IE67507B1 - Cyclopentane derivatives process for their production and their pharmaceutical use - Google Patents

Cyclopentane derivatives process for their production and their pharmaceutical use

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Publication number
IE67507B1
IE67507B1 IE265491A IE265491A IE67507B1 IE 67507 B1 IE67507 B1 IE 67507B1 IE 265491 A IE265491 A IE 265491A IE 265491 A IE265491 A IE 265491A IE 67507 B1 IE67507 B1 IE 67507B1
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μπιοί
isolated
title compound
prepared according
cyclopentyl
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IE265491A
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IE912654A1 (en
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Ulrich Dr Klar
Hartmut Dr Rehwinkel
Karl-Heinz Dr Thierauch
Peter Dr Verhallen
Helmut Prof Vorbruggen
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Schering Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The invention relates to cyclopentane derivatives of formula (I) and their salts with physiologically tolerables bases and the $g(a), $g(b) or $g(g)-cyclodextrin clathrates and the liposome-encapsulated compounds of formula (I), a process for producing them and their pharmaceutical use.

Description

The invention relates to cyclopentane derivatives, to processes for the preparation thereof and to the use thereof as auxiliaries for pharmacological investigations and as medicaments .
In recent years cyclopentane derivatives have been the subject of intensive work since prostaglandins derived from the cyclopentane system, such as, for example, PGA2, PGB2 , PGE2 e 6—oxo"PGBi, PGD2 , PGF2^, PG«j2 and their analogues, have an extremely wide variety of biological *0 actions, for example on the cardiovascular system, the central nervous system or the immune system.
It has surprisingly been found that the introduction of a fluorine atom or a hydroxy group in the 9-position (prostaglandin numbering method) of the prostane structure in combination with an extremely wide variety of structural features in the lower chain and in the 11position results in chemically and metabolically stable prostaglandin analogues which are capable of antagonising the pharmacological properties of the unstable thromboxane A2 (TXA2) or PGK2 and its stable analogues, such as, for example, U45619 or U44069, at the receptor.
The compounds of this invention are therefore valuable auxiliaries in the selective treatment of diseases that are attributable to an excess of TXA2 or PGH2.
The invention relates to cyclopentane derivatives of the formula I x.
R’ (I) in which «β or COOR5, wherein R5 may represent hydrogen or cl~c10" alkyl, C3~C10~cycloalkyl or C7-Cx6-aralkyl that are optionally substituted by halogen, phenyl, Cx~C4"alkoxy or by di-(Cx-C4)-alkylamino, Y-substituted phenacyl or Cg-CX2-aryl, or a 5- or 6-membered heterocyclic radical having at least one N, 0 or S atom, or R1 may be -CONHR7, wherein R7 represents hydrogen, Cx-Cxo-alkyl, C6-CX2arvlsulphonvl, CX"CX0-alkanoyl or Cx-CXQ-alkanesulphonvl, X may be -(Cn2)p-, -CH2-O- or -CH2-S-, Z and A, each independently of the other, may be a direct bond, (Z)-CH=CH-, (E)-CH=CH- or -C=C~, p may be from 0 to 5, R2 may be fluorine or OH, n and r, each independently of the other, may be from 0 to 2, R3 may be OR6 or R6, W may be a direct bond, a -[(CH2)V]G- group, a -(CH2)n"V~(CH2)q-V- 9r°up, a free or functionally modified hvdroxymethvlene group or a free or functionally H3C OH modified group, it being possible for the hydroxy group in each case to be in the a- or B-configuration , q may be 1 or 2, D may be a direct bond, a straight-chained saturated alkylene group having from 1 to 5 carbon atoms, a branched saturated alkylene group or a straight-chained or branched unsaturated alkylene group having from 2 to 5 carbon atoms, each of which may optionally be substituted by fluorine atoms, or D may be _ '7 —(CH^riX. „ Ο Ν I Η br ν Η Η I I a»· Ο '—\ . Y '/ -(CH2)n-NH-NH-SO2-, or /CH· V may be an 0 or S atom, E may be a direct bond, -C=c~ or -CH=CR8-, wherein R8 may be hydrogen, C^Cg-alkyl, halogen or trifluoromethyl, AWDE together may be a direct bond, AW together may be a direct bond, DE together may be a direct bond, c3=GlO-cycloalRyl' or c1-clo-alkyl that is optionally substituted by Y, . in may be 1 or 2, Y^ and Y2 are identical or different and represent Y, '4 5 Y may be hydrogen, halogen, N3, CF3, OR6, NO2, NH2, CN, COOR6 or C1-C10~alkyl, and R6 may be hydrogen, C^-C^Q-alkyl, optionally halosubstituted Cg-C12-aryl or Cy-C^g-aralkvl, and, when R6 represents hydrogen, the salts thereof with physiologically tolerable bases, as well as the c?-, B- or y-cyclodextrin clathrates, as well as the compounds of formula I encapsulated with liposomes.
The definition 5- or 6-membered heterocyclic radical relates to heterocycles which contain at least one hetero atom, preferably nitrogen, oxygen or sulphur, and are mono- or bi-cyclic. Examples that may be mentioned are: 2-furvl, 3-furyl, 2-thienyl, 3-thienvl, 2-pyridyl, 3pyridyl, 4"-pyridyl, quinolyl and isoquinolyl.
As alkyl groups R4 , R5, R6, E and Y there come into consideration straight-chained or branched alkyl groups having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl.
The alkyl groups R4, R5, R6, E and Y may be substituted by halogen atoms, hydroxy groups, c^-C^-alkoxy groups, Cg-Ci2-aryl groups, which may be substituted by halogen, di-iC^-C^-alkylamines and tri-(C^-C^)-alkylammonium. Preference is given to those alkyl groups which are mono30 substituted.
Substituents that may be mentioned by wav of example are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy and ethoxy.
Preferred alkyl groups R4, R^, rs , e and Y are those having from 1 to 5 carbon atoms, such as, for example, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, tertbutyl, chloroethyl, 1- and 2-chloropropvl, hydroxyethyl and 1- and 2-hydroxypropyl.
Aryl groups R5 and R® that come into consideration are, for example: phenyl, diphenyl, ί-naphthyl and 2-naphthvl which may be substituted by from 1 to 3 halogen atoms, a phenyl group, from 1 to 3 alkyl groups each having from 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, carboxyl, C^-C^-alkoxy or hydroxy group. Substitution in the 3- and 4-positions on the phenyl ring is preferred, for example by fluorine, chlorine, Cj-C^-alkoxy or trifluoromethyl or, in the 4-position, by hydroxy.
The cycloalkyl groups R5 may contain from 3 to 10, preferably from 3 to 6, carbon atoms in the ring. The rings may be substituted by alkyl groups having from 1 to 4 carbon atoms. There may be mentioned by way of example cyclopropyl, cyclobutyl, cyclopentyl, cvclohexyl, methylcyclopentyl and methylcyclohexvl.
The Cji-C^Q-alkvl groups mentioned under the definitions are to be straight-chained or branched alkyl groups, as have already been mentioned for the above alkyl groups.
The hydroxy groups in R2, R3, Y and w can be functionally modified, for example by etherification or esterification, it being possible for the free or modified hydroxy group in R2 and W to be in the a- or β-configuration, with free hydroxy groups being preferred.
As ether and acyl radicals there come into consideration the radicals known to the person skilled in the art.
Readily removable ether radicals are preferred, such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and tribenzylsilyl radical. Acyl radicals that come into consideration are, for example, acetyl, propionyl, butyryl and benzoyl.
Halogen in the definitions of R5, R6, E and Y is fluorine, chlorine, bromine and iodine.
The radicals C1-C10"alkanoyl,s and ’’C^-CiQ-alkanesulphonyl" for R7 correspond to the alkyl groups of the same length already mentioned except that they are bonded to a carboxyl group and sulphonyl group, respectively. C1-C4-alkanoyl and C1-C4~alkanesulphonyl, respectively, are preferred.
For salt formation with the free acids (R^ = H) there are suitable inorganic and organic bases, as are known to the person skilled in the art for the formation of physiologically tolerable salts. There may be mentioned by way of example: alkali metal hydroxides, such as sodium or potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)methylamine etc. .
Preference is given to the compounds of the formula I Ί ·wherein R1 is a group COOR5 or CONHR7, R3 is hydrogen, hydroxy, optionally halo-substituted C1-C4-alkyl, C6-C12-aryl or C7~C16-aralkyl, R5 is hydrogen or optionally halo-substituted C7-C16- >· aralkyl, Cg-Cgcycloalkyl or Cj-CjQ-alkyl, R7 is C1-C7-alkanovl, C5-C12-arvlsulphonyl or Cy-C-jalkanesulphonvl, p is from 0 to 4 n and r, each independently of the other, are 0 or 1.
Special preference is given to the compounds of the formula T wherein R1 is the group COOR5, R3 is hydrogen, hydroxy, phenyl or phenylethvl, R5 is hydrogen or methyl, R7 is methanesulphonyl, p is from 0 to 4, n and r, each independently of the other, are 0 or 1.
The compounds of formula I according to the Application can be prepared as described in greater detail below,: A« wherein R1, R2, R3, Rz-, X and Z have the meanings given above, Hal is bromine or chlorine, A, DE are direct, bonds, R1 is a -COOR5 ester.
B. wherein R^, R3, R4, A, Ε, X and Z above, D is optionally alkyl-substituted have the meanings given alkylene, or ^CH-Z , / R1 is a -COOR5 ester, R' is hydrogen or bromine, W is -CH(OH)-. - 9 II -C. e) Ha!-SO2-R4 (IX) or O=C=N’R4 (XII) g) (I) (VUI) wherein R2, R3 , R4, X, Z and Hal have the meanings given above, AW,e are direct bonds, D 1s'(CH2)0-nAn^ ,-(CHJo-NH-SO,-, Η H R1 is a -COOR5 ester.
D.
H2N-O-R4 (X) or H2M-NH-SO2-R4 (ΧΙΠ) or ι i Η Η (XI) (I) h) IV wherein R2, R3, R4, X and Z have the meanings given above, AW,E are direct bonds, R1 is a -COOR5 ester, D is V.,o "(CH^ O.
N I H H rN N. Η H 'ι Η H wherein R2, R3, R4, X, Z and Hal have the meanings given above, AW,E are direct bonds, O d is -(csy X 1 'N N Η H -(CH^-NH-SOr R1 is a -COOR5 ester.
The compounds of the formula I can be prepared according to claim 3 in accordance with the alternative processes described above. The starting compounds of the formula II are prepared in accordance with the instructions given in Examples lg-ln, 24a-24g and 34a-34b.
The reaction conditions of the subsequent process steps are as follows: a) II —I (Process A) In the presence of aqueous alkali or alkaline earth metal solutions and using phase transfer catalysts (such as, for example, tetrabutylammonium hydrogen phosphate or sulphate), compounds of the formula II are reacted at from 20 to 100’C for from 1 to 16 hours with the reactant III as an organic phase or a solution of III in an inert water-immiscible organic solvent, optionally, as described in Example 1, a fluorine atom is introduced for R2, or a hydroxy group is removed, as described in Example 74 and 74a. b) II — iv (Process B) The oxidation of compounds of the formula II is effected 20 according to known processes, such as, for example, in accordance with Swern or Collins or using pyridinium dichromate or chlorochromate, in solvents such as dichloromethane, diethyl ether, tetrahydrofuran, benzene or toluene at from -80C to -50°C (swern) or up to 4-30°C (for the other oxidations) in the course of from 10 minutes to 8 hours. c) IV—5»vi (process B), d) VI—-I (Process B) The reaction of the compounds IV with the phosphonates V and th® subsequent reduction or HBr elimination are carried out analogously to the conditions mentioned in - 12 DE-OS 28 45 770. e) II—-VII (Process C) The oxidation of the compounds of the formula II is preferably carried out with Jones reagent or pyridinium chlorochromate in accordance with the reaction conditions known to the person skilled in the art. Reaction is then carried out with thionyl chloride under the customary conditions to form the acid chloride, followed by reaction with phase transfer catalysis with aqueous sodium azide solution and rearrangement as described in Example lc to form compounds of the formula VIII, and optionally a C-C multiple bond in Z is hydrogenated or a fluorine atom is introduced as described in Example l. f) VII—VIII (Process C) The reaction of the compounds of the formula VII to form compounds of the formula VIII is effected as described in Example lc. g) VIII—-I (Process C) The reaction of the compounds of the formula VIII with the compounds of the formula IX or XII is carried out as in Examples lb and 78 which are mentioned therefor. h) IV—I (Process D) The reaction is carried out analogously to the process described in wo 90/02740 (Process C, p. 16) . i) II— XIV (Process E) 25 The reaction of the compounds of the formula II to form compounds of the formula XIV is carried out as described in Examples 78a to 78c., k) XIV—I (Process E) The reaction of the compounds of formula XIV with the compounds of the formula IX or XII is carried out as described in Examples lb and 78.
The freeing of the functionally modified hydroxy groups R2, R3, R4 and W is effected in accordance with the methods known to the person skilled in the art. For example, the removal of ether protecting groups is carried out in an aqueous solution of an organic acid, such as, for example, acetic acid, propionic acid, citric acid, etc., or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid, or, in the case of tetrahydropyranyl ethers, using pyridinium ptoluenesulphonate, preferably in alcohols as solvent or using anhydrous magnesium bromide, preferably in diethyl ether as solvent.
In order to improve solubility when aqueous-acidic reaction conditions are used it is advantageous to add a water-miscible inert solvent. Suitable inert solvents are, for example, alcohols, such as methanol and ethanol, ethers, such as dimethoxyethane, dioxane and tetrahydrofuran ; tetrahvdrofuran is preferably used, The removal of the silyl ether protecting groups is carried out, for example, with tetrabutylammonium fluoride in accordance with the methods known to the person skilled in the art. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc.. The removal is preferably carried out at temperatures of from 20‘C to 80*C.
The hydrolysis of acyl groups and esters in COOR5 of the cyclopentane derivatives is carried out in accordance with the methods known to the person skilled in the art, such as, for example, with basic catalysts, such as, for example, alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. Alcohols that come into consideration are aliphatic alcohols, such as, for example, methanol, ethanol, butanol etc., but preferably methanol. Alkali metal carbonates and hydroxides that may be mentioned are lithium, sodium and potassium salts. The lithium and potassium salts are preferred. Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is carried out generally at from -10’C to +70’c, but preferably at +25°C.
The introduction of the ester group CO2R5 for R1 or CO2R6 for Y in which R5 or R6 is an alkyl group having from 1 to 10 carbon atoms is carried out in accordance with the methods known to the person skilled in the art. The 0 carboxy compounds (R5 = H or R6 = H) are reacted, for example, with diazohydrocarbons in a manner known per se. The esterification with diazohydrocarbons is carried out, for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound dissolved in the same or in a different, likewise inert, solvent, such as, for example, methylene chloride. When the reaction is complete in 1 to 60 minutes, the solvent is removed and the ester is purified in customary manner. Diasoalkanes are either known or can be prepared in accordance with known methods [Org. Reactions Vol. 8, pages 389-394 (1954)].
The introduction of the ester group CO2R5 for R1 or CO2RS for Y in which R5 or R6 is a substituted or unsubstituted aryl group is carried out according to methods known to the person skilled in the art. For example, the 1-carboxy compounds are reacted with the corresponding arylhydroxv compounds with dicyclohexylcarbodiimide in the presence of a suitable base, such as, for example, pyridine, DMAP or triethylamine, in an inert solvent, such as, for example, methylene chloride, ethylene chloride, chloroform, ethyl acetate and tetrahydrofuran, hut preferably chloroform. The reaction is carried out at temperatures of from -30 C to +-50°C, preferably at +-10°C.
The cyclopentane derivatives of the formula I wherein R5 or R6 is a hydrogen atom can be converted into salts with neutralisation with suitable amounts of the corresponding inorganic bases. For example, the solid inorganic salt is obtained by dissolving the corresponding acids in water that contains stoichiometric amounts of the base, and then evaporating the water or adding a water-miscible solvent, for example alcohol or acetone.
' The preparation of the amine salts takes place in the customary manner. For this purpose, the acid is dissolved in a suitable solvent, such as, for example, ethanol, acetone, diethyl ether or benzene, and from 1 to 5 equivalents of the respective amine is added to that solution. In this case, the salt is usually precipitated in solid form or is isolated in customary manner after evaporation of the solvent.
The functional modification of the free hydroxy groups is carried out according to the methods known to the person skilled in the art. The ether protecting groups are introduced, for example, with dihydropyran or methyl vinyl ether in methylene chloride or chloroform using catalytic amounts of an acidic condensation agent, such as, for example, p-toluenesulphonic acid. The respective enol ether is added in excess, preferably in 1.2 to 10 times the amount theoretically required. The reaction takes place normally at -10 ’C to +30 C and is complete after 2 to 45 minutes.
For the introduction of silyl ether protecting groups, reaction is carried out, for example, with tert-butvli0 diphenylchlorosilane or tert-butyldimethylchlorosilane in dimethylformamide using a base, such as, for example, imidazole. The silyl chloride in question is added in excess, preferably in an amount from 1.05 to 4 times the amount theoretically required. The reaction is carried 15 out normally at from 0°C to 30°C and is complete after from 1 to 24 hours.
The acyl protecting groups are introduced by reacting a compound of the formula I in a manner known per se with a carboxylic acid derivative, such as, for example, an acid chloride, acid anhydride, etc..
Cvclodextrin clathrates are obtained analogously to the procedure in WO 87/05294.
Liposomes are prepared in accordance with the preparation process described in i3Pharmazie in unserer Zeit" ll 98 (1982).
The invention relates also to all stereoisomeric forms.
Biological action and-field of use_o.;c _che novel TXA2 antagonists: The compounds of this invention are suitable for the treatment of diseases of the cardiovascular system, the stomach, the pancreas, the liver and the kidneys. They have a blood pressure-reducing and bronchodilatatory action. They are excellently suitable for the inhibition of thrombocyte activation, as a result, the new TXA2 antagonists of the formula I represent valuable pharma'0 ceutical active ingredients. Furthermore, the compounds are distinguished by a higher selectivity, a considerably longer duration of action and greater stability in comparison with similar TXA2 antagonists.
The new TXA2 antagonists have properties typical of this 15 class of compound, such as, for example, reduction of the peripheral arterial, the coronary and the pulmonary vascular resistance, lowering of the pulmonary blood pressure, lowering of the systemic blood pressure without at the same time reducing cardiac output and coronary 20 blood flow, promotion of renal blood flow and the blood flow in other peripheral organs, increasing of the cerebral blood flow, inhibition of thrombocyte activation and dissolution of thrombi, inhibition of bronchoconstriction, inhibition of gastric acid secretion, 25 cytoprotection of the heart, of the gastric and intestinal mucosa, of the liver, cytoprotection in the pancreas and in the kidneys, and also anti-allergic properties.
The novel TXA2 antagonists are therefore suitable in principle for the treatment of stroke, the prophylaxis 30 and treatment of coronary heart diseases, for example coronary thrombosis, for the treatment of myocardial infarction, peripheral arterial diseases, for prophylaxis and treatment in other thromboembolic disorders and in arteriosclerosis, in CNS ischaemic attacks and other circulatory disorders of the brain, such as, for example, migraine, for the treatment of hypertonia and for the treatment of diseases associated with an increase in the pulmonary vascular resistance, such as, for example, pulmonary hypertonia and in the treatment of shock, of asthma and allergic rhinitis. They can also be used for inhibiting labour pains and for the treatment of toxaemia of pregnancy.
The new TXA2 antagonists can also be used for improving organ function after transplantation, for example in the case of kidney transplantation, for preventing rejection reactions, in place of heparin or as an adjuvant in dialysis or haemofiltration, and in the preservation of blood plasma reserves, for example blood platelet reserves.
The new TXA2 antagonists have an antimetastatic action and antiproliferative properties. They are suitable in principle for the treatment of neoplasias. The novel TXA2 antagonists can be used in combination, for example with carbocyclines, prostacvcline and its analogues, 7-oxoprostacvclines, prostaglandins and derivatives thereof and 6-oxo-PGEi and 6"Oxo=9"fluoro-prostaglandin derivatives, with TXA2-synthetase inhibitors, with phosphodiesterase inhibitors, with antagonists and receptor antagonists of various thrombocyte stimulators (for example ADP, thrombin, collagen, PAF, adrenaline, serotonin, fibrinogen), with calcium antagonists, with fibrinolytics and thrombolytics, for example t-PA, streptokinase, with heparin and other anticoagulants, with cyclooxygenase inhibitors, for example acetylsalicylic acid, with inhibitors of lipoxygenases and antagonists of lipoxygenase products, with vasodilatators such as, for example, nitro compounds, with antihypertensives such as, for example, β-blockers, or with diuretics.
The dose of the compounds is from 0.1 to 1000 mg/day, preferably from 0.1 to 500 mg/day, also in several partial doses, when administered to human patients. The unit dose for the pharmaceutically acceptable carrier is from 0.1 to 100 mg. For parenteral administration sterile, injectable aqueous or oily solutions are used. For oral administration there are suitable, for example, tablets, dragees or capsules.
The invention therefore relates also to medicaments based on the compounds of the general formula I and customary excipients and carriers.
The active ingredients according to the invention are intended for use in conjunction with the excipients known and customary in galenics, for example for the manufacture of blood-pressure reducing drugs.
The unit dose range for an ampoule is from 0.1 to 100 mg, and for a tablet from 0.1 to 100 mg.
Example 1: 7-[ (IR,2S,5R)-2=(4-toluenesulphonylamino)-5-fluorocyclopentyl]-5(Z)-heptenoic acid methyl ester: 55 mg (139 pmol) of the alcohol prepared according to Example la are dissolved in 2.5 ml of anhydrous toluene; 56 μΐ of anhydrous pyridine are added and the mixture is cooled to -60 C under an atmosphere of dry argon and μΐ of diethylaminosulphur trifluoride are added. The mixture is allowed to rise to 0°C in the course of 3.5 hours, quenched by the addition of 1 ml of a saturated sodium hydrogen carbonate solution, diluted with water and extracted repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on four analytical thin-layer plates. A mixture of n-hexane and acetone is • 0 used as mobile solvent, and diethyl ether is used as eluting agent. 20 mg (53 gmol, 38 %) of 7-[5 (S)-(4toluenesulphonylamino)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester and 16 mg (40 gmol, 29 %) of the title compound are isolated, each in the form of a colourless 1 5 oil.
IR (KBr): 3430, 3310, 3050, 3020, 2940, 2860, 1735, 1600, 1450, 1320, 1240, 1160, 1095, 920, 815, 670, 580 and 550 cm'1.
Example la: 7- [(IR,2S,5S)-2-(4-toluenesulphonylamino)-5-hydroxycyclopentyl]-5(Z)-heptenoic acid methyl ester: mg of finely pulverised potassium carbonate are added to a solution of 140 mg (280 p.mol) of the compound prepared according to Example lb in 1.5 ml of methanol and the mixture is heated at 70°C for 1 hour. After cooling, the mixture is acidified with saturated citric acid, diluted with water and extracted repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on two analytical thin-layer plates. A mixture of n-hexane and ethyl acetate is used as mobile solvent, and diethyl ether is used as eluting agent. 96 mg (243 /imol, 87 %) oi the title compound are isolated in the form of a colour21 less 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- [(IR,2S,5S)-2-(4-toluenesulphonylamino)-5-benzoyloxycyclopentvl]-5(Z)-heptenoic acid methyl ester: 1.52 ml of triethylamine and 483 mg of p-toluenesulphonic acid chloride are added to a solution of 340 mg (984 gmol) of the amine prepared according to Example lc in 30 ml of anhydrous dichloromethane and the mixture is stirred at 23°C under an atmosphere of dry argon for 1.5 hours. The mixture is poured into a semi-concentrated sodium chloride solution and extracted repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on approximately 70 ml of fine silica gel using a gradient system of n-hexane and ethyl acetate. 330 mg (660 gmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 2940, 2870, 1730, 1710, 1600, 1450, 1330, 1270, 1160, 1110, 1090, 1025, 905, 815, 710 and 665 cm‘T Example lc: 7- [ (IR, 2S, 5S)-2-amino-5-benzoyloxy-cyclopentyl) -5(Z)heptenoic acid methyl ester (Ά) and 7- [(IR,2S,5S)-2-trifluoroacetamido-5-benzoyloxycyclopentyl]-5(Z)-heptenoic acid methyl ester (B): 1.47 ml of trifluoroacetic acid are added to the solution obtained according to Example Id and the mixture is heated at reflux for 6 hours. The mixture is allowed to stand at 23°C for 14 hours, then concentrated and the residue is purified by chromatography on approximately 250 ml of fine silica gel using a gradient system of diehloromethane and methanol. 2.0 g (5.79 mmol, 43 % based on starting material in Example le) of title compound A and 1.53 g (3.47 mmol, 26 % based on starting material in Example le) of title compound B are isolated. IR (CHC13) of A: 3500-2600, 2950, 2870, 1710, 1670, 1450, 1275, 1190, 1140 and 835 cm'1.
IR (film) of B: 3320, 2950, 2870, 1740-1690, 1600, 1550, 1450, 1435, 1270, 1210, 1180, 1110, 1070, 1025 and 710 cm-1.
Example Id: 7- { (IR, 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 diehloromethane and the solution is cooled to 3°C; 10 mg of tetrabutylammonium hydrogen sulphate and a solution of 1.04 g of sodium azide in 3.5 ml of water are added. The mixture is stirred for 2.5 hours, then diluted with diehloromethane, and the organic phase is separated off and dried over freshly calcined magnesium sulphate. The solution obtained after filtration is further reacted immediately.
Example le: - [ (1R,2S,5S) -2-chlorocarbonyl-5-benzoyloxy-cyclopentyl] 5(Z)-heptenoic acid methyl ester: 2.13 ml of freshly distilled thionyl chloride are added to a solution of 5.0 g (13.4 mmol) of the compound prepared according to Example lf in 133 ml of anhydrous diehloromethane while cooling with ice and the mixture is stirred at 23°C under an atmosphere of dry argon for hours. The mixture is concentrated and the resulting residue is reacted further without being purified.
Example lf: 7-[(IR,2S,5S)-2-hydroxycarbonyl-5-benzoyloxy-cyclo5 pentyl]-5(Z)-heptenoic acid methyl ester: A solution of 30.2 g (83.9 mmol) of the alcohol prepared according to Example lg in 725 ml of acetone is cooled to -15°C; 44 ml of a standard chromosulphuric acid solution (Jones reagent) are added and the mixture is stirred at -10°C for 3 hours and excess oxidising agent is decomposed by the addition of 13 ml of isopropanol. The mixture is diluted with water, extracted repeatedly with diethyl ether, and the combined organic extracts are washed with water and saturated sodium chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 1 litre of coarse silica gel using a gradient system of n-hexane and ethyl acetate. 29.3 g (78.3 mmol, 93 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2500, 3060, 2950, 2860, 1740-1690, 1600, 1580, 1450, 1435, 1360, 1310, 1270, 1170, 1110, 1070, 1025 and 710 cm'·'·.
Example lg: 7- [ (IR, 2S , 5S) -2-hydroxymethyl- 5-benzoyloxy-cyclopentyl] 5(Z)-heptenoic acid methyl ester: 155 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 57.9 g (96.7 mmol) of the compound prepared according to 30 Example Ih in 124 ml of anhydrous tetrahydrofuran and the mixture is stirred at 23°C under an atmosphere of dry argon for 17 hours. Water is added and extraction is carried out repeatedly with diethyl ether; the combined organic extracts are washed with water and saturated sodium chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of coarse silica gel using a gradient system of n-hexane and ethyl acetate. 30.2 g (83.8 mmol, 87 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3060, 2940, 2860, 1735, 1710, 1600, 1580, 1360, 1310, 1275, 1170, 1110, 1070, 1025 and 715 cm1.
Example lh: 7-[(IR,2S,5S)-2-(tert-butyldiphenylsilyloxymethyl)-55 benzoyloxy-cyclopentyl]- 5(Z)-heptenoic acid methyl ester: A solution of 47.9 g (96.7 mmol) of the compound prepared according to Example li in 212 ml of anhydrous pyridine is cooled to 5°C under an atmosphere of dry argon; 29 ml of benzoyl chloride are added in the course of 30 minutes 20 and the mixture is stirred at 23°C for 1.5 hours. The mixture is poured into 600 ml of ice-water and extraction is carried out repeatedly with diethyl ether, and the combined organic extracts are washed with 2N hydrochloric acid, water and saturated sodium chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of fine silica gel using a gradient system of n-hexane and ethyl acetate. 57.9 g (96.7 mmol, 100 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3040, 3000, 2950, 2930, 2850, 1735, 1710, 1600, 1450, 1425, 1360, 1310, 1270, 1110, 820, 740 and 705 cm-1.
Example li: 7-[(IR, 2S, 5S)-2-(tert-butyldiphenylsilyloxymethyl)-5hydroxy-cyclopentyl]-5 (Z)-heptenoic acid methyl ester: 33.4 g of potassium carbonate and 41.2 g of methyl iodide are added to a solution of 154 g of the crude product prepared according to Example lj in 150 ml of acetone and the mixture is heated at 80°C for 6 hours. The mixture is concentrated, taken up in 400 ml of dichloromethane, washed with water and saturated sodium ’θ chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of coarse silica gel using a gradient system of n-hexane and ethyl acetate. 47.9 g (96.8 mmol, 88 % based 15 on starting material in Example lj) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 3040, 3000, 2940, 2920, 2850, 1735, 1585, 1460, 1425, 1240, 1165, 1110, 1005, 820, 740 and 700 cm-1.
Example l~i : - [ (IR, 2S, 5S) - 2- (tert -buty ldiphenyl si lyloxyme thyl) -5hydroxy-cyclopentyl]-5(Z)-heptenoic acid: A total of 50 g of finely pulverised potassium tertbutanolate is added in portions in the course of one hour to an emulsion of 99.7 g of carboxybutyltriphenylphosphonium bromide in 256 ml of anhydrous tetrahydrofuran and 600 ml of anhydrous dimethyl sulphoxide. The mixture is stirred until a clear red solution is formed, then a solution of 43.8 g (110 mmol) of the compound 0 prepared according to Example lk in 130 ml of anhydrous tetrahydrofuran is quickly added dropwise and the mixture is allowed to react for 2 hours at 23°C under an atmosphere of dry argon. The mixture is poured into ice26 water and the pH value is adjusted to 4-5 by the addition of a saturated citric acid solution and extraction is carried out repeatedly with dichloromethane, followed by washing with water and saturated sodium chloride solu5 tion, drying over magnesium sulphate, filtration and concentration. The resulting residue is reacted further without being purified.
Example lk: (IS,3RS,5R,6S)-3-hydroxy-6-(tert-butyldiphenylsilyloxy10 methyl)-2-oxabicyclo[3.3.0]octane : A solution of 45.8 g (116 mmol) of the compound prepared according to Example 11 in 1.4 litres of anhydrous toluene is cooled to -70°C under an atmosphere of dry argon; 202 ml of a 1.2M diisobutylaluminium hydride solution in toluene are added dropwise in the course of one hour and the mixture is stirred for 1 hour. Excess reducing agent is decomposed by the addition of 13 ml of isopropanol. The temperature is allowed to rise to 0°C; 100 ml of water are added dropwise and the mixture is stirred at 23°C until a fine-grained precipitate is formed. The precipitate is filtered off with suction, followed by washing with dichloromethane and, after removal of the solvent, 43.8 g (110 mmol, 95 %) of the title compound are isolated in the form of a colourless 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: (IS,5R,6S) -3-oxo-6- (tert-butyldiphenylsilyloxymethyl) -2oxabicyclo[3.3.0]octane : 136 g of sodium iodide, 118 g of zinc powder and 79 ml of water are added to a solution of 67 g (119 mmol) of the tosylate prepared according to Example lm in 1.3 litres of dimethoxyethane and the mixture is heated at reflux for 16 hours. After cooling, undissolved residues are filtered off and the filtrate is concentrated to approximately 200 ml; water is added and extraction is carried out repeatedly with diethyl ether. The combined organic extracts are washed with 10 % sodium hydrogen sulphate solution, water and saturated sodium chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of coarse silica gel using a gradient system of n-hexane and ethyl acetate. 45.8 g (116 mmol, 98 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3050, 2950, 2930, 2850, 1775, 1590, 1470, 1425, 1165, 1110, 1005, 820, 740 and 705 cm'1.
Example lm: (IS,5R,6S,7R)-3-OXO-6-(tert-butyldiphenylsilyloxy20 methyl)-7-toluenesulphonyloxy-2-oxabicyclo[3.3.0]octane : 62.8 g of p-toluenesulphonic acid chloride are added to a solution of 67.3 g (164 mmol) of the alcohol prepared according to Example In in 260 ml of anhydrous pyridine and the mixture is stirred at 50°C under an atmosphere of dry argon for 27 hours. The mixture is concentrated; water is added and extraction is carried out repeatedly with dichloromethane, followed by washing with water and saturated sodium chloride solution and drying over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of coarse silica gel using a gradient system of n-hexane and ethyl acetate. 67 g (119 mmol, 72 %) of the title compound are isolated in the form of a colourless oil.
IR (CHC13): 3070, 3030, 2960, 2930, 2860, 1770, 1600, 1470, 1425, 1365, 1190, 1175, 1110, 1040, 980, 960, 895, 875, 820 and 700 cm_l.
Example In: (IS, 5R, 6S, 7R) -3-OXO-6- (tert-butyldiphenylsilyloxymethyl) -7-hydroxy-2-oxabicyclo [3.3.0] octane : 14.9 g of potassium carbonate are added to a solution of 129 g (251 mmol) of (IS,5R,6S,7R)-3-oxo-6-(tert-butyldiphenylsilyloxymethyl) -7-benzoyloxy-2-oxabicyclo10 [3.3.0] octane in 1 litre of methanol and the mixture is stirred at 23°C under an atmosphere of dry argon for 3 hours. Water is added and the mixture is neutralised by the careful addition of 2N hydrochloric acid, concentrated and extracted repeatedly with diehloromethane, followed by washing with water and saturated sodium chloride solution and drying over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 2 litres of fine silica gel using a gradient system of n-hexane and ethyl acetate. 97 g (236 mmol, 94 %) of the title compound are isolated in the form of a colourless 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 : - [ (1R,2S,5R) - 2- (4 -toluenesulphonylamino) -5-f luoro-cyclopentyl]-5(Z)-heptenoic acid: 0.5 ml of a 5 % lithium hydroxide solution is added to a 0 solution of 16 mg (44 /zmol) of the compound prepared according to Example 1 in 1 ml of methanol and the mixture is stirred at 23°C for 1.5 hours. The mixture is acidified by the addition of saturated citric acid, diluted with water and extracted repeatedly with dichloromethane, followed by washing with water and saturated sodium chloride solution and drying over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on an analytical thin-laver plate. A mixture of dichloromethane and methanol is used as mobile solvent and a mixture of chloroform and isopropanol is used as eluting agent. 15.7 mg (41 μπιοί, 93 %) of the title compound are isolated in the form of a colourless solid.
IR (KBr): 3600-2400, 3430, 3310, 3050, 3020, 2950, 2930, 2860, 1715, 1600, 1450, 1320, 1240, 1160, 1095, 920, 815, 670, 580 and 550 cm-1.
I 5 Example 3: 7-[(1R,2S,5R)-2-(benzenesulphonylamino)-5-fluoro-cyclopentyl] -5 (Z) -heptenoic acid methyl ester: mg (210 μπιοί) of the compound prepared according to Example 3a are reacted analogously to Example 1, and after working-up and purification 23 mg (63 μπιοί, 30 %) of 7-[5(S)-(benzenesulphonylamino)-cyclopent-l-enyl] 5 (Z)-heptenoic acid methyl ester and 26 mg (68 μιηοΐ, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3430, 3310, 3040, 3020, 2950, 2860, 1730, 1600, 1450, 1320, 1240, 1160, 1095, 930, 755, 720 and 690 cm-1.
Example 3a: 7-[(1R,2S,5S)-2-benzenesulphonylamino-5-hydroxy-cyclo30 pentyl]-5(Z)-heptenoic acid methyl ester: 270 mg (556 grnol) of the compound prepared according to Example 3b are reacted analogously to Example la, and after working-up and purification 212 mg (556 μπιοί, 100 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3260, 3060, 2930, 2850, 1725, 1445, 1320, 1265, 1160, 1090, 1020 and 735 cm1.
Example 3b: 7-[(IR,2S,5S)-2-benzenesulphonylamino-5-benzoyloxy-cyclopentyl] -5 (Z) -heptenoic acid methyl ester: 250 mg (724 μπιοί) of the compound prepared according to Example Ic are reacted analogously to Example lb with benzenesulphonic acid chloride, and after working-up and purification 270 mg (556 μπιοί, 77 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 3060, 3000, 2950, 2860, 1730, 1715, 1600, 1585, 1450, 1330, 1315, 1270, 1160, 1110, 990, 1025, 910, 755, 715 and 690 cm1.
Example 4: 7- [(IR, 2S,5R)-2-(benzenesulphonylamino)-5-fluoro -cyciopentyl] -5(Z)-heptenoic acid: 0 26 mg (68 μπιοί) of the compound prepared according to Example 3 are reacted analogously to Example 2, and after working-up and purification 23.6 mg -(64 μπιοί, 94 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13): δ= 1.5-2.2(m, 11H), 2.34(t, 2H), 3.33.45(m, IH) , 4.7(m, IH) , 5.1(s, NH) , 5.2-5.5(m, 2H) , 7.45-7.65{m, 3H), 7.9{m, 2H).
Example 5: Ί-[(IR,2S, 5R)-2-(4-fluorobenzenesulphonylamino)-5-fluorocyclopentyl]-5(Z)-heptenoic acid methyl ester: mg (210 gmol) of the compound prepared according to Example 5a are reacted analogously to Example 1, and after working-up and purification 25 mg (66 gmol, 31 %) of 7-[5(S)-(4-fluorobenzylsulphonylamino)-cyclopent-1enyl]-5(Z)-heptenoic acid methyl ester and 26 mg (65 μπιοί, 31 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3300, 3060, 3020, 2940, 2860, 1735, 1605, 1595, 1490, 1440, 1325, 1250, 1160, 835, 790, 735 and 700 cm-}-.
Example 5a: 7-[(IR, 2S, 5S)-2-(4-fluorobenzenesulphonylamino)-5hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 240 mg (477 μπιοί) of the compound prepared according to Example 5b are reacted analogously to Example lb, and after working-up and purification 175 mg (438 gmol, 92 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3310, 3060, 3020, 2940, 2860, 1730, 1610, 1595, 1490, 1440, 1325, 1250, 1160, 835, 790,- 740 and 700 cm-1.
Example 5b: 7-[(IR, 2S, 5S)-2-(4-fluorobenzenesulphonylamino)-5benzoyloxy-cvclopentyl]-5(Z)-heptenoic acid methyl ester: 250 mg (724 μπιοί) of the compound prepared according to Example lc are reacted analogously to Example lb with 30 4-fluorobenzenesulphonic acid chloride, and after working-up and purification 243 mg (483 μπιοί, 67 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 3060, 3000, 2950, 2870, 1730, 1710, 1590, 1570, 1490, 1450, 1335, 1270, 1165, 1150, 1090, 1025, 910, 715 and 670 cm1.
Example 6: 7- ((IR, 2S,5R)-2-(4-fluorobenzenesulphonylamino)-5-fluorocyclopentyl]-5(Z)-heptenoic acid: mg (65 μπιοί) of the compound prepared according to Example 5 are reacted analogously to Example 2, and after working-up and purification 22.5 mg (58 μπιοί, 89 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13): δ = 1.5-2.2(m, 11H), 2.35(t, 2H), 3.3-3.45(m, IH), 4.7(m, IH), 5.15(s, NH), 5.255.5(m, 2H) , 7.1-7.3(m, 2H) , 7.9(m, 2H) .
Example 7: - [(IR, 2S,5R) -2-(quinon-8-ylsulphonylamino)-5-fluorocyclopentyl]- 5(Z)-heptenoic acid methyl ester: 74 mg (171 μπιοί) of the compound prepared according to Example 7a are reacted analogously to Example 1, and after working-up and purification 29 mg (70 μπιοί, 41 %) of 7- [5(S)-(quinon-8-ylsulphonylamino)-cyclopent-l-enyl] 5 (Z)-heptenoic acid methyl ester and 19 mg (44 μπιοί, 25 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 3060, 2950, 2860, 1730, 1610, 1595, 1365, 1490, 1435, 1330, 1265, 1160, 1145, 835, 790, 735 and 700 cm*1.
Example 7a: 7-[(IR,2S,5S)-2-(quinon-8-ylsulphonylamino)- 5-hydroxycyclopentyl]-5 (Z)-heptenoic acid methyl ester: 339 mg (632 μπιοί) of the compound prepared according to Example 7b are reacted analogously to Example la, and after working-up and purification 259 mg (596 μπιοί, 94 %) of the title compound are isolated in the form of a colourless 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.
Example 7b: 7-[(IR,2S,5S)-2-(quinon-8-ylsulphonylamino)- 5-benzoyloxycyclopentyl]-5(Z)-heptenoic acid methyl ester: 250 mg (724 μπιοί) of the compound prepared according to Example lc are reacted analogously to Example lb with quinon-8-ylsulphonic acid chloride, and after working-up and purification 339 mg (632 μπιοί, 87 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 3060, 2950, 2860, 1730, 1710, 1675, 1600, 1565, 1490, 1450, 1435, 1330, 1270, 1245, 1165, 1145, 1110, 1070, 1045, 1025, 900, 835, 790 and 715 cm-1.
