solution of 0.46 g of 13t-1"-bromo-6~H-6~9c-~-oxide-15S-methoxy-16S-methyl-prost-13-enoic acid methyl ester in anhydrous dimethy]sulfoxide ~5 ml), potassium tert-butylate ~0.15 g) is added and the stirring is continued for 30 minutes. The reaction mixture is diluted with 2 volumes of water and stirred for 15 minutes, then extracted with ethyl ether. The organic phases are re-extracted ~ith 2 x 5 ml of 0.2N NaOH and then with ~ater until neutral and evaporated to dryness to give 30 mg of 6~H-6~9c~)-oxide-lss-methoxy-l6s-methyl-prost-l3-ynoic acid methyl ester. The combined aqueous phase are acidified -to p~ 5.1 and extracted ~ith ethyl ether. After evaporation of the solvent, 0.28 g of 6~1-6~9c~)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid is obtained.
Example 79 Under an atmosphere of inert gas, with stirring and rigorous ex-clusion o humidity, 0.84 g of trimethylsilylimidazole is adcled to an anhydrous dimethylsulfoxlde solution of 0.445 g of 13t-5c~ll-5(9ci)-oxicle-14-bromo-16R-methyl-prost-13-enoic acicl. Stirring is continuecl ~or 30 minutes ~md then a solution of 0.]9 g of ~ tert-butylate is addc?d. ~fter 30 minutes stirring, the mixture is diluted with 3 volumes of water ancl stirred for 2 more hours.
~ter acidific.tion to p~l 5.2, it is extracted ~ith ethyl ether:hexane 80:20 an(l the org;mic e~tracts are dried and evaporated to dryness to give 0.31 g ~83~
of 5c~ 5(9cY)-oxide-16R-methyl-prost-13-ynoic acid.
Example 80 To a solution of sodium methylsulfinylcarbanion, obtained by heating at 60C for 3 hours and 30 minutes a suspension of 50 mg of 80% Na~l in 8 ml of anhydrous dimethylsulfoxide, a solution of 13t-6 ~1-6(9~)-oxide-llc~,15S-dimethoxy-14-bromo-16~S,R)-fluoro-20-methyl-prost-13-enoic acid methyl ester ~0.86 g) in 5 ml of dimethyl sulfoxide is added with stirring under an at-mosphere of inert gas, at a temperature of 18 - 20 C. After ~0 minutes of stirring an excess of 25% NaH2P04 ls poured in and the mixture extracted with ethyl ether to give 0.51 g of 6~H-6~9cY)-oxide-llcY,15S-dimethoxy-16~S,R)-fluoro-20-methyl-prost-13-ynoic acid methyl ester.
Example 81 . . _ To a solution of 80 mg of sodium amide in 10 ml of dimethyl-sulfoxide a solution of 13t-14-bromo-5cYH-5~9cY)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenoxy-l7~l8~l9~2o-tetranor-prost-l3-enoic acid-11,15-bis-tetrahydropyranyl-ether ~0.65 g) in 5 ml of dimethylsulfoxide is added.
It is stirred for 2 hours and then diluted with water and extracted with ethyl ether. The ether extracts, after re-extraction w1th alkali are dis-carded. The aqueous alkaline extracts are acidified to pll ~.5 and extracted with ethyl ether to give 0.54 g of 5~H-5(9~)-oxide-11~,15S-dihydroxy-16-m-trifluoromethylphenoxy-17,1S,19,20-tetranor-prost-13-ynoic acid-11,15-bis-tetrahydropyranyl ether. A solution of this compound ~0.23 g) in anhydrous ethanol ~5 ml) and 2,2-diethoxypropane ~3 ml) is treated Wit]l 20 mg of p-tolucnesulfonic acid. ~fter 5 hours at room temperature it is neutralized ~Yi th aqueous NallCO_, evaporatcd under vacuum and the residue pnrtitioned ~etwcen IYater and etllyl ether. Tlle organic phnse is evaporated nnd after passin~ the resid~le througll silica gel 0.1 g of 5~l-1-5~9~)-oxide-llcY,15S-dihyclroxy-16-ill-tri:fluorollletilylphenoxy-17~18~19~20-tetranor-prost-13-ynoic ~;>
'I'l''-' i ,~
.~ e~
~3~
acid ethyl ester is obtained~ Deacetalizatioll carried out on another 0.2 g of product dissolved in 5 ml of acetone and treated with 3.5 ml of 0.2N oxalic acid for 8 hours at 40C, after evaporation of the acetone under vacuum, ex-traction of the aqueous phase with ethyl ether and chromatography on silica gel with ethyl ether:ethyl acetate 95:5 the free acid (95 mg) is obtained.
