AU624078B2 - 9-halogen-(z)-prostaglandin derivatives, process for manufacturing them, and their use as drugs - Google Patents

Description

2 n P4J

WELTO

INTERNATIONALE ANMELDI INTERNATIONALE ZUSAMM HT14AC EM VERTRAG OBER DIE GEBIET DES PATENTWESENS (PCT) (51) Internationale Patentklassifikation 4 (11) Internationale Verdffentlichungsnummer: WO 89/ 00559 CO7C 177/00, A61K 31/557 Al (43) Internationales Veroffentlichungsdatum: 26. Januar 1989 (26.01.39) (21) Internationales Aktenzeichen: PCT/DE88/00452 Bekassinenweg 37, D-1000 Berlin 27 ELGER, Walter Schorlemerallee 12 B, D-1000 Berlin 33 (22) Internationales Anmeldedatum: 15. Juli 1988 (15.07.88) STORZEBECHER, Claus-Steffen Brigittenstrage 6 a, D-1000 Berlin 46 THIERAUCH, Karl-Heinz Hochwildpfad 45, D-1000 Berlin 37 (31) Prioritiitsaktenzeichen: P 37 24 189.3 (DE).

P 37 24 190.7 (32) Priorititsdaten: 17. Juli 1987 (17.07.87) (81) Bestimmungsstaaten: AU, DK, HU, JP.

17. Juli 1987 (17.07.87) (33) Priorititsland: DE Veroffentlicht Mit internationalem Recherchenbericht.

(71) Anmelder: SCHERING AKTIENGESELLSCHAFT BERLIN UND BERGKAMEN [DE/DE]; Miillerstraae 170/78, D-1000 Berlin 65 A..Jp. 6 APR 89 (72) Erfinder: BUCHMANN, Bernd Flemingstrage 5 a, D- 1000 Berlin 21 SKUBALLA, Werner; Olwenstrage 13, D-1000 Berlin 28 VORBRUGGEN, AUSTRALIAN Helmut Wilkestrae 7, D-1000 Berlin 27 RA- DOCHEL, Bernd; Gollanczstrage 132, D-1000 Berlin 1 3 FEB 1989 28 LOGE, Olaf ;PATENT OFFICE PAENT OFFICE (54)Title: 9-HALOGEN-(Z)-PROSTAGLANDIN DERIVATIVES, PROCESS FOR MANUFACTURING THEM, AND THEIR USE AS DRUGS (54) Bezeichnung: 9-HALOGEN-(Z)-PROSTAGLANDINDERIVATE, VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG ALS ARZNEIMITTEL Hal R b

R

1 0 (C) /-OR1

-C-OR

2 oder i or

A

0 R 0 (d)

/-C-HR

-C-NHR

3

CH

-C-

OH

A-W-D-E-R

5 (57) Abstract 9-Halogen-(Z)-prostane derivatives have the formula where Z is one of the residues or (b),-Hal is a chorine or fluorine atom in the a or P position, R, is the residue CH20H or where R 2 is a hydrogen atom or an alkyl, cycloalkyl, aryl, or heterocyclic residue, or R, is the residue where R 3 is an acid residue or the R 2 residue, A is a -CH 2

-CH

2 a trans-CH =CH or a -C=C-group, W is a free or functionally modified hydroxymethylene group or a free or functionally modified group, in which the corrcsponding OH groups can be in the a or P position, D and E together .represent a direct bond or D is a straight-chain alkylene group with 1-10 C-atoms, a branched-chain alkylene group with 2-10 C-atoms, or a cyclic alkylene group with 3-10 C-atoms, which may, if necessary, be substituted by fluorine atoms, and E is an oxygen or sulphur atom, a direct bond, a -CM C- bond, or a -CR 6

CR

7 -group, where R 6 and R 7 are different and stand for a hydrogen atom, a chlorine atom, or a C 1

-C

4 alkyl group, R 4 is a fre3 or functionally modified hydroxy group, Rs is a hydrogen atom, an alkyl group, a halogen-substituted alkyl group, a cycloalkyl group, a heterocyclic or possibly aryl-substituted group. The invention also concerns the salts of these derivatives with physiologically innocuous bases and their cyclodextrin chlathrates, in the case in which R, is a hydrogen atom. Also described are the process for manufacturing these derivatives and their pharmaceutical use.

Zusammenfassung Die Erfindung betrifft 9-Halogen-(Z)-prostanderivate der Formel worin Z die Reste (0) oder Hal emn a- oder 3-standiges Chior- oder Fluoratom, R, den Rest CH 2 0H oder mit R 2 in der Bedetung eines Wasserstoffatoms, eines Alkyl-, Gycloalkyl-, Aryl- oder heterocyclischen Restes oder R, den Rest mit R 3 in der Bedeutung eines Silurerestes oder des Restes R 2 und A eine -CH 2

-GH

2 eine trans-CH CH- oder eine -C =-C-Gruppe, W eine frei oder funktionell abgewandelte Hydroxymethylengruppe oder eine frei oder t'unktionnell abgewandelte Gruppe, wobei die jeweiligen OH-Gruppen a- oder f-sttandig sein kdnnen, D und E gemneinsam eine direkte Binduing oder D eine geradkettige mit 1 10, eine verzweigtkettige 2 10 oder eine ringf6rmige Alkylengruppe mit 3 10 C-Atomnen, die gegebenenfalls durch Fluoratome substituiert sein k6nnen, und E emn Sauerstoff- oder Schwefelatom, eine direkte Bindung, eine -C=C-Bindung oder eine -GR 6

=CR

7 -Gruppe darstelit, wobei R 6 und R 7 sich unterscheiden und eine Wasserstoffatomn, ein:Chloratom oder eine C 1

-C

4 -Alkylgruppe bedeur~en, R 4 emn freie oder funktionell abgewandelte Hydroxygruppe, R 5 eim Wasserstoffatom, eine Alkyl-, eine Halogen-substituierte Alkyl-, eine Cycloalkyl-, eine gegebenenfals substituierte Aryloder-eine'heterocyclischie Gruppe, und falls die Bedeutung eines Wasserstoffatoms hat, deren Saize mit physiologisch vertriiglidhen Basen bedeuten und deren Cyclodextrinchlathrate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung.

.un V r.

LEDIGLJCH ZUR INFORMATION Code, die zur Identifizierung von PCT.-Vertragsstaaten auf den Topfb6gen der Schriften, dieiternationale Anmeldungen gemaiss dem PCT ver6ffentlichen.

Osterreich Australien Barbados Belgien Bulgarien Ben in Brasilien Zentrale Afrikanische Republik Kongo Schweiz Kamerun Deutschland, Bundesrepublik Ditnemark Firniand Frankreich Gabun Vereinigtes Konigreich Ungarn Itaien Japan Demnokratische Volksrepublik Korea Republik Korea Liechtenstein Sri Lanka Luxemburg Monaco Madagaskar Mali Mauritanien Malawi Niederlande Norwegen RumAnien Sudan Schweden Senegal Soviet Union Tachad Togo Vereinigte Staaten von Amerika

I

7 VERIFIED TRANSLATION OF 17gs/s8 1 9-Halogen-(Z) prostaglandin derivatives, process for their production and their use as pharmaceutical agents 2 This invention relates to new 9-halogen-(Z) prostaglandin derivatives, a process for their production and their use as pharmaceutical agents.

From the very extensive prior art of prostaglandins and their analogs it is known that this class of substances because of its biological and pharmacological properties is suitable for treating mammals, including man. However, it use as a pharmaceutical agent often run- into difficulties. Most natral prostaglandins have too short a duration of effect for therapeutic purposes, since they are metabolically broken down too quickly by various enzymatic processes. All structure changes have the aim of increasing the duration of effect and the selectivity of the effectiveness.

It has now been found that the new 9 halogen-(Z) prostaglandin derivatives have an outstanding specificity of action, a better effectiveness and a prolonged duration of effect than natural prostaglandins and their derivatives and are especially suitable for oral application.

The invention relates to 9-halogen-(Z) prostaglandin derivatives of formula I Hal

A-W-D-E-R

R4 in which Z represents the radicals /'or Hal I a Hal represents a chlorine or fluorine atom in the 1 T 0 r 3 alpha or beta position, 0

R

1 represents the radical CH 2 0H or -C-OR 2 with R 2 meaning a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical

O

or R 1 represents the radical -C-NHR 3 with R 3 meaning an acid radical or the radical R 2 and A represents a -CH 2

-CH

2 a trans-CH=CH or-C-C group, W represents a free or a functionally modified hydroxymethylene group or a free or functionally modified

CH

3 C group, and the respective OH groups can be in the alpha or OH beta position, D and E together represent a direct bond or D represents a straight-chain alkylene group with 1-10 C atoms, a branched-chain alkylene group with 2-10 C atoms or an annular alkylene group with 3-10 C atoms, which optionally can be substituted by fluorine atoms, and E represents an oxygen or sulfur atom, a direct bond, a-C=C bond or a -CR 6

=CR

7 group, and R 6 and R 7 are different and mean a hydrogen atom, a chlorine atom or a C 1

-C

4 alkyl group,

R

4 represents a free or functionally modified hydroxy group, means a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, an optionally substituted aryl or a heterocyclic group, and if R 2 means a hydrogen atom, its salts with physiologically compatible bases or its cyclodextrin chlathrates.