Example 8: 7-[(1R,2S,5R)-2-(quinon-8-ylsulphonylamino)-5-fluorocyclopentyl]-5(Z)-heptenoic acid: mg (44 μπιοί) of the compound prepared according to Example 7 are reacted analogously to Example 2, and after working-up and purification 14 mg (33 μπιοί, 77 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3290, 3060, 2950, 2860, 1710, 1610, 1590, 1360, 1490, 1435, 1330, 1265, 1160, 1145, 835, 790, 735 and 700 cm-1.
Example 9 : 7-[(IR, 2S,5R)-2-(benzenesulphonylamino)-5-fluoro-cyclopentyl]-heptanoic acid methyl ester: 109 mg (284 gmol) of the compound prepared according to Example 18 are reacted analogously to Example 1, and after working-up and purification 42 mg (115 μπιοί, 40 %) of 7-[5(S)-(benzenesulphonylamino)-cyclopent-l-enyl] heptanoic acid methyl ester and 34 mg (88 Mmol, 31 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3370, 3060, 2930, 2860, 1725, 1440, 1325, 1160, 1090, 1070, 930, 755, 720 and 690 cm-1.
Example 10: 7- [(IR, 2S,5R)-2-(benzenesulphonylamino)- 5 - fluoro-cyclopentyl] -heptanoic acid: mg (88 μπιοί) of the compound prepared according to Example 9 are reacted analogously to Example 2, and after working-up and purification 29 mg (78 μπιοί, 89 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13) : δ = 1.0-1.35(m, 7H) , 1.5-2.05(m, 8H) , 2.35(t, 2H) , 3.3-3.45(m, IH) , 4.7(m, IH) , 4.93(d, NH) , 7.45-7.65(m, 3H), 7.88(m, 2H).
Example 11: 7- [ (IR, 2S, 5R) - 2- (4 -fluorobenzenesulphonylamino) - 5-fluorocyclopentyl]-heptanoic acid methyl ester: 120 mg (299 μπιοί) of the compound prepared according to Example 19 are reacted analogously to Example 1, and after working-up and purification 44 mg (115. μπιοί, 38 %) of 7-[5(S)-(4 - fluorobenzylsulphonylamino)-cyclopent-1enyl]-heptanoic acid methyl ester and 33 mg (82 μπιοί, 27 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3370, 3070, 2930, 2860, 1730, 1665, 1595, 1490, 1450, 1435, 1330, 1290, 1230, 1160, 1090, 1115, 950, 925, 840 and 820 cm1.
Example 12: 7-[(IR,2S,5R)-2-(4-fluorobenzenesulphonylamino) -5-fluorocyclopentyl]-heptanoic acid: 3 mg (82 μπιοί) of the compound prepared according to Example 11 are reacted analogously to Example 2, and •5 after working-up and purification 31 mg (80 μπιοί, 97 %) of the title compound are isolated in the form of a colourless oil.
(CDC13): δ= 1.05-1.35(m, 8H), 1.5-2.05(m, 7H), 2H) , 3.38(m, IH) , 4.7(m, IH) , 4.95(d, NH) , 2H), 7.9(m, 2H).
Example 13: 7-[(1R,2S,5R)-2-(quinon-8-ylsulphonylamino)-5 - fluorocyclopentyl]-heptanoic acid methyl ester: mg (179 μπιοί) of the compound prepared according to Example 20 are reacted analogously to Example 1, and after working-up and purification 24 mg (57 μιηοΐ, 32 %) of 7- [5 (S) - (quinon-8-ylsulphonylamino) -cyclopent-lenyl]-heptanoic acid methyl ester and 19 mg (43 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 3060, 2940, 2850, 1730, 1610, 1595, 1565, 1490, 1435, 1330, 1160, 1140, 835, 795, 735 and XH-NMR 2.35(t, 680 cm'l.
Example 14: 7-[(IR, 2S, 5R)-2-(quinon-8-ylsulphonylamino)-5-fluorocyclopentyl]-heptanoic acid: mg (73 gmol) of the compound prepared according to Example 13 are reacted analogously to Example 2, and after working-up and purification 26 mg (62 μπιοί, 84 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2500, 3400, 3280, 2920, 2850, 1705, 1600, 1510, 1460, 1290, 1085, 1055, 1030 and 735 cm-1.
Example 15: 7-[(IR,2S,5R) -2-(4-toluenesulphonylamino)-5-hydroxycyclopentyl)-5(Z)-heptenoic acid methyl ester: A solution of 241 mg (612 μπιοί) of the compound prepared according to Example 15a is dissolved in 8 ml of anhydrous methanol; the solution is cooled to -30°C under an atmosphere of dry argon and a total of 6 9 mg of sodium borohydride is added in portions. The mixture is allowed to react for a further 30 minutes, excess reducing agent is decomposed by the addition of 120 μΐ of acetic acid, then water is added and extraction is carried out repeatedly with diehloromethane, followed by washing with water and saturated sodium chloride solution and drying over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on twelve analytical thin-layer plates. A mixture of n-hexane and ethyl acetate is used as mobile solvent and diethyl ether is used as eluting agent. 108 mg (273 μπιοί, 4 5 %) of the title compound are isolated as a more polar component and 48 mg (121 μπιοί, %) of the title compound of Example la as a less polar component.
IR (film): 3600-3200, 2950, 2920, 2850, 1730, 1600, 1450, 1325, 1155, 1090, 895, 815, 735 and 670 cm-1.
Example 15a: 7-[(IR,2S)-2-(4-toluenesulphonylamino)-5-oxo-cyclopentyl]-5(Z)-heptenoic acid methyl ester: mg (619 μπιοί) of the compound prepared according to Example la are oxidised analogously to Example If, and after working-up 241 mg (612 gmol, 99 %) of the title compound are isolated in the form of a pale yellow oil.
IR (film): 3360, 2950, 2920, 2850, 1735, 1600, 1450, 1325, 1155, 1090, 900, 815, 735 and 665 cm-1.
Example 16: 7-[(IR,2S, 5S)-2-(4-toluenesulphonylamino)-5-fluoro15 cyciopentyl]-5(Z)-heptenoic acid methyl ester: 108 mg (273 μπιοί) of the compound prepared according to Example 15 are reacted analogously to Example 1, and after working-up and purification 9 mg (24 μπιοί, 9 %) of 7- [5 (S)-(4-toluenesulphonylamino)-cyclopent-l-enyl]-5(Z)20 heptenoic acid methyl ester and 23 mg (60 μπιοί, 22 %) of the title compound are isolated, each in the form of a colourless oil.
IR (film): 3250, 3010, 2960, 2930, 2870, 1730, 1600, 1450, 1380, 1325, 1305, 1290, 1240, 1160, 1095, 925, 910, 25 815 and 665 cm1.
Example 17: 7-[(IR,2S,5S)-2-(4-toluenesulphonylamino)-5-fluorocyclopentyl]-5(Z)-heptenoic acid: mg (76 μmol) of the compound prepared according to 30 Example 16 are hydrolysed analogously to Example 2, and after working-up and purification 14 mg (37 μιτιοί, 48 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3700-2400, 3260, 3010, 2960, 2930, 2870, 1710, 5 1600, 1450, 1405, 1380, 1325, 1305, 1290, 1240, 1160, 1095, 925, 910, 815, 665, 620 and 550 cm'1.
Example 18: 7- ((IR,2S,5S)-2-(benzenesulphonylamino)-5-hydroxy-cyclopentyl]-heptanoic acid methyl ester: 132 mg (346 μπιοί) of the compound prepared according to Example 3a are dissolved in 5 ml of ethyl acetate; 50 mg of Pd/C (5 £) are added and hydrogenation is carried out at 1 atm. until the theoretical amount of hydrogen has been absorbed, followed by filtration, washing and concentration. 109 mg (284 μπιοί, 82 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3260, 2930, 2850, 1725, 1445, 1320, 1265, 1160, 1095, 1020 and 735 cm*1.
Example 19: 7-[(IR,2S,5S)-2-(4-fluorobenzenesulphonylamino)-5hydroxy-cyclopentyl]-heptenoic acid methyl ester: 141 mg (355 μπιοί) of the compound prepared according to Example 5a are hydrogenated analogously to Example 18, and after working-up 120 mg (300 μπιοί, 84 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3270, 2930, 2850, 1730, 1660, 1600, 1445, 1320, 1260, 1160, 1095, 1020, 925, 840 and 820 cm'1.
Example 20: 7- [ (1R,2S,5S)-2-(quinon-8-ylsulphonylamino)-5-hydroxycyclopentyl]-heptanoic acid methyl ester: 9 mg (344 μπιοί) of the compound prepared according to Example 7a are hydrogenated analogously to Example 18, and after working-up 142 mg (327 μπιοί, 95 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3520, 3410, 3280, 2940, 2850, 1725, 1665, 1595, 1490, 1455, 1430, 1320, 1160, 1140, 1020, 890, 840, 790, 735 and 675 cm-1.
Example 21: 7-[(IR,2S,5S)-2-(quinon-8-ylsulphonylamino)-5-hydroxycyclopentyl]-heptanoic acid: 0 mg (69 μπιοί) of the compound prepared according to Example 20 are hydrolysed analogously to Example 2, and after working-up and purification 25 mg (59 μπιοί, 86 %) of the title compound are isolated in the form of a colourless oil.
^-H-NMR (CDC13) : δ = 1.0-1.9(m, 16H) , 2.32(t, 2H) , 3.4(m, IH), 4.12(m, IH), 6.27(d, NH), 7.57(dt, IH), 7.66(t, IH), 8.06(dd, IH), 8.3(dd, IH), 8.43(dd, IH), 9.03(dd, IH).
Example 22: 7-[(IR,2S,5S)-2-(4-toluenesulphonylamino)-5-hydroxycyclopentyl]-5(Z)-heptenoic acid: 7 mg (119 μπιοί) of the compound prepared according to Example lb are hydrolysed analogously to Example 2, and after working-up and purification 41 mg (107 μπιοί, 90 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3470, 3260, 3000, 2940, 2870, 1710, 1600, 1445, 1320, 1160, 1095, 910, 810, 670, 570 and 550 cm'k Example 23: - [ (IR, 2S, 5S) - 2- (quinon-8-ylsulphonylamino) -5-hydroxy5 cyclopentyl]-5(Z)-heptenoic acid: mg (44 μπιοί) of the compound prepared according to Example 7b are hydrolysed analogously to Example 2, and after working-up and purification 16 mg (38 μπιοί, 85 %) of the title compound are isolated in the form of a waxy solid. 1H-NMR (CDC13) : δ= 1.0-2.35(m, 14H) , 3.43(m, IH) , 4.Km, IH) , 5.15-5.35(m, 2H) , 6.47(d, NH) , 7.52(dd, IH) , 7.66(t, IH) , 8.04(dd, IH) , 8.27(dd, IH) , 8.43(dd, IH) , 9.03(dd, IH). 1 5 Example 24: 7- [ (IR, 2S, 3RS, 5R) - 2-bensyloxymethyl-3-phenyl - 5 - fluorocyclopentyl] -5(E/Z)-heptenoic acid: 0.4 ml of a 50 % KOH solution, 257 μΐ of benzyl chloride and 4 mg of tetrabutylammonium hydrogen sulphate are 20 added to 3 3 mg (99 μπιοί) of the compound prepared according to Example 24a and the mixture is stirred intensively at 23°C for 18 hours. The mixture is poured into ice-water and extraction is carried out repeatedly with diehloromethane; the organic phase is dried over magnesium sulphate and excess benzyl chloride is removed by chromatography on four analytical thin-layer plates. A mixture of n-hexane and ethyl acetate is used as mobile solvent and chloroform is used as eluting agent. The resulting residue is hydrolysed analogously to Example 2, and after working-up and purification 17 mg (41 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2850, 1710, 1600, 1495, 1455, 1360, 1240, 1210, 1100, 970, 755, 735 and 700 cm-1.
Example 24a: 7-[(IR,2S,3RS,5R)-2-hydroxymethyl-3-phenyl-5 - fluorocyclopentyl]-5 (E/Z)-heptenoic acid methyl ester: 305 mg (532 /mol) of the compound prepared according to Example 24b are reacted analogously to Example lg, and after working-up and purification 176 mg (526 μπιοί, 99 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3030, 2920, 2850, 1730, 1450, 1435, 1370, 1150, 1045, 755 and 700 cm1.
Example 24b: 7- [(IR, 2S,3RS,5R)-2-(tert-butyldiphenvlsilyloxymethyl)-3phenyl-5-fluoro-cyclopentyl)-5(E/Z)-heptenoic acid methyl ester : 742 mg (1.30 mmol) of the compound prepared according to Example 24c are reacted analogously to Example 1, and 20 after working-up and purification 294 mg (532 μπιοί, 41 %) of 7-[(4RS,5S)-4-phenyl-5-(tert-butyldiphenylsilyloxymethyl)-cyclopent-l-enyl]-5(E/Z)-heptenoic acid methyl ester and 337 mg (588 μπιοί, 45 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3030, 2960, 2930, 2860, 1735, 1600, 1590, 1425, 1110, 820, 740 and 700 cm-1.
Example 24c: 7- [ (IR, 2S, 3RS, 5S) -2- (tert-butyldiphenylsilyloxymethyl) --3phenyl-5-hydroxy-cyclopentyl] -5 (E/Z) -heptenoic acid methyl ester (A) and 7-[ (IR, 2S, 3RS, 5R) -2-(tert-butyldiphenylsilyloxymethyl) -3-phenyl-5-hydroxy-cyclopentyl] 42 (E/Z)-heptenoic acid methyl ester (B) : I. 97 g (3.47 mmol) of the compound prepared according to Example 24d are reacted analogously to Example 15, and after working-up and purification 742 mg (1.30 mmol, 37 %) of title compound A and 925 mg (1.62 mmol, 47 %) of title compound B are isolated, each in the form of a colourless 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 24d: 7- [ (IR, 2S, 3RS) -2- (tert-butyldiphenylsilyloxymethyl) -3phenyl-5-oxo-cyclopentyl]-5 (E/Z)-heptenoic acid methyl ester: 500 mg of copper (II) acetate are added to a solution of II. 82 g (24.0 mmol) of the compound prepared according to 20 Example 24e in 120 ml of anhydrous tetrahydrofuran and the mixture is cooled to -78°C under an atmosphere of dry argon. 3.04 ml of trimethylchlorosilane and then 12.8 ml of a 3M solution of phenylmagnesium bromide in diethyl ether are added. After 45 minutes, the mixture is poured 25 into saturated ammonium chloride solution and extraction is carried out repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on approximately 200 ml of fine silica gel. A gradient system of n-hexane and ethyl acetate is used as eluant. 9.78 g (17.2 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3030, 2950, 2930, 2850, 1735, 1600, 1465, 1450, 1425, 1110, 1055, 820, 780, 740 and 700 cm'1.
Example 24e: 7-[(IR,2S)-2-(tert-butyldiphenylsilyloxymethyl)-5-oxocyclopent-3-enyl]-5(E/Z)-heptenoic acid methyl ester: A solution of 5.84 g (11.5 mmol) of the compound prepared according to Example 24f in 52 ml of anhydrous pyridine is cooled to 3°C under an atmosphere of dry argon; 2.17 ml of methanesulphonic acid chloride are added dropwise and the mixture is stirred at 3°C for a further 2 hours. Ice is added and the mixture is diluted with water and extracted repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on approximately 200 ml of fine silica gel. A gradient system of n-hexane and ethyl acetate is used as eluant. 4.93 g (10.0 mmol, 87 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3040, 2950, 2930, 2850, 1735, 1705, 1585, 1425, 1110, 820, 740 and 700 cm1.
Example 24f: 7- [ (IR, 2S,3R)-2-(tert-butyldiphenylsilyloxymethyl)-325 (tetrahydropyran-2-yloxy) -5-oxo-cyclopentyl] -5 (E/Z) heptenoic acid methyl ester: 11.9 g (20.0 mmol) of the compound prepared according to Example 24g are reacted analogously to Example If, and after working-up and purification 9.39 g (15.8 mmol, 79 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3040, 2940, 2850, 1740, 1590, 1425, 1110, 1075, 1030, 970, 820, 740 and 700 cm1.
Example 24q: 7-[(IR,2S,3R,5S)-2-(tert-butyldiphenylsilyloxymethyl)-3(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl]-5(E/Z)5 heptenoic acid methyl ester: 22.4 g (47.8 mmol) of (IS,3RS,5R,6S,7R)-7-(tetrahydropyran-2-yloxy) -6- (tert-butyldiphenylsilyloxymethyl) -2oxabicyclo[3.3.0]octan-3-ol are reacted analogously to Example Ij using KOH-containing potassium tert-butan10 olate, and after working-up and esterification with an ethereal solution of diazomethane and after purification by chromatography on approximately 1.3 litres of fine silica gel using a gradient system of n-hexane and ethyl acetate, 21.6 g (36.3 mmol, 76 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 3040, 2940, 2850, 1730, 1595, 1425, 1110, 1075, 1025, 970, 820, 740 and 700 cm1.
Example 25: 7- [ (IR, 2S, 3RS, 5R) - 2- (4 -cyanobenzyloxymethyl) - 3 -phenyl - 5 20 fluoro-cyciopentyl]-5(Ξ/Z)-heptenoic acid: mg (84 μπιοί) of the compound prepared according to Example 24a are reacted analogously to Example 24 using 4-cyanobenzyl bromide, and after working-up and purification 14 mg (32 μπιοί, 38 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3015, 1930, 2860, 2230, 1705, 1600, 1455, 1435, 1360, 1290, 1240, 1150, 1110, 1090, 970, 795, 755, 700 and 685 cm1.
Example 26: 7- [ (IR, 2S,3RS,5R)-2-(3-methylbenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (81 gmol) of the compound prepared according to Example 24a are reacted analogously to Example 24 using 3-methylbenzyl bromide, and after working-up and purification 23 mg (54 μπιοί, 67 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2860, 1705, 1600, 1450, 1360, 1245, 1160, 1105, 1090, 970, 780, 755 and 700 cm-1.
Example 27: 7-[(IR,2S,3RS,5R)-2-(3,5-bis-trifluoromethylbenzyloxymethyl) -3-phenyl-5-fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: 9 mg (87 μπιοί) of the compound prepared according to Example 24a are reacted analogously to Example 24 using 3,5-bis(trifluoromethyl)benzyl bromide, and after working-up and purification 28 mg (51 μπιοί, 59 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2870, 1710, 1625, 1600, 1455, 1380, 1355, 1280, 1175, -1135, 970, 885, 840, 760, 700 and 680 cm-1.
Example 28: 7- [ (IR, 2S,3RS,5R)-2-(1-naphthylmethoxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: 9 mg (87 μπιοί) of the compound prepared according to Example 24a are reacted analogously to Example 24 using 1-bromomethylnaphthalene, and after working-up and purification 26 mg (56 μπιοί, 65 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2930, 2860, 1705, 1600, 1455, 1240, 1165, 1100, 970, 800, 790, 775, 755 and 700 cm'}.
Example 29: 7-[(IS,2R,3RS,5S)-2-[2-(4-fluorophenoxy)-ethoxymethyl]-3phenyl-5-fluoro-cyclopentyl3-5(Z)-heptenoic acid: mg (129 μπιοί) of the compound prepared according to Example 29a are reacted analogously to Example 24 using 1-bromo-2-(4-fluorophenoxy)-ethane, and after working-up and purification 12 mg (26 μπιοί, 20 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2930, 2870, 1710, 1600, 1505, 1455, 1250, 1210, 1130, 100, 1050, 830, 760, 745 and 700 cm'1.
Example 29a: 7-[(IS,2R,3RS,5S)-2-hydroxymethvl-3-phenyl-5-fluorocyclopentyl] -5(Z)-heptenoic acid: 2.36 g (4.12 mmol) of the compound prepared according to Example 29b are reacted analogously to Example lg, and after working-up and purification 1.24 g (3.71 mmol, %) of the title compound are isolated in the form of -a colourless oil.
IR (film): 3600-3200, 3020, 2920, 2850, 1730, 1600, 1450, 1435, 1330, 1150, 1045, 965, 755 and 700 cm-1.
Example 29b: 7-[(IS,2R,3RS,5S)-2-(tert-butyldiphenylsilyloxymethyl)-3phenyl-5-fluoro-cyclopentyl]-5(S)-heptenoic acid: Starting from (IR,3RS,5S,6R,7S)-7-(tetrahydropvran-230 yloxy) -6- (tert-butyldiphenylsilyloxymethyl) -2-oxabicyclo- 47 [3.3.0]ocean-3-ol, 7 - [ (4RS,5R)-4-phenyl-5-(tert-butyldiphenylsilyloxymethyl)-cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester and the title compound are prepared analogously to the described Examples 24b to 24g. By the use of freshly sublimed potassium tert-butanolate (see Example 24g) in each case only the Z-isomer in respect of the double bond in the 5-position is obtained.
Example 30: 7-[(IS,2R,3RS,5S)-2-benzyloxymethyl-3-phenyl- 5 -fluoro10 cyclopentyl]-5(Z)-heptenoic acid: mg (129 Mmol) of the compound prepared according to Example 29a are reacted analogously to Example 24, and after working-up and purification 25 mg (61 Mmol, 47 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2930, 2860, 1710, 1600, 1495, 1455, 1360, 1240, 1210, 1100, 755, 735 and 700 era'1.
