CA1072549A

CA1072549A - Thiaprostaglandine

Info

Publication number: CA1072549A
Application number: CA264,881A
Authority: CA
Inventors: Dieter Orth; Klaus Irmscher; Hans-Eckart Radunz; Manfred Baumgarth
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1975-11-07
Filing date: 1976-11-04
Publication date: 1980-02-26
Also published as: DE2550004A1; ES453043A1; CH625211A5; NL7612320A; ES463723A1; DE2550004C2; JPS5259138A; SE7612368L; JPS6032625B2

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to novel 13-thiaprostanoic acid derivatives of Formula I

I

wherein A is -CO- or -CHOH-, B is -CH2-CH2- or -CH=CH-, R1 is H or an alkyl group with 1 to 4 carbon atoms, m is an integer between 0 to 5, n is an integer between 0 to 3, or, when B is -CH=CH-, also 4, 5, 6, 7, 8 or 9.
R2 is alkoxy with 1 to 4 carbon atoms, phenory, pyridyl, thienyl, naphthyl. phenyl substituted by F, C1, Br, OH
OCH3 or CF3, or phenoxy substituted by F, C1, Br, OH, OCH3, CH3 or CF3, or when B is -CH=CH-, also hydrogen, phenyl or toyl, and B3 is H, methyl or ethyl, and the wavy line (?) designates that these compounds are either .alpha.- or .beta.-positioned;
as well, the invention relates to the physiologically accept-able salts of same.
The compounds of Formuls I have useful pharmacological properties.

Description

Thi:aprostaglandins ..
The invention relates to novel 13-thiaprostanoic acid derivatives of Formula I

J~CH2-B-~CH2~3-COOR

CnH2n-R
~ S-CH2-C(OR
HO ~
Cm~2m+ 1 wherein .~ A is -CO- or -CHOH-, B is -CH2-CH2- or -CH=CH-, Rl is H or an alkyl group with 1 to 4 carbon atoms, m is an integer between 0 to 5, n is an integer between 0 and 3, or, when B is -CH=CH-, also 4, 5, 6, 7, 8 or 9, R2 is alkoxy with 1 to 4 carbon atoms, phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, Cl, Br, OH, OCH3 or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CN3 or CF3, or, when B is -CH=CH-, also hydrogen, phenyl or tolyl, and R is H, methyl or ethyl, and the wavy line (~W~) designates that these compounds are : either ~- or ~-positioned;
. 20 as well, the invention relates to the physiologically acceptable salts of same.
It is an object of the present inventi.on to provide a new medicine. Thi.s object is achieved by the discovery of new compounds of Formula I which can be used in the product-ion of medicine due to their properties.
It has been found that the derivatives of 13--thia-- prostanoic acid of Formula I possess useful pharmacological properties. Thus, for instance they possess blood pressure _]- ~

lowering properties which are apparent e.g at a continuous infusion into barbiturate-narcotized cats. In such tests, the arterial blood pressure was registered kymographically.
The testing substances were immersed in an aqueous propylene glycol solution for a period of 10 minutes.
Moreover, 13-thiaprostanoic acid derivatives of Formula I possess vasodilatoric, antiphlogistic, diuretic, bronchial relaxing properties as well as the properties of gastric juice secretion controlling, thrombocytes-aggregation inhibiting, lipid breakdown and the noradrenaline release inhibiting and swollen mucous membrane (nasal) shrinking - properties, which can also be achieved by known methods.
The prostanoic acid derivatives of Formula I can also influence the function of corpus luteum, the egg passage through the oviduct, the nidation and fertility. Thus, ; particularly the compounds of Formula I with B = cis-1,2-vinyl possess an oestrus synchronizing property, e.g. in cattle.
The compounds of Formula I and/or -their physiologically acceptable salts can thus be used as a medicine or also as ` 20 intermediate products in the production of other medicinal agents.
The subject of the invention includes compounds of Formula I wherein A, B, R , R2, R3, m and _ have the above meaning~
The compounds of Formula I contain at least 3 asymmetrical carbon a-toms looped to form a five-membered ring.
When A designates -CHOH-, then four asymmetrical centers are present in the ring. Furt~er asymmetrical centers are present in the ether side-chain. The compounds of Formula I
-thus occur in a plurality of stereoisomeric forms; usually they are of the type of racem:ic mixtures.

-2-., ' ' ' ~' ' 2 c~

Besides the individual racemates and racemic mixtures, the subject of the present inven-tion also includes the optically active isomers of Formula I.
Furthermore~ the subject of the invention includes a method for the production of a compound of Formula I, as . well as of its physiologically acceptable salts, character-ized in that a compound of Formula II

~ CH2-B-(CH2)3-COOR II

HO
wherein 10 Z is a nucleofugal group, and A, B, R have the above meaning, is reacted with a compound of Formula III

n 2n MS-CH2-C(OR ) ~ III

.
wherein M is H, an equivalent of an alkali- or alkaline earth metal atom or ammonia, and R2, R3, m and n have the above meaning, or in that a compound of Formula IV

OH

'' 0~
IV
S-CH2-C(OR ) HO m 2m-~1

-3-,.' :

~'7~

wherein R2, R3, m and n have the above meaning;

is reacted with a compound of Formula V

[(R )3P-(CH2~4-COOR ~ X( ) V

wherein R4 is alkyl with 1 - 6 carbon atoms, phenyl, naphthyl or a phenyl or naphthyl group substituted with alkyl having 1 - 4 carbon atoms, and X is Cl, Br or I, and Rl has the above meaning, and, where desired, forming a pharmaceutically acceptable salt of the compound of formula I so produced.
Alternatively, the method is characterized in that a compound corresponding to Formula I but having at least one hydroxy group and/or the carbonyl group and/or the COORl group present in a functionally modified form, is reacted with a solvolyzing agent or with a hydrogenolyzing agent and/or that a compound of Formula I (A = -CO-) is transformed into another compound of Formula I (A = -CHOH-) by conversion with a reduction agent, and/or that a compound of Formula I (R = H) is modified into another compound of Formula I (Rl = alkyl with 1 to 4 carbon atoms) by reacting with an esterifying agent, and/or that a compound of Formula I is transformed into another compound of Formula I
by reacting with a solvolyzing agent, and/or that a compound of Formula I is separated into its~ racemates and/or enantiomers, and/or that an acid of Formula I (Rl = H) is transformed into one of its physiologIcally acceptable salts by processing with a base or liberated from one of its salts by processing with an acid. These last-mentioned methods are disclosed and claimed in our copending Canadian Application Ser. No. 226,634,

-4-filed in May, 1975.
Similarly, the subject o~ the present invention includes pharmaceutical preparations containing a-t least one compound of Formula I and/or one of its physiologically accept-able salts, as well as a method for producing such pharmaceu-tical preparatïons, characteri.zed in that a compound of Formula I is brough.t into a suitable dosage form together with a solid, liquid or semiliquid additive auxiliary agent or carrier agent, and, if ne¢essary, with a further agent.
When A is a -CHOH- group, then the OH group can be in an ~- or ~-position. When B designates a 1,2-vinyl radical, then the same is preferably cis-substituted.
In the foregoing formulas, Rl designates particularly hydrogen, but also an alkyl radical, preferably an unbranched . one with up to 4 carbon atoms, such as methyl, ethyl, propyl or n-butyl, but also a branched one, such as isopropyl or tert.-butyl.
_ is preferably 0, 1 or 2 but may also be preferred as 5, when _ is also 5 and R is H.
CmH2m+l is then, besides hydrogen (m = 0) an alkyl with 1 to 5 carbon atoms, preferably unbranched, such as methyl, ethyl, propyl, butyl or pentyl; but also a branched . one such as isopropyl or isobutyl.
When B is -CH=CH- and R is H, then n designates preferably 5, 6 or 7. When R2 is other than H, then _ is preferably 0 or 1.
In the compounds of Formula I of the type wherein CnH2n is a branched alkyl radical, the radical CmH2m~l is usually an unbranched alkyl radical because of a possible .~ 30 steric blocking, preferably methyl or ethyl, particularly when the branching in CnH2n is present in the l-position.
If CnH2n is a branched alkyl radi.cal, then, in general, _5 _ .

:~3'~

the branching - if still necessary - in CmH2m+l is shiftèd as Ear as possible from the l-posltion.
CnH2 designates, besides a C-C or C-O single bond (n = 0, R other than H~, alkylene with 1 to 3 carbon atoms, preferably methylene, e-thylidene or isopropylidene. When B is -CH=CH , then CnH2n can, moreover, further designate alkyl with 4 to 9 carbon atoms, preferably non~branched alkyl with 4 to 9 carbon atoms such as tetramethylene, pentamethylene, hexamethylene or heptamethylene, but also branched alkyl with 4 to 9 carbon atoms such as -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2~
-C(CH3)2CH2-, -CH~CH3)CH~CH3)-, -CH(C2H51CH2-, -CH(CH3)CH2 CH2CH2-, -CH2CH(CH3)CH2CH2 , C(C 312 2 2 3 ( 31CH2 , CH(C2H5)CH2CH2-, -CH(CH3)CH2CH2CH2CH --C(CH3)2CH2CH2CH2-, -CH(CH3)CH(CH3)CH2CH2-, CH(CH3)CH2CH2 CH2CH2CH2-, -CH(CH3)CH(CH3)CH2CH2CH2-, -CH2CH2CH2CH2C(CH3)2-, -CH(CH3)-(CH2)6- or -C(CH3)2 ( 2)6 In the grouping CnH2n-R with R = H is involved, besides hydrogen, preferably an alkyl with 1 to 9 carbon atoms, preferably an unbranched alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or nonyl, but above all also an alkyl radical, particularly of the type branched in l-position, with 3 to 9 carbon atoms such as isopropyl, sec.-butyl, tert.-butyl, l-methylbutyl, l-methyl-pentyl, l,l-dimethylbutyl, l-ethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1-ethyl-2-methylpropyl, l--ethyl-l-methylpropyl, l-methylhexyl, l,l-dimethylpentyl, l-ethylpentyl, l,l-dimethylhexyl, l,l-dimethylheptyl, 1,3,3-trimethylbutyl or 1,1,2,2-tetramethylpropyl; but also e.g. a 3,3 dimethyl-butyl or 4,4-dimethylpentyl.