Straight-chain or branched-chain alkyl groups with 1-10 C ii SI t -4atoms such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl are suitable as alkyl groups R 2 Alkyl groups R 2 can optically be substituted singly to multiply by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups, dialkylamino and trialkylammonium, and a single substitution is to be preferred.

As substituents there can be mentioned.'e.g., fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, etioxy.

As preferred alkyl groups R 2 are to be mentioned those with 1-4 C atoms such as, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.

Suitable as aryl groups R 2 are both substituted and unsubstituted aryl groups such as, for example, phenyl, 1naphthyl and 2--naphthyl, which in each case can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with 1-4 C atoms in each case, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Substituents in the 3 and 4 position on the phenyl ring, for example, by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4 position by hydroxy are preferred.

The cycloalkyl group R 2 can contain 3-10, preferably 5 and 6, carbon atoms in the ring. The rings can be substituted alkvl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopentyl, cyclohexyl or methylcyclohexyl.

Suitable as heterocyclic groups R 2 are 5- and 6-membered heterocycles, which contain at least one heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl,

A

4 Tn 5 thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3thienyl, 2-tetrazolyl, etc.

Suitable as acid radicals are physiologically compatible acid radicals. Organic carboxylic acids and sulfonic acids with 1-15 carbon atoms are suitable, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. Alkyl, hydroky, alkoxy, oxo or amino groups or halogen atoms can be mentioned as examples for the substituents. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valerianic acid, isovalerianic acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myrisitic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with halogen, trifluoromethyl, hydroxy, alkoxy or carboxy groups substituted benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred acyl radicals those are suitable with up to carbon atoms. Sulfonic acids are, for example, alkanesulfonic acids with 1-10 C atoms are suitable such as, e.g., 6 methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid and butanesulfonic acid as well as beta-chloroethanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-diethylaminosulfonic acid, N,N-bis(beta-chloroethyl)-aminosulfonic acid, N,Ndiisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- And morpholino- sulfonic acid. Acyl radicals and alkanesulfonic acids with 1-4 C atoms are preferred.

The hydroxy groups in W and R 4 can be functionally modified, for example, by etherification or esterification, and also the modified hydroxy group in W can be in the alpha or beta position, and free hydroxy groups are preferred.

Radicals known to a man of the art are suitable as ether and acyl radicals. Preferred are easily cleavable ether radicals such as, for example, the tetrahyropyranyl, tetrahydrofuranyl, alpha-ethoxyethyl, trimethlsilyl, dimethyl tert-butylsilyl, dimethyl thexylsilyl, diphenyl tert-butylsilyl and tirbenzylsilyl radical. As suitable acyl radicals the same ones are suitable as mentioned for R 3 under organic carboxylic acids, namely, there can be mentioned, for example, acetyl, propionyl, butyryl and benzoyl.

As alkyl and alkenyl groups R 5 are suitable straight-chain or branched-chain alkyl radicals with 1-10 C atoms and alkenyl radicals with 2-10 C atoms, especially 1-6 and 2-6 C atoms, which optionally can be substituted by substituents phenyl, alkyl with 1-4 C atoms or halogen. There can be mentioned, for example, Th y

I

.7methyl, ethyl, propyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl as well as benzyl, and for the case, that D and E together mean a direct bond, optionally alkinyl with 2-6 C atoms substituted in the 1 position by fluorine or C 1

-C

4 alkyl. Suitable as alkinyl radicals are: ethinyl, propin-1-yl, propin-2-yl, 1methylpropin-2-yl, l-fluoropropin-2-yl, 1-ethylpropin-2-yl, 1fluorobutin-2-yl, butin-2-yl, butin-3-yl, 1-methylbutin-3-yl; 1methyl-3-yl, 1-fluoropentin-3-yl, 1-methylpentin-2-yl, 1fluoropentin-2-yl, 1-methylpentin-4-yl, l-fluoropentin-4-yl, hexin-l-yl, l-methylhexin-2-yl, 1-fluorohexin-2-yl, 1methylhexin-3-yl, l-methylhexin-4-yl, hexin-3-yl, 1,1dimethylpropin-2-yl, 1,l-dimethylbutin-3-yl, 1,l-dimethylpentin- 3-yl, 1,1-dimethylpentin-4-yl, 1,1-dimethylhexin-3-yl, 1,1dimethylhexin-4-yl, etc.

Bromine, chlorine and fluorine are suitable for halogen as substituent of alkyl or alkenyl groups R 5 Chlorine and fluorine are preferred.

Cycloalkyl groups R 5 can contain 3-10, preferably 3-6 carbon atoms, in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. There can be mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and methylcyclohexyl.

Suitable as substituted or unsubstituted aryl groups Rg are for example: phenyl, l-naphthyl and 2-naphthyl, which in each case can be substituted by 1-3 halogen atoms, a phenyl group,1-3 alkyl groups with 1-4 C atoms in each case, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, alkoxy, or hydroxy r i ii i1

:I

i Id if:i qU~~i 8 group. Substitution in the 3 and 4 position on the phenyl ring is preferred, for example, by fluorine, chlorine, alkoxy or trifluormethyl or in the 4 position by hydroxy.

Suitable as heterocyclic groups R 5 are 5- and 6-membered heterocycles, which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. There can be named, for example: 2furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3thienyl, etc.

Suitable as alkylene group D are straight-chain and branched-chain, annular, saturated or unsaturated alkylene radicals, preferably saturated with 1-10, especially 1-5 C atoms, which optionally can be substituted by fluorine atoms. There can be mentioned, for example: methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,1difluoroethylene, 1-fluoroethylene, 1- methyl tetramethylene, 1methyl trimethylene, 1- methylene ethylene, 1-methylene tetramethylene, 1-methyl trimethylene, 2-methyl tetramethylene, 1,1-trimethylene ethylene, 1,2-methylene ethylene. If a double bond is present, it is in the 2, 3 or 4 position in the alkylene radicals.

Inorganic and organic bases are suitable for salt formation, as they are known to a man of the art for formation of physiologically compatible salts. There can be mentioned, for example, alkali hydroxides such as sodium and potassium hydroxide, alkaline-earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, 9 triethanolamine, N-methylglucamine, morpholine, tris- (hydroxymethyl)methylamine, etc.

The invention further relates to a process for the production of 9-halogen-(Z) prostane derivatives of formula I according to the invention, characterized in that in a way known in the art a compound is reacted of formula II

QH

(If),

A-W-D-E-R

R in which Z 1 means the radicals or O R which can be the 9-OH group in alpha or beta position and 0

R

1 represents the radical -C-OR 2 with R 2 meaning alkyl, 0 cycloalkyl, aryl or heterocyclic radical C with R 3 meaning

NHR

3 an acid radical, an alkyl, cycloalkyl, aryl or a heterocyclic radical and A, D, E and R 5 have the meanings already indicated above, after previous protection of the free OH groups in R 4 and w.

a) by an intermediate sulfonic acid ester with a halide of general formula III,

R

8 X (III) in which R 8 has the meaning of lithium, sodium, potassium or tetraalkyl or trialkylbenzyl ammonium with alkyl as saturated C 1

C

6 radical and X meaning fluorine or chlorine, or i 'r 1 0 9- ,r 7 10 b) with the reagent diethylaminosulfur trifluoride (DAST) to the compounds of formula I in which Hal is a fluorine atom in the alpha or beta position or with carbon tetrachloride or hexachloroethane/triphenylphosphine to the compounds of formula I in which Hal is a chlorine atom in the alpha or beta position, and then in any sequence protected hydroxide groups are freed and/or free hydroxy groups are esterified or etherified and/or double bonds are hydrogenated and/or an esterified carboxyl group 0

(R

1

-C-OR

2 is saponified and/or a free carboxyl group (R 2 0 H) is converted into an amide (R 1

C-NHR

3 or salt and/or a free 0 or esterified carboxyl group (R 1

-C-OR

2 is reduced.

