AT376430B - METHOD FOR PRODUCING NEW AND KNOWN BICYCLIC PROSTAGLANDINES AND THEIR SALTS AND ISOMERS - Google Patents

Description

  

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 EMI1.1
 
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 EMI2.1
 
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 EMI2.3
    -CH20H, nl and n2 is zero or an integer from 1 to 5, X is -O-, -S- or - (CH2) n and the meaning of zero or 1 is m and R 6 is (a ') Hydrogen (b C.-C, -alkyl, (c ') a Cg-C-cycloaliphatic radical which is optionally at least monosubstituted by C, -C6-alkyl and / or Cl-C6-alkoxy, (d') optionally by halogen , Halogen-C1-C6-alkyl, C1-C6-alkyl and / or CI-C6-
 EMI2.4
 
Alkoxy (e ') optionally by halogen, halogen-Ct-Ce-alkyl,

   Ci-Ce-alkyl and / or Ci-Ce-alkoxy at least monosubstituted saturated or unsaturated heterocyclic radical, and of pharmaceutically or veterinarily usable salts and isomers of these compounds.



   Furthermore, within the scope of the invention, the pharmaceutically or veterinary salts, and the optical antipodes, i.e. H. the enantiomers, the racemic mixtures of the optical antipodes, the geometric isomers and their mixtures and the mixtures of the
 EMI2.5
 a residue attached to the cyclopentane ring in the a configuration, d. H. is below the ring level, a substituent attached to the 2-oxa-bicyclic system is in the endo configuration and a substituent attached to the chain is in the S configuration.

   The thick, continuous bond (-) means that a substituent attached to the cyclopentane ring is in the ss configuration, i.e. H. is above the ring plane, a substituent attached to the 2-oxa-bicyclic system is in the exo configuration and a substituent attached to a chain is in the R configuration. The wavy bond line () means that a substituent has no clear stereochemical arrangement, i. that is, a substituent attached to the cyclopentane ring can be in both the a and ss configurations, and a substituent attached to the 2-oxa-bicyclic system can be found in both the endo and exo configurations and a chain-linked substituent can be in both the S and R configurations.



   In the compounds of formula (I) above, the heterocyclic ring B is linked to the cyclopentane ring A in the cis position, and the two (...) bonds indicated by dotted lines are both in the a with respect to the ring A. -Configuration.



   The side chain bonded to the cyclopentane ring A in the SS position is in the trans configuration, based on the a-linked heterocyclic ring B, and is accordingly an exo substituent based on the 2-oxa-bicyclic system.
 EMI2.6
 

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 EMI3.1
 Ring B-bonded hydrogen atom inevitably has the absolute ss configuration as 6ssH-6, 9a-oxide (formula (I), q = 1) and 5ssH-5, 9a-oxide (formula (I), q = 2) -prostanoic acid derivatives (prostaglandin figures) are shown.
 EMI3.2
 a higher Rr value) and a lower positive turning capacity ([α] D) than the corresponding 6ssH-6,9α-oxide and 5ssH-5,9a-oxide derivatives.



   All of the above information relates to natural compounds. The d. I compounds are mixtures which contain equimolar amounts of the nat compounds which have the absolute stereochemical arrangement shown above and the ent compounds which are mirror images of the former. In the ent compounds, the stereochemical configuration at all asymmetric centers is opposite to the configuration of the natural compounds, and the prefix ent indicates this.



   The alkyl, alkenyl, alkynyl, alkoxy and alkanoyloxy groups are branched or straight chain groups.



   R is preferably a free, salted or esterified carboxy group.
 EMI3.3
 -C 6 alkoxy group trifluoromethyl.



   A C1-C6 alkyl group is preferably methyl, ethyl or propyl.



   A C1-C6 alkoxy group is preferably methoxy, ethoxy or propoxy.



   A C2-C6 alkenyl radical is preferably vinyl.



   A C2-C6 alkynyl radical is preferably ethynyl.
 EMI3.4
 a -COOR Rc is a C-C-alkyl radical, in particular methyl, ethyl, propyl and heptyl, or a C-C-alkenyl radical, in particular allyl. p is preferably an integer from 1 to 3.



   If R is acyloxy, it is preferably C2-C'2-alkanoyloxy (in particular C2-Cs-alkanoyloxy, e.g. acetoxy, propionyloxy) or benzoyloxy.



   If Z2 is halogen, it is preferably chlorine, bromine or iodine.



   R 3 and R .. preferably belong independently of one another to the group hydrogen, C1-C6-alkyl and fluorine. n is preferably zero or an integer from 1 to 3; n2 is preferably an integer from 1 to 3.



   If R6 is a C-Cs-cycloaliphatic radical, it is preferably a Cg-Cg-cycloalkyl radical, e.g. B. cyclopentyl, cyclohexyl and cycloheptyl or a C3-C9 cycloalkenyl group, e.g. Cyclopentenyl, cyclohexenyl and cycloheptenyl.



   If Re is a heterocyclic ring, it can be either a heteromonocyclic ring or a heterobicyclic ring and it contains at least one heteroatom from the group N, S and O.



   Examples of preferred heteromonocyclic radicals are tetrahydrofuryl, tetrahydropyranyl,

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Pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl.



   Examples of preferred heterobicyclic radicals are 2-oxa-bicyclo [3.3.0] octyl, 2-oxa-bicyclo [3.4.0] nonyl, 2-thia-bicyclo- [3.3.0] octyl, 2 -Thia-bicyclo [-3. 4. 0] -nonyl and its aromatic analogues.



  Pharmaceutically or veterinarily useful salts of the compounds of formula (I) are, for example, those with pharmaceutically and veterinarily acceptable bases. Pharmaceutical
 EMI4.1
 Dibutylamine, N-methyl-N-hexylamine, decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, ss-phenylethylamine, ethylenediamine, diethylenetriamine, morpholine, piperidine, and pyrrolidine diepiperidine the latter four bases, mono-, di- and triethanolamine, ethyldiethanolamine, N-methylethanolamine, 2-amino- - 1-butanol, 2-amino-2-methyl-l-propanol, N-phenylethanolamine, galactamine, N-methylglucamine, N -Methylgluocosamine, ephedrine, procaine, dehydroabietylamine, lysine, arginine and other a- or ss-amino acids.



   Preferred salts of compounds of formula (I) are those in which R is -COORd, where Rd is a pharmaceutically or veterinary cation derived from one of the bases mentioned above.



   Particularly preferred compounds produced according to the invention are 6ssH-6, 9a-oxide and 5ssH-5, 9a-oxide compounds of the formula (I), in which R is a free carboxy group and R5 is C1-C4-alkyl, C 5 -C 7 -cycloalkyl or optionally substituted phenyl.



   The prefixes nor, dinor, trinor, tetranor etc. are used to denote those compounds of the formula (I) in which the side chain bonded to the cyclopentane ring A is one, two, three, four etc. carbon atoms shorter than the analog chain in the natural prostaglandins.
 EMI4.2
 
 EMI4.3
 
 EMI4.4
 and R. taken together form an oxo group and Y is the group - CH = CZz -, where Za corresponds to the above definition, is reduced to a compound of the formula (I) in which one of the radicals R2 and R:

   Is hydrogen and the other hydroxy and Y is the group -CH = CZ2-, where Z2 corresponds to the above definition, or if desired a resultant compound of formula (I) wherein R2 and R taken together form an oxo group and Y is the group -CH = CZ2, where Z2 is as defined above, into a compound of formula (I), wherein one
 EMI4.5
 

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 wherein one of the radicals R 2 and Rs is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C 2-C. -Alkynyl or aryl and Y is the group -CH = CZ2 -, where Z2 corresponds to the above definition, to a compound of the formula (I) in which one of the radicals Ru and Rs is C, -C.

   -Alkoxy
 EMI5.1
 or is aryl, and Y is the group -CH = CZ2-, where Z2 corresponds to the above definition, is etherified and / or, if desired, a compound of the formula (I) obtained, where Y is the group -CH = CZz- , where Z2 is hydrogen, is hydrogenated to a compound of formula (I) in which Y is the group -CHCHz- or, if desired, a compound of formula (I) in which Y is the group -CH = CZz-where Z2 Is halogen, to a compound of formula (I) in which Y is the group-CEC- is dehydrohalogenated or, if desired, a compound of formula (I) in which R2 and R 5 taken together form an oxo group and Y is the group -CHCHz- where Z2 is hydrogen,

   to a compound of formula (I) in which R2 and R 5 taken together form an oxo group and Y is the group -CH2 CH2 -, or, if desired, a compound of formula (I) obtained wherein R 2 and Rs taken together are one Form an oxo group and Y is the group -CH = CZ2-, where Z2 is halogen, to a compound of the formula (I) in which Ru and Rs taken together form an oxo group and Y is the group-C = C-, is dehydrohalogenated and, if desired a connection obtained
 EMI5.2
 or, if desired, a compound of formula (I) in which R2 and Rs taken together form an oxo group is converted into a compound of formula (I) in which one of the radicals R:

     and Rs is converted to hydroxy and the other C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, and, if desired, a compound of formula (I) wherein one of R2 and Rs is hydroxy and the other Is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, is etherified to a compound of formula (I) in which one of the radicals R2 and
 EMI5.3
 in which R represents a free carboxy group, is esterified and / or a compound of the formula (I) obtained, in which R represents an esterified carboxy group, is saponified and / or
 EMI5.4
 or if desired, a mixture of isomers is split into the individual isomers.



   If only one or a few substituents are specifically mentioned in the optional stages for a compound, this is to be understood as meaning that the other substituents encompass all the possibilities which were previously indicated for the formula (I).



   The known protecting groups, i. H. Ether groups are under mild reaction conditions, e.g. B. by acid hydrolysis, convertible to hydroxyl groups. Examples are acetal ether, enol ether and silyl ether. Preferred groups are
 EMI5.5
   wherein W is -0- or -CH2 - and Alk is a lower alkyl group.



  If the radical Q in the compound of the formula (II) represents a group Hg Z,

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 EMI6.3
 
 EMI6.4
 
 EMI6.5
 driden, with alkaline earth borohydrides, e.g. B. calcium or magnesium borohydrides in an inert solvent, preferably a water-miscible solvent such as tetrahydrofuran, dimethoxyethane or lower aliphatic alcohols, e.g. B. methanol or ethanol; or with tri (n-butyl) tin hydride in benzene or toluene, preferably benzene, or by treatment with hydrazine hydrate in a lower aliphatic alcohol, e.g. B. methanol or ethanol as a solvent, or with chromium (II) acetate at temperatures which vary from room temperature to the reflux temperature of the solvent used.



   If it is desired to obtain compounds of formula (I) in which R2 and R: taken together form an oxo group, reduction of the compound of formula (II) is preferably with tri- (n-butyltin hydride) for a short reaction time, preferably a time which varies from about 5 minutes to about half an hour.



   During the above-mentioned reduction of a compound of formula (II), the carbon atom which carries the substituent Q loses its asymmetry and accordingly the number of possible diastereoisomers contained in the reaction mixture at the end of the reduction process is half the number of diastereoisomers which the starting material contains were.



   The compound of formula (I) in which Y is trans-CH = CZ2-, where Z2 corresponds to the above definition, can be separated from the mixture by crystallization with an appropriate solvent, while the compound of formula (I) in which Y is cis -CH-CZ2-, where Z2 corresponds to the above definition, by concentrating the mother liquor and then chromatographically separating the residue, either by column chromatography or by preparative thin-layer chromatography using silica gel or magnesium silicate as a carrier and e.g. B. methylene chloride, diethyl ether, isopropyl ether, ethyl acetate, benzene, cyclohexane or mixtures thereof can be obtained as eluents.



   Final deprotection, if any, can be accomplished by mild acid hydrolysis as described above for the compounds obtained by the halocyclization and reduction processes.



   Either the optional reduction of a compound of formula (I) wherein R2 and R; taken together form an oxo group and Y-CH = CZ2 -, where Z2 corresponds to the above definition, to a compound of formula (I), wherein Y is -CH = CZ2 -, where Z2 corresponds to the above definition and wherein one of the radicals R and R s is hydrogen and the other hydroxy or the optional conversion of a compound of formula (I) wherein R2 and R s taken together form an oxo group and Y is -CHCZ: -, where Z2 is as defined above, to a compound of Formula (I), in which Y-CH = CZ: -, where Z2 corresponds to the definition above.
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 Reduction of a compound of formula (I) obtained, wherein R:

     and R 5 taken together form an oxo group and Y-CH = CZ:, where Za corresponds to the above definition, to a

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 Binding of formula (I), wherein Y-CH = CZ2-, where Z2 corresponds to the above definition, and wherein one of the radicals R2 and Rs is hydrogen and the other is hydroxy, is preferably with alkali or alkaline earth metal borohydrides, preferably sodium -, Lithium, calcium, magnesium or zinc borohydride carried out using 0.5 to 6 moles of the reducing agent for each mole of the compound of formula (I). The reduction can either be in aqueous or in water
 EMI7.1
 
B. containing solvents, e.g. B. ethyl, methyl or isopropyl alcohol or mixtures of these solvents.



   The reaction temperatures can be between about -40 C and the boiling point of the used
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 EMI7.3
 
 EMI7.4
 fractional crystallization, e.g. B. with diethyl ether, n-hexane, n-heptane, cyclohexane, but preferably by chromatography either on silica gel or on magnesium silicate columns or by preparative thin layer chromatography with, for example, silica gel and eluting z. B. with CHzClz, ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane or mixtures thereof or by means of high-speed liquid chromatography.



   The optional conversion of a compound of formula (I) in which R2 and Rs taken together form an oxo group and Y is -CHCZz-, where Z2 corresponds to the above definition, to a compound of formula (I) in which one of the radicals R 2 and R 5 Hydroxy and the other CI-Ce-alkyl, C-Ce-alkenyl, C-Ce-alkynyl or aryl, and Y is -CH = CZ2-, where Z2 corresponds to the above definition, can be treated by a Grignard reagent of the formula R "" - MgHal, where Hal is halogen, preferably bromine or iodine, and R "" is C, -Cs-alkyl, C -C- alkenyl, Cz-C -alkynyl or aryl, preferably methyl, vinyl , Ethynyl, phenyl.

   The Grignard reaction is carried out with 1.05 to 2 mol of the magnesium derivative / mol of ketone.
 EMI7.5
 
B.Z2 corresponds to the above definition and one of the radicals R2 and Rs is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, to give a compound of the formula (I), wherein Y-CH = CZ2-, where Z2 corresponds to the definition above, and one of the radicals R2 and R., C, -Cc-alkoxy or aralkoxy and the other hydrogen, C, -C6 -alkyl, C2-C6-alkenyl , C2 is -Co alkynyl or aryl, e.g.

   B. by reaction with an optionally aryl-substituted diazoalkane in the presence of a catalyst such as fluoroboric acid or boron trifluoride and in an organic solvent such as dichloromethane or by reaction of the free or salted hydroxy group with an alkyl or aralkyl halide in the presence of a base, such as silver oxide and in a solvent such as dimethyl sulfoxide or dimethylformamide.



   The optional hydrogenation of a compound of formula (I), wherein Y is -CH = CZz-, where Z2 is hydrogen, to a compound of formula (I), where Y is -CH2 -CH2 - is e.g. B. catalytically, preferably in an alcoholic solvent, in the presence of platinum or palladium on charcoal as a catalyst, at temperatures which are from about-40 C to the return

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 flow temperature of the solvent vary. If it is desired to obtain compounds of formula (I) wherein Y is -CHz-CHz-, the hydrogenation is preferably carried out at temperatures in the range from about -40 to about -20 ° C.



   The optional dehydrohalogenation of a compound of formula (I) wherein Y-CH = CZ2-, where Z2 is halogen, to obtain the corresponding compounds of formula (I), wherein
 EMI8.1
 nonen, and an amide or alkoxide of an alkali metal. 1 to 5 and preferably 1.5 to 1.8 molar equivalents of the basic dehydrohalogenating agent can be used for each mole of the compound of the formula (I) in which Y-CH = CZ2-, where Z2 is halogen.



   This dehydrohalogenation process is preferably carried out in the absence of atmospheric oxygen in an inert solvent such as dimethyl sulfoxide, dimethylformamide, hexamethyl
 EMI8.2
 a mixture of these solvents. The reaction temperature can vary between the liquefaction point of the ammonia and about 100 ° C, but the preferred temperature is room temperature.



   Depending on the solvent, the reaction temperature and the molar ratio used between the reagent and the compound, the reaction time can vary from a few minutes to a few hours.



   The optional reduction of a compound of formula (I), wherein R 2 and Rs taken together form an oxo group and Y is a group -CHz-CHz-or-CC-, to a compound of formula (I), wherein one of the radicals R2 and Rs is hydrogen and the other hydroxy and Y is a group -CH2-CH2-or-CEC-, as above for the analogous reduction of a compound of formula (I), wherein R 2 and R; taken together form an oxo group and Y-CH = CZ2-, where Z2 corresponds to the above definition described.



   The optional conversion of a compound of formula (I), wherein R and R s together form an oxo group and Y is a group -CHz-CHz-or-C = C-, to a compound of formula (I), wherein one of the radicals R2 and Rs hydroxy and the other C, -Cs alkyl, C2-Cs-
 EMI8.3
 
Alkenyl, C2 -Cs alkynylZ2 corresponds to the above definition, have been described.



   The optional etherification of a compound of the formula (I) in which one of the radicals R2 and Rs is hydroxy and the other is hydrogen or C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl and Y is a group - CHz-CHz-or-C = C- can be as above for the etherification of a compound of formula (I), wherein one of the radicals R 2 and R s is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6 -Alkenyl, C2-C6-alkynyl or aryl and Y is -CH = CZ2-, in which Z2 corresponds to the above definition.



   The optional conversion of a compound of formula (I) into another compound of formula (I), as well as salt formation from a compound of formula (I), the preparation of a free compound from a salt and the separation of the isomers from a mixture can be carried out according to known methods are carried out.
 EMI8.4
 taken form an oxo group, can be converted by means of oxidation. The oxidation can be carried out by treating with an excess of activated manganese dioxide in an inert solvent, preferably a halogenated inert solvent such as dichloromethane or chloroform, at room temperature for a reaction time which varies between several hours and one or more days.



   In another way, the oxidation can be carried out by reaction with 1.1 to 1.2 molar equivalents of dichlorodicyanobenzoquinone (DDQ) in an inert solvent such as dioxane, tetrahydrofuran, benzene or a mixture thereof at temperatures in the range from about 40 C to the boiling point of the Solvent are run.

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   A compound of formula (I) in which R is a free carboxy group can be converted into a compound of formula (I) in which R is an esterified carboxy group, e.g. B. a C-Cn-carbalkoxy group, can be converted by known methods, for. B. by reaction with the appropriate alcohol, e.g. B. an aliphatic C, -C, 2-alcohol in the presence of an acid catalyst, e.g. B. p-toluenesulfonic acid, and also by treatment with a diazoalkane.



   The optional conversion of a compound of formula (I) in which R is hydroxy to a compound of formula (I) in which R is acycloxy can, if desired, be carried out in a conventional manner, e.g. B. by treatment with an anhydride or a halide, such as a chloride of the appropriate carboxylic acid in the presence of a base. If one of the radicals R2 and Rs is hydroxy, this hydroxy group can be protected from acylation by one of the known protective groups mentioned above.



   The optional conversion of a compound of formula (I) in which R is an esterified carboxy group to a compound of formula (I) in which R is a free carboxy group can, if desired, be carried out according to conventional methods of saponification, e.g. B. by treatment with an alkali or alkaline earth metal hydroxide in an aqueous or alcoholic-aqueous solution and subsequent acidification. For a compound of formula (I) wherein R is an esterified carboxy group and R, acycloxy, the optional saponification can, if desired, be carried out selectively with respect to the esterified carboxy group by transesterification, i.e. H. by reaction in the same alcohol which esterifies the carboxy group and in the presence of a base such as an alkali or alkaline earth metal oxide or KzCOa.



   The optional conversion of a compound of formula (I) in which R is hydroxy to a compound of formula (I) in which R is Ct-Ce alkoxy or aralkoxy can, if desired, be carried out according to the usual etherification procedures, e.g. B. as described above for the etherification of a compound of formula (I) in which one of the radicals R 2 and R 5 is hydroxy.



   If it is desired to etherify only one of several hydroxyl functions present, it is advantageous to protect the hydroxy groups from the etherification which, as desired, should not be etherified, e.g. B. with the above-mentioned known protecting groups, which are then removed at the end of etherification using the methods already described above.



   The optional conversion of a compound of formula (I), wherein R is a free or esterified carboxy group, to a compound of formula (I), wherein R is -CH2-OH can, if desired, e.g. B. by the reduction of the ester with LiAlH., In ethyl ether or tetrahydrofuran at the reflux temperature.
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 Reaction with thionyl chloride or oxalyl chloride in dioxane or dichloroethane at reflux temperature, subsequent reaction of the halide, for. B. with ammonia to the amide, dehydration of the amide to the nitrile, e.g.

   B. with p-toluenesulfonyl chloride in pyridine at about 90 to 100 C, and finally reaction of the nitrile with sodium azide and ammonium chloride in dimethylformamide
 EMI10.3
 
 EMI10.4
 
 EMI10.5
 Way to run.



   The optional separation of the optically active compounds from a racemic mixture and the optional separation of the diastereoisomers or the geometric isomers from their mixtures can be carried out by conventional methods.



   The compounds of formula (II) are already known compounds and can be prepared, such as. B. described by E. J. Corey et al, Ann. of New York Acad. of Sciences, 180.24 (1971), J. Fried et al, J. Med. Chem. 16, 429 (1973), G.L. Bundy et al, Amer. Chem. Soc., 94,2124 (1972), Gandolfi et al, 11 Farmaco Ed. Sc. 27, 1125 (1972), U.S. Patent No. 3,935,254 (Derwent Farmdoc 20717 X), DE-OS 2611788 (Derwent Farmdoc 61615 X), DE-OS 2610503 (Derwent Farmdoc
 EMI10.6
 



   A compound of the general formula (II), in which Q is halogen, can be prepared by a compound of the general formula
 EMI10.7
 where p, q, Y, n t, n:. R:, R, X and R6 correspond to the definition above,
D eis- or trans-CH = CH-, R "(a") is a free or esterified carboxy group,
 EMI10.8
 
 EMI10.9
 

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 EMI11.1
 
 EMI11.2
 
 EMI11.3
 
 EMI11.4
 
 EMI11.5
 Definition is, can be prepared by cyclizing a compound of formula (II) in the presence of a source of Hg (++) ions.



   Suitable sources of Hg ions can be, for example, either compounds of the formula Hg (Z) 2 or compounds of the formula Hg (OH) Z.



   The above cyclization can e.g. B. using 1, 01 to 1, 5, preferably 1, 2
 EMI11.6
 Response time ranges from about 5 minutes to about 2 hours. The cyclization gives a mixture of four diastereoisomers of the formula (II), which differ from one another in the configuration (endo or exo) of the side chains bonded to the heterocyclic ring B or in the configuration (S or R) of the substituent Q.



   The separation of the diastereoisomers from the mixture, which by known methods, for. B. those already described above can be carried out at this point or, if desired, after the reduction of the compound of formula (II).



   The compounds prepared according to the invention can generally be used in human as well as in veterinary medicine for the same therapeutic indications as the natural prostaglandins.



   In particular, those compounds which have an acetylene bond instead of an ethylene bond in the 13, 14-position and those with mono- and di-substituents such as methyl and fluorine groups show the advantages of a superior resistance to degradation by the 15-PG- Dehydrogenase enzymes, which quickly inactivate natural compounds, as well as the advantage
 EMI11.7
 have therapeutic-like effectiveness, they were first tested using a superfusion cascade technique according to the method of Piper and Vane Nature 223, 29 (1969).

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   In order to increase the sensitivity of drug testing, a mixture of antagonists (Gilmore et al. Nature 218, 1135 [1968]) is added to Krebs-Henseleit and indomethacin (4 / lg / ml) is also added to improve the endogenous biosynthesis of prostaglandins prevent.



   The contraction of the rat colon (RC) rat gastric strip (RSS) and the bovine coronary artery (BCA) and the relaxation of the rabbit mesenteric artery (RbMA) are believed to reflect prostaglandin-like activity. A TXAz-like activity is indicated when RbMA is contracted and must be confirmed by an aggregation-promoting effect on platelets in vitro that PGF2 a-like compounds also contract RbMA, in contrast to PGE. Finally, PGX-like activity is indicated by the relaxation of BCA and confirmed in vitro by an anti-aggregation effect on platelets.



   Synthetic PGE2 and biosynthetic both TXA2 and PGX are used as standard compounds. They are effective in a concentration range of 1 to 5) ig / ml.



   The compounds produced according to the invention were used in a few shortly before the test
 EMI12.1
 bond and is referred to as 6ssH-6, 9a-oxide, the diastereoisomeric 13-trans- - llla, 15S-dihydroxy-6aH-6, 9a-oxide-prostatic acid is then referred to as 6aH-6, 9a-oxide. The chemical names of the other compounds tested are also related to those of the parent compounds. The compounds were tested at concentrations up to 100 ng / ml.



   The results obtained showed that in general the 6ss H-diastereoisomers, i.e. H. the compounds 6ssH-6, 9a-oxide, 6ssH-6, 9a-oxide-16-m-CF3-phenoxy-w-tetranor and 6ssH-6, 9a-oxide- - 16-m-chlorophenoxy-N-tetranor a BCA -relaxing activity and therefore have a PGX- - similar effect.



   Among the 6 ssH derivatives, only the compound dl-6ss H-6, 9 a-oxide-16-methyl-16-butoxy-w- - tetranor shows a BCA-contracting activity. The 6aH derivatives, e.g. B. the compounds 6aH-6, 9a-
 EMI12.2
 de effect.



   In general, the exo configuration is associated with a BCA contraction. Furthermore, the compounds according to the invention have a hypotensive effect in mammals, as is the case with the natural compound PGX. However, compared to PGX, they show the great advantage of higher chemical stability and can be used in pharmaceutical preparations.



   The hypotensive effect was demonstrated using the limb perfusion test. During perfusion of the left rat leg through the left femoral artery under constant perfusion pressure, both the 6ssH and 6aH-6,9a oxide compounds caused the mean perfusion pressure values to decrease at all doses over the range of 0.05 to 1 gag (up to -42.5% for 6ssH and -32% for 6aH). In addition, both systolic and diastolic organ pressure were reduced, from 0.05 gg / kg to 5 / lg / kg (approximately -45%).



   With regard to their hypotensive and vasodilatory effects, the compounds produced according to the invention are valuable for the treatment of gangrene cases of the lower limbs.



  For this therapeutic purpose, they have been shown to be more effective than PGE and PGE2. They are also valuable for disorders of the peripheral vascular system and thus for the prevention and treatment of diseases such as phlebitis (inflammation of the vein), hepatorenal syndrome, ductus arteriosus, nonobstructive mesenteric ischemia, arteritis and ischemic ulcers of the legs.



   Among the compounds produced according to the invention, the 6ss H derivatives in particular also have a high anti-aggregation activity.



   Among the 6ssH compounds, the more important in the series of increasing activity are the compounds dl-6ssH-6, 9a-oxide and 6ssH-6, 9a-oxide.



   Using a platelet rich plasma (PRP) from healthy human

  <Desc / Clms Page number 13>

 Donors who had not taken any medication for at least one week and monitored the platelet aggregation by means of continuous recording of the
 EMI13.1
 tion, before adding the aggregating agents arachidonic acid (0.4 mol), ADP (10 gaol), collagen (38 mol) or adrenaline (15 (mol). The activity ratio for the compound is, for example,



  1:10 for arachidonic acid-induced aggregation and 1: 100 for ADP-induced aggregation compared to biosynthetic PGX.



   A very interesting increase in anti-aggregation activity follows the 20-methyl substitution in both the 6ssH and the 6aH-6, 9a-oxide parent compounds.



   Similarly, the 6ssH-13,14-didehydro-20-methyl compound is a very effective anti-aggregating agent.



   The compounds produced according to the invention are therefore particularly valuable in mammals for inhibiting platelet aggregation, for preventing and inhibiting thrombus formation and for reducing the adherence of platelets.



   Therefore, they are valuable for the treatment and prevention of thrombosis and myocardial infarction, for the treatment of arteriosclerosis and in general for all syndromes which are etiologically based on or associated with lipoid imbalance or hyperlipidemia, and for the treatment of geriatric patients for preventing cerebral ischemic sections, and for long-term treatment after a myocardial infarction.



   If the compounds prepared according to the invention are administered as anti-aggregation agents, the routes of administration are the usual, oral, intravenous, subcutaneous and intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary from 0.005 to about 10 mg / kg / day. The exact dose will depend on the patient's condition, weight, age and route of administration.



   The compounds produced according to the invention were also contractile to their uterus
 EMI13.2
 In a rabbit after ovary removal, the same compounds were 5.9 and 8.25 times as effective as PGF2 a (see the table below).
 EMI13.3
 
 <tb>
 <tb> in <SEP> vitro <SEP> in <SEP> vivo
 <tb> uterus <SEP> ileum
 <tb> PGFa <SEP> l <SEP> l <SEP> l <SEP>
 <tb> 6 <SEP> aH-6, <SEP> 9 <SEP> a-oxide-16-m-chlorine <SEP>
 <tb> phenoxy <SEP> w-tetranor <SEP> 1, <SEP> 3 <SEP> 0, <SEP> 05 <SEP> 5, <SEP> 9 <SEP>
 <tb> 6ssH-6, <SEP> 9a-oxide-16-m-CF3- <SEP>
 <tb> phenoxy <SEP> w-tetranor <SEP> 3, <SEP> 1 <SEP> 0, <SEP> 1 <SEP> 8, <SEP> 25 <SEP>
 <tb>
 
The table shows that the compounds have a stronger effect on the uterus than on the gastrointestinal tract.



   These compounds, which are valuable for inducing labor, for rejecting dead fetuses by the pregnant (pregnant) female in both human and veterinary medicine, are free from the undesirable side effects of natural prostaglandins, such as vomiting and diarrhea.

  <Desc / Clms Page number 14>

 



   For this purpose, the compounds produced according to the invention can be administered intravenously
Infusion with a dosage of about 0.01 / lg / kg / min to be administered until the end of labor.
At the same dosage, the compounds produced according to the invention expand the cervix and facilitate a therapeutic abortus and in this situation are preferably administered in the form of vaginal tablets or suppositories.



   The compounds prepared according to the invention, in particular the compound dl-6ssH-6, 9a -oxide-16-m-chlorophenoxy-w-tetranor, also show luteolytic activity and are therefore useful for fertility control.



   The 6ss H-6, 9 a-oxide and the 6aH isomers were also examined for their effect on the gastrointestinal tract to determine: (a) a cell-protecting effect against pathological
Changes caused by nonsteroidal anti-inflammatory drugs (b) the ability to prevent ulcers induced by the Togagi-Okabe method (Japan J. Pharmac. Vol. 18, 9 [1968]) and (c) die antisecretory effectiveness according to
Shay et al Gastroenter. 26.906 (1954).



   The cell-protecting ability is a common sign of all connections. For example, the 6ssH-6,9a oxide, administered subcutaneously, is somewhat more active (1.5 to 2 times) than the comparative PGE2 as a gastric, anti-secretory agent.



   In general, the cell protective activity of the 6ssH compounds is doubled if an acetylene bond is present in the 13, 14 position; it is quadrupled when a 16- alkyl group, usually methyl, is in the 16 (S) configuration.
 EMI14.1
 



   Furthermore, a significant oral antisecretory effect occurs when there is a methyl group in the C-15 position of the parent 6ssH-6, 9a oxide or in the 16, 16-dimethyl compounds, as in the 6ash-6, 9ct oxide. 16-methyl-16-butoxy-M-tetranor derivative.



   For this purpose, the compounds are preferably administered by intravenous injection or infusion, subcutaneously or intramuscularly. With intravenous infusion, the doses vary from about 0.1 gag to about 500 / lg / kg body weight / min. The total daily dose, whether by injection or infusion, is in the range of 0.1 to 20 mg / kg, the exact dose depending on the age, weight and condition of the patient or animal being treated and the route of administration.



   In addition, the compounds are also valuable for the treatment of obstructive pulmonary diseases such as bronchial asthma, since they have considerable bronchodilatory activity.



   To treat obstructive pulmonary disorders, e.g. B. bronchial asthma, the compounds produced according to the invention can be administered in various ways: orally in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups; rectally in suppositories; intravenously, intramuscularly or subcutaneously; by inhalation, as aerosols or solutions for atomizers; or by blowing in powder form.



   Doses in the range of 0.01 to 4 mg / kg can be administered 1 to 4 times a day, the exact dosage depending on the age, weight and condition of the patient and the route of administration. For use as an anti-asthmatic, the compounds prepared according to the invention can be combined with other anti-asthmatic agents, such as sympathicomimetic drugs, such as isoproterenol, ephedrine, etc., xanthine derivatives, such as theophylline and aminophylline or corticosteroids.



   Dosages for use as hypotensive and vasadilatory agents are approximately the same as those used for the anti-aggregation effects.



   As mentioned above, the compounds prepared according to the invention can be administered to humans or animals in a variety of dosage forms, e.g. B. orally in the form of tablets, capsules or liquids, rectally in the form of suppositories; parenterally, subcutaneously or intramuscularly, with intravenous administration preferred in emergencies; by inhalation in the form of aerosols or nebulizer solutions; in the form of sterile implants for prolonged action; or intravaginally in the form of e.g. B. Bougies.

  <Desc / Clms Page number 15>

 



   The pharmaceutical or veterinary preparations which contain the compounds prepared according to the invention can be prepared in a conventional manner and contain conventional carriers and / or diluents.



   For example, sterile, aqueous, isotonic solutions are preferred for intravenous injection or infusion. Sterile solutions or suspensions in aqueous or non-aqueous media can be used for subcutaneous or intramuscular injection; for tissue implants, a sterile tablet or a silicone rubber capsule containing or impregnated with the compound is used.



   Conventional carriers or diluents are e.g. As water, gelatin, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth, alginic acid or alginate, lecithin, polysorbate, vegetable oils, etc. For administration by means of a A suspension or solution of the compound prepared according to the invention, preferably in the form of a salt, such as the sodium salt in water, is used in the atomizer. Alternatively, the pharmaceutical preparation can be in the form of a suspension or a solution of the compound prepared according to the invention in one of the customary liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, which is administered from a pressurized container, such as an aerosol bomb.

   If the compound is not soluble in the propellant, it may be necessary to add a solubilizer, such as ethanol, dipropylene glycol and / or a surfactant, to the pharmaceutical preparation.



   The following examples illustrate the invention without restricting it, the abbreviations "THF", "DME", "DMSO", "THP", "EtzO" refer to tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, tetrahydropyranyl or ethyl ether .



   Example 1: A solution of 0.35 g of mercuric acetate in methanol is stirred at room temperature while stirring a solution of 0.54 g of 5c, 13t-9a, IIIa, 15S-trihydroxy-prostadienic acid methyl ester-11, 15- - bis-THP- ether (PGF: a-bis-THP ether methyl ester) added. After stirring for 15 min, 50 mg of sodium borohydride are added in small portions, the elemental mercury formed is removed by filtration and the methanol is evaporated under vacuum.

   The residue is partitioned between dichloromethane and water; the organic phase is evaporated after washing with sodium bicarbonate and neutral washing with water and gives 0.51 g of crude 13t-11a, 15S-dihydroxy-6 H-6 (9a) - -oxid-prostensäure-methyl ester-11, 15-bis-THP -ether. A solution thereof in 10 ml of acetone is added to 8 ml of 0.2N oxalic acid and heated to 40 to 45 ° C. for 6 hours. After removal of the acetone under vacuum, the aqueous suspension is extracted with 3 times 15 ml of ethyl acetate.



  The organic phase is washed neutral and evaporated to dryness. The residue (about 0.45 g) is adsorbed on 50 g of silica gel and eluted with ethyl ether, collecting 20 ml fractions. From fractions 11 to 50, 0.11 g of 13t-1la, 15S-dihydroxy-6aH-6 (9a) - -oxid-prostensäure-methyl ester (mp. = 67 to 69 C) are obtained. Then, after a mixture of the
 EMI15.1
 
16 + 111.6 (EtOH). The mass spectrum of the compound shows the following peaks (M / e, intensity, structure):
336 7% [M-H2O] +, 318 3% [M-2H2O] +; 292 100% [M-H2O-44] +; 264 30% [M-HsO-CHCHCOzH];
235 4% [M-H2O- (CH2) 4CO2H].



   The mass spectrum of the 6aH diastereoisomer is essentially similar.



   Example 2: A solution of 0.19 g of 5c, 13t-9a, 11a, 15S-trihydroxy-15-methyl-PGF2 a-methyl ester in 2.5 ml of THF becomes 0.3 g of mercuric acetate in 1.5 ml of water / 3.0 ml of THF were added. After stirring for 30 minutes, 60 mg of sodium borohydride in 1.2 ml of water are added to the deep yellow suspension. As soon as the mercury has separated off, the tetrahydrofuran is removed under vacuum and the aqueous suspension is extracted repeatedly with ethyl acetate.

   The organic phase

  <Desc / Clms Page number 16>

 after neutral washing and evaporation to dryness gives 0.16 g of product which is purified by thin layer chromatography and 0.04 g of 13t-11α, 15S-dihydroxy-6αH-6 (9α) - oxide-15-methyl- - PGFzCt methyl ester, [a] D = + 6.20 (CHCh) and 0.034 g of the 6ssH-6 (9α) oxide isomer, [α] D = +19.62 (CHCI3).



   Example 3: 0.43 g of 5c, 13t-9α, 15S-dihydroxy-16R-methyl-prostadienic acid methyl ester-15-dioxanyl ether in 2.5 ml of methanol are reacted with a solution of 0.38 g of mercuribromide in methanol .



  The reaction mixture is kept at room temperature for 15 min and at 0 C overnight.



  The crystalline precipitate that forms is separated off by filtration and gives 0.36 g
 EMI16.1
   (9a) -6ssH-6 (9α) oxide diastereoisomers.



   Example 4: A solution of 0.55 g of 5c-9α, 11α, 15S-trihydroxy-prostenic acid methyl ester in 2.5 ml of DME is added to a solution of 0.5 g of mercuric acetate in 2 ml of water / 4 ml of DME. After 15 minutes, the reaction mixture is treated with a solution of 0.08 g of sodium borohydride in 1.2 ml of water, the mercury is separated off, the DME is removed under vacuum and the residue is extracted several times with dichloromethane. The organic phase is evaporated to dryness, adsorbed on silica gel and eluted with ethyl ether / ethyl acetate to give 0.11 g of 11a, 15S-dihydroxy-6aH- -6 (9α) -oxid-prostenic acid methyl ester and 0.18 g of 6ssH -6 (9α) oxide isomers.

   (M + = 368, M-HzO = 350, M + -2H2O = 332, M-HsO-CHO = 306)
Example 5: A solution of 116 mg of 5c-9α, 11α, 15S-trihydroxy-17-cyclohexyl-20,19,18-trinor- -prost-5-en-13-acidic acid-methyl ester-11,15-bis -THP ether in 1.5 ml of methanol is treated with 64 mg of mercuric acetate in 1.5 ml of methanol. After 10 minutes, 25 mg of sodium borohydride are added.



  The methanol is removed under vacuum, the mercury is separated off and the product is dissolved in water /
 EMI16.2
 
15S diet ether; this is treated in 4 ml of acetone with 2.5 ml of 0.2 N oxalic acid overnight at 40.degree. After removing the acetone under vacuum, the mixture is extracted with ethyl acetate.

   Evaporation of the solvent gives a residue which is purified on silica gel (eluent: ethyl ether) to give 28 mg of 11α, 15S-dihydroxy-17-cyclohexyl-20-19,18-trinor-6αH-6 (9α) - oxide-prost-13-
 EMI 16.3
 of the 6ssH-6 (9α) oxide isomer are obtained from the reaction of 1.01 molar equivalents of mercuric acetate (636 mg) in 10 ml of methanol and 1.1 g of 5c, 13t-9α, 11α, 15S-trihydroxy- