DE2627422A1 - 16,16-DIMETHYL-PROSTAGLANDINS, THE METHOD OF MANUFACTURING THEM AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

50 389 - BR

Applicant: Carlo Erba S.p.Α., Via Carlo Imbonati, 24 1-20159 Milan / Italy

16,16-dimethyl prostaglandins, process for their preparation and medicines containing them

The invention relates to new 16,16-dimethyl-prostaglandins, a process for their production and medicaments containing them (pharmaceutical preparations).

The novel compounds forming an object of the invention are optically active or racemic Common Pormula prostaglandins

.which mean:

A -CH ₂ OH or -COOH ₅ in which H represents a hydrogen atom, an Oyj-G ^^ - alkyl group or a cation aia.au ¹ pharmaceutically acceptable base ?,

50S884 / 1012

the symbol a single bond or a double bond, where if the symbol denotes a double bond, E denotes hydrogen and E ^, and Rp together form an oxo group, while when the symbol ; denotes a single bond, R ^ denotes hydrogen or hydroxy and one of the radicals R ^. and R _{2 is} hydrogen and the other is hydroxy or R 1 and R 2 together form an oxo group;

B trans-CH = CH- or -C ^ c-;

one of the radicals R ₂ and Er is hydrogen and the other is hydroxy or C ^ -C ^ -alkoxy;

X is -0- or -OH-, with the proviso that X is only -CH ₂ - when B is -C ^ C-;

η is the number 0 or an integer from 1 to 5;

₆ jg, cycloalkyl with 3 to 7 ring carbon atoms or phenyl which is unsubstituted or optionally substituted by one or more substituents from the group halogen, C ^ - * ^c gÄ.lkoxy and trihalomethyl.

The double bond in the 5 (6) position is a cis double bondo

In the formulas given here, the broken lines (,,,,,) indicate that the substituents are in the α-configuration, ie below the ring or chain plane, while the thick lines ■) indicate that the substituents in the ß-configuration, ie above the hanging or chain level _? iropiiegen; the bond represented by a .. wavy line ( %} _»indicates? that the groups f ^{l /::} "^; -

s o s a a 4 / 1Q ι

either in the α configuration, i.e. below the ring or chain level, or in the β configuration, i.e. above the hanging or chain level, may be present.

As can be seen from the Forme1 Ϊ given above, the Hydroxyl group bonded to the carbon atom in the 15-position or C 1 -C 4 alkoxy group either in the α configuration (15 5S derivatives) or in the configuration

(J C. 5R derivatives) are available.

It also follows that if the symbol

means a double bond and E ^ therefore represents hydrogen, this hydrogen bonded to a carbon atom that is no longer asymmetric, obviously can exist in only one fixed position, i.e. in the input plane, and it can therefore neither be in the α-position (i.e. below the input level) high in the ß-position (i.e. above the input level).

The alkyl and alkoxy groups can be branched-chain or straight-chain (unbranched) groups. Ityl or heptyl. If E is ₆ G ^ -Og-alkyl, it is preferably methyl, isopropyl, isobutyl or tert -butyl. If Eg is a cycloalkyl group, it is preferably cyclopentyl or cyclohexyl. in the case of the MDrihalomethyl group, it is preferably trifluoromethyl or Hiriehlprmethyl. If Rg is cycloalkyl or phenyl, η is preferably the number 0 or 1,

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Examples of cations of pharmaceutically acceptable bases are either metal cations, such as sodium, potassium, Calcium and aluminum cations, or cations of organic, ni see amines, like trialkylamines.

Specific examples of compounds according to the invention are the following:

15S-dihydroxy-16-methyl-16-butoxy-18 _f 19,2O-.trinor-prosta- -5i 13-dienoic acid,

5c, 13t-9-0'XO-11o {, 15S-dihydroxy-16 ~ methyl-16-pentyloxy-18,19,20-trinor-prosta- -5113-dienoic acid,

5C | 13t-9-Cxo-11o (, ^ S-dihydroxy-io-methyl-io-propoxy-ie, 19,20-trinor-prosta- -5,13-dienoic acid, =

5c, 13t-9- ° xo-15S-hydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13- -dienic acid,

5c, 13t-9-Oxo-15S-hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13- - service pigs,

5c, ^ t ^ -Oxo- ^ S-hydroxy-io-nisthyl-io-pentyloxy-ie, 19,20-tri2ior-prosta- -5i 13-dienoic acid, -

5c ^ 9-O / xo-11oi ι ^ S-dihydroxy-io-methyl-ie-butoxy-iS, 19,20-trinor ~ prost-5-en- -13-ynoic acid,

Sc ^ -oxo-Hc ^, 152-dihydroxy-i6, i6-dimethyl-prost-5-en-13-yn acid, 5c-9-Qxo-15S-hydroxy-16-methyl-16-butoxyJl 8,19,20-trinor-prost-5-en-13-in_ acid,

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5 ° -9 ß> ι1 ¹ ° (, 15S-trihydroxy-16-methyl-i6-bu1; oxy-i8,19,20-trinor-prost-5-en-

-13-ynoic acid,

5c-9oi. 11 lot, £ 15 JDrihydroxy-16-methyl-i6-bu-toxy-18,19,20-trinor-prost-5-en-

5c, 13t-9 ß, 1 ld, 15S- ^ ihydroxy-i6-raethyl-i6-butoxy-i8,19,20-irinor-prosta- -5,13-diensa-are,

5cj 13t-9 Ρ 111oL, ^ S-Trihydroxy-io-me'-thyl-io-propoxy-ie, 19,20-trinor-prosta-

5c, 13t-9ß, 11 d., ISS-trihydroxy-io-methyl-io-pentyloxy-ie, 19,20-trincr-prosta- -5,13-dienoic acid,

5 ^C »13t-9cl, 11o (, ^ S-Tribydroxy-io-methyl-ib-butoxy-iS, 19,20-trinor-proGta- -5,13-dienoic acid,

5c, 13t-9-Oxo-15S-hydroxy-i6-! Acthyl-i6-butoxy-i8,19, 20-trinor-prosta-5,10 (11),

-trienoic acid,. ·

5c ~ 9-oxo-15S-liydroxy-16-m3thyl-16 ~ butoxy-18,1o, 20-trinor-prosta-5 _f 10 (ii) -dien- -13-yoic acid.

as well as the 15E epimers and the methyl esters thereof.

The compounds of the general formula I given above are prepared according to a further subject of the invention forming process, which is characterized in that an optically active compound or a racemic Mixture of compounds of the general formula

H OH

^ "V ^ C (CHJ -X-CCH) -R

II

wherein n, R _g and X have the meanings given above, B «-G = C- or

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trans-C = G-, where Y is hydrogen or bromine,

R'-z is hydrogen or a known protective group which is bonded to the ring via an ether oxygen atom, and one of the radicals R ^f ^ and SV is hydrogen and the other is CL -C ₁ . -Alkoxy or a known protective group that is bonded to the chain via an ether oxygen atom, mean

with a Wittig reagent of the general formula - ₂ ^, in which A ¹ -COOR, in which R has the meanings given above, or -GHo-R ", in which R" is a known protective group as defined above,

with formation of a compound of the general formula

^R 3 ^H s ^p v

where η, X, Rg, R ¹ ^, R ' ₄ , R ¹ ^, have meanings,

C (CH) -X- (CH.) -R ο 2> 2 η η

III

¹ d-ie given above

which, after any esterification carried out in the 1-position, if A ^{1 is} carboxy, is then optionally converted into the corresponding 9β-hydroxy derivative and then optionally the protective groups in the 1 and / or 11 and / or 15 positions are removed to form a compound of the general formula I in which A, R ^, B, R ^, Rj-, X, η and Rg have the meanings given above

have the icon a single bond, one of the

R ^ and Rp radicals are hydrogen and the other is hydroxy and one of the R ^ and R ₁ radicals is hydrogen and the other is hydroxy or C ^ -C ^ _- alkoxy, or

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if desired, the 9α- or 9β-hydroxy group of a Ver
binding the general formula

IHa

where B, A ¹ , R'z » ^Rl ii» - ^ ¹ R * - ^ » ^{n un <i} ■% ^ ^e ° ^ ^en have the meanings given and one of the Eeste R ¹ ^ and R ' _{2 is} hydrogen and the other Mean hydroxy,

oxidizes to form a compound of the general formula

IV

wherein A ·, R ¹ ^ »B, R ¹ λ, R ¹ c, X, η and Rg have the meanings given above,

from which in turn the protective groups in the 1 and / or 11 and / or 15 positions are then removed, depending on
according to the reaction conditions used either one

Compound of the general formula I, in which the symbol

mean a single bond, R, hydrogen or hydroxy
and R ^ and Rp together form an oxo group, or one
Compound of general formula I is obtained by anyone who has Öynbol

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a double bond, R, 'hydrogen' mean and R ^ j and Rp together form an oxo group ^ and / or if desired a compound of the formula I in which A is -COOR, in which R is hydrogen, and in which the Hydroxy group in the 11- and / or 15-position, if present, optionally protected as indicated above is reacted with a base and then, if necessary, the protecting groups are removed to form a compound of the general formula I, in which A is -COOR, in which R is a cation, or a compound of the general formula I in which A is -COOR in which R is Y / hydrogen and wherein the hydroxyl group in the 11- and / or 15-position, if present, optionally as above is protected, esterifiesv to form a compound of the general formula I, in which A is -GOOR, wherein R is C ^ -C ^ .- alkyl, or a compound of general formula I, where A is -COOR, where R is C ^ tC ^ - Alkyl represents ^ and in which the hydroxyl group in the 11- and / or 15-position, if present, is optionally protected as indicated above, hydrolyzed and then if necessary the protecting groups are removed therefrom to form a compound of general formula I wherein A -COOR denotes in which R is hydrogen.

The term "Wittig reagent" as used herein means compounds the general formula

(\) ₃ - I - (CH ₂ ) ₄ - A- Hai ⁽ ->

where R is alkyl or aryl, preferably phenyl, A ^{1 has} the meanings given above and Hal is halogen, preferably bromine or chlorine, if R is alkyl, it is preferably ethyl.

*) and then, if necessary, the protective groups are removed

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The preparation of the Wittig reagent is in Tripett, "Quart. Rev. ", 1963, XVII, No. 4, 406.

The Wittig reaction is carried out using the conditions customarily used in this type of reaction be used, i.e. in an organic solvent such as diethyl ether, hexane, dimethyl sulfoxide, tetrahydrofuran. Dimethylformamide or hexamethyl phosphoramide, in the presence a base, preferably an alkali hydride such as sodium hydride, of an alkali tert-butoxide, such as potassium tert-butoxide, or of a sodium dimethylsulfonylcarbanion, at O C up to the reflux temperature of the reaction mixture, preferably at Room temperature or below.

^{If B 1} denotes trans-CH = CH- in the lactol of the formula II, compounds of the formula III in which B denotes trans-CH = CH- are obtained. If in the lactol of the formula II B ¹ denotes -C =C- or trans-CH =CY-, in which Y is bromine, compounds of the formula III in which B denotes -C =C- are obtained.

The Wittig reaction is preferably carried out using from about 2 to about 3 moles of Wittig reagent per mole of lactol and the reaction lasts from 10 to 20 minutes to 2 to 3 hours.

The known protective groups (i.e. ether groups) should be used under mild reaction conditions, e.g. by acid hydrolysis, be convertible into hydroxyl groups. Suitable examples are acetal ethers, vinyl ethers, enol ethers and silyl ethers. Preferred groups are as follows:

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CH CH, 3.3

CH.- C - Si - O-, (CHj.-SiO-, 3 sj ο ό

OAIk

CH "CH_

O ό

0-

ΟΙ J

ο-

wherein W -0- or -CHp- und.Alk is a lower alkyl group mean.

The conversion of the 9oc-hydroxy derivatives of the formula III into the corresponding 9-β-hydoxy derivatives takes place by esterification of the 9 <x -hydroxy group with a carboxylic acid in the presence of a compound of the formula M ^T Y, where M ^{T is} a metalloid of the group Y of the Periodic Table of the elements, and Y is an alkyl or dialkylamino _t a _r mean yl group, and a hydrogen to form a 9SS-Acyloxyderivats, that is with complete inversion of the configuration of the hydroxy group at the 9-position, This reaction is preferably carried out at room temperature carried out in an inert anhydrous solvent, which is preferably from the group of aromatic. Hydrocarbons such as benzene and toluene, the linear or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane is selected. All reagents used, ie the compounds of the formula M ^V Y ,, the esterifying carboxylic acid and the hydrogen acceptor, are used in an amount of at least 1.5 moles per mole of alcohol; preferably 2 to 4 moles of the reagents are used per mole of alcohol.

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In the compound of the formula M Ϊ, "M ^v preferably _{denotes P 1} As, Sb, in particular P _0. In the same compound, if Y denotes alkyl, it is preferably methyl, while if Y denotes aryl, it is preferably phenyl; if Y is dialkylamino, it is preferably dimethylamino · The compound of the formula M Y- is preferably selected from the group triphenylphosphine, triphenylarsine, triphenylstibine and hexamethyltriaminophosphine of the formula C (CH ^) ₂ N], P.

The hydrogen acceptor used is preferably an ester or an amide of azodicarboxylic acid, preferably ethyl azodicarboxylate, but other hydrogen acceptors can also be used, e.g. 2,3,5, e-tetrachlorobenzoquinone, 2,3-dicyano-5,6-dichlorobenzoquinone or azobisformamide

The 9β-acyloxy derivative obtained in the esterification reaction with reversal of the configuration of the 9-hydroxy group is then used saponified in the usual way, the corresponding compound with the free 9β-hydroxy group receives

The removal of protective groups, if any, in the 1 and / or 11 and / or 15 positions of the connection of the formula III or in the corresponding 9β-hydroxy derivative takes place under the conditions of a mild acid hydrolysis, e.g. with mono- or polycarboxylic acids, such as formic acid, acetic acid, oxalic acid, citric acid and tartaric acid, and in a solvent such as water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols · Preferably 0.1 to 0.25 N polycarboxylic acid (e.g. oxalic acid or citric acid) in the presence of a suitable low-boiling cosolvent that is miscible with water is easy and in a vacuum after completion of the reaction

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can be removed, used. The oxidation of the 9 <x- or 9β-hydroxy groups to form an oxo group can, for example, with the Jones reagent or with the Moffatt reagent be performed.

As indicated above, one obtains on removal of the protecting groups in a compound of formula IV depending on the used Reaction conditions either a compound of

Formula I, in which the symbol a single bond, R ^

Are hydrogen or hydroxy and R ^ and R ₂ together form an oxo group, or a compound of the formula I,

in which the symbol a double bond, R ^ hydrogen

and R ^ and R ₂ together form an oxo group. The first-mentioned compound can be obtained as the only product when working at temperatures within the range of about 25 to about 35 to 38 ° C, while when working at higher temperatures, for example at the reflux temperature for a period of about 3 hours, the last-mentioned compound is obtained as the only product. In this case, too, mono- or polycarboxylic acids, such as formic acid, acetic acid, oxalic acid, citric acid and tartaric acid, and a solvent, as indicated above, are used ο

The salt formation, esterification and hydrolysis stages carried out subsequently, if appropriate, are carried out in the customary manner. The hydrolysis of a compound of the formula I in which R ^ and R ₂ together form an oxo group and A-COOR is, in which R is Cj-C ^ -alkyl, to a compound of the formula I in which R ^ and R ₂ together are Forming an oxo group and A is -COOR, in which R is hydrogen, however, it is preferably carried out by an enzymatic route, for example using a yeast esterase.

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The lactol of the formula II can in turn be carried out by a multistage process, one being as Starting material is an optically active or raceric lactone the general formula used

It 0

C (CH) -X- (CH) -R, 3 2 2 η ο

where R "^ is hydrogen or acyloxy, Y, X, η and Rg have the meanings given above and the double bond is a trans double bond «,

If in the lactone of the formula Y R "- * denotes acyloxy, it is preferably formyloxy, acetoxy, eropionyloxy, benzoyloxy and p-phenylbenzoyloxy V comprises the following stages:

a) Reduction of the 15-oxo group (according to the irostaglandin ITumeration) of the lactone of the formula Y to form a mixture of 15S and 15R oils of the general formulas

OM H

^ -JC- (CO el 2

2 η

MR

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H OH

(VI b)

. 01)

where R "*» Υ »X» n and. Rg have the meanings given above to have,

subsequent separation of the 15S-OI from the I5R-OI and if desired Dehydrobromination of the separated alcohols, in which T is bromine, with formation of a compound the general formula

VIIa

HO H
or a compound of the general formula

VIIb

HR " ^C ^ X ^ C (CH VX- (CHJ -R.

H OH

where R "*» Σ, η and Rg have the meanings given above to have.

If desired, the reduction can follow the dehydrobromination. The reduction of the 15-oxo group can expediently in an organic solvent such as diethyl ether, tetrahydrofuran, dirnethoxyethane, dioxane, benzene, methylene chloride or mixtures thereof using λτοώ. For example, metal borohydrides, especially sodium borohydride, lithium borohydride, zinc borohydride or sodium trimethoxyborohydride, are carried out. The separation of the 15S-OIs from the 15R-01 can be carried out by chromatography,

609884/1012

for example by silica gel chromatography or by fractional crystallization. The dehydrobromination can in a solvent such as dimethyl sulfoxide, dimethylformamide and hexamethylphosphoramide, in the presence of a base which is, for example an alkali metal amide, potassium tert-butoxide or the

Anion CH ^ -S '* -

can act;

b) optionally converting a compound of the general formula

(VIII)

BKe- (CH) _X _ _(CH , 3 f ^ ^{ό Δ} 2 η 6

R ", R"
4 5

where E ",, B ¹ , X, η and Eg have the meanings given above and one of the radicals E" ^ and E ¹ V is a hydrogen atom and the other is hydroxy,
into a compound of the general formula

(EC)

η in ρ

where E ", B ¹

the meanings given above

, B, X, η and g

and one of the radicals E ¹ "^" and E "'^ is hydrogen and the other is C ^ -C ^ alkoxy.

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The conversion is carried out in the usual way, for example by reacting the compound of formula VIII with a diazoalkane in methylene chloride in the presence of Fluoroboric acid and / or BF ^ etherate;

c) Conversion of a compound of the general formula

MR"

wherein E ",, B ', X, η and Eg have the meanings given above have and one of the radicals R ^ and R, - hydrogen and the other Mean hydroxy or C ^ -C ^ -alkoxy,

into a compound of the general formula

XI

where E ¹ ,, B ¹ , X, η and Rg have the meanings given above and one of the radicals R ¹ ^ and EV is hydrogen and the other is CL-C.alkoxy or a known protective group attached to the chain via an ether oxygen atom. The conversion of the compound of the formula X into a compound of the formula XI occurs when in the compound of

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Formula X R "^ means an acyloxy group, a saponification, for example by mild treatment with an alkali, advance to form a compound of formula X, wherein R "^ is hydroxy The conversion of the compound of Formula X into a compound of formula XI is preferably reacted with an acetal ether or a vinyl ether, e.g. those of the formulas

Π0 -

where W -0- or -CH ₂ - in the presence of catalytic amounts of, for example, phosphorus oxychloride, p-toluenesulfonic acid or benzenesulfonic acid or with a silyl ether, for example by reacting a trisubstituted chlorosilane in the presence of an acceptor base (e.g. a trialkylamine) for the hydrohalic acid formed , or with an enol ether, for example by reaction in the presence of an acid catalyst with a 1,1-dialkoxycyclopentane or cyclohexane or with a cyclopentanone or cyclohexanone diacetal, at the reflux temperature in an inert solvent and distilling the alcohols formed to form mixed dialkoxy ethers or mixed acetals or enol ethers ^ depending on the amount of catalyst used or the duration of the heating, carried out;

d) Reduction of the compound of the formula XI to the lactol of the formula II. The reduction can be carried out, for example, by treatment with diisobutylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride in an inert solvent such as toluene, η-hexane, n-heptane, Benzene or mixtures thereof, are carried out ^{at a temperature below 30 ° C.}

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For all of the above under sections a) to d) Compounds can be either optically active compounds or racemic mixtures thereof.

The lactone of the formula V can in turn be produced by reacting an optically active or racemic compound of the general formula

(XU)

wherein R "^ has the meanings given above, with a phosphonate carbanion of the general formula

ROOY ζ .- ■

^a \ r ι '·

R 0 ^{/ (} - ^{} 3? 2 n 6}

wherein R _{n is} lower alkyl and X, X, η and R, - have the meanings given above. The reaction is expediently carried out in a solvent which is selected, for example, from the group consisting of dry benzene, dimethoxyethane, tetrahydrofuran or mixtures thereof, and using a suspension of 1.05 "to 2 molar equivalents of the phosphonate carbanion per mol of aldehyde.

The aldehyde of formula XII can be prepared essentially as described by EJ Corey et al in "Ann. Of New Xork Acad. Of Sciences", 180 , 24 (1971).

The phosphonate carbanion of the formula XIII can in turn be prepared by reacting a phosphonate of

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general formula

^R 0 0 Y

RAW " ⁶

wherein E, Y, X, η and Eg have the meanings given above to have,

with 1 equivalent of a base, which is preferably selected from the group consisting of sodium hydride, lithium hydride, calcium hydride, an alkyllithium derivative and an anion CIL-SOCHp "* is selected.

The phosphonate of the formula XIV, in which Y is hydrogen, can be prepared by known processes, for example after E.J. Corey et al in "J. Am. Chem. Soc", 90, 324-7 (1968) and E.J. Corey and G.K. Kwiatkowsky, "J. Am. Chem. Soc. 88: 5654 (1966). The phosphonate of formula XIV, wherein Y Means hydrogen, is preferably prepared by reacting lithium methyl phosphonate with a lower alkyl ester or a halide of the optionally substituted aliphatic acid. For example, the phosphonate of the formula XIV, in which Y is hydrogen and X is -0-, are prepared by reacting a lithium methylphosphonate the general formula

• · ^R a ° \?

; p - CH Li,

R θ '.
a

wherein E _{0 has} the meanings given above,

el

with a compound of the general formula

wherein η and E _{c have} the meanings given above and

Z mean a lower alkoxy group or a halogen atom »

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The compound of formula XVI can be based on conventional Way to be prepared from the corresponding acid, which in turn according to the information in British patent specification 578 082 or in "J. Gen. Chenu (U.S.S.R.), 12, 1327 (194-7) »can be produced.

The phosphonate of the formula XIV, where Y is bromine, can be prepared by reacting a phosphonate of the formula XIV, where Y is hydrogen _} with an excess of a brominating agent from the group consisting of bromine, bromodioxane, pyrrolidone hydrotribromide, pyridine hydrotribromide in an inert solvent such as benzene, Tetrahydrofuran, dimethoxyethane, dioxane, methylene chloride or mixtures thereof.

The bromination of the phosphonate of the formula XIV, in which Y is hydrogen, is preferably carried out in methylene chloride at room temperature and using 1.05 molar equivalents of Br ₂ . The yields obtained in the reaction of an aldehyde of the formula XII with the phosphonate carbanion of the formula XlII, in which Y is Br, for the preparation of a lactone of the formula V, in which Y is Br, are generally unsatisfactory and therefore the compounds of the formula V can optionally , in which Y is Br, are prepared from the compounds of the formula "V in which Y is hydrogen by reaction with an excess of a brominating agent from the group consisting of bromine, bromodioxane, pyrrolidone hydrotribromide, pyridine hydrotribromide in an inert solvent such as benzene, tetrahydrofuran, dimethoxyethane, Dioxane, methylene chloride or mixtures thereof to form a mixture of dibromo derivatives of the formulas XVIIa, XVIIb and XVIIc given below:

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2 η η

" ₇ / '\ x _c ^ C (CHJ -X- (CH) -R ₁

(XVI la)

Ii O

(XVI

viii / η ^Η 0

C (CH) -X- (CH ₀ ^ -R _r (XVI Ic)

wherein R ",, X, η and Eg have the meanings given above to have,

and then the dibromo compound mixture is dehydrobrominated with formation of compounds of the formula V in which Y is Br. The dehydrobromination reaction can either with the mixture of the compounds of the formulas XVIIa, XVIIb and XVIIc or with the separated isomers. The separation of the mixture of the compounds of the formulas XVIIa, XVIIb and XVIIc for the preparation of the one isomers can be done, for example, by chromatography on silica gel.

In either case, the dehydrobromination reaction results in both Compounds in which the carbon atom in the 13th the hydrogen atom bonded to the carbon atom and the bromine atom bonded to the carbon atom in the 14 ~ position (according to the Prostaglandin numbering) in the trans position (geometric trans-isomers or Z-isomers) exist, as well as compounds, wherein the atoms are in the cis position (geometric cis isomers or Ε isomers).

The geometric trans isomer (Z isomer) of the general formula

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can easily be derived from the geometric cis-isomers

the general formula
0

. · B

be distinguished that the H. vinyl protons of the two Isomers in different positions resonate and that the coupling constants of the H, vinyl per tons with the H-g proton are clearly different from each other (9 Hz for the trans isomer and 10.2 Hz for the cis isomer).

The bromination of the compounds of the formula V in which Y is hydrogen to form the dibromo derivatives of the formulas XVIIa, XVHb and XVIIc is preferably carried out in methylene chloride at room temperature and using 1.05 molar equivalents of Br ₂

The dehydrobromination reaction can be carried out using, for example, pyridine at one temperature which varies between room temperature and reflux temperature. The same dehydrobromination can also take place Use of an alkali or alkaline earth metal acetate in an inert solvent such as a lower aliphatic Alcohol, such as methanol or ethanol, or a ketone, such as acetone or methyl ethyl ketone, as well as in one Amide, preferably dimethylformamide and dimethylacetamide, at a temperature between room temperature and reflux temper at irr. The rrozeuusuende. the cis isomers (Ε isomers) and the trans isomers (Z isomers)

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vary depending on the reaction conditions used in the dehydrobromination. Thus, the trans-isomers, for example when working in pyridine at about 8O ⁰ C virtually the only products obtained necessary, can be separated from the trans isomers for example by crystallisation and chromatographic purification of the cis-isomer.

Of the intermediates described here, the compounds given below are additional ones New compounds forming the subject of the invention:

1.) Phosphonates of the general formula

^R a ° O 0

* _y P - CH - B - C (CH) -0- (CHJ - R R0 ^/ ■ ^{2n 6}

in which R, η and Rg have the meanings given above; 2.) Compounds of the general formula

wherein B ¹ , X, η and R ^ have the meanings given above, one of the radicals QL and Qo is hydrogen and the other is hydroxy or Q ₁ ^ and Q2 together form an oxo group, R " ¹ , hydrogen, hydroxy, acyloxy or a Protective group bonded to the ring via an ether oxygen atom, one of the radicals R ^, and R ₁ - hydrogen and the axiviere hydroxy,

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C * -CL-alkoxy or one via an ether oxygen atom to the Chain-bound, known protecting group, or when Q ^ and QU together form an oxo group, E. and Reg together also form an oxo group;

3 ·) Compounds of the general formula

XX

where A ^! , B, X, η and Eg h are as defined above _a ben, _x one of the radicals R, and are each Rp is hydrogen and the other is hydroxy or R ^ and R ₂ together form an oxo group and R ¹ * "R ¹ ^ and E 't- have the meanings given above, with the proviso that when A' is different from -OHpR ", in which R" has the meanings given above, at least one of the radicals R'zj R '/ j. and R'r was a known protecting group as defined above

The compounds of formula I can be used for the same therapeutic Indications such as natural prostaglandins are used, but over which they have the advantage that they are not substrates for the enzyme 15-prostaglandin dehydrogenase represent the well-known natural prostaglandins quickly inactivated, and moreover they are characterized by a more selective therapeutic effect. The compounds of formula I also prevent competing the use of natural prostaglandins as Substrate by this enzyme, the compounds according to the invention of the formula I have, in particular, a hypotensive and antihypertensive activity (effectiveness) as well as a

609884/1012

A-ntibronchienspasm en activity ^ effectiveness) and they are particularly suitable as gastro-antisecretory and antiulcerous agents, as can be seen from the table below, which shows that they also have a very low spasmogenic activity, ie a very low one inclination have smooth muscles as z'.B _o the ileum of guinea pigs and the uterus of rats to stimulate _o

Tabel

examined
links isolated
organs .n-
Had-
uterus
(* ·) Rats gastro-anti
secretory
activity
(*** ■ *) PGE
16,16-diraethyl-
-PGE ₂
17 ~ Oxa-i6,16,20-
trimethyl PGS 'Äeerschv / e
shen-ile-
UHl
l ·} 1
0.45
0.01 antiulcer
activity BCPO
1
24 1
7 0.6 1
3.6
0.11 ε.cpO
1 1
15 30
11 14

809884/1012

Footnotes:

(*) In 10 ml of a thermostatic held at 35 ° C The ileus of male guinea pigs were bathed under a tension of 0.5 g of carbon dioxide in exposed to Tyrode's solution; the preparation was Left to its own devices for 30 minutes to stabilize before testing connections. The responsiveness was measured using an isotonic frontal lever that was long enough was to increase the sensitivity to 4 x, 5 times to reinforce recorded.

(**) In 10 ml of a thermostatic held at 29 ° C Eattenuteri treated with estrogen were placed under a tension of 0.5 g of carbon dioxide in baths exposed to Dejalon saline solution. The preparation was allowed to stabilize for 30 minutes before the compounds were tested. The responsiveness was made using an isotonic frontal lever long enough to increase responsiveness 4 to 5 times amplify, measured.

(***) According to the method of Takagi-Okabe (K. Takagi et al, "Jap? J. Pharm.", 18 »9 (1968)) became ulcers induced;

(****) According to Shay (H. Shay et al, "Gastroenter.", 26, 906 (1954-)).

As can be seen from the table above, the therapeutic index of the compound 17-0xa-16,16,20-trimethyl-PGE ₂ , ie the 5c, 13t-9-oxo-11a, 15S-dihydj? Ö ^ 6methyl-16- butoxy-18,19,20-trinor-prosta-5,13-dienoic acid, in that this compound has antiulcer and gastro-antisecretory activity 0.5 to 0.8 times that of compound 16 , 16-dimethyl-PGEp, while its spasmogenic activity is 30 to 40 times lower,

609884/1012

what to the non-existence of undesirable effects, such as nausea, vomiting, diarrhea and abdominal pain, which is attributed precisely to the stimulation of smooth muscles are, indicates.

The compounds of the formula I can be used orally, parenterally or intravenously or intrauterine (extraamniotic or intraamniotic), in the form of rectal suppositories or through Inhalation can be administered. You can, for example, by intravenous infusion of a sterile isotonic saline solution administered in an amount from 0.01 to 10, preferably from 0.03 "to 1 ng / kg mammalian body weight per minute will.

The invention also relates to at least one compound of the general formula I, optionally in combination medicament containing a pharmaceutically acceptable carrier or diluent (pharmaceutical preparation).

The medicaments can be produced by conventional methods and they can, for example, in the form of tablets, Capsules, pills, suppositories or bougies or in liquid form, e.g. in the form of solutions, suspensions or Emulsions

Examples of substances that can serve as carriers or diluents are water, gelatin, lactose, starches, Magnesium stearate, talc, vegetable oil, benzyl alcohol and cholesterol.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto. The abbreviations THF, THP, DIOX and DIBA used therein each stand for tetrahydrofuran, tetrahydropyranyl, dioxanyl and diisobutylaluminum hydride ”. The sj. Unless otherwise stated, specific rotation values were measured in a chloroform solution with a concentration of 1% at 20 ^{° C.} 609884/1012

example 1

A stirred solution of 2.8 g of 5/3 -hydroxymethyl ^ d. , 4d. -dihydroxycyclopentan-ic * - -acetic acid / -lactone-A-p-phenylbenzoate in 25% dimethyl sulfoxide in benzene (20 ml) was mixed with 2.3 g of dicyclohexylcarbodiimide and with a solution of 3 ^ 5 ml of pyridine trifluoroacetate in 25% Dimethyl sulfoxide in benzene prepared from 2 ml of pyridine and 1 ml of trifluoroacetic acid in 25 ml of 25% dimethyl sulfoxide in benzene. After 3 hours, the excess carbodiimide was destroyed by adding 40 ml of an aqueous solution of 1.4 g of oxalic acid, and the reaction mixture was diluted with 80 ml of benzene and filtered. The organic layer was washed until neutral, dried and evaporated to dryness under vacuum, after which, after crystallization from CHoCTo / ethyl ether, 2.52 g of 5/3 -EOrmyl-2ct, 4d- -dihydroxycyclopentane-idL acetic acid- J -lactone- 4-p-phenylbenzoate, P. 154-156 ° C.

Using the same procedure, starting from the corresponding 5β-hydroxymethyl compounds, a 5/5 formyl ^ d- -hydroxy-cyclopentane-idL -acetic acid-T -lactone and a 4-ester (acetate, propionate, benzoate, p -Phenylbenzoat) des 5 β -Pormyl-2oL, 4oL -dihydroxy-cyclopentane-i cX -essigsaure- y -lactones either in the optically active or in the racenic form.

Example 2

25 g of dimethyl (2-oxo-3-methyl-3-butoxybutyl) phosphonate in 35 ml of dry benzene was added to a stirred suspension of an 80% sodium hydride dispersion in mineral oil (2.8 g) in 350 ml of dry benzene were added dropwise. The mixture became wider Stirred for 2 hours, then a solution of 26, ^ g

609884/1012

2d- ^ ck-dibydroxy-cyclopentan-id. -acetic acid-Y lactone-4-p-phenylbenzoate added. After 11/2 hours the reaction mixture was diluted with water, then the organic phase was separated off, washed until neutral and evaporated to dryness, after which, after crystallization from hexane / ethyl ether, 32 g of $ fi - (3'-oxo-4 '-methyl-4'-butoxypent-1'-trans-1'-enyl) -2d-, 4a-dihydroxy-cyclopentane-icL-acetic acid-Y-lactone-4-p-phenylbenzoate, mp 95 to 97 ° O , M _{d =} .114.9O ₁ M ₄₅₆ O. = -279.5 °.

Using the same procedure, alkylation of the corresponding 5/3 -Pormylderivate the following Ketones made:

5 /? - (3'-Oxo-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -2ct, 4ct-dihydroxy-cyclopentane-1 cL-acetic acid- / -lactoii-4-acetate , 227 myLi ( C = 8300) and

5ß - (3 '-oxo-4' -methyl-4 ¹ -butoxy-pent-1 · -trans-1 · -enyl) -2ahydroxy-cyclopentane-1d-acetic acid- γ- lactone, X ^e 228 m / χ U = 9000).

Example 3

Using dimethyl (2-oxo-3-methyl-3-propoxybutyl) phosphonate and dimethyl - ^ - oxo ^ -methyl-J-pentyloxybutyl) phosphonate, the following CL ₁ / => -unsaturated ketones were obtained as indicated in Example 2 manufactured:

5/3 - (3 ¹ -oxo-4 ¹ -methyl-4 ¹ -propoxy-pent-1'-trans-1'-enyl) -2 cL, -4d-dihydroxy-cyclopentane-1 et -acetic acid-y - lactone-4-pphenylbenzoate, P. 109 to 111 ⁰ C (from MeOH), [olI ^ = -124.8 °, 5β - (3'-Oxo-4'-methyl-4 ¹ -pentyloxy-pent-1 '-trans-1'-enyl) -2 oL, 4 OL -dihydroxy-cyclopentane-i oil -acetic acid-Γ -lactone-4-pphenylbenzoate, F. ^ ¹ S to 119 ° -, f ^ l- = ■ - 97 °,

5 β _ (3'-Oxo-4 ¹ -methyl-4'-propoxy-pent-1'-trans-1'-enyl) -2 a. -

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hydroxy-cyclopentane-i cL-acetic acid v - lactone, X _m 227 πι / Χ (ε = 9900),

> ^ - (3'-Oxo-4'-methy1-4'-pentyloxy-pent-1'-trans-1'-enyl) -2d.-hydroxy-cyclopentane-1ci acetic acid / lactone, A 22?

Q HLgUX

(£ = 9850).

Example 4

A solution of 0.07 mol of zinc borohydride in 700 ml of ethyl ether was stirred, then a solution of 21 g of 5β - (3'-0xo-4 '-methyl-4 ¹ -butoxy-pent-1'-trans-1'- enyl) -2 α, 4 α-dihydroxycyclopentane-1 el. -acetic acid- Y- lactone-A-p-phenylbenzoate in dry dimethoxyethane was added. After 2 hours the excess reagent was disturbed by the careful addition of 2N I ^ SO ^ ser, the organic layer was separated, washed with water until neutral and evaporated to dryness and the residue was absorbed on a silica column (2 kg). After eluting with ethyl ether / isopropyl ether (1/1), 9.2 g of 3β - (3 'S-hydroxy-4-'-methyl-4'-butoxypent-1 ^! -Trans-1'-enyl) -2 were obtained oi. , 4cL -dihydroxy-cyclopentan-i et acetic acid- / · -lactone-4-p-phenylbenzoate, £ & -] $ = -83.9 °, LccC- = -377 °, 8.2 g of its 3'R -Hydroxy isomers, = -89.6 °, Td] ₃₆₅ O = -392 °.

example 3

Using the ketones of Examples 2 and 3 and below Using the procedure described in Example 4 were used the alcohols listed below are produced:

5 β - (3 'S-hydroxy-4- ¹ -methyl-4' -propoxy-pent-1 '-trans-1'-enyl) · 2 oL, 4οι -dihydroxy-cycloperitane-i ot- -acetic acid- Y -lactone-4-p-phenylbenzoate, oil, LcO _D = -51 * 6 °, and its 3'R-isomer

609884/1012

F. 98 to 101 ⁰ C, M _D = -106 °,

5/3 - (3 ¹ R-Hydroxy-4 '-methyl-4' -pentylozy-pent-1 '-trans-1' enyl) -2 et, 4-OL -dihydroxy-cyclopentane-1 cL-acetic acid- r -lactone-4-p-phenylbenzoate, oil, CoJ- ^ = -40 °, and its 3'S isomer, fd1 _D = -74.5 °,

5/3 - (3 'S-Hydroxy ~ 4'-methyl-4 ¹ -propoxy-pent-1'-trans-1'-enyl) -2di-hydroxy-cyclopentane-1 d.-acetic acid- ^ -lactone and its 3'R isomer,

5/3 ~ (3 'S-Hydroxy-4 ¹ -methyl-4' -butoxy-pent-1 '-trans-1' -enyl) -2 <^ - hydroxy-cyclopentane-ick-acetic acid-J-lactone and its 3'R isomer,>

5/3 - (3'S-Hydroxy-4- '-methyl-4 ¹ -pentyloxy-pent-1' -trans-1 'enyl) -2oi -hydroxy-cyclopentane-i dL -acetic acid- ν -lactone and its 3' E ~ isomer.

Compartment Performing a chromatographic separation on a silica gel column (using a methylene chloride / ethyl ether (980/20) mixture or isopropyl ether / ethyl ether (800/200, 700/300, 500/500) mixtures as eluants).

Example 6

An excess of diazomethane in CH 2 Cl 2 was added to a solution of 0.8 g of 5y5 - (3 ¹ S-hydroxy-4- ¹ -methyl-4'-butoxy-pent-1'-trans-1'-enyl) -2cL ^ dl-dihydroxy-cyclopentan-idl -acetic acid- ^ lactone-4-p-phenylbenzoate in 8 ml CH ₂ Cl ₂ and 0.02 ml BF ^ - etherate, cooled to -10 ⁰ C, added until there is a pale yellow color stayed. The organic layer was washed with 5% NaHCO ^ and water, _{dried over Na 2} SO ^ and concentrated to a small volume. After filtering through a silica gel column, 0.72 g of 5/3 - (3'S- ^ '- A' -methyl-4 '-buto3Q ^T »r: nt-1' -traiic-1 '-ε,.;, l) -2 α, 4α-

dihydroxy-cyclopentane-1 ö- -acetic acid- 1- -lactone-4-p-phenyl-

609884/1012 '

benzoate.

Using this procedure, the alcohols became the Examples 4 and 5 by reaction with diazomethane or diazoethane converted into their 3'-methoxy and 3'-ethoxy derivatives.

Example 7

A solution of 0.7 g of 5/3 - (3'S-Hydroxy-4'-methyl-4'-pentyloxy-pent-1'-trans-1'-enyl) -2 cL, 4ol -dihydroxy-cyclopentane-i cl acetic acid y- lactone-4-p-phenylbenzoate in 12 ml of absolute methanol was reacted for 3 hours with 0.23 g of anhydrous KpCO- *, then acidified to pH 4-.2 with 2N ILjSO ^ and stirred for 1 hour. After diluting with water and removing the methanol in vacuo, the reaction mixture was extracted with ethyl ether to give a crude product which was purified by silica gel column chromatography. Compartment eluting with ethyl ether and ethyl ether / ethyl acetate (70/30) gave 0.4-1 g of 5 ^ (3'S-Hydro3qy-4 -'-methyl-4 ^I -pentyloxy-pent-1'-trans-1 * - enyl) -2α, 4-Ci-dihydroxy-cyclopentane-1 O ^ -acetic acid-r-lactone, m.p.M 72 ° C TdJ 284 ° M 6 °

Ms 72 ° C, TdJ ₁ J = + 2.84 °, M ₃₆₅ O = + 6.5 °

Using an ester of Example 4, 5 or 6 in the following alcohols were produced using the process according to the invention:

5/3 - (3'S-Hydroxy-4 ¹ -methyl-4'-propoxy-pent-1'-trans-1'-enyl) -2ol ^ ct-dihydroxy-cyclopentane-i ö - acetic acid-y-lactone, F. to 92 ⁰ C ft J 39 ° di 3'RI fiJ 2

up to 92 ⁰ C, fet J ₀ = + 3.9 °, and its 3'R-isomer, foiJ-p = -20.3 °, 5 β - (3'S-Hydroxy-4 ¹ -methyl-4'-butoxy -pent-1 '-trans-1' -enyl) -2öl ^ ck-dihydroxy-cyclopentane-i cl -acetic acid-y-lactone,

fd] _D = -o, 8 °,

- (3 'S-methoxy-4' -methyl-4 ¹ -butoxy-pent- ' ¹ ' -trate: s-1 ^r -enyi) -

609884/1012

2 ei-, 4-cl -dihydroxy-cyclopentane-i cL -acetic acid- T -lactone, W = -0.5 °, and its 3'R-derivatives: 3'R-hydroxy W _D = -19.4 ° and 3'E-methoxy [(Q ^ = -17 °)

5 / 3- (3'R-Hydroxy-4 ¹ -methyl-4 ^1- pentyloxy-pent-1'-trans-1'-enyl) -2a, 4 & -dihydroxy-cyclopentan-ioL-acetic acid-γ-lactone , F. 53 to 55 ° C, i & \ = -22.3 °.

Example 8

A solution of 4 g of 5/3 - (3 ¹ S-HyOrOXy-V-methyl-4 -'- pentylo: xypent-1 '-trans-1' -enyl) -2 oil, ^ c * - -dihydro ^ - cyclopentane-i ^ c - acetic J-lactone in 60 ml of methylene chloride was stirred, then nil 2,3-dihydropyran and 22 mg of p-toluenesulfonic acid was treated with 5 »^ 3 1/2 hours at room temperature" The mixture was extracted with. a saturated aqueous NaHCO, solution and water "washed to neutrality, then dried and evaporated to dryness, whereby the * => ß - (3'S-Hydroxy ~ 4'-methyl-4- ¹ -pentyloxy-pent-1 '-trans-1'-enyl) -2 oil, 4oL-dihydroxycyclopentane-1 oil -acetic acid- v -lactone-3 ', 4- "bis-THP-ether, fol3 _D = -10 °, ToL] ₃₆₅ O = -43.8 °.

Example 9

A solution of 3 »26 g of 5β - (3'S-methoxy-4'-methyl-4 ^l -butoxypent-1 '-trans-1'-enyl) -2 cl, 40L -dihydroxy-cyclopentane-i d-acetic acid-V "-lactone in methylene chloride was stirred, treated with 0.84 g of et-ethoxyvxnylether in the presence of 20 mg of p-toluenesulfonic acid for 3 hours" at room temperature ", washed with an 10% aqueous NaHCO ^ solution and water, then dried and evaporated to dryness, giving 3 »9 g of 5 β - (3'S-methoxy-4'-methyl-4 ^l -butoxy-pent-1'-trans-1'-enyl) -2cL , 4ck-dihydroxy-cyclopentane-1 Oil-acetic acid - / - lactone-4- (oL-ethoxy) ethyl ether received.

6 0 9 8 8 A / 1 012

Example 10

A solution of 0.31 g of 5/3 - (^ 'S-Hydroxy - ^' - methyl - ^ '- propoxypent-1'-trans-1'-enyl) -2cL-hydroxy-cyclopentan-i OL-acetic acid- τ lactone in 8 ml of methylene chloride was treated with 0.11 g of 1,4-DIQX-2-en and 2.1 mg of p-toluenesulfonic acid for 2 hours at room temperature. The mixture was treated with a 5% aqueous FaHCO ^ - Washed solution and water, dried and evaporated to dryness, while adding 0.32 g of 5/3 - (3'S-Hydroxy ~ 4 ^! -Methyl-4 ¹ -propoxy-pent-1'-trans-1'-enyl) - 2cx -hydroxy-cyclopentane-10-acetic acid-V "-lactone-3'-DIOX-ether received.

Analogously, by treatment with a vinyl ether from the group 2,3-dihydropyran, 1,4-DIOX-2-en and cL-ethoxy vinyl ether the alcohols of Examples 5 and 7 in their corresponding Acetal ether: THP ether, DIOX ether and 1- (a-itoxy) ethyl ether convicted.

Example 11

Under a nitrogen atmosphere, a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (1.1 ml), diluted with 12 ml of dry toluene, was added to a solution of 0.62 g of 5/3 - (3 'S-Meth03cy-4-' -methyl-4 '-butoxy-pent-1' -trans-1 'enyl) -2o - hydroxy-cyclopentane-1dL-acetic acid -> ^ - lactone in 15 ml of toluene, the was stirred beforehand, added dropwise and then cooled to «65 ° C. Stirring was continued for 3 hours, the excess reagent was destroyed by the addition of 5% acetone in toluene, then the mixture was heated to 0-2 ° C, _{treated with a saturated aqueous HaHoPO 2} I solution and then filtered. The filtrate was evaporated to dryness in vacuo, yielding 0.62 g of 5/3 - (3 ¹ S-methoxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -2a-hydroxy -cyclopentane-1OL-äthanal-γ - lactol received.

609884/1012

Example 12

A solution of 0.5 mol of DIBA in 55 ml of toluene was converted into a solution of 5/3 -O'S-Hydro ^^ '- methyl ^' - butoxy-pent-i '-trans-1' -enyl) -2 <dl ^ cL-dihydroxy-cyclopentane-i c ^ -acetic acid / • -lactone-3 ¹ , 4 ~ bis-THP ether in dry toluene (100 ml) was added dropwise, then cooled to a temperature between -60 and -70 ⁰ C fluctuated. After 1 1/2 hours, the reaction mixture was treated with a 2M isopropanol solution in 65 ml of toluene, warmed to 0-2 ° C., then treated with 5 ml of water, 3 g of Celite and 5% of anhydrous sodium sulfate. After filtering, the solvents were evaporated in vacuo, yielding 6.42 g of 5/3 - (3'S-hydroxy-4 '-methyl - ^ - ^1- butoxy-pent-1' -trans-1 '-enyl) -2 oL, 4 <3-dihydroxy-cyclopentane-i oL-ethane-lactol-3 ', 4-bis-THP-ether obtained in the form of an oil, Ο = -40.2 °, Fd] ₃₆₅ O = -112, 6 °.

Using the same procedure and starting from the y , 4-bis-DIOX ether of the 3'R-epimeric alcohol, 5/2 - (3'R-hydroxy-4 · ¹ -methyl-4 · ¹ -but02qy- pent-1 '-trans-1 ■ -enyl) -2a, 4c * - -dihydroxy-cyclopentane-icL -ethanol-y-lactol-3', 4-bis-DlOX -ether in the form of an oil, / ToOtj = 4 °

Example 13

By reducing any of those mentioned in Examples 8, 9 and 10 Acetal-v "-lactones and using that in the examples 11 and 12, the compounds listed below were prepared:

2 d, 4 et -Dihydroxy-cyclopentan-i el -äthanal-ν * -lactol;

5jS - (3'S-Hydro2cy-4 ^I -methyl-4 '-propoxy-pent-1' -trans-1 '-enyl) 3', 4-bis-THP-ether, oil, foljp = -21 °,

609884/1012

5/3 - (3 'S-Hydroxy-4- ¹ -methyl-4 * -pentyloxy-pent-1' -trans-1 'enyl) -3', 4- bis-THP-ether, oil, Td) ₁ , = -14.9 °, 5j3 - (3 'S-methoxy-4- ¹ -methyl-4-'-butoxy-pent-1'-trans-1'-enyl) -4- (cL-ethoxy) ethyl ether , Cd-I- ^ = -10 ° and its 3'R-epimeric derivatives

2oL -Hydroxy-cyclopentane-i <t-ethane- γ- -lactol:

5/3 - (3 'S-Hydroxy-4-' -methyl-4- ¹ -propoiqy-pent-i '-trans-1'-enyl) -3'-DI0X-ether,

5/3 - (3'S-Hydroxy-4 ¹ -methyl-4 ¹ -tmtoxy-pent-1 · trans-1'-enyl) -3 ^! -DI0X-ether,

- (3 'S-Hydroxy - ^ - ¹ -methyl-4-' -pentyloxy-pent-1 '-trans-1' enyl) -3'-DI0X ~ ether and its 3'R-epimeric derivatives.

Example 14-

A solution of 18.1 g of 5-bromopentanoic acid in 50 ml of tetrahydrofuran was stirred, then cooled to 0 "to 5 ° C and with a 1.1M solution of BEU in tetrahydrofuran (100 ml). After 3 hours the excess reagent was destroyed by adding water, the "tetrahydrofuran was under Distilled off in vacuo and the aqueous phase was extracted with ether, 13j4- g of 5-bromopentan-i-ol being obtained. One Solution of this compound in 50 ml of methylene chloride was 8 g ot.-ethoxy vinyl ether and 0.12 g p-toluenesulfonic acid for 3 hours treated for a long time at room temperature. The reaction mixture was washed with a saturated aqueous NaHCO ^ solution and water Washed to neutrality over anhydrous Na2S0 ^ dried and evaporated under: vacuum. A solution of the 5-bromopentane-1-oil <x -ethoxyethyl ether obtained in this way in 50 ml of acetonitrile was 4-8 hours with triphenylphosphine heated under reflux, v / obei one 28 g of triphenyl

609884/1012

|] 4-hydroxymethyl (<X -ethoxyethyl ether) butyl] phosphonium bromide received.

example

Under a nitrogen atmosphere, 4.4-3 g of triphenyl (4-carboxybutyl) phosphonium bromide were added to a previously stirred solution of 2.25 g of potassium tert-butoxide in 12 ml of dry dimethyl sulfoxide, and the mixture was then cooled to 8-10 ° C , whereby a deep orange-red solution of the ylid was obtained which was mixed with a solution of 0.62 g of 5/3 - (3'S-methoxy-4 ^T -methyl-4 '-butoxy-peiTt-1' -trans-1 '- enyl) -2a-hydroxy-cyclo ~ pentane-1d-ethanal-y - lactol was reacted in 1.1 ml of dry dimethyl sulfoxide. After 3 hours, the reaction mixture was diluted with 15 nil water and extracted with ethyl ether in order to remove the triphenylphosphine oxide. The combined ether extracts were back extracted with 0.5N KOH and discarded. The combined aqueous phases were acidified to pH 4.9 and extracted with ethyl ether / pentane (1/1). The combined organic extracts were washed until neutral, dried and evaporated, giving 0.73 g

prosta-5,13-dienoic acid-15-ißethylether received.

In a similar manner, starting from 0.68 g of des (3'S-methoxy-4 ¹ -methyl-4 ^1- butoxy-pent-1'-trans-1'-enyl) -2 cn, 4 cL-dihydroxy-cyclopentane -i α -äthanal- Y'-lactol ^ -TIIP-ethers den 5c, 13t-9a, 11cL, 15S-Trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13- dienoic acid 15-methyl ether 11-THP ether.

609884/1012

26274

Example 16

Under a nitrogen atmosphere, a suspension of 3.55 S NaH (80% dispersion in mineral oil) in 50 nil dry dimethyl sulfoxide was heated to 58 °> is 64 ° C. for 3 hours until no more hydrogen was evolved. After cooling to ⁰ ° C., 24 g of triphenyl (4-carboxybutyl) phosphonium bromide were added and the mixture was stirred until it was completely dissolved and a dark red solution of the ylid had formed. Then a solution of 4.7 g of 5/3 (3 ■ S-hydroxy-4 ¹ -methyl-4'-butoxy-pent-1'-trans-1'-enyl) - 2oL, 4oL-dihydroxy-cyclopentane IOL äthanal- γ -lactol-3 ^1, 4-bis-THP ether was added. The mixture was stirred for 4 hours, diluted with 60 ml of a 0.5N KOH solution and extracted with ether to remove the triphenylphosphine oxide. The combined ether extracts were back-extracted with 0.5 η KOH and water, then discarded. The combined aqueous phases were acidified to pH 4.9 with 2N sulfuric acid and extracted with ethyl ether / pentane (1/1). The combined organic extracts were washed until neutral, dried over NaoSOn and evaporated to dryness, the 5c, 13t-9 OL, 11oL, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor- prosta-5,13-dienoic acid-11,15-bis-THP-ether, Γ & Ι ^^ ο = -7.8, (acetone), L <^ \ - q - -2.9 °. The corresponding methyl ester was prepared by treating a solution of 0.6 g of 5c, 13t-9ot, 11oi. , 15S-Trihydroxy-16 ~ methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid-11,15-bis-TEP-ether in 10 ml of ethyl ether with a solution of diazomethane in ether and Evaporation of the solvent in vacuo.

Example 17

Under a nitrogen atmosphere a stirred solution previously vmrde of 0.67 g of potassium tert-butoxide in 8 ml of dry _e

809884/1012

Dimethyl sulfoxide was cooled to 8 to 10 ⁰ C and then with a solution of 3 S triphenyl- [4-hydroxymethyl- (oL-ethoxy) ethyl ether butyl] phosphonium bromide in dry dimethyl sulfoxide and then, after a solution had been obtained, with a solution of 0, 72 g 5/3 - (S'S-Hydroxy-V-methyl-V-butoxypent-1 '-trans-1' -enyl) -2oL, 4-cL -dihydroxy-cyclopentane-ioL ethanal-y-lactol-3 ', 4-bis-TKP-ether treated in 2 ml dry dimethyl sulf oxide. Stirring was continued for 4 hours, then the mixture was diluted with 10 ml of water and after neutralizing with 2N E ^ SO ^ to pH 7 it was extracted with ethyl ether / pentane (1/1) The organic phases were combined, washed until neutral, dried and evaporated to dryness. The crude product was adsorbed on silica gel, 0.8 g of 5c, 13t-1.9 d , 11 oL, 15S-tet rahydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5 , 13-diene-11,15-bis-THP-ether-1OL-ethoxyethyl ether was obtained.

Following the same procedure and using the lactols mentioned in Examples 11 and 13, the following were made listed prostanoic acid derivatives:

5c, ti3t-1,9o £, 1IdL, 15S-tetrahydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-diene-11,15-bis-THP-ether igL -ethoxyethyl ether,

5c, 13t-1,9OL, ^ S-Trihydroxy-ie-methyl-ie-propoxy-iejig ^ O-trinor-prosta-5,13-diene-15-DIOX-ether-1α-ethoxyethyl ether,

5c, 13t-1.9 OL, 15S-trihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-diene-15-DIOX-ether-1- (α-ethoxy) ethyl ether,

5c-1.9 OL, 11α, 15S-tetrahydroxy-16-methyl-16-propoxy-18,19,20-trinor-pro st-5-en-13-yn-11,15-bis-THP-ether-1- (OC-ethoxy) -ethyl ether.

609884/1012

Example 18

By a process described in the examples of the UNAE 1_5 ^ method of a dimethyl sulfoxide solution of Tlids of triphenyl- (4 ~ carboxybutyl) phosphonium bromide (6 moles) with 1 mole of a T-lactol of Examples 11 were prepared by reacting, 12 and 13, the following listed prostate 5, i3-dienoic acids produced:

5c, 13t-9 el, 15S-Dihyaro3qr-16-methyl-16-butosy-18 ”. 19,20-trinorprost-5,13-dienoic acid-15-methyl ether,

50 ^ -90 «. , 11 oL, 15E-Trihydro3iy-16-methyi-16-biitoxy-18 _? 19 ₅ 20-trinor-prost-5i13-dienoic acid-11 ₅ i5-Ms-DTOX-ether, + 18.5 ° (acetone),

5c, 13t-9 OL, ^ ¹ dL, 15S-trihydroxy-16-methyl-16-propo2q7-18,19,20-trinor-pr

(Acetone),

trinor-prost-5,13-dienoic acid-11 _s i5 ~ bis-! THP-ether ₅ [<tl _B = -2 °

-16-methyl-16-penty loxy-20-trinor-prost-5, i3-dienoic acid-11,15-bis-THP-ether, TolJ-q = + 6.7 ° (acetone),

5c, 13t-9 cL, 11 oL, 15S-trihydroxy-16-methyl-16-buto2cy-18,19,20-trinor-prost-5,13-dienoic acid-15-methyl ether-11- (cL-ethoxy) - ethyl ether, ToL] ₁ ) = + 1 ° (acetone),

5c, 13t-9 OL, 15S-dihydrosy-16-methyl-16-propoxy-18,19,20-trinorprost-5,13-dienoic acid-15 ~ I) IOX ether,

5c, 13t-9 dL, 15S-dihydroxy-16-methyl-16-butosy-18,19,20-trinorprost-5 , 13-dienoic acid-i5-DIOX-ether,

5c, 13t-9 α, 15S-dihydroxy-16-methyl-16-pentylo3q5T-18,19,20-trinor-prost-5,13-dienoic acid-i5-I ⁾ IOX-ether,

then by reaction with a diazoalkane solution in ether can be converted into their esters.

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.- 41 -

Example 19

A solution of 1.4-5 g of bromine in 50 ml of carbon tetrachloride became a solution of 4.44 g of 5 / 3- (3'-Oxo-4 ^1- methy 1-4 '-bi: to3cy-pent -1'-trans-1'-enyl) -2ol, 4cL-dihydroxy-cyclopentane-1 <± -acetic acid- # - lactone-4-p-phenylbenzoate in methylene chloride, which had been stirred beforehand, was added dropwise. The solution was evaporated in vacuo and a solution of the residue (the crude 1 '^ ₅ 2' £ -dibromo derivative) in 25 ml of dry pyridiii was heated to 80 ° C. for 2 hours. The reaction mixture was given 30 nal water and 30 ml ben-;:! diluted and after removal of the solvent under vacuum with 4N HpSO ^ acidified and extracted with ethyl acetate. The organic phases were collected, washed until neutral, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel, 2.6 g of pure 5β - (2'-bromo-3'-oxo-4 ^l -methyl-4 ^l -butox5 ⁷ "pent-1 '-trans-1'- enyl) ~ 2a, ^ c ^ -diLydroxy-eycloperrcan-i & -esnigsäur-e- -lactone-4-p-phenyrbeneQat received in the form of an oil,

₁₃ = -77.2 °. A solution of the 5β - (2 ¹ -Bromo-3'-oxo-4 ¹ -methyl-4 ¹ -butoxy-pent-1 '-trans-1' -enyl) -2oi, 4 (λ-dihydroxy-cyclopentane-1d Acetic acid £ -1actone-4-p-pheny! benzoate in ethyl ether i.20 rslj was added dropwise to a solution of 0.05 mol Ζη (ΒΕ ^,) ρ in 180 ml ethyl ether, which had previously been stirred After stirring for 3 hours, the excess reagent was ^{removed with 2n ^ 2 ^ 4 3ers} *, the organic layer was separated until ζυχ neutrality gs ^ assiisn, dried and singsäampft aur Trccloie; ^ c "; si one obtained? S0 g of crude product, which was absorbed on silica gel einsr After elution with Methylenchlirid and Hsthylenchlorid / Äthyiätlier (985/15) gave 0.49 g 5fi ^{-.! (2-bromo-5} 3'S hyäroxy-4 = .methyl-4 ^s butoxy-pent -1'-trans-1'-enyl) -2o £. ^ OL-dihydroxy-cyclopentan- ^ oil-acetic acid-y-lactone-4-p-phen: flbenc; oat, Lei. Jj) = -70 ° _T - ] = -3 '''9' ^J ^ il after further eluting with methylene

S09884 / 1012

Chloride / ethyl ether (90/10) gave 1.25 g of the 3'R isomer, FdL] ₁ , = -78.4 °, [cCL ^ o = -34-9 °.

A solution of 0.45 g of the 3'S-alcohol-4-p-phenylbenzoate in 12 ml of absolute methanol was mixed with 0.12 g of anhydrous KpCO? For 4 hours at room temperature. treated, neutralized with 2N HpSO ₂ and evaporated to dryness. Each dilution with water, the aqueous layer was extracted with CH 4 Clp, the combined organic phases were evaporated to dryness and the residue was absorbed on silica gel. Compartment of the eluent with methylene chloride and methylene chloride / ethyl acid (70/30) gave the 5/3 - (2'-bromo-3'S-hydroxy-4'-msthyl-4'-butoxy-pent-1'-trans-1 ' -enyl) -2oL, 4cL-dihydroxycyelopentane-icL-acetic acid-Y-lactone in the form of an oil, £ k] _D = -6 ₉ 6 °, fd] ₀ = -16.2 °. The 5/3 - (2 ^I -Brom-3 ^l S-hydrosy- ¹ I- ^: ~ methyl-4 ⁱ ~ butoxy-pent-1 '-trans-1' -enyl) -2ck, 4O ⁵ - -dihydroxy- ; -yalopentane-1dl-acetic acid-1-lactone was obtained by treatment with 0.5 ml of 2,3-dihydropyran and 2 mg of p-toluenesulfonic acid in 8 nl of methylene chloride for a period of 3 hours at room temperature in its 3's , 4-bis-THP-ether (W _D = -18 °) transferred. The reaction mixture was diluted with 0.1 ml of pyridine and 50 ail of ethyl ether, washed with a 5% aqueous KaHCQ solution and water until neutral , dried and evaporated we dryness' was Under a nitrogen atmosphere, ■ AEI free of moisture, xvurde over a period of 20 minutes a solution of 0.5 mol of DIBA in 6.4 ml .Toluol to 3lner solution of 37S mg 3'ScA- Bis-THP ether in 7 ml of dry "Ι · 3ΐ · αο1, which ^{had been cooled to -70 0} G and had previously been stirred", was added ₃ The stirring was continued for 30 minutes, then the reaction mixture became with 2M isopropanel ± li foluene bslian Then after 15 minutes it delts to 0 to 2 ⁰ O er ⁷ Va ^ ¹ EIt ₉ with 0.5 ml of water., 1.2 g of gelite and 2 g of water = J:, - 3% hatriimium sulfate and finally filtered _o The 7'iltrat wurcs * an-5er Takuum zv. ~ Troder.s oinr ^ -. "^, where ~ cn

8098-84 / 101

trans-1'-enyl) -2 ei, 4ol -dihydroxy-cyclopentane-ioL -ethanal- ^ r lactol-3'S, 4-bis-THP-ether received

Under a nitrogen atmosphere, 1.38 g of triphenyl (4-carboxybutyl) phosphonium bromide were added to a previously stirred solution of 0.68 g of potassium tert-butoxide in 4 ml of dry dimethyl sulfoxide and the mixture was then cooled ^{to 10 to 12 ° C.} Denaeh, a solution of 5/3 - (2'-BrOm-J'S-hydroxy-V-methylol- ^1- butoxy-pent-1'-trans-1'-enyl) - was added to the deep orange-red solution of the ylid obtained. 2o (-, 4 OL-dihydroxy-cyclopentane-1dL-ethanol - ^ - lactol-3'S, 4-bis-THP-ether in 1.1 ml of dimethyl sulfoxide was added and stirring was continued for 2 hours at room temperature. The reaction mixture was with an aqueous n / 10 KOH solution and extracted repeatedly with ethyl ether to remove the triphenylphosphoxide. The combined ethereal phases were washed with an n / 10 KOH solution and then discarded. The combined aqueous alkaline phases were collected, to pH 4 , 5 to 4.8 acidified and several sharks extracted with ethyl ether / pentane (50/50) The combined organic extracts were washed with a saturated (KU ^^ SO ^ solution, dried over I ^ SO ^. And evaporated to dryness , 0.37 g of the 5c-9oi, 11 oil, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-5-en-13-yn acid-11.15 -bis-THP-ether obtained in the form of an oil, / ci} _D = -20.2 °, -57.2 ° (acetone).

Using the same procedure and starting from 0.74 g of 5/3 - (2'-bromo-3 ¹ R-hydroxy-4 ¹ -methyl-4'-butoxy-pent-1'-trans-1'-enyl) -2 ei ^ cL-dihydroxy-cyclopentane-iot -acetic acid- ^ -lactone, Id] ₁₃ = -31.8 °, Td] ₃₆₅ O = -116.5 °, one obtained 0.93 g of the 5c-9oL, 11 o (., ^ R-trihydroxy-ie-methyl-ie-bu 20-trinor-prost-5-en-13-yn acid-11,15-bis-THP-ethers, + 44 °, Td] ₅₆₅ O = + 116 ° (acetone).

6098-84 / 1012

Example 20

1.7 S bromine in 50 ml CCl ^ were added to a previously stirred solution of 2.96 g dl-5/3 - (3'-OxO-V, 4'-dimethyl-oct-1'-trans-1 '- enyl) -2ci. Hydroxy-cyclopentan-ioL -acetic acid- γ- lactone in 60 ml of CII ₂ Gl _{2 was} added dropwise "until a pale red color persisted. The solvents were evaporated off under vacuum and the resulting 5y3- (1 '£, 2" ζ -Dibromo ^ '- oxo-V, 4'dimethyl-oct-1'-yl) -2cL-hydroxy-cyclopentane-1d -acetic acid- T -lactone in 10 ml of pyridine. Heated to 80 ^° C. for 4 hours. The mixture was then cooled, acidified with 2N ILpSO ^ and extracted with ethyl acetate, after chromatographic purification on silica gel (100 g) using cyclohexane / CILjCl-p (1/1) as the eluent, 1.79 g of dl-5 /? - (2'-Bromo-3'-oxo-4 ', 4 -'-dimethyl-oct-1'-trans-1' -enyl) -2oi -hydroxy-cyclopentane-iot. Acetic acid Y lactone received (} ^ f ° ^H 252m / l, ε = 3200). A solution of 0.98 g dl-5ß - (2'-bromo-3'-oxo-4 ^1, 4'-dimethyl-oct-1'-trans-1'-enyl) -2oL hydroxy-cyclopentane-id. Acetic acid r- lactone in dry ether was added to a solution of 0.14 mol of zinc borohydride in 30 ml of ethyl ether, which had previously been stirred. After 1 hour the excess reagent was destroyed by the addition of 2N HgSO ^ and the organic layer was washed to neutrality and evaporated to dryness, after chromatography on silica gel (70 g) using cyclohexane / CH ₂ Cl2 (20 / 80) as eluent 0.53 g of dl-5/3 - (2 · -Bromo-3'S-hydroxy-4 ', 4'-dimethyl-oct-1'-trans-1'-enyl) -2oi-hydroxy-cyclopentane -ioL -acetic acid-V-lactone and 0.41 g of its 3'R-hydroxy-epimer.

The dl-5ß - (2 * -Brom-3'S-hydroxy-4 '', 4'-dimethyl-oct-1'-trans-1'-enyl) -2ol -hydroxy-cyclopentane-1 oil -acetic acid- - f -lactone was vcr with 2,3-di-hydropyran in CH ₂ Cl ₂ in its 3 '-tetrahydropyranyl ether and then by reduction with a solution. 0.5 mol of DIBA in toluene in the dl-5 /> - (2 ¹ -Brom-3'S-hydroxy-

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4 ¹ ^ '- dimethyl-oct-i ^e -trans-1' -enyl) -2ci -hydroxy-cyclopentane-1 & -ethanal- j -lactol-3-THP-ether transferred.

A suspension of NsH (80% dispersion in mineral oil, 1.22 g) in 50 ml of dry dimethyl sulfoxide, which had been stirred beforehand, was heated to 58 to> is 65 ° C. until no more hydrogen evolution occurred, then to 8.92 g of triphenyl- (4-carboxybutyl) phosphonium bromide were added to the mixture with stirring and with external cooling to form a red solution of the Tlid, which was then reacted with a solution of 0.82 g of the lactol in 4 ml of dry dimethyl sulfoxide. The reaction mixture was stirred for 4 hours, then diluted with 35% v / water and extracted repeatedly with ethyl ether in order to remove the triphenylphosphine oxide. After washing the combined organic extracts with 0.5N HaOH, the aqueous alkaline phases were collected, acidified to pH 4.2 to 4.4 and extracted with ethyl ether / pentane (1/1). These organic extracts were combined, washed until neutral, concentrated to a small volume, and finally treated with a diazomethane solution in ethyl ether to give 0.64 g of a crude methyl ester. Using Hexsn / ethyl ether as eluant to yield, after purification of the crude on a silica gel Methylesters 0,42 g of the pure dl-5c-9 d ₁ 15S-dihydroxy-16,16-dimethyl-prost-5-en ^/ l3 -'in. acid methyl ester-15-THP-ether, mass spectrum m / e 462 M ⁺ , m / e 444 (M ⁺ -

- H ₂ O), m / e 99 [(CH ^) ₂ O- (CH ^ -ChJ, m / e 84 Äj

Using this procedure, the 3'R-epimer: dl-5β - (2'-bromo-3'S -hydroxy-4 ·, 4'-dimethyl-oct-1 · -trans-1 · enyl) - 2qL -hydroxy- cyclopentan-iol -acetic acid-τ -lactone, dl-5> c-9 #. , 15R-dihydroxy-16,16-dimethyl-prost-5-en-13-ynoic acid-15-THP-ether, mass range m / e 462 M ⁺ , m / e 444 (M ⁺ - H ₂ O), manufactured.

609884/1012

Example 21

A solution of 0.25 g of dl-5c-9oL, 15-Dil ^ aroxy-16,16-diniethyl-prost-5-en-13-ynoic acid methyl ester-i5-THP in 4 ml of MeOH and 0.5 ml of water was saponified by treatment for 4 hours at normal temperature with 0.05 S LiOH. After removing the methanol under vacuum, acidifying the reaction mixture with an aqueous saturated HaH-pPO4 solution and then extracting it with ethyl acetate, 0.25 g of a crude free acid was obtained, the solution of which in 6 ml of acetone was cooled to -10 to -12 ⁰ C ITacli ml ^ 0.3 with Jones reagent was treated. 4-5 Hinuten the reaction mixture was diluted with 60 ml of benzene, _{for example} with a saturated aqueous solution (WH ^,) p, -Lösling to Washed neutrality and evaporated to dryness in vacuo, giving 0.25 g of dl-5c-9-oxo-15S-hydrox3r-16 ₉ 16 ~ dimetiiyi-prost-5-en-13-iric acid-15-THP ether. A solution of the dl-5c-9-oxo-15S-hydro3qy-16,16-dimethyl-prost-5-en-13-yn acid = 15-THP ether in 10 ml of acetone and 6 ml of 0.2N oxalic acid was used for 8 hours heated to 40 ⁰ C long, then the acetone was evaporated under vacuum and the itfässrige phase was extracted with ethyl ether. the combined organic Sxtrafcte were washed until neutral, concentrated by evaporation, since The residue was then absorbed onto 6 g of an acid washed silica gel. Tray eluting with cyclohexane / CH ₂ Cl ₂ (10/90) and with CH _{2 Cl 2} gave 0.12 g of dl-5c-9-oxo-15S-byclroxy-16,16-dimethyl-prost-5-ene -13-ynic acid, mass spectrum m / e 362 (M ⁺ ), m / e 3 ^ 4 (M ⁺ - H ₃ O), m / e 288 (M ⁺ - 74), m / e 263 [li ⁺ - 99 ^ (CHj) ₂ - (CH ₂ ) ^ - CH ₃ ]. The dl-5c-9-oxo-15E-hydroxy-16,16-dimethyl-pro st-5-en-13-yoic acid was prepared in an analogous manner.

Example 22

One solution of 3% Br ₂ in 35 el CEpCl ₂ was added to a solution

609884/1012

of 2.8 g of 5 &-O'-Oxo - ^ - '^' - dimethyl-oct-i'-trans ~ 1'-enyl) -2dL ^ di-aihydroxy-cyclopentane-ioi. acetic acid - ^ - lactone-4-pphenylbenzoate (F. 99 "to 100 ⁰ C, JdQ ₁ , = -129 °) in 60 ml of CH ₂ Cl which had been stirred beforehand, added over a period of 30 minutes until The reaction mixture was then cautiously treated with 68 ml of pyridine and, after the excess CH ₂ Cl _{2 had been} removed, heated for 12 hours at 80 ^° C. The pyridine was evaporated under vacuum, the residue was washed with CH ₂ Cl _{Treated 2} and 2N H ₂ SO ^, the organic layer was separated, washed until neutral, dried and evaporated to dryness, After chromatographic purification of the residue on 40 g of silica gel using CHgClg / cyclohexane (65/35) as the eluent there was obtained 0.98 g of 5/3 (2'-bromo-3'-oxo-4 ^l, 4'-dimethyl-oct-1'-trans-1'-enyl) -2oi, dihydroxy-cyclopentane-1 ei. -acetic acid- y- lactone-4-p-phenylbenzoate in the form of an oil, £ oQt) ⁼ -57 ° » [cßzctz ⁰ = -186

Example 23

Using the ketones mentioned in Examples 2 and 3 and using the method described in Example 22, the following ot -Bromo- oL, β trans-ketones were prepared:

5 /? - (2 ¹ -Bromo-3'-oxo-4 ¹ -methyl-4'-propoxy-pent-1'-trans-1'-enyl) -2oi, 4d-dihydroxy-cyclopentane-ioL -acetic acid-V "- lactone-4-p-phenylbenzoate,

- (2 ■■ -Bromo-3 '-oxo-4 ¹ -methyl-4 ¹ -pentyloxy-pent-1' -trans-1 'enyl) -2ot, 4ςΙ -dihydroxy-cyclopentane-icL-acetic acid- y- lactone-4-p-phenylbenzoate,

5Λ - (2'-Bromo-3 ¹ -oxo-4 ¹ -methyl-4 ¹ -propoxy-pent-1'-trans-1 'enyl) -2c <> -hydroxy-cyclopentane-idL-acetic acid- ϋ -lactone ,

5Λ - (2'-Bromo-3'-oxo-4 ¹ -methyl-4 ¹ -butoxy-pent-1 · trans-1'-

609884/101 2

enyl) -2oL -hydroxy-cyclopentane-ioL-acetic acid- ν -lactone,

5ß - (2'-Bromo-3'-oxo-4 ¹ -methyl-4'-pentyloxy-pent-1 · -trans-1 · - enyl) -2 ql -hydroxy-cyclopentane-1 cL -acetic acid- jh - lactone.

Example 24

1 * 1 g of 5/3 - (2'-bromo-3'-0X0-4 ', 4'-dimethyl-oct-1'-trans-1'-enyl) -2cL, 4o-dihydroxy-cyclopentane-i El -acetic acid τ -lacton-4-p-phenyrbenzoate was reduced by the method described in Examples 4 and 20 with 0.07 mol of zinc borohydride in 92 ml of ethyl ether. The resulting crude mixture of 3'S and 3 'R alcohols (from which the individual 3 ¹ S and 3 ¹ R compounds are produced in pure form by preparative liquid chromatography using methylene chloride / ethyl ether (980/20) as the eluent can be) was dissolved in 30 ml of absolute methanol and treated with 0.37 g of anhydrous Έ-ςρΟ-, ^ hours at room temperature, after neutralization with Amberlite IR-400 (E ⁺ form) and after evaporation of the solvent obtained a crude product which was reacted in 15 nil of dry methylene chloride with 0.9 ml of 2,3-dihydropyran and 4.2 mg of p-toluenesulfonic acid. After 3 hours the reaction mixture was treated with 0.03 pyridine, evaporated to dryness and the residue was absorbed on 80 g of silicon dioxide, after eluting with cyclohexane / ethyl acetate / pyridine (900/100/1), 120 mg of 5/3 - (2'-Bromo-3'S-hydroxy-4 ¹ ^ '- dimethyl-oct-i'-trans-1'-enyl) -2ot, 4d -dihydroxy-cyclopentan-ioL -acetic acid-y'-lactone-3', 4-bis-THP-ether, [dj _D = -32.4 °, [0Lj ₃₆₅ O = -77 ° (MeOH), 160 mg of the 3'R-isomer, LdJ ^ - +15.6, / ^ tJz ₆₅ O = + 50.2 ° (MeOH) and a 1/1 mixture of the two 3'S- and 3'-Re; pimer-alcohol-bis-THP derivatives.