R designates methoxy, ethoxy, phenoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, l-naphthyl, 2-naphthyl, a phenyl mono-, di- or tri-substituted by F, Cl, Br, OH, OCH3 or CF3, or a phenoxy mono-, di- or tri-substituted by F, Cl, Br, OH, OCH3, CH3 or CF3. When B is -CH=CH-, then R can also be hydrogen, phenyl or tolyl. When R2 is a substituted phenyl or a substituted phenoxy radical, then it is preferably monosubstituted such that the substituent can be found in the o-position, particularly in the m- or in the p-position.
Hence, R2 is preferably- m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, p-bromophenyl, p-hydroxyphenyl, p-methoxyphenyl, m-trifluoromethylphenyl, p-trifluoromethyl-phenyl, phenoxy, m-fluorophenoxy, p-fluorophenoxy 7 m-chloro-phenoxy, p-chlorophenoxy, p-bromophenoxy, p-hydroxyphenoxy, p-methoxyphenoxy, p-methylphenoxy, m-trifluoromethylphenoxy or p-trifluoromethylphenoxy, and also for instance 2,4-dichloro-, 3,4-dichloro-, 2,4-dibromo-, 2,4-dimethyl-, 3,4-dimethyl-, 2,4-dimethoxy-, 2,3-dimethoxy-, 2,4,6-trimethyl, or 3,4,5-trimethoxyphenyl or -phenoxy.
R3 designates, besides methyl or ethyl, preferably hydrogen.
Particularly useful are the compounds of Formula I
wherein at least one of the symbols Rl, R2, R3, A, B, m and n have one of the above mentioned meanings . _ .
The particularly preferred groups of the compounds can be characterized by partial formulas Ia through In which otherwise correspond to Formula I and in which the symbols not described in greater detail have the meaning as given in Formula I, but wherein in Ia R = H, in Ib R = methyl or ethyl, in Ic A = -CO-, in Id A - -CHOH-, in Ie B = cis-CH=CH-, 7~ 3 in If n = 0 or 1, in Ig m = 1, in Ih R2 = m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p-fluorophenoxy, m-chlorophenoxy or p-chlorophenoxy, in li R = R = H, A = -CO-, B = -CH2-CH2-, and R
m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p-fluorophenoxy, m-fluorophenoxy or p-chlorophenoxy, in Ij Rl = methyl or ethyl, R3 = H, A = -CO-, B = -CH2-CH2-and R2 = m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p-fluorophenoxy, m-chlorophenoxy or p-chlorophenoxy, in Ik Rl = R3 = H, A = -CHOH-, B = -CH2-CH2-, and R
m-f1uoropheny~ p-fluoropheny~ m-chlorophenyl, - p-chlorophenyl, m-fluorophenoxy, p-fluorophenoxy, ;~ m-chlorophenoxy or p-chlorophenoxy, ^ in Il R = methyl or ethyl, R3 = H, A = -CHOH-, B = -CH2--CH2- and R2 = m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p-chlorophenoxy, m-chlorophenoxy, p-fluorophenoxy, in Im Rl = H, methyl or ethyl, R3 = H, A = -CO- or -CHOH-, B = -CH=CH-, CnH2n-R2 = pentyl, hexyl, heptyl, l-methylpentyl, or l,l-dimethylpentyl, and CmH2m+l = H or methyl, in In R - R3 = H, A = -CHOH-, B = cis-CH=CH-, CnH2n - R
= pentyl, phenoxymethyl or m-chlorophenoxymethyl, and CmH2m+l = H or methyl-- The compounds of Formula I are structurally related to prostaglandins derived from 7 (2-octyl cyclopentyl)-heptanoic acid (prostanoic acid~. The compounds of Formula I are derived from 13-thiaprostanoic acid.

: .
;'' ~

M preferably designates H, Na, K, 1/2Ca or NH4. More-over, M can also he an equivalent of another alkali or alkaline earth metal atom or ammonium substituted by 1 to 4 alkyl radicals with preferably 1 to 6 carbon atoms, by cycloalkyl radicals with preferably 5 - 7 carbon atoms, or by aralkyl radicals with preferably 5 to 7 carbon atoms.
The radicals R4 can be same or different and designate particularly phenyl. Preferably radicals R4 are also the methyl- and the ethyl groups. ~esides, R4 may have all other above mentioned meanings, for instance propyl, butyl, isobutyl, pentyl, isopentyl, hexyl~ naphthyl, o-, m- or p-tolyl.
X designates particularly Br, but also Cl and, if necessary, I.
Z designates a nucleofugal group. As such, the following are particularly suitable: Cl, Br, I, trialkyl ammonium groups such as trimethylammonium, dialkyl-benzyl ammonium groups such as benzyldimethylammonium, alkylsulfonyl-oxy groups with 1 to 4 carbon atoms, such as methylsulfonyloxy or 2-hydroxyethylsulfonyloxy and, if necessary, substituted arylsulfonyloxy groups with 6 to 11 carbon atoms, such as phenylsulfonyloxy, p-tolylsulfonyloxy r p-bromophenylsulfonyl-oxy, l-naphthylsulfonyloxy or 2-naphthylsulEonyloxy.
In the reactions described hereinafter, for the production of starting compounds, but also of the compounds of Formula I, analogous methods are employable. Their reaction requirements can be readily obtained from routine works relating to synthetic organic chemistry, e.g. HOUBEN-WEYL, Met'noden der organischen Chemie ~Methods of Organic Chemistry~, Georg Thieme Verlag, Stuttgart, or ORGANIC
SYNTHESES, J. Wiley, New York~London-Sydney.
The compounds of Formulas II through V are known or can be produced from known compounds in analogy with the _g_ known methods. Thus, for instance, a compound of Formula II
with A = -CO~, R = CH.3 and z - Cl, Br or I can be obtained :. from the known compound 7-~3-hydroxy-5-oxo-1-cyclopentyl)-5-heptenoic acid methyl ester ~TETRAHEDRON IETTERS, 1975, vol.
25, pp. 2313 -2316) by- addition of HZ (Z = Cl, Br or I). The obtained 7-(3-hydroxy-2-Z-5-oxo-1-cyclopentyl)-5-heptenoic :~
acid methylester can then be reduced by reacting with a complex borohydride, for instance with NaBH4 to 7-(3,5-dihydroxy-2-Z-l-cyclopentyl)-5-heptenoic acid methylester 10 and/or can be reacted by a careful basic hydrolysis, e.g.
: with KOH in dioxane/water:mixtures at approximately room temperature to obta;n the corresponding free acids. It is particularly advantageous to produce the compounds of Formula . II with A = -CHOH- and Z = I, from the known 1,4-dibenzyloxy-. 2-(1,3-dioxolane-2-yl-methyl~-3-p-toluenesulfonyloxy-cyclopentane by reacting with NaI in dimethylformamide, acetone or another aprotic dipolar solvent, if necessary in .
: the presence of water, by hydrolysis or the obtained 1,4-dibenzyloxy-2-(1,3-dioxolane-1-yl-methyl)-3-iodo-cyclopentane :. 20 with diluted hydochloric acid, by reacting the obtained ; 2-(3,5-dibenzyloxy-2-iodo-cyclopentyl)-acetaldehyde with a .~ compound of Formula V in the presence of a strong base and by a hydrogenolysis separation of both benzyl groups.
The compounds of Formula II with Z = alkylsulfonyloxy with 1 to 4 carbon atoms, or arylsulfonyloxy with 6 to 11 ~ carbon atoms can be obtained from the above described other compounds of Formula II with Z = Cl, Br, or I by modification . of the existing OH groups according to the known methods, into tetrahydropyranyloxy groups, by basic hydrolysis e.g. with KOH in a dimethylformamide/water mixture at temperatures between about 35 and about 80, and by finally reacting the obtained (~after acidification) 7-(2-hydroxy-5-oxo-3-tetrahydro--:
.. .

pyranyloxy-1-cyclopentyl)~ or 7-(3,5-ditetrahydropyranyloxy-2-hydroxy-1-cyclopentyl)-5-heptenoic acid with the corresponding sulEonic acid chlorides such as methylsulfonic acid-, benzene-sulfonic acid-, or p-toluenesulfonic acid chloride. However, it i5 also possible, for instance, to process 1,4-dihydroxy-2-(1,3-dioxolane-2-yl-methyll-3~p-toluenesulfonyloxy-cyclo-pentane ( J. Amer. Chem. Soc. 94, 4342 [1972]) with diluted hydrochloric acid and to modify the obtained 2-oxa-3,7-dihydroxy-6-p-toluene-sulfonyloxy-bicyclo [3,3,0] octane with a compound of Formula V in the presence of a strong base.
The compounds of Formula III are partly known. They can be produced by known methods, for instance from the g (CnH2n R 1-2-CmH2m+l-oxiranes by reacting with H2S and, if desired, by final transformation into its alkali-metal-, alkaline earth metal- or ammonium salts.

the 2-(CnH2n~R )-2-cmH2m~l-oxiranes can be directly reacted with alkali metal-, alkaline earth metal~ or ammonium hydrogen sulfides, whereby the compound of Formula III is directly obtained of the type with M being other than H.
; The compounds of Formula IV are obtained from the compounds of Formula VI

. ~ ~
~i~ ~ CnH2n~R
~ S-CH2-C(oR3) ~ VI
HO m 2m~1 wherein T5 is -CO- or -CHOR -, and : R is methyl or ethyl, and R , R , m and n have the above mentioned meaning, . .

by a reduction (when T is -CO-~ with diisobutyl aluminum hydride in toluene at approximately - 90 to approx. -70 or by acid hydrolysis (when T is -CHoR5-] e.g. with 0.03-N
hydrochloric acid in acetonitrile/water mixtures at room temperature.
The compounds of Formula VI themselves can be obtained by reacting the known compounds VIIa or VIIb ~ ~ VIIa r ~ VIIb with a compound of Formula III.
The phosphonium salts of Formula V are known, e.g.
from DOS (German patent application open for inspection) -2,431,930, published January 30, 1975, and from TETRAHEDRON
.~ LETTERS, 1970, vol. 4, pp. 311-313.
Particularly important intermediate products of Formula III are those of Formula IIIa, which corresponds to Formula III, wherein M, m and _ have the meaning as defined above, but wherein R2 is phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, Cl, Br, OH, OCH3 or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, and ~3 is hydroyen. Of particular significance are the inter-mediate products of Formula IIIb, which corresponds to Formula IIIa except for _ being l. However, above all, the intermediate products of Formula IIIc are useful, Formula IIIc corresponding to Formula IIIb wherein _ is zero or l.
The compounds of Formula III and particularly -the preferred Formulas IIIa - IIIc can be ob-tained by reac-ting the carbonyl compounds of Formula VIII
CmH2m~l~cO-cnH2n-R VIII

' wherein m, _ and R2 have the above meaning, with a methylene radical forming agent, for instance diazo-methane or trimethylsulfoxoniumiodide, to obtain the epoxide of Formula IX

ClmH2m-~1 CH -C-C H -R IX

, \ I
., O

wherein m, n and R have the above meaning, and by reacting such epoxide with H2S, preferably in the presence of a suitable inert solvent, e.g. a lower alkanol such as methanol or ethanol and particularly in the presence ~; of a basic catalyst, e.g. an alkali metal hydroxide such as NaOH or KOH, or an amine such as diethylamine, triethylamine, piperidine or morpholine.
Among the starting products of Formula VIIa or VIIb, the ones of particular significance are those wherein all bonds associated with the five-membered ring are in an ~-position:

OCH

~ ~ VIIa' ~ \~ VIIb' ,~, O, ' 'O` ~0 The compounds corresponding to Formula I except that at least one hydroxy group and~or one carbonyl group and/or one COOR group is in a functionally modified form, can be preferably produced by a method that will also produce the compounds of Formula I but wherein it is started from an D~

initial product wherein the corresponding hydroxy groups and/or one carbonyl group and~or one COORl group is in a functionally modified form. The radicals by which the above groups are functionally modified have to be easily separable, but usually should be resistant to compounds of Formula V.
In the functionally modified OH-groups, preferably organic acids or sulfonic acids are involved or saturated aliphatic, cycloaliphatic or aromatic, substituted or un-substituted types, or also OH-groups of esterified inorganic acids. Preferred carbonic acid esters are derived from fatty acids containing 1 to 18, preferably 1 to 6 carbon atoms, such as formic acid, acetic acid, butyric acid or isobutyric acid, but also for instance pivalic, trichloro-acetic, benzoic~ p-nitrobenzoic, palmitic, stearic, or oleic acid. The preferred sulfonic acid esters are derived from alkylsulfonic acids with 1 to 6 carbon atoms, for instance methane- or ethanesulfonic acid or arylsulfonic acids with 6 to 10 carbon atoms, for instance benzene , p-toluene, 1- and ` 2-naphthalenesulfonic acid, furthermore from substituted sulfonic acids such as 2-hydroxyethane or 4-bromobenzene-sulfonic acid. The preferred inorganic acid esters are sulfates and phosphates.
The functionally modified OH-groups can also be in an etherified form, for instance as aralkoxy with preferably 7 to 19 carbon atoms such as benzyloxy, p-me-thylbenzyloxy, 1- and 2-phenylethoxy, diphenylmethoxy, triphenylmethoxy, or 1- or 2-naphthylmethoxy; alkoxy with preferably up to 6 carbon atoms, particularly methoxy, ethoxy or tert.-butoxy;
tetrahydropyranyloxy; or trialkylsilyloxy, preferably trimethylsilyloxy.
Keto groups can preferably be functionally modified as hemiketals such as -C~OH)(OR6)-, ketals such as -C(OR6)2 ", --l~L--' ~7~t~

or cyclic, e.g. ethyleneketals/ wherein the radicals R6 a`re same or different and, as a rule, contain lower alkyl-radicals with 1 to 6 carbon atoms. However, as the radicals R6 only contaln blocking groups whl:ch do not occur in the final product of the present invention, their nature pe.r se is not critica.l.
The preferable functionally modified COORl-groups ~ are those. which can be converted under mild reaction conditions, above all in basic, neutral or only weak acid environment, lQ into COORl-groups. In the functionally modified COORl-groups, particularly ~CON3, -CN, -C(=NH~ oR7 ! -c (=NR7)oR8, -CoSR7, -CSOR , -CSSR , -C(OR ~3 or -COOR . R and R are similar .~ or different and designate, besides H, a low molecular weight organic radical whose nature per se is not critical as it does not appear in the final product according to the invention, for instance alkyl with up to 6 carbon atoms. R9 ; can, in itself, have the features referred to with reference to R7 and R8, with the exception of those for Rl. R9 designates particularly an organic silicone radical, preferably a trialkylsilyl group such as trimethylsilyl or dimethyl-tert.-butylsilyl.
The reaction of a compound of Formula II with a thiol of Formula III is usually carried out in the presence of a :~ basic catalyst and in the presence or absence of an inert solvent, at temperatures between about -20 and +50, prefer-ably between 0 and 30. Suitable solvents are preferably alcohols such as methanol or ethanol; further, hydrocarbons such as benzene or toluene; water or liquid ammonia are also suitableO Suitable basic catalysts are for instance alkali-metal-or alkaline earth metal hydroxides such as NaOH, KOH, or Ca(OH~2; alkali metal alcoholates such as NaOCH3, NaOC2H5 or K-tert.-0-C4Hg; basic salts, preferably carbonates or tj~

acetates such as K2CO3 or NaOCOCH3; ammonia; amines such ; as triethylamine, tert.-butylamine, cyclohexylamine, dicyclo-hexylamine, dimethylaniline, piperidine, pyrrolidine, pyridine, quinoline, diazabicyclo-~3,4,0]-nonene; or qua-ternary ammonium hydroxïdes such as tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide.
The reaction of a compound of Formula IV with a compound of Formula V is carried out according to the known methods, for instance by the Wittig-reaction (effected in the presence of a strong base, for instance an alkali-metal hydride such as NaH or of a lithium alkyl compound such as butyllithium~, preferably in dimethylsulfoxide (DMSO) as a solvent at temperatures between approximately 15 to approx.
80C. It is particularly suitable to carry out the reaction under an inert gas atmosphere, for instance under nitrogen.
In the thus obtained compounds of Formula I, B designates a cis-C=C- double bond.
;~; The modification of compounds corresponding to Formula I
-` but having at least one hydroxy group and/or a carbonyl group and/or the COORl group in a functionally modified form, is carried out with a solvolyzing agent, e.g. at temperatures between -20 and 40. As a rule, the reaction is carried out in the presence of an acidic or, preferably, a basic catalyst, under the utilization of an inert solvent.
The solvolyzing agents are preferably hydrolyzing agents such as pure water or water in mixture with organic solvents, mostly in the presence of an acidic or a basic catalyst. As the organic so]vent, e.g. alcohols such as methanol, ethanol, ,~ propanol, isopropanol, butanol, -tert.--butyl alcohol, amyl alcohol, 2-methoxyethanol or 2-ethoxyethanol, ether such as diethylether, THF, dioxane or ethylene glycol dimethyl ether, acids such as formic acid, acetic acid, propionic acid or '' butyric acid, esters such as ethylacetate or butylacetate, ketones such as acetone; amides such as dimethylformamide (DMF~ or hexamethylphosphoric acid triamide (HMPT); nitriles such as acetonitrile; s~lfoxides such as DMSO; sulfones such as tetrahydrothiophen-S-dioxide are useful, as well as mixtures of such solvents.
Inorganic acids, for instance hydrochloric, sulfuric, phosphoric, or hydrobromic; organic acids such as chloroacetic acid, trichloroacetic acid or trifluoroacetic acid, formic acid, acetic acid, benzene- or p-toluenesulfonic acid, are suitable as catalysts in a solvolysis. Suitable basic catalysts for use in a solvolysis are alkali metal or alkaline earth metal hydroxide such as sodium, potassium or calcium hydroxide or basic salts such as sodium- or potassium carbonate.
Organic bases, for instance ethyl-, diethyl-, triethyl-, isopropyl-, n-butyl- or tri-N-butylamine, ethanolamine, triethanolamine, cyclohexylamine, dimethylaniline, pyrrolidine, piperidine, morpholine, pyridine, ~-picoline or quinoline; or ; quaternary ammonium hydroxides such as tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide can also be used as basic catalysts. The excess of the catalyst can also be used in lieu of a solvent.
The solvolysis time periods are between approximately ; 1 hour and about 48 hours; the temperatures axe between about . -5 and about 80, preferably at about room temperature.
The hydrogenolyzing agent is particularly a catalytically stimulated hydrogen.
Hydrogenolysis separations of the protection groups, for instance of benzyl groups, are obtained by known reaction conditions, preferably in the presence of a metal catalyst such as Raney-nickel or Raney-cobalt, above all in the presence of a rare metal catalyst, such as Pt or Pd, if : .

., ' .

necessary with a carrier such as carbon or CaSO4; oxide catalysts, e.g. PtO, can also be used. Suitable solvents for carrying out the hydrogenolysis separation are e.g. alcohols - such as methanol or ethanol, organic acids such as formic acid or acetic acid, esters such as ethylacetate or ethyl-butyrate, or mixtures of such solvents. The hydrogenolysis is preferably carried out at temperatures between room temperature and about 40`
A compound of Formula I (A = -CO-) can be reduced e.g. with metal hydrides, particularly complex metal hydrides, to a corresponding alcohol. The reduction potential of the hydride must not be so great as to modify the COORl group.
Suitable compounds are e.g. sodium borohydride, if necessary in the presence of lithium bromide; further, lithium borohydride, particularly also complex trialkylborohydrides such as lithiumhexyllimonylborane or borohydrides such as lithium-perhydro-9b-borophenalylhydride; calcium borohydride, magnesium borohydride, lithium- and sodium alkoxyaluminum hydrides e.g. LiAl(0-tert.-C4Hg)3H, sodium trialkoxyborohydrides ` 20 e.g. sodium trimethoxyborohydride.
- The reduction is suitably carried out in an inert solvent - e.g. an alcohol such as methanol, ethanol or isopropylalcohol, an ether such as diethylether, tetrahydrofurane or dioxane, ; or also in water, or in mix-tures of these solvents, at temperatures between -20 and 40C, preferably at room temperature. The reaction time is between 15 minutes and ~; 6 hours.
An ester of Formula I (R = alkyl with 1 to 4 carbon atoms) can be produced from an acid of Formula I tR]` - H) by ; 30 reacting with an esterifying agent. The esterifying agents : are for instance alcohols with up to 4 carbon atoms, preferably in the presence of an inorganic or organic acid such as HC1, ':

HBr, HI, H2SO4, H3PO4, trifluoroacetic acid, sulfonic aci~d such as benzenesulfonic acid or p-toluenesulfonic acid, or an acid ion exchanger; diazoalkanes with up to 4 carbon atoms, preferably diazomethane; olefines Ce.g. isobutylene), prefer-ably in the presence of an acid catalyst (e.g. ZnC12, BF3, H2SO4, arylsulfonic acld, pyrophosphoric acid, boric acid, oxalic acid); alkylhalogenides with up to 4 carbon atoms, preferably bromides such as ethyl-, propyl-, isopropyl- or butyl bromide, and also the corresponding chlorides or iodides; carbonic acid or sulfonic acid alkylester, wherein the acid radical can be freely selected and the alkyl radical contains up to 4 carbon atoms, preferably methyl-, ethyl-, propyl-, isopropyl- or butyl-acetate,-formate, -methylsulfonate, -ethylsulfonate or- p-toluenesulfonate; and particularly also a dialkylsulfuric acid ester with up to 4 carbon atoms, such as dimethylsulfate or diethylsulfate.
The esterification takes place suitably in an inert, preferably anhydrous solvent, for instance an ether such as diethylether or THF, an alcohol, preferably one of the above alcohols with up to 4 carbon atoms or also in a hydrocarbon such as petroleum ether, hexane, benzene or toluene or in mixtures of these solvents, at temperatures between -10 and 40, preferably at room temperature. The reaction time is usually between 30 minutes and 20 hours.
The esters of Formula I (R = alkyl with 1 to 4 carbon atoms~ can be modified by solvolysis into other compounds of Formula I (preferably with R = Hl. It is preferred to use the basic hydrolysis to the acids of Formula I (or their salts~. It is preferable to operate in an aqueous medium, for instance in mixtures of water with alcohols, preferably lower alkanols such as methanol or ethanol or with ethers - such as ethylene glycol monomethyl ether, ethylene glycol ' 19-^~v~ g~

dimethylether, THF or dioxane, at temperatures between 0`and 40, preferably at a room temperature. The reaction period amounts to approximately 1 hour through 12 hours.
The free organic acids of Formula I (Rl = H) can also be modified by reacting with a base into one of their physiologically acceptable metal or ammonium salts, As the salts, particularly sodium-, potassium-, magnesium-, calcium-, and ammonium salts are preferred. Furthermore, substituted ammonium salts such as dimethyl and diethyl ammonium, monoethanol-, diethanol- and triethanol ammonium, cyclohexyl-; ammonium-, dicyclohexylammonium-, and dibenzylethylenediammonium salts. On the other hand, the acids of Formula I can be liberated from their metal and ammonium salts by processing with acids, above all with inorganic acids such as hydro-chloric acid or sulfuric acid.
The compounds of Formula I are mainly obtained in the form of mixtures of different stereoisomeric forms, as a rule as mixtures of racemates. Racemates can be isolated from the racemic mixtures and can be purified e.g. by recrystallization . , of the compounds per se or of well crystallizable derivatives, by distillation, particularly also with the aid of chromato-graphic methods, wherein both the adsorption and distribution , chromatography methods as well as their combined forms can ; be used.
The racemates can be resolved into their optical anti-podes by known methods as disclosed in the literature. The methods of chemical resolution are preferred. Thus, it is possible to replace an active base with the carboxyl group of a compound of Formula I. For instance, diastereomeric salts can be formed by optically active amines such as quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindiamine, morphine, l-phenylethylamine, l-naphthylethylamine, phenyloxy-'" :

naphthylmethylamine, quinidine, strychnine, basic amino acids such as lysine, and arginine, and amino acid esters. In a similar way, it i5 possible to produce esterdiastereomeres by esterification of organ;c acids of Formula I (R = H) with optically active alcohols such as camphenol, methanol, octanol-2.
The obtained diasteromeric salts or ester can be separated by crystallization and the optically active compounds can be isolated from the mixture.
However, the other functional groups contained in the compounds of Formula I can also be brought up for the formation of diastereomeres. Thus, it is possible to esterify e.g.
OH-groups with optically active acids such as (+)- and (-)-tar-taric acid or camphoric acid, or to react keto groups with optically active hydrazines such as methylhydrazine, and to develop from such derivatives the pure enantiomeres Furthermore, it is naturally possible to obtain optically active compounds according to the described methods~
wherein a starting compound is used which is already optically active.
The new compounds of Formula I and their physiologically acceptable salts can be used in the production of pharmaceutical ` products, wherein the compounds are combined with at least one carrier or auxiliary agent and, if necessary, together with one or more further active agents, in a suitable dose form.
The thus obtained products can be used as a medicine in human or veterinary medicine. As carriers, organic or inorganic materials can be used, suitable for enteral, parenteral or topical application and which do not react with the new compounds, for instance water, vegetable oils, benzylalcohols, polyethyleneglycols, gelatines, carbohydrates such as lactoses or starches, magnesium stearate, talc, "Vaseline"*. For enteral application, particularly pills, dragees, capsules, * Trademark for pe-troleum jelly.

syrops, juices, drops or suppositories are suitable, for parenteral application, it is suitable to use solutions, preferably oily or aqueous solutions, further suspensions, ; emulsions or implants, for topical application ointments, creams or powder. The new compounds can also be lyophilized and the obtained lyophilisate can be used in the production of injection preparations. The obtained products can be steriliæed and/or mixed with additives such as lubricants, preservatives, stabilization and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavour or fragrance agents. If desired, they can also be mixed with other active agents.
The substances are preferably produced in a dosage of 0.01 to 200 mg per dose unit; the dosage is dependent on the processed species~ the application and the purpose of the use; accordingly, it may be over or below the above indicated values.
For instance, if it is desired to use the estrus synchronizing activity of the compounds of Formula I, particularly of Formula Ie and In, then it is especially suitable to intramuscularly inject into the cattle (cows or heifers) about 0.1 mg to about 20 mg, preferably abou-t 0.5 mg to about 15 mg, particularly 1.5 mg to about 10 mg of the active substance. It is suitable to administer the ~ active dose by a single injection between about the 7th and ;; the 12th day of the cycle, however, it is also possible to administer a plurality of partial doses over a span of severa] days. The estrus can be synchronized by the use of the compound of Formula I, particularly of Formula Ie and In, in dogs, horses, sheep and pigs.
The active doses vary in such applications in :

~ -22-dependence on the average body weight of the treated species.
They can easily be determined by those skilled in the art with the assistance of the above figures given for the cattle.
The infra-red spectra ~IRJ have been characterized as a film by specifying the ma;n bonds.
The nuclear magnetic resonance spectra (NMR) were measured in CdC13 ayainst tetramethylsilane and characterized by defining the signals in ppm; in the same, m = multiplet, q = quartet, t = triplet, d = duplet and s = singlet.
Each of the compounds of Formula I referred to in the following examples is particularly suitable for the production of medicine.
E~AMPLE 1 A mixture of 0.35 mg of 7 (3-hydroxy-5-oxo-2-iodo-cyclopentyl~-heptanoic acid (obtainable from 7-(3-hydroxy-5-oxo-l-cyclopentenyl~-heptanoic acid by addition of HI), 0.23 g of sodium-2-hydroxy-3-p-fluorophenoxy-2-methyl-propylthiolate, 10 ml of tetrahydrofurane and 10 ml of ethanol was stirred for 4 hours at room temperature; the mixture was then mixed with 40 ml of CHC13 and 30 ml of saturated aqueous NaCl solution, the organic phase was separated, the aqueous phase with CHC13 extracted, the combined organic phases washed with water, dried over MgSO4, the solvent distilled away and, following chromatographic purification (siliceous gel/
chloroform : methanol - 9:1), 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid as an oil was obtained.
IR: 1215, 1500, 1710, 1740 and 3350 cm NMR: 1.4(s), 2.3(t~, 3.9(s~, 4.3(m~, 6.8 - 7.1(m).
Analogously, the following substances can be obtained frcm 7-(3-hydroxy-5-oxo-2-;odo-cyclopentyl~-heptanoic acid -22a-1~'7 by reacting ~ith the sodium salt of one of the correspondin~
thi.ols of Formula III: :
11,15-dihydroxy-15-methy1-16-phenoxy-9-oxo-13-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-p-chlorophenoxy-9-oxo-13-thia 17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-15-methyl-16-p-bromophenoxy-9-oxo-l3-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-p-hydroxyphenoxy-9-oxo-13-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl~16-p-methoxyphenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-15-methyl-16-p-tolyloxy-9-oxo-13-thia-~ 17,18,19,20-tetranor prostanoic acid, .~ 11,15-dihydroxy-15-methyl-16-m-chlorophenoxy-9-oxo-13-thia 17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-m-trifluoromethylphenoxy-9-~ oxo-13-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-p-tri~luoromethylphenoxy-9-oxo-13-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-(2,4-dichlorophenoxy)-9-oxo-13 thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-(2,4-dimethoxyphenoxy)-9-oxo-13-thia-17,18,19,20-tetranor prostanoic acid, : 11,15-dihydroxy-15-methyl-16-(2,4,6-trimethylphenoxy)-9-:~ oxo-13-thia-17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-(3,4,5-trimethoxyphenoxy)-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-15-methyl-16-meth.oxy-9-oxo-13-thia-17,18, 19,20-tetranor prostanoic acid, 11,15-dihydroxy-15-methyl-16-ethoxy-9-oxo-13-thia-17,18,19, 20-tetranor prostanoic acid, .

2t~

11,15-dihydroxy-16-phenoxy-9-oxo-13-thia-17,18,19,20-tetra-nor prostanoic acid, 11,15-dihydroxy-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19, 20-tetranor prostanoic acid, 11,15-dihydroxy-16-p-chlorophenoxy-9-oxo-13-thia 17,18,19,20-tetranor prostanoic acid, 11,15-dihydroxy-16-p-trifluoromethylphenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-16-p-methoxyphenoxy-9-oxo-13-thia-17,18,19, 20-tetranor prostanoic aeid, 11,15-dihydroxy-16-m-trifluoromethylphenoxy-9-oxo-13-thia-~ 17,18,19,20-tetranor prostanolc acid, -~ IR: 1160, 1230, 1490, 1590, 1700, 1730, 2950 and 3410 cm NMR: 2.3(t), 4.1(ml, 4.2 - 4.5(m), 7.0 - 7.5(m)O
EXAMPLE_2_ ~ ~
A mixture containing a. 4 g of 7-(3-hydroxy-5-oxo 2-p-toluenesulfonyloxy-cyclopentyl)-heptanoic acid, 6 ml of dry ethanol and 0.2 g of 2-p-fluorophenyl-2-hydroxy-propyl-thiol, is stirred for 2 hours at a room temperature, added to the reaction mixture of 20 ml of H2O and 30 ml of CHC13 and processed as deseribed in Example 1. 11,15-dihydroxy-15-p-fluorophenyl-9-oxo~13-thia-17,18,19,20-tetranor-prostanoie aeid is obtaïned in the form of oil.
IR: 1220, 1505, 1605, 1708, 1740 and 3400 em 1 NMR: 1.61(s), 2.3(t), 4.2(m), 6.9 - 7.15(m), 7.3 - 7.5(m). ~-Analogously, the following compounds are obtained from 7-(3-hydroxy-5-oxo-2-p-toluenesulfonyloxy-eyclopentyl)-heptanoic acid by reaction with the sodium salt of a corres-ponding thiol of Formula III:
11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-18,19,20-trinor-prostanoic acid, lq~ 3~

11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-19,20- ~ -` dlnor-prostanoic acid, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-20-nor-prostanoic acid, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-chlorophenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-bromophenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-hydroxyphenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-methoxyphenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-trifluoromethylphenyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-~3,4,5-trimethoxyphenyl)-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, IR: 1130, 160Q, 1670, 1710, 1740, 2950, 3450 cm 1 NMR: 1.63(s), 2.3(t), 3.8(s), 4.23(q), 11,15-dihydroxy-15-methyl-16-m-chlorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, IR: 1400, 1495, 1700, 1740, 2950, 3450 cm 1 NMR: 1.25(s), 2.35(t), 4.3(m), 5.6(m), 7.0 - 7.4(m), ` 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-16,17,18,19, 20-pentanor-prostanoic acid, 11,15-dihydroxy-15-p-chlorophenyl-9-oxo-13-thia-16,17,18,19, 20-pentanor-prostanoic acid, 11,15-dihydroxy-15-p-methoxyphenyl-9-oxo-13-thia-16,17,18,19, 20-pentanor-prostanoic acid, 11,15-dihydroxy-15-p-trifluoromethylphenyl-9-oxo-13-thia-16,17,18,19,20-pentanor-prostanoic acid, , . .

:
'"

11,15-dihydroxy-16-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15 dihydroxy-16-p-chloropheny1-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-16-p-methoxyphenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-16-p-trifluorome-thylphenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, 11,15-dihydroxy-15-(2-naphthyl~-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, IR: 1600, 1705 - 1740 and 2900 - 3400 cm 1, NMR: 1.76~s), 2.28(t), 4.2~m~, 7.42(m), 7.8(m~;
11,15-dihydroxy-15-m-chlorophenyl-9-oxo-13-thia-17,18,19,20-- tetranor-prostanoic acid, 11,15-dihydroxy-15-p-chlorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, IR: 1710, 1740 and 3400 cm ;
NMR: 1.65~s), 2.3(t), 4.25(q), 7.3~m).
_AMPLE 3 Analogously with Example 1, the following compounds can be obtained by reacting 7-(3-hydroxy-5-oxo-2-iodo-cyclopentyl)-heptanoic acid with the sodium salt of a corresponding thiol of Formula III:
11,15-dihydroxy-15-p-fluorophenoxymethyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p chlorophenoxymethyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-bromophenoxymethyl~9-oxo-13-thia-prostanoic acid, 11,15-dihy-droxy-15-p-hydroxyphenoxymethyl 9-oxo-13-thia-prostanoic acid, :' .
.. . . . .

7~5~

11,15-dihydroxy-15-p-methoxyphenoxymethyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-trifluoromethylphenoxymethyl-9-oxo-13-thîa-prostanoic acid, 11,15-dihydroxy-15-p-fluorobenzyl-9-oxo-13-thia-prostanoic acid, 11,15-dihydroxy-15-p-chlorobenzyl-9-oxo-13-thia-prostanoic acid, and 11,15-dihydroxy-15-p-methoxybenzyl-9-oxo-13-thia-prostanoic acid.

Analogously with Example l, the following compounds can be obtained from 7-(3-hydroxy-5-oxo-iodo-cyclopentyl)-`. 5-heptenoic acid ~obtainable from 7-(3-hydroxy-5-oxo-l-cyclo-pentenyl)-5-heptenoic acid by addition of HI), by reac-ting with the sodium salt of a corresponding thiol of Formula III, 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-phenoxy-9-oxo-13-thia-17,18,19, 20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-p-chlorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-p-bromophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid.
11,15-dihydroxy-15-methyl-16-p-hydroxyphenoxy-9-oxo-13-thia-. 17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-p-methoxyphenoxy-9-oxo-13-thia-.. 17,18,19,20-tetranor-5-pros-tenoic acid, 11,15-dihydroxy-15-me-thyl-16-p-tolyloxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, ~v~

11,15-dihydroxy-15-methyl-16 p-trifluoromethylphenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-(2,4-dichlorophenoxy~-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15~dihydroxy-15-methyl-16-(2,4-dimethoxyphenoxy)-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-(2,4,6-trimethylphenoxy)-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-(3,4,5-trimethoxyphenoxy)-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid 11,15-dihydroxy-15-methyl-16-methoxy-9-oxo-13-thia-17,18,19, 20-tetranor-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-ethoxy-9-oxo-13-thia-17,18,19, 20-tetranor-5-prostenoic acid; and 11,15-dihydroxy-16-m-chlorophenoxy-9-oxo-13-thia-17,18,19,20-;; tetranor-5-prostenoic acid.
EXAMPLE _ A mixture of 3.05 g of 7-(3-hydroxy-5-oxo-2-bromo-cyclopentyl)-5-heptenoic acid (obtainable from 7-3-hydroxy-

5-oxo-1-cyclopentenyl)-5-heptenoic acid by addition of HBr), 60 ml of dry ethanol and 2.1 g of sodium-2 p-fluorophenyl-2-hydroxy-propylthiolate is mixed for 3 hours at 0. The mixture is then left for 2 hours at a room temperature, added to the reaction mixture of 30 ml of a saturated aqueous NaCl-solution and 60 ml of C~C13, then worked as described in Example 1. 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid is obtained.
Analogously, the following compounds are obtained from 7-~3-hydroxy-5-oxo-2-bromo-cyclopentyl~-5-heptenoic acid by reacting with the sodium salt of a corresponding thiol of Formula III:
11,15-dihydroxy-15-p~fluorophenyl-9-oxo-14-thia-18,19,20-trinor-5-prostenoic acid, ~ 7~a~

11,15-dihydroxy-15-p-fluoropheny1-9-o~o-13-thia-19,10-dinor-5-prostenoic acid, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-20-nor-5-prostenoic acid, 11, 15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-5-prostenoic acid, 11, 15-dihydroxy-15-p-chlorophenyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-bromophenyl-9-oxo-13-thia-5-prostenoic acid, - 11,15-dihydroxy-15-p-hydroxyphenyl-9-oxo-13-thia-5-prostenoic : acid, 11,15-dihydroxy-15-methoxyphenyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-trifluoromethylphenyl-9-oxo-13-thia-5-prostenoic acid, ; 11,15-dihydroxy-16-p-fluarophenyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-16-p-chlorophenyl-9-oxo-thia-5-prostenoic acid, 11,15-dihydroxy-16-p-bromophenyl-9-oxo-13-thia-5-prostanoic acid, 11,15-dihydroxy-16-p-hydroxyphenyl-9-oxo-13-thia-5-prostenoic acld, . 11,15-dihydroxy-16-p-methoxyphenyl-9-oxo-13-thia-5-prostenoic ; acid, . 11,15-dihydroxy-16-p-trifluoromethylphenyl-9-oxo-13-thia-5-prostenoic acid, Analogously with Example 1, the following compounds can be obtained from 7-(3-hydroxy-5-oxo-iodo-cyclopentyl~-5-heptenoic acid by reacting with the sodium salts o:E the .

l~3~r~

corresponding thiols of Formula II:I:
11,15-dihydroxy-15-p-fluorophenoxymethyl-9-oxo-13-thia-5-prostenoic ac;d, 11,15-dihydroxy-15-p-chIorophenoxymethyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-bromophenoxymethyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-hydroxyphenoxymethyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-16-methyl-g-oxo-13-thia-5-prostenoic acid, ; 11,15-dihydroxy-17-ethyl-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-5-p-methoxyphenoxymethyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-trifluoromethylphenoxymethyl-9-oxo-:: 13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-fluorobenzyl-9-oxo-13-thia-5-prostenoic acid, llr15-dihydroxy-15-p-chlorobenzyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-methoxybenzyl-9-oxo-13-thia-5-prostenoic acid, ` Analogously to Example 1, the following compounds are . obtainable by reacting of 7-(3-hydroxy-5-oxo-2-iodo-cyclo-pentyl)-5-heptenoic acid with the sodium salts of the corres-pondingthiols of Formula III:
:. 11,15-dihydroxy-9~oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-methyl-15-9-oxo-13-thia-prostenoic acid, 11,15-dihydroxy-15,16-dimethyl-9-oxo-13-thia-5-prostenoic acid, . 30 11,15-dihydroxy-16,16-dimethyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15,16,16-trimethyl-9-oxo-13-thia-5~prostenoic acid, S'~

11,15-dihydroxy-15-ethyl-9-oxo-13-thia-5-prostenoic acid;
11,15-dihydroxy-15-propyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-butyl-9-oxo-13-thia-5-prostenoic acid; and 11,15-dihydroxy-15-pentyl-9-Qxo-13-thia-5-prostenoic acid.
_ AMPLE 8 Analogously with Example 5, the following compounds can be obtained by reactïng 7-(3-hydroxy-5-oxo-bromo-cyclopentyl)-5-heptenoic acid with the sodium salts of ~he corresponding thiols of Formula III:
11,15-dihydroxy-9-oxo-13-thia-20-homo-5-prostenoic acid, 11,15-dihydroxy-15-methyl-9-oxo-].3-thia-20-homo-5-prostenoic acid, 11,15-dihy-droxy-15-16-dimethyl-9-oxo-13-thia-20-homo-5-prostenoic acid, 11,15-dihydroxy-16,16-dimethyl-9-oxo-13-thia-20-homo-5-prostenoic acid, ~ 11,15-dihydroxy-15,16,16-trimethyl-9-oxo-13-thia-20-homo-:. 5-prostenoic acid, 11,15-dihydroxy-9-oxo-13-thia-20-ethyl-5-prostenoic acid, 11,15-dihydroxy-15-methyl-9-oxo-13-thia-20-ethyl-5-prostenoic acid, 11,15-dihydroxy-15,16-dimethyl-9-oxo-13-thia-20-ethyl-5-prostenoic acid, 11,15-dihydroxy-16,16-dimethyl-9-oxo-13-thia-20-ethyl-5-prostenoic acid; and 11,15-dihydroxy-15,16,16-trimethyl-9-oxo-13-thia-20-ethyl-5-` prostenoic acid.

Analogously with Example 1, the following compounds ~ 30 can be obtained from 7-(3-hydroxy-5-oxo-2-iodo-cyclopentyl)-5-heptenoic acid with the sodium salts of the corresponding thiols of Formula III:

~3~X~

11,15-dïhydroxy-15-phenyl-9-oxo-16,17,18,19,20-pentanor-- 13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-tolyl-9-oxo-16,17,18,19,20-pentanor-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-pheny-1-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-toly1-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, 11,15-dihydroxy-16-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoïc acid, 11,15-dihydroxy-16-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-phenyl-9-oxo-17,18,19,20-tetranor-- 13-thia-5-prostenoic acid, 11,15-dihydroxy-15-methyl-16-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid.
11,15-dihydroxy-15,16-dimethyl-16-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, 11,15-dihydroxy-15,16-dimethyl-16-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, 11,15-dihydroxy-16,16-dimethyl-16-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid, and 11,15-dihydroxy-16,16-dimethyl-16-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid.

Analogously with Example 1, the following compounds can be obtained by reacting 7-(3-hydroxy-5-oxo-2-iodo-cyclo-pentyl)-5-heptenoic acid with the sodium salts of the corres-ponding-thiols of Formula III:
11,15-dihydroxy-15-phenyl-9-oxo-13-thia-5-prostenoic acid, 11,15-dihydroxy-15-p-tolyl-9-oxo-13-thia-5-prostenoic acid, Sf~;

11,15-dihydro-15-benzyl-9-oxo-13-thia-5-prostenoic aci.d and : 11,15-dihydro-15-p-tolylmethyl-9-oxo-13-thia-5-prostenoi.c acid.

A solution of 2.5 g of 5-triphenylphosphoniovalerianic acid is drop-added under ni.trogen, dissolved in 10 ml of dry DMSO to a stirred solution, obtained by addition of 0.27 g of NaH (:as a 50% suspension in a mineral oil) to 10 ml of dry DMSO, and the mixture i.s maintained at 70 for one hour.
Followïng the cooling to room temperature, 0.3 g of 2-oxa-~ 10 3,7-dihydroxy-6-(2-hydroxy-2-methyl-heptylmercapto)-bicyclo ~.
. ~3,3,0] octane is added under nitrogen and stirred, dissolved in 5 ml of dry DMSO to dissolve the phosphorylides and stirred for a further period of 2 hours at 50. Following the cooling, the reaction mixture is poured into a mixture containing 10 ml of ethylacetate, 40 g of dry ice and 50 ml of water, the organic phase is separated, the aqueous phase is washed three times each with 50 ml of ethylacetate containing 20 g of .~ dry ice, washed with the combined organic phases with water, dried over MgSO4, the solvent distilled away and, following chromatographic purification of the residue (siliceous gel/
chloroform), 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid is obtained, . IR: 1710, 2200 and 3700 cm NMR: 0.85(t), 1.2(s), 1.0 - 2.6(m), 2.6 - 3.05(m-~s), 4.15(m), 5.1 - 5.4(m).
. Analogously, the following compounds can be obtained by reacting the corresponding starting compounds of Formula IV
with the ylid of 5-triphenyl-phosphoniovalerianic acid:
9,11,15-~rihydroxy-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, ~ qZLi~3 :
IR: 1210, 1505, 1710, 270Q, 2940, 3700 cm NMR: 1.1 - 2.6(m), 2.7 - 3.1(ml, 4.05(m~, 4.2(m)~ 5.30(m), 5.45(m~, 6.85(s), 6.95(d~
(with the use of 2-oxa-3,7-dihydroxy-6-(2-hydroxy-3-p-fluorophenoxy-propylmercapto)-bicyclo [3,3,0] octane as a starting compound IV);
9,11,15-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, IR: 1710, 2400, 3650 cm NMR: 1.1 - 2.6(ml, 2.6 - 3.1(m), 4.05(m), 4.2(m), 5.3(m), 5.4(m), 6.6 - 7.4(m) (with the use of 2-oxa-3,7-dihydroxy-6-(2-hydroxy-3-m-chlorophenoxy-propylmercapto)-bicyclo [3,3,0] octane as a starting compound IV);
9,11-dihydroxy-15-methoxy-16-p-fluorophenoxy-13-thia-17,18, 19,20-tetranor-5-prostenoic acid, IR: 1210, 1505, 1710, 2700, 2940, 3700 cm NMR: 1.1 - 2.6(m), 2.95(m), 3.50(s), 3.75(m), 4.0(m), 4.10(m), - 5.40(m), 5.60(m~, 6.85(d), 6.95(d), (with the use of 2-oxa-3,7-dihydroxy-6-(2-methoxy-3-p-; fluorophenoxy-propylmercapto)-bicyclo [3.3.0] octane as the starting compound IV):
9,11,15-trihydroxy-16-methyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-16,16-dimethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-15,16,16-trimethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-15-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-15-p-tolyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, ; 9,11,15-trihydroxy-15-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-16-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-17-ethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-16-p-tolyl-13-thia-17,18~19,20-tetranor-5-prostenoic aci.d, 9,11,15-trihydroxy-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-15-m-chlorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-16-m-chlorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid 9,11,15-trihydroxy-15-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, .~ 9,11,15-trihydroxy-15-p-toly-loxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-15-phenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, . 9,11,15-trihydroxy-15-p-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-15-m-chlorophenoxy~13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-16-p-tolyloxy-13-thia-17,18,19,20-tetranor-- 5-prostenoic acid, - 9,11,15-trihydroxy-16-phenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-16-p-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid.

1 g or 11,15-dihydroxy-15-rnethyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid, dissolved in 10 ml of dry THF, is added under nitrogen to a suspension of 3.3g of LiAl (0-tert.-C~Hg)3H in 25 ml of dry THF, the -mixture then being left for 1 hour at a room temperature,~
poured into 70 ml of ice cold lN HCl, extracted by CHC13, and the organic phase processed as in Example 1. 9,11,15-tri-hydroxy-15-methyl-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid ïs obtained in the form of oil.
IR: 1220, 1710 and 3400 cm NMR: 1.37(s), 2.30(t), 3.85(s~, 4.14(m~, 6.7 - 7.0(m).
Analogously, the following compounds can be obtained from the corresponding 9-oxo-compounds of Formula I, by reacting with LiAl(0-tert.-C4Hg)3H:
9,11,15-trihydroxy-15-m-chlorophenyl-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-p-chlorophenyl-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-phenoxy-13-chia-17,18,19,20-tetranor-prostanoic acid, ., 9,11,15-trihydroxy-15-methyl-16-p-tolyloxy-13-thia-17,18,19, 20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-p-chlorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-methoxy-13-thia-17,18,19,20-; tetranor-prostanoic acid, ; 9,11,15-trihydroxy-15-methyl-16-ethoxy-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-p-chlorophenyl-13-thia-17,18, 19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid, . .