The reaction of the compounds of formula II to the compounds of formula I takes place first by conversion with a sulfonic acid chloride or sulfonic acid anhydride into a sulfonic acid ester in a way known to a man of the art and then reaction with a halide of formula III in an inert solvent as, for example, benzene, toluene, diethyl ether, tetrahydrofuran, methylene chloride, acetonitrile, dimethylformamide at temperatures between 0°C and 100 0 C, preferably 20 0 C to 70 0

C.

The reaction of the compounds of formula II to the compounds of formula I with carbon tetrachloride and triphenylphosphine or hexachloroethane/triphenylphophine takes place in an inert solvent such as, for example, dimethylformamide, dimethylacetamide, acetonitrile, methylene chloride at temperatures between 0 C and 80 0 C, preferably 20 0 C to 45 0 C in the PIT 0 t^ -q- 11 presence of a base such as, for example, pyridine, triethylamine, etc.

The reaction of the compounds of formula II to the compounds of formula I with Hal meaning a fluorine atom takes place with diethylaminosulfur trifluoride in a solvent such as, for example, dichloromethane at temperatures between -120 0 C and 0°C, preferably at -70 0 C, optionally in the presence of a tertiary base such as, for example, pyridine.

If an alcohol of formula II with a 9-hydroxy group in beta position is used, compounds of formula I with a halogen atom in the 9alpha position are obtained, if an alcohol with a hydroxy group in alpha position is used, compounds with a halogen atom in the 9beta position are obtained.

Reduction to the compounds of formula I with R 1 meaning a group is performed with a reduction agent such as, for example, lithium aluminum anhydride, diisobutyl aluminum hydride, etc., suitable for the reduction of esters of carboxylic acids.

Suitable as solvents are diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc. The reduction is performed at temperatures of -30°C to the boiling temperature of the solvent used, preferably 0 0 to 300C.

Freeing of the functionally modified hydroxy groups takes place according to known methods. For example, cleavage of hydroxy protecting groups such as, for example, the tetrahydropyranyl radical, in an aqueous solution of an organic acid such as, oxalic acid, acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid such as, hydrochloric acid. To improve the solubility, an inert 12 organic solvent miscible with water is suitably used. Suitable organic solvents are, alcohols such as methanol and ethanol, and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. Cleavage is preferably performed at temperatures between 20 0 C and 80 0

C.

Saponification of the acyl groups takes place, for example, with alkali or alkaline-earth carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol. Suitable aS alcohols are aliphatic alcohols such as, methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and hydroxides there can be mentioned potassium and sodium salts.

The potassium salts are preferred.

Suitable as alkaline-earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at -10 0 C to +70 0

C,

preferably at +25 0 C. 0 The introduction of the ester group -C for R 1 in

OR

2 which R 2 represents an alkyl group with 1-10 C atoms, takes place according to the methods known to a man of the art. The 1carboxy compounds, for example, are reacted with diazocarbons in a way known in the art. Esterification with the diazohydrocarbons takes place, by a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, being mixed with 1-carboxy compounds in the same or in another inert solvent such as, methylene chloride. After the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester purified in the usual way. Diazoalkanes are either

IIS

ATg 13 known or can be produced according to known methods [Org.

Reactions, Vol. 8, pp. 389-394 (1954)].

0 Introduction of the ester group -C-OR 2 for R 1 in which R 2 represents a substituted or unsubstituted aryl group, takes place according to methods known to a man of the art. For example, the 1-carboxy compounds are reacted with the corresponding aryl hydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, DMAP, triethylamine, in an inert solvent. Suitable as solvents are methylene chloride, ethylene chloride, chloroform. The reaction is performed at temperatures between 0 C and +50 0 C, preferably at 100C.

The prostaglandin derivatives of formula I with R 2 meaning a hydrogen atom can be converted with suitable amounts of the corresponding inorganic bases under neutralization into a salt.

For example, the solid inorganic salt it obtained by dissolving of the corresponding PG acids in water, which contains the stoichiometric amount of the base, after evaporation of the water or after addition of a solvent miscible with water, alcohol or acetone.

For production of an amine salt, which takes place in the usual way, the PG acid, is dissolved in a suitable solvent, for example, ethanol, acetone, diethyl ether, acetonitrile or benzene and at least the stoichiometric amount of the amine is added to this solution. In this case, the salt usually precipitates in solid form or is isolated after evaporation of the solvent in the usual way.

14 0 Introduction of the amide group -C-NHR 3 for R 1 takes place according to method known to a man of the art. The carboxylic acids of formula I (R 2 H) are first converted in the presence of a tertiary amine such as, for example, triethylamine, with chloroformic acid isobutyl ester into the mixed anhydride.

Reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R 3 H) or of the corresponding amine takes place in an inert solvent or solvent mixture such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide at temperatures between -30 0 C and +60 0 C, preferably at G0C to 30 0

C.

Another possibility for the introduction of the amide group 0

C-NHR

3 for R 1 with R 3 meaning an acid radical consists in the reaction of a 1-carboxylic acid of formula I (R 2 in which hydroxy groups optionally are intermediately protected, with compounds of formula IV O C N R 3

(IV)

in which R 3 has the above-indicated meaning.

Reaction of the compound of formula I (R 2 H) with an isocyanate of formula IV takes place optionally with addition of a tertiary amine such as, triethylamine or pyridine. The reaction can be performed without solvent or in-an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 0 C and 100 0 C, preferably at 0 to 30 0

C.

If the initial product contains OH groups in the prostane /.v Ia.A4 15 radical, these OH groups are also brought to reaction. Finally if end products are desired that contain free hydroxyl groups in the prostane radical, a start is made from initial products in which these are intermediately protected by preferably easily cleavable ether or acvl radicals.

The compounds of formula II serving as initial material with a 9alpha hydroxy group and Z 1 as R are either known or can be produced according to the process.

indicated in DE-OS 2317019 and 2320552.

The compounds of formula II serving as initial material with a 9alpha hydroxy group and Z 1 as can be produced, for example, by a lactone of formula V in a way known in the art 0 ii A- W- D E Rin which A, D, E and R 5 which have the meanings already indicated and the OH groups present in R 4 and W are provided with a basic-resistant protecting group such as, by etherification with dihydropyran, by treatment with bases such as, for example, sodium hydroxide, and then careful acidification are converted into the hydroxy acids of formula VI:

HO

Co"" H (VI) 2 R'4 A-W-D-E- After esterification of the acid with diazomethane and

"NT

16 etherification of the free OH group with dimethyl tertbutylsilyl chloride, the ester in a way known to a man of the art is either reduced directly to the aldehydes of formula VII -HO (VI I R W D E R 4 or first is reduced to the corresponding alcohols and then oxidized to the aldehydes of formula VII.

By reaction of these aldehydes with tetrabromomethane/ triphenylphosphine in the presence of zinc and treatment of the resulting raw products with butyllithium, the alkines of formula VIII is attained -Si

(VIII)

R4 A W D E R After metalation of the alkines of formula VIII, for example with butyllithium, and reaction with formaldehyde, the resulting propargyl alcohols are etherified under basic conditions with bromoacetic acid tert-butyl ester and yield the esters of formula I Ic

IX.

c 2t (iX) 4 4 A W D E R By Lindlar hydrogenation of the alkine esters of formula IX L. 0 T IL D -E -R 17 and then selective cleavage of the silyl protecting groups in the 9 position the compounds of formula II with a 9alpha hydroxy group are obtained serving as initial material.

The compounds of formula II with a 9beta. hydroxy group are obtained from the 9alpha hydroxy compounds by inversion reaction as it is described, in Synthesis, 292-294 (1980).

The new prostaglandin analogs are marked by a considerable stability in comparison with PGE derivatives.

The new prostaglandin analogs of formula I are valuable pharmaceutical agents, since in a similar activity spectrum they exhibit a substantially improved (higher specificity) and especially substantially prolonged action than the corresponding natural prostaglandins.

The active ingredients according to the invention show a cytoprotective and ulcer-healing effect, inhibit gastric acid secretion and thus counteract the undesirable sequelae of nonsteroid anti-inflammatory substances. Moreover, they act cytoprotectively on the liver, kidneys and also the pancreas.

The new prostaglandin analogs act strongly luteolytically, for triggering a luteolysis substantially smaller doses are needed than in the case of the corresponding natural prostaglandins.

Te an tp i n e e serto n hsconeatteudsial euleo noseodat-nlamtr usacs.Mroete c cyopoecil on th iekdesadas h aces 18 For inducing abortions, especially after oral or intravaginal application, substantially smaller amounts of the new prostaglandin analogs are necessary in comparison with the natural prostaglandins.