Example 31: -[(IS,2R,3RS, 5S)-2-(4 -cyanobenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl] -5(Z)-heptenoic acid: mg (129 Mmol) of the compound prepared according to Example 29a are reacted analogously to Example 24 using 4-cyanobenzyl bromide, and after working-up and purifica25 tion 31 mg (71 μπιοί, 55 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2940, 2860, 2230, 1710, 1610, 1450, 1235, 1220, 1130, 1100, 820, 760 and 700 cm'1.
Example 32: 7- [ (IS, 2R, 3RS, 5S) -2- (3-methylbenzyloxymethyl) -3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (129 μπιοί) of the compound prepared according to Example 29a are reacted analogously to Example 24 using 3-methylbenzyl bromide, and after working-up and purification 26 mg (61 μπιοί, 47 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2940, 2860, 1710, 1600, 1495, 1455, 1360, 1250, 1160, 1105, 1090, 780, 760 and 700 cm-1.
Example 33: 7- [ (IS, 2R, 3RS, 5S) -2- (3 -cyanobenzyloxymethyl) -3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (129 μπιοί) of the compound prepared according to Example 29a are reacted analogously to Example 24 using 3-cyanobenzyl bromide, and after working-up and purification 36 mg (83 μπιοί, 64 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2930, 2860, 2230, 1710, 1600, 1495, 1455, 1435, 1360, 1240, 1150, 1105, 1090, 795, 760, 700 and 685 cm'1.
Example 34: - [ (IR, 2S, 3RS, 5S) - 2- [2 - (4-f luorophenoxy) -ethoxymethyl] - 3phenyl-5-fluoro-cyclopentyl] -5 (E/Z) -heptenoic acid: 3 mg (99 μπιοί) of the compound prepared according to Example 34b are reacted analogously to Example 24 using 1-bromo-2-(4-fluorophenoxy)-ethane, and after working-up and purification 17 mg (37 μπιοί, 37 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3000, 2930, 2870, 2850, 1710, 1600, 1505, 1455, 1250, 1210, 1140, 995, 1050, 825, 760, 745 and 700 cm-1.
Example 34a: - [ (IR, 2S, 3RS, 5S) -2-hydroxymethyl-3-phenyl-5-fluoro5 cyclopentyl]-5(E/Z)-heptenoic acid methyl ester: 6 mg (1.02 mmol) of the compound prepared according to Example 34b are reacted analogously to Example lg, and after working-up and purification 335 mg (1.00 mmol, %) of the title compound are isolated in the form of a 10 colourless oil.
IR (film): 3600-3200, 3060, 3030, 3000, 2940, 2870, 1735, 1600, 1490, 1450, 1435, 1245, 1175, 1065, 1045, 1030, 945, 865, 760 and 700 cm'1.
Example 34b: 7 - [ (IR, 2S, 3RS, 5S) - 2 - (tert - butyldiphenylsilyloxymethyl )-3phenyl-5-f luoro-cyclopentyl]-5 (E/Z) -heptenoic acid methyl ester : mg (1.62 mmol) of the more polar compound B prepared according to Example 24c are reacted analogously to Example 1, and after working-up and purification 98 mg (165 μπιοί, 10 %) of 7-[(4RS,5S)-4-phenyl-5- (tert-butyldiphenylsilyloxymethyl) -cyclopent-l-enyl] -5 (E/Z) heptenoic acid methyl ester and 586 mg (1.04 mmol, 64 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3020, 3000, 2950, 2930, 2850, 1735, 1600, 1585, 1490, 1465, 1450, 1425, 1360, 1110, 1005, 965, 870, 820, 760, 740 and 700 cm1.
Example 35: 7-[(lR,2S,3RS,5S) -2-benzyloxymethyl - 3-phenyl - 5 - fluorocyclopentyl] -5 (E/Z)-heptenoic acid: mg (93 gmol) of the compound prepared according to 5 Example 34a are reacted analogously to Example 24 using benzyl chloride, and after working-up and purification 14 mg (34 gmol, 37 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3020, 2930, 2850, 1705, 10 1600, 1490, 1465, 1100, 1070, 1030, 950, 760, 735 and 700 cm-1.
Example 36: 7- [ (IR, 2S, 3RS, 5S) -2-(3,5-bis-trif luoromethylbenzyloxymethyl) -3-phenyl-5-fluoro-cyclopentyl] -5 (E/Z) -heptenoic acid : mg (75 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 3,5-bis-(trifluoromethyl)-benzyl bromide, and after working-up and purification 27 mg (49 μπιοί, 66 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3070, 3030, 2940, 2860, 1710, 1610, 1600, 1360, 1280, 1180, 1140, 700 and 680 cm'1.
Example 37: 7- [ (IR, 2S, 3RS, 5S) - 2- (1-naphthylmethoxymethyl) -3-phenyl-5 fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (69 μmol) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 1-bromomethylnaphthalene, and after working-up and purification 13 mg (28 μπιοί, 41 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3020, 3000, 2930, 2850, 1710, 1600, 1505, 1455, 1250, 1220, 1100, 950, 800, 790, 780, 760 and 700 cm-1.
Example 38: 7-[(IR,2S,3RS,5S)-2-(4-cyanobenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (60 gmol) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 4-cyanobenzyl bromide, and after working-up and purifica10 tion 10 mg (24 μπιοί, 44 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2850, 2220, 1710, 1605, 1505, 1495, 1455, 1415, 1130, 1100, 950, 820, 760 and 700 cm-1.
Example 39: 7-[(IR, 2S, 3RS,5S)-2-(3-methylbenzvloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (60 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 3-methylbenzyl bromide, and after working-up and purification 16 mg (38 μπιοί, 63 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2850, 1710, 1600, 1495, 1455, 1435, 1240, 1155, 1100, 1090, 950, 760 and 700 cm-1.
Example 40: 7-[(IR,2S, 3RS,5S)-2-(3-cyanobenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (60 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 3- cyanobenzyl bromide, and after working-up and purification 17 mg (39 μπιοί, 65 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2860, 2230, 1710, 1600, 1585, 1455, 1435, 1355, 1285, 1200, 1150, 1105, 1085, 795, 760, 700 and 685 cm-1.
Example 41: 7-[(IS,2R,3RS,5R)-2-[2-(4-fluorophenoxy)-ethoxymethyl]-3phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: 43 mg (128 μπιοί) of the compound prepared according to Example 41a are reacted analogously to Example 24 using 4- fluorophenoxyethyl bromide, and after working-up and purification 12 mg (26 μπιοί, 20 %) of the title compound are isolated in the form of a colourless oil.
IR (film); 3600-2400, 3070, 3030, 2930, 2870, 1710, 1600, 1505, 1455, 1250, 1210, 1140, 1100, 1055, 830, 760, 750 and 700 cm'L Example 41a: 7-[(IS,2R,3RS,5R)-2-hydroxymethyl- 3-phenyl- 5 -fluoro20 cyclopentyl]-5 (Z)-heptenoic acid: 3.63 g (6.34 mmol) of the compound prepared according to Example 41b are reacted analogously to Example lg, and after working-up and purification 2.05 g (2.04 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3060, 3030, 3000, 2940, 2870, 1735, 1600, 1490, 1450, 1435, 1245, 1220, 1170, 1150, 1070, 945, 870, 760 and 700 cm'1.
Example 41b: 7- [ (IS,2R,3RS,5R)-2-(tert-butyldiphenylsilyloxymethyl) -3 phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: 6.15 g (10.8 mmol) of 7-[(IS, 2R,3RS,5S)-2 - (tert-butyl5 diphenylsilyloxymethyl)-3-phenyl-5-hydroxy-cyclopentyl] 5(Z)-heptenoic acid methyl ester, which is obtained analogously to Example 24c in the course of the synthesis described under Example 29b, are reacted analogously to Example 1, and after working-up and purification 610 mg (1.1 mmol, 10 %) of 7-[(4RS,5R)-4phenyl-5-(tert-butyldiphenylsilyloxymethyl)-cyclopent-lenyl]-5(Z)-heptenoic acid methyl ester and 3.63 g (6.34 mmol, 59 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3020, 2950, 2930, 2850, 1735, 1600, 1585, 1425, 1110, 820, 760, 740 and 700 cm'1.
Example 42: 7-[(IS,2R,3RS,5R)- 2-benzyloxymethyl-3-phenyl-5-fluorocyclopentyl] -5(Z)-heptenoic acid: 43 mg (129 Mmol) of the compound prepared according to Example 41a are reacted analogously to Example 24 using benzyl chloride, and after working-up and purification 23 mg (56 M^ol, 43 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2940, 2860, 1710, 1600, 1495, 1450, 1100, 760, 740 and 700 cm'1.
Example 43: 7-[(IS,2R,3RS,5R)-2-(4-cyanobenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid: 43 mg (129 μπιοί) of compound prepared according to Example 41a are reacted analogously to Example 24 using 4-cyanobenzvl bromide, and after working-up and purification 21 mg (48 μπιοί, 37 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2940, 2860, 2230, 1710, 1610, 1455, 1275, 1130, 1100, 820, 780 and 700 cm-1.
Example 44: 7-[(IS,2R,3RS,5R)-2-(3-methvlbenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid: 3 mg (12 9 μιηοΐ) of the compound prepared according to 10 Example 41a are reacted analogously to Example 24 using 3-methylbenzyl bromide, and after working-up and purification 21 mg (4 9 μπιοί, 3 8 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2850, 1710, 1600, 1455, 1240, 1160, 1100, 950, 780, 760 and 700 cm1.
Example 45: 7-[(IS,2R,3RS,5R)-2-(3-cyanobenzyloxymethyl)-3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (129 μπιοί) of the compound prepared according to 20 Example 41a are reacted analogously to Example 24 using 3-cyanobenzyl bromide, and after working-up and purification 41 mg (94 μπιοί, 73 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2940, 2860, 2230, 1710, 25 1600, 1580, 1450, 1430, 1360, 1240, 1150, 1110, 1090, 950, 795, 760, 700 and 690 cm-1.
Example 46: 7-[(IR, 2S,3RS,5S)-2-(2,4-bis-trifluoromethylbenzvloxymethyl)- 3-phenyl-5 - fluoro-cyclopentyl]-5(E/Z) -heptenoic acid: 2 0 mg (60 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 2,4-bis-(trifluoromethyl)-benzyl bromide, and after working-up and purification 20 mg (37 μπιοί, 61 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3030, 3000, 2920, 2850, 1710, 1630, 1600, 1455, 1345, 1275, 1170, 1130, 1055, 910, 860, 840, 760 and 700 cm’1.
Example 47: 7-[(lR,2S,3RS,5S)-2 - (4-methylbenzyloxymethyl) -3 - phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid: mg (60 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 4-methylbenzyl bromide, and after working-up and purif20 ication 15 mg (35 μπιοί, 59 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3020, 3000, 2920, 2850, 1705, 1600, 1455, 1100, 1085, 1070, 950, 800, 760 and 700 cm'1.
Example 48: 7- [ (IR, 2S, 3RS, 5S) - 2- (2-naphthylmethoxymethyl) -3-phenyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid (A) and 7[ (IR, 2S, 3RS, 5S) -2- (2-naphthylmethoxymethyl) -3-phenyl-5fluoro-cyclopentyl)-5(E)-heptenoic acid (B) : mg (60 μπιοί) of the compound prepared according to Example 34a are reacted analogously to Example 24 using 2-bromome thy Inaphtha lene, and after working-up and purif ication 15 mg (33 μπιοί, 50 %) of title compound A and 7 mg (14 μπιοί, 21 %) of title compound B are isolated, each in the form of a colourless oil.
IR (film) of A: 3600-2400, 3060, 3020, 2930, 2850, 1705, 1600, 1490, 1455, 1435, 1410, 1345, 1270, 1240, 1125, 1100, 950, 855, 820, 755 and 700 cm-1.
IR (film) of B: 3600-2400, 3060, 3030, 2930, 2850, 1705, 1600, 1455, 1435, 1410, 1345, 1125, 1100, 1090, 1070, 970, 950, 855, 815, 755 and 700 cm'1.
Example 49: 7- [ (IR, 2S, 3RS, 5R) -2- [2- (4-f luorophenoxy) -ethoxymethyl] -3phenyl-5-fluoro-cyclopentyl] -5 (E/Z) -heptenoic acid: mg (93 μπιοί) of the compound prepared according to Example 24a are reacted analogously to Example 24 using l-bromo-2-(4-fluorophenoxy)-ethane, and after working-up and purification 15 mg (32 μπιοί, 35 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2930, 2870, 1710, 1600, 1505, 1455, 1250, 1210, 1130, 825, 760, 740 and 700 cm'1.
Example 50: 7- [ (1R,2S,3RS,5S) - 2- [ (3RS,4S) -3 -hydroxy-4-methyl-non1(E) -en-6-ynyl] -3 - phenyl-5-f luoro-cyclopentyl] -5 (Z) heptenoic acid methyl ester (A) and 7-[ (IR, 2S, 3RS, 5S) -2[ (3RS , 4S) -3 - hydroxy-4 -methyl-non-1 (E) -en-6-ynyl] -3 phenyl-5-fluoro-cyclopentyl]-5 (E) -heptenoic acid methyl ester (B): mg (91 μπιοί) of the compound prepared according to Example 50a are reacted analogously to Example 15, and after working-up and purification 21 mg (46 μπιοί, 51 %) of title compound A and 15 mg (33 μπιοί, 36 %) of title compound B are isolated, each in the form of a colourless oil· .
IR (film): 3600-3200, 3060, 3030, 2970, 2930, 2850, 1735, 1600, 1495, 1450, 1240, 1125, 970, 760 and 700 cm-1.
Example 50a: 7- [ (IR, 2S, 3RS, 5S) -2- [3-oxo-4S-methyl-non-l (E) -en-6-ynyl] 3-phenyl-5-fluoro-cyclopentyl] -5 (E/Z) -heptenoic acid methyl ester: A solution of 45 mg of dimethyl-(2-oxo-3S-methyl-oct-5ynyl) -phosphonate in 330 μΐ of tetrahydrofuran is added dropwise under an atmosphere of dry argon to a slurry of mg of sodium hydride dispersion (55 %) in 410 μΐ of anhydrous tetrahydrofuran and the mixture is stirred at 23°C for 20 minutes. The mixture is cooled to -30°C; a solution of 70 mg (164 μπιοί) of the aldehyde prepared according to Example 50b in 490 μΐ of tetrahydrofuran is added dropwise and the mixture is stirred at -15°C for 14 hours. Acetic acid is added and extraction is carried out repeatedly with diethyl ether. The combined organic extracts are washed with dilute sodium hydrogen carbonate solution and dried over magnesium sulphate, and the residue obtained after removal of the solvent is purified by chromatography on five analytical thin-layer plates. A mixture of n-hexane and ethyl acetate is used as mobile solvent, and diethyl ether is used as eluting agent. 41 mg (91 μπιοί, 55 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3030, 3000, 2970, 2930, 2870, 1735, 1690, 1665, 1625, 1450, 1435, 1170, 1040, 980, 760 and 700 cm-1.
Example 50b: 7- ((IR, 2S,3RS,5S)-2 - formyl-3-phenyl-5-fluoro-cyciopentyl ]-5 (E/Z)-heptenoic acid methyl ester: A solution of 63 μΐ of dimethyl sulphoxide in 280 μΐ of dichloromethane is added dropwise to a solution of 34 μΐ of freshly distilled oxalyl chloride in 690 μΐ of anhydrous dichloromethane at -60°C under an atmosphere of dry argon, and the mixture is allowed to react for 15 minutes and then a solution of 114 mg (341 μπιοί) of the alcohol prepared according to Example 34a in 690 μΐ of dichloromethane is added thereto. The mixture is allowed to react for 4 hours; 107 μΐ of triethylamine are added, followed by pouring into ice-water and extraction repeatedly with dichloromethane. The combined organic extracts are dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is reacted further without being purified.
Example 51: 7-[(IR,2S,3RS,5S)-2-[(3R or 3S,4S) -3-hydroxy-4-methylnon-1 (E) -en-6-ynyl] -3-phenyl-5-f luoro-cyclopentyl] -5 (E) heptenoic acid (A) and 7- [ (IR,2S,3RS,5S)-2-[ (3S or 3R, 4S) -3-hydroxy-4-methyl-non-1 (E) -en-6-ynyl] -3-phenyl-5fluoro-cyclopentyl] -5(E)-heptenoic acid methyl ester (B) : mg (33 μπιοί) of compound B prepared according to Example 50 are reacted analogously to Example 2, and after working-up and purification 5 mg (11 μπιοί, 33 %) of a less polar component, which is assigned the structure of title compound A, and 5.3 mg (12 μπιοί, 36 %) of a more polar component, which is assigned the structure of title compound B, are isolated, each in the form of a colourless oil.
IR (film) of A: 3600-2400, 3060, 3030, 2970, 2930, 2850, 1710, 1600, 1495, 1455, 1435, 1240, 1130, 970, 760 and 700 cm-1.
IR (film) of B: 3600-2400, 3060, 3030, 2970, 2930, 1710, 1600, 1495, 1455, 1435, 1385, 1240, 1070, 1030, 1015, 970, 760 and 700 cm-1.
Example 52: 7-[(IR,2S,3RS, 5S) -2-[(3RS,4S)-3-hydroxy-4-methyl-non1 (E) -en-6-ynyl) -3-phenyl-5-fluoro-cyclopentyl] -5 (Z) heptenoic acid: mg (4 6 μπιοί) of compound A prepared according to Example 50 are reacted analogously to Example 2, and after working-up and purification 17 mg (3 9 μπιοί, 84 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3080, 3060, 3030, 3000, 2970, 2930, 2870, 1710, 1600, 1495, 1455, 1435, 1405, 1345, 1320, 1240, 1035, 1010, 970, 760 and 700 cm'1.
Example 53: 7- [ (1R,2S,3RS,5S) - 2- [3(RS)-hydroxy-oct-1(E)-enyl)-3phenyl-5-fluoro-cyclopentyl]-5(E)-heptenoic acid methyl ester (A) and 7-[(IR, 2S, 3RS,5S)-2-[3(RS)-hydroxy-oct1(E)-enyl]-3-phenyl-5-fluoro-cyclopentyl] -5(Z) -heptenoic acid methyl ester (B): mg (14 2 μπιοί) of the compound prepared according to Example 53a are reacted analogously to Example 15, and after working-up and purification 47 mg (109 μπιοί, 77 %) of title compound A and 12 mg (28 μπιοί, 20 %) of title compound B are isolated, each in the form of a colourless oil.
IR (film): 3600-3200, 3030, 3000, 2950, 2930, 2850, 1735, 1600, 1450, 1435, 1245, 1170, 1070, 1030, 970, 755 and 700 cm-1.
Example 53a: 7-[(IR,2S,3RS,5S)-2-[3-oxo-oct-1(E)-enyl]-3-phenyl-5fluoro-cyclopentyl]-5(E/Z)-heptenoic acid methyl ester: mg (168 μπιοί) of the compound prepared according to Example 50b are reacted analogously to Example 50a using dimethyl-(2-oxo-heptyl)-phosphonate, and after working-up and purification 61 mg (142 μπιοί, 77 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3030, 2950, 2930, 2850, 1730, 1690, 1670, 1625, 1450, 1430, 1165, 1070, 980, 760 and 700 cm-1.
Example 54: 7-[(1R,2S,3RS,5S)-2-[(3S or 3R)-3-hydroxy-oct-l(E)-enyl]3-phenyl-5-fluoro-cyclopentyl]-5(E)-heptenoic acid (A) and 7-[(IR,2S,3RS,5S)-2-[(3R or 3S)-3-hydroxy-oct-1(E)enyl]-3-phenyl-5-fluoro-cyclopentyl]-5(E)-heptenoic acid (B) : mg (27 μπιοί) of compound A prepared according to Example 53 are reacted analogously to Example 2, and after working-up and purification 5.3 mg (13 μπιοί, 47 %) of a less polar component, which is assigned the structure of title compound A, and 4.9 mg (12 μπιοί, 44 %) of a more polar component, which is assigned the structure of title compound B, are isolated, each in the form of a colourless oil.
IR (film) of A: 3600-2400, 3080, 3060, 3030, 2950, 2930, 2860, 1690, 1600, 1495, 1455, 1305, 1260, 1035, 965, 755 and 700 cm-1.
IR (film) of B: 3600-2400, 3080, 3060, 3030, 2950, 2930, 2860, 1700, 1600, 1495, 1455, 1340, 1325, 1260, 1135, 1070, 1015, 965, 755 and 700 cm1.
Example 55: 7-[(IR,2S,3RS,5S)-2-[3(RS)-hydroxy-oct-1(E)-enyl]-3phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (77 Mmol of compound B prepared according to 5 Example 53 are reacted analogously to Example 2, and after working-up and purification 17 mg (41 μπιοί, 53 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3080, 3060, 3030, 3000, 2950, 2930, 10 2860, 1710, 1600, 1495, 1465, 1405, 1345, 1240, 1035, 970, 760 and 700 cm1.
