CA2088159A1

CA2088159A1 - Cyclopentane derivatives, process for producing them and their pharmaceutical use

Info

Publication number: CA2088159A1
Application number: CA002088159A
Authority: CA
Inventors: Ulrich Klar; Hartmut Rehwinkel; Helmut Vorbruggen; Karl-Heinz Thierauch; Peter Verhallen
Original assignee: Individual
Current assignee: Bayer Pharma AG
Priority date: 1990-07-27
Filing date: 1991-07-22
Publication date: 1992-01-28
Also published as: WO1992002494A1; DK0541593T3; PT98465A; DE4024345A1; PT98465B; IE912655A1; IL98969A0; ATE127788T1; IE73476B1; ES2080956T3; EP0541593A1; ZA915903B; DE59106490D1; AU8227491A; JPH05509090A; EP0541593B1; GR3018360T3

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to cyclopentane derivatives of formula (I) in which there is a double bond between the carbon atoms of centers a-b or b-c, and their salts with physiologically tolerable bases, and .alpha., .beta. or .gamma.-cyclodextrin clathrates and the liposome-encapsulated compounds of formula (I), process them and their pharmaceutical use.

Description

Cyclopentene Derivatives, Process for their Production and their Pharmaceutical Use Description:
The invention relates to cyclopentene derivatives, process for their production as well as their use as auxiliary agents for pharmacological studies and as pharmaceutical agents.
Cyclopentane derivatives have been dealt with intensively in recent years, since prostaglandins derived from the cyclopentane system, such as, e.g., PGA2, PGB2, PGE2, 6-oxo-PGE1, PGD2, PGF2a, PGJ2 and their analogs, have the most varied biological actions, e.g., on the cardiovascular s~stem, the central nervous system or immune system.
It has been found, surprisingly, that by the introduction of a double bond in 9- or 10-position (prostaglandin numbering system) of the prostaglandin sXeleton in combination with the most varied structural features in the lower chain as well as in 11-position, chemically and metabolically stable prostaglandin analogs are obtained which are able to antagonize the pharmacological properties of unstable thromboxane A2 (TXA2) or PGH2 as well as its stable analogs, such as, e.g., U46619 or U44069 on the receptor.
The compounds of this invention therefore constitute valuable auxiliary agents for selective treatment of diseases, which are attributable to an excess of TXA2 or PGH2.

- . . : ~. .

; ~

, :
`

2 ~ L ~ ~

The invention relates to cyclopentene derivatives of for~ula I, b a Z~X~ R1 c ~ (I3, RZ A' `D R3 in which there is a double bond between the carbon atoms of centers a-b or b-c, R1 c~n be ~ / ~ ~ ~ ~ ~ ~/ N or CooR4, R4 can mean hydroyen or C1-C10 alkyl, C3-C10 cycloalkyl, 7 16 aralkyl, optionally substituted by halogen, phenyl, C1-C4 alkoxy or di-( C~-C4) -alkylamino, phenacyl or C6-C12 aryl substituted by Y
or a 5- or 6-membered heterocyclic radical with at least one N, O
or S atom, or -CONHR6 with Rh meaning hydrogen, C1-C1o alkyl, C1-C1o alkanoyl, C6-C12 arylsulfonyl or C1-C1o alkanesulfonyl, X means -(CH2)p-, -CH2-O-, or -CH2-S-, Z,A, independent of one anoth~r, mean a direct bond, (Z)-CH=CH-, (E)-CH=CH-, or -C_C-, p means O to 5, n,r, independent of one another, mean O to 2, R2 means oR5 or Rs, W means a direct hond, a ~[(CH2)n~V]q group, a -(CH2)n~V-(CH2)q~V group, a free or functionally modified hydroxymethylene .
:. :
' ' . ~ ; ~ . .

. . : ~ :, group, or a free or functionally modified ~ group, and the hydroxy group can be res~ectively in ~- or ~-position, q means 1 or 2, D means a direct bond, a straight-chain saturated alkylene group with 1-5 C atoms, a branched saturated alkylene group or a straight-chain or branched unsaturated alkyiene group with 2-5 C
atoms, which can be optionally substituted by fluorine atoms, --(CH2) n--NH--S2 H--~CH~n~ N ~

~ H

,N ~ N ~ -(CHz n~NrN ~ N ~, -(C~z)n N ~ N SOz-n ~ N J~ N ' . CH~ Y

V can be an O or S atom, E can be a direct bond, -C_C- or -CH=CR7-, and R7 hydrogen, C1-Cs alkyl, halogen or trifluoromethyl, AWDE together can be a direct bond, AW together can be a direct bond, DE together can be a direct bond, ..

: , ;
' ' - ` ' . ; , , (Cl12)~

R3 _(CH~ ~ Y~ ~ y2 yl ~l ~ y2 _(CH~ (CH~

-(CH~ ~ )r C3-C10 cycloalkyl, or C1-C10 alkyl optionally substituted by Y, m means l or 2, y1 and y2 are the same or different and mean Y, Y means hydrogen, halogen, N3, CF3, oR5, NO2, NHz, CN, COORs or C1-C10 alkyl, Rs can be hydrogen, C1-C1o alkyl, C6-C12 aryl or C7-C16 aralkyl optionally substituted by halogen and, if R4 means hydrogen, their salts with physiologically compatible bases, as well as the - or y-cyclodextrin clathrates, as well as the compounds of formula I encapsulated with liposomes.
The definition of 5- or 6-membered heterocyclic radical relates to heterocycles, which contain at least one heteroatom, preferably nitrogen, oxygen or sulfur, and are monocyclic or bicyclic. For example, there can be mentioned 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, quinolyl, isoquinolyl.

" : , .. .. . . ..

: :-. . ~ , .- , .
:. ,, : : .
,.:

As alkyl groups R3, R4, Rs, E and Y, straight-chain or branched-chain alkyl groups with 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl, are suitable.
Alkyl groups R3, R4, Rs, E and Y can be substituted by halogen atoms, hydroxy groups, C1-C4 alkoxy groups, C6-C12 aryl groups, which can be substituted by halogen, di-(C1-C4)-alkylamines and tri-(C1-C4j-alkylammonium. Those alkyl groups which are singly substituted are preferred.
As substituents, for example, there can be mentioned -fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
As preferred alkyl groups R3, R4, Rs, E and Y, those with 1-5 C atoms, such as, e.g., methyl, ethyl, propyl, isobutyl, butyl, neopentyl, tert-butyl, chloroethyl, 1- or 2-chloropropyl, hydroxyethyl and 1- or 2-hydroxypropyl can be mentioned.
As aryl groups R4 and RS, for example, phenyl, diphenyl, l-naphthyl and 2-naphthyl, whi~h can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with l-4 C atoms, a chloromethyl group, fluoromethyl group, carboxyl group, C1-C4 alkoxy group or hydroxy group, are suitable. The substitution in 3- and 4-position on the phenyl ring is preferred, for example, by fluorine, chlorine, C1 -C4 alkoxy or trifluoromethyl or in 4- -position by hydroxy.
Cycloalkyl groups R5 can contain 3-10, preferably 3-6 carbon atoms, in the ring. The rings can be substituted by alkyl groups .

, ~: , .

with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, methylcyclohexyl.
The C1-C10 alkyl groups mentioned under the definitions should be straight-chain or branched alkyl groups, as they were already mentioned for the alkyl groups above.
The hydroxy groups in R2, Y and W can be functionally modified, for example, by etherification or esterification, and the free or modified hydroxy group in W can be in ~- or ~-position, and free hydroxy groups are preferred.
As ether and acyl radicals, the radicals known to one skilled in the art are suitable. Easily cleavable ether radicals, such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl radical, are preferred.
As acyl radicals, e.g., acetyl, propionyl, butyryl, benzoyl, are suitable.
Halogen in the definitions for R4, Rs, E and Y means fluorine, chlorine, bromine and iodine.
Radicals "C1~C10 alkanoyl" or "C1-C~O alkanesulfonyl" for R6 correspond to the already mentioned alkyl groups OI the same length with the difference that they are bound on a carboxyl group or sulfonyl group. C1-C4 alkanoyl or C1-C4 alkanesulfonyl are preferred.
Inorganic and organic bases are suitable for salt formation with the free acids (R4 = H), as they are known to one skilled in the art for forming physiologically compatible salts. For .
. : ~ : . : - -g example, there can be mentioned: alkali hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)methylamine, etc.
Preferred are the compounds of formula I, in which R1 means the group CoOR4 or CONHR6, R2 means hydrogen, hydroxyl, C1-C4 alkyl, C6-C12 aryl or C7-C16 aralkyl optionally substituted by halogen, R4 m~ans hydrogen or C7-C16 aralkyl, C5-C6 cycloalkyl or C1-C10 alkyl optionally substituted by halogen, R6 means C1-C7 alkanoyl, C6-C12 arylsulfonyl or C~-C7 alkanesulfonyl, p means O to 4, n,r, independent of one another, mean O or 1.
Especially preferred are the compounds of formula I, in which R1 means the group CooR4~
R2 means hydrogen, hydroxyl, phenyl or phenylethyl, R4 means hydrogen or methyl, R6 means methanesulfonyl, p means O to 4, n,r, independent of one another, mean O or 1.
The compounds of formula I according to the application can ~' .

- ~ .
, 2 ~
be produced as described in more detail helow:

,z,X~ ~ ,X ~R (HCO)2PJI~ ~E~R3 OH CHO b) R2 ` (I~R2 ~a~

Z ' ~ c) ~ ",f~ Z
D~ ,R d) ~ A'W'D'E`R3 R2 o R2 with R2, R3, A, R, X, Z in the above-indicated meanings, D as alkylene optionally substituted by alkyl, \ ~ Y
CH

R1 meaning a -CooR4 ester, R8 as hydrogen or bromine, W as -CH(OH)-.

,X~" Hal-502-R3 (VII) R2 2 o=C=N-R3 (VIII) R2 ~) f) with RZ, R3, X, Z, Hal in the above-indicated meanings, AW, E as a direct bond, o D meaning -(CH2~1-NH SO2-, ( 2)1 ~ ~ N~
H H

:, ,~ , .

, , , . -; . ... , ,. . . ~

Rl meaning a -CooR4 ester.
C.

r Z g~, .',~,.,f~--Z;

'W` D ' E ` R3 (IX) (I) with R2, R3, X, Z, Hal in the above-indicated meanings, AW, E as a direct bond, D meaning -(CH2~0-N~-S02-~ ~ O or ~~ N~

R1 meaning a -CooR4 ester.

D.

X~

) (XI) R
Hal-R3 ~1~ X~

i) ~ A' D R3 (I) ~r~J~

with R2, ~3, n, V, X, Z, Hal in the above-indicated meanings, A, DE as a direct bond, W meaning -[(CHz) n~V] n~ ~
R1 meaning a -CooR4 ester.
E.

,X ~R
~' D R ~ A W~D F~R3 (X~
with RZ, R3, n, V, W, X, Z, Hal in the above-indicated meanings, A, DB as a direct bond, W meaning -[ (CH2)n V]n R1 meaning a -CooR4 ester.
The compounds of formula I can be produced according to claim 3 corresponding to the above-described process alternatives.
The reaction conditions of the following process stages are:
a) II ~ III (Process A) The oxidation of the compounds of formula II takes place according to known processes, such as, e.g., according to that of Swern, Collins as well as with use of pyridinium dichromate or pyridinium chlorochromate in solvents such as dichloromethane, diethyl ether, tetrahydrofuran, benzene or toluene at -80C to -50C (Swern) or up to +30C (in the other oxidations) within 10 minutes to 8 hours.
b) III ~ V (Process A), c), d) V I (Process A) The reaction of compounds III with phosphonates IV as well as the subsequent reduction or HBr elimination take place analogously to the conditions mentioned in DE-OS 2845770.

;

e) II ~ VI (Process B) The conversion of the compounds of formula II to compounds of formula VI takes place as in examples 38a to 38c mentioned in this respect.
f) VI ~ I (Process B) The reaction of the compounds of formula VI with the compounds of formula VII or VIII takes place as in example 38 mentioned in this respect.
g) IX I ~Process C) The reaction of the compounds of formula IX to compounds of formula I takes place as described in example 1, and C-C multiple bonds previously contained in D are optionally hydrogenated according to the methods known to one skilled in the art.
h) X XI (Process D) The reaction of the compounds of formula X to compounds of formula XI takes place as described in example 1, and the C-C
multiple bonds previously contained in D are optionally hydrogenated according to the methods known to one skilled in the art.
i) XI I (Process D) The reaction of the compounds of formula XI with compounds of formula XII to compounds of formula I takes place as described in example 15.
k) XIII I (Process E) The reaction of the compounds of formula XIII to compounds of formula I takes place as described in example 1, and C-C
multiple bonds previously contained in D are optionally .