During registration of the isotonic uterus contractions on anesthetized rats and on the isolated rat uterus it it shown that the substances according to the invention are substantially more effective and their actions last longer than in the case of natural prostaglandins. The new prostaglandin derivatives are suitable, after a single enteral or .parente- l application, for inducing a menstruation or interrupting a pregnancy. Further they are suitable for synchronization of the sexual cycle of female mammals such as rabbits, cows, mares, sows, etc. Further, the prostaglandin derivatives according to the invention are suitable for cervix dilatation as preparation for diagnostic or therapeutic operations.

The good tissue specificity of the antifertilely active substances is shown in research on other smooth muscle organs such as, for example, guinea pig ileum or on the isolated rabbit trachea, where substantially less stimulation can be observed than by natural prostaglandins. The substances according to the invention also have a bronchospasmolytic action. Further, they also cause a shrinking of the nasal A- mucous membrane.

Some of the compounds are effective in lowering blood pressure, in regulating cardiac dysrhythmia and in inhibiting platelet aggregation with the resulting possibilities of use -19 such as, in coronary heart disease and myocardial infarction. The new prostaglandins can also be used in combination, with beta-blockers, diuretics, phosphodiesterase inhibitors, calcium antagonists, thromboxane antagonists, thromboxane synthetase inhibitors and cyclooxygenase inhibitors, anticoagulant substances such as fibrinolytic agents, leukotriene antagonists, leukotriene synthetase inhibitors and antigestagens.

3 Compared with H-PGD 2 (5Z, 13E)-(9R,llR,15S)-9chloro-3-oxa-15-cyclohexyl-ll,15-dihydroxy-16,17,18,.19,20pentanor-5,13-prostadienoic acid in the receptor test showed a competition factor of 0.5. Moreover, compared with (5Z,13E)-(9R,llR,15S)-9-chloro-15-cyclohexyl-ll,15-dihydroxy-16, 17,18,19,20-pentanor-5,13-prostadienoic acid from WO 86/05488, compound A after I.V. administration reduced the blood pressure more than twice as well.

The new prostaglandin analogs have a great affinity for receptors in membrane preparations from brains and as a result of their properties can serve for influencing psychic processes such as, sleep.

The dosage of the compounds is 1-1500 micrograms/kg/day, if they are administered to human patients.

For medical use the active ingredients can be converted Sinto a form suitable for inhalation, for oral, parenteral or local vaginal) application. Aerosol solutions are suitably produced for inhalation.

Tablets, dragees or capsules, for example, are suitable for oral application.

,K 4 f~jl) y -r a

I

20 Sterile, injectable, aqueous or oil solutions are used for parenteral administration.

Suppositories, are suitable and customary for vaginal application.

The invention thus also relates to pharmaceutical agents on the basis of the compounds of formula I and the usual auxiliary

V

A4 'VNT 0' -7

I

21 agents and carriers, including cyclodextrin clathrates.

The active ingredients according to the invention are to serve in combination with auxiliary agents, which are usual and known in galenicals, for the production of preparations for inducing an abortion, for cycle control, for inducing a birth, for treatment of hypertonia or for treatment of gastrointestinal disorders such as, for healing of-gastric or duodenal ulcers. For this purpose but also for other uses the preparations can contain 0.01-100 mg of active compound.

The following examples are to illustrate the invention in greater detail, without thereby limiting it.

Example 1 (4Z, 13E)-(9R,1R,15R)-9-chloro-ll,15-dihydroxy-16,16-dimethyl- 4,13-prostadienoic acid methyl ester 319 mg of methane sulfonic acid chloride is added at 0°C to a solution of 1.00 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 10 ml of pyridine. It is stirred for 4 hours at 20 0 C and the solution is added to a suspension of 9.99 g of tetrabutylammonium chloride in 10 ml of toliene. After hours stirring at 0°C it is stirred for another 7 hours at 0 C. Then it is added to 100 ml of ice water and extracted three times with 50 ml each of ether. After the organic phase is washed twice with 20 ml of brine, dried over MgSO 4 and is concentrated by evaporation in a vacuum a residue is obtained which is chromatographed on silica gel with hexane /0-40% ether.

839 mg of oily (4Z,13E)-(9R,11R,15R)-9-chloro-16,16-dimethyl- 11,15-bis(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl i:I LL i .II 22 ester is obtained. For cleavage of the protecting groups, the resulting ester is stirred with 31 ml of a mixture of acetic acid/water/ tetrahydrofuran (65/35/10) for 24 hours at 20 0

C.

After addition of toluene and concentration of the solution by evaporation in a vacuum the residue is chromatographed on silica gel. With toluene/0-10% isopropanol as eluant, 326 mg of the title compound is obtained as colorless-oil.

IR (CHC1 3 3500, 3420, 2945, 1730, 1021, 977/cm.

The 9alpha alcohol used as initial material is obtained as follows: la) (5 EZ, 13E)-(9S, 11R, 15R)-9-hydroxy-5-methoxy-16,16-11,15bis-(tetrahydropyran-2-vloxy)-1,2,3 4-tetranor-5,13-prostadiene 10.6 g of potassium tert-butylate is added to a solution of 32.5 g of (methoxymethyl)-triphenylphosphonium chloride in 135 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran in a ratio of 2:1 at 0 0 C and stirred for 30 minutes at 0°C.

Then a solution of 7.15 g of (2RS,3aR,4R,5R,6aS)-4-[(E)- (3R)-4,4-dimethyl-3-( (tetrahydropyran-2-yl-oxy)-perhydrocyclopenta[b]furan-2-ol is instilled in 56 ml of tetrahydrofuran. It is stirred for hours at 20 0 C, then added to 300 ml of brine, extracted three times with 200 ml each of ether, dried over MgSO 4 and concentrated by evaporation in a vacuum. The oily residue is chromatographed on silica gel with hexane/0-50% ethyl acetate.

7.83 g of the title compound is obtained as oil.

23 IR (CHCl 3 3510, 2950, 1655, 1022, 977/cm.

1b) (5EZ,13E)-(9S,11R,15R)-9-acetoxy-5-methoxy-16,16-dimnethyl- 11, 15-bis- (tetrahydropyran-2-yloxy) -1,2,3 ,4-tetranor-5, 13prostadiene 4.8 ml of acetic anhydride is added to a solution of 7.83 g of (5EZ,l3E,, (9S.lR,15R) -9-hydroxy-5-methoxy-16, 16-dimethyl- 1l,15-bis-(tetrahydropyran-2-yloxy) -1,2,3 ,4-tetranor--5,13prostadiene in 9.6 ml of pyridine at 0 0 C and is stirred for 210 hours at 20 0 C. Then it is concentrated by evaporation in a vacuum and the oily residue is chromatographed on silica gel with hexane/0-j0% ethyl acetate. 7.72 g of the title compound is obtained as oil.

IR (CHCl 3 2945, 1730, 1657, 1022, 975/cm.

1c) (13E)-(9S,llR,15R)-9-acetoxy-ll,15-dihydroxy-16,16dimethvl-2 .3,4 .5-tetranor-13-prostenal.

A solution of 7.72 g of (5EZ,13E)-(9S,llR,15R)-9-acetoxy-5methoxy-16, 16-dimethyl-1l, 15-bis- (tetrahydropyran-2-yloxy) l,2,3,4-tetranor-5,13-prostadiene in 345 ml of mixture of acetic acid/water/tetrahydrofuran (65/35/10) is stirred for 20 hours at 0 C. After addition of toluene and concentration of the solution in a vacuum, the residue is chromatographed on silica J gel with hexane/0-50% ethyl acetate and 4.98 g of the title compound is obtained as oil.

IR (CHCl 3 3605, 3425, 2963, 2935, 2233, 1728, 1020, 973/cm.

1d) (13E)-(9S,11R,15R)-9-acetoxy-16,16-dimethyl-1,1--bis- ?WA~jf I I 24 (tetrahydropyran-2-yloxy)-2,3,4,5-tetranor-13-prostenal 5.14 ml of dihydropyran and 46 mg of p-toluenesulfonic acid are added at 0°C to a solution of 4.98 g of (13E)-(9S,11R,15R)- 9-acetoxy-1l,15-dihydroxy-16,16-dimethyl-2,3,4,5-tetranor-13prostenal in 145 ml of methylene chloride. After 1-hour stirring at 200C, 0.1 ml of triethylamine is added and it is allowed to stir for 15 minutes more at 200C. After concentration of the solution by evaporation in a vacuum, the residue is chromatographed on silica gel with hexane/0-30% ethyl acetate and 5.43 g of the title compound is obtained as oil.