Example 56 : 7-[(IS,2R,3RS,5R)-2-[(3RS,4S)- 3-hydroxy-4-methyl-non1(E)-en-6-ynyl]- 3-phenyl-5 - fluoro-cyclopentyl]-5 (Z)15 heptenoic acid methyl ester: 183 mg (404 Mm°b of the compound prepared according to Example 56a are reacted analogously to Example 15, and after working-up and purification 184 mg (404 Mm°l100 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3030, 2960, 2920, 2870, 1735, 1450, 1435, 1245, 1170, 1145, 1025, 970, 760 and 700 cm1.
Example 56a: 7-[(IS,2R,3RS,5R)-2-[3-oxo-4S-methyl-non-1(E)-en-6-ynyl] 25 3-phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester : 274 mg (561 Mm°b of the compound prepared according to Example 56b are reacted analogously to Example 50a, and after working-up and purification 183 mg (404 m^oI, 72 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3060, 3030, 3000, 2970, 2930, 2870, 1735, 1690, 1670, 1625, 1450, 1430, 1370, 1170, 1040, 970, 760 and 700 cm1.
Example 56b: 7-((IS,2R, 3RS,5R)- 2 - formyl-3-phenyl-5-fluoro-cyclopentyl] -5 (Z)-heptenoic acid methyl ester: 500 mg (1.5 mmol) of the compound prepared according to Example 41a are reacted analogously to Example 50b, and after working-up 500 mg (1.5 mmol, 100 %) of the title compound are isolated in the form of a colourless oil which is reacted further without being purified.
Example 57: 7- [(IS,2R,3RS,5R)-2-[(3RS,4S)- 3 -hydroxy-4-methyl- non1 (E)-en-6-ynyl]- 3-phenyl-5 - fluoro-cyclopentyl]-5(Z)15 heptenoic acid: 184 mg (4 04 μπιοί) of the compound prepared according to Example 56 are hydrolysed analogously to Example 2, and after working-up and purification 132 mg (300 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2970, 2950, 1710, 1600, 1455, 1240, 970, 760 and 700 cm'1.
Example 58: 7-[(IS,2R,3RS,5R)-2-[3(RS)-hydroxy-oct-1(E)-enyl]-325 phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester : 298 mg (695 μπιοί) of the compound prepared according to Example 58a are reacted analogously to Example 15, and after working-up and purification 260 mg (603 μπιοί, 3° 87 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3060, 3030, 3000, 2950, 2930, 2850, 1735, 1600, 1450, 1435, 1245, 1170, 1070, 1030, 970, 760 and 700 cm-1.
Example 58a: 7-[(IS,2R,3RS,5R)-2-[3-oxo-oct-1 (E)-enyl]-3-phenyl-5 fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 270 mg (74 8 μπιοί) of the compound prepared according to Example 56b are reacted analogously to Example 56a using dimethyl-(2-oxo-heptyl)-phosphonate, and after working-up and purification 298 mg (695 μπιοί, 93 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3030, 2950, 2920, 2850, 1730, 1690, 1670, 1625, 1450, 1430, 1240, 1165, 980, 760 and 700 cm-1.
Example 5 9 : 7- [ (IS, 2R, 3RS, 5R) -2- [3 (RS) -hydroxy-oct-1(E) -enyl] -3phenyl-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: 0 mg (6 04 μπιοί) of the compound prepared according to Example 58 are hydrolysed analogously to Example 2, and after working-up and purification 235 mg (564 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 2960, 2920, 2850, 1710, 1600, 1450, 1270, 970, 760 and 700 cm1.
Example 6 0: 7- [ (IS, 2R, 3RS, 5R) -2- [ (3RS, 4RS) -3-hydroxy-4-phenyl-pent1 (E) -enyl] -3-phenyl-5-f luoro-cyclopentyl] -5 (Z) -heptenoic acid methyl ester: 172 mg (372 μπιοί) of the compound prepared according to Example 60a are reacted analogously to Example 15, and after working-up and purification 170 mg (366 μπιοί, 98 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3060, 3030, 2960, 2940, 1730, 1600, 1495, 1450, 1240, 1020, 970, 760 and 700 cm-1.
Example 60a: 7- [ (IS, 2R, 3RS, 5R) -2- [3-oxo-4RS-phenyl-pent-1 (E) -enyl] -3phenyl-5-f luoro-cyclopentyl]-5 (Z)-heptenoic acid methyl ester: 274 mg (561 gmol) of the compound prepared according to Example 56b are reacted analogously to Example 56a using dimethyl-(2-oxo-3-phenylbutyl) -phosphonate, and after working-up and purification 172 mg (372 μπιοί, 66 %) of the title compound are isolated in the form of a colour15 less oil.
IR (film): 3060, 3030, 2950, 2930, 2850, 1735, 1690, 1670, 1625, 1490, 1450, 1430, 1370, 1245, 1165, 1070, 1030, 980, 760 and 700 cm1.
Example 61: 7- ( (IS, 2R, 3RS, 5R)-2- [ (3R or 3S, 4RS) -3-hydroxy-4-phenylpent-1 (E) - enyl] -3 - phenyl-5-f luoro-cyclopentyl] -5 (Z) heptenoic acid (A) and 7-[(IS,2R, 3RS, 5R)-2-[ (3S or 3R, 4RS) -3-hydroxy-4-phenyl-pent-1 (E) -enyl] -3-phenyl-5fluoro-cyclopentyl]- 5(Z)-heptenoic acid methyl ester (B) : 170 mg (366 μπιοί) of the compound prepared according to Example 6 0 are hydrolysed analogously to Example 2, and after working-up and purification 24 mg (53 μπιοί, 15 %) of a non-polar component, which is assigned the structure of title compound A, and 45 mg (100 μπιοί, 27 %) of a polar component, which is assigned the structure of title compound B, are isolated, each in the form of a colourless oil.
IR (film) Of A: 3600-2400, 3060, 3030, 2960, 2940, 1710, 1600, 1500, 1450, 1240, 1020, 970, 760 and 700 cm'1.
IR (film) of B: 3600-2400, 3060, 3030, 2960, 2950, 1710, 1600, 1495, 1455, 1240, 1030, 1010, 980, 760 and 700 cm'1.
Example 62: 7- [(IS , 2R,3R,5R)-2-[(E/Z)-diphenylmethoxyiminomethyl) 3,5-dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: 1.2 ml of a mixture of acetic acid, water and tetrahydrofuran (65:35:10) are added to 108 mg (207 μπιοί) of the compound prepared according to Example 62a and the mixture is stirred at 23°C for 15 hours. The mixture is concentrated; residual acetic acid is removed by repeated azeotropic distillation with toluene and the residue is purified by chromatography on approximately 20 ml of fine silica gel. 75 mg (171 μπιοί, 83 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3700-2400, 3090, 3060, 3030, 3010, 2940, 1710, 1490, 1450, 1245, 1035, 1020, 940, 745 and 700 cm'1.
Example 62a: 7- [ (IS , 2R, 3R, 5R) -2- [ (E/Z) -diphenylmethoxyiminomethyl] -3(tetrahydropyran-2-yloxy) -5-hydroxy-cyclopentyl] -5 (Z) heptenoic acid: 1.18 g (1.84 mmol) of the compound prepared according to Example 62b are hydrolysed analogously to Example 2, and after working-up and purification 943 mg (1.81 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3090, 3060, 3030, 3010, 2940, 2870, 1740, 1710, 1600, 1495, 1450, 1240, 1130, 1115, 1035, 1020, 935, 920, 870, 815, 745 and 705 cm'1.
Example 62b: 7-[(IS,2R,3R,5R)-2-[(E/Z)-diphenylmethoxyiminomethyl ]-3(tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)heptenoic acid methyl ester: 0.4 ml of anhydrous pyridine and 588 mg of diphenylmethoxyamine are added to a colourless solution of 1.0 g (2.18 mmol) of the compound prepared according to Example 62c in 16 ml of anhydrous ethanol and the mixture is heated at 50°C under an atmosphere of dry argon for 3.5 hours. The mixture is concentrated, and the residue is taken up in dichloromethane, washed with water and saturated sodium chloride solution, and the residue obtained after drying over magnesium sulphate, filtration and concentration is purified by chromatography on approximately 50 ml of silica gel with a mixture of nhexane/ethyl acetate. 1.18 g (1.84 mmol, 85 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3030, 3010, 2950, 2870, 1740, 1715, 1605, 1585, 1495, 1450, 1360, 1275, 1115, 1025, 940, 920, 870, 815, 745, 715 and 705 cm-1.
Example 62c: 7-[(IS, 2R,3R,5R)-2-formyl-3-(tetrahydropyran-2-yloxy)-5benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: g (19.5 mmol) of the compound prepared according to Example 62d are reacted analogously to Example 50b, and after working-up there are isolated 9 g (19.5 mmol, 100 %) of the title compound which is reacted further without being purified.
Example 62d: - [ (IS,2R,3R,5R)-2-hydroxymethyl-3- (tetrahydropyran-2yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 22.4 g (32 mmol) of the compound prepared according to Example 62e are reacted analogously to Example lg, and after working-up and purification 13.7 g (29.7 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 2950, 2870, 1740, 1720, 1605, 1585, 1450, 1370, 1315, 1275, 1245, 1115, 1075, 1030, 870, 810 and 715 cm'1.
Example 62e: 7- [ (IS,2R,3R,5R)-2-(tert-butyldiphenylsilyloxymethyl) - 315 (tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl)5 (Z)-heptenoic acid methyl ester: 19.8 g (33.4 mmol) of the compound prepared according to Example 62f are reacted analogously to Example lh, and after working-up and purification 22.4 g (32 mmol, 96 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3050, 3010, 2940, 2860, 1740, 1720, 1605, 1590, 1455, 1430, 1275, 1115, 1070, 1025, 825, 740 and 710 cm'1.
Example 62f: 7-[(IS,2R,3R,5R)-2-(tert-butyldiphenylsilyloxymethyl)-3(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl)-5(Z)heptenoic acid methyl ester: .8 g (44.4 mmol) of the compound prepared according to 30 Example 62g are reacted analogously to Example li, and after working-up and purification 19.9 g (33.4 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 3050, 3010, 2940, 2860, 1740, 1590, 1430, 1200, 1110, 1075, 1020, 1000, 870, 825, 740 and 705 cm-1.
Example 62c?: 7-[(IS,2R,3R, 5R)-2- (tert-butyldiphenylsilyloxymethyl)-3(tetrahydropyran-2-yloxy)-5-hydroxy-cyclopentyl) -5(Z)heptenoic acid: 23.8 g (47.9 mmol) of the compound prepared according to Example 62h are reacted analogously to Example 1j, and after working-up and purification 25.8 g (44.4 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3700-2400, 3070, 3050, 2940, 2860, 1710, 1590, 1430, 1390, 1260, 1200, 1110, 1075, 1045, 1020, 995, 880, 825, 740 and 705 cm-1.
Example 62h: (IR,3RS,5S,6R,7R)-3-hydroxy-6- (tert-butyldiphenylsilyl20 oxymethyl)-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo[3.3.0] octane : 23.8 g (48.1 mmol) of the compound prepared according to Example 62i are reacted analogously to Example lk, and after working-up and purification 23.8 g (47.9 mmol, 99 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 3050, 2940, 2860, 1740, 1590, 1430, 1390, 1375, 1355, 1240, 1110, 1075, 1020, 870, 820, 740 and 705 cm-1.
Example 62i: (1R,5S,6R,7R)-3 - oxo-6-(tert-butyldiphenylsilyloxymethyl)-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo[3.3.0]octane: 6.83 ml of dihydropyran and 135 mg of p-toluenesulphonic acid are added at 0°C to a solution of 20.7 g (50.4 mmol) of the compound prepared according to Example 62j in 400 ml of anhydrous dichloromethane and the mixture is stirred under an atmosphere of dry argon for 1.5 hours. The mixture is diluted with dichloromethane, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution and dried over magnesium sulphate. The residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 300 ml of fine silica gel. 23.8 g (48.1 mmol, 95 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3050, 2940, 2860, 1780, 1740, 1590, 1470, 1430, 1390, 1375, 1355, 1245, 1170, 1110, 1075, 1035, 870, 825, 745 and 705 cm-1.
Example 62~i ·.
(IR,5S,6R,7R)-3-oxo-6-(tert-butyldiphenylsilyloxymethyl)-7-hydroxy-2-oxabicyclo[3.3.0]octane : 3.32 g of potassium nitrite are added to a solution of 1.5 g (2.66 mmol) of the compound prepared according to Example 62k in 74 ml of anhydrous dimethylformamide and the mixture is heated at 85°C under an atmosphere of dry argon for 16 hours. The mixture is concentrated, diluted with water and extracted repeatedly with dichloromethane. The combined organic extracts are washed with saturated sodium chloride solution and dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on approximately 100 ml of fine silica gel. 700 mg (1.70 mmol, 64 %) of the title compound are isolated in the form of a colourless 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 62k: (IR, 5S, 6R, 7S) -3-OXO-6- (tert-butyldiphenylsilyloxymethyl) 7-toluenesulphonyloxy-2-oxabicyclo [3.3.0] octane : 2.37 g (5.77 mmol) of (IR,5S,6R,7S)-3-OXO-6-(tertbutyldiphenylsilyloxymethyl) -7-hydroxy-2-oxabicyclo[3.3.0]octane are reacted analogously to Example lm, and after working-up and purification 2.9 g (5.17 mmol, 90 %) of the title compound are isolated in the form of a colourless oil.
IR (CHC13): 3070, 3050, 3030, 3000, 2960, 2930, 2860, 1770, 1600, 1425, 1365, 1190, 1175, 1110, 1040, 980, 960, 895, 875, 820 and 700 cm-1.
Example 63: 7- [ (IS, 2R, 3R, 5R) -2- [ (E/Z) -phenylureidoiminomethyl] -3,5dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: 99.5 mg (210 μπιοί) of the compound prepared according to Example 63a are reacted analogously to Example 62, and after working-up and purification 77 mg (198 μπιοί, 94 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3380, 3260, 3010, 2950, 2860, 1710, 1670, 1600, 1590, 1500, 1450, 1240, 750 and 690 cm'1.
Example 63a: 7- [ (IS, 2R, 3R, 5R) -2- [ (E/Z) -phenylureidoiminomethyl] -3(tetrahydropyran-2-yloxy) -5-hydroxy-cyclopentyl] -5(Z) heptenoic acid: 345 mg (583 μπιοί) of the compound prepared according to Example 63b are hydrolysed analogously to Example 2, and after working-up and purification 248 mg (418 μπιοί, 72 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3380, 3220, 3100, 3010, 2940, 2870, 1710, 1690, 1590, 1535, 1450, 1320, 1230, 1115, 1030, 1020, 985, 870, 810, 755 and 690 cm'1.
Example 63b: 7-[(IS,2R,3R,5R) -2-[(E/Z)-phenylureidoiminomethyl]-315 (tetrahydropyran-2-yloxy) - 5-benzoyloxy-cyclopentyl] 5(Z)-heptenoic acid methyl ester: 600 mg (1.31 mmol) of the compound prepared according to Example 62c are reacted analogously to Example 62b using 4-phenylsemicarbazide, and after working-up and purifica20 tion 775 mg (1.31 mmol, 100 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3380, 3200, 3100, 2950, 2870, 1715, 1690, 1595, 1535, 1450, 1275, 1225, 1115, 1035, 1025, 980, 870, 815, 760, 715 and 695 cm1.
Example 64: - [(IS,2R,3R,5R) - 2-(2 -fluorobenzyloxymethyl)-3,5-dihydroxy-cyclopentyl]-5 (Z)-heptenoic acid: 50.6 mg (112 μπιοί) of the compound prepared according to Example 64a are reacted analogously to Example 62, and after working-up and purification 34.9 mg (95 μπιοί, 85 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2930, 2870, 1710, 1620, 1595, 1495, 1455, 1230, 1110, 1085, 1020, 995 and 760 cm'1.
Example 64a: 7- [ (IS, 2R, 3R, 5R) -2- (2-fluorobenzyloxymethyl) -3- (tetrahydropyran-2-yloxy) -5-hydroxy-cyclopentyl] -5 (Z) -heptenoic acid: 127 mg (224 μπιοί) of the compound prepared according to Example 64b are hydrolysed analogously to Example 2, and after working-up and purification 69 mg (153 μπιοί, 69 %) of the title compound are isolated in the form of a colourless oil.
IR (film) : 3600-2400, 3010, 2930, 2870, 1710, 1620, 1590, 1495, 1455, 1235, 1115, 1085, 1020, 995, 870, 810 and 760 cm'1.
Example 64b: - [ (1S,2R,3R, 5R) - 2- (2 - f luorobenzyloxymethyl) - 3- (tetrahydropyran-2-yloxy) -5-benzoyloxy-cyclopentyl] -5 (Z) heptenoic acid methyl ester: 3.5 ml of a 25 % aqueous sodium hydroxide solution, mg of tetrabutylammonium hydrogen sulphate and 1.03 g of 2 - fluorobenzyl bromide are added to a solution of 500 mg (1.09 mmol) of the compound prepared according to Example 62d in 8.5 ml of toluene and the two-phase system is stirred at 23°C for 5 days. The mixture is diluted with water, adjusted to a pH value of 5 by the addition of saturated citric acid and extracted repeatedly with diethyl ether. The combined organic extracts are dried over magnesium sulphate and the residue obtained after removal of the solvent is purified by chromatography on approximately 100 ml of silica gel with a mixture of n-hexane and ethyl acetate. 137 mg (241 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3010, 2950, 2870, 1740, 1720, 1620, 1605, 1590, 1495, 1455, 1365, 1315, 1275, 1115, 1025, 870, 815, 760 and 715 cm-1.
Example 65: 7-[(IS,2R,3R,5R)-2-benzyloxymethyl-3,5-dihydroxy-cyclopentyl] -5 (Z) -heptenoic acid: 57.5 mg (13 3 μπιοί) of the compound prepared according to Example 65a are reacted analogously to Example 62, and after working-up and purification 40 mg (115 μτηοΐ, 86 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3700-2400, 3070, 3030, 3010, 2930, 2870, 1710, 1450, 1240, 1100, 1070, 740 and 700 cm-1.
Example 65a: 7-[(IS, 2R,3R,5R)-2-benzyloxymethyl-3-(tetrahydropyran-2yloxy) -5-hydroxy-cyclopentyl]-5(Z) -heptenoic acid: 126 mg (229 μπιοί) of the compound prepared according to Example 65b are hydrolysed analogously to Example 2, and after working-up and purification 77 mg (178 μπιοί, 78 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2940, 2870, 1710, 1455, 1365, 1260, 1240, 1200, 1115, 1075, 1020, 995, 870, 810, 740 and 700 cm-1.
Example 65b: 7-((IS,2R,3R,5R)-2-benzyloxymethyl-3-(tetrahydropyran-2yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester : 500 mg (1.09 Mmol) of the compound prepared according to Example 62d are reacted analogously to Example 64b using benzyl bromide, and after working-up and purification 134 mg (243 Mmol, 22 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3030, 3010, 2940, 2860, 1735, 1720, 1605, 1585, 1450, 1365, 1275, 1115, 1075, 1025, 870, 815, 740, 715 and 700 cm-1.
Example 66: 7-[(IS,2R,3R,5R)-2-(3-methylbenzyloxymethyl)-3,5-dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: 36.3 mg (81 Mmol) of the compound prepared according to Example 66a are reacted analogously to Example 62, and after working-up and purification 23 mg (63 μ.π\ο1, 78 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2930, 2870, 1710, 1610, 1410, 1245, 1155, 1085, 885, 785, 745 and 700 cm-1.
Example 66a: 7-[(IS,2R,3R,5R)-2-(3-methylbenzyloxymethyl)-3-(tetrahydropyran-2 -yloxy) - 5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid: 68.7 mg (122 Mmol) of the compound prepared according to Example 66b are hydrolysed analogously to Example 2, and after working-up and purification 41.4 mg (93 Mmol, 76 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2940, 2870, 1710, 1610, 1455, 1440, 1355, 1200, 1160, 1115, 1075, 1020, 995, 870, 780, 740 and 695 cm-1.
Example 66b: 7- [ (IS,2R,3R,5R)-2-(3-methylbenzyloxymethyl)-3-(tetrahydropyran-2-yloxy) -5-benzoyloxy-cyclopentyl] -5(Z) heptenoic acid methyl ester: 1.3 g (2.82 mmol) of the compound prepared according to Example 62d are reacted analogously to Example 64b using 3-methylbenzyl bromide, and after working-up and purification 424 mg (751 μπιοί, 27 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3060, 3010, 2940, 2860, 1740, 1720, 1605, 1585, 1450, 1360, 1315, 1275, 1115, 1075, 1025, 780 and 715 cm1.
Example 67: 7-[(IS,2R,3R,5R)-2-(4 -fluorobenzyloxymethyl)-3 , 5-dihydroxy-cyclopentyl] -5(Z)-heptenoic acid: 66.8 mg (148 Mmol) of the compound prepared according to Example 67a are reacted analogously to Example 62, and after working-up and purification 39.2 mg (107 Mm°l/ %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2940, 2870, 1710, 1605, 1510, 1225, 1090, 855 and 825 cm-1.
Example 67a: 7-[(IS,2R,3R,5R)-2-(4-fluorobenzyloxymethyl)-3-(tetrahydropyran-2 -yloxy) -5-hydroxy-cyclopentyl] - 5 (Z) -heptenoic acid: 136 mg (238 μπιοί) of the compound prepared according to - 76 Example 67b are hydrolysed analogously co Example 2, and after working-up and purification 87.5 mg (194 gmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2940, 2870, 1710, 1605, 1510, 1225, 1115, 1075, 1020, 995, 855 and 825 cm’1.
Example 67b: 7-[(IS,2R,3R,5R)-2-(4-fluorobenzyloxymethyl)-3-(tetrahydropyran-2-yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)10 heptenoic acid methyl ester: 500 mg (1.09 mmol) of the compound prepared according to Example 62d are reacted analogously to Example 64b using 4 - fluorobenzyl bromide, and after working-up and purification 144 mg (253 gmol, 23 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3010, 2950, 2870, 1740, 1715, 1605, 1510, 1450, 1365, 1315, 1275, 1225, 1115, 1025, 1000, 825 and 715 cm-1.
Example 68: 7 - [(IS, 2R,3S,5S)-2-[(E/Z)-diphenylmethoxyiminomethyl]-3 hydroxy-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: mg (134 gmol) of compound A prepared according to Example 68 are reacted analogously to Example 62, and after working-up and purification 46 mg (101 gmol, 76 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3060, 3030, 3010, 2940, 2870, 1730, 1600, 1495, 1455, 1240, 1020, 935, 745 and 700 cm1.
Example 68a: 7-[(IS, 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-[(E/Z)- diphenylmethoxyiminomethyl] -4- (tetrahydropyran-2-yloxy) cyclopent-l-enyl]-5(Z)-heptenoic acid methyl ester: 252 mg (471 μπιοί) of the compound prepared according to Example 68b are reacted analogously to Example 1, and after working-up and purification 72 mg (134 μπιοί, 28 %) jq of title compound A and 58 mg (112 μπιοί, 24 %) of title compound B are isolated, each in the form of a colourless oil.
IR (film): 3600-3200, 3060, 3030, 3010, 2940, 2870, 1730, 1600, 1455, 1245, 1020, 935, 870, 820, 745 and 700 cm1. j 5 Example 68b: 7- [ (IS, 2R, 3S, 5R) -2- [ (E/Z) -diphenylmethoxyiminomethyl] -3(tetrahydropyran-2-yloxy) -5-hydroxy-cyclopentyl] -5 (Z) heptenoic acid methyl ester: An ethereal solution of diazomethane is added to a solution of 257 mg (493 μπιοί) of the compound prepared according to Example 68c in 10 ml of diehloromethane, and when the reaction is complete the mixture is concentrated. 262 mg (489 μπιοί, 99 %) of the title compound are isolated in the form of a colourless 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 cm-1.
Example 68c: 7- [ (IS, 2R, 3S, 5R) -2- [ (E/Z) -diphenylmethoxyiminomethyl] -3(tetrahydropyran-2-yloxy) -5-hydroxy-cyclopentyl] -5(Z) heptenoic acid: 569 mg (889 μπιοί) of the compound prepared according to Example 68d are hydrolysed analogously to Example 2, and after working-up and purification 399 mg (765 μπιοί, 86 % of the title compound are isolated in the form of a colourless 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 cm1.
Example 68d: - [ (1S,2R,3S,5R) - 2- [ (E/Z) -diphenylmethoxyiminomethyl ] - 3 1 5 (tetrahydropyran-2-yloxy) -5-benzoyloxy-cyclopentyl] -5 (Z) heptenoic acid methyl ester: 300 mg (654 μπιοί) of the compound prepared according to Example 68e are reacted analogously to Example 62b, and after working-up and purification 268 mg (453 μπιοί, 20 69 %) of the title compound are isolated in the form of colourless oil.
IR (film): 3380, 3210, 3100, 3010, 2950, 2870, 1735, 1715, 1690, 1600, 1535, 1450, 1360, 1320, 1275, 1115, 1070, 1030, 970, 870, 815, 760, 715 and 695 cm1. 2 3 Example 6 8e: 7- [ (IS, 2R, 3S, 5R) -2-formyl-3- (tetrahydropyran-2-yloxy) -5benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester 1.2 g (2.61 mmol) of the compound prepared according to Example 68f are reacted analogously to Example 50b, and 3Q after working-up there are isolated 1.2 g (2.61 mmol, 100 %) of the title compound which is reacted further without being purified.
Example 68f: 7-[(IS,2R, 3S,5R) -2-hydroxymethyl-3-(tetrahydropyran-2yloxy)-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 2.16 g (3.09 mmol) of the compound prepared according to Example 68g are reacted analogously to Example lg, and after working-up and purification 1.2 g (2.61 mmol, 85 %) of the title compound are isolated in the form of a colourless 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 68cf: 7-[(IS,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 the compound 7-[(IS,2R,3S,5R)- 2(tert-butyldiphenylsilyloxymethyl)-3-(tetrahydropyran-22θ yloxy)-5-hydroxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester prepared analogously to Example 29b are reacted analogously to Example lh, and after working-up and purification 62.5 g (89.4 mmol, 90 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3070, 3050, 3010, 2950, 2860, 1740, 1715, 1600, 1585, 1450, 1425, 1275, 1110, 1025, 970, 870, 825, 790, 710, 690, 610 and 500 cm'1.
Example 69: 7-[(IS,2R,3S,5S)-2-[(E/Z)-diphenylmethoxyiminomethyl] -3hydroxy-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (101 μπιοί) of the compound prepared according to Example 68 are hydrolysed analogously to Example 2, and after working-up and purification 29 mg (66 μπιοί, 65 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2940, 2870, 1710, 1600, 1495, 1455, 1240, 1020, 935, 745 and 700 cm-1.
Example 70: 7-[(IS,2R,3S,5R)-2 - [ (E/Z)-diphenylmethoxyiminomethyl]3,5-dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: 128 mg (244 μπιοί) of the compound prepared according to Example 68c are reacted analogously to Example 62, and after working-up and purification 84 mg (192 μπιοί, 78 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3060, 3030, 3010, 2940, 1710, 1605, 20 1495, 1450, 1375, 1245, 1045, 1020, 935, 920, 745 and 700 cm1.
Example 71: 7- [(IS, 2R,3R,5S)-2-[(E/Z)-phenylureidoiminomethyl]-3,5dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: 137.6 mg (271 μπιοί) of the compound prepared according to Example 71a are hydrolysed analogously to Example 2, and after working-up and purification 93.8 mg (241 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3370, 3010, 2940, 1730-1680, 1600, 1540, 1450, 1375, 1240, 1115, 1045, 760 and 695 cm-1.
Example 71a: 7-[(IS,2R,3R,5S)-2-[(E/Z)-phenylureidoiminomethyl]-3hydroxy-5-benzoyloxy-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 248 mg (419 μπιοί) of the compound prepared according to Example 71b are reacted analogously to Example 62, and after working-up and purification 149 mg (294 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3380, 3070, 3010, 2950, 2870, 17401680, 1600, 1540, 1450, 1360, 1315, 1275, 1175, 1115, 1070, 1030, 940, 760, 715 and 695 cm’1.
Example 71b: 7-[(IS,2R,3R,5S)-2-[(E/Z)-phenylureidoiminomethyl]-3(tetrahydropyran-2-yloxy) -5-benzoyloxy-cyclopentyl] -5 (Z) heptenoic acid methyl ester: 00 mg (6 54 μπιοί) of the compound prepared according to Example 68e are reacted analogously to Example 62b, and after working-up and purification 268 mg (453 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3380, 3210, 3100, 3010, 2950, 2860, 1735, 1715, 1690, 1595, 1530, 1450, 1315, 1275, 1115, 1025, 970, 870, 810, 755, 715 and 695 cm’1.
Example 72: 7- [ (IS, 2R, 3S, 5S) -2- (3-methylbenzyloxymethyl) -3-hydroxy-5fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 201 mg (435 μτηοΐ) of the compound prepared according to Example 72a are reacted analogously to Example 62, and after working-up and purification 89 mg (235 μπιοί, 54 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3010, 2940, 2860, 1735, 1610, 1440, 1360, 1250, 1220, 1155, 1100, 1090, 780, 745 and 695 cm-1.
Example 72a: 7-[(IS,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-methylbenzyl10 oxymethyl) -4- (tetrahydropyran-2-yloxy) -cyclopent-lenyl]-5 (Z)-heptenoic acid methyl ester (B): 800 mg (1.74 mmol) of the compound prepared according to Example 72b are reacted analogously to Example 1, and after working-up and purification 201 mg (436 gmol, 25 %) of title compound A and 212 mg (480 gmol, 28 %) of title compound B are isolated, each in the form of a colourless 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 72b: 7- [(IS,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 prepared according to Example 68f are reacted analogously to Example 64b, and after working-up and purification 1.18 g (2.56 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3300, 3010, 2940, 2860, 1740, 1610, 1595, 1440, 1355, 1250, 1200, 1155, 1115, 1075, 1020, 975, 905, 870, 815, 780, 745 and 695 cm-1.
Example 73 : 7-[(IS,2R,3S,5S) -2-(3-methylbenzyloxymethyl)-3-hydroxy-5fluoro-cyclopentyl] -5(Z)-heptenoic acid: .7 mg (81 μπιοί) of the compound prepared according to Example 72 are hydrolysed analogously to Example 2, and after working-up and purification 19.8 mg (54 μτηοΐ, 67 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2930, 2860, 1710, 1610, 1590, 1455, 1440, 1360, 1240, 1155, 1100, 1085, 780, 745 and 695 cm1.
Example 74: 7-[(IS,2R,5S)-2-(3-methylbenzyloxymethyl)-5-fluorocyclopentyl] - 5 (Z) -heptenoic acid methyl ester: 76 mg (148 μπιοί) of the compound prepared according to Example 74a are reacted analogously to Example 11, and after working-up and purification 36.4 mg (106 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3010, 2930, 2850, 1730, 1610, 1590, 1455, 1410, 1355, 1240, 1160, 1100, 1090, 780, 755 and 695 cm'1.
Example 74a: 7- [ (IS, 2R, 3S, 5S) -2- (3-methylbenzyloxymethyl) -4-toluene25 sulphonyloxy-5-fluoro-cyclopentyl]-5 (Z) -heptenoic acid methyl ester: mg (162 μπιοί) of the compound prepared according to Example 72 are reacted analogously to Example 1m, and after working-up and purification 76 mg (148 μπιοί, 92 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3050, 3010, 2950, 2920, 2860, 1735, 1600, 1435, 1360, 1190, 1175, 1095, 975, 945, 885, 815, 780, 745 and 665 cm1.
Example 75: 7- [ (IS,2R,5S)-2-(3-methylbenzyloxymethyl)-5-fluorocyclopentyl] -5(Z)-heptenoic acid: mg (106 μπιοί) of the compound prepared according to Example 74 are hydrolysed analogously to Example 2, and after working-up and purification 8.6 mg (26 μπιοί, 25 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2920, 2850, 1705, 1610, 1590, 1455, 1410, 1355, 1240, 1155, 1105, 1085, 780, 755 and 695 cm1.
Example 76: 7-[(1S,2R,3S,5R)- 2 -(3-methylbenzyloxymethyl) -3,5-dihydroxy-cyclopentyl]-5 (Z)-heptenoic acid methyl ester: 87.2 mg (189 μπιοί) of the compound prepared according to Example 72b are reacted analogously to Example 62, and after working-up and purification 63.4 mg (168 μπιοί, _89 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3100, 3010, 2950, 2930, 2860, 1735, 1610, 1440, 1360, 1245, 1160, 1100, 780, 745 and 695 cm1.
Example 77: 7-[(IS, 2R,3S,5R)-2-(3-methylbenzyloxymethyl)-3,5-dihydroxy-cyclopentyl]-5(Z)-heptenoic acid: mg (141 μπιοί) of the compound prepared according to 30 Example 76 are hydrolysed analogously to Example 2, and after working-up and purification 40 mg (110 μπιοί, 79 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-2400, 3010, 2930, 2860, 1710, 1610, 1590, 1455, 1430, 1405, 1355, 1245, 1155, 1100, 780, 745 and 695 cm-1.
Example 78: 6-[(IR,2S,5R)-2-[3-(4 - fluorophenyl) -ureidomethyl]-5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 21 μΐ of 4 - fluorophenyl isocyanate are added to a solution of 80 mg (max. 136 Mmol) of the amine prepared according to Example 78a in 1 ml of dichloromethane and the mixture is stirred at 23°C for 2.5 hours. Purification is effected by chromatography on three analytical thin-layer plates. A mixture of n-hexane and ethyl acetate is used as mobile solvent, and ethyl acetate is used as eluting agent. 25 mg (66 Mm°l, 48 of the title compound are isolated in the form of a colourless oil.
IR (film): 3250-3450, 3050, 2950, 2850, 1730, 1640, 1595, 1555, 1515, 1490, 1430, 1325, 1235, 835, 735 and 705 cm-1.
Example 78a: 6-[(IR,2S,5R)-2-aminomethyl-5-fluoro-cyclopentyl)-4(Z)hexenoic acid methyl ester: 874 mg of triphenylphosphine are added to a solution of 747 mg (2.77 mmol) of the compound prepared according to Example 78b in 24 ml of tetrahydrofuran and the mixture is heated at 50°C under an atmosphere of dry argon for 3.5 hours. 3 ml of water are then added and the mixture is heated at reflux for 1 hour. The mixture is concentrated, taken up in dichloromethane and dried over magnesium sulphate, and after filtration and removal of the solvent there are isolated 1.62 g (max. 2.77 mmol) of amine which is contaminated with triphenylphosphine and triphenylphosphine oxide and which is reacted further without being purified.
Example 78b: 6- [ (IR, 2S, 5R) -2-azidomethyl-5-f luoro-cyclopentyl] -4 (Z) hexenoic acid methyl ester: 9 mg of sodium azide are added to a solution of 934 mg (3.04 mmol) of the bromide prepared according to Example 78c in 67 ml of dimethylformamide and the mixture is heated at 60°C under an atmosphere of dry argon for 4 hours. The mixture is poured into ice-water and extracted repeatedly with diethyl ether, and the organic phase is dried over magnesium sulphate and the residue obtained after filtration and removal of the solvent is purified by chromatography on approximately 200 ml of fine silica gel using a gradient system of nhexane and ethyl acetate. 747 mg (2.77 mmol, 91 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 2950, 2870, 2100, 1735, 1435, 1360, 1245 and 1160 cm'1.
Example 78c: - [ (IR, 2S, 5R) -2-bromomethyl-5-fluoro-cyclopentyl] - 4 (Z) hexenoic acid methyl ester: 2.05 ml of collidine, 5.05 g of tetrabromomethane and 4.0 g of triphenylphosphine are added to a solution of 74 3 mg (3.04 mmol) of the alcohol prepared according to Example 78d in 22 ml of acetonitrile and the mixture is stirred at 23°C under an atmosphere of dry argon for 17 hours. The mixture is concentrated and the resulting residue is purified by chromatography on approximately 200 ml of fine silica gel using a gradient system of nhexane and ethyl acetate. 934 mg (3.04 mmol, 100 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 2950, 2860, 1735, 1435, 1360, 1245, 1220, 1160 and 950 cm-1.
Example 78d: 6- [ (IR, 2S, 5R) -2-hydroxymethyl-5-fluoro-cyclopentyl] -4 (Z) hexenoic acid methyl ester (A) and 6-[ (5S)-5-hydroxycyclopent-1-enyl]-4(Z)-hexenoic acid methyl ester (B): 3.69 g of the substance mixture prepared according to Example 78e are reacted analogously to Example lg, and after working-up and purification 943 mg (4.20 mmol, %) of title compound B as a non-polar component and 758 mg (3.10 mmol, 30 %) of title compound A as a polar component are isolated, each in the form of a colourless oil.
IR (film) of A: 3200-3600, 3050, 2950, 2870, 1735, 1435, 1360, 1165, 1040, 945 and 875 cm-1.
IR (film) of B: 3200-3600, 3050, 2940, 2850, 1735, 1435, 1360, 1200, 1160 and 1025 cm'1.
Example 78e: 6- [ (IR, 2S, 5R) -2-tert-butyldiphenylsilyloxymethyl-5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester and 6- [ (5S) -5- (tert-butyldiphenylsilyloxymethyl) -cyclopent-lenyl] -4(Z)-hexenoic acid methyl ester: .0 g (10.4 mmol) of the compound prepared according to Example 78f are reacted analogously to Example 1, and after working-up and purification 3.81 g of a mixture of the two title compounds are isolated in the form of a colourless oil.
Example 78f: - [ (IR,2S,5S) - 2 - tert-butyldiphenylsilyloxymethyl - 5hydroxy-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 6.26 g (max. 58.3 mol) of the compound prepared according 5 to Example 78g are reacted analogously to Example 68b, and after working-up and purification 26.8 g (55.7 mmol, 96 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3600-3200, 3070, 3040, 2950, 2930, 2850, 1735, 1585, 1460, 1425, 1240, 1160, 1110, 1005, 820, 740 and 700 cm-1.
Example 78q: - [ (IR, 2S, 5S) -2-tert-butyldiphenylsilyloxymethyl-5hydroxy-cyclopentyl] -4 (Z) -hexenoic acid: 23.1 g (58.3 mmol) of the compound prepared according to Example lk are reacted analogously to Example lj using carboxypropyltriphenylphosphonium bromide, and after working-up 62.6 g of the title compound are isolated in the form of a crude product which is reacted further without being purified.
Example 79: 6- [ (IR, 2S, 5R) -2- [3- (4 - fluorophenyl) -ureidomethyl] -5fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (66 μπιοί) of the compound prepared according to Example 78 are hydrolysed analogously to Example 2, and after working-up and purification 21 mg (57 μπιοί, 87 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.4-2.4 (m, 12H) , 3.12-3.35 (m, 2H) , 4.74(m,lH), 5.4-5.55(m,2H), 6.92-7.04(m,2H), 7.28-7.38 (m,2H).
Example 80: 6-[(IR,2S,5R)-2- [3-(4-phenylphenyl)-ureidomethyl]-5fluoro-cyclopentvl]-4(Z)-hexenoic acid methyl ester: 0 mg (max. 13S μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example 78 using 4-phenyl-phenyl isocyanate, and after working-up and purification 25 mg (57 μπιοί, 42 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3450, 3030, 2950, 2860, 1735, 1645, 1590, 1550, 1485, 1310, 1265, 1230, 835, 765, 735 and 700 cm'1.
Example 81: 6-[(IR,2S,5R)-2-[3-(4-phenylphenyl)-ureidomethyl]-5fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (57 μπιοί) of the compound prepared according to Example 80 are hydrolysed analogously to Example 2, and after working-up and purification 14 mg (33 μπιοί, 58 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.5 - 2.4(m,12H) , 3.17-3.35(m,2H) , 4.78(m,lH), 5.4-5.55(m,2H) , 7.22 - 7.6(m,9H) .
Example 82: 6-[(IR,2S,5R)-2-[3-(4-methylphenyl)-ureidomethyl]-5fluorocyclopentyl]-4 (Z)-hexenoic acid methyl ester·. mg (max. 136 μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example 78 using 4-methylphenyl isocyanate, and after working-up and purification 28 mg (74 gmol, 55 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3250-3450, 3050, 2950, 2860, 1730, 1640, 1600, 1555, 1515, 1260, 815, 735 and 705 cm-1.
Example 83: 6-[(IR,2S,5R)-2-[3-(4-methylphenyl)-ureidomethyl]-5fluoro-cyclopentyl] -4(Z)-hexenoic acid: mg (74 gmol) of the compound prepared according to Example 82 are hydrolysed analogously to Example 2, and after working-up and purification 14 mg (39 gmol, 52 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD): δ = 1.45-2.4(m,15H), 3.12-3.34(m,2H), 4.76(m,lH), 5.4-5.55(m,2H), 7.06(d,2H), 7.21(d,2H).
Example 84: 6-[(IR,2S,5R)-2-[3-(3-chlorophenyl)-ureidomethyl] -5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: mg (max. 136 gmol) of the compound prepared according to Example 78a are reacted analogously to Example 78 using 3-chlorophenyl isocyanate, and after working-up and purification 25 mg (63 gmol, 46 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3450, 3040, 2950, 2860, 1730, 1650, 1590, 1550, 1480, 1435, 1420, 1300, 1265, 1230, 1165, 775, 735, 700 and 680 cm'1.