In the same way, starting from 13t-14-chloro-6~H-6~9a)-oxide-11~, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid-11,15-bis-dioxanylether the 6~H-6(9~)-oxide~11~,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor prost-13-ynoic acid is obtained.
Example 82 To a solution of 0.48 g of~l3t-1~ bromo-6~H-6(9~)-oxide~ ,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester in 3 ml of anhydrous dimethylsulfoxide is added after 30 minutes a solu-tion of 1,5-diazabicyclo[5.4.01undec-5-ene (0.25 g) in 2 ml of anhydrous di-methylformamide and the reaction mixture maintained for 6 hours at 65C. It is diluted with water acidified to pH 4.5, extracted ~ith ethyl ether. From the organic phase, after evaporation of the solvent and purification on silica gel ~eluted ~ith ben~ene-ethyl ether S0:20), 6~H-6(5~)-oxide-11~,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-ynoic acid methyl ester (0.29 g) is obtained.
Example 83 Using one of the procedurcs described in examples 78 to 82 and `starting from the corresponding 13t-14-halo-prost-13-enoic acids, the follo~-ing prost-13-ynoic acids are prepared:
6~1-6(9~-oxide-llu,15S-dihydro~y-prost-13-ynoic acid;
6~ 6~9~)-oxide-11~,15R-dihydroxy-prost-13-ynoic acid;
6~l-6~9~)-oxide-15-methoxy-prost-13-ynoic acid;
6~ 6(9~)-o.~ide-11~,15S-diilydroxy-16S-methyl-prost-13-ynoic acid;
A.11 j ~3~
6~H-~(9~)-oxide~ ,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
6~H-6(9c~)-oxide-11~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
68H-6~9~)-oxide-llc~,15S-dihydroxy-l~S-fluoro-prost-13-ynoic acid;
6~H-6~9~)-oxide-11~,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;
6~H-6(9~)-oxide-llcY,15S-dihydroxy-20-methyl-prost-13-ynoic acid;
6~H-6(9c~)-oxide-11~,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
? 6~H-6~9~)-oxide-11~,15S-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-prost-13-ynoic acid;
6~H-6(9~-oxide-11~,15S~dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic acld;
5~H-5(9~)-oxide-11~,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;
5~l-5(9~)-oxide-11~,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
5~H-5(9~)-oxide~ ,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
5~H-5(9~)-oxide-llc~,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
5~H-5(9c~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
5~H-5~9~)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid.
Starting from c~H-(9u)-oxide compounds and using the same procedure, the epimeric ~H-(9~)-oxide~13-ynoic compounds are prepared.
Exam~le 84 .
A solution of 0.35 g of mercuric acetate in methanol is added at room temperature, with stirring, to a solution o 0.54 g of 5c,13t-9~ ,15S-trihydroxy-prosta~ienoic acid methyl ester-11,15-bis-TIIP-etller ~PGE2 -bis-Tl-lP-ether-methyl ester). After stirring for 15 minutes, 50 mg of sodiwn borohydricle is adcled in small portions, the elemental mercury generated is romoved ~y Eiltratioll and the methanol is evaporated under vacuum. The resi-due is partitioned bet~een dichloromethane/~ater; the organic phase, after ~38~
washing with sodium bicarbonate and water until neutral, is evapora-ted to give 0.51 g of crude 13t-llc~,15S-dihydroxy-6~H-6(9~)-o,cide-prostenoic acid methyl ester-11,15-bis-T~lP-ether. A solution of this in 10 ml of acetone added to 8 ml of 0.2N oxalic acid is heated to 40 - 45C for 6 hours. After the removal of the acetone under vacuum, the aqueous suspension is extracted with ethyl acetate (3 x 15 ml). The organic phase is washed until neutral and evaporated to dryness. The residue (approximately 0.45 g) is adsorbed on silica gel ~50 g) and eluted with ethyl ether collecting fractions of 20 ml.
From fractions 11 to 50, 13t-llc~,15S-dihydroxy-6c~1-1-6(9cY)-oxide-prostenoic acid methyl ester (0.11 g; m.p. 67 - 69C) is obtained. Then, after a mixture of diastereoisomers as 5 - 10% of ethyl acetate is added to ethyl ether, 13t-llc~,15~-dihydroxy-6~1-1-6(9c~)-oxide-prostenoic acid methyl ester (0.16 g;
~a]D = + 19.62 (CHC13)) is collected.
A sample of the later compound, after crystallization, shows m.p.
40 - 41 C, [cl]D = +25-2 ~ ['~365 = +S3.8 (CIIC13).
The crude free acid has [~]D = +18.3 ~EtOH).
A sample i.s crystallized from pentane-ethyl ether affording pure crystalline 13t-6~H-6(9c~)-oxide-llc~15S-dihydroxy-prost-l3-enoic acid, m.p.
80 - 81 C, [c~]D = +32.5 ~ [~]365 = +111.6 (EtOII). The mass spectrum of the compound shows the follo~-ing peaks (m/e, intensity, structure):
336 7% [M-H20] , 318 3% [hI-2I-I20] ; 292 100% [M-H20-44] ;
264 30% [M-H O-C~I2CHC02Il] ; 235 4% [M H2 ( 2 ~ 2 The mass spectrum of the 6c~1-I-diastereoisomer is substantially similar.
Examt~le 85 .
A solution of 0.19 g of 5c,13t-9c~,11c~15S-trillycIroxy-15-metilyl_ PGE2~-metIlyl ester in 2.5 ml of TIIF is addecl to 0.3 g of mercuric acetate in l . 5 ml water/3.0 ml TiIF. After 30 Ininutc?s of stirring, 60 Itlg of sodium ~83~
borohydride in 1.2 ml of ~ater is added -to the deep yellow suspension. After the mercury is separated, the TIIF is removed under vacuum and the aqueous sus-pension is extracted repeatedly with ethyl acetate. The organic phase, when ~ashed until neutral and evaporated to dryness, yie]ds 0.16 g of product which is purified by ~hin layer chromatography to give 0.04 g of 13t~ ,15S-di-hydroxy~6~I-6(9~)-oxide-15-methyl-PGF2 -methyl ester, [~]D = ~6.2 (CHC13) and 0.034 g of the 6BH-6(9~)-oxide-isomer, [~]D = ~19.62 (CIIC13).
E~ample 86 0.43 g of 5c,13t-9~,15S-dihydroxy-16R-methyl-prostadienoic acid methyl ester-15-dioxanyl ether in methanol (2.5 ml) is reacted with a solution of 0.38 g of mercuric bromide in methanol. The reaction mixture is held at room temperature for 15 minutes and overnight at 0 C. The crystalline pre-cipitate which forms is isola~ed by filtration to give 0.36 g of 13t-15~-hydroxy-16R-methyl-6~H-6(9~)-oxide-5-bromomercuric prostenoic acid methyl ester, from which the mercury is removed upon treatment with sodium borohydride to give 0.12 g of 13t-15S-hydroxy-16R-methyl-6~H-6(9~)-oxide-prostenoic acid methyl ester. Column chromatography on silica gel affects the separation into the 6~H-6(9~)-oxide and 6~H-6(9~)-oxide diastereoisomers.
Example 87 A solution of 0.55 g of 5c-9~ ,15S-trihydroxy-prostenoic acid methyl ester in 2.5 ml of D~iE is added to a solution of 0.5 g of mercuric acetate in 2 ml of water/ 4 ml of D~IE. After 15 minutes, the reaction mixture is treated with a solution of 0.08 g of sodium borollydride in 1.2 ml of ~aterJ
the mercury is separatocl, the D~IE is removed under vacuum, and the residue is extracted sevcral times with dichlorometIlane. The organic phase is evap-orate(I to dryness, adsorbed on silica gel and eluted ~ith ethyl ether/ethyl acctate to give 0.21 g of 11~,15S-dihydroxy-6~I-6(9~)-oxide-prostenoic acid methyl estcr and 0.18 g of the 6~H-6(9~)-oxide isomer.
,,d~3~`` . , ~
3~
Example 88 A solution of 116 mg of 5c-9N,llcl,15S-trihydroxy-17-cyclohe.Yyl-20, 19,18-trinor-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether in 1.5 ml of methanol is treated with 6~ mg of mercuric acetate~ in 1.5 ml of methanol. After 10 minutes, 25 mg of xodium borohydride is added. ~letIlanol is removed under vacuum, the mercury is separated and the product is dissolved in ~ater/ethyl acetate. Evaporation of the organic phase to dryness affords crude llc~,15S-dihydroxy-6~H-6(9N)-oxide-17-cyclohexyl-20,19,18-trinor-prost-13-ynoic acid methyl ester-11,15-bis-THP-ether (100 mg); this is treated in acetone (4 ml) with 2.5 ml of 0.2N oxalic acid overnight at 40 C. After re-moval of the acetone under vacuum, the mixture is extractcd lith ethyl acetate.
Evaporation of solvent gives a residue which is purified on silica gel (elu-ent, ethyl ether) to give 28 mg of llN,15S-dihydroxy-17-cyclohe.~cyl-20,19,1S-trinor-6NH-6~9N)-oxide-prost-13-ynoic acid methyl ester, [N]D = + 17.2, [N]365O = +54, and 12.5 mg of the 6~H-6(9N)-oxide-isomer, [u]D = + 26.5, [N] -65 = + 84 ~EtOH); M 406, ~1-H2O 388.