~a~
hydrogenated according to the methods known to one skilled in the art.
The release ~f functionally modified hydroxy groups R2, R3, and W takes place according to the methods known to one-skilled in the art. For example, the cleavage of ether protecting groups is performed in an aqueous solution of an organic acid, such as, e.g., acetic acid, propionic acid, citric acid, i.a, or in an aqueous solution of an inorganic acid, such as, e.g., hydrochloric acid, or in the case of tetrahydropyranyl ethers with use of pyridinium-p-toluenesulfonate, preferably in alcohols as solvent or with use of anhydrous magnesium bromide, preferably in diethyl ether as solvent.
To improve the solubility, a water-miscible inert solvent is suitably added with use of aqueous-acid reaction conditions.
Proven as suitable, there are, e.g., alcohols, such as methanol and ethanol, ethers, such as dimethoxyethane, dioxane and tetrahydrofuran, and tetrahydrofuran is preferably used.
The cleavage of silylether protecting groups takes place, for example, with tetrabutylammonium fluoride according to the methods known to one skilled in the art. As solvent, for example, tetrahydrofuran, d~ethyl ether, dioxane, methylene chloride, etc., are suitable. The cleavage is performed preferably at temperatures between 20C and 80C.
The saponification of the acyl groups and ester in CoOR4 of the cyclopentene derivatives is performed according to the methods known to one skilled in the art, such as, for example, with basic catalysts, such as, e.g., with alkali or alkaline-`~
:.

~881~

earth carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. As alcohols, aliphatic alcohols, such as, e.g., methanol, ethanol, butanol, etc., but preferably methanol, are suitable. As alkali carbonates and hydroxides, lithium, sodium and potassium salts can be mentioned. The lithium and potassium salts are preferred. As alkaline-earth ~arbonates and hydroxides, for example, calcium carbonate, calcium hydroxide and barium carbonate are suitable. Thq reaction generally takes place at -10C to +70C, but preferably at +25C.
The introduction of ester group Co2R4 for R1 or COzRs for Y, in which R4 or Rs represents an alkyl group with 1-10 C atoms, takes place according to the methods known to one skilled in the art. The carboxy compounds (R4 = H or Rs = H) are reacted, for example, with diazohydrocarbons in a way known in the art. The esterification with diazohydrocarbons takes place, e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the carboxy compound, dissolved in the same or in another likewise inert solvent, such as, e.g., methylene chloride. After completion of the reaction within 1 to 60 minutes, the solvent is removed and the ester is purified in the usual way. Diazoalkanes are either known or can be produced according to known methods [Org. Reactions, Vol. 8, pages 389-394 (1954)].
The introduction of ester group Co2R4 for R1 or CO2Rs for Y, in which R4 or Rs represents a substituted or unsubstituted aryl group, takes place according to the methods known to one skilled .

. . 14 in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, such as, e.g., pyridine, DMAP, triethylamine, in an inert solvent, such as, e.g., methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, but preferably with chloroform.
The reaction is performed at temperatures between -30C and +50C, preferably at +10C.
The cyclopentene derivatives of formula I with R4 or R5 meaning a hydrogen atom can be converted to salts with suitable amounts of the corresponding inoryanic bases with neutralization.
For example, by dissolving the corresponding acids in water, which contains stoichiometric amounts of the base, the solid inorganic salt is obtained after evaporation of the water or after addition of a water-miscible solvent, e.g., alcohol or acetone.
The production of the amine salts takes place in the usual way. For this purpose, the acid is dissolved in a suitable solvent, such as, e.g., ethanol, acetone, diethyl ether or benzene and 1 to 5 equivalents of the respective amine is added to this solution. In this case, the salt usually accumulates in solid form or is isolated in the usual way after evaporation of the solvent.
The functional modification of the free hydroxy groups takes place according to the methods known to one skilled in the art.
For the introduction of the ether protecting groups, it is reacted, for example, with dihydropyran or methyl vinyl ether in ~ .
:, .

;,~

c~ ' methylene chloride or chloroform with use of catalytic amounts o~
an acid condensing agent, such as, e.g., p-toluenesulfonic acid.
The respective enol ether is added in excess, preferably in 1.2 to 10 times the amount of the theoretical requirement. -The reaction normally takes place at -10C to +30C and is completed after 2 to 45 minutes.
For the introduction of silylether protecting groups, it is reacted, for example, with t-butyl-diphenylchlorosilane or t-butyl-dimethylchlorosilane in dimethylformamide with use of a base, such as, e.g., imidazole. The respective silyl chloride is added in exc~ss, preferably in 1.05 to 4 times the amount of the theoretical requirement. The reaction normally takes place at 0C to 30C and is completed after 1 to 24 hours.
The introduction of the ac~l protecting groups ta~es place by a compound of formula I being reacted in a way known in the art with a carboxylic acid derivative, such as, e.g., acid chloride, acid anhydride, etc.
Cyclodextrin clathrates are obtained analogously to the instructions in W0 87/05294.
Liposomes are produced according to the production process described in "Pharmazie in unserer Zeit [Pharmaceutics in Our Time] 11, 98 (1982)."
All stereoisomeric forms also relate to the object of the invention.

, .

~3~ '3~

Bioloaical Action and Area of Use of the New TXA2 Antaaonist~:
The compounds of this invention are suitable for treatment of diseases of the cardiovascular system, the stomach, the pancreas, the liver and the kidneys. They work in an antihypertensive and bronchodilatory manner. They are excellently suited for inhibition of the activation of platelets.
Consequently, the new TXA2 antagonists of formula I represent valuable pharmaceutical active ingredients. Moreover, the compounds are distinguished by higher selectivity, a substantially longer effectiveness and a greater stability as compared to similar TXAz antagonists.
The new TXA2 antagonists have the properties typical for this family of compounds, such as, e~g., reduction of the peripheral arterial, the coronary and-the pulmonary vascular resistance, reduction of the pulmonary blood pressure, reduction of the systemic blood pressure without reducing the cardiac output and coronary blood circulation at the same time, promotion of the ~idney blood circulation and the blood circulation of other peripheral organs, increase of the cerebral blood circulation, inhibition of the platelet activation and dissolution of blood clots, inhibition o~ bronchoconstriction, inhibition of gastric acid secretion, cytoprotection o~ the heart, the stomach and intestinal mucous membrane, the liver, cytoprotection in the pancreas and in the kidneys as well as antiallergic properties. Therefore, the new TXA2 antagonists are suitable on principle for treatment of stroke, prophylaxis and treatment of coronary heart diseases, for example, coronary , ~ - j - .. . , - - , -. : - . ~
." ,., .: . . .: .

. . , - : , . . : .

thrombosis, for treatment of myocardial infarction, peripheral arteriopathies, for prophylaxis and treatment of other thromboembolic diseases and in arteriosclerosis, in ischemic attacks of the central nervous sys~em and other disturbances of the blood circulation of the brain, such as, e.g., migraine, for treatment of hypertonia and for treatment of diseases which accompany an increase of the pulmonary vascular resistance, such as, e.g., the pulmonary hypertonia and for treatment of shock, asthma and allergic rhinitis. They can further be used to inhibit labor pains and for treatment of toxicoses in -pregnancles.
Further, the new TXA2 antagonists can be used to improve the organ function after transplantation, for example, in kidney transplantation, to prevent rejection reactions, instead of heparin or as adjuvant in the case of dialysis or hemofiltration and in the case of storing dried blood plasma, for example, dried blood platelets.
The new TXA2 antagonists have an antimetastatic action and antiproliferatiYe properties. They are suitable on principle for treatment of neoplasias.
The new TXA2 antagonists can be used in combination with, for example, carbacyclins, prostacyclin and its analogs, 7-oxoprostacyclins, prostaglandins and their derivatives and 6-oxo-PGE1- and 6-oxo-9-fluoroprostaglandin derivatives, with TXA2-synthetase inhibitors, with phosphodiesterase inhibitors, with antagonists and receptor antagonists of various platelet stimulators (e.g., ADP, thrombin, collagen, PAF, adrenaline, .

, . 18 2~ 3 ~
serotonin, fibrinogen~, with calcium antagonists, with fibrinolytic agents and thrombolytic agents, e.g., t-PA, streptokinase, with heparin and other anticoagulants, with cyclooxygenase inhibitors, e.g., acetylsalicylic acid, with inhibitors of lipoxygenases as well as antagonists of lipoxygenase products, with vasodilators, such as, e.g., nitro compounds, with antihypertensive agents, such as, e.g., ~-blockers or with diuretics.
The dose of the compounds is 0.1-lO00 mg/day, preferably 0.1-500 mg/day, also in several partial doses, if they are administered to human patients. The unit dose for the pharmaceutically acceptable vehicle is 0.1-100 mg. For parenteral administration, sterile, injectable aqueous or oily solutions are used. For oral administration, for example, tablets, coated tablets, or capsules are suitable.
Thus, the invention also relates to pharmaceutical agents ~ased on the compounds of general formula I and usual auxiliary agents and vehicles.
The active ingredients according to the invention are to be used in connection with the auxiliary agents known and usual in galenicals, e.g., for the production of antihypertensive agents.
The unit dose range for the ampule is 0.1-lO0 mg, for the tablet 0.1-100 mg.

:....

- lg Example 1:
7-t5S)-(4-Toluenesulfonylamino)-cyclopent-l-enyl]-5(Z.)-heptenoic acid methyl ester:
55 mg (139 ~mol) of the compound produced according to example la is dissolved in 2.5 ml of anhydrous toluene, mixed with 56 ~1 of anhydrous pyridine, cooled under an atmosphere of dry argon to--60C and mixed with 42 ~1 of diethylaminosulfur trifluoride. It is allowed to heat within 3.5 hours to 0C, quenched by adding 1 ml of a saturated sodium bicarbonate solution, diluted with water and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on 4 analytic thin-layer slabs. A mixture of n-hexane and acetone is used as mobile solvent, diethyl ether is used as eluant. 16 mg (40 ~mol, 38%) of 7-[(lR,2S,5R)-2-(4-toluenesulfonylamino)-5-fluoro-cyclop~ntyl]-5(Z)-heptenoic acid methyl ester as well as 20 mg (53 ~mol, 29~) of the title compound are each isolated as colorless oil.
IR (Film): 3270, 3050, 3010, 2930, 2860, 1730, 1600, 1440, 1330, 1305, 1160, 1100, 950, 910, 815 and 670 cm~1.

~xample la:
7-~(lR,2S,5S)-2-(4-Toluenesulfonylamino)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 140 mg (280 ~mol) of the compound,-produced according to example lb, in 1.5 ml of methanol is mixed with 20 mg of finely pulverized potassium carbonate and heated for 1 hour to 70C. After the cooling, it is acidified with saturated citric acid, diluted with water and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on 2 analytic thin-layer slabs. A mixture of n-hexane and ethyl acetate is used as mobile solvent, diethyl ether is used as eluant. 96 mg (243 ~mol, 87~) of the title compound is isolated as ~olorless oil.
IR (Film): 3600-3200, 3270, 2940, 2870, 1735, 1600, 1450, 1330, 1270, 1160, 1110, 1090, 1025, 815 and 665 cm~1.

Example lb:
7-[(lR,2S,5S)-2-(4-Toluenesulfonylamino)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 340 mg (984 ~mol) of the amine, produced according to example lc, in 30 ml of anhydrous dichloromethane is mixed with 1.52 ml of triethylamine, 483 mg of p-toluenesulfonic acid chloride and stirred for 1.5 hours at 23C under an atmosphere of dry argon. It is poured on a semiconcentrated sodium chloride solution and extracted several times with dichloromethane. The combined organic extracts are dried on . .

. , ~ ~ 8 g 1 3~
magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on about 70 ml of fine silica gel with a gradient system of n-hexane and ethyl acetate.
330 mg (660 ~mol, 67%) of the title compound is isolated as colorless oil.
IR (Film): 3270, 2940, 2870, 1730, 1710, 1600, 1450, 1330, 1270, 1160, 1110, 1090, 1025, 905, 815, 710 and 665 cm~1.

Example lc:
7-[(lR,2S,5S)-2-Amino-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester (A) and 7-[(lR,2S,5S)-2-trifluoroacetamido-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester (B):
The solution obtained according to example ld is mixed with 1.47 ml of trifluoroacetic acid and refluxed for 6 hours. It is allowed to stand for 14 hours at 23C, concentrated by evaporation and the residue is purified by chromatography on about 250 ml of fine silica gel with a gradient system of dichloromethane and methanol. 2.0 g (5.79 mmol, 4~% relative to the feedstock in example le) of title compound A as well as 1.53 g (3.47 mmol, 26o relative to the feedstock in example le) of title compound B are isolated.
IR (CHCl3) of A: 3500-2600, 2950, 2870, 1710, 1670, 1450, 1275, 1190, 1140 and 835 cm~1.
IR ~Film3 of B: 3320, 2950, 2870, 1740-1690, 1600, 1550, 1450, 1435, 1270, 1210, 1180, lllO, 1070, 1025 and 710 cm-1 .

:

Example ld:
7-[(lR,2S,5S)-2-Azidocarbonyl-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The residue obtained according to example le is dissolved in 20 ml of dichloromethane, cooled to 3C, mixed with 10 mg of tetrabutylammonium hydrogen sulfate and the solution of 1.04 g of sodium azide in 3.5 ml of water. It is stirred for 2.5 hours, diluted with dichloromethane, the organic phase is separated and dried on freshly annealed magnesium sulfate. The solution obtained after filtration is immediately further reacted.

Example le:
7-[(lR,2S,5S)-2-Chlorocarbonyl-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 5.0 g (13.4 mmol) of the compound, produced according to example lf, in 133 ml of anhydrous dichloromethane is mixed under ice cooling with 2.13 ml of freshly distilled thionyl chloride and allowed to stir for 20 hours at 23C under an atmosphere of dry argon. It is concentrated by e~aporation and the resulting residue is further reacted without purification.