Example 85: 6- [ (IR,2S,5R)-2-[3-(3-chlorophenyl)-ureidomethyl]-5fluoro-cyclopentyl] -4. (Z) -hexenoic acid: mg (63 μπιοί) of the compound prepared according to Example 84 are hydrolysed analogously to Example 2, and after working-up and purification 10 mg (26 μπιοί, 41 %) of the title compound are isolated in the form of a colourless oil.
^H-NMR (CD3OD) : δ = 1.45-2.4 (m, 12H) , 3.15 - 3.35 (m, 2H) , 4.76(m,lH), 5.4-5.57(m,2H) , 6.9-6.98(m,IH) , 7.15-7.24 (m,2H) , 7.57(s,IH) .
Example 86: 6-[(IR,2S,5R)-2-[3-phenyl-ureidomethyl]-5-fluoro-cyclopentyl] -4 (Z) -hexenoic acid methyl ester: mg (max. 136 μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example 78 using phenyl isocyanate, and after working-up and purifi cation 24 mg (66 μπιοί, 49 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3450, 3050, 2950, 2860, 1730, 1645, 1595 1550, 1495, 1435, 1310, 1230, 1170, 750, 735 and 695 cm-1.
Example 87: 6-[(IR,2S,5R)-2-[3-phenyl-ureidomethyl]-5-fluoro-cyclopentyl] -4 (Z) -hexenoic acid: mg (66 μπιοί) of the compound prepared according to Example 86 are hydrolysed analogously to Example 2, and after working-up and purification 16 mg (46 μπιοί, 70 %) of the title compound are isolated in the form of a colourless oil.
(CD3OD) : δ = 1.45-2.4(m,12H), 3.12-3.35(m,2H), 4.75(m,lH), 5.4-5.55(m,2H), 6.96(t,lH), 7.2-7.38(m,4H).
Example 88 : 6-[(IR, 2S, 5R)-2-[3-(3,4-dichlorophenyl) -ureidomethyl]-5fluoro-cyclopentyl]-4 (Z)-hexenoic acid methyl ester: 80 mg (max. 136 μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example 78 using 3,4-dichlorophenyl isocyanate, and after working-up and purification 26 mg (60 μπιοί, 44 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3500, 3200-3450, 3010, 2950, 2860, 1730, 1650, 1585, 1540, 1470, 1375, 1265, 1230, 1130, 1025, 815, 735, and 700 cm-1.
Example 8 9 : 6-[(1R,2S,5R)-2- [3-(3,4-dichlorophenyl) -ureidomethyl] -515 fluoro-cyclopentyl]-4(Z)-hexenoic acid: 6 mg (60 μπιοί) of the compound prepared according to Example 88 are hydrolysed analogously to Example 2, and after working-up and purification 15 mg (36 μπιοί, 60 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.5-2.4 (m,12H) , 3.16-3.35(m,2H) , 4.75(m,lH), 5.4-5.55(m,2H) , 7.21(dd,lH), 7.35(d,lH), 7.71(d,IH).
Example 90: 6- [ (IR, 2S, 5R) - 2- [3- (4-nitrophenyl) -ureidomethyl] -5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 100 mg (max. 170 Mmol) of the compound prepared according to Example 78a are reacted analogously to Example 78 using 4-nitrophenyl isocyanate, and after working-up and purification 32 mg (79 μπιοί, 46 %) of the title compound are isolated in the form of a yellow oil.
IR (film): 3200-3450, 3010, 2950, 2870, 1730, 1700, 1670, 1610, 1600, 1550, 1500, 1330, 1300, 1230, 1175, 1110, 850, 735 and 700 cm'1.
Example 91: 6-[(IR,2S,5R) - 2- [3-(4-nitrophenyl)-ureidomethyl]-5fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (79 Mmol) of the compound prepared according to Example 90 are hydrolysed analogously to Example 2, and 'θ after working-up and purification 31 mg (79 μ^οΐ, 100 %) of the title compound are isolated in the form of a yellow oil. 1H-NMR (CD3OD) : δ = 1.5-2.4(m,12H) , 3.18-3.35(m,2H) , 4.76(m,lH), 5.4-5.55(m,2H), 7.58(d,2H), 8.14(d,2H).
Example 92: - [(1R,2S,5R)-2-[3-(4-chlorophenyl)-ureidomethyl]-5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 100 mg (max. 170 m^oI) of the compound prepared according to Example 78a are reacted analogously to Example 78 20 using 4-chlorophenyl isocyanate, and after working-up and purification 38 mg (101 μτηοΐ, 59 %) of the title compound are isolated in the form of a colourless solid.
IR (KBr) : 3200-3450, 3030, 2960, 2850, 1735, 1650, 1590, 1545, 1470, 1420, 1375, 1265, 1230, 1160, 780, 735 and 700 cm'1.
Example 93: 6- [ (IR, 2S,5R)-2-[3-(4-chlorophenyl)-ureidomethyl]-5f luoro-cyclopentyl] - 4 (Z) -hexenoic acid: mg (101 Mmol) of the compound prepared according to Example 92 are hydrolysed analogously to Example 2, and after working-up and purification 33 mg (86 Mmol, 85 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.45-2.4(m,12H) , 3.15-3.35(m,2H) , 4.76(m,lH), 5.4 - 5.55(m,2H) , 7.21(dd,2H), 7.35(dd,2H).
Example 94: 6- [ (IR, 2S, 5R) -2- (3- (4-aminophenyl) -ureidomethyl] -5fluoro-cyclopentyl]-hexanoic acid: mg of palladium-on-carbon (10 %) are added to a solution of 15 mg (38 mmol) of the compound prepared according to Example 91 in 1 ml of ethyl acetate and hydrogenation is carried out at 1 atm. hydrogen. After the theoretical amount of hydrogen has been absorbed, the mixture is filtered and concentrated, and the residue is purified by chromatography on an analytical thin-layer plate. A mixture of dichloromethane and ethanol is used as mobile solvent, and a mixture of trichloromethane and isopropanol is used as eluting agent. 13 mg (36 μπιοί, %) of the title compound are isolated in the form of a waxy solid. 1H-NMR (CD3OD) : δ = 1.2-2.0(m,14H) , 2.26(t,2H), 3.1-3.3 (m,2H), 4.76(m,lH), 6.71(d,2H), 7.08(d,2H).
Example 95: - [ (1R,2S,5R) - 2- [3 - (4-chlorophenyl) -ureidomethyl] -525 fluoro-cyclopentyl]-hexanoic acid: mg (44 Mmol) of the compound prepared according to Example 93 are reacted analogously to Example 94, and after working-up and purification 16 mg (42 Mmol, 94 %) of the title compound are isolated in the form of a colourless solid. (acetone dg) : δ = 1.25-1.9 (ffl, 14H) , 2.28(t,2H), 2.5-3.5 (s, IH) , 3.18(m,lH), 3.32(m,lH), 4.77(m,lH), .99(t,lH), 7.21 (d,2H), 7.5(d,2H), 8.08(s,lH).
Example 96: 6- [ (IR, 2S, 5R) -2- [ (2-nitrophenyl) -sulphonylaminomethyl] -5fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 147 mg (max. 250 gmol) of the compound prepared according to Example 7 8a are reacted analogously to Example lb using 2-nitrobenzenesulphonic acid chloride, and after working-up and purification 54 mg (126 gmol, 50 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3100, 3010, 2950, 2920, 2860, 1730, 1590, 1540, 1435, 1415, 1360, 1165, 1070, 855, 780, 740 and 655 cm'1.
Example 97: 6- [ (IR, 2S, 5R) -2- [ (2 - nit rophenyl) -sulphonylaminomethyl] -5fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (126 gmol) of the compound prepared according to Example 96 are hydrolysed analogously to Example 2, and after working-up and purification 48 mg (116 gmol, 92 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.4 - 2.4(m,12H) , 2.99(dd,lH), 3.15 (dd, IH) , 4.7(m,lH), 5.33 - 5.5(m,2H), 7.38-7.48(m,3H) , 8.03-8.1(m,IH).
Example 98: 6- [ (IR, 2S, 5R) -2-((4 -methylphenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 147 mg (max. 250 gmol) of the compound prepared according to Example 78a are reacted analogously to Example lb using tosyl chloride, and after working-up and purifica96 tion 83 mg (209 gmol, 84 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3010, 2950, 2870, 1730, 1600, 1435, 1330, 1285, 1160, 1090, 1075, 815 and 665 cm'1.
Example 99: 6- [ (IR, 2S, 5R) -2- [ (4-methylphenyl) -sulphonylaminomethyl] 5- fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (209 gmol) of the compound prepared according to Example 98 are hydrolysed analogously to Example 2, and ]° after working-up and purification 69 mg (180 gmol, 86 %) of the title compound are isolated in the form of a colourless solid.
IR (film) (CD3OD) : δ = 1.4-1.55(m,IH) , 1.63-2.38(m,11H) , 2.42(s,3H), 2.77(m,lH), 3.92(m,lH), 4.7(m,lH), 5.33-5.5 15 (m,2H), 7.38(d,2H), 7.72(d,2H).
Example 100: 6- [(IR,2S,5R)-2-((3,4-dichlorophenyl) -sulphonylaminomethyl]-5-f luoro-cyclopentyl]-4 (Z)-hexenoic acid methyl ester : 2o 147 mg (max. 250 μτηοΐ) of the compound prepared according to Example 78a are reacted analogously to Example lb using 3,4-dichlorobenzenesulphonic acid chloride, and after working-up and purification 81 mg (179 μπιοί, 72 %) of the title compound are isolated in the form of a colourless oil.
IR (film) : 3090, 3010, 2950, 2850, 1730, 1565, 1450, 1380, 1170, 1140, 1095, 1030, 885, 825, 780, 735, 710, 675 and 625 cm'1. - 97 Example 101: 6-[(IR,2S,5R)-2-((3,4-dichlorophenyl)-sulphonylaminomethyl]-5-fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (179 μπιοί) of the compound prepared according to Example 100 are hydrolysed analogously to Example 2, and after working-up and purification 68 mg (155 μπιοί, 87 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD): δ = 1.4-2.4(m,12H), 2.83(dd,lH), 2.97 (dd, IH), 4.7(m,lH), 5.35-5.5(m,2H), 7.73(m,2H), 7.98 (d,IH).
Example 102: 6-[(1R,2S,5R)-2-[(4-fluorophenyl)-sulphonylaminomethyl] 5- fluoro-cyclopentyl]-4(Z)-hexenoic acid methyl ester: 147 mg (max. 250 μτηοΐ) of the compound prepared according to Example 78a are reacted analogously to Example lb using 4 -fluorobenzenesulphonic acid chloride, and after working-up and purification 56 mg (139 μπιοί, 56 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3010, 2950, 2860, 1730, 1600, 1490, 1430, 1330, 1235, 1160, 1090, 840 and 670 cm'1.
Example 103: 6- [(IR,2S,5R)-2-[(4-fluorophenyl)-sulphonylaminomethyl]25 5-fluoro-cyclopentyl]-4(Z)-hexenoic acid: mg (139 μπιοί) of the compound prepared according to Example 102 are hydrolysed analogously to Example 2, and after working-up and purification 51 mg (132 μπιοί, 95 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD): δ = 1.4-2.36(m,12H), 2.8(dd,lH), 2.95 (dd, IH), 4.7(m,lH), 5.33-5.5(m,2H), 7.3(m,2H), 7.9 (m,2H).
Example 104: 6- [ (IR, 2S, 5R) -2- [phenylsulphonylaminomethyl] -5-fluoro5 cyclopentyl]-4(Z)-hexenoic acid methyl ester: 147 mg (max. 250 μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example lb using benzenesulphonic acid chloride, and after workingup and purification 51 mg (133 μπιοί, 53 %) of the title !0 compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3060, 3010, 2950, 2860, 1730, 1445, 1325, 1160, 1095, 755, 720 and 690 cm-1.
Example 105: 6- [ (IR, 2S, 5R) -2- [phenylsulphonylaminomethyl] -5-fluoro•5 cyclopentyl]-4(Z)-hexenoic acid: mg (133 μπιοί) of the compound prepared according to Example 104 are hydrolysed analogously to Example 2, and after working-up and purification 43 mg (116 μπιοί, 88 %) of the title compound are isolated in the form of a !0 colourless oil.
^-H-NMR (CD3OD) : δ = 1.4-2.4 (m, 12H) , 2.78(dd,lH), 2.93 (dd, IH) , 4.7(m,lH), 5.33-5.5(m,2H) , 7.52-7.65(m,3H) , 7.86(m,2H).
Example 106: 6- [ (IR, 2S, 5R) -2- [ (4-chlorophenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-4 (Z)-hexenoic acid methyl ester: 147 mg (max. 250 μπιοί) of the compound prepared according to Example 78a are reacted analogously to Example lb using 4-chlorobensenesulphonic acid chloride, and after θ working-up and purification 60 mg (143 μπιοί, 57 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3090, 3010, 2950, 2870, 1730, 1585, 1470, 1435, 1330, 1160, 1090, 1010, 830, 750 and 620 cm-1.
Example 107: 6-[(IR,2S,5R)-2-[(4-chlorophenyl)-sulphonylaminomethyl]5 - fluoro-cyclopentyl]-4(Z)-hexenoic acid: 0 mg (143 μπιοί) of the compound prepared according to Example 106 are hydrolysed analogously to Example 2, and after working-up and purification 45 mg (111 μπιοί, 78 %) of the title compound are isolated in the form of a colourless oil. 1H-N14R (CD3OD) : δ = 1.4-2.4(m,12H), 2.8(dd,lH), 2.95 (dd,lH), 4.7(m,lH), 5.33-5.5(m,2H), 7.58(d,2H), 7.82 (d,2H).
Example 108: 6-[(IR,2S,5R)-2-[(4-methylphenyl)-sulphonylaminomethyl]5 - fluoro-cyclopentyl]-hexanoic acid: mg (52 μπιοί) of the compound prepared according to Example 99 are reacted analogously to Example 94, and after working-up and purification 20 mg (52 μπιοί, 99 %) of the title compound are isolated in the form of a colourless oil. l-H-NMR (CD3OD) : δ = 1.2 -1.9 (m, 14H) , 2.28(t,2H), 2.42 (d,3H), 2.76(dd,lH), 2.92(dd,lH), 4.68(m,lH), 7.48 (d,2H), 7.72(d,2H). 100 Example 109: 6-[(IR,2S, 5R) -2- [phenyIsulphonylaminomethyl] - 5-f luorocyclopentyl] -hexanoic acid: mg (51 Mmol) of the compound prepared according to Example 105 are reacted analogously to Example 94, and after working-up and purification 19 mg (51 μτηοΐ, 100 %) of the title compound are isolated in the form of a colourless oil.
^-H-NMR (CD3OD) : δ = 1.2-1.9(m,14H), 2.28(t,2H), 2.77 (dd,IH) , 2.92(dd,lH), 4.7(m,lH), 7.52-7.66(m,3H) , 7.85 (m,2H) .
Example 110: 6- [ (IR, 2S , 5R) -2 - [ (4-chlorophenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-hexanoic acid: mg (47 gmol) °f the compound prepared according to Example 107 are reacted analogously to Example 94, and after working-up and purification 17 mg (42 Mm°l' 89 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD) : δ = 1.2-1.9 (m,14H) , 2.29(t,2H), 2.81 (dd,lH), 2.95(dd,lH), 4.72(m,lH), 7.58 a2H) , 7.82(d,2H) Example 111: - [ (IR, 2S, 5R) - 2- [ (4 - fluorophenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-hexanoic acid: mg (4 9 μτηοΐ) of the compound prepared according to Example 103 are reacted analogously to Example 94, and after working-up and purification 19 mg (49 Mmol, 100 %) of the title compound are isolated in the form of a colourless oil. 1H-NRjR (CD3OD) : δ = 1.2-1.96(m,14H), 2.28(t,2H), 2.78 (dd, IH), 2.93(dd,lH), 4.72(m,lH), 7.3(m,2H), 7.9(m,2H). 101 Example 112: 6- [ (IR, 2S, 5R) -2- [3- (4-fluorophenyl) -ureidomethyl] -5fluoro-cyclopentyl]-hexanoic acid: mg (27 Mmol) of the compound prepared according to 5 Example 79 are reacted analogously to Example 94, and after working-up and purification 10 mg (27 μπιοί, 100 %) of the title compound are isolated in the form of a colourless oil.
^-H-NMR (CD3OD) : δ = 1.25-2.0 (m, 14H) , 2.26(t,2H), 3.110 3.32(m,2H), 4.76(m,lH), 6.97{m,2H), 7.31(m,2H).
Example 113: 7- [ (IR, 2S, 5R) -2- [ (4 -chlorophenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 129 mg (max. 245 Mmol) of the compound prepared according 15 to Example 113a are reacted analogously to Example lb using 4-chlorobenzenesulphonic acid chloride, and after working-up and purification 49 mg (113 Mmol, 46 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3010, 2950, 2860, 1730, 1585, 1435, 1330, 1160, 1090, 830, 750, 735, 700 and 620 cm·1.
Example 113a: 7- [ (IR, 2S, 5R) -2-aminomethyl-5-fluoro-cyclopentyl] -5 (Z) heptenoic acid methyl ester: 416 mg (1.47 mmol) of the compound prepared according to Example 113b are reacted analogously to Example 78a, and after working-up and purification 776 mg (max. 1.47 mmol, approx. 50 %) of the title compound are isolated in the form of a colourless oil. 102 Example 113b: 7- [ (IR, 2S,5R)-2-azidomethyl-5-fluoro-cyclopentyl]-5(Z)heptenoic acid methyl ester: 502 mg (1.56 mmol) of the compound prepared according to Example 113c are reacted analogously to Example 78b, and after working-up and purification 416 mg (1.47 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film) : 2950, 2870, 2100, 1735, 1435, 1360, 1245 and 1160 cm-1.
Example 113c: 7- [ (IR, 2S, 5R) -2-bromomethyl-5-fluoro-cyclopentyl] -5 (Z) heptenoic acid methyl ester: 410 mg (1.59 mmol) of the compound prepared according to Example 113d are reacted analogously to Example 78c, and after working-up and purification 502 mg (1.56 mmol, %) of the title compound are isolated in the form of a colourless oil.
IR (film) : 2950, 2870, 1735, 1435, 1360, 1245, 1225, 1170 and 950 cm'1.
Example 113d: 7- [ (IR, 2S, 5R) -2-hydroxymethyl-5-fluoro-cyclopentyl] -5 (Z) heptenoic acid methyl ester (A) and 7-[ (5S)-5-hydroxycyclopent-l-enyl]-5 (Z)-heptenoic acid methyl ester (B) : 3.75 g of the substance mixture prepared according to Example 113e are reacted analogously to Example 78d, and after working-up and purification 941 mg (3.95 mmol, 8 %) of title compound B as a non-polar component and 820 mg (3.17 mmol, 31 %) of title compound A as a polar component are isolated, each in the form of a colourless oil. 103 IR (film) Of A: 3200-3600, 3050, 2950, 2870, 1735, 1435, 1360, 1165, 1040, 945 and 875 cm'1.
IR (film) of B: 3200-3600, 3050, 2950, 2860, 1735, 1435, 1360, 1200, 1160 and 1025 cm-1.
Example 113e: 7- [ (IR, 2S, 5R) -2-tert-butyldiphenylsilyloxymethyl-5fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester and 7- [ (5S) -5- (tert-butyldiphenylsilyloxyme thyl) -cyclopent-lenyl] -5(Z)-heptenoic acid methyl ester: .08 g (10.3 mmol) of the compound prepared according to Example li are reacted analogously to Example lg, and after working-up and purification 3.75 g of a mixture of the two title compounds are isolated in the form of a colourless oil.
I 5 Example 114: 7- [ (IR, 2S, 5R) -2- [ (4-chlorophenyl) -sulphonylaminomethyl] 5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: 9 mg (113 μπιοί) of the compound prepared according to Example 113 are hydrolysed analogously to Example 2, and after working-up and purification 47 mg (112 μπιοί, 99 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13) : δ = 1.3 5 - 2.2 (m, 12H) , 2-38(t,2H), 2.93 (t,2H), 4.79(m,lH), 5.35-5.58(m,3H), 7.48(d,2H), 7.79 (d,2H).
Example 115: 7- [(1R,2S,5R) - 2- [(4-fluorophenyl) - sulphonylaminomethyl] 5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 129 mg (max. 24 5 μπιοί) of the compound prepared according to Example 113a are reacted analogously to Example lb 104 using 4 -fluorobenzenesulphonic acid chloride, and after working-up and purification 50 mg (120 gmol, 49 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3060, 3010, 2940, 2860, 1730, 1590, 1490, 1435, 1330, 1235, 1165, 1150, 1090, 840, 735, 700 and 670 cm-1.
Example 116: 7- [ (IR, 2S,5R)-2-[(4-fluorophenyl)-sulphonylaminomethyl]10 5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (120 gmol) of the compound prepared according to Example 115 are hydrolysed analogously to Example 2, and after working-up and purification 44 mg (110 gmol, 91 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13) : ό = 1.35-2.2(m,12H) , 2.38(t,2H), 2.92 (t,2H), 4.77(m,1H), 5.35-5.58(m,3H) , 7.2(m,2H), 7.79 (m, 2H) .