IR (CHC1 3 2950, 2230, 1725, 1020, 975/cm.

le) (2RS,4aR,5R,6R,7aS)-5[(E)-(3R)-4,4-dimethyl-3- (tetrahydropyran-2-yloxy)-l-octenyl]-6-(tetrahydropyran-2-yloxy)perhydrocyclopenta[b1pyran-2-ol 2.13 g of anhydrous potassium carbonate is added to a solution of 5.43 g of (13E)-(9S,11R,15R)-9-acetoxy-16,16dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-2,3,4,5-tetranor-13prostenal in 120 ml of methanol at 200C and then stirred for hours at this temperature. The pH is adjusted to 6 with citric acid and the solution is concentrated by evaporation in a vacuum.

The residue is taken up in 200 ml of methylene chloride, washed twice with 30 ml each of brine and dried on MgSO 4 After concentration of the solution by evaporation in a vacuum, the residue is chromatographed on silica gel with hexane/0-30% ethyl acetate and 4.43 g of the title compound is obtained as oil.

IR (CHC1 3 3600, 3420, 2945, 1020, 977/cm.

J I If) (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis- (tetrahydropran-2-yloxy) -4,13-prostadienoic acid methyl ester 108 g of potassium tert-butylate is added to a solution of 23.7 g of (3-carboxypropyl)-triphenylphosphinum bromide in 81 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran in a ratio of 2:1 at OOC and is stirred for 30 minutes at 0 0 C. A solution of 4.43 g of (2RS,4aR,5R,6R,7aS)-5[(E)-(3R)-4,4-dimethyl-3- (tetrahydropyran-2-yloxy)-1-octenyl]-6-(tetrahydropyran-2yloxy)-perhydropenta[b]pyran-2-ol is instilled in 33 ml of tetrahydrofuran and is stirred for 3 hours at 20 0 C. It is added to 500 mi of ice water, acidified with citric acid to pH 4 and extracted several times with methylene chloride. The organic extract is then washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is dissolved with 210 ml of methylene chloride. It is treated for minutes with excess ethereal diazomethane and the solution is concentrated to dryness by evaporation. The oily residue is chromatographed on silica gel with hexane/0-90% ether. 4.61 g of the title compound is obtained as oil.

IR (CHC1 3 3600, 2950, 1735, 1022, 977/cm.

Example 2 (4Z,13E)-(9S,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl- 4,13-prostadienoic acid methyl ester Analogously to example 1, 185 mg of the title compound is obtained as oil from 612 mg of (4Z,13E)-(9R,11R,15R)-9-hydroxy- 16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13prostadienoic acid methyl ester.

IR (CHCl 3 3600, 3420, 2960, 1735, 1022, 976/cm.

A t ;T 0 26 The 9beta alcohol used as initial material is produced as follows: 2a)(4Z,13E)-(9R,llR,15R)-9-hydroxy-16,16-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester 715 mg of p-toluenesulfonic acid chloride is added to a solution of 1.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 16 ml of pyridine at 0°C. After 1 hour; the ice bath is removed and it is allowed to stand for 48 hours at 0 C. Then it is again cooled to 0°C, mixed with 0.1 ml of water and stirred for 1 hour. For working up, it is diluted with icecold ether, shaken successively with ice-cold 10% sulfuric acid, sodium bicarbonate solution and brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. 1 43 g of oily 9tosylate is obtained, which is dissolved in 50 ml of dimethyl sulfoxide, mixed with 3.7 g of potassium nitrite and heated 3 hours at 80 0 C. Then it is diluted with water, extracted with ether, the extract is washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel with hexane/0-50% ethyl acetate and 612 mg of the title compound is obtained as oil.

IR (CHC13): 3600, 3415, 2945, 1735, 1020,977/cm.

Example 3 (4Z,13E)-(9R,llr,15R)-9-chloro-aa,15-dihydroxy-16,16-dimethyl- 4,13-prostadienoic acid 400 mg of potassium hydroxide dissolved in 5 ml of water is added to a solution of 326 mg of (4Z,13E)-(9R,11R,15R)-9-chloro- I 4 J, 1 27 11,15-dihydroxy-16,16-dimethyl-4,13-prostadienoic acid methyl ester in 15 ml of methanol and allowed to stir for 4 hours at 0 C. After concentration by evaporation in a vacuum it is diluted with 70 ml of water, acidified with citric acid to pH 4 and extracted several times with ethyl acetate. The extract is washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel with methylene chloride/0-90% acetone and 215 mg of the title compound is obtained as oil.

IR (CHCl 3 3600, 3400, 2955, 1712, 1020, 975/cm.

Example 4' (4Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy- 17,18,19,20-tetranor-4,13-prostadienoic acid methyl ester Analogously to example 1, 470 mg of the title compound is obtained as colorless oil from 1.48 g of (4Z,13E)-(9S,11R,15R)-9hydroxy-16-phenoxy-11,15-bis-(tetrahydropyran-2-yloxy)- 17,18,19,20-tetranor-4,13-prostadienoic acid methyl ester.

IR (CHC1 3 3600, 3425, 2958, 1732, 1600, 1585, 1020, 977/cm.

The initial material for the production of the title compound is obtained from (2RS,3aR,4R,5R,6aS)-4-[(E)-(3R)-4phenoxy-3-(tetrahydropyran-2-yloxy)-l-butenyl]-5- (tetrahydropyran-2-yloxy)-perhydrocyclopenta b]furan-2-ol according to example la.

Example (4Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy- 17,18,19,20-tetranor-4,13-prostadienoic acid Analogously to example 3, 411 mg of the title compound is A. 1 SA t,, Z)Yua TnI~ 4 28 obtained as oil from 470 mg of (4Z,13E)-(9E,11R,15R)-9-chloro- 11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-4,13prostadienoic acid methyl ester.

IR (CHC1 3 3600, 3420, 2948, 1712, 1600, 1587, 1022, 977/cm.

Example 6 (4Z,13E)-(9R,11R,15R)-9-fluoro-11,15-dihydroxy-16,16-dimethyl- 4,13-prot-tadienoic acid methyl ester 0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9hydroxy-16,16-dimethyl-ll,15-bis-(tetrahydropyran-2-yloxy)-4,13prostadienoic acid methyl estcr in 43 ml of methylene chloride and 1.1 ml of pyridine at -70 0 C and stirred for 3.5 hours at 0 C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0oC and allowed to stir vigorously for minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 200C with 60 ml of a mixture of acetic acid/ water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.

IR (CHCl 3 3605, 3420, 2958, 1732, 1018, 975/cm.

Example 7 (4Z,14E)-(9R,11R,15R)-9-fluoro-1l,15-dihydroxy-16,16-dimethyl- 4,13-prostadienoic acid Analogously to example 3, 252 mg of the title compound is AV 0

.T

29 obtained as oil from 306 mg of (4Z,l3E)-(9R,llR,l5R)-9-fluoro- 11, 15-dihydroxy-16, l6-dimethyl-4, 13-prostadienoic acid methyl ester.

IR (CHCl 3 3600, 3420, 2950, 1710, 1020, 977/cm.

Example 8 l3E) liR, 15S) -9-chloro-15-cyclohexyl-l1, 15-dihydroxy-3oxa-16,17,18,19, 20-pentanor-5, 13-prostadienoic acid tert-butyl ester 2.32 g of oily (5Z,l3E)-(9R,llR,l5S)-9-chloro-l5-cyclohexyl- 3-oxa-li, 15-bis- (tetrahydropyran-2-yloxy) -16, 17, 18, 19,20pentanor--5,13-prostadienoic acid tert-butyl ester is obtained from 2.54 g of (5Z,13E)-(9S,llR,l5S)-l5-cyclohexyl-9-hydroxy-3oxa-ll, 15-bis- (tetrahydropyran-2-yloxy) -16, 17, 18,29, 5,13- prostadienoic acid tert-butyl ester and 773 mg of methanesulfonic acid chloride analogously to example 1. Cleavage of the protecting groups takes place analogously to example 1.

With methylene chloride/0.5% acetone as eluant, 915 mg of the title compound is obtained as colorless oil.

IR (CHCl 3 3605, 3410, 2928, 1742, 1020, 974/cm.