~. ~S~ f,~

Example lf:
7-[(lR,2S,5S)-2-Hydroxycarbonyl-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 30.2 g (83.9 mmol) of the alcohol,-produced according to example lg, in 725 ml of acetone is cooled to -15C, mixed with 44 ml of a standardized chromosulfuric acid solution (Jones reagent), stirred for 3 hours at -10C and excess oxidizing agent is decomposed by adding 13 ml of isopropanol. It is diluted with water, extracted several times with diethyl ether, the combined organic extracts are washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 1 l of coarse silica gel with a gradient system of n-hexane and ethyl acetate.
29.3 g (78.3 mmol, 93%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2500, 3060, 2950, 2860, 1740-1690, 1600, 1580, 1450, 1435, 1360, 1310, 1270, 1170, 1110, 1070, 1025 and 710 cm~1.

Example lq:
7-[(lR,2S,5S)-2-Hydroxymethyl-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 57.9 g (96.7 mmol) of the compound, produced according to example lh, in 124 ml of anhydrous tetrahydrofuran is mixed with 155 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and stirred for 17 hours at 23C

, .
' : ' ' ~ ' , , : - 24 ~8~
under an atmosphere of dry argon. It is mixed with water, extracted several times with diethyl eth4r, the combined organic extracts are washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 2 l of coarse silica gel with a gradient system of n-hexane and ethyl acetate. 30.2 g (83.8 mmol, 87%) of the title compound is isolated as colorless oil.
IR (Film~: 3600-3200, 3060, 2940, 2860, 1735, 1710, 1600, 1580, 1360, 1310, 1275, 1170, 1110, 1070, 1025 and 715 cm~1.

Example lh:

7-t(lR,2S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-benzoyloxy-cyclopentyl]-5(z)-heptenoic acid methyl ester:
The solution of 47.9 g (96.7 mmol) of the compound, produced according to example li, in 212 ml of anhydrous pyridine is cooled under an atmosphere of dry argon to 5C, mixed within 30 minutes with 29 ml of benzoyl chloride and stirred for 1.5 hours at 23C. It is poured on 600 ml of ice water, extracted several times with diethyl ether, the combined organic extracts are washed with Z n hydrochloric acid, water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after ~iltration and removal of the solvent is purified by chromatography on about 2 l of fine silica gel with a gradient system of n-hexane and ethyl acetate. 57.9 g (96.7 mmol, 100~) of the title compound is isolated as colorless oil.

' ~. , , , ~ 25 .

'~ ~ 8 ~
IR (Film3: 3070, 3040, 3000, 2950, 2930, 2850, 1735, 1710, 1600, 1450, 1425, 1360, 1310, 1270, 1110, 820, 740 and 705 cm~1.

Example li: ~
7-[(lR,2S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 154 g of the crude product, produced according to example lj, in 150 ml of acetone is mixed with 33.4 g of potassium carbonate, 41.2 g of methyl iodide and heated for 6 hours to 80C. It is concentrated by evaporation, taken up in 400 ml of dichloromethane, washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 2 1 of coarse silica gel with a gradiènt system of n-hexane and ethyl acetate. 47.9 g (96.8 mmol, 88~ relative to the feedstock in example lj) of the title compound is isolated as colorless oil.
IR (Filmj: 3600-3200, 3070, 3040, 3000, 2940, 2920, 2850, 1735, 1585, 1460, 1425, 1240, 1165, 1110, 1005, 820, 740 and 700 cm-1 -,~ ' :

` . ' ' ' ~ - 26 JI~
Example li:
7-[(lR,2S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-hydroxy-cyclopentyl]-5(~)-heptenoic acid:
A total of 50 g of finely pulverized potassium-tert--butanolate is added within one hour in portions to the emulsion of 99.7 g of carboxybutyltriphenylphosphonium bromide in 256 ml of anhydrous tetrahydrofuran and 600 ml of anhydrous dimethyl sulfoxide. It is stirred until a clear red solution results, the solution of 43.8 g (110 mmol) of the compound, produced according to example lk, is instilled continuously in 130 ml of anhydrous tetrahydrofuran and allowed to react for 2 hours at 23C under an atmosphere of dry argon. It is poured in ice water, adjusted to a pH of 4-5 by adding a saturated citric acid solution and extracted several times with dichloromethane. It is washed with water and saturated sodium chloride solution, dried on magnesium sulfate, filtered and concentrated by evaporation. The resulting residue is further reacted without purification.

~a~
(lS,3RS,5R,6S)-3-Hydroxy-6-(tert-butyldiphPnylsilyloxymethyl)-2-oxabicyclo[3.3.0]octane:
The solution of 45.8 g (116 mmol) of the compound, produced according to example 11, in 1.4 l of anhydrous toluene is cooled under an atmosphere of dry argon to -7GC, 202 ml of a 1.2 M
diisobutylaluminum hydride solution in toluene is instilled within one hour and stirred for 1 hour. Excess reducing agent is decomposed by adding 13 ml of isopropanol. It is allowed to heat ' " . ~ ' j~ :' , ` . , , -' ` 27 to OC, 100 ml of water is instilled and stirred at 23C until afine granular precipitate has formed. It is suctioned off, rewashed with dichloromethane and, after removal of the solvent, 43.8 g (110 mmol, 95%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3070, 3050, 2940, 2850, 1590, 1465, 1425, 1390, 1360, 1260, 1110, 1010, 940, 820, 740 and 700 cm~1.

Example 11:
(lS,5R,6S)-3-Oxo-6-(tert-butyldiphenylsilyloxymethyl)-2-oxabicyclo[3.3.0]octane:
The solution of 67 g (119 mmol) of the tosylate, produced according to example lm, in 1.3 l of dimethoxyethane is mixed with 136 g of sodium iodide, 118 g of zinc dust, 79 ml of water and refluxed for 16 hours. After the cooling, it is filtered off from undissolved residues, the filtrate is concentrated by evaporation to about 200 ml, mixed with water and extracted several times with diethyl ether. The combined organic extracts are washed with 10% sodium bisulfate solution, water, saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 2 l of coarse silica gel with a gradient system of n hexane and ethyl acetate. 45.8 g (116 mmol, 98%) of the title compound is isolated as colorless oil.
IR (Film): 3070, 3050, 2950, 2930, 2850, 1775, 1590, 1470, 1425, 1165, 1110, 1005, 820, 740 and 705 cm~1.

,, ~ ' - ~ 28 Example lm:
(lS,5R,6S,7R)-3-Oxo 6-(tert-butyldiphenylsilyloxymethyl)-7-toluenesulfonyloxy-2-oxabicyclo[3.3.0]octane:
The solution of 67.3 g (164 mmol) of the alcohol, produced according to example ln, in 260 ml of anhydrous pyridine is mixed with 62.8 g of p-toluenesulfonic acid chloride and stirred for 27 hours under an atmosphere of dry argon at 50C. It is concentrated by evaporation, mixed with water and extracted several times with dichloromethane. It is washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 2 1 of coarse silica gel with a gradient system of n-hexane and ethyl acetate.
67 g (119 mmol, 72~) of the title compound is isolated as colorless oil.
IR (CHCl3): 3070, 3030, 2960, 2930, 2860, 1770, 1600, 1470, 1425, 1365, 1190, 1175, 1110, 1040, 980, 960, 895, 875, 820 and 700 cm~1.

Example ln:
(lS,5R,6S,7R)-3-Oxo-6-(tert-butyldiphenylsilyloxymethyl)-7-hydroxy-2-oxabicyclo[3~3~0]octane:
The solution of 129 g (251 mmol) of (lS,5R,6S,7R)-3-oxo-6-(tert-butyldiphenylsilyloxymethyl)-7-benzoyloxy-2-oxabicyclo[3.3.0]octane in 1 1 of methanol is mixed with 14.9 g of potassium carbonate and stirred for 3 hours at 23C under an atmosphere of dry argon. It is mixed with water, neutralized by "
.

, ' ` - ~ ~ ,.
:

~ 29 ~8~ ~39 carafully adding 2 n hydrochloric acid, concentrated by e~aporation and extracted several times with dichloromethane. It is washed with water, saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after-filtration and removal of the solvent is purified by chromatography on about 2 l of fine silica gel with a gradient system of n-hexane and ethyl acetate. 97 g (236 mmol, 94%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3070, 3050, 2940, 2960, 1770, 1590, 1430, 1240, 1170, 1115, 1075, 825, 745, 705, 615 and 510 cm~1.

Example 2:
7-[5(S)-(4-Toluenesulfonylamino)-cyclopent-l-enyl]-5(Z)-heptenoic acid:
The solution of 20 mg (58 ~mol) of the compound, produced according to example 1, in 1 ml of methanol is mixed with 0.5 ml of a 5% lithium hydroxide solution and stirred for 1.5 hours at 23C. It is acidified by adding saturated citric acid, diluted with water and extracted several times with dichloromethane. It is washed with water, saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on an analytic thin-layer slab. A mixture of dichloromethane and methanol is used as mobile solvent, a mixture of chloroform and isopropanol is used as eluant. 12 mg (34 ~mol, 59%) of the title compound is isolated as colorless oil.

:, . ., :
. . .
., : . : :

:

. 30 IR (Film): 3600-2400, 3270, 3050, 3010, 2930, 2860, 1710, 1600, 1440, 1330, 1305, 1160, 1095, 950, 910, 815, 665, 575 and 550 cm~1.

Example 3:
7-[5(S)-(Benzenesulfonylamino)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
80 mg (210 ~mol) of the compound produced according-to example 3a is reacted analogously to example 1 and, after working up and purification, 23 mg (63 ~mol, 30%) of 7-[5(S)-(benzenesulfonylamino)-cyclopent l-enyl3-5(Z)-heptenoic acid methyl ester as well as 26 mg (68 ~mol, 32%) of the title compound are isolated as colorless oil.
IR (Film): 3270, 3050, 3010, 2930, 2860, 1730, 1450, 1330, 1160, 1095, 755, 720 and 690 cm~1.

Example 3a:
7-[(lR,2S,5S)-2-Benzenesulfonylamino-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: -270 mg (556 ~mol~ of the compound produced according to example 3b is reacted analogously to example la and, after working up and purification, 212 mg (556 ~mol, 100%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3260, 3060, 2930, 2850, 1725, 1445, 1320, 1265, 1160, 1090, 1020 and 735 cm~l.

, ,, ~ , ~ , ~, .
.
~ , .. . . .
, ; 31 ~xample 3b:
7-[(lR,2S,5S)-2-Benzenesulfonylamino-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
250 mg (724 ~mol) of the compound produced according to example lc is reacted analogously to example lb with benzenesulfonic acid chloride and, after working up and purification, 270 mg (556 ~mol, 77%) of the title compound is isolated as colorless oil.
IR (Film): 3270, 3060, 3000, 2950, 2860, 1730, 1715, 1600, 1585, 1450, 1330, 1315, 1270, 1160, lllo, 990, 1025, 910, 755, 715 and 690 cm~1.

Example 4:
7-t5(S)-(Benzenesulfonylamino)-c~clopent-l-enyl~-5(Z)-heptenoic acid:
23 mg (63 ~mol) of the compound produced according to example 3 is saponified analogously to example 2 and, after working up and purification, 22 mg t63 ~mol, 100%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.35-2.4(m,10H~, 2.45-2.55(m,lH), 2.75-2.9(m,1H), 4.25(m,1H), 4.9(s,NH), 5.3-5.55(m,3H), 7.45-7.6(m,3H), 7.9(m,2H).

~, , . :
: .

- .
'; :~. ' :

Exam~le 5:
7-[5(S)-(4-Fluorobenzylsulfonylamino)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
84 mg (210 ~mol) of the compound produced according to example 5a is reacted analogously to example 1 and, after working up and purification, 26 mg (65 ~mol, 31%) of 7-[(lR,2S,5R)-2-(4-fluorobenzenesulfonylamino)-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester as well as 25 mg (66 ~mol, 31%) of the title compound are each isolated as colorless oil.
IR (Film): 3270, 3050, 2930, 2860, 1730, 1600, 14-40, 1330, 1225, 1160, 1100, 840, 735 and 670 cm~1.

Example 5a:
7-[(lR,2S,5S)-2-(4-Fluorobenzenesulfonylamino)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
240 mg (477 ~mol) of the compound produced according to example 5b is reacted analogously to example lb and, after working up and purification, 175 mg (438 ~mol, g2%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3310, 3060, 3020, 2940, 2860, 1730, 1610, 1595, 1490, 1440, 1325, 1250, 1160, 835, 790, 740 and 700 cm-~.

.' ' " ' Example 5b: ~881~
7-[(lR,2S,SS)-2-(4-Fluorobenzenesulfonylamino)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
250 mg (724 ~mol) of the compound produced according to example lc is reacted analogously to example lb with 4-fluorobenzenesulfanic acid chloride and, after working up and purification, 243 mg (483 ~mol, 67~ of the title compound is isolated as colorless oil.
IR (Film): 3270, 3060, 3000, 2950, 2870, 1730, 1710, 1590, 1570, 1490, 1450, 1335, 1270, 1165, 1150, 1090, 1025, 910, 715 and 570 cm~1.