-9,11,15-trihydroxy-16-phenoxy-13-thï.a-17,18,19,2Q-tetranor-. prostanoic aci.d, 9,11,15-trihydroxy-16-p-tolyloxy-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-16-p-chlorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydroxy-16-methoxy-13-thia-17,18,19,20-tetranor-- prostanoic acid, 9,11,15-trihydroxy-16-methyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-17-ethyl-13-thia-5-prostenoic acid, , 9,11,15-trihydroxy-16-ethoxy-13-thia-17,18,19120-tetranor-prostanoic acid, 9,11,15-trihydroxy-16-chlorophenyl-13-thia-17,18,19,20-. tetranor-prostanoic acid, 9,11,15-trihydroxy-15-methyl-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid, 9,11,15-trihydro~y-15-methyl-16-m-tri~luoromethylphenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid.

Analogously with Example 12, the following compounds can be obtained from the corresponding 9-oxo-compounds of . Formula I by reacting with LiAl(0-tert.-C4Hg)3H:
. 9,11,15-trihydroxy-15-p-fluorophenyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-chlorophenyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-p-bromophenyl-13-thia prostanoic acid, : 9,11,15-trihydroxy-15-p~hydroxyphenyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-p-methoxyphenyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-p-trifluoromethylphenyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-phenyloxymethyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-p-fluorophenoxymethyl-13-thia-prostanoic acid, ..

~)7~

9,11,15-trihydroxy-15-p-tol~loxymethyl-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-methoxymethy1-13-thia-prostanoic acid, 9,11,15-trihydroxy-15-ethoxymethyl-13-thia-prostanoic acid, and 9,11,15-trihydroxy-15-p-fluorobenzyl-13-thia-prostanoic acid.

Analogously with Example 12, the following compounds are obtainable from the corresponding 9-oxo-compounds of Formula I
by reacting wi ~ LiAl (0-tert.-C4Hg)3H:
9,11,15-trihydroxy-13-thia-5-prostenoic acid, -9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid, IRo 1710, 2200 and 3700 cm NMR: 0.85(t), 1.2(s), 1.0 - 2.6(m), 2.6 - 3.05(m+s), 4.15(m), 5.1 - 5.4(m), 9,11,15-trihydroxy-15,16-dimethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-16,16,-dimethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-15,16,16-trimethyl-13-thia-5-prostenoic acid, 9,11,15-trihydroxy-13-thia-20-homo-5-prostenoic acid, 9,11,15-trihydroxy-15-methyl-13-thia-20-homo-5-prostenoic acid, 9,11,15-trihydroxy-13-thia-20-ethyl-5-prostenoic acid, and 9,11,15-trihydroxy-15-methyl-13-thia-20-ethyl-5-prostenoic acid.

A mixture of 1 g of 11,15-dihydroxy-15-methyl-16-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 0.6 g of NaBH4 and 15 ml of methanol is stirred Eor 3 hours at room temperature and then the reaction mixture is processed as described in Example 11. 9,11,15-trihydroxy~
15-methyl-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, in the form of oil, is obtained. Analogously, by reacting the corresponding 9-oxo-compounds of Formula I
with NaB~I4, the following compounds can be ob-tained:

t~ q~

- -9,11,15-trihydroxy-15-pheny1-13-thia-17,18,19,20-tetranor-. 5-prostenoic acid 9,11,15-trihydroxy-15-p-tolyl-13-thia-17,18,19,20-tetranor-. 5-prostenoic acid, 9,11,15-trihydroxy-15-pheny1-13-thia-16,17,18,19,20-pentanor-: 5-prostenoic aci.d, 9,11,15-trihy-droxy-15-p-fluorophenyl-13-thia-16,17,18,19,20-pentanor-5-prostenoic acid, 9,11,15-trihydroxy-15-p-tolyl-13-thia-16,17,18,19,20-pentanor-. 10 5-prostenoic acid . 9,11,15-trihydroxy-16-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, 9,11,15-trihydroxy-16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid, : 9,11,15-trihydroxy-16-p-tolyl-13-thia-17,18,19,20-tetranor-. 5-prostenoic acid, 9,11,15-trihydroxy-15-methyl-16-phenyl-13-thia-17,18,19~20-tetranor-5-prostenoic acid, and 9,11,15-trihydroxy-15-methyl-16-p-tolyl-13-thia-17,18,19,20-. 20 tetranor-5-prostenoic acid.

'''~
~: 100 mg of 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid is dissolved in 10 ml of diethylether with an excess of etheric diazomethane solution, until no further nitrogen Eorming occurs. The solvent is distilled away and, following chromatographic purification (si.liceous gel/benzol : chloroform = 1:1~ of the residuej 11,15,-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostenoic acid methylester is obtained.
. 30 Analogously, the corresponding me-thylesters are obtain-. able from the compounds of Formula I whi.ch can be obtained according to Examples 1 through 9, by reacting wi-th di.azo-~7~rj~

methane, namely:
11,15-dih.ydroxy-15-methyl-16-phenoxy-9-oxo-13-th.ia-17,18,19,20-: tetranor-prostanoic aci.d meth.ylester, 11,15-dihydroxy-15-methyl-16-p-tolyloxy-9-oxo-13-thia-17,18, : 19,2Q-tetranor-prostanoic acid methylester, 11,15-dihydroxy-15-methyl-16-methoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid me-thylester, 11,15-dihydroxy-15-methyl-16-ethoxy-9-oxo-13-thia-17,18,19,20-tetranor-prostanoi.c acid methylester, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-prostanoic acid methylester, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-prostanoic : acid methylester, 11,15-dihydroxy-16-p-fluorophenyl-9-oxo-13-thia-prostanoic acid methylester, 11,15-dihydroxy-15-p-fluorophenoxymethyl-9-oxo-13-thia-prostanoic acid methylester, 11,15-dihydroxy-15-p-fluorobenzyl-9-oxo-13-thia-prostanoic acid methylester, 11,15-dihydroxy-15-methyl-16-phenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid methylester, 11,15-dihydroxy-15-methyl-16-p-tolyloxy-9-oxo-13-thia-17,18, 19,20-tetranor-5-prostenoic acid methylester, 11,15-dihydroxy-15-methyl-16-methoxy-9-oxo-13-thia-17,18,19,20-; tetranor-5-prostenoic acid methylester, 11,15-dihydroxy-15-methyl-16-ethoxy-9-oxo-13-thia-17,18,1~,20-tetranor-5-prostenoi.c acid methylester, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoi.c acid methylester, 30 11,15-dihydroxy-15-p-fluoropheny:L-9-oxo 13-thia-5-pros-tenoic acid methylester, La~3 11,15-dihydroxy-16-p-fluorophenyl-9-oxo-13-thi.a-5-prostenolc acid methylester, 11,15-dihydroxy--15-p-fluorophenoxymethyl-9-oxo-13-thia-5-prostenoic aci.d methylester, 11,15-dihydroxy-15-p-fluorobenzyl-9-oxo-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-9-oxo-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy--15-methyl-9-oxo-13-thia-5-prostenoic acid methylester, 11,15-di.hydroxy-15,16-dimethy1-9-oxo-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-16,16-dimethyl-9-oxo-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-15-penty1-9-oxo-13-thia-5-prostenoic acid - methylester, 11,15-dihydroxy-9-oxo 13-thia-20-homo-5-prostenoic acid methylester, 11,15-dihydroxy-15-methyl-9-oxo-13-thia-20-homo-5-prostenoic acid methylester, 11,15-dihydroxy-9-oxo-13-thia-20-ethyl-5-prostenoic acid methylester, 11,15-dihydroxy-15-methyl-9-oxo-13-thia-20-ethyl-5-prostenoic acid methylester, 11,15-dihydroxy-15-phenyl-9-oxo-16,17,18,19,20-pentanor-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy~15-p-tolyl-9-oxo-16,17,18,19,20-pentanor-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-15-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-15-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid methylester, : . .

;t25'~
' .:
11,15-dihydroxy-16-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-16-p-tolyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid methylester, 11,15-dihydroxy-15 methyl-16-phenyl-9-oxo-17,18,19,20-tetranor-13-thia-5-prostenoic acid methylester.

Analogously to Example 16, the eorresponding methyl-esters can be obtained from the eompounds of Formula I

obtainable aecordi.ng to Examples 12 through 15, by reacting . with diazomethane, particularly:
9,11,15-trihydroxy-15-methyl-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic acid methylester, 9,11,15-trihydroxy-15-methyl-16-phenoxy-13-thia-17,18,19,20-tetranor-prostanoic aeid methylester, 9,11,15-trihydroxy-15-methyl-16-p-tolyloxy-13-thia-17,18, .
~ 19,20-tetranor-prostanoic aeid methylester, : 9,11,15-trihydroxy-16-p-fluorophenyl-13-thia-17,18,19,20-.. tetranor-prostanoie aeid methylester, 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-prostanoic aeid methylester, .: 9,11,15-trihydroxy-16-phenoxy 13-thia-17,18,19,20-tetranor-;. prostanoie aeid methylester, 9,11,15-trihydroxy-16-p-tolyloxy-13-thia-17,18,19,20-tetranor-. prostanoi.c acid methylester, 9,11,15-trihydroxy-15-p-fluorophenyl-13-thia-prostanoie aeid methylester, 9,11,15-trihydroxy-15-phenyloxymethyl-13-thia-prostanoie acid methylester, . 30 9,11,15-trihydroxy-15-p-fluorophenoxymethyl-13-thia-prostanoie . aeid methylester, '`

. -42-' -' ' .

~ 3 9,11,15-trihydroxy-15-p-tolyloxymethy-1-13-thi.a-prostanoic acï.d methylester, 9,11,15-trihydroxy-15-p-fluoro~enzyl-13-thia prostanoic acid methylester, 9,11,15-trihydroxy-13-thîa-5-prostenoic acid methylester, 9,11,15-trïhydroxy-15-methyl-13-thia-5-prostenoic acid methylester, 9,11,15-trihydroxy-15,16-dimethyl-13-thia-5-prostenoic acid methylester, 9,11,15-trihydroxy-16,16-dimethyl-13-thia-5-prostenoic acid methylester, 9,11,15-trihydroxy-13-thia-20-homo-5-prostenoic acid methylester, 9,11,15-trihydroxy-13-thia-20-ethyl-5-prostenoic acid methylester, 9,11,15-trihydroxy-15-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid methylester, 9,11,15-trihydroxy-15-p-tolyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid methylester, 9,11,].5-trihydroxy-15-phenyl-13-thia-16,17,18,19,20-pentanor-5-prostenoic acid methylester, 9,11,15-trihydroxy-15-p-~luorophenyl-13-thia-16,17,18,19,20-pentanor-5-prostenoic acid methylester, 9,11,15-trihydroxy-15-p-tolyl-13-thia-16,17,18,19,20 pentanor-5-prostenoic acid methylester, 9,11,15-trihydroxy-16-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid methylester, 9,11,15-trihydroxy~16-p-fluorophenyl-13-thia-17,18,19,20-tetranor-5-prostenoi.c acid methylester, 9,11,15-trihydroxy-15-methyl-16-phenyl-13-thia-17,18,19,20-tetranor-5-prostenoic acid methylester.