6 0 9 8 8 4/1012

Example 25

A solution of 7.2% DIBA in 10 ml of toluene was added over a period of 15 minutes to a previously stirred solution of 0 ⁸ 9 S 5 ß - (2'-bromo-3 · R-hydroxy-4 ', 4'- dimethyl-oct-1'-trans-1 '-enyl) -2cL, 4ot dihydroxy-cyclopentane-IOL -acetic acid y- - lactone 3 ^1, 4-bis-THP ether in 20 ml of dry toluene, which on -6O ⁰ C had been cooled, added. After 30 minutes, the mixture was treated with 2M isopropanol in 6 ml of toluene, ^{warmed to 0 to 2 °} C., then treated with 1 ml of water, 2 g of anhydrous sodium sulfate and 2 g of Celite and finally filtered. The filtrate was evaporated to dryness in vacuo, yielding 0.86 g of 5β - (2'-bromo-3'R-hydroxy-4 ', 4'-dimethyl-oct-1'-trans-1'-enyl) - 2d, 4oL-dihydroxy-cyclopentane-1oL-ethanol - ^ - lactol-3 ¹ , 4-bis-THP-ether received. A solution of the 5β - (2 '-Brom-3' R-hydroxy-4 ¹ , 4 -'-dimethyl-oct-1 '-trans-1' enyl) -2oL, ^ OL-dihydroxy-cyclopentane-ioL -ethanol - jf-lactol-3 ¹ , 4-bis-THP-ether in 2 ml of dry dimethyl sulfoxide was a previously stirred red solution of the ylid, which by adding 6.3 g of triphenyl- (4-carboxybutyl) phosphonium bromide to a solution of 3 ₅ 45 g of potassium tert-butoxide had been prepared in 13 ml of dry dimethyl sulfoxide and which had been cooled to 10 to 12 ° C. under a nitrogen atmosphere. After 3 hours, the reaction mixture was diluted with 15 ml of a 0.1N KOH solution, extracted with ethyl acetate to remove the triphenylphosphoxide, and acidified to pH 4.5-4.8 with 2N sulfuric acid. Extraction with ethyl ether / pentane (1/1) gave 0.64 g of crude 5c-9oL, 11oL, ^ R-trihydroxy-iejiö-dimethyl-prost ^ -eni3-yn acid-11, i5-bis-THP- ether that has been treated with a diazomethane essential solution. Purification on silica gel then gave the pure 5c-9cl, HoL, 15R-Ti'ihydroxy- -16,16-dimethyl-prost-5-en-13-yn acid 11,15-bis-THP-ether methyl ester, foc] _D = ^ 3.4 °, W36S ^{0 :: 4MG} ° d ^ ""'^), mass spectrum m / e 562 (M ⁺ ), m / e 460 (M ⁺ "- 1 HO- / \), m / e 358

609884/1012

(M ⁺ - 2 HO- ^ J)), m / e 99 (C - (GH ₂ ^ -CH

CH,
ο

A solution of 0.25 g of 5c-90L 11 oil, 15R-trihydroxy-16, 16-dimethyl-prost-5-en-13-yn acid-11, 15-bis-THP-ether-methyl ester in 7 nil acetone which had been cooled to -10 to -12 ° C was treated with 0.3 ml of Jones reagent. After 30 minutes, the mixture was diluted with 60 ml of benzene, washed with a saturated (NH ^,) pSO ^, solution until neutral, and dried over NapSO ^. After removal of the solvent under vacuum, the residue dissolved in 20 ml of acetone was dissolved and for 7 hours at 4O ⁰ C with a 0.2 I7 η aqueous oxalic acid treated ml. After the acetone had been removed in vacuo, the aqueous phase was extracted with ethyl ether, giving a crude product which was purified by chromatography on 4 g of silica gel. After eluting with ethyl ether / cyclohexane (40/60), 95 mg of the pure 5c-9-oxo-11ck, 15R-dihydroxy-16,16-dimethyl-prost-5-en-13-yn acid, = -7, were obtained 3 °, TcQ ₃₆₅ O = -112 ° (ItOH).

In an analogous way, starting from the 3'S alcohol and the mixture of the 3 ¹ S- and 3'R-epimeric alcohols (1/1) ^ the 5c-9oL, 11oL, 15S-trihydroxy-16,16-dimethyl- Prost-5-en-13-yn acid-11,15-bis-THP-ether and the 5c-9oL, 11dL, 15 (S ₁ R) -trihydroxy-16,16-dimethyl-prost-5-en-13- in acid-11,15-bis-THP-ether and its methyl ester.

Example 26

Using the method described in Examples 4 and 20, the oil bromine et, β- unsaturated ketones mentioned in Example 23 gave, after reduction with zinc borohydride, a mixture of the 3 ¹ S-and 3'R-epimeric alcohols, which by Chromatography on silica gel according to the method of

609884/1012

Examples 19 Vüciä 20 were separated from each other. The alcohols thus obtained:

5ö - (2'-Bromo-3'S-hydroxy-V-methyl-4 ^! -Propo: xy-pent-1 '-trans-1' -enyl) -2oL, 4-c / L · -dihydroxy-cyclopentane-icL -acetic acid-ν lactone-4-p-phenylbenzoate,

5 β - (2 '-Broia-3' S-hydroxy-4 '-methyl-4- · pentyloxy-pent-1 · trans-1'-enyl) -2 ei. , 4-cL -dihydroxy-cyclopentane-i oL -acetic acid- Ϋ -1act on-4-p-phenyIbenz ο at,

5/3 - (2 '-Bromo-3' S-hydroxy-4 '-methyl-4 ¹ -propoxy- ^ pent-i' -trans-1 '-enyl) -2 οί. -hydroxy-cyclopentane-i oL -acetic acid- Y- lactone,

5ß - (2 · -Bromo-3'S-hydroxy-4'-methy1-4'-butoxy-pent-1'-trsns-1'-enyl) -2ot-hydroxy-cyclopentane-iot-acetic acid-y-lactone, 5β - (2 '-Bromo-3' S-hydroxy-4 ¹ -methyl-4 ¹ -pentylo3q5r-pent-1 'trans-1' -enyl) -2oL -hydro ^ -cyclopentane- 10 ~ -acetic acid-y lactone,

and their 3 ¹ R-epimeric derivatives were treated with 2,3-dihydropyran in methylene chloride after the saponification of the 4-p-phenyrbenzoates with K ^ CO ^ in dry methanol in the presence of p-toluenesulfonic acid as a catalyst, the corresponding 3 ' , 4-bis-iDHP-ether or 3'-THP-ether.

Using the method described in Examples 11, 12, 19, 20 and 25, the 3 ¹ , ^ - bis-THP ethers of the compounds given below were prepared by reducing these compounds:

5/3 - (2 ¹ -Bromo-3 'ß-hydroxy-4 ¹ -methyl-4- ¹ -propoxy-pent-1' -trans-1 '-enyl) -2oL, 4 <JL-dihydroxy-cyclopentane iot -ethanal-y-lactol, 5 / S - (2 '-Bromo-3' S-hydroxy-4- ¹ -methyl-4 '-pentylo ^ -pent-i'trans-1'-enyl) -2oil , ^ d-dihydroxy-cyclopentan-ioi. -äthanal-y'-lactol, and the 3'-THP ethers of the following lactols:

5fi> - (2 '-Bromo-3'S-hydroxy-4 -'-methyl-4' -propo} ~ ^r -rrit-1'-trans-1'-enyl) -2oi-hydroxy-cyclopentane-ioil -ethanol- y-lactol,

609884/1012

5β - (2 '-Bromo-3' S-hydroxy-Λ ¹ -iaethyl-4 ¹ -pentyloxy-pent-1 'trans-1' -enyl) -2dL-hydro3qy-cyclopent8H-1 al -ethanol- j'- lactol, '5/3 - (2' -Brom-3 'S-hydroxy-4 ¹ -niethyl-4- ¹ -butoxy-pent-1' -trans-1 'enyl) -2 c ^ -hydroxy-cyclopentane i ei-äthanal- ^ - lactol,

and the epimeric 3'R derivatives of all of these compounds.

Example 27

The lactols of Example 26 are mixed with an excess of the ylide prepared from the triphenyl- (4-carboxybutyl) -phosphonium bromide by reaction with freshly sublimed potassium tert-butoxide according to the process ₉ described in Examples 15 "and 25 or with methylsulfinylcarbamide , as described in Examples 16 and 20, reacted to form the following prostic acids:

5c-9dL, 11cL, 15S-trihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-5-en-13-yoic acid-11,15-bis-THP-ether (also as 5c-9dL, 11ÖL, 15S-trihydroxy-16,16-dimethyl-17-oxa-prost-5-en-13-yn acid-11,15-bis-THP-ether designated),

5c-9 dL, 11d, 15S-trihydroxy-16-methyl-16-pentyloxy-18,19,20-trinor-prost-5-en-13-yn acid-11,15-bis-THP-ether,

5c-9 oL, 15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinorprost-5.-en-13-yn acid-15-THP-ether,

5c-9oL, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinorprost-5-en-13-ynoic acid-15-THP-ether,

5c-9 dl -15S-Mhydroxy-16-methy 1-16-pentyloxy-18,19,20-t rinorprost-5-en-13-yoic acid-15-THP-ether and their 15-R epimers,

Example 28

A mixture of O ₉ 58 g 5c ₉ 13t- »9oi ₉ 11 Ck ₉ IJS = Sribydro2iy-16-

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meth.yl-16-but oxy-18,19,20-trinor-prost a-5 »13-dienoic acid methyl ester-11, 15-bis-THP-ether, 1.01 g triphenylphosphine and 18A mg formic acid in tetrahydrofuran stirred, then
cooled to 0 to 1 ° C and then treated with a solution of 0.7 g of diethylazo-bis-carboxylate in 5 ml of tetrahydrofuran over a period of 30 minutes. After removing the solvent in vacuo, the residue was absorbed on a silica gel column (30 g). After eluting with cyclohexane / ethyl ether (70/30), 0.59 g of 5c, 13t-9y &, Hcjl 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5, 13-dienoic acid methyl ester-11, ^ - bis-THP-ätber-g-formate, which was treated in 10 ml of absolute methanol with 70 mg of anhydrous Έ. ^ 0- . After 1 hour the mixture was evaporated to dryness and the residue was treated with ethyl ether and water. The organic layer was separated, washed until neutral and evaporated to give 0.5 g
5c, 13t-9 / &, 11 oil, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13- <aienic acid-11,15-bis-THP-ether- methyl ester received.

Example 29

To a mixture of 525 mg triphenylphosphine, 24-5 mg
Benzoic acid and 0.57 g of 5c-9 &, 11 a, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-5-en-13-yoic acid methyl ester-11,15-bis -THP ether in 15 ml of benzene, which had been stirred beforehand, a solution of 250 mg of diethylazo-bis-carboxylate in benzene was added. After 30 minutes the solvent was evaporated to a small volume in vacuo and the mixture was absorbed onto silica gel. Eluting with ethyl ether / cyclohexane (20/80) gave 0.52 g
5c-9 $ L, 11 ö., ^ S-Trihydroxy-ie-methyl-i 6-but oxy-18,19,20-trinor-prost-5-en-13-yoic acid methyl ester-11,15-bis-THP ether methyl ester 9-benzoate.

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A solution of the 5c-9, &, 11 ei, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-5-en-13-ynoic acid methyl ester-11, i5-bis-THP- ether methyl ester 9-benzoate was converted into the free 9 / O-hydroxy carboxylic acid by treatment for 2 hours at the reflux temperature with 4% KpCKU in aqueous methanol. The solvent was evaporated, the mixture was diluted with water, acidified and extracted with ethyl ether. The crude product was treated with 10 ml of 0.2N oxalic acid and 12 ml of acetone at 50 ° C. for 8 hours. After the acetone had been removed in vacuo, the aqueous phase was extracted with ethyl ether. The chromatographic purification on an acid-washed silica gel gave 0.2 g of 5C-9 / SL, 11 oil _v 15S-! Eril3ydroxy-16-methyl-16-buto3sy-18,19,20-trinor-prost-5- en-13-yoic acid.

Example 30

A solution of 0.7 g of diethylazo-bis-carboxylate became a stirred solution λγοώ over a period of 15 minutes. 0.61 g 5c, 13t-1.9 cL, 11 dL, 15S-tetrahydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-diene-11,15-bis- TEP-ether-1- (d - ethoxy) ethyl ether and 0.79 g of p-phenylbenzoic acid in 25 ml of THF were added. For 30 minutes the solvent was evaporated to dryness under vacuum and the remaining oil was absorbed on a silica gel column. When eluting with cyclohexane / ether (80/20) as the eluent, 0.72 g of 5c, 13t-1,9 & -, 11cL, 15S-tetrahydroxy-16-methyl-16-propoxy-18,19 were obtained , 20-trinor-prosta-5,13-diene-11,15-bis-THP-ether-1- (d-ethoxy) ethyl ether-9-p-phenylbenzoate. This compound, the 5c, 13t-1,9 ß- , 11 d-, 15S-tetrahydroxy-16-methyli6-propoxy-18,19,20-trinor-prosta-5,13-diene-11,15-bis- THP-ether-1- (dL-ethoxy) äthylether was treated in 80% aqueous methanol with 0.15 g of KpCO ^ for 2 hours at the reflux temperature, after the usual work-up

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received the corresponding free 9β- alcohol.

Example 31

Using the 9d-hydroxyprostanoic acid of Examples 15 to 20, 25 and 27 and using the procedure described in Examples 28, 29 ″ and 30 it was possible to achieve the corresponding 9β-ester (pormate, acetate, benzoate, p-phenylbenzoate) to produce which were saponified to their corresponding free 9ß-hydroxy alcohols:

5c _t i3t-9/3, i5S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinorpro st a-5 j 13 - dienoic acid e-methyl st er-15-DIOX-ether,

5c, 13t-9ß, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinorprosta-5 »13-dienoic acid-15-diethyl ether-methyl ester,

5c-9 [i, 11d- _ί 15S-trihydroxy-16,16-dimethyl-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether,

5C-9/3, 11c * -; i5S-a? Rihydro3qy - 16-methyl-i6-propoxy-18,19,20-trinor-prosta-5,13-dienoic acid-methyl ester-11,15-bis-THP -ether,

5C-9/5, 11dL, 15S-TΓihyäroxy-16-methyl-16-pentyloxy-18,19,20-trinor-prosta-5,13-aienoic acid-methyl ester-11,15-bis-TBP-ether,

and their 15R epimers.

These compounds were converted into the corresponding free by treatment with LiOH or JLpCO ^ in aqueous methanol Acids transferred.

Example 32

To a solution of 0.3 6 5c I3T-9d '' ^{1 '1} c ^| - »' ¹ 5S-Trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5, i3-dienoic acid-11,15-bie-iDHP-ether in 10" ml acetone, which is stirred and then -I5 bie -12 ⁰ C was cooled, 0.68 ml Jonee-Reagene

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admitted. Stirring was continued for 25 minutes, the reaction mixture was diluted with 50 ml of benzene and the organic phase was ^{washed with a saturated (I 1} TH ^) 2SO4. Solution until neutral, dried and evaporated to dryness, whereby 0.22 g-5c, i3t-9 = Oxo-11nL, 15S-dihydroxy-16-methyl-16-but oxy ~ 18,19,20-trinor-prosta-5,13-dienoic acid-11,15-bis-THP-ether , [d] _D = -21.8 ° (acetone), methyl ester LdLj τ. = -17 ° * received ο

Example 33

To a solution of 0.42 g 5c ₉ 13t-9ß _S 11 ei siS i 6-but oxy-18.19 ₉ 2Q-trinor = pro st a ~ 5,13-dienoic acid = 11.15-

■ bis-THP ether in 14 ml of acetone, which was stirred and then ^{cooled to -12 0} O, 0.79 ml of Jones-Beagens were added. The reaction mixture ΐ-juräe diluted with benzene after 30 minutes, with a saturated (ΙΗ ^ ) 2SOj ^ = solution washed and evaporated to dryness, 0.38 g of 5e _? 13t-9-0: xo ~ 11 d Bihydroxy-16-methyl-16-butoxy-18,19 _? 20-trinor »prosta-5 ₉ dienoic acid-11.15-bis-THP-ether, [ό-] _Ώ = -17 °, received _s

example

Burch oxidation of 0.22 g of the corresponding derivative in 6 ml of acetone at a temperature of -10 ⁰ C with 0.5 ml of Jones reagent to yield the 5c, 13t-9-oxo-11 <dL, 15R-dihydroxy-16 -methyl-16-butoxy-prost.a-59 ^/ '3-dienoic acid = 11.15 = bis-DIOX-ether, QQ-q = -20.5 ° -

Example 35

To a solution τοπ O ₉ S g 5c, 13t-1 _? 9oC, 11 oil, 15S-0? Etrahydroxy

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16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-diene-11,15-bis-THP-ether-1- (oL -ethoxy) ethyl ether in 20 ml of acetone, which is stirred and Was cooled to -12 ⁰ C, 1.4 ml of Jones reagent were added. After 30 minutes, the mixture was diluted with 80 ml of benzene, washed until neutral, dried and evaporated to dryness, yielding 0.7 g of 5c, 13t-9-oxo-1,11a, 15S-trihydro2y-16-methyl -16-butoxy-18, 19, 20-triiorprosta-5, i3-diene-11, i5-bis-THP-ether-1- (dL-ethoxy) ethyl ether. According to this procedure, using the 9d -hydroxy compound of Example 17, the compounds listed below were prepared:

5c, 13t-9-oxo-1,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost a-5,13-diene ~ 15-DI0X-ether-1c * - -ethoxy-ethyl ether,

5c, 13t-9-Oxo-i, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost a-5 , 13-diene-15-DIOX-ether-1 d-ethoxy -äthylätJier,

5c, 13t-9-Oxo-1,11 ^, 15S-trihydroxy-16-methyl-16-propoxy-

ethoxy-ethyl ether,

5c-9-oxo-1,11ö-, 15S-trihydroxy-16-methyl-16-propo3q5r-18,19,20-trinor-prost-5-en-13-yn-11,15-bis-! EHP -ätlier-1cL-ethoxy-ethyl ether and their 15R epimers.