Example 6:
7-[5(S)-(4-Fluorobenzylsulfonylamino)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
25 mg (66 ~mol) of the compound produced according to example 5 is saponified analogously to example 2 and, after working up and purification, 22 mg (60 ~mol, 91~) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.35-2.4(m,10H~, 2.45-2.55(m,lH), 2.8-2.9(m,lH), 4.25(m,lH), 4~98(d,NH), 5.3-5.55(m,3H~, 7.2(m,2H), 7.9(m,2H).

- , , - - - ~ ~

,. ~ ~ ,, , . : :
,~

, . . . ... .

ExamPle 7:
7-[5(S)-(Quinon-8-ylsulfonylamino)-cyclopent-1-enyl3-5(Z)-heptenoic acid methyl ester:
74 mg (171 ~mol) of the compound produced according to example 7a is reacted analogously to example 1 and, after working up and purification, 19 mg (44 ~mol, 25%) of 7-[(lR,2S,5R)-2-(quinon-8-ylsulfonylamino)-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester as well as 29 mg (70 ~mol, 41%) of the.title compound are isolated as colorless oil.
IR (Film): 3280, 3010, 2940, 2850, 1730, 1610, 1595, 1560, 1490, 1430, 1330, 1210, 1165, 1140, 1060, 835, 790 and 680 cm~1.

Example 7a:
7-[(lR,2S,5S)-2-(Quinon-8-ylsulfonylamino) 5-hydroxy-cyclopentyl]-5(z)-heptenoic acid methyl ester:
339 mg (632 ~mol) of the compound produced according to example 7b is reacted analogously to example la and, after working up and purification, 259 mg (596 ~mol, 94%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3280, 3060, 3000, 2940, 2860, 1730, 1665, 1610, 1595, 1565, 1490, 1435, 1325, 1215, 1165, 1145, 1090, 835 and 790 cm~1.

- ,. , ~ : , ..

:, . . --- , , :

~Z ~
Exam~le 7b:
7-~(lR,2S,5S)-2-(Quinon-8-ylsulfonylamino)-5-benzoyloxy-cyclopentyl]-s(z)-heptenoic acid methyl ester:
250 mg (724 ~mol) of the compound produced according to example lc is reacted analogously to example lb with quinon-8-ylsulfonic acid chloride and, after working up and purification, 339 mg (632 ~mol, 87%) of the title compound is isolated as colorless oil.
IR (Film): 3270, 3060, 2950, 2860, 1730, 1710, 1675, 1600, 1565, 1490, 145~, 1435, 1330, 1270, 1245, 1165, 1145, lllO, 1070, 1045, 1025, 900, 835, 790 and 715 cm~1.

Example 8:
7-[5(S)-(Quinon-8-ylsulfonylamino)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
~ 29 mg (70 ~mol) of the compound produced according to example 1 is saponified analogously to example 2 and, after working up and purification, 24 mg (61 ~mol, 87%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3280, 3010r 2940, 2850, 1710, 1610, 1600, 1560, 1490, 1430, 1330, 1210, 1160, 1060, 835, 790 and 680 , , : :-~ , . ~

: : ~- : . :: : -~, ~ : , .. :::

. : ,:: :
, . . .

. 36 Example 9:
7-[5(S)-(Benzenesulfonylamino)-cyclopent-l-enyl]-heptanoic acid methyl ester:
109 mg t284 ~mol) of the compound produced according to example 9a is reacted analogously to example 1 and, after working up and purification, 34 mg (88 ~mol, 31~) of 7-[(lR,2S,5R)-2-(benzenesulfonylamino3-5-fluoro-cyclopentyl]-heptanoic acid methyl ester as well as 42 mg (115 ~mol, 40~) of the title compound are each isolated as colorless oil.
IR (Film): 3270, 3060, 2930, 2850, 1730, 1455, 1325, 1160, 1090, 755, 720 and 690 cm-1.

Exam~le 9a:
7-[(lR~2S,5S)-2-(Benzenesulfonylamino)-5-hydroxy-cyclopentyl]-5(z)-heptanoic acid methyl ester:
132 mg (346 ~mol) of the compound produced according to example 3a is dissolved in 5 ml of ethyl acetate, mixed with 50 mg of Pd/C (5%~ and hydrogenated at 1 atm, until the theoretically calculated amount of hydrogen is taken up. It is filtered, rewashed and concentrated by evaporation. 109 mg (284 ~mol, 82~) of the title compound is isolated as colorless oil.
IR (Film3: 3600-3200, 3260, 2g30, 2850, 1725, 1445, 1320, 1265, 1160, 1095, 1020 and 735 cm~1.

, , ~ ~, , , Example 10:
7-[5(S)-(Benzenesulfonylamino)-cyclopent-1-enyl]-heptanoic acid:
42 mg (115 ~mol) of the compound produced according to example 9 is saponiEied analogously to example 2 and, after working up and purification, 37 mg (105 ~mol, 92%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.1-2.3(m,14H~, 2.35(t,2H), 4.23(m,lH), 4.5~d,NH), 5.48(d,1H), 7.45-~.6(m,3H), 7.9(m,2H).

Example 11 7-[5(S) (4-Fluorobenzylsulfonylamino)-cyclopent-1-enyl]-heptanoic acid methyl ester:
120 mg (299 ~mol) of the compound produced according to example lla is reacted analogously to example 1 and, after working up and purification, 33 mg (82 ~mol, 27%) of 7 [(lR,2S,5R)-2-(4-fluorobenzenesulfonylamino)-5-fluoro-cyclopentyl]-heptanoic acid methyl ester as well as 44 mg (115 ~mol, 38%) of the title compound are each isolated as colorless oil.
IR (Film): 3270, 3060, 2930, 2850, 1730, 1590, 1490, 1435, 1330, 1230, 1155, 1095, 840, 735 and 670 cm~1.

~8~
Example lla:
7-[(lR,2S,5S)~2-(4-FluorobenzPnesulfonylamino)-5-hydroxy-cyclopentyl]-5(Z)-heptanoic acid methyl ester:
141 mg (355 ~mol) of the compound produced according to example 5a is hydrogenated analogously to example 9a and, after working up, 120 mg (300 ~mol, 84~) of the title compound is isolated as colorless oil.
IR (Film): 3270, 2930, 2850, 1730, 1660, 1600, 1445, 1320, 1260, 1160, 1095, 1020, 925, 840 and 820 cm~1.

Example 12:
7-[5(S~-(4-Fluorobenzylsulfonylamino)-cyclopent-l-enyl]-heptanoic acid:
44 mg (115 ~mol) of the compound~produced according to example 11 is saponified analogously to example 2 and, after working up and purification, 38 mg (103 ~mol, 89%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.18(m,14H), 2.38(t,2H), ~.23(m,1H), 4.52(d,NH), 5.48(d,lH), 7.2(t,2H), 7.9(m,2H).

Example 13:
7-[5(S)-(Quinon-8-ylsulfonylamino)-cyclopent-1-enyl]-heptanoic acid methyl ester:
78 mg (179 ~mol) of the compound produced according to example 13a is reacted analogously to example 2 and, after working up and purification, 19 mg (43 ~mol, 24~) of 7-t(lR,2S,5R)-2-(quinon-8-ylsulfonylamino)-5-fluoro-cyclopentyl]-' ~

' ' ', `~g8~f~9 heptanoic acid met~yl est~r as well as 24 mg (57 ~mol, 32%) ofthe title compound are each isolated as colorless oil.
IR (Film): 3280, 3040, 2930, 2850, 1730, 1610, 1595, 1560, 1490, 1430, 1330, 1165, 1145, 1065, 835, 790 and 680 cm-1.

Example 13a:
7-[(lR,2S,5S)-2-(Quinon-8-ylsul~onylamino)-5-hydroxy-cyclopentyl]-5(z)-heptanoic acid methyl ester:
149 mg (344 ~mol) of the compound produced according to example 7a is hydrogenated analogously to example 9a and, after working up, 142 mg (327 ~mol, 95%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3520, 3410, 3280, 2940, 2850, 1725, 1665, 1595, 1490, 1~55, 1430, 1320, 1160, 1140, 1020, 890, 840, 790, 735 and 675 cm~1.

Example 14:
7-[5(S)-(Quinon-8-ylsulfonylamino)-cyclopent-1-enyl~-heptanoic acid:
74 mg (177 ~mol) of the compound produced according to example 13 is saponified analogously to example 2 and, after working up and purification, 61 mg (152 ~mol, 86%) of the title compound is isolated as colorless oil.
H-NMR (CDCl3) ~ = 0.98-2.2(m,14H), 2.32(t,2H), 4.3(m,1H), 5.43(d,1H), 6.14(d,NH), 7.56(dd,1H), 7.65(t,1H), 8.06tdd,1H), 8.29(dd,1H), 8.45(dd,1H), 9.02(dd,1H).

, , ; , ,. . . . , .: : :
.' , , .

- ` 40 C~g~

Example 15:
7-t(4RS,5S)-4-Phenyl-5-benzyloxymethyl-cyclopent-1-enyl]-5(E/Z)-heptenoic acid:
32 mg (102 ~mol) of the compound produced according to example 15a is mixed with 0.42 ml of a 50% KOH solution, 265 ~l -of benzyl chloride, 4 mg of tetrabutylammonium hydrogen sulfate and stirred intensively for 18 hours at 23C. It is poured in ice water, extracted several times with dichloromethane,-the organic phase is dried on magnesium sulfate and excess benzyl chloride is removed by chromato~raphy on 4 analytic thin-layer slabs. A mixture of n-hexane and ethyl acetate is used as mobile solvent, chloroform is used as eluant. The resulting residue is saponified analogously to example 2 and, after working up and purification, 11 mg (28 ~mol, 28~) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3060, 3020, ~920, 2850, 1710, 1600, 1495, 1455, 1405, 1240, 1100, 1070, 1030, 755, 735 and 700 cm~1.

Example 15a:
7-[(4RS,SS)-4-Phenyl-5-hydroxymethyl-cyclopent 1-enyl]-5(E/Z)-heptenoic acid:
The solution of 365 mg (660 ~mol) of the compound, produced according to example 15b, in 7.8 ml of anhydrous tetrahydrofuran is mixed with 1.59 ml of a l M solution of tetrabutylammonium ~luoride in tetrahydro~uran and stirred for 3 hours at 23C under an atmosphere of dry argon. It is mixed with water, extracted several times with diethyl ether, the combined organic extracts :. . `

. . .

are washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 30 ml of fine silica gel with a-gradient system of n-hexane and ethyl acetate. 165 mg (524 ~mol, 80%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3060, 3020, 2920, 2850, 1730, 1450, 1315, 1255, 1150, 965, 760 and 700 cm~1. .

Example 15b:
7-[(4RS,5S)-4-Phenyl-5-(tert-butyldiphenylsilyloxymethyl)-cyclopent-1-enyl]-5(E/Z)-heptenoic acid methyl ester:
742 mg (1.30 mmol) of the compound produced according to example 15c is reacted analogously to-example 1 and, after working up and purification, 294 mg (532 ~mol, 41%) of the title compound as well as 337 mg (588 ~mol, 45~) of 7-[(lR,2S,3RS,5R)-2-(tert-butyldiphenylsilyloxymethyl)-3-phenyl-5-fluoro-cyclopentyl]-5(E/~)-heptenoic acid methyl ester are isolated as colorless oil.
IR (Film): 3070, 3030, 2960, 2930, 2860, 1735, 1600, 1590, 1425, 1110, 820, 740 and 700 cm~1.

ExamPle 15c:
7-[(lR,2S,3RS,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-3-phenyl-5-hydroxy-cyclopentyl]-5(E/Z)-heptenoic acid methyl ester (A) and 7-[(lR,2S,3RS,5R)-2-(tert-butyldiphenylsilyloxymethyl)-3-.
! ~
' .

phenyl-5-hydroxy-cyclopentyl]-5(E/Z~-heptenoic acid methyl es~er (B) 1.97 g ~3.~7 mmol) of the compound produced according to example 15d is reacted analogously to example 15 and, after working up and purification, 742 mg (1.30 mmol, 37%) of title compound A as well as 925 mg (1.62 mmol, 47~) of title compound B
are each isolated as colorless oil.
IR (Film) of A: 3600-3200, 3070, 3020, 2950, 2920, 2850, 1735, 1600, 1585, 1450, 1425, 1110, 820, 760, 740 and 700 cm~1.
IR (Film) of B: 3600-3200, 3060, 3020, 2950, 2920, 2850, 1730, 1600, 1590, 1450, 1425, 1265/ 1110, 1060, 820, 740 and 700 cm~1 ~

Example 15d:
7-[(lR,2S,3RS)-2-(tert-Butyldiphenylsilyloxymethyl)-3-phenyl-5-oxo-cyclopentyl]-5(E/Z)-heptenoic acid methyl ester:
The solution of 11.82 g (24.0 mmol) of the compound, produced according to example 15e, in 120 ml of anhydrous tetrahydrofuran is mixed with 500 mg o* copper(II) acetate and cooled under an atmosphere of dry argon to -78C. 3.04 ml of trimethylchlorosilane and then 12.8 ml of a 3 M solution of phenylmagnesium bromide in diethyl ether are added. After 45 minutes, it is poured into saturated ammonium chloride solution and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on about 200 ml of fine silica gel. A gradient .

system of n-hexane and ethyl acetate is used as mobile solvent.
9~78 g (17.2 mmol, 72%) of the title compound is isolated as colorless oil.
IR (Film): 3070, 3030, 2950, 2930, 2850, 1735, 1600, 1465, 1450, 1425, 1110, 1055, 820, 780, 740 and 700 cm~1.