Example 117: 7-((IR,2S,5R)-2-[3-(4-chlorophenyl)-ureidomethyl]-5fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 129 mg (max. 245 gmol) of the compound prepared according to Example 113a are reacted analogously to Example 78 using 4-chlorophenyl isocyanate, and after working-up and purification 60 mg (146 gmol, 60 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3040, 2950, 2850, 1730, 1650, 1595, 1545, 1470, 1420, 1375, 1260, 1225, 1160, 785, 735 and 700 cm-1 . 105 Example 118: 7-[(IR,2S,5R)-2-[3-(4-chlorophenyl)-ureidomethyl]-5fluoro-cyclopentyl] -5(Z)-heptenoic acid: 0 mg (14 6 μπιοί) of the compound prepared according to Example 117 are hydrolysed analogously to Example 2, and after working-up and purification 42 mg (106 μπιοί, 72 %) of the title compound are isolated in the form of a colourless oil.
}-H-NMR (CDC13) : δ = 1.38-2.2(m,12H), 2.36(t,2H), 3.2 (t,2H), 4.78(m,lH), 5.35 - 5.48(m,2H) , 5.58(t,lH), 7.157.25(m,4H), 7.49(s,IH).
Example 119: 7-[(IR,2S,5R)-2-[3-(4-nitrophenyl)-ureidomethyl]-5fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 129 mg (max. 245 μπιοί) of the compound prepared according to Example 113a are reacted analogously to Example 78 using 4-nitrophenyl isocyanate, and after working-up and purification 53 mg (126 gmol, 51 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200-3400, 3080, 3010, 2950, 2860, 1730, 1700, 1670, 1610, 1600, 1550, 1500, 1325, 1300, 1230, 1175, 1110, 850, 735 and 700 cm'1.
Example 120: - [ (IR,2S,5R)-2-[3-(4-nitrophenyl)-ureidomethyl] -525 fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (126 μπιοί) of the compound prepared according to Example 119 are hydrolysed analogously to Example 2, and after working-up and purification 44 mg (105 μπιοί, 83 %) of the title compound are isolated in the form of a 3θ yellow oil. 1H-MR (CDCI3) : δ = 1.32-2.15 (m, 12H) , 2.29(t,2H), 3.12 106 (t,2H), 4.72(m,lH), 5.25-5.4(m,2H), 5.5(t,lH), 7.087.15(m,4H) , 7.4 (s,lH) .
Example 121: 7-[(IR,2S,5R)-2-[(E/Z) -3-(3,4-dichlorophenyl)-ureido5 iminomethyl]-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: mg (max. 199 μπιοί) of the compound prepared according to Example 121a are reacted analogously to Example 62b using 4- (3,4-dichlorophenyl)semicarbazide hydrochloride, and after working-up and purification 75 mg (164 μπιοί, %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3360, 3200, 3100, 2940, 1730, 1690, 1580, 1520, 1470, 1390, 1290, 1220, 1130, 1025, 950, 875, 815, 740 and 690 cm-1.
Example 121a: 7- (IR,2S,5R) - 2-formyl-5-fluoro-cyclopentyl]-5(Z) heptenoic acid methyl ester: 410 mg (1.59 mmol) of compound A prepared according to Example 113d are reacted analogously to Example 50b, and after working-up 440 mg (max. 1.59 mmol) of the title compound are isolated in the form of a colourless oil which is reacted further without being purified.
Example 122: 7-[(IR,2S,5R)-2-[(E/Z) - 3-(3,4-dichlorophenyl)-ureidoiminomethyl]-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: 8 mg (83 μπιοί) of the compound prepared according to Example 121 are hydrolysed analogously to Example 2, and after working-up and purification 28 mg (63 μπιοί, 76 %) of the title compound are isolated in the form of a 107 colourless oil. 1H-NI4R (CDCI3) : δ = 1.62-2.5(m,14H), 2.77-2.88(m,0.25H), 4.78(m.lH), 5.2-5.3(m,0.25H), 5.42-5.58(m,1.75H), 6.52 (d,0.25H), 7.21(d,0.75H) , 7.23 - 7.4(m,2H) , 7.72(dd,lH), 8.02(s,0.75H), 8.28(s,0.25H) , 9.62 (s,0.75H), 10.01 (s,0.25H).
Example 123: 7-[(IR,2S,5R)-2-[(E/Z)-3-(4-chlorophenyl)-ureidoiminomethyl]-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: 165 mg (max. 596 /zmol) of the compound prepared according to Example 121a are reacted analogously to Example 62b using 4-(4-chlorophenyl)semicarbazide hydrochloride, and after working-up and purification 198 mg (467 μπιοί, 78 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3370, 3200, 3100, 2940, 2870, 1730, 1685, 1590, 1525, 1400, 1310, 1225, 1090, 950, 825 and 740 cm'1.
Example 124 : 7-[(IR,2S,5R)-2-[(E/Z)-3-(4-chlorophenvl)-ureidoiminomethyl]-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid: mg (142 Mmol) of the compound prepared according to Example 123 are hydrolysed analogously to Example 2, and after working-up and purification 50 mg (122 Mmol, 86 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDCI3): δ = 1.62-2.5(m,14H), 2.77-2.88(m,0.25H), 4.76(m,lH), 5.2-5.3(m,0.25H), 5.42-5.58(m,1.75H), 6.52 (d, 0.25H), 7.2(d,0.75H), 7.28(m,2H), 7.43(m,2H), 8.02 (s,0.75H), 8.24(s,0.25H), 9.64(s,0.75H), 9.98(s,0.25H). 108 Example 125: 7- [ (IR, 2S, 5R) -2- [3- (4-nitrophenyl) -ureidomethyl] -5fluoro-cyclopentyl]-heptanoic acid: mg (56 μπιοί) of the compound prepared according to 5 Example 120 are reacted analogously to Example 94, and after working-up and purification 18 mg (44 μπιοί, 79 %) of the title compound are isolated in the form of a yellow oil.
^H-NMR (CD3OD) : δ = 1.25 - 2 , (m, 16H) , 2.23(t,2H), 3.1210 3.36(m,2H), 4.76(m,lH), 7.58(d,2H), 8.13(d,2H).
Example 126 : - [(IR,2S,5R) - 2- [3 - (4-chlorophenyl) -ureidomethyl] - 5fluoro-cyclopentyl]-heptanoic acid: mg (52 μπιοί) of the compound prepared according to 15 Example 118 are reacted analogously to Example 94, and after working-up and purification 20 mg (50 μπιοί, 96 %) of the title compound are isolated in the form of a colourless solid. 1H-NMR (CD3OD): δ = 1.25-2(m,16H), 2.23(t,2H), 3.1220 3.32(m,2H), 4.75(m,lH), 7.21(d,2H), 7.35(d,2H).
Example 127: 7- [ (IR, 2S, 5R) -2- [ (4 - fluorophenyl) -sulphonylaminomethyl] 5 - fluoro-cyclopentyl]-heptanoic acid: mg (55 μπιοί) of the compound prepared according to 2 5 Example 116 are reacted analogously to Example 94, and after working-up and purification 19 mg (47 μπιοί, 86 %) of the title compound are isolated in the form of a colourless solid.
XH-NMR (CDCI3) : δ = 1.1-2, (m, 16H) , 2.36(t,2H), 2.8330 3.08(m,2H), 4.73(m,lH), 5.08(t,lH), 7.2(m,2H), 7.89 (m,2H) . 109 Example 128: 7-[(IR,2S,5R)-2- [ (4-chlorophenvl)-sulphonylaminomethyl]5-fluoro-cyclopentyl]-heptanoic acid: 3 mg (56 μπιοί) of the compound prepared according to Example 114 are reacted analogously to Example 94, and after working-up and purification 20 mg (48 μπιοί, 85 %) of the title compound are isolated in the form of a colourless solid. 1H-NMR (CDC13) : δ = 1.1-1.95(m,16H) , 2.3(t,2H), 2.76-3, (m,2H), 4.68(m,lH), 5.02(t,lH), 7.42(d,2H), 7.73(d,2H).
Example 129: 7-[(IR,2S,5R)-2- [ (E/Z)-2- (4-fluorophenylsulphonyl)hydrazonomethyl]-5-fluoro-cyclopentyl]-5(Z)-heptenoic acid methyl ester: mg (max. 596 μπιοί) of the compound prepared according to Example 121a are reacted analogously to Example 62b using 4 -fluorobenzenesulphonyl hydrazide, and after working-up and purification 225 mg (525 μπιοί, 88 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3180, 2950, 2860, 1730, 1710, 1590, 1490, 1435, 1365, 1320, 1235, 1170, 1155, 1090, 835 and 670 cm-1.
Example 130: - [(IR, 2S,5R)-2- [ (E/Z)-2-(4-fluorophenylsulphonyl)hydrazonomethyl] -5-f luoro-cyclopentyl] -5 (Z) -heptenoic acid: mg (140 μmol) of the compound prepared according to Example 129 are hydrolysed analogously to Example 2, and after working-up and purification 52 mg (125 μπιοί, 90 %) 110 of the title compound are isolated in the form of a colourless oil. 1H-NMR (CDC13): δ = 1.54-2.5(m,14H), 4.8(m,lH), 5.225.56(m,lH), 7.1-7.23(m,3H).
Example 131: - [ (IR,2S,5R)-2-[(Ξ/Ζ)-2- (4 -methylphenylsulphonyl)hydrazonomethyl] -5-fluoro-cyclopentyl] -5(Z) -heptenoic acid methyl ester: mg (max. 199 gmol) of the compound prepared according to Example 121a are reacted analogously to Example 62b using 4-toluenesulphonyl hydrazide, and after working-up and purification 78 mg (192 gmol, 97 %) of the title compound are isolated in the form of a colourless oil.
IR (film): 3200, 3000, 2950, 2870, 1730, 1710, 1595, 1435, 1360, 1320, 1160, 1090, 1030, 930, 810, 705 and 670 cm'1.
Example 132: 7- [ (IR, 2S, 5R) -2- [ (E/Z) -2- (4-methylphenylsulphonyl) hydrazonomethyl] -5-f luoro-cyclopentyl] -5(Z) -heptenoic acid : mg (96 gmol) of the compound prepared according to Example 131 are hydrolysed analogously to Example 2, and after working-up and purification 33 mg (84 gmol, 88 %) of the title compound are isolated in the form of a colourless solid.
^-H-NMR (CDCI3) : δ - 1.55-2.2 (m, 12H) , 2.32(t,2H), 2.42 (s,3H), 4.77(m,lH), 5.23 - 5.55(m,2H), 6.69(d, 0.IH), 7.13 (d,0.9H), 7.3(d,2H), 7.8(d,2H).
Ill Example 133: 7-[(IR,2S,5R)-2-[(E/Z)-2-(4 - fluorophenylsulphonyl) hydrazonomethyl]-5-fluoro-cyclopentyl]-heptanoic acid: 7 mg (89 μπιοί) of the compound prepared according to 5 Example 130 are reacted analogously to Example 94, and after working-up and purification 14 mg (34 μπιοί, 38 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD): δ = 1.0-1.75(m,15H), 2.08-2.22(m,3H), 4.62 (m,lH), 7.04(d, IH) , 7.21(m,2H), 7.82(m,2H).
Example 134: 7-[(1R,2S,5R)-2-[(E/Z)-2-(4-methylphenylsulphonyl) hydrazonomethyl]-5-fluoro-cyclopentyl]-heptanoic acid: mg (4 9 μπιοί) of the compound prepared according to Example 132 are reacted analogously to Example 94, and after working-up and purification 9 mg (23 μπιοί, 47 %) of the title compound are isolated in the form of a colourless oil. 1H-NMR (CD3OD): δ = 1.12-1.94(m,16H), 2.16-2.32(m,3H), 20 2.92(s,3H), 4.7(m,lH), 7.12(d,lH), 7.37(d,2H), 7.76 (d,2H).
Example 135: 7-[(IR,2S,5R)-2-[(E/Z)-3- (4-chlorophenyl)-ureidoiminomethyl]-5-fluoro-cyclopentyl]-heptanoic acid (A) and 725 [(IR, 2S, 5R)-2-[3-(4-chlorophenyl)-ureidoaminomethyl] -5fluoro-cyclopentyl]-heptanoic acid (B) : mg (4 9 μπιοί) of the compound prepared according to Example 124 are reacted analogously to Example 94 using PtC>2, and after working-up and purification 11 mg 30 (27 μπιοί, 54 %) of title compound A as a non-polar component and 8 mg (19 μπιοί, 3 9 %) of title compound B 112 are isolated, each in the form of a waxy solid.
(CD3OD) of Α: δ = 1.27-2.12(m,15H) , 2.23 (t,2H), 2.43(m,lH), 4.78(m,2H), 7.22(d,lH), 7.27(d,2H), 7.5(d,2H) 1H-NMR (CD3OD) of Β: δ = 1.25-2(m,16H) , 2.26(t,2H), 2.74 (dd,IH), 2.95(dd,lH), 4.76(m,lH), 7.27(d,2H), 7.45(d,2H). 113

Claims (7)

1. Patent claims
1. Cyclopentane derivatives of the formula I in which R 3 (I) R 1 may be or COOR, wherein R^ may represent hydrogen or C-^-C^qalkyl, C3-C 10 -cycloalkyl or C 7 -C 16 -aralkyl that are optionally substituted by halogen, phenyl, C^-C^-alkoxy or by di-(C 1 -C 4 )-alkylamino, Y-substituted phenacyl or C 6 -C 12 -aryl, or a 5- or 6-membered heterocyclic radical having at least one N, 0 or S atom, or R 1 may be -CONHR 7 , wherein R 7 represents hydrogen, C^C^-alkyl, C 6 -C 12 arylsulphonyl, C^-C 10 -alkanoyl or C 1 -C 10 -alkanesulphonyl, X may be -(CH 2 ) p -, -CH 2 -O- or -CH 2 -S-, Z and A, each independently of the other, may be a direct bond, (Z)-CH=CH-, (E)-CH=CH- or -C=C-, p may be from 0 to 5, R 2 may be fluorine or OH, n and r, each independently of the other, may be from 0 to 2, R 3 may be OR 6 or R 6 , it being possible for R 3 to be OR 6 only when A, on its own or together with W, represents a direct bond, W may be a direct bond, a - [ (CH 2 ) n -V]g- group, a -(CH 2 ) n -V-(CH 2 )q-V- group, a free or functionally modified hydroxymethylene group or a free or functionally modified group, it being possible for the 114 ΙΟ hydroxy group in each case to be in the a- or Bconfiguration, q may be 1 or 2, D may be a direct bond, a straight-chained saturated alkylene group having from 1 to 5 carbon atoms, a branched saturated alkylene group or a straight-chained or branched unsaturated alkylene group having from 2 to 5 carbon atoms, each of which may optionally be substituted H by fluorine atoms, or D may be q , Ν' ’ Η H -fCH^ N ,O^ I ‘N H ,N II v s D 'N Z ' γ V x. . Λ ,so r n N N Η H -{CH^ X n'N N « I Η H Η H I N 'Ν''” X ’ SO, ^CH^-NH-NH-SO,- or \ , V /SIX * · V may be an O or S atom, E may be a direct bond, -Cs=C- or -CH=CR 8 -, wherein R 8 may be hydrogen, C^-Cg-alkyl, halogen or trifluoromethyl, AWDE together may be a direct bond, AW together may be a direct bond, DE together may be a direct bond, / R 4 may be ~{CH2)5= n -(CH^ V a 2 115 - C 3 ~Ci 0 -cycloalkyl, or C x -C 10 -alkyl that is optionally substituted by Y, m may be 1 or 2, 5 Y x and Y 2 are identical or different and represent Y, Y may be hydrogen, halogen, N 3 , CF3 , OR 6 , N02, NH2, cm, COOR 6 or Cx-c X Q~alkyl, and R 6 may be hydrogen, C x -C 10 -alkyl, optionally halosubstituted Cg-C X2 -aryl or C7-C ls -aralkyl, JO and, when R 5 represents hydrogen, the salts thereof with physiologically tolerable bases, as well as the α-, B- or S'-cyclodextr in clathrates, as well as the compounds of formula I encapsulated with liposomes.
2. Medicament comprising one or more compounds of 15 claim 1 and customary adjuvants, carriers and additives.
3. Process for the preparation of cyclopentane derivatives of formula I, characterised in that the hydroxy compound of formula II in which R 1 , R 2 , R 3 , R 4 , X and Z have the meanings given above and R 1 represents a -COOR 5 ester group, wherein R 5 has the meanings given above except for hydrogen, is reacted, in the presence of sodium hydride or sodium hydride/bromine, with a halogen compound of the formula Hal-w-R 4 (III), wherein Hal, M and R 4 have the meanings 116 given above, or, after oxidation with oxalyl chloride/DMSO, with a dimethyl phosphonate of formula V O II (H 3 CO) 2 P (V), wherein D, E and R 4 have the meanings given above, and then the resulting product is reduced and, where appropriate, hydrogen bromide is removed, or the oxidation product of II and oxalyl chloride/DMSO is reacted with an amine of the formula H2N-O-R 4 (X), H2N-NH-SO 2 -R 4 (XIII) or R (XI) wherein R 4 has the meanings given above, or, thionyl chloride of formula after oxidation and reaction with and sodium azide, the intermediate amine (VIII), is reacted with a compound of the formula Hal-SO 2 ~R 4 (IX) or O=C=N-R 4 (XII), wherein Hal and R 4 have the meanings given above, or, after bromination, azide formation and reduction, the intermediate amine of formula (XIV) is reacted with a compound of the formula Hal-SO 2 -R 4 (IX) or O=C=N-R 4 (XII), wherein Hal and R 4 have the meanings given above, C-C multiple bonds are optionally hydrogenated, and the resulting esters are hydrolysed, converted - 117 into salts, converted into cyclodextrin clat'nratas or encapsulated with liposomes.
4. Use of a compound of formula I as defined in claim I for Che preparation of a medicament for use in a method of 5. Prophylaxis or treatment.
5. Ac ompound with reference substantially as hereinbefore described to the Examples.
6. A compos i t ion with reference to substantially as hereinbefore described the Examp 1e s .
7. 10 7. A use substantially as hereinbefore described with reference to the Examples.
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DE4036140A1 (en) * 1990-11-09 1992-05-14 Schering Ag 9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
AU687906B2 (en) * 1993-12-15 1998-03-05 Alcon Laboratories, Inc. Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension
SK3382000A3 (en) * 1997-09-09 2000-10-09 Procter & Gamble A compound having structure of aromatic substituted prostaglandins and its use for the treatment of bone disorders
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US6242493B1 (en) 1998-03-13 2001-06-05 Merck Frosst Canada & Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
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US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US7323591B2 (en) * 2006-01-10 2008-01-29 Allergan, Inc. Substituted cyclopentanes or cyclopentanones as therapeutic agents
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Publication number Priority date Publication date Assignee Title
GB1431561A (en) * 1973-01-31 1976-04-07 Ici Ltd Cyclopentane derivatives
IT1053781B (en) * 1974-09-25 1981-10-10 Erba C S P A Ora Farmitalia OMEGA NOR CICLOALCIL 13.14 DEIDRO PROSTAGLANDINE
FR2349328A1 (en) * 1976-04-30 1977-11-25 Roussel Uclaf (11)-Deoxy-prostaglandin analogues - for use as hypotensives, smooth-muscle contractants and luteolytic agents
DE3126924A1 (en) * 1981-07-03 1983-01-20 Schering Ag, 1000 Berlin Und 4619 Bergkamen 9-FLUOR PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT
DE3325175A1 (en) * 1983-07-08 1985-01-17 Schering AG, 1000 Berlin und 4709 Bergkamen 11-HALOGEN PROSTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
DE3510978A1 (en) * 1985-03-22 1986-09-25 Schering AG, Berlin und Bergkamen, 1000 Berlin NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
ES2054860T5 (en) * 1987-07-17 2003-11-01 Schering Ag DERIVATIVES OF 9-HALOGEN- (Z) -PROSTAGLANDINAS, PROCEDURE FOR ITS PREPARATION AND ITS USE AS MEDICATIONS.
DE3923797A1 (en) * 1989-07-14 1991-01-24 Schering Ag 9-FLUOR-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE

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EP0541594B1 (en) 1995-05-03
DE4191848D2 (en) 1993-10-07
IE912654A1 (en) 1992-01-29
IL98970A0 (en) 1992-07-15
CA2088161A1 (en) 1992-01-28
DE59105400D1 (en) 1995-06-08
ES2074721T3 (en) 1995-09-16
WO1992002495A1 (en) 1992-02-20
PT98464B (en) 1997-10-31
ZA915905B (en) 1992-04-29
DK0541594T3 (en) 1995-10-02
PT98464A (en) 1992-05-29
AU8221291A (en) 1992-03-02
JPH06502390A (en) 1994-03-17
ATE122036T1 (en) 1995-05-15
DE4024347A1 (en) 1992-01-30
EP0541594A1 (en) 1993-05-19

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