(a) Analogously with Example 1, 0.37 g o~ 7~(3-hydroxy-5-oxo-2-iodo-cyclopentyl)-5-heptenoic acid methylester was ;, -~3-reacted with 0O24 g of sodium-2-hydroxy-3-p-fluorophenoxy-~
2-methylpropylthiolate. 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thi`a-17,18,19,20-tetranor-5-prostenoic acid methylester was obtained.
(b) 0.1 g of 11,15-dihydroxy-15-methyl-16-p-fluoro-phenoxy-9-oxo-13-thia-17,18,19,2U-tetranor-prostenoic acid methylester is stirred for 90 hours in a mixture of 2ml of an aqueous saturated NaCN-solution and 6 ml of methanol. The mixture is saturated with NaCl~ extracted with chloroform, the organic phase washed with water, dried over MgSO4, -the solvent distilled away and, following chromatographic purification of the residue (siliceous gel/CHC13 : CH30H = 9:1), 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18, 19,20-tetranor-5-prostenoic acid was obtained.
~-- (c~ 2.2 g of 11,15-dihydroxy-15-methyl-16-p-fluoro-phenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid is added in drops to an ethanolic sodium ethanolate solution produced from 0.12 g of sodium and 10 ml of dry ethanol, the mixture is dissolved in 10 ml of dry diethylether, the solven-t distilled away to ob-tain as a residue the sodium salt of 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19, 20-tetranor-5-prostenoic acid.
(d) A mixture of 1.54 g of the silver salt of 11,15-; dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18, 19,20-tetranor-5-prostenoic acid and 0.62 g of ethyl iodide and 10 ml of dry ethanol is stirred for 4 hours at a room temperature, 20 ml of dry diethylether is added, the mixture is filtered, the solvent distilled away and 11,15-dihydroxy-15-methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid ethylester is obtained as a residue.

Analogously with Example 1, -the following compounds ., -4~-'' ' 3?;j~ ~Z Lj ~
~, .

can be obtained by converting the corresponding sodium thiolates of Formula III to the corresponding cyclopentane derivatives of Formula II:
11,15-dihydroxy-15-(4-pyridyl~-9-oxo-13-thia-17,18,19,20-tetranor-prostano;c acid methylester, IR: 1600, 1740 and 3000 - 3500 cm NMR: 1.63(s), 2.28(t~, 3.70(sl, 4.29(ml, 7.33(m~ and 8.45(m);
11,15-dihydroxy-15-~2-thienyl)-9 oxo-13-thia-17,18,19,20-; tetranor-prostanoic acid, 1l~l5-dihydroxy-l5-methyl-9-oxo-l3-thia-l9-oxa-prostanoic acid, IR: 1115, 1710, 1740 and 3400 cm 1, NMR: 1.27(s), 2.32(t), 3.31~s), 4.22(q);
11,15-dihydroxy-15-methyl-9-oxo-13-thia-19-oxa-prostanoic acid, IR: 1715, 1740, and 3400 cm NMR: 1.21(t), 1.32(s), 2.31(t), 3.50(q), 4.28(q);
11,15-dihydroxy-15,19-dimethyl-9-oxo-13-thia-18-oxa-prostanoic acid, 11,15-dihydroxy-15-methyl-20-ethyl-9-oxo-13-thia-18-oxa-prostanoic acid, 11,15-dihydroxy-15,20,20-trimethyl-0-oxo-13-thia-19-oxa-prostanoic acid, as well as the methylesters of the last listed compounds.

Analogously with Example 15, the following compounds can be obtained from the corresponding 9-oxo-compounds of Formula I (A = -CO-, B = -CH-CH-) by reacting with NaBH~:
9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acïd, IR: 1210, 1505, 1710, 2700, 2940, 3700 cm 1;
NMR: 1.1 - 2.6(m), 2.7 - 3.1(m), 4.05(m), 4.2(m), 5.30(m), 5~45(m), 6.85(sl, 6.95(d), -9,11,15-trihydroxy-16-m-chIorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, IR: 1710, 2400, 365Q cm ; -NMR: 1.1 - 2.6(m~, 2.6 - 3.1(m~, 4.05(m~, 4.2(m), 5.3(m), 5.4(m~, 6.6 - 7.4~m), 9,11-dihydroxy-15-methoxy-16-p-fluorophenoxy-13-thia-17,18,19, 20-te-tranor-5-prostenoic acid, IR: 1210, 1505, 1710, 2700, 2940, 3700 cm NMR: 1.1 - 2.6(m), 2.95(ml, 3.50(s~, 3.75(m), 4.0(m), 4.10(m), 5.40(m), 5.60(m), 6.85(d), 6.95(d).

2.84 g of 9~ -dibenzyloxy-15-hydroxy-15-methyl-13-thia-5-cis-prostenoic acid is hydrogenated, dissolved in 20 ml of glacial acetic acid in the presence of 0.7 g of 10% Pd/C-catalyst at a room temperature up to the absorption of 2 equivalents of hydrogen, filtered, poured into 100 ml of water, - extracted three times each with 20 ml of methylenechloride, the purified organic phases then being washed with water, dried over MgSO4, the solvent distilled away and, following chroma-tographic purification of the residue, 9~ ,15-trihydroxy-15-methyl-13-thia-5-cis-prostenoic acid is obtained.
IR: 1710, 2200 and 3700 cm NMR: 0.85(t~, 1.2(s), 1.0 - 2.6(m), 2.6 - 3.05(m-~s), 4.15(m), 5.1 - 5.4(m).
The starting product can be obtained as follows:
4~-diben~yloxy-2~ (1,3-dioxolane-1-yl-methyl)-3~-p-toluene-sulfonyloxy-cyclopentane is stirred for 8 hours with excess NaI in DMF at 40; the mixture is then poured into water, extracted with methylenechloride, the organic phase dried, the solvent distilled away, the residue absorbed in ethanol, sodium-2-hydroxy-2-methyl-heptanethiolate added, stirred for 2 hours at room temperature, the reaction mixture is -then ~46-poured into a saturated aqueous NaCl-solution, extracted with methylenechloride, dried over MgSO4, the solvent then distilled away, the residue stirred for 2 hours with 0.03 of normal aqueous HCl, the aqueous phase extracted with methylenechloride, the mixture then being dried over MgSO4, the solvent distilled away to obtain 2-[3~,5~-d;benzyloxy-2-~2-hydroxy-2-methyl-. heptylmercapto)-l~-cyclopentyl~-acetaldehyde. This is then reacted with 5-triphenylphosphoniovalerianic acid in the presence of a strong base under the reaction conditions as described in Example 11.
Analogously, other compounds can be produced correspond-ing to Formula I, wherein the two OH groups linked with the five-membered ring are isolated as benzylether.

Analogously with Example 21, 9~ ,15-trihydroxy-16-m-chlorophenoxy-13-thia~17,18,19,20-tetranor-5-cis-prostenoic acid can be obtained by hydrogenizing of 9~ -dibenzyloxy-15-hydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-; 5-cis-prostenoic acid, IR: 1710, 2400, 3650 cm NMR: 1.1 - 2.6(m), 2.6 - 3.1(m), 4.05(m), 4.2(m), 5.3(m), 5.4(m), 6.6 - 7.4(m).

A solution of 4.2 g of 5-triphenylphosphoniovalerianic acid is drop-added under nitrogen, dissolved in 20 ml of dry DMSO to a stirred solution obtained by addition of 0.54 g of NaH (.as a 50% suspension in mineral oil) to 20 ml of dry DMSO, the mixture then being stored for 1 hour at 65. Following - the cooling down to room temperature, 0.6 g of 2-oxa-3,7-Syn-dihydroxy-6-anti-(2-hydroxy-2-methyl-heptylmercapto]-cis--bicyclo ~3,3,0~ octane is drop-added under nitrogen and stirred, dissolved in 10 ml of dry DMSO to the solution of the phospho-rylide and stirred for further 2 hours at 50. The mixtu~re is processed as described in Example 11 to obtain 9~ ,15-trihydroxy-15-methyl-13-thia-5-cis-prostenoic acid.
IR: 1710, 2200, 370a cm NMR: 0.85(t), 1~2(s~, 1.0 - 2.6~m), 2.6 - 3.05(m+s~, 4.15(m), 5.1 - 5.4(m), Analogously, by reacting 5-triphenylphosphoniovalerianic acid with 2-oxa-3,7-syn-dihydroxy-6-anti-(2-hydroxy-3-m-chloro-phenoxy-propylmercaptolcis-bicyclo [3,3,0] octane in the presence of NaH, 9~ ,15-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-cis-prostenoic acid can be obtained, IR: 1710, 2400, 3650 cm NMR: 1.1 - 2.6~m), 2.6 - 3.1(m), 4.05(m~, 4.2(m), 5.3(m), 5.4(m~, 6.6 - 7.4(m~.
The compounds designated as starting products, 2-oxa-3,7-syn-dihydroxy-6-anti-(2-hydroxy-2-methyl-heptylmercapto)-cis-bicyclo [3,3,0] octane and 2-oxa-3,7-syn-dihydroxy-6-anti-(:2-hydroxy-3-m-chlorophenoxypropylmercapto)-cis-bicyclo [3,3,0]
~o octane can be produced for instance by reacting the compound ; of Formula VIIa', 2-oxa-6,7-cis-epoxy-3-oxo-cis-bicyclo [3,3,0]
octane (i.e. compound I from J.AMER.CHEM.SOC. 94,4344[1972]) with 2-hydroxy-2-methyl-heptanethiol, or with 2-hydroxy-3-chlorophenoxypropanethiol and by the eventual reduction of the reaction product with diisobutylaluminum hydride in toluene at -78C.
In the following Example 24, the production of a compound of Formula III will be described:

(a~ 20 g of a 20% sodium hydride-dispersion in paraffin oil is washed three times with 30 ml of dry n-pentane, the solvent removed, 33g of trimethylsulfoxonium iodide is added, lO0 ml of dimethylsulfoxide is drop-added, the mixture is then stirred for 20 minutes at room temperature until the gas ; formation ceases, a solution of 14.2 g of 2-heptanone is drop-added to 15 ml of dimethylsulfoxide, stirred for further 2 hours, 500 ml of water is added under ice cooling, extraction carried out three times each with 250ml of ether, the combined ether extract washed with water, dried with sodium sulfate, the solvent distilled away, to obtain, following fractionation of the residue, 2-methyl-2-pentyloxirane in the form of a colourless liquid: bp - 55 (20 mm Hg).
(b) Hydrogen sulfide is introduced in 150 ml of ethanol under ice cooling, until the weight addition of 3.2 is obtained, a solution of 370 mg of diethylamine in ll ml of methanol and 4.8 g of 2-methyl-2-pentyloxirane is added to 18 ml of methanol, hydrogen sulfide gas is again introduced into the solution for 15 minutes, the mixture left for 12 hours at room temperature, the solvent distilled away, the residue dissolved in 50 ml of petroleum ether (bp - 50 - 70), washed with w-ater, dried with sodium sulfate, the solvent distilled away, to obtain as a residue, 2-hydroxy-2-methyl-heptanethiol in the form of a colourless liquid;
IR: 920, 1140, 1380, 1465, 2570 and 3450 cm l;
NMR: signals at 0.96 ppm, 1.26 ppm, 2.27 ppm and 2.67 ppm.