Under the same conditions, 5c-9N,llc~,15S-triIIydroxy-16S-metllyl-prost-5-en-13-ynoic acid methyl ester~ l5-bis-THp-ether gives llc~,15S-dihydroxy-16S-methyl-6NH-619c~)-oxide-prost-13-ynoic acid methyl ester and its 6~H-6(9N)-oxide isomer.
Example 89 0.2~ g of 13t-llN,15S-dihydroxy-6NH,6(9N)-o-Yide-16-metlIyl-16-butoxy-20,19,18-trinor-prostenoic acid methyl ester ancl 0.13 g of the 6~H-6(9N)-o~yide isomer are obtained from the reaction of 1.01 molar equiv.llent of mercuric acetate (636 mg) in 10 ml of methanol and l.l g of 5c,l3t-9c~,11N,15S-trihy-droxy-16-Inetllyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-ll, 15-bis-TIlP-ether in 5 ml of methanol. The mercury compound so prepared is roduced in situ l)y the cautious addition of 85 mg of sodium boroilydride in '~ ~ 5i'C) 33~
small portions. The methanolic solution is then decanted frcm the solid resi-due and reduced in ~olume. 10 ml of 0.2N aqueous oxalic acid and 20 ml of acetone are added, and the resulting mixture is held at 50C for 12 hours.
The organic solvents are removed under vacuum, and the resulting solution is saturated ~ith sodium sulfate and extracted with ethyl acetate. The organic phase is washed with 30% ammonium sul~ate (2 x 5 ml) and 2.5 ml of water;
after drying over NaS04, it is evaporated to give a crude residue which is purified on silica gel using an eluent containing an increasing ~raction o~
~enzene-methyl acetate, to give the isomeric 6~1-6(9~)-oxide and 6~H-6(9~)-oxide.
From the above reaction with 16-_-chloro-phenoxy,16-~-fluoro-phenoxy, and 16-m=trifluoromethyl-phenoxy-5c,13t-9~ ,15S-trihydroxy-20, 19,18,17-tetranor-prost-5,13-dienoic acid methyl ester-11,15-bis-TllP-ether and the analogous 17-phenyl-18,19,20-trinor-derivative were obtained respec-tively:
13t-11~,15S-dihydroxy-6~I-6(9~)-oxide-17-phenyl-20,19,18-trinor-prostenoic acid methyl ester, [~]D = + 28;
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-16-m-chloro-phenoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = + 31 ;
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-16-p-fluoro-phelIoxy-20,19,18,17-tetranor-prostenoic acid methyl ester, [~]D = + 30C;
13t-11~,15S-dihydroxy-6~I-I-6(9~)-oxide-16-m-trifluoromethyl-phenoxy-20,19,18, 17-tetranor-prostenoic acid methyl ester, [~]D = ~ 33;
and their 6~ll-6~9~)-oxide isomcrs t~hiCIl sho~ ]D ranging bet~een +8 and 12 in CIIC13.
E~alnplc 90 Using the lGS-Eluoro-17-cyclohe,~yl-5c,13t-9~ ,15S-trihydro~y-20,19,1S-trinor-prosta-5,13-dienoic acid mctlIyl ester-11,15-bis-THP-ether, in ~1~3~
the procedure of example 89~ the 13t~ ,15S-dihydroxy-6aH-6~9a)-oxide-16S-fluoro-17-cyclohexyl-20,19,18-trinor-prost-13-enoic acid methyl ester, and its 6~H-6(g~)-oxide diastereoisomer are obtained.
Example 91 0~12 g of 13t-lla,15S-dihydroxy-6~H-6(Sa)-oxide-prost-13-enoic acid methyl ester in 6 ml of methanol is reacted with a 0.5 N aqueous solution of lithium hydrate (2 ml). After six hours, the methanol is removed under vacuum.
The residue is diluted with water (2 ml) and extracted with ethyl ether to ~emove neutral impurities. The alkaline aqueous phase is acidified by treat-ment ~Yith 4 ml of 30% aqueous NaH2PO4 and extracted several times with ethyl ether. The later combined ether extracts are washed with wa~er (2 x 1 ml) and dried; removal of the solvent affords 91 mg of 13t-11~,15S-dihydroxy-6~H-6(9a)-oxide-prost-13-enoic acid, m.p. 78 - 80C, ~a]D = ~ 31 (EtOH). This procedure is used for saponification of the esters from the preceding examples to the corresponding free acids.
Example 92 11~,15S-dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost-13-ynoic acid ~0.11 g) in methylene chloride is treated with 1.5 molar equivalent of di-azomethane in methylene chloride. After 15 minutes, solvent is removed under ~acuum and the residue adsorbed on silica gel. Elution with ethyl ether/
benzene (70:30) gives, in the following order, 12 mg of 11-hydroxy-15S_ methoxy-6~H-6(9a)-oxide-16s-methYl-prost-l3-ynoic acid methyl ester and 78 mg of 11~,15S-dihydrox~r-6~H-6~9a)-oxide-16S-metilyl-prost-13-~noic acid methyl ester. Using in this procedure diazoethane instead of thc diazomethane, lla-hydroxy-15S-ethoxY-6~H-6(9a)-oxide-l6s-methyl-prost-l~-ynoic acid ethyl ester is obtained.
9~
31~
Example 93 A solution Of 12 ~0-33 g) in methylene chloride is added to a sus-pension of finely divided calcium carbonate in 6 ml of methylene chloride con-taining 0.5~ g of 5c,13t-9cY,llcY,15S-trihydroxy-prostadienoic acid methyl ester-11,15-bis-tetrahydropyranyl ether (PGF2 -bis-tetrahydropyranyl ether methyl ester). The reaction mixture is cooled in an ice/water bath and kept in darkness.~ After three hours of stirring~ inorganic compounds are removed by filtration and the organic phase is washed wi~h 0.25 N sodium thiosulfate and water. Removal of the solvent affords 0.66 g of crude 13t-5-iodo-6~H-6 (9c~)-oxide-llcy~l5s-dihydroxy-prost-l3-enoic acid methyl ester-11,15-bis-tetra--hydropyranyl ether. A solution of this in 10 ml of acetone is added to 8 ml of 0.lN oxalic acid and heated to 45 - 46C for 4 hours. The acetone is then removed at reduced pressure and the aqueous suspension is extracted with ethyl acetate (3 x 12 ml); the organic phase is washed ~mtil neutral and evaporated to dryness. The residue ~0.42 g) is separated on silica gel with ethyl ether el~lent. Elution of the high Rf fraction with acetone gives 0.14 g o~ 13t-5-iodo-6c~l-6(9c~)-oxide-llc~,15S-dihydroxy-prost-13-enoic acid methyl ester, t~hile the low Rf portion is 0.20 g of 13t-5-ioclo-6~-6(9cY)-oxide-llcy, ! 15S-dihydroxy-prost-13-enoic acid methyl ester.
The methyl ester of the following acids were prepared analogously:
i 13t-l6s-methyl-5-iodo-6~H-6~9a)-oxide-llc~l5s-dihyclroxy-prost-l3-enoic acid;
13t-20-methyl-5-iodo-6~1-6~9c~)-oxide-llcY,15S-dihydroxy-prost-13-enoic acid, [~D ~ + 23 , ~cY~365O = ~ 78 ~Cl-lC13);
13t-5-ioclo-6~1t-6~9cY) -oxide-llcY,15S-dihydro~y-lS,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-iodo-6c~ll-6(9c~)-oxide-llc~,15S-dihydroxy-lS,19,20-trinor-17-cyclohexyl-prost-13-clloic acicl;
~ 3 ~ 3~
3~
13t-5-iodo-6~I-6~9a)-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid;
13t-5-iodo-6a~1-6(9a)-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6c~-6~9a)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
13t-5-iodo-6c~-6(9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9a)-oxide-16S-methyl-lla,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9a)-oxide-20-methyl-lla,15S-dihydroxy-prost-13-ynoic acid, [a]D = ~ 20 (C~IC13).
Example 9~
To a solution of 0.22 g of 5c,13t-9a,11a,15S-trihydroxy-15-metIlyl-PGF2 -methyl ester in 10 ml of C~I2C12 and 0.1 ml of pyridine is added drop-wise to a solution of 180 mg of iodine in methylene chloride. The resulting mixture is stirred for 1 hour. After dilution with water and washing of the organic phase with O.lN sodium thiosulfate and water until neutral, the solu-tion is evaporated in vacuum to a small volume and adsorbed on a silica gel plate 0.5 mm in thickness. After development with ethyl ether and elution with acetone, 0.052 g of 13t-15-methyl-5-iodo-6~H-6(9a)-oxicle-lla,15S-di-hydroxy-prost-l3-enoic acid methyl ester and 0.021 g of the isomeric 5-iodo-6a~1-6(9a)-oxide are obtained.
Example 95 0.2S~ g of 5c-l6~l6-dimethyl-9a~lla~l5s-tri~lydroxy-prost-s-cnoic acid methyl ester in a solution of 60 mg of pyricIiIle in me-th~leIle chloride ~ ml) is reactecl witII 115 ml of bromine in methylene chloride. After 30 minutes, starting material has completely clisapyearecI; tlIe organic yhase is ~asl~ccl liith I~ter, then 5o aqueous met~bisIllfite~ ancl then ~ater until neu-~d ~
3l5 ~
tral to give, after removal of the solvent and purification by TLC on silica gel with ethyl ether as eluent, 0.083 g of 16,16-dimethyl-5-bromo-6~H-6(9a)-oxide-prostanoic acid methyl ester and 0.04 g of 6aH-dias~ereoisomer.
The following compounds were prepared analogously:
13t-16,16-dimethyl-5-bromo-6~H-6(g~)-oxide-lla,15S-dihydroxy-prost-13-enoic acld;
13t-16,16-dimethyl-5-bromo-6aH-6~9a)-oxide-lla,lSS-dihydroxy-prost-13-enoic acid.
Example 96 To a solution of hydrotribromide pyrrolidone ~1.1 molar equivalents) in anhydrous tetrahydrofuran (6 ml) is added a solution of 5c,13t-9a,11a,15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5,13-dienoic acid methyl ester-11,15-bis-tetrahydropyranyl ether ~0.7 g) in 6 ml of tetrahydrofuran. The mixture is stirred for 12 hours, the precipitate which forms is removed by filtration, and the tetrahydrofuran solution is diluted with 2 ~-olumes of acetone and treated with 4 g of potassium iodide. After 4 hours at room temperature, the iodine liberated is decomposed with sodium metabisulfate.
1.5 volumes of O.lN aqueous oxalic acid is then added and the mixture heated to 48C for 4 hours. The mixture is reduced under vacuum and extracted with ethyl acetate, Separaticn on TLC gives 0.14 g of 13t-5-bromo-6aH-6~9a)-oxide_ lla~l5s-dihydroxy-l8~l9~zo-trinor-l7-cyclohexyl-prost-l3-enoic acid methyl ester and 0~11 g of the 5-bromo-6~H-6~9~)-oxide.
Using procedures of the examples 95 and 96, the following 6(9~)-oxides were obtained:
5-bromo 6~H~6~9al-oxide-lla,lSS-dihydroxy-18,19,20-trinor~17-cyclohexyl-prost-13~ynoic acid niethyl ester;
5-brolllo-6~1-6~9a)-oxide-lla~15S-dihydroxy-prostanoic acid;
.1[,~ ~I .Y~
~3~
13t-5-bromo-6~H-6(9a)-oxide~ ,lSS~dihydroxy-prost-13 enoic acid;
13t-20-methyl-5-bromo-6~H~6(9~)-oxide~ ,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-15-methyl-5-bromo-6all-6~9)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-16S-methyl-5-bron~o-6~H-6(9~)-oxide-:Ll~,15S-dihydroxy-prost-13-enoic acid;
13t S-bromo-6~H-6(9~-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-13-enoic acid;
13t-5-bromo-S~H-6(9~)-oxide-11~,15S-dihydroxy-17,18,19,20-tetranor-16-m-tri-fluoromethyl-phenoxy-prost-13-enoic acid.
Example 97 A solution of 0.1 x 10 M of a methyl ester, prepared according to examples 93 to 96 in 2 ml of methanol is treated with 1 ml of an aqueous solution of lithium hydrate ~0.2 x 10 3 moles). The mixture is stirred for 3 hours, evaporated nearly to dryness, diluted with 5 ml of water, and extracted with ethyl ether.
The organic phase is washed with 0.lN LiOH ~2N) and water, and is then discarded. The aqueous phase is acidified to pH 4.8 with 30% aqueous NaH2PO4 and extracted with ethyl ether to give the free acid.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of formula I
(I) wherein R is a free or esterified carboxy group; Y is -CH2CH2- or -CH=CH-trans; R2 is hydrogen; R5 is hydroxy; R3 is hydrogen or C1-C6 alkyl; R4 is hydrogen or C1-C6 alkyl; n1 is zero or an integer of 1 to 6; n2 is zero, 1 or 2; X is -O- or -(CH2)m-, wherein m is zero or 1; R6 is hydrogen, C1-C4 alkyl or an unsub-stituted C3-C9 cycloaliphatic radical, provided that (a) when X
is -O- and n2 is zero R6 is C1-C4 alkyl or an unsubstituted C3-C9 cycloaliphatic radical; (b) when X is -O- and n2 is 1 or 2 R6 is C1-C4 alkyl; and (c) when X is -(CH2)m- R6 is hydrogen or C1-C4 alkyl and n1 is zero, 1 or 2, n2 is zero, and the pharmaceutically or veterinarily acceptable salts thereof, the process comprising reacting a compound of formula IV
(IV) wherein R is as defined above and R'1 is hydroxy or a known pro-tecting group bound to the ring by an ethereal oxygen atom, with a compound of formula V
(V) (+) wherein E is a group (C6H5)3P- or a group (ReO)- wherein each of the Re groups, which are the same or different, is alkyl or aryl and R3, R4, n1, n2, X and R6 are as defined above, so obtaining, after the removal of the known protecting groups, if present, a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is trans-CH=CH- and reducing the obtained compound to give a compound of formula I wherein one of R2 and R5 is hydrogen and the other is hydroxy and Y is trans-CH=CH-, and, if desired, hydrogenating the compound of formula I