The 9alpha alcohol used as initial material is obtained as follows: 8a) (13E)-(9S, 11R, 15S)-15-cyclohexyl-9-(tertbutyldimethylsilyloxy) -11 ,15-bis- (tetrahydropyran-2-yloxy) 2,3,4,5,6,16,17,18,19,20-decanor-13-prostenoic acid methyl ester 56 ml of a 1 N aqueous sodium hydroxide solution is added to a solution of 6.45 g of (3aR, 4R, 5R, cyclohexyl-3- (tetrahydropyran-2-yloxy) -1-propenyl] (tetrahydropyran-2-yloxy) -perhydrocyclopenta[b] furan-2-one in 56 ii 4 i 30 ml of methanol and is stirred for 24 hours at 20 0 C. Then the methanol portion is removed by concentration in a vacuum and the resulting aqueous solution is adjusted to pH 4.5 with cold sulfuric acid. Then it is first extracted with 400 ml of methylene chloride/ethyl acetate and then twice more with 100 ml each of ethyl acetate. The organic extracts are washed neutral with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is dissolved in 63 ml of methylene chloride, treated for 15 minutes with excess ethereal diazomethane and the solution is concentrated to dryness in a vacuum. The oily residue is dissolved in 73 ml of dimethylformamide and, after addition of 3.51 g of imidazole and 3.88 g of tert-butyldimethylsilyl chloride, is stirred for 4 hours at 20 0 C. Then the reaction mixture is diluted with 600 ml of hexane/ether washed with 100 ml of water and then washed neutral with brine. It is dried over MgSO 4 concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/0-30% ethyl acetate. 5.89 g of the title compound is obtained as oil.

IR (CHC1 3 2930, 1728, 1018, 975/cm.

8b) (13E)-(9S, 11R, 15S)-15-cyclohexyl-9-(tertbutyldimethylsilyloxy-il,15-bis-(tetrahydropyran-2-yloxy)-2, 3, 4, 5,6, 16, 17. 18. 19, 20-decanor-13-prostenal 24.2 ml of a 1.2 molar DIBAH solution in toluene is instilled in a solution of 5.76 g of (13E)-(9S, 11R, 15S)-15cyclohexyl-9-(tert-butyldimethylsilyloxy)-11,15-bis- (tetrahydropyran-2-yloxy)-2, 3, 4, 5, 6, 16, 17, 18, 19, Sis a si f i s 31 decanor-13 prostenoic acid methyl ester in 240 ml of toluene at and is stirred for two more hours at this temperature.

Then 3 ml of isopropanol is added, stirred for 10 minutes, to instill then 12 ml of water. After removal of the cold bath, after 3-hours stirring at 20 0 C it is filtered from the resulting precipitate and rewashed with ethyl acetate. The filtrate is concentrated to dryness by evaporation and the residue is chromatographed on silica gel with hexane/0-40% ethyl acetate.

4.15 g of the title compound is obtained as oil.

IR (CHC1 3 2930, 2725, 1718, 1020, 972/cm.

8c) (13E)-(9S,11R,15S)-15-cyclohexyl-9-(tertbutyldimethylsilyloxy)-11.15-bis-(tetrahydropyran-2-yloxy)-1, 2, 3, 4. 16, 17, 18, 19, 20-nonanor- 13-prosten-5-in 7.20 g of triphenylphosphine is added a suspension of 9.09 g of tetrabromomethane and 1.79 g of zinc powder in 180 ml of methylene chloride at 20 0 C and is stirred for 24 hours at this temperature. Then 3.59 g of (13E)-(9S, 11R, 15S)-15-cyclohexyl- 9-(tert-butyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2yloxy)-2, 3, 4, 5, 6, 16, 17, 18, 19, 20-decanor-13-prostenal is instilled in 37 ml of methylene chloride and is stirred for hours at 20 0 C. Then the mixture is added to 2 liters of pentane with stirring, filtered and the filtrate is concentrated by evaporation in a vacuum. The oily residue is dissolved in 143 ml of tetrahydrofuran, 10.9 ml of a 1.6-molar butyllithium solution in hexane is instilled at -70 0 C and stirred for 1 hour at this temperature. Then it is allowed to warm to 20 0 C and stirred once more for 1 hour. Then it is concentrated by evaporation in a IT and y chlod a teprtr.Te .9go 1E-9,1R 5)1-ylhxl 9(etbtliehlilyoy-l1-i-ttayrprn2 T4 32 vacuum, diluted with 300 ml of ether and washed neutral with brine. After drying over Na 2

SO

4 it is concentrated by evaporation in a vacuum. The resulting residue is chromatographed with hexane/0-20% ethyl acatate as eluant on silica gel. 4.34 of the title compound is obtained as oil.

IR (CHC1 3 3210, 2930, 970/cm.

8d) (13E)-(9S, 11R, 15S)-15-cyclohexyl-9-(tertbutyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-2, 3, 4, 16. 17. 18. 19, 20-octanor-13-prosten-5-inol 9.6 ml of a 1.6-molar butyllithium solution in hexane is instilled to a solution of 4.33 g of (13E)-(9S, 11R, 15S)-15cyclohexyl-9-(tert-butyldimethylsilyloxy)-11,15-bis- (tetrahydropyran-2-yloxy)-l, 2, 3, 4, 16, 17, 18, 19, 13-prosten-5-in in 51 ml of tetrahydrofuran at -20 0 C and is stirred for 1 hour at 0 C. Then 468 mg of dried paraformaldehyde is added and stirred for 90 minutes at GoC. Then it is diluted with 50 ml of water and extracted three times with 50 ml each of ether. The organic extracts are washed twice with 50 ml each of brine, dried over Na 2

SO

4 and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with hexane/0-30% ethyl acetate. 3.11 of the title compound is obtained as oil.

IR (CHC1 3 3610, 3425, 2930, 1020, 977/cm.

8e) (13E)-(9S, 11R, 15S)-15-cyclohexyl-3-oxa-9-(tertbutyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 20-pentanor-13-prosten-5-inic acid tert-butyl ester I 'I rj: 33 To a solution of 1.72 g of 11R, 15S)-15cyclohexyl-9-(tert-butyldimethylsilvl rMy)-11,15-bis- (tetrahydropyran-2-yloxy)-2, 3, 4, 16, 17, 18, 19, 13-prosten-5-inol in 22 ml of toluene are added 2.84 g of bromoacetic acid tert-butyl ester, 8.8 ml of 25% sodium hydroxide solution and 42 mg of tetrabutylammoniumi hydrogen sulfate. After 16-hours of stirring at 20 0 C, it is diluted with 100 ml of ether and acidified with citric acid to pH 6. It is extracted three times with 50 ml each of ether, the combined organic phases are washed with brine and dried over MgSO 4 After concentration by evaporation in a vacuum, the residue is chromatographed on silica gel with hexane/0-20% ethyl acetate. 1,65 g of the title compound is obtained as oil.

IR (CHCl 3 2937, 1745, 1020, 977/cm.

8f) (5Z, 13E)-(9S, 11R, 15S)-15-cyclohexyl-3-oxa-9-(tertbutyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19. 20-pentanor-5,13-prostadienoic acid tert-butyl ester A mixture of 1.73 g of (13E)-(9S, 11R, 15S)-15-cyclohexyl-3oxa-9-(tert-butyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2yloxy)-16, 17, 18, 19,20-pentanor-13-prosten-5-inic acid tertbutyl ester and 519 mg of Lindlar catalyst in 480 ml of toluene is stirred in a hydrogen atmosphere. After absorption of an equivalent of hydrogen it is filtered. After concentration of the filtrate in a vacuum, the residue is chromatographed on silica gel. With hexane/0-20% ethyl acetate as eluant, 1.74 g of the title compound is obtained as oil.

IR (CHCl 3 2930, 1745, 1020, 976/cm.

-7e V Ts 34 8g) (5Z, 13E)-9S, 11R, 15S)-15-cyclohexyl-9-hydroxy-3-oxa- 11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 5,13-prostadienoic acid tert-butyl ester 3.24 g of (5Z, 13E)-(9S, 11R, 15S)-15-cyclohexyl-3-oxa-9- (tert-butyldimethylsilyloxy)-11,15-bis-(tetrahydropyran-2yloxy)-16, 17, 18, 19, 20-pentanor-5,13- prostadienoic acid tertbutyl ester is added to 18.3 ml of a 1-molar tetrabutylammonium fluoride solution in tetrahydrofuran and stirred for 2 hours at 0 C. It is mixed with 150 ml of water and extracted twice with 100 ml each of methylene chloride. The organic extracts are washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The resulting residue is chromatographed on silica gel with hexane/0-50% ethyl acetate.

2.54 g of the title compound is obtained as oil.

IR (CHCl 3 3600, 3480, 2930, 1743, 974/cm.

Example 9 13E)-(9R, 11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy- 3-oxa-16, 17, 18, 19, 20-pentanor-5,13- prostadienoic acid 7.7 ml of a 0.5 normal sodium hydroxide solution is added to a solution of 857 mg of (5Z, 13E)-(9R, 11R, 15S)-9-chloro-15cyclohexyl-11,15-dihydroxy-3-oxa-16, 17, 18, 19, 5,13- prostadienoic acid tert-butyl ester in 7.7 ml of methanol and stirred for 18 hours at 20 0 C. It is diluted with 50 ml of water and acidified with citric acid to pH 5. It is extracted three times with 50 ml each of methylene chloride, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with methylene chloride/0-15%

/AL/~

NT

35 acetone. 75 mg of the title compound is obtained as oil.