Example 36

15 ml of a 0.2N aqueous oxalic acid was used L3 to a solution of 5c, 13t-9-oxo-1,1Id, 15S-trihydroxy-16-methyl-16-butoxy-18,19-trinor-20 _i pros1se5j ^/ -11 cL , 15-bis-TiiP-ether-1- (dl ethoxy-ethyl ether) was added and the mixture was heated to 38 ° G for 12 hours. The excess acetone was evaporated under vacuum, the aqueous phase was extracted with ethyl acetate, then evaporated and the crude product was absorbed onto silica gel. According to the Elute with GH

p Cl acetate obtained the 5c, i3t-9-Oxo-1, Hol, 15S-trihydroxy-16-

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metb.yl-16-t) utoxy-18,19 ₁ 20-trinor-prosta-5, i3-diene. The following connections were made in an analogous manner:

5c, 13t-9-0xo-1,15S-dihydroxy-16-methyl-16-butoxy-18,19 _l 20-trinor-prosta-5,13-diene,

5c, 13t-9-oxo-1,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5.1 3-dien,

5c-9-Oxo-1,11d-, 15S-trihydroxy-16-methyl-16-propoxy-18,19,20

5C-9-OXO-1,11 cL, 15S-trihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-diene, and their 15R epimers.

Example 37

A mixture of 0.2N aqueous oxalic acid and 0.35 S 5c, 13t-1.9 / 3 , 11d-, 15S-tetrahydrox3Γ-16-πlethyl-16- ■ butoxy-prosta-5,13-diene-11,15-bis-THP-ether-1- (d - ethoxy) ethyl ether in 15 ml of acetone was refluxed for 3 hours. The acetone was evaporated and the aqueous phase was extracted with ethyl acetate, after which chromatographic Purification on silica gel using ethyl acetate and ethyl acetate / acetone (95/5) as eluents 0.25 g 5c, 13t-1.9) 8., 11aL, 15S-tetrahydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-diene received. Using this procedure and using the alcohols of Example 17 the following compounds were made:

3c-1,9cL, 1IdL, 15S-tetrahydroxy-16-methyl-i6-butoxy-18,19 ₃ 20-trinor-prost-5-en-i3-yne,

5c, 13t-1,9dL, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5 »^ 3-diene,

5c, 13t-1.9 oil, ¹ 5S-trihydroxy-16-methy1-16-propoxy-18,19,20-trinor-prosta-5> 13-diene ₉

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5c, i3t-1,9oL, 11 dL, 15S-tetrahydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-diene,

5c, 13t-1.9 &, 11 dL, i5S-Tetrahydroxy-i6-methyl-16-butoxy-18,19,20-trinor-prosta-5, i3-diene.

Example 38

To a solution of 0.4-5 g of 5c, 13t-9d _s 15S-dihydroxy-16-methyl-16-butoxy-18,19-20-trinor-prosta-5,13-dienoic acid-15-ethyl ether in 25 ml acetone, which was stirred and then cooled to -12 ⁰ C were 0.9 ml of Jones reagent were added. The mixture was stirred for a further 35 minutes at this temperature, then diluted with 100 ml of benzene. The organic phase was washed to neutrality with a saturated (ETH / ^ SO ^ solution and evaporated to dryness. The residue was added to 30 g of silica gel eluting absorbed and with MethylenchloridA ethyl ether (70 / 30.und 50/50) to give _0? 4 g 5c, 13t-9-0x0-15S-hydroxy-16-methyl-16-butoxy-18,19,20-trinor -prosta-5 »13-dienoic acid-15-methyl ether. Ana] qg, oxidation of the methyl ester gave 5c, 13t-9-oxo-15S-hydroxy-16-methyl-16-butoxy-18,19,20- trinor prosta 5,13-dienoic acid 15-methyl ether methyl ester.

Example 39

Using the procedure described in Example 38 and using 0.8 g of the corresponding 11d - hydroxy-11-THP ether derivative the 5c, i3t-9-oxo-11 was obtained d-, 15S-aihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid-15-methyl-ether-11-TEP-ether (0.72 g), [dip = -6 ° (acetone). A solution of this 5c, 13t-9-Oxo-11 oL, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid-15-diethyl ether-11-THP- ether in 25 ml of acetone was

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For 12 hours at 38 ⁰ C with 15 ml of an aqueous O _2n-1 treated oxalic acid. The organic solvent was taking
Evaporated in vacuo and the aqueous phase was extracted with ethyl acetate. The organic layer was up to
Washed neutrality, evaporated to dryness and the residue gave 0.4-1 g of 5c, 13t-9-Oxo-11d, 15S-dihydroxy-1e-methylie-bu-tcxy-IS, 19,20-trinor-prosta-5, 13-aienoic acid-15-methyl ether, £ cL] j) - -52 °, after chromatographic purification on acid-washed silica gel using CHpClp / -HeOH (95/5) as the eluent.

Example 40

By deacetalization at the reflux temperature in the in
Example 39 described method, 0.26 g of 5 ^C , -

prosta-5,10 (11), 13-trienoic acid 15-methyl ether.

Example 4-1

By deacetalization of the 5c, 13t-9oL, 11 et, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prο st a-5,13-dienoic acid-11,15-bis-THP- ether methyl ester for a period of 3 hours
at the reflux temperature with 15 ml of an aqueous 0.2N
Oxalic acid in 25 ml of acetone and subsequent purification of the resulting crude product by extraction of the reaction mixture after removal of the acetone under vacuum with ethyl acetate gave 0.83 g of 5c, 13t-9tf. , 11 et, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid methyl ester. This compound, the 5c, 13t-9dL, 11oL, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid methyl ester, ^ * was dissolved in 6 ml SO ^ irceii väscr? ^^ methanol treated with 120 mg LiOH for 2 hours at room temperature.

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After removing the methanol in vacuo, the mixture was diluted with water and extracted with 3 × 5 ml of ethyl ether. The organic extracts were Gex with 0.2 N ZOH and water. ^"R waste and then discarded. The aqueous alkaline phases were gesamme.lt, acidified to pH 5" 2 and extracted with ethyl acetate. These organic extracts were collected, washed with water and evaporated to dryness, giving 0.72 g of 5c, 13t-90L, 11d, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid.

Example 4-2

Following the procedure of Example 4-1, by deacetalization of the 11,15-bis- and the 11- and 15-monoacetal derivatives of the 9d- and 9β-hydroxyprostanoic acids of Examples 15, 16, 18 ₅ 19, 20, 25, 27, 28 , 29 and 30 made the following compounds;

5c, 13t-9cL, 15S-dihydroxy-16-methy1-16-but oxy-18,19,20-trinorprosta-5,13-aienoic acid and their 15-methyl ether,

5c, 13t-9 d-, 11 dL, 15S-trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13-dienoic acid and their 15-methyl ether,

, 15S-trihydroxy-16-methyl-16-propoxy ~ 18,19,20-trinor-prosta-5 ₅ 13-dienoic acid,

5c, 13t-9 cL, 11 oL, 15S- ^r Drihydroxy-16-methyl-16-pentyloxy = 18,19120-trinor-prosta-5 513-dienoic acid,

5c, 13t-9 d, 15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13-uienoic acid,

5c, 13t-9 d, 15S-dihydroxy-16-methyl-16-pentyloxy-18,19,20-trinor-prost a-5,13 * -dienoic acid,

5c-9 egg _? 11 ck, 15S-terihydroxy-16-methyl-16-butosy-18,19,20-trinoi - pros b-5-en-13-insä

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5c-9cL, 15S-dihydroxy-16, i6-dimethyl-prost-5-en-13-yoic acid,

5c-9d, 11d. ₉ 15S-trihydroxy-16,16-dimethyl-prost-5-en-13-insanre,

5c-9 cj ^ , 11 cL, 15S-trihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prost-5-en-13-yoic acid,

5c-9dL, 11 d. ₅ 15S-0} rihydroxy-16-methyl-i6-butoxy-18,19,2O-trinor-prost-5-en-13-yoic acid,

5c-9de, 11cL, 15S-trihydroxy-16-methyl-16-pentyloxy-18,19,20-

5c-9 d. , 15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinorprost-5-en-13-iic acid,

5c-9 Ci-, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinorprost-5-en-13-yoic acid,

5c-9 dl, 15S-dihydroxy-16-methyl-16-pentyloxy-18,19,20-trinorppost-5-en-13-yoic acid,

5 & j 13t-9/3, 11 Λ, 15S- ^f Prihydro3iy-16-methy 1-16-butoxy-18,19,20-

tr-iiior-pros'G a-5 , 13-ienoic acid,

5e-9 p, 11 α-, 15S-trihydroxy-16 ~ methyl-16-butoxy-18,19,20-trinor-prost-5-en-13-yoic acid,

5c, 13t-9 β , 15S-Mhydroxy-16-methyl-16-but oxy-18,19,20-trinor prOsta-5, i3-dienoic acid and its 15-methyl ether,

fic-9 p , 11 ο ¹ - _s 15S-Trihydroxy-16,16-dimetbyl-prost-5-en-13-iIl-

trinor-prosta-5,13-oienoic acid ₉

5e, H3t-9ß, ^'11 Ol _s 15S-Trihydro2qy-16-methyl-16-pentyloxy-18 _i 19,20-trinor-prosta-5,13-oienoic acid _?

as well as their 15R epimers in the form of the free acids or their Ethyl ester «,

609834/1012

Example 43

A solution of 0.4-5 g of 5c-9cl, 11c ^,

THP ether in 10 ml of acetone was stirred and cooled to -12 ° C and then treated with 0.9 nil Jones reagent. The stirring continued Continued for 40 minutes and the mixture was diluted with 80 ml of benzene. The organic layer was separated with a 25% aqueous (NH ^) 2SO ^ solution until neutral washed and dried over anhydrous MgSO ^. After this Evaporation of the solvents, the crude product was purified on acid washed silica gel to give 0.4-1 g of 5c-9-Oxo-11 dL, 15S-dihydroxy-16-methyl-16-propoxy-18,19,20-trinorprost-5-en-13-ynoic acid-11,15-bis-THP-ether received.

example

Using that described in Examples 32, 34 and 43 Method based on the acetal hydroxyprostanoic acids (the free acids or the methyl esters) of Examples 15, 16, 18, 20 and 27, and by oxidation with Jones reagent, the following 9-oxo compounds were obtained:

5c, 13t-9-oxo-11 A-, 15S-dihydroxy-16-methyl-16-butoxy-18,19,20-trinor-prost-5 '13-äiensäure-15-methyl ether 11- (cK -ethoxy ) -ethyl ether,

5c, 13t-9-Oxo- 11d ~ _t 15S-dihydro2y-16-methyl-16-butoxy-18,19 »20-trinor-prosta-5,13-dienoic acid-11,15-bis-THP-ether,

5c _f i3t-9-Oxo-11 <JL, I ^ S-dihydroxy-ie-methyl-iö-propoxy-ie, 19,20-trinor-prost a-5,13-dienoic acid-11,15-bis-THP -ether,

5c j 13t-9-0x0-11 cJL, ^ S-dihydroxy-ie-methyl-ie-pentyloxy-18,19,20-trinor-prosta-5,13-dienoic acid-11,15-bis-THP-ether,

5c, i3t-9-Oxo-15S-hydroxy-16-methyl-16-propo> ^ r-'io, 19.20-

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trinor-prosta-5 _? i3-aienic acid-15-DIOX-ether ₅

5c, 13t-9-Oxo-15S-hydroxy-16-methyl-16 ~ but Oily-18,19 ₅ 20-t rinorpro st a-59 1 3-dienoic acid-15-DIOX-ether,

5c, 13t-9-oxo-15S-hydroxy-16-methyl-16-pentyloxy-18,19,20-trinor-prosta-5 _? i3-dienoic acid-15-DIOX-ether,

5c-9-oxo-11oil, 15S-dihydroxy-16,16-dimethyl-prost-5-en-13-yoic acid-11,15-Ms-THP-et here,

5c-9-Oxo-11dL, 15 (S, R) -dihydroxy-16,16-dimethyl-prost-5-en-13-ynoic acid-11,15-bis-TKP-ether,

5q-9-Oxo-11 cL, i5S-dihydroxy-16 ~ methyl-i6-propoxj-prost-5-eiii3-yn acid-11,15-bis-THP-ether,

5e-9-0xo-11d- < ₎ 15S-dihydroxy-16-methyl-16-'bTitoxj-prost-5 = -en-13-insäure-11,15-bis-THP-ä-cher,

5c-9-Oxo-11 et, 15S-aillydroxy-16-πlethyl-16-pentyloxJ-prost-5-en-13-yn acid-11,15-bis-THP-ether,

5c-9-Oxo-15S-hydroxy-16-methyl-1 e-propoxy-prost ^ -en-i 3-yn acid-15-TEP-ether,

5c-9-0xo-15S-hydroxy-16-methyl-16-l) utoxy-prost-5-en-13-yn acid-15-THP-ether,

5c-9-Oxo-15S-hydroxy-16-methyl-16-pentyloxy-prost-5-eii-13-yn acid-15-THP-ether,

and their i5H-epimeric alcohols (or free acids or Methyl ester).

example

A solution of 0.35 S 5c, i3t-9-oxo-11d-, 15S-dihydroxy-i6-methyl-i6-propoxy-prosta-5j13- ⁽ etheric acid-11 _s i5-dis-THP-ether in 30 ml acetone was heated to reflux temperature with 10 ml of 0.2N oxalic acid After 6 hours the acetone was reduced

609884/1012

The vacuum was evaporated and the aqueous phase was extracted with ethyl acetate. The organic phase was _{dried over MgSO 2} , and evaporated to give a crude product which was chromatographed on acid washed silica gel. After eluting with CH ₂ Cl ₂ / ethyl acetate (85/15), 0.16 g of 5c, 13t-9-oxo-15S-hydroxy-16-methyl-16-propoxyprosta-5,10 (11) _i 1_3- trienoic acid. Using this procedure to the 9-oxo compounds of Example 4-4, the following compounds were made:

5c, 1Jt-9-Οχο-Ί5S-hyäroxy-16-methyl-16-butoxy-18,19,20-trinorprosta-5, iO ( 1), 13-trienoic acid and its' 15-methyl ether,

5c, 13t-9-Oxo-15S-hydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5, iO (11), 13-trienoic acid,

5c, 13t-9-oxo-15S-hydroxy-16-methyl-16-pentyloxy-18,19,20-trinor-prost 8.-5.10 (11), 13-tri enic acid,

5c-9-Oxo-15S-hyaro2y-16-dimethyi-prosta-5,10 (11) -dien-13-yn acid,

5c-9-0>: o-15S-hydroxy-16-methyl-16-propoxy-18,19,20-trinorprosta-5,1O (11) -dien-13-yoic acid,

and their 15R epimers (as free acids or methyl esters).

Example 46

8 ml of a 0.2N aqueous oxalic acid were added to a solution of 0.22 ζ 5c ₅ i3t-9-Cteö ~ 11cl, 15S-aihydroxy-16-methyl-16-but03cy-18.1 $, 20-trdnox-prosta- 5,13-dienoic acid-11,15-bis-THP-ether was added in 12 ml of acetone and the mixture was heated for 32 hours at 37 ⁰ C. The acetone was evaporated in vacuo and the aqueous phase extracted with ethyl acetate. The organic extracts were collected, washed until neutral and evaporated to dryness. The crude product was then chromatographed on acid washed silica gel

609884/1012

(δ g) and eluted with cyclohexane / ethyl acetate (60/40), whereby 79 mg of pure 5c _s 13t ~ 9-oxo-11o ( _? 15S-dihydro3iy <= IS-methyl-IS-butoxy-ie, 19 ₉ 2G-trinor-prosta-5,13-dienoic acid obtained in the form of an oil, fd] _B = -38 °, fdÜ ^ o = -103 ° (ItOH) ₅ methyl ester foi] _D = -35 ° o

Example 4-7

vrarden ^T i nter using the procedure described in Example 46, starting from the acetal-9-oxo-Terbindungen of Example 44 the following prostanoic-9-ketone (in the form of
free acids or methyl esters):

5c, 13t-9-Oxo-15S-hydrox3--16-metbyl-16-propoxy-18,19,20-trinor-prosta-5? 13-dienoic acid,

5c _? 13t-9-02ro-15S-hyäroxy-16-niethyl-16-buto2y-18,19,20-trinorprosta-5,15-dienoic acid,

5c - i3t-9-0 :: o-15S-hydroxy-16-niethyl-16 ~ pentyloxy-18,19,20-trinor-pros "äa-5» ^ 3-dienoic acid,

5c-9-0xo-1 frS-hydroxy-i 6-methy 1-16-propoxy-18,19,20-trinor ~

5c-9-Oxo-15S-hydroxj-16-methyl-16-but oxy-18,19,20-trinorprost-5-en-13-yoic acid _s

xy-16-methyl-16-pentyloxy-18,19,20-trinorprost-5-en-13-insäurs _?

50-9-Oxo-i 1 ei, 15S-dihydro3qy-16 _s 16-dimethyl-prost-5-en-13-in- = c-9-0xo-11 d-, 15 (S, E) -dihydro2q5T- 1 &, 16-dimethyl-prost-5-en-13 »

5C-9-OXO-11d-315S-dihydr 02cy-16-methyl-16-propoxj-18 ₉ 19 ₉ 20
trinor-prost-5-en-i J> -insär: right.

= -t? - 9-0xo-11 yl ₅ 15S-dihydro3qf-16-inetbyl-16-pentylo3qy ~ 18,19 ₅ 20 ~

60988 4/1012

trinor-prost-5-en-13-ynoic acid,

5c-9-oxo-.11 dL, 15S-dihydroxy-16-methyl »16-buto3qr-18,19,20-trinor-prost-5-en-13-yoic acid, fdl-p = -21 °, Td] ₃₆₅ O = -I52 ⁰

md its 15-epiderivative, [d] _D = -14.7 °, Dl ₃₆₅ O = -157 °,

/4.36 ^{0 =} -

5c, 13t-9-Oxo-11 dl, 15S ~ dihydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13 ~ dienoic acid, [^ lq = -38 °, Γ0Γ / ( ItOH),

5c, 13t-9-oxo-11 dl, 15S-dihydroxy-16-methyl-16-but oxy-18,19,20-trinor-prosta-5,13-dienoic acid, [JIq = -38 ° »LoU ^ ₆ O = -103 °

q ^ ₆

(ItOH), lind you 15R epimers _$ fd ^ = -57 ° (EtOH),

5c, 13t-9-0x0-11 O- , 15S-dihydroxy-16-methyl-16-pentyloxy-18,19,20-trinoΓ-prosta-5 _ί 13-dienoic acid, [dl ^ = -32.7 °,

W436 ^{0 =} ~ 9 ⁸ ? 3 ° (EtOH) wid you 15E-epimer, [d] ^ = -54 °

Example 48

With stirring, 24.3 g of sodium in the form of small pieces were added to 405 ml of n-butanol and the mixture was heated to reflux temperature, complete dissolution of the metal being achieved. The resulting solution of sodium butoxide in n-butanol was cooled to 0 to 5 ° C and then treated with a solution of 48 g of anhydrous 2-methyl-1,1,1-trichloro-2-propanol in 67.5 ml of n-butanol, which was added over a period of 1 hour. The excess butanol was distilled off and the residue was treated with 122 ml of 4N H2SO4 and extracted with ethyl ether to give, after distillation under vacuum, 24 g of 2-methyl-2-butoxy-propanoic acid (Kp. 12O ⁰ C). A solution of this 2-methyl-2-butoxypropanoic acid was converted into the corresponding methyl ester (boiling point 98 ° C.) by treatment with methyl iodide of a solution of the sodium salt in hexamethylphosphoric acid triamide. In an analogous way, 3i * Z-

609884/1012

(. b.p. 103 ° C) propanoic acid (Methylester: Kp 118-119 ⁰ C.) was prepared and the 2-methyl-2-pentyloxy-propanoic acid (b.p. 125 "to 127 ° C.).

Example 4-9

69 ml of 20% strength butyllithium in n-heptane were added dropwise to a stirred solution of 19 g of methylphosphoric acid dimethyl ester in 138 ml of dry THF, then cooled to -65 "to -70 ° C. for a period of 1 hour. Stirring was continued continued for 15 minutes, then a solution of 13 was g of 2-methyl-2-butoxy-propanoic acid methylesters in 25 ml of dry THF under cooling at -60 to -70 ⁰ C to the reaction mixture. stirring was 1 1 / continued for 2 hours, then the mixture to room temperature, was heated (20 to 25 ⁰ C) and after 3 hours it was diluted with 1A, treated for 5 ml of acetic acid. after removal of THP under vacuum, the residue is treated with 100 ml of water was diluted and repeatedly extracted with ethyl ether After distillation was obtained 13 g of dimethyl (2-oxo-3-methyl-3-butoxybutyl) phosphonate - In an analogous manner the following compounds were prepared. (Kp ^ ^ 138 to 140 ⁰ C.).:

Dimethyl (2-oxo-3-methyl-3-propoxybutyl) phosphonate (Kp. _2123-125 ⁰ C) and

Dimethyl- (2-oxo-3-methyl-3-pentyloxybutyl) phosphon8t (bp. ^ C 125 to 126 ° C).

609 884/1012

Claims (1)

Claims (■ · ^! Optically active or racemic prostaglandins, characterized by the general formula where mean: A -CHpOH or -COOR, where R is a hydrogen atom, a Cj-C ^ -alkyl group or a cation of a pharmaceutical represents a compatible base; the symbol a single bond or a double bond, where if the symbol a double bond means, R, represents hydrogen and R ^ and R ₂ together form an oxo group, while when the symbol denotes a single bond, R, hydrogen or hydroxy and one of the radicals R ^ and Rp are hydrogen and the other is hydroxy or R ^ and R ₂ together form an oxo group; B trans-CH = CH- or -C ~ C-; one of the radicals R ^ and R ₁ - hydrogen and the other hydroxy or C ^ -C ^ -alkoxy; X -0- or -CH-, with the proviso that X is only -OHp-, when B represents -C = C-; 609884/1012 - 2Γ - η is the number O or an integer from 1 to 5; R ^ α, -Cc-alkyl, cycloalkyl with 3 to 7 ring carbon atoms or phenyl which is unsubstituted or optionally substituted by one or more substituents from the group halogen, C ^ -C ^ -alkoxy and Trihalomethyl. 2. Compound characterized by the formula: 5c, 13t-9-Oxo-11ö (, ISS-dihydroxy-iö-methyl-io-butoxy-ie, 19,20-trinor-prosta- ~ 5113-di en acid, - 5c, 13t-9-Oxo-11, ^, 15B-dihydroxy-i6-methyl ~ i6-pentyloxy-i8,19, | 20-trinor-prosta- -5s 13-dienoic acid, - - " 5c, 13t-9-Oxo-11 οι 115S-U ^ ydroxy-16-msthyl-16-propoxy-18,19,20-trinor-prosta- 5c, 13t-9-oxo-15S-hydroxy-16-methyl-16-propoxy-18,19,20-trinor-prosta-5,13- -disn acid, 5c, 13t-9-Cbco-15S-hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prosta-5,13- -dien acid, 5c 113t-9-O ' ^x ° -1 SS-hyäroxy-i 6-methyl-16-pentyloxy-18,19,20-trinor-prost a- -5113-dienoic acid, 5c-r9-0) co-11 oi, ^ S-dihydroxy-io-raethyl-ie-butoxy-iSj ^^ O-trinor-prost ^ -en- -13-oxylic acid ,. 5c-9-oxo-11ct (, 15S-dihydroxy-16, 16-diraethyl-prost-5-en-13-'ic acid, 5c-9-Oxo-15S-hydroxy-16-xsthyl-16-butoxy_18.1 °, 20-trinor-prost-5-en-13-yn acid, 609884/1012 -13-, ynoic acid, 5 ^c ~ 9ol 11 1 © t, 15S- ^} rihydroxy-1NC-methyl-i6-butoxy-18,19,20-trinor-prost-5-en-13-.insäure, 5c , 13t-9 ß, 11 <λ, 15S-Trihydroxy-16-methyl-16-butoxy-18,19,20-trinor-pros-ta- · ~ 5i13-diene acid, 5C | 13t-9 Ρ 111oL f 15S-5) rihydroxy-iö-rae-thyl-iö-propoxy-iß, 19,20-trinor-prosta- -5,13-dienoic acid, - SS 111 C ^ ₁ ISS-CDrihydroxy-i ^ methyl-IOE-pentyloxy-ie, 19,20 - trinor prostaglandin -5 _"t äien acid ^13: 5ci 13t-9C ^, 11 oil ₁ 15S-trihydroxy-16 ~ methyl-16-butoxy-18,19,20-trir.or-prosta- ~ 5i13-dienoic acid, 5ci 13t-9-iOxo-15S-hydroxy-i6-methyl ~ i6-butoxy-i8,19,2O-trinor-prosta-5,10 (11), 13- ydiOx'y-io-methyl-io-butoxy-iB, 19,20-trinor-prosta-5,1O (1 i) -diene- -13-ynoic acid, as well as the 15R epimers and the methyl esters thereof. 5. Process for the preparation of the optically active or racemic Prostaglandins according to Claim 1 or 2, characterized in that an optically active compound or a racemic mixture of compounds of the general formula OH (H) 609884/1012 -4- wherein η, R, - and X have the meanings given in claim 1, B ¹ -G = G- or Y
trans-C = C-, where Y is hydrogen or bromine, R '? Hydrogen or a known protective group, which is bonded to the Hing via an ether oxygen atom, and one of the Eeste R ¹ ^ and R ¹ , - hydrogen and the other O ^ -C ^ -alkoxy or a known protective group, which is connected via an ether oxygen atom the chain is tied mean ^ with a Wittig reagent of the general formula ₂ ^ ■, in which A ¹ -COOR, in which R has the meanings given in claim 1, or -CHp-R ", in which R" is a known protective group as defined above, with formation of a compound of the general formula VX- (CH 1 - (III) wherein n, R ^, X, R ¹ ^ »EV ₁ EV and A ^{1 have} the meanings given above and B is as defined in claim 1, which, after any esterification carried out in the 1-position, if A ^{1 is} carboxy, is then optionally converted into the corresponding 9β-hydroxy derivative and then optionally the protective groups in the 1 and / or 11 and / or 15 positions are removed to form a compound of those specified in claim 1 609884/1012 Formula I, in which A, M ^, B, R ^, R ₁ -, X, η and Rg have the meanings given in claim 1, the symbol - ^ - ^ and Rp hydrogen a single bond, one of the radicals and the other hydroxy and one of the radicals R ₂ , and R 1 - hydrogen and the other hydroxy or C ^, - C ^ alkoxy, or if desired the 9oc- or 9ß-hydroxy group of a compound of the general formula (HIa) where B, A ¹ , R '^ »R ¹ ^.» E ', -, X, η and R have meanings and one of the radicals is substance and the other is hydroxy, the above ^ and R ^ water_ oxidizes to form a compound of the general formula wherein A ¹ , R ¹ ^ ₁ B, have meanings, 'r, X, η and Rg those given above from which in turn then the protective groups in the 1- and / or 11 and / or 15 positions can be removed, depending on the the reaction conditions used either a compound of the formula I indicated in claim 1, wherein the Symbol a single bond, R _T hydrogen or Hydroxy and R ^, and Hp together represent an oxo group 609884/1012 form, or a compound of those specified in claim 1 Formula I is obtained, in which the symbol - a double bond, R ^ is hydrogen and R 'and R ₂ together form an oxo group, and / or, if desired wherein R is hydrogen is a compound of formula I given in claim 1, wherein A is -COOR _Cj and wherein the hydroxyl group at the 11- mid / or 15-position, if it is present, is optionally protected as indicated above, reacted with a base and then, if necessary, the protective groups are removed to form a compound of the formula I ₅ given in claim 1 in which A is -GOOR, in which R is a cation represents ₉ or a compound of the formula I ₅ given in claim 1 in which A is -COOR, in which R is hydrogen and the hydroxyl group in the 11- and / or 15-position, if present, is optionally protected as indicated above , esterified *) to form a compound of the formula I given in claim 1, in which A is -GOOR, in which R is -C ^ -C ^ -alkyl, or a compound of the given in claim 1 n Formula I, in which A is -GOOR, in which R is 1 -C 4 -alkyl, and in which the hydroxyl group in the 11- and / or 15-position, if present, is optionally protected as indicated above, hydrolyzed and then if necessary, the protective groups are removed therefrom to form a compound of the formula I given in claim 1, in which A is -COOR, in which R is hydrogen, 4. Medicament, characterized in that there is at least one prostaglandin of the general formula given in claim 1 as active ingredient!, Optionally in combination with a suitable carrier and / or diluent _? contains. 5c compound characterized by the general formula ROO 0 ^a } * ^CK 2 - ^ß "" ^C <CHJ ₂ -0- (CH 1 -Ή, Bo 'CiVIII) 609884 / 10.12 ~ nS then, if necessary, the protective groups are removed where R _{& is} lower alkyl vind η raid Eg have the meanings given in claim 1. 6. Compound characterized by the general formula (XIX) • ^{R //} 3 \ c ^{y R} 4 "5 wherein B ^{1 has} the meanings given in claim 3, X, η and Rg are as defined in claim 1, one of the radicals Q ^ and Q _{2 are} hydrogen and the other is hydroxy or Q ^ and Q ₂ together form an oxo group, R "', Hydrogen, hydroxy, acyloxy or a known protective group bonded to the ring via an ether oxygen atom, one of the radicals IV IV
and R [- IV
and R [- is hydrogen and the other is hydroxy, C 1 -C 4 -alkoxy or a known protective group bonded to the chain via an ether oxygen atom or in which, if e n, and Qo together form an oxo group, R ^ and Re together also form an oxo group. 7e compound, characterized by the general formula C (CH ₃ YX- (CH ₂ ) _n -R _{6 (xx)} wherein A ^{1 has} the meanings given in claim 3, B, X, η and Rg are as defined in claim 1, one of R ^ and R _{2 is} hydrogen and the other is hydroxy or R ₁ and R 2 together form an oxo group , and R '^ j 609884/1012 E \ and E'c have the meanings given in claim 3 , with the proviso that when A ^{1 is} different from -GH ₉ R ", in which R" represents a known protecting group bonded to the ring via an ether oxygen atom, at least one of the remainders ^s ' z »R'4. and RV represents a known protecting group as defined above. 609884/1012