wherein Y is trans-CH=CH- to give a compound of formula I wherein Y is -CH2-CH2- or hydrogenating a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is trans-CH=CH-, to give a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group Y is -CH2-CH2- and reducing the obtained compound to give a compound of formula I wherein Y is -CH2-CH2- and/or, if desired, converting a compound of formula I into another compound of formula I and/or, if desired, salifying a compound of formula I and/or, if desired, obtaining a free compound of formula I from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
(I) wherein R is a free or esterified carboxy group; Y is -CH2CH2- or -CH=CH-trans; R2 is hydrogen; R5 is hydroxy; R3 is hydrogen or C1-C6 alkyl; R4 is hydrogen or C1-C6 alkyl; n1 is zero or an integer of 1 to 6; n2 is zero, 1 or 2; X is -O- or -(CH2)m-, wherein m is zero or 1; R6 is hydrogen, C1-C4 alkyl or an unsub-stituted C3-C9 cycloaliphatic radical, provided that (a) when X
is -O- and n2 is zero R6 is C1-C4 alkyl or an unsubstituted C3-C9 cycloaliphatic radical; (b) when X is -O- and n2 is 1 or 2 R6 is C1-C4 alkyl; and (c) when X is -(CH2)m- R6 is hydrogen or C1-C4 alkyl and n1 is zero, 1 or 2, n2 is zero, and the pharmaceutically or veterinarily acceptable salts thereof, the process comprising reacting a compound of formula IV
(IV) wherein R is as defined above and R'1 is hydroxy or a known pro-tecting group bound to the ring by an ethereal oxygen atom, with a compound of formula V
(V) (+) wherein E is a group (C6H5)3P- or a group (ReO)- wherein each of the Re groups, which are the same or different, is alkyl or aryl and R3, R4, n1, n2, X and R6 are as defined above, so obtaining, after the removal of the known protecting groups, if present, a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is trans-CH=CH- and reducing the obtained compound to give a compound of formula I wherein one of R2 and R5 is hydrogen and the other is hydroxy and Y is trans-CH=CH-, and, if desired, hydrogenating the compound of formula I
wherein Y is trans-CH=CH- to give a compound of formula I wherein Y is -CH2-CH2- or hydrogenating a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group and Y is trans-CH=CH-, to give a compound corresponding to one of formula I wherein R2 and R5, taken together, form an oxo group Y is -CH2-CH2- and reducing the obtained compound to give a compound of formula I wherein Y is -CH2-CH2- and/or, if desired, converting a compound of formula I into another compound of formula I and/or, if desired, salifying a compound of formula I and/or, if desired, obtaining a free compound of formula I from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
2. A process according to claim 1 wherein X is -O-, n2 is zero and R6 is an unsubstituted C5-C7 cycloalkyl group.
3. A compound of formula I as defined in claim 1 whenever prepared by the process claimed in claim 1 or an obvious chemical equivalent thereof.
4. A process according to claim 1 wherein R is a methoxy-carbonyl group, p is 3, Z1 is hydrogen, q is 1, R1 is hydroxyl in the .alpha.-position, R3 and R4 are both hydrogen, n1 is 2, X is -CH2-, n2 is zero and R6 is methyl or ethyl and the process in-cludes the step of reducing the oxo group to obtain a compound in which one of R2 and R5 is hydroxyl and the other is hydrogen, and Y is trans-CH=CH-and, if required, the process includes a saponification step to convert R to a free carboxyl group.
5. A process according to claim 1 wherein R is a methoxy-carbonyl group, p is 3, Z1 is hydrogen, q is 1, R1 is hydroxyl in the .alpha.-position, one of R3 and R4 is methyl and the other is hydrogen, n1 is zero, X is -O-, n2 is zero and R6 is butyl or cyclohexyl and the process includes the step of reducing the oxo group to obtain a compound in which one of R2 and R5 is hydroxyl and the other is hydrogen and Y is trans -CH=CH-.
6. A process according to claim 1 wherein R is a methoxy-carbonyl group, p is 3, Z1 is hydrogen, q is 1, R1 is hydroxyl in the .alpha.-position, one of R3 and R4 is methyl and the other is hydrogen or methyl, n1 is zero, X is -CH2-, n2 is zero and R6 is n-propyl and the process includes the step of reducing the oxo group to obtain a compound in which one of R2 and R5 is hydroxyl and the other is hydrogen and Y is trans -CH=CH- and, if required, the process includes a saponification step to convert R to a free carboxyl group.