IR (CHC1 3 3605, 3410, 2930, 1738, 1020, 973/cm.

Example (5Z,13E)-(9S, 11R, 15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3oxa-16, 17 18, 19. 20-pentanor-5,13- prostadienoic acid Analogously to examples 8 and 9, the title compound is obtained as oil from (5Z, 13E)-(9R, 11R, 15S)-15-cyclohexyl-9hydroxy-3-oxa-11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 20-pentanor-5,13- prostadienoic acid tert-butyl ester.

IR (CHC1 3 3605, 3420, 2930, 1740, 1022, 975/cm.

The'9beta alcohol used as initial material is obtained as follows: (5Z, 13E)-(9R, 11R, 15S)-15-cyclohexyl-9-hydroxy-3-oxa- 11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 5,13- prostadienoic acid tert-butyl ester 1.71 g of p-toluenesulfonic acid chloride is added to a solution of 2.68 g of (5Z, 13E)-(9S, 11R, 15S)-15-cyclohexyl-9hydroxy-3-oxa-11,15-bis-(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 20-pentanor-5,13- prostadienoic acid tert-butyl ester in 37 ml of pyridine at 0 0 C. After 1 hour the ice bath is removed and it is allowed to stand for 48 hours at 2000. Then it is cooled again to 00C, mixed with 0.2 mi of water and stirred for 1 hour. For working up it is diluted with ice-cold ether, successively shaken with ice-cold 10% sulfuric acid, sodium bicarbonate and brine, dried over MgSO 4 and concentrated by evaporation in a vacuum.

The resulting oily 9-tosylate is dissolved in 120 ml of dimethyl sulfoxide, mixed with 9 g of potassium nitrite and heated for 3 hours to 80 0 c. It is then diluted with water, extracted with -36 ether, the extract is washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel with hexane/0-50% ethyl acetate as eluant and 1.63 g of the title compound is obtained as oil.

IR (CHCl 3 3605, 3460, 2935, 1745, 1022, 975/cm.

Example 11 13E)-(9R, 11R, 15R)-9-chloro-ll,15-dihydroxy-16,16-dimethyl- 3-oxa-5,13- prostadienoic acid Analogously to examples 8 and 9, the title compound is obtained'as oil from (5Z, 13E)-(9S, 11R, 15R)-9-hydroxy-16,16dimethyl-3-oxa-l, 15-bis- (tetrahydropyran-2-yloxy) -5,13prostadienoic acid tert-butyl ester.

IR (CHCl 3 3600, 3400, 2935, 1740, 1020, 977/cm.

The initial material for the production of the title compound is obtained according to example 8a from (2RS, 3aR, 4R,5R,6aS) -4 ,4-dimethyl-3-(tetrahydropyran--2-yloxy) 1-octenyl] (tetrahydropyran-2-yloxy) perhydrocyclopenta furan-2-ol.

Example 12 13E) 11R, iSS) -15-cyclohexyl-9-fluoro-l, 3-oxa-16. 17, 18, 19, 20-pentanor--5,13-prostadienoic acid 0.3 ml of diethylaininosulfur trifluoride (DAST) is added to a solution of 1.31 g of (5Z, 13E)-(9S, 11R, 15S)-15-cyclohexyl- 9-hydroxy-3-oxa-ll, 15-bis-(tetrahydropyran-2-yloxy) -16, 17, 18, 19, 20-pentanor-5,13- prostadienoic acid tert-butyl ester in I 37 ml of methylene chloride and 0.5 ml of pyridine at -70 0 C and after 15 minutes 0.1 ml of DAST is added once more. After another 15 minutes it is mixed with 50 ml of 5% sodium bicarbonate solution, the cold bath is removed, it is stirred vigorously for 10 minutes at 20 0 C, then extracted with methylene chloride, the extract is washed with brine, dried over MgSO 4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20 0 C with 20 ml of a mixture of acetic acid/water/ tetrahydrofuran (65/35/10), it is concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. (5Z, 13E)-(9R, 11R, 15R)-15cyclohexyl-9-fluoro-ll,15-dihydroxy-3-oxa-16, 17, 18, 19, pentanor-5,13-prostadienoic acid tert-butyl ester is obtained, which analogously to example 9 is saponified. 52 mg of the title compound is obtained as oil.

IR (CHC1 3 3600, 3410, 2930, 1740, 1022, 977/cm.

i!

I/

Claims (4)

1. 9-Halogen-(Z) prostanes of formula I Hal R in whichR or R 1 or Z represents the radicals Hal represents a chlorine or fluorine atom in the alpha or beta position, O 1 I R represents the radical -C-OR 2 with R 2 meaning o. a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic S radical 00 S or R represents the radical -C-NHR 3 with R meaning 1 3 3 an acid radical or the radical R 2 and A represents a -CH -CH2-, a trans-CH=CH or-C=C group, CH S 3 W represents a -CH-group or a -c-group with R 8 "OR 8 OR 8 meaning hydrogen tetrahydropyranyl, tetrahydroduranyl, alpha-ethoxy-ethyl, trimethylsilyl, dimethyl tert -butylsilyl, dimethyl-thexylsilyl, diphenyl tert -butylsilyl, tribenzylsilyl, acetyl, propionyl, butyryl and benzoyl, and the respective OR 8 group can be in the alpha or beta position. D and E together represent a direct bond or D represents a straight-chain alkylene group with 1-10 C atoms, a branched-chain alkylene group with 2-10 C atoms or an annular alkylene group with 3-10 C atoms, which optionally can be substituted by fluorine atoms, and I 0159d/LFP 39 E represents an oxygen or sulfur atom, a direct bond, a-C=C bond or a -CR=CR group, and R 6 and R 7 are different and mean a hydrogen atom, a chlorine atom or a C1-C 4 alkyl group, R 4 represents a OR 8 group with R 8 as defined above R 5 means a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, l-napthyl