Analogously with Example 24~a), the following compounds can be obtained by reacting the following oxiranes:
- 2-p-fluorophenoxymethyloxirane, - 2-m-fluorophenoxymethyloxirane, 2-p-chlorophenoxymethyloxirane, 2-m-chlorophenoxymethyloxirane, 2-p-bromophenoxymethyloxirane, 2-m-bromophenoxymethyloxirane, , ,S3 2-p-hydroxyphenoxymethyloxirane, 2-m-hydroxyphenoxymethyloxirane, 2-p~methoxyphenoxyme.thyloxirane, 2-m-methoxyphenoxymethyloxirane, 2-p-trifluoromethylphenoxyme-thyloxirane, 2-m-trifluoromethylphenoxymethyloxirane, 2-phenoxymethyloxirane, 2-~-pyridylmethyloxirane, 2-~-pyridylmethyloxirane, 2-~-thienylmethyloxirane, 2-~-thienylmethyloxirane, 2-~-naphthylmethyloxirane, and 2-~-naphthylmethyloxirane with H2S in the presence of diethylamine:
2-hydroxy-3-p-fluorophenoxy-propanethiol, 2-hydroxy-3-m-fluorophenoxy-propanthiol, 2-hydroxy-3-p-chlorophenoxy-propanthiol, 2-hydroxy-3-m-chlorophenoxy-propanthiol, 2-hydroxy-3-p-bromophenoxy-propanthiol, 2-hydroxy-3-m-bromophenoxy-propanthiol, 2-hydroxy-3-p-hydroxyphenoxy-propanthiol, 2-hydroxy-3-m-hydroxyphenoxy-propanthiol, 2-hydroxy-3-p-methoxyphenoxy-propanthio]., 2-hydroxy-3-m-methoxyphenoxy-propanthiol, 2-hydroxy-3-p-trifluoromethylphenoxy-propanthiol, 2-hydroxy-3-m-trifluoromethylphenoxy-propanthiol, 2-hydroxy-3-phenoxy-propanthiol, 2-hydroxy-3-~-pyridyl-propanthiol, 2-hydroxy-3-~-pyridyl-propanthiol, 2-hydroxy-3-~-thienyl-propanthiol, 2-hydroxy-3-~-thienyl-propanthiol, 2-hydroxy-3-~-naphthyl-propanthiol, and `~

l~t~
-2-hydroxy--3-~-naphthyl-propanthiol.
The following examples reIate to pharmaceutical preparations containing compounds of general Formula I or their pharmaceutically acceptable salts:
EXAMPLE A: PILLS
A mixture containing 30 g of the sodium salt of 11,15-dihydroxy-15~methyl-16-p-fluorophenoxy-9-oxo-13-thia-17,18,19, 20-tetranor-prostanoic acid, 50g of lactose, 16g of maize starch, 2g of cellulose powder and 2 g of magnesium stearate, are molded into pills such that each pill contains 30 mg of the active substance.
FXAMPLE B: DRAGEES
Analogously with Example A, pills are molded and even-tually provided in a known manner with a surfacing containing sugar, maize~starch, talc, and tragacanth.
Analogously, pills and dragees can be obtained contain-- ing one or more of the remaining active substances of Formula I
; or of their physiologically acceptable salts.
; EXAMPLE C: INJECTION SOLUTION
10 g of 9~ ,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid is dissolved in 4 litres of distilled water, 0.5 1 of ethanol and 0.5 1 o~ ethyleneglycol, and the solution is sterile~filtered. The obtained injection solution is filled in ampoules containing 2.5 ml, 5 ml or 10 ml of the injection solution.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a compound of general Formula I

wherein A is -CO- or -CHOH-, B is -CH2-CH2- or -CH=CH-, R1 is H or an alkyl group with 1 to 4 carbon atoms, m is an integer between 0 to 5, n is an integer between 0 and 3, or, when B is -CH=CH-, also 4, 5, 6, 7, 8 or 9, R2 is alkoxy with 1 to 4 carbon atoms, phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, Cl, Br, OH, OCH3 or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, or, when B is -CH=CH-, also hydrogen, phenyl or tolyl, and R3 is H, methyl or ethyl, the wavy line (?) designates that these compounds are ei-ther .alpha.- or .beta.-positioned;
as well as the physiologically acceptable salts of same, characterized in that a compound of Formula II

II

wherein Z is a nucleofugal group, and A, B, R1 have the above meaning, is reacted with a compound of Formula III

I I I

wherein M is H:, or an equivalent of an alkali- or alkaline earth metal atom or ammonia, and R2, R3, m and n have the above meaning, or in that a compound of Formula IV

IV

wherein R2, R3, m and n have the above meaning;
is reacted with a compound of Formula V

V

wherein R4 is alkyl with 1 - 6 carbon atoms, phenyl, naphthyl or a phenyl or naphthyl substituted with alkyl having 1 -4 carbon atoms and X is C1, Br or 1, and R1 has the above meaning, and, where desired, forming a pharmaceutically acceptable salt of said compound of formula I.

2. A process according to claim 1 wherein R1 is H.

3. A process according to claim 1 wherein A is -CO-.

4. A process according to claim 1 wherein A is -CHOH-.

5. A process according to claim 1 wherein B is -CH=CH-.

6. A process according to claim 1 wherein m and n each are 0 or 1 and R2 is phenyl substituted by F, Cl, Br, OH, OCH3, or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3; or, when B is -CH=CH-, R2 is also phenyl or tolyl.

7. A process according to claim 1 wherein R1 and R3 each are H, A is -CO-, B is -CH2-CH2-, m and n each are 0 or 1, and R2 is phenyl substituted by F, C1, Br, OH, OCH3, or CF3; or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3.

8. A process according to claim 1 wherein R1 and R3 each are H, A is -CHOH-, B is -CH=CH-, m and n each are 0 or 1 and R2 is phenyl or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, or is unsubstituted phenyl.

9. A process according to claim 1 wherein R1 is H, methyl or ethyl, R3 is H, B is -CH=CH-, CnH2n-R2 is pentyl, hexyl, heptyl, l-methylpentyl or l,l-dimethylpentyl and CmH2m+1 is H or methyl.

10. A process according to claim 1 wherein R and R each are H, A is -CHOH-, B is -CH=CH-, CnH2n-R2 is pentyl, phenoxymethyl or m-chloro-phenoxymethyl and CmH2m + l is H or methyl.

11. A process aecording -to Claim 1 which eomprises reaeting 7-(3-hydroxy-5-oxo-2-iodo-eyclopentyl)-heptanoic aeid with sodium-2-hydroxy-3-p-fluorophenoxy-2-methyl-propyl-thiolate, thereby to produce 11,15-dihydroxy-16-p-fluoro-phenoxy-15-methyl-9-oxo-17,18,19,20-tetranor-13-thia-prostanoic acid.

12. A process aeeording to Claim 1 which comprises reacting 7-(3-hydroxy-5-oxo-2-p-toluenesulEonyloxy-cyclopentyl)-heptanoic acid with 2-p-fluorophenyl-2-hydroxy-propylthiol, thereby to produce 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-17,18,19,20-tetranor-13-thia-prostanoic acid.

13. A process according to Claim 1 which comprises reacting 5-triphenyl-phosphonio-valerianic acid with 2-oxa-3, 7-dihydroxy-6-(2-hydroxy-3-p-fluorophenoxy-propylmercapto)-bieyclo [3,3,0] octane, thereby to produee 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoie acid.

14. A process according to Claim 1 which comprises reacting 5-triphenyl-phosphonio-valerianic acid with 2-oxa-3, 7-dihydroxy-6-(2-hydroxy-3-m-chlorophenoxy-propylmereapto)-bieyclo [3,3,0] octane, thereby to produce 9,11,15-trihydroxy-16-m-chlorophenoxy-17,18,19,20-tetranor-13-thia-5-prostenoic acid.

15. A process according to Claim 1 which comprises reacting 5-triphenyl-phosphonio-valerianic acid with 2-oxa-3,7-dihydroxy-6-(2-hydroxy-2-methyl-heptylmercapto)-bicyclo [3,3,0]
octane, thereby to produce 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid.

16. A compound of the formula I
wherein A is -CO- or -CHOH-, B is -CH2-CH2- or -CH=CH-, R1 is H or an alkyl group with 1 to 4 carbon atoms, m is an integer between 0 to 5, n is an integer between 0 and 3, or, when B is -CH=CH-, also 4, 5, 6, 7, 8 or 9, R2 is alkoxy with 1 to 4 carbon atoms, phenoxy, pyridyl, thienyl, naphthyl, phenyl substituted by F, Cl, Br, OH, OCH3 or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, or, when B is -CH=CH-, also hydrogen, phenyl or tolyl, and R3 is H, methyl or ethyl, and the wavy line (?) designates that these compounds are either .alpha.-or .beta.-positioned; as well as the physiologically acceptable salts of same, whenever produced according to the process of claim 1 or an obvious chemical equivalent thereof.

17. A compound of claim 16 wherein R1 is H, whenever produced according to the process of claim 2 or an obvious chemical equivalent thereof.

18. A compound of Claim 16 wherein A is -CO-, whenever produced according to the process of claim 3 or an obvious chemical equivalent thereof.

19. A compound of Claim 16 wherein A is -CHOH-, whenever produced according to the process of claim 4 or an obvious chemical equivalent thereof.

20. A compound of Claim 16 wherein B is -CH=CH-, whenever produced according to the process of claim 5 or an obvious chemical equivalent thereof.

21. A compound of Claim 16 wherein m and n each are 0 or 1, and R2 is phenyl substituted by F, Cl, Br, OH, OCH3, or CF3; or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3; or when B is -CH=CH-, R2 is also phenyl or tolyl, whenever produced according to the process of claim 6 or an obvious chemical equivalent thereof.

22. A compound of Claim 15 wherein Rl and R3 each are H, A is -CO-, B is -CH2-CH2-, m and n each are 0 or 1 and R is phenyl substituted by F, C1, Br, OH, OCH3, or CF3, or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, whenever produced according to the process of claim 7 or an obvious chemical equivalent thereof.

23. A compound of Claim 16 wherein Rl and R3 each are H, A is -CHOH-, B is -CH=CH-, m and n each are 0 or 1 and R2 is phenyl or phenoxy substituted by F, Cl, Br, OH, OCH3, CH3 or CF3, or is unsubstituted phenyl, whenever produced according to the process of claim 8 or an obvious chemical equivalent thereof.

24. A compound of Claim 16 wherein R is H, methyl or ethyl, R is H:, B is -CH=CH-, CnH2n-R2 is pentyl, hexyl, hepty, l-methylpentyl or 1,1-dimethylpentyl and CmH2m + 1 is II or methyl, whenever produced accordïng to the process of claim 9 or an obvious chemical equivalent thereof.

25. A compound of Claim 16 wherein Rl and R3 each are H, A is -CHOH-, B iS -CH=CH-, CnH2n-R2 is pentyl, phenoxymethyl or m-chlorophenoxymethyl and CmH2m + 1 iS H or methyl, whenever produced according to the process of claim 10 or an obvious chemical equivalent thereof.

26. The compound, 11,15-dihydroxy-16-p-fluorophenoxy-15-methyl-9-oxo-17,18,19,20-tetranor-13-thiaprostanoic acid, whenever produced according to the process of claim 11 or an obvious chemical equivalent thereof.

27. The compound, 11,15-dihydroxy-15-p-fluorophenyl-9-oxo-17,18,19,20-tetranor-13-thiaprostanoic acid, whenever produced according to the process of claim 12 or an obvious chemical equivalent thereof.

28. The compownd, 9,11,15-trihydroxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenoic acid, whenever produced according to the process of claim 13 or an obvious chemical equivalent thereof.

29. The compound, 9,11,15-trihydroxy-16-m-chIorophenoxy-17,18,19,20-tetranor-13-thia-5-prostenoi.c acid, whenever produced according to the process of claim 14 or an obvious chemical equivalent thereof.

30. The compound, 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid, whenever produced according to the process of claim 15 or an obvious chemical equivalent thereof.