7. A process for preparing 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15R-dihydroxy-prostenoic acid methyl ester, 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha., 15R-dihydroxy-prostenoic acid methyl ester, 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15S-dihydroxy-prostenoic acid methyl ester or 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15S-dihydroxy-prostenoic acid methyl ester which com-prises reacting 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo-[3.3.0]octan-3'?-yl)-pentanoic methyl ester with the product of reaction between (2-oxo-heptyl) dimethoxyphosphonate with sodium hydride, to obtain 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.-hydroxy-15-oxo-prost-13-enoic acid methyl ester and the corresponding 6.alpha.H isomer, separating the 6.alpha.H and 6.beta.H isomers and subjecting the 6.alpha.H or 6.beta.H
isomer to reduction with zinc borohydride to obtain the desired product.
isomer to reduction with zinc borohydride to obtain the desired product.
8. The compound 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15R-dihydroxy-prostenoic acid methyl ester, 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15R-dihydroxy-prostenoic acid methyl ester, 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha., 15S-dihydroxy-prostenoic acid methyl ester or 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15S-dihydroxy-prostenoic acid methyl ester when prepared by a process according to claim 7 or an obvious chemical equivalent thereof.
9. A process according to claim 7 which further comprises the step of saponifying the obtained methyl ester to yield the free acid.
10. The compound 13t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15R-dihydroxy-prostenoic acid, 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15R-dihydroxy-prostenoic acid, 13-t-6.beta.H-6(9.alpha.)-oxide-11.alpha.,15S-dihydroxy-prostenoic acid or 13t-6.alpha.H-6(9.alpha.)-oxide-11.alpha.,15S-dihydroxy-prostenoic acid when pre-pared by a process according to claim 9 or an obvious chemical equivalent thereof.
11. A process for preparing 13t-6.alpha.H-6(9.alpha.)-oxide-20-methyl-11.alpha.,15S-dihydroxy-prost-13-enoic acid methyl ester or 13t-6.beta.H-6(9.alpha.)-oxide-20S-methyl-11.alpha.,15S-dihydroxy-prost-13-enoic acid methyl ester which comprises reacting 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octan-3?-yl)-pentanoic acid methyl ester with the product of reaction between 2-oxo-octyl-triphenyl-phosphonium bromide and potassium t-butylate, to obtain 13t-6?H-6(9.alpha.)-oxide-11.alpha.-hydroxy-15-oxo-20-methyl-prost-13-enoic acid methyl ester and reducing this compound by reaction with zinc borohydride.
12. The compound 13t-6.alpha.H-6(9.alpha.)-oxide-20-methyl-11.alpha.,15S-dihydroxy-prost-
13-enoic acid methyl ester or 13t-6.beta.H-6(9.alpha.)-oxide-20S-methyl-11.alpha.,15S-dihydroxy-prost-13-enoic acid methyl ester when prepared by a process according to claim 11 or an obvious chemical equivalent thereof.
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT31041A/76 | 1976-12-31 | ||
| IT3104176A IT1072541B (en) | 1976-12-31 | 1976-12-31 | 6,9-Oxido prostaglandin analogues - useful as antihypertensives, vasodilators, thrombocyte aggregation inhibitors, etc. |
| IT1928377A IT1079103B (en) | 1977-01-14 | 1977-01-14 | 6,9-Oxido prostaglandin analogues - useful as antihypertensives, vasodilators, thrombocyte aggregation inhibitors, etc. |
| IT19283A/77 | 1977-01-14 | ||
| IT21171A/77 | 1977-03-14 | ||
| IT2117177A IT1085878B (en) | 1977-03-14 | 1977-03-14 | 6,9-Oxido prostaglandin analogues - useful as antihypertensives, vasodilators, thrombocyte aggregation inhibitors, etc. |
| IT214177 | 1977-03-21 | ||
| IT2L4L2A/77 | 1977-03-21 | ||
| IT21863A/77 | 1977-03-31 | ||
| IT2186377A IT1115636B (en) | 1977-03-31 | 1977-03-31 | 6,9-Oxido prostaglandin analogues - useful as antihypertensives, vasodilators, thrombocyte aggregation inhibitors, etc. |
| CA294195 | 1977-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1183841A true CA1183841A (en) | 1985-03-12 |
Family
ID=27543294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000366521A Expired CA1183841A (en) | 1976-12-31 | 1980-12-10 | Bicyclic prostaglandins and process for their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1183841A (en) |
-
1980
- 1980-12-10 CA CA000366521A patent/CA1183841A/en not_active Expired
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