2-napthyl, 2-furyl, 2-thienalkyl, 2-pyridyl, 3-pyridyl,

4-pyridyl, oxazolyl, thiazolyl, pyrimidyl, pyridazinyl, 3-furyl, 3-thienyl-group or phenyl which may be substituted by trifluormethyl or in the 4 position by hydroxy and if R2 means a hydrogen atom, its salts with physiologically compatible bases or its cyclodextrin chlathrates. 2. Process for the production of 9-halogen-(Z) prostanes of formula I, as defined in claim 1, characterized in that in a way known in the art a compound is reacted of S. formula II t. C C ss 1 C(II), A-W-D-E-RS Sin which Z 1 means the radicals which can be the 9-OH group in alpha or beta position and 0 R 1 represents the radical -C-OR 2 with R 2 meaning alkyl, cycloalkyl, aryl or a heterocyclic radical or the radical with R 3 meaning NHR 3 an acid radical, an alkyl, cycloalkyl, aryl or a heterocyclic radical and A, D, E and R 5 have the meanings already indicated above, after previous protetion of the 0 0159d/LFP r- -l 40 S- 40 free OH groups in R 4 and W. a) by an intermediate sulfonic acid ester with a halide of general formula III, R8X (III) in which R 8 has the meaning of lithium, sodium, potassium or tetraalkyl or trialkylbenzyl ammonium with alkyl as saturated C 1 -C 6 radical and X meaning fluorine or chlorine, or b) with the reagent diethylaminosulfur trifluoride (DAST) to compounds of formula I in which Hal is a fluorine atom in the alpha or beta position or with carbon tetrachloride or hexachloroethane/triphenylphosphine to compounds of formula I in which Hal is a chlorine atom in the alpha or beta position, and then in any sequence protected hydroxide groups are freed and free hydroxy groups are esterified or etherified and double bonds are hydrogenated and an esterified carboxyl group S.0' (R 1 -C-OR 2 is saponified and a free carboxyl group 2 (R 2 H) is converted into an amide (R C-NHR 3 or i-12 1 3 salt and a free or esterified carboxyl group 0 (R -C-OR is reduced and a free carboxyl group (R 2 is converted into a salt. 3. Pharmaceutical agents consisting of one or more compounds according to claim 1 and the usual auxiliary agents and carriers. 4. 9-Halogen-(Z) prostanes of the Formula 1 substantially as herein defined with reference to any one of the Examples. DATED this 4th day of March, 1992. SCHERING AKTIENGESELLSCHAFT BERLIN UND BERGKAMEN By Its Patent Attorneys ARTHUR S. CAVE CO. S159d/LFP 1 4;1 41 Abstract The invention relates to 9-halogen-(Z) prostane derivatives of formula I Hal A--D-E-R A_ _DE_ in which Z represents the radicals R1 or Hal represents a chlorine or fluorine atom in the alpha or beta position, 1' 0 R 1 represents the radical -C-OR 2 with R 2 meaning a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical 0 or R 1 represents the radical -C-NHR 3 with R 3 meaning an acid radical or the radical R 2 and A represents a -CH 2 -CH 2 a trans-CH=CH or-C CSgroup, W represents a free or a functionally modified hydroxymethylene group or a free or functionally modified CH 3 C group, and the respective OH groups can be in the alpha OH or beta position, D and E together represent a direct bond or D represents a straight-chain alkylene group with 1-10 C atoms, a branched-chain alkylene group with 2-10 C atoms or an annular alkylene group with 3-10 C atoms, which optionally can be Q5,1-~ TC" L 42 substituted by fluorine atoms, and E represents an oxygen or sulfur atom, a direct bond, a-CEC bond or a -CR 6 =CR 7 group, and R 6 and R 7 are different and mean a hydrogen atom, a chlorine atom or a C 1 -C 4 alkyl group, R4 represents a free or functionally modified hydroxy group, R 5 means a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl or an optionally substituted aryl or a heterocyclic group, and if R 2 means a hydrogen atom, its salts with physiologically compatible bases or its cyclodextrin chlathrates, process for their production and their pharmaceutical use. s- 2 i i S 1 INTERNATIONAL SEARCH REPORT International Application No PCT/DE 88/00452 I. CLASSIFICATION OF SUBJECT MATTER (If several classification symbols apply, indicate all) According to International Patent Classification (IPC) or to both National Classification and IPC Int.C 4 CO7C 177/00;A61K 31/557 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols Int.Cl C07C 177/00;A61K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched III. DOCUMENTS CONSIDERED TO BE RELEVANT* Category Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 I Relevant to Claim No. 13 Y EP, A, 0030377 (SCHERING AG) 17 June 1981 see claims 1-3 Y EP, A, 0069696 (SCHERING AG) 12 January 1983 see claims 1-3 Y WO, 86/05488 (SCHERING AG) September 1986 see claims 1-3 Special categories of cited documents: i° later document published after the international filing date document defining the general state of the art which is not or priority date and not In conflict with the application but considered to be of particular relevance cited to understand the principle or theory underlying the invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International 3earch Date of Mailing of this International Search Report 11 October 1988 (11.10.88) 28 October 1988 (28.10.88) International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE Form PCTIISA/210 (second sheet) (January 1985) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. DE 8800452 SA 23342 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained'in the European Patent Office EDP file on 20/10/88 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date EP-A- 0030377 17-06-81 DE-A- 2950027 11-06-81 JP-A- 56092860 27-07-81 AT-B- E6364 15-03-84 US-A- 4444788 24-04-84 AU-B- 543797 02-05-85 CA-A- 1196327 05-11-85 EP-A- 0069696 12-01-83 JP-A- 58008059 18-01-83 AU-A- 8552882 06-01-83 DE-A- 3126924 20-01-83 US-A- 4454339 12-06-84 CA-A- 1218060 17-02-87 AU-B- 559449 12-03-87 WO-A- 8605488 25-09-86 DE-A- 3510978 25-09-86 EP-A- 0215860 01-04-87 JP-T- 63500795 24-03-88 SFor more details about this annex :see Official Journal of the European Patent Office, No. 12/82 I 7 INTERNATIONALER RECHERCHENBERICHT Internationales Aktenzoichen PCT/DE 88 /00452 1. KILASSIFIKATION DES ANMEILDUNGSGEGENSTANDS (bei mehrutmfl Klasslflkationtsymbolen zind ali. anzugeben) 6 Nach der Intornationalen Patentkclassifilcation (IPC) oei nach der nationalen Klassifilcation und der IPC int.C14 C 07 C 177/00; A 61 K 31/557 fl. RECHERCHIERTE SACHGEBIETE R~echerchierier Mindestorufstoff 7 Recherchierte nicht zumn Mindestpr~fstoff gihorende Veroffentlichungen, soweit diese unior die recherchierten Sachgebiate fallen 8 Ill. EINSCHLAGIGE VEROFFENTLICHUNGEN 9 Art* Kennzeichnung der Verotfentichung 1 ,3oweI? orfordertich unter Angabe der matgeblichen Teile 1 z Betr. Anspruch Nr. 13 Y EP, A, 0030377 (SCHERING AG) 17. Juni 1981, 1-3 siehe Anspriiche Y EP, A, 0069696 (SCHERING AG) 12. Januar 1983, 1-3 siehe Ansprtiche Y WO, A, 86/05488 (SCHERING AG) 25. September 1-3 1986, siehe Ansprtiche *Besondero Kategorien von angegenen Verotfintlichungtn 1 0 VeroffentIlichung, die den aligemeinon Stand der Technik Spitero Veraffomrlichung, die nach dem internationalen An- definiart, abet nicht ala besonders bodeutsam anzusehen ist meldedatum odor dem Priorititsdatumn verdtfentlicht worden ltees Dlcuent.dosjeclch rst m oer nch am itere- st und mit der Anmeldung nicht kollidiert, sondern nur zumn tE" alon Dokmaie.das eoc s m vrfet odnc i t ora Verstindnis des dir Erfindung zugrundiiendin Prinzips trnnlenAnmededtumver~lenlict wadenlitoder der ihr zugrundeiegenden Theorie angoebon ist Veroffentlichung, die geeignat ist, omnen Prioritiksonspruch "X Vebenlhngvnbodre detg;debnsrc- zweifelhaft erschelnen zu laesn, odor durch die das Verof. to Verffeinung vonnnct ala nie odo auf rideiae bosr Titi fentlichungadatm siner anderen im Richorchenbericht go- kto bErfnung bean cht as o oedoren efnershrTtg naton \obrbffntlichung beagt warden soil odor die asina wtwrihn btrctw are anderin besonderen Gnind angeebn st (We ausgWf(hrt) Voroffentlichung von besonderir Bediultung; die beanspruch- erbfenlichngdiesic aufsin mindlche ffebarng, to Erfindung kann nicht ala aut orfinderiacher Tatigkceit be- sine Verffntung, ins Asichaluf oor ndce Offenbarun ruhend betrachtat yerden, venn die Veroffontlichung mit eaieBnun, leAselugoe ner anhe 6ev oder mehroren andiron Veroffentlichungen dieser Kate. besightgorle in Verbindung gebracht wird und dieme Verbindung ft~r Verbtfenthichung, die var dim intornationalen Anmeldeda- gino,, Fachmann naheiiegend mat turn. abet nach dim beenspruchten Priorititsdatum veroffont- "I"Vrfilcug i igie isle aetaii s licht worden istVVnfetihndeMtie eslo aetaii s IV. BESCHEINIGUNG_____________ Datum des Abschlusis der internationalen Rechercho Absendedmaumn des internationelen Recherchenberichts

11.u Oktober 1988 28OT18 Iernationals Recherchenbehordo Untw if-des bevo cige Bediensteten Europiischo Patenumt NDRPr~ Faumblart PCT/ISA/21 0 (Stant 2) (Januar 1985) ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT IDBER DIE INTERNATIONALE PATENTANMELDUNG NR. DE 8800452 SA 23342 In diescm Anhang sind die Mi(glieder dcr Patenttamilien der im obengenannten internationalcn Recherchenbericht angef-uhrten Patentdokuniente angegeben. Die Angaben Ober die FamilienmitgIieder entsprechen dem Stand der Datei des Europiiischcn Patentamis am 20/10/ 88 Diese Angabcn dienen nur zur Unterrichtung und erfoigen ohine Gewahr. EP-A- 0030377 17-06-81 OE-A- 2950027 11-06-81 JP-A- 56092860 27-07-81 AT-B- E6364 15-03-84 US-A- 4444788 24-04-84 AU-B- 543797 02-05-85 CA-A- 1196327 05-11-85 EP-A- 0069696 12-01-83 JP-A- 58008059 18-01-83 AU-A- 8552882 06-01-83 DE-A- 3126924 20-01-83 US-A- 4454339 12-06-84 CA-A- 1218060 17-02-87 AU-B- 559449 12-03-87 WO-A- 8605488 25-09-86 OE-A- 3510978 25-09-86 EP-A- 0215860 01-04-87 JP-T- 63500795 24-03-88 Fur niahere Einzelheiten zu diesem Anhang :siehe Amtsbl~tt des E-,ropischen Patcntamts, Nr.12/82