Example 15e:
7-[(lR,2S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-oxo-cyclopent-3-enyl]-5(E/Z)-heptenoic acid methyl ester:
The solution of 5.84 g (11.5 mmol) of the compound-j produced according to example 15f, in 52 ml of anhydrous pyridine is cooled undPr an atmosphere of dry argon to 3C, 2.17 ml of methanesulfonic acid chloride is instilled and stirred for another 2 hours at 3C. It is mixed with ice, diluted with water and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on about 200 ml of fine silica gel. A gradient system of n-hexane and ethyl acetate is used as mobile solvent.
4.93 g (10.0 mmol, 87~) of the title compound is isolated as colorless oil.
IR (Film): 3070, 3040, 2950, 2930, 2850, 1735, 1705, 1585, 1425, 1110, 820, 740 and 700 cm~1.

,: :,,', ': " ..

-: ~ . ~:
~ :. ' ; 44 ~8~
Example 15f:
7-[(lR,2S,3R~-2-(tert-Butyldiphenylsilyloxymethyl)-3-(tetrahydropyran-2-yloxy)-5-oxo-cyclopentyl]-5(E/Z)-heptenoic acid methyl ester: --11.~ g (20.0 mmol) of the compound produced according toexample 15g is reacted analogously to example lf and, after working up and purification, 9.39 g (15.8 mmol, 79%) of the title compound is isolated as colorless oil.
IR (Film): 3070, 3040, 2940, 2850, 1740, 1590, 1425, lllO, 1075, 1030, 970, 820, 740 and 700 cm~1. -Example 15q:
7-[(lR,2S,3R,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-3-(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(E/Z)-heptenoic acid methyl ester:
22.4 g (47.8 mmol) of (lS,3RS,5R,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-(tert-butyldiphenylsilyloxymethyl)-2-oxabicyclo[3~3~o]octan-3-ol is reacted analogously to example lj with use of potassium-tert-butanolate containing KOH and, after working up and esterification with an ethereal solution of diazomethane after chromatographic purification on about 1.3 1 of fine silica gel with a gradient system of n-hexane and ethyl acetate, 21.6 g (36.3 mmol, 76~o) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3070, 3040, 2940, 2850, 1730, 1595, 1425, 1110, 1075, 1025, 970, 820, 740 and 700 cm~1.

, 8~i ~9 Example 16:
7-[~4RS,5S)-4-Phenyl-5-[2-(4-fluorophenoxy)-ethoxymethyl]-cyclopent-l-enyl]-5(E/Z)-heptenoic acid:
30 mg (95 ~mol) of the compound produced according--to example 15a is reacted analogously to example 15 with use of 2-bromo-(4-fluorophenoxy)-ethane and, after working up and purification, 11 mg (25 ~mol, 26~) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3080, 3050, 3020, 2920, 2860, 1710, 1600, 1505, 1455, 1250, 1210, 11~0, 825, 755, 745 and 700 cm~1.

Example 17:
7-[(4RS,5S)-4-Phenyl-5-(3-methylbenzyloxymethyl)-cyclopent-l-enyl]-5(E/Z)-heptenoic acid:
24 mg (76 ~mol) of the compound produced according to example 15a is reacted analogously to example 15 with use of 3-methylbenzyl bromide and, af~er working up and purification, 20 mg (49 ~mol, 65%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3030, 2920, 2850, 1705, 1605, 1495, 1455, 1360, 1240, 1160, 1110, 1090, 970, 780, 755 and 700 cm~1.

Example 18:
7-[(4RS,5S)-4-Phenyl-5-(4-cyanoben2yloxymethyl)-cyclopent-l-enyl]-5(E/Z)-heptenoic acid:
25 mg (80 ~mol) of the compound produced according to example 15a is reacted analogously to example 15 with use of 4-; ~
;
.
::
,, ' ~': ~ '` ~ : ' ~ 46 ~881~g '., cyanobenzyl bromide and, after working up and purification, 12 mg(29 ~mol, 36~ of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3050, 3020, 2930, 2850, 2230, 1705, 1600, 1490, 145S, 1435, 1360, 1290, 1240, 1150, 1110, 1090, 970, 795, 760, 700 and 690 cm~1.

Example 19: ..
7-[(4RS,5S)-4-Phenyl-5-(3,5-bis-trifluoromethylbenzyloxymethyl)-cyclopent-l-enyl]-5(E/Z)-heptenoic acid:
26 mg (83 ~mol) of the compound produced according to example 15a is reacted analogously to example 15 with use of 3,5-bis(trifluoromethyl)benzyl bromide and, after working up and purification, 23 mg (44 ~mol, 53%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3080, 3060, 3030, 2930, 2860, 1710, 1625, 1600, 1495, 1455, 1380, 1355, 1280, 1175, 1135j 970, 885, 845, 755, 700 and 680 cm~l.

Example 20:
7-[(4RS,5S)-4-Phenyl-5-(1-naphthylmethoxymethyl)-cyclopent-1-enyl]-5(E/Z)-heptenoic acid:
24 mg (76 ~mol) of the compound produced according to example 15a is reacted analogously to example 15 with use of 1-bromomethylnaphthalene and, after working up and purification, 16 , :: , , ~- 47 , ~ 3~

mg (36 ~mol, 48%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3050, 3020, 2930, 2850, 1705, 1600 1455, 1280, 1235, 1165, 1100, 800, 790, 775, 760 and 700 cm~1.

Exam~le 21:
7-[(4RS,5R)-4-Phenyl-5-benzyloxymethyl-cyclopent-1-enyl]-5(Z)-heptenoic acid: ..
43 mg (137 ~mol) of the compound produced ac~ording to example 21a is reacted analogously to example 15 and, after working up and purification, 18 mg (46 ~mol, 34%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3090, 3060, 3030, 2930, 2860, 1710, 1600, 1495, 1455, 1410, 1360, 1240, 1205, llOo, 1075, 1025, 755, 740 and 700 cm~1.

Example 2la:
7-[(4RS,5R)-4-Phenyl-5-hydroxymethyl-cyclopent-1-enyl]-5(Z)-heptenoic acid:
2.27 g (4.11 mmol) of 7-[(4RS,5R)-4-phenyl-5-(tert-butyldiphenylsilyloxymethyl)-cyclopent-1-enyl~-5(Z)-heptenoic acid methyl ester, which is produced from (lR,5S,6R,7S)-3-oxo-6-(tert-butyldiphenylsilyloxymethyl)-1-benzoyloxy-2-oxabicyclo[3.3.0]octane analogously to examples 15b to 15g and lj to ln, is reacted analogously to example 15a and, after working up and purification, 1.2~ g (4.07 mmol, 99%) of the title compound is isolated as colorless oil.

~ 48 ~88~L3~
IR (Film): 3600-2400, 3060, 3030, 2920, 2850, 1710, 1605, 1455, 1405, 1240, 1110, 1070, 1030, 755, 735 and 700 cm~1.

~xample 22: ~
7-[(4RS,5R)-4-Phenyl-5-[2-(4-fluorophenoxy)-ethoxymethyl]-cyclopent-l-enyl]-5(z)-heptenoic acid:
43 mg (137 ~mol) of the compound produced according to example 21a is reacted analogously to example 15 with use of 2-bromo-(4-fluorophenoxy)-ethane and, after working up and purification, 15 mg (34 ~mol, 25%) of the title compoun~ is isolated as colorless oil.
IR (Film): 3600-2400, 30~0, 3050, 3030, 2930, 2870, 1710, 1600, 1505, 1455, 1250, 1210, 1130, 830, 760, 745 and 700 cm~1.

Example 23:
7-[(4RS,5R)-4-Phenyl-5-(3-methylbenzyloxymethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid:
43 mg (137 ~mol) of the compound produced according to example 2la is reacted analogously to example 15 with use of 3-methylbenzyl bromide and, after working up and purification, 27 mg (67 ~mol, 49~ of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3080, 3030, 2930, 2860, 1710, 1605, 1495, 1455, 1410, 1360, 1240, 1155, 1010, 985, 780, 760 and 700 ~ 49 ~881.~9 2xample 24:
7-[(4RS,5R)-4-Phenyl-5-(4-cyanobenzyloxymethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
43 mg (137 ~mol) of the compound produced according to example 21a is reacted analogously to example 15 with use of 4-cyanobenzyl bromide and, after working up and purification, 28 mg (67 ~mol, 49%) of the title compound is isolated as colorless oil~
IR (Film): 3600-2400, 3080, 3060, 3030, 2930, 2850, 2230, 1710, 1610, 1455, 1415, 1360, 1240, 1125, 1110, B20, 760 and 700 cm .

Exam~le 25:
7-[(4RS,5R)-4-Phenyl-5-(3-cyanobenzyloxymethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid: :
43 mg (137 ~mol) of the compound produced according to example 21a is reacted analogously to example 15 with use of 3-cyanobenzyl bromide and, after working up and purification, 33 mg (79 ~mol, 58%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3080, 3060, 3030, 2930, 2850, 2230, 1710, 1600, 1490, 1455, 1435, 1410, 1360, 1240, 1150, 1115, 1090, 795, 760, 700 and 690 cm1.

.
.......
:
:

3 g ~

Example 26:
7-[(4RS,SR)-4-Phenyl-5-[(3RS,4S)-3-hydroxy-4-methyl-non-l(E)-en-6-inyl]-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 206 mg (476 ~mol) of the co~pound produced according to example 26a is dissolved in 6 ml of anhydrous methanol, cooled under an atmosphere of dry argon to -40C and mixed in portions with a total of 105 mg of sodium boron hydride. It is allowed to react for another 15 minutes, QXcess reducing agent is decomposed by adding 180 ~1 of-acetic acid, mixed with water and extracted several times with dichloromethane. It is washed with water, saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 30 ml of fine silica gel with use of a gradient system of n-hexane and ethyl acetate. 175 mg (403 ~mol, 85%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3050, 3020, 2960, 2920, 2850, 1735, 1~00, 1490, 1450, 1435, 1315, 1240, 1150, 1020, 970, 755 and 700 cm'1 .

Exam~le 26a:
7-[(4RS,5R)-4-Phenyl-5-[3-oxo-4S-methyl-non-l(E)-en-6-inyl]-cyclopent-l-enyl]-5(z)-heptenoic acid methyl ester:
The solution of 205 mg of dimethyl-(2-oxo-3S-methyl-oct-S-inyl)-phosphonate in 1~13 ml of tetrahydrofuran is instilled in the suspension of 36.5 mg of sodium hydride dispersion (55%) in , , --- 51 ~ 9 1.4 ml of anhydrous tetrahydrofuran at -10C under an atmosphere of dry argon and stirred for lS minutes. The solution of 273 mg (748 ~mol) of the aldehyde, produced according to example 26b, is instilled in 1.68 ml of tetrahydrofuran and stirred for-1.5 hours at 5C. It is mixed with acetic acid and extracted several times with diethyl ether. The combined organic extracts are washed with diluted sodium bicarbonate solution, dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on about 30 ml of fine silica gel with a gradient system of n-hexane and ethyl acetate. 206 mg (476 ~mol, 64%) of the title compound is isolated as colorless oil.
IR (Film): 3060, 3030, 2970, 2930, 1730, 1690, 1665, 1625, 1490, 1450, 1430, 1360, 1170, 1040, 980, 760 and 700 cm~1.

ExamPle 26b:
7-[~4RS,5R)-4-Phenyl-5-formyl-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 348 ~l of dimethyl sulfoxide in 1.22 ml of dichloromethane is instilled in the solution, introduced under an atmosphere of dry argon at -60C, of 190 ~l of freshly distilled oxalyl chloride in 3.04 ml of anhydrous dichloromethane, allowed to react for 15 minutes and then mixed with the solution of 470 mg (1.50 mmol) of the alcohol, produced according to example 21a, in 3 ml of dichloromethane. It is allowed to react for 3 hours, mixed with 5g6 ~l of triethylamine, poured in ice water and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate. The residue ,, ;

.

-. 52 2 ~

obtained after filtration and removal of the solvent is reacted without further purifieation.

Example 27:
7-[(4RS,SR)-4-Phenyl-5-[(3RS,4S)-3-hydroxy-4-methyl-non-l(E)-en-6-inyl]-cyclopent-1-enyl]-5(Z)-heptenoic acid:
175 mg (403 ~mol) of the compound produeed according to example 26 is saponified analogously to example 2 and, after working up and purifieation, 143 mg (340 ~mol, 84%) of the title eompound is isolated as colorless oil.
IR (Film): 3600-~400, 3080, 3030, 2960, 2930, 2860, 1710, 1600, 1460, 1290, 1270, 1070, 1010, 970, 760 and 700 cm~1.

Exam~le 28:
7-[(4RS,5R)-4-Phenyl-5-[(3RS,4RS)-3-hydroxy-4-phenyl-pent-l(E)-enyl]-cyclopent-l-enyl]-5(Z) heptenoie aeid methyl ester:
279 mg (630 ~mol) of the compound produced according to example 28a is reacted analogously to example 26 and, after working up and purification, 239 mg ~537 ~mol, 85%) of the title eompound is isolated as eolorless oil.
IR (Film): 3600-3200, 3050, 3020, 2950, 2930, 2850, 1730, 1600, 1490, 1450, 1260, 1150, 1010, 970, 755, 740 and 700 cm~1.

Example 28a:
7-[(4RS,5R)-4-Phenyl-5-[(4RS)-3-oxo-4-phenyl-pent-l(E)-enyl]-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
273 mg (748 ~mol) of the compound produced according to example 26b is reacted analogously to example 26a with use of dimethyl-(2-oxo-3-phenyl-butyl)-phosphonate and, after working up and purification, 279 mg (630 ~Lmol, 84~) of the title compound is isolated as colorless oil.
IR (Film): 3060, 3020, 2950, 2930, 2850, 1730, 1710, 1690, 1615, 1490, 1450, 1260, 1160, 1070, 1025, 980, 755, 735~and 700 cm~1 ~

Exam~le 29:
7-[(4RS,5R)-4-Phenyl-5 [~3RS,4RS~-3-hydroxy-4-phenyl-pent-l(E)-enyl]-cyclopent-1-enyl]-5(Z~-heptenoic acid:
239 mg (538 ~mol) of the compound produced according to example 28 is saponified analogously to example 2 and, after working up and purification, 175 mg (406 ~mol, 76%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3080, 3060, 3030, 2960, 2930, 2860, 1710, 1670, 1600, 1500, 1~50, 1240, 980, 760 and 700 cm-1.

Exam~le 30:
7-[(4RS,5R)-4-Phenyl-5-[3(RS)-hydroxy-oct-l~E)-enyl]-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
174 mg (426 ~mol) of the compound produced according to example 30a is reacted analogously to example 26 and, after ; 54 2 ~ 8 ~
working up and purification, 173 mg (421 ~mol, 99%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3030, 2920, 2850, 1735, 1455, 1260, 1150, 1025, 970, 740 and 700 cm~1.

Exam~le 30a:
7-[(4RS,5R)-4-Phenyl-5-[3-oxo-oct-l(E)-enyl]-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
245 mg (784 ~mol) of the compound produced according to example 26b is reacted analogously to example 26a with use of dimethyl-(2-oxo-heptyl)-phosphonate and, after working up and purification, 174 mg (426 ~mol, 54%) of the title compound is isolated as colorless oil.
IR (Film): 3030, 2950, 2930, 28~0, 1735, 1690, 1670, 1620, 1450, 1430, 1365, 1240, 1160, 1025, 860, 755 and 700 cm~1.

Example 31:
7-[(4RS,5R)-4-Phenyl-5-[3(RS)-hydroxy-oct-l(E)-enyl]-cyclopent-1-enyl]-5(Z~-heptenoic acid:
173 mg (421 ~mol) of the compound produced according to example 30 is saponified ar.aloyously to example 2 and, after working up and purification, 100 mg (252 ~mol, 60%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3060, 3030, 2940, 2860, 1710, 1605, 1455, 1410, 1240, 970, 760 and 700 cm~1.

~ " 55 Example 32:

7-r (4S,5R)-4-Hydroxy-5-t(E/Z)-diphenylmethoxyiminomethyl]-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
46 mg (89 ~mol) of the compound produced according-to example 32a is mixed with 2 ml of a mixture of acetic acid, water and tetrahydrofuran (65:35:10) and stirred for 18 hours at 23C.
It is concentrated by evaporation, residual acetic acid is removed by repeated azeotropic distillation with toluene and the residue is purified by chromatography on about 10 ml of fine silica gel. 33 mg (76 ~mol, 86%~ of the title compound is isolated as colorless oil.
IR (Film): 3~00-3200, 3060, 3030, 3010, 2930, 2860, 1735, 1600, 1495, 1455, 1240, 1080, 1030, 1020, 935, 740 and 700 cm~1.

Example 32a:
7-[(lS,2R,3S,5S)-2-[(E/Z)-Diphenylmethoxyiminomethyl]-3-(tetrahydropyran-2-yloxy)-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester (A) and 7-[(5R,4S)-5-[(EJZ)-diphenylmethoxyiminomethyl]-4-(tetrahydropyran-2-yloxy)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
252 mg (471 ~mol) of the compound produced according to example 32b is reacted analogously to example 1 and, after working up and purification, 72 mg (134 ~mol, 28%) of title compound A as well as 58 mg (112 ~mol, 24%) of title compound B
are each isolated as colorless oil.
IR (Film~: 3600-3200, 30~0, 3030, 3010, 2940, 2870, 1730, 1600, 1455, 1245, 1020, 935, 870, 820, 745 and 700 cm~1.

, , ~': ~ ' ,.
:

~ 56 ~8159 Example 32b:
7-~(lS,2R,3S,5R)-2-[(E/Z)-Diphenylmethoxyiminomethyl]-3-(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The solution of 257 mg (493 ~mol) of the compound, produced according to example 32c, in 10 ml of dichloromethane is mixed with the ethereal solution of diazomethane and concentrated by evaporation after completion of the reaction. 262 mg (489 ~mol, 99%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3070, 3030, 3010, 2950, 2870, 1740~
1455, 1440, 1350, 1200, 1130, 1080, 1025, 975, 910, 870, 815, 745 and 705 cm1 Example 32c:
7-[(lS,2R,3S,5R~-2-[(E/Z)-Diphenylmethoxyiminomethyl]-3-~tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid:
569 mg (889 ~mol) of the compound produced according to example 32d is saponified analogously to example 2 and, after working up and purification, 399 mg (765 ~mol, 86%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3070, 3030, 3010, 2940, 270, 1730, 1710, 1605, 1495, 1445, 1345, 1245, 1205, 1185, 1130, 1080, 1020, 975, 920, 870, 810, 745 and 705 cm~1.

, ~xample 32d: 2~81~9 7-[(lS,2R,3S,5R)-2-[(E/Z)-Diphenylmethoxyiminomethyl]-3-(tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
The colorless solution of 300 mg (654 ~mol) of the compound, produced according to example 32e, in 16 ml of anhydrous ethanol is mixed with 120 ~1 of anhydrous pyridine, 176 mg of diphenylmethoxyamine and heated for 3.5 hours under an atmosphere of dry argon to 50C. It is concentrated by evaporation, the residue is taken up in dichloromethane, washed with wat-er and saturated sodium chloride solution and the residue obtained after drying on magnesium sulfate, filtration and concentration by evaporation is purified by chromatography on about 50 ml of silica gel with an n-hexane/ethyl acetate mixture. 268 mg (453 ~mol, 69%) of the title compound is isolated as colorless oil.
IR (Film): 3380, 3210, 3100, 3010, 2950, 2870, 1735, 1715, 1690, 1600, 1535, 1450, 1360, 1320, 1275, 1115, 1070, 1030, 970, 870, ~15, 760, 715 and 695 cm~1.

Example 32e:
7-C(lS,2R,3S,5R)-2-Formyl-3-(tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5( æ ) -heptenoic acid methyl ester:
1.2 g (2.61 mmol3 of the compound produced according to example 32f is reacted analogously to example 26b and, after working up, 1.2 g (2.61 mmol, 100%) of the title compound is isolated, which is further reacted without puri~ication.

- . : . . ~
,' ~ " " ' .

2 ~ 9 Example 32f:
7-[(lS,2R,3S,5R)-2-~ydroxymethyl-3-(tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: -2.16 mg (3.09 mmol) of the compound produced according toexample 32g is reacted analogously to example lg and, after working up and purification, 1.2 g (2.61 mmol, 85%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3060, 3000, 2940, 2860, 1735, 1710, 1600, 1585, 1450, 1355, 1310, 1270, 1110, 1070, 1025, 865, 810 and 710 cm~1.

Example 32q:
7-[(lS,2R,3S,5R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-~tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid.methyl ester:
59.4 g (99.9 mmol) of 7-[(lS,2R,3S,5R)-2-(tert-butyldiphenylsilyloxymethyl~-3-(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(z)-heptenoic acid methyl ester is reacted analogously to example lh and, after working up and purification, 62.5 g (89.4 mmol, 90%) of the title compound is isolated as colorless oil~
IR (Film): 3070, 3050, 3010, 2g50, 2860, 1740, 1715, 1600, 1585, 1450, 1425, 1275, 1110, 1025, 970, 870, 825, 790, 710, ~90, 610 and 500 cm~1.

, .

....:
., ~ .
:

~8813~
Example 33:
7-[(4S,5R)-4-Hydroxy-5-[(E/Z)-diphenylmethoxyiminomethyl~-cyclopent-l-enyl]-5(Z)-heptenoic acid:
25 mg (58 ~mol) of the compound produced according to example 32 is saponified analogously to example 2 and, after working up and purifica~ion, 19.5 mg (46 ~mol, 80%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3090, 3060, 3030, 3010, 2930, 2860, 1710, 1600, 1495, 1455, 1240, 1080, 1030, 1020, 935, 745 and 700 cm~1 ~

Example 34:
7-[(4S,5R)-4-Hydroxy-5-(3-methylbenzyloxymethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
212 mg (478 ~mol) of compound B produced according to example 34a is reacted analogously to example 32 and, after working up and purification, 92 mg (2~7 ~mol, 54%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3010, 2950, 2920, 2860, 1735, 1610, 1590, 1440, 1360, 1245, 1155, 1085, 1035, 780, 740 and 695 cm~1.

.

' ' : ' ''' : ' ' ' .
, ExamDle 34a:
7-[(lS,2R,3S,5S)-2-(3-Methylbenzyloxymethyl)-3-(tetrahydropyran-2-yloxy)-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester (A~ and 7-[(5R,4S)-5-(3-methylbenzyloxymethyl)-4-(tetrahydropyran-2-yloxy)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester (B):
800 mg (1.74 mmol) of the compound produced according to example 34b is reacted analogously to example 1 and, after working up and purification, 201 mg (436 ~mol, 25%) of title compound A as well as 212 mg (480 ~mol, 28%) of title compound B
are each isolated as colorless oil.
IR (Film): 3600-3200, 3010, 2940, 2850, 1730, 1610, 1440, 1360, 1250, 1225, 1155, 1095, 870, 815, 780, 745 and 695 cm~1.

Example 34b:
7-[(lS,2R,3S,5R)-2-(3-Methylbenzyloxymethyl)-3-(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester:
1.23 g (2.75 mmol) of the compound produced according to example 32f is reacted analogously to example 15 and, after working up and purification, 1.18 g (2.56 mmol, 93%) of the title compound is isolated as colorless oil.
I~ (Film): 3600-3300, 3010, 2940, 2860, 1740, 1610, 1595, 1440, 1355, 1250, 1200, 1155, 1115, 107S, 1020, 975, 905, 870, 815, 780, 745 and 695 cm~1.

. .
, - :

, ;' Example 35:
7-[(4S,5R)-4-Hydroxy-5-(3-methylbenzyloxymethyl)-cyclopent-1-enyl]-S(Z)-heptenoic acid:
34 mg (95 ~mol) of the compound produced according to example 34 is saponified analogously to example 2 and, after working up and purification, 17 mg (49 ~mol, 52%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3010, 2930, 2860, 1710, 1610! 1590, 1455, 1405, 1355, 1240, 1155, 1080, 780, 745 and 695 cm~1.

Example 36:
7-[5R-(3-Methylbenzyloxymethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 61 mg (115 ~mol) of the tosylate, produced according to example 36a, in 0O9 ml of dimethoxyethane is mixed with 89.5 mg of sodium iodide, 77 mg of zinc dust, 670 ~1 of water and refluxed for 3O5 hours. After the cooling, it is filtered off from undissolved residues, the filtrate is diluted with diethyl ether, mixed with water and extracted several times with diethyl ether. The combined organic extracts are washed with 10% sodium bisulfate solution, water, saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 20 ml of silica gel with a gradient system of n-hexane and ethyl acetate. 32.9 mg (91 ~mol, 79%) of the title compound is isolated as colorless oil.

.
, . ~ , . .

. .

,, . ,~

2 ~
IR (Film): 3010, 2950, 2860, 1740, 1610, 1590, 1440, 1360, 1245, 1220, 1160, 1105, 1090, 780, 745 and 695 cm~1.

Example 36a:
7-[(4S,5R)-4-Toluenesulfonyloxy-5-(3-methylbenzyloxymethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 58.3 mg (154 ~mol) of the alcohol, produced according to example 34, in 1 ml of anhydrous pyridine is mixed with 122 mg of p-toluenesulfonic acid chloride and stirred for 1.5 hours under an atmosphere of dry argon at 55C. It-is concentrated by evaporation, mixed with water and extracted several times with dichloromethane. It is washed with water and saturated sodium chloride solution and dried on magnesium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on about 20 ml of silica gel with a gradient system of n-hexane and ethyl acetate.
61 mg (115 ~mol, 74%) of the title compound is isolated as colorless oil.
IR (Film): 3010, 2950, 2860, 1735, 1600, 1440, 1360, 1190, 1175, 1095, 990, 885, 840, 815, 785, 695, and 665 cm~1.

Example 37:
7-[5R-(3-Methylbenzyloxymethyl)-cyclopent-l-enyl]-51Z)-heptenoic acid:
24 mg (67 ~mol) of the compound produced according to example 36 is saponified analogously to example 2 and, after . - : ~
:

8 r~ lJ
working up and purification, 21.6 mg (62 ~mol, 93%) of the title compound is isolated as colorless oil.
IR (Film): 3600-2400, 3010, 2930, 2860, 1710, 1610, 1590, 1455, 1435, 1360, 1240, 1160, 1105, 1090, 955, 780, 745-and 695 cm-l Example 38:

6-t(5S)-(~-Nitrophenylsulfonylaminomethyl)-cyclopent-l-enylJ-4(Z)-hexenoic acid methyl ester:
The solution of 55 mg (max. 125 ~mol) of the amine-, produced according to example 38a, in 0.4 ml of anhydrous dichloromethane is mixed with 125 ~1 of triethylamine, 38 mg of 2-nitrobenzenesulfonic acid chloride and stirred for 0.5 hours at 23C under an atmosphere of dry argon, It is poured on a semiconcentrated sodium chloride solution and extracted several times with dichloromethane. The combined organic extracts are dried on magnesium sulfate and the residue obtained after removal of the solvent is purified by chromatography on 2 analytic thin-layer slabs. A mixture of n-hexane and ethyl acetate is used as mobile solvent, trichloromethane is used as eluant. 22 mg (54 ~mol, 43%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3j: ~ = 1.6-1.75(m,lH), 2-2.24(m,6H), 2.55-2.8(m,3H), 2.97(dd,1H), 3.2-3.3(m,1H), 3.66(s,3H), 5.26(s,1H), 5.32-5.54(m,3H), 7.74(m,2H), 7.87~m,1H), 8.13(m,1H).

, . . - ~ : ,. -.
, ; `: `

J(~

Example 38a:
6-[(5S~-(Aminomethyl)-cyclopent-l~enyl]-4(Z)-hexenoic acid methyl ester:
The solution of 392 mg (1.57 mmol) of the compound, produced according to example 38b, in 13 ml of tetrahydrofuran is mixed with 495 mg of triphenylphosphine and stirred for 17 hours under an atmosphere of dry argon at 23C. Then, it is mixed with 2.5 ml of water and heated for 1 hour to 80C. It is concentrated by evaporation, taken up with dichlorom~thane, dried on magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by ~iltration on about loO
ml of coarse silica gel with a gradient system of dichloromethane, methanol and triethylamine. 621 mg ~max. 1.57 mmol) of still contaminated amine is isolated, which is further reacted without additional purification.

Example 38b:
6-[(5S)-(Azidomethyl)-cyclopent-1-enyl]-4(Z)-hexenoic acid methyl ester:
The solution of 523 mg (1.82 mmol) of the bromide, produced according to example 38c, in 39 ml of dimethylformamide is mixed with 502 mg of sodium azide and heated for 2.5 hours under an atmosphere of dry argon to 60C. It is poured in ice water, extracted several times with diethyl ether, the organic phase is dried on magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about 70 ml of fine silica gel with use of a , ~
`

, . .
,, : i ::

.

~88~

gradient system of n-hexane and ethyl acetate. 352 mg (1.57 mmol, 86%) of the title compound is isolated as colorless oil.
IR (Film): 2950, 2930, 2850, 2100, 1735, 1435, 1355, 1265 and 1160 cm~1.

Exam~le 38c:
6-[(5S)-(Bromomethyl)-cyclopent-1-enyl]-4(Z)-hexenoic acid methyl ester.
The solution of 680 mg (2.78 mmol) of compound B, produced according to example 38d, in 20 ml of acetonitrile is mixed with 1.87 ml of collidine, 4.62 g of tetrabromomethane, 3.65 g of triphenylphosphine and stirred for 7 hours at 23C under an atmosphere of dry argon. It is concentrated by evaporation and the resulting residue is purified by chromatographY on about 200 ml of fine silica gel with use of a gradient system of n-hexane and ethyl acetate. 682 mg (2.37 mmol, 85~) of the title compound is isolated as colorless oil.
IR ~Film): 2950, 2850, 1735, 1440, 1245, 1215 and 1160 cm~1 ~

Example 38d 6-[(lR,2S,5R)-2-Hydroxymethyl-5-fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester (A) and 6-[(5S)-5-hydroxy-cyclopent-1-enyl]-4(Z)-hexenoic acid methyl ester (B):
3.69 g of the substance mixture produced according to example 38e is reacted analogously to example lg and, after working up and purification, 943 mg (4.20 mmol, 40~) of title .. ~. . ~; . ~
- .
, ' . , . , ' ' . ~ ~ . -. ~ , ' ,: .

.

~8~

compound ~ as a nonpolar component as well as 758 mg (3.10 mmol, 30%) of title compound A as a polar component are each isolated as colorless oil.
IR (Film) of A: 3200-3600, 30S0, 2950, 2870, 1735,-1435, 1360, 1165, 1040, 945 and ~75 cm~1.
IR (Film) of B: 3200-3600, 3050, 2940, 2850, 1735, 1435, 1360, 1200, 1160 and 1025 cm-1.

Example 38e:
6-[(lR,2S,5R)-2-tert-Butyldiphenylsilyloxymethyl-5-fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester and 6-[(5S)-S-(tert-butyldiphenylsilyloxymethyl)-cyclopent-l-enyl]-4(z)-hexenoic acid methyl ester:
5.0 g (10.4 mmol) of the compoun~ produced according to example 38f is reacted analogously to example 1 and, after working up and purification, 3.81 g of a mixture of both title compounds is isolated as colorless oil.

Example 38f:
6-[(lR,2S,5S)-2-tert-Butyldiphenylsilyloxymethyl-5-hydroxy-cyclopentyl]-4(Z)-hexenoic acid methyl ester:
62.6 g (max. 58.3 mmol) of the compound produced according to example 38g is reacted analogously to example 32b and, after working up and purification, 26.8 g (55.7 mmol, 96%) of the title compound is isolated as colorless oil.
IR (Film): 3600-3200, 3070, 3040, 2950, 2930, 2850, 1735, 1585, 1460, 1425, 1240, 1160, 1110, 1005, 820, 740 and 700 cm~l.

~- ..
. .

. 67 L ~3 ~

Exam~le 38q:
6-[(lR~2s~5s)-2-tert-Butyldiphenylsilyloxymethyl-5-hydr cyclopentyl]-4(Z)-hexenoic acid:
23.1 g (58.3 mmol) of the compound produced according to example lk is reacted analogously to example lj with use of carboxypropyltriphenylphosphonium bromide and, after working up, 62.6 g of the title compound is isolated as crude product, which is further reacted without purification.

Example 39: ~
6-[(5S)-(2-Nitrophenylsulfonylaminomethyl)-cyclopent-1-enyl]~4(Z)-hexenoic acid:
22 mg (54 ~mol) of the compound produced according to example 38 is saponified analogously ~o example 2 and, after working up and purification, 18 mg (46 ~mol, 85%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.55-1.68(m,1H), 1.9-2.4(m,7H~, 2.5-2.8(m,3H), 2.92(m,lH), 3.19(m,lH), 5.19(dd,lH), 5.25-5.5(m,3H), 7.67(m,2H), 7.79(m,lH), 8.06(m,lH).

' ' ' .

Example 40:
6 [(5S)-t4-Fluorophenylsulfonylaminomekhyl)-cyclopent-1-enyl3-4(Z)-hexenoic acid methyl ester:
55 mg (max. 125 ~mol) of the compound produced according to example 38a is reacted analogously to example 38 with use of 4-fluorobenzenesulfonic acid chloride and, after working up and purification, 19 mg (50 ~mol, 40%) of the title compound is isolated as colorless oil.
lH-NMR (CDCl3): ~ = 1.63-1.75(m,lH), 1.95-2.4(m,7H), 2.5-2.78(m,3H), 2.88(m,1H), 3.1(m,1H), 4.79(dd,1H), 5.32-5.5(m,3H), 7.19(m,2H), 7.89(m,2H).

Example 41:
6-t(5S)-(4-Fluorophenylsulfonylaminomethyl)-cyclopent-1-enyl]-4(Z)-hexenoic acid:
19 mg (50 ~mol) of the compound produced according to example 40 is saponified analogously to example 2 and, after working up and purification, 17 mg (46 ~mol, 93%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1. 5-lo 65(m,lH), 1.87-2.4(m,7H), 2.45-2.72(m,3H), 2.8(m,lH), 3.02(m,lH~, 4.78(dd,lH), 5.3-5.44(m,3H), 7.12(m,2H), 7.8(m,2H).

.. . .
. . : .

; - ' ~ ' ` '~ ' , , .

Example 42:
6-[(5S)-(Phenylsulfonylaminomethyl~-cyclopent-1-enyl]-4(Z~-hexenoic acid methyl ester:
55 mg (max. 125 ~mol) of the compound produced according to example 38a is reacted analogously to example 38 with use of benzenesulfonic acid chloride and, after working up and purification, 19 mg (52 ~mol, 42%) of the title compound is isolated as colorless oil.
1H-MMR (CDCl3): ~ = 1.63-1.75(m,1H), 1.95_2.4(m,6H), 2.48-2.75(m,3H), 2.88(m,lH), 3.12(m,lH), 3.68(s,3H), 4.69(dd,lH), 5.32-5.5(m,3H), 7.48-7.62(m,3H), 7.88~m,2H).

Example 43:
6-[(5S)-(Phenylsulfonylaminomethyl)-cyclopent-1-enyl]-4(Z)-hexenoic acid:
19 mg (52 ~mol) of the compound produced according to example 42 is saponified analogously to example 2 and, after working up and purification, 16 mg (46 ~mol, 88~) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.52-1.64(m,lH), 1.87-2.7(m,9H), 2.8(m,1H), 3.02(m,1H), 4.72(dd,1H), 5.25-5.45(m,3H), 7.4-7.56(m,3H), 7.8(m,2H).

Example 44:
6-[(5S)-(4-Methylphenylsulfonylaminomethyl)-cyclopent-1-enyl]-4(Z)-hexenoic acid methyl ester:
55 mg (max. 125 ~mol) of tha compound produced according to example 38a is reacted analogously to example 38 with use of 4-toluenesulfonic acid chloride and, after working up and puri~ication, 20 mg (53 ~mol, 42%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.66-1.79(m,lH), 2-2.45(m,6H), 2.49-2.8(m,3H), 2.91(m,1H), 3.12(m,1H), 3.68~s,3H), 5.07(dd,1H), 5.35-5.5(m,3H), 7.6(d,1H), 7.7(dd,1H), 7.98(d,1H).

Example 45:
6-[(5S)-(4-Methylphenylsulfonylaminomethyl)-cyclopent-l-enyl]-4(Z)-hexenoic acid:
20 mg (53 ~mol) of the compound produced according to example 44 is saponified analogously to example 2 and, after working up and purification, 18 mg (50 ~mol, 93%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.5-1.63(m,lH), 1.86-2.4(m,10H), 2.45-2.7(m,3H), 2.76(m,1H), 3(m,1H), 3.67(s,3H), 4.67(dd,1H), 5.27-5.42(m,3H), 7.22(d,2H), 7.68(d,2H).

:
.

g ~

Example 46:
6-[(5S)-(3,4-Dichlorophenylsulfonylaminomethyl)-CyClopent-1-enyl]-4(Z)-hexenoic acid methyl ester:
55 mg (max. 125 ~mol) of the compound produced according to example 38a is reacted analogously to example 38 with use of 3,4-dichlorobenzenesulfonic acid chloride and, after working up and purification, 21 mg (49 ~mol, 39%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.65-1.78(m,lH), 2-2.45(m,7H), 2.48-2.82(m,3H), 2.92(m,lH), 3.12(m,lH~, 5.08(dd,lH), 5.35-5;5(m,3H), 7.6(d,lH), 7.7(dd,2H), 7.98(d,lH). --Example 47:
6-[(5S)-(3,4-Dichlorophenylsulfonylaminomethyl)-cyclopent-1-enyl] 4(Z)-hexenoic acid:
21 mg (75 ~mol) of the compound produced according to example 46 is saponified analogously to example 2 and, after working up and purification, 15 mg (36 ~mol, 48%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.5S-1.68(m,lH), 1.92-2.4(m,8H), 2.45-2.75(m,3H), 2.82(m,lH), 3.04(m,lH), 4.94(dd,lH), 5.3-5.45(m,3H), 7.53(d,1H), 7.62(dd,1H), 7.9(d,1H).

, :

72 ~ ;w ~J

Exam~le 48:
6-[(5S)-(4-Chlorophenylsulfonylaminomethyl)-cyclopent-l-enyl]-4(Z)-hexenoic acid methyl ester: -55 mg (max. 125 ~mol) of the compound produced according to example 38a is reacted analogously to example 38 with use of 4-chlorobenzenesulfoni~ acid chloride and, after working up and purification, 25 mg (63 ~mol, 50%) of the title compound is isolated as colorless oil.
lH-NMR (CDCl3): ~ = 1.62-1.74(m,lH), 1.96-2.4(m,7H), 2.5-2.77(m,3H), 2~88(m,lH), 3.08(m,lH), 3.67(s,3H), 4.8(dd,lH~, 5.35-5.5(m,3H), 7.49~d,2H), 7.82(d,2H).

Example 49:
6-[(5S)-(4-~hlorophenylsulfonylaminomethyl)-cyclopent 1-enyl]-4(Z)-hexenoic acid:
25 mg ~63 ~mol) of the compound produced according to example 48 is saponified analogously to example 2 and, after working up and purification, 18 mg (47 ~mol, 74%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.58-1.7(m,lH), 1.95-2.45(m,7H), 2.53-2.78(m,3H), 2.86(m,lH), 3.08(m,lH), 4.84(dd,lH), 5.35-5.5(m,3H), 7.49(d,2H), 7.8(d,2H).

.. ..
:

.
:

~81~

~xample ~0:

7-t(5S)-(2,4-Difluorophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
143 mg (max. 246 ~mol) of the compound produced according to example 50a is reacted analogously to example 38 with use of 2,4-difluorobenzenesulfonic acid chloride and, aft~r working up and purification, 12 mg (Z9 ~mol, 12%) of the title compound is isolated as colorless oil.
IR (Film~: 3200-3350, 3010, 29~0, 2850, 1730, 1590, 1490, 1435, 1330, 1235, 1170, 1150, 1095, 840 and 670 cm~1. ~

Example 50a:
7-[(5S)-(Aminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 765 mg (3.07 mmol) of the compound, produced according to example 50b, in 26 ml of tetrahydrofuran is mixed with 969 mg of triphenylphosphine and heated for 3.5 hours under an atmosphere of dry argon to 50C. Then, it is mixed with 3.3 ml of water and refluxed for 1 hour. It is concentrated by evaporation, taken up with dichloromethane, dried on magnesium sulfate and, after filtration and removal of the solvent, 1.79 g (max. 3~07 mmol) of the amine contaminated with triphenylphosphine and triphenylphosphinoxide is isolated, which is further reacted without purification.

' ; ' , ~ ' ~'; ' `'` `

:

' ~ 74 Example Sob:
7-t(5S)-(Azidomethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 933 mg (3.09 mmol) of the bromide, produced according to example 50c, in 67 ml of dimethylformamide is mixed with 853 mg of sodium azide and heated for 3 hours under an atmosphere of dry argon to 60C. It is poured in ice water, extracted several times with diethyl ether, the organic phase is dried on magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about Z00 ml of fine silica gel with use of a gradient system of n-hexane and ethyl acetate. 765 mg (2.90 mmol, 94%) of the title compound is isolated as colorless oil.
IR (Film): 2950, 2850, 2100, 1735, 1435, 1355, 1260, and 1160 cm~1.

Example 50c:
7-[(5S)~(Bromomethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
The solution of 941 mg (3.95 mmol) of 7-[(5S)-5-hydroxy-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester, which is produced analogously to examples 38d to 38g and lj with use of carboxybutyltriphenylphosphonium bromide, in 29 ml of acetonitrile is mixed with 2.66 ml of collidine, 6.56 g of tetrabromomethane, 5.18 g of triphenyIphosphine and stirred for 6 hours at 23C under an atmosphere of dry argon. It is concentrated by evaporation and the resulting residue is purified " - , ~ ~. . .,:
. ~ :
, : ,.
:' ~

~ 75 ~ ~

by chromatography on about 200 ml of fine silica gel with use of a gradient system of n-hexane and ethyl acetate. 933 mg (3.25 mmol, 82%) of the title compound is isolated as colorless oil. -IR (Film): 2950, 2850, 1735, 1435, 1245, 1215 and 1160 cm~1 ~

Example 51:
7-[(5S)-(2,4-Difluorophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
12 mg (30 ~mol) of the compound produced according to example 50 is saponified analogously to example 2 and, after working up and purification, 4 mg (10 ~mol, 33%) of the title compound is isolated as colorless oil.
lH-NMR (CDCl3): ~ = 1.6-1.75(m,3H), 1.95-2.4(m,8H), 2.5-208(m,3H), 2.97(m,lH), 3.13(m,lH), 5.03(dd,lH), 5.37-5.54(m,3H), 6.93-7.05(m,2H)~ 7.92(m,lH).

Example 52:
7-[(5S)-(3,4-Dimethoxyphenylsulfonylaminomethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester:
144 mg (max. 246 ~mol) of the compound produced according to example 50a is reacted analogously to example 38 with use of 3,4-dimethoxybenzenesulfonic acid chloride and, after working up and purification, 14 mg (32 ~mol, 13%) of the title compound is isolated as colorless oil.

1H-NMR (CDC13): ~ = 1.5-1.72(m,3H), 1.85-2.5(m,8H), 2.56-2.74(m,2H), 2.86(m,1H), 2.98(m,1H), 3.65(s,3H), 3.83(s,3H), : , :

,, ~ ~ 76 ~ ~3 $ ~ 1 ~3 ~
3.87(s,3H), 4.8(dd,1H), 5.28-5.45(m,3H), 6.86(d,1H), 7.29(d,1H), 7.4(dd,lH).

Example 53:
7-[(5S) (3,4-dimethoxyphenylsulfonylaminomethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid.
11 mg (34 ~mol) of the compound produced according to example 52 is saponified analogously to example 2 and, after working up and purification, 8 mg (19 ~mol, 56%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.49-1.7(m,3H), 1.87-2.48(m,8H), 2.59-2.73(m,2H), 2.85(m,lH), 2.98(m,lH), 3.85(s,3H), 3.88(s,3H), 4.8(dd,1H), 5.28-5.45(m,3H), 6.87(d,1H), 7.3(d,1H), 7.42(dd,1H).

Example 54:
7-[(5S)-(4-Fluorophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl ester:
143 mg (max. 246 ~mol) of the compound produced according to example 50a is reacted analogously to example 38 with use of 4-fluorobenzenesulfonic acid chloride and, after working up and purification, 35 mg (88 ~mol, 36%) of the title compoulld is isolated as colorless oil.
IR (Film): 3200-3400, 3010, 2940, 2850, 1730, 1590, 1490, 1435, 1330, 1235, 1175, 1150, 1090, 840 and 670 cm~1.

' .
, '3 Example 55:
7-[(5S)~(4-Fluorophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
28 mg (73 ~mol) of the compound produced according to example 54 is saponified analogously to example 2 and, after working up and purification, 14 mg (37 ~mol, 50%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.5-1.7(m,3H), 1.85-2.52(m,11H), 2.55-2.7(m,2H), 2.85(m,lH~, 3(m,lH), 5(m,lH), 5.25-5.45(m,3H), 7.12(m,2H), 7.82(m,2H).

Example 56:
7-[(5S)-~2-Nitrophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid methyl est~r:
143 mg (max. 246 ~mol) of the compound produced according to example 50a is reacted analogously to example 38 with use of 2-nitrobenzenesulfonic acid chloride and, after working up and purification, 32 mg (76 ~mol, 31~) of the title compound is isolated as colorless oil.
IR (Film): 3200-3400, 3090, 3010, 2940, 2850, 1730, 1590, 1540, 1435, 1410, 1360, 1340, 1170, 850, 780, 740, 730 and 655 cm~1 .

. 78 Example 57:
7-[(SS)-(2-Nitrophenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z)-heptenoic acid:
32 mg (76 ~mol) of the compound produced according to example 56 is saponified analogously to example 2 and, after working up and purification, 19 mg (47 ~mol, 61%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.6-1.75(m,3~), 1.95-2.4(m,7H~, 2.53-2.83(m,3H), 2.99(m,lH), 3.24(m,1~), 5.26(dd,lH), 5.33-5.55(m/3H), 7.75(m,2H), 7.87(m,lH), 8.12(m,lH).

Example 58:
7-[(5S)-(3,4-Dichlorophenylsulfonylaminomethyl)-cyclopent-l-enyl]-5(z)-heptenoic acid methyl ester:
143 mg (max. 246 ~mol) of the compound produced according to example 50a is reacted analogously to example 38 with use of 3,4-dichlorobenzenesulfonic aci-d chloride and, after working up and purification, 34 mg (76 ~mol, 31%) of the title compound is isolated as colorless oil.
IR (Film): 3200-3350, 3010, 2940, 2850, 1730, 1450, 1370, 1335, 1160, 1030, ~20 and 675 cm~1.

,, ~ .
' ' - ' '. ' ' :
:

~a~

Example 59:
7-[(5S)-(3,4-Dichlorophenylsulfonylaminomethyl)-cyclopent-1--enyl]-5(Z)-heptenoic acid:
34 mg (76 ~mol) of the compound produced according to example 58 is saponified analogously to example 2 and, after working up and purification, 19 mg (44 ~mol, 58%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.5-1.7Z(m,3H), 1.88-2.5(m,9H), 2.58-2.73~m,2H), 2.88(m,lH), 3.03(m,lH), 5.02(dd,lH), 5.27-5.45(m,3H), 7.52(d,1H), 7.63(dd,1H), 7.9(d,1H).

Example 60:
7-[(5S)-(Phenylsulfonylaminomethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester: ~
143 mg (max. 246 ~mol) of the compound produced according toexample 50a is reacted analogously to example 38 with use of benzenesulfonic acid chloride and, after working up and purification, 31 mg (85 ~mol, %) of the title compound is isolated as colorless oil.
IR (Film)- 3200-3350, 3010, 2940, 2850, 1730, 1445, 1325, 1160, 1090, 755, 720 and 690 cm~1.

Example 61:
7-[(5S)-(Phenylsulfonylaminomethyl)-cyclopent-1-enyl]-5(Z~-heptenoic acid:
31 mg (85 ~mol) of the compound produced according to example 60 is saponified analogously to example 2 and, after working up and purification, 20 mg (55 ~mol, 65%) of the title compound is isolated as colorless oil.
1H-NMR (CDCl3): ~ = 1.45-1.7(m,3H), 1.85-2.5(m,8H), 2.57-2.7(m,2H), 2.83(m,1H), 3.01(m,1H), 4.83(dd,1H), 5.26-5.45(m,3H), 7.4-7.57(m,3H), 7.8(m,2H).

' ~ ' ~' ~ , ' -: ,~ .
, .

'~ ;

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Cyclopentene derivatives of formula I, (I).

in which R1 can be , , , or COOR4, and R4 can mean hydrogen or C1-C10 alkyl, C3-C10 cycloalkyl, C7-C16 aralkyl, optionally substituted by halogen, phenyl, C1-C4 alkoxy or di-(C1-C4)-alkylamino, phenacyl or C6-C12 aryl substituted by Y
or a 5- or 6-membered heterocyclic radical with at least one N, O

or S atom, or -CONHR6 with R6 meaning hydrogen, C1-C10 alkyl, C1-C10 alkanoyl, C6-C12 arylsulfonyl or C1-C10 alkanesulfonyl, X means -(CH2)p-, -CH2-O- or -CH2-S-, Z,A, independent of one another, mean a direct bond, (Z)-CH=CH-, (E)-CH=CH or -C?C-, p means 0 to 5, n,r, independent of one another, mean 0 to 2, R2 means OR5 or R5, W means a direct bond, a -[(CH2)n-V]q group, a -(CH2)n-V-(CH2)q-V group, a free or functionally modified hydroxymethylene group or a free or functionally modified group, and the hydroxy group can be respectively in .alpha.- or .beta.-position, q means 1 or 2, D means a direct bond, a straight-chain saturated alkylene group with 1-5 C atoms, a branched saturated alkylene group or a straight-chain or branched unsaturated alkylene group with 2-5 C
atoms, which optionally can be substituted by fluorine atoms, - (CH2)n-NH-SO2-, , , , or , V means an O or S atom, E means a direct bond, -C?C- or -CH=CR7-, and R7 means hydrogen, C1-C5 alkyl, halogen or trifluoromethyl, AWDE together can be a direct bond, AW together can be a direct bond, DE together can be a direct bond, R3 means , , , , , , , , C3-C10 cycloalkyl or C1-C10 alkyl optionally substituted by Y, yl and R3 can be only if A or W mean a direct bond, m means 1 or 2, y1 and y2 are the same or different and mean Y, Y means hydrogen, halogen, N3, CF3, OR5, NO2, NH2, CN, COOR5 or C1-C10 alkyl, R5 can be hydrogen, C1-C10 alkyl, C6-C12 aryl or C7-C16 aralkyl optionally substituted by halogen and, if R4 means hydrogen, their salts with physiologically compatible bases, as well as the .alpha.-, .beta.- or .gamma.-cyclodextrin clathrates, as well as the compounds of formula 1 encapsulated with liposomes.

2. Pharmaceutical agent consisting of one or more compounds of claim 1 and usual auxiliary agents, vehicles and additives.

3. Process for the production of cyclopentene derivatives of formula I, characterized in that the hydroxy compound of formula II

(II), in which R1, R2, X and Z have the above-indicated meanings and R1 represents a -COOR4 ester group with R4 in the above-indicated meaning with the exception of hydrogen, after oxidation with oxalyl chloride/DMSO, is reacted with a dimethyl phosphonate of formula V , in which D, E and R3 have the above-mentioned meaning, in the presence of sodium hydride or sodium hydride/bromine, then it is reduced and hydrobromic acid is optionally cleaved off or, after bromation, formation of azide and reduction, the intermediate amine of formula VI

(VI) is reacted with a compound of formula Hal-SO2-R3 (VII) or O=C=N-R3 (VIII), in which Hal and R3 have the above-indicated meaning, or a compound of formula IX or X is fluorinated , (IX) (X) optionally with a compound of formula Hal-R3 (XII), in which Hal and R3 have the above-indicated meaning, C-C multiple bonds are optionally hydrogenated and the resulting esters are saponified, converted to salts, converted to cyclodextrin clathrates or encapsulated with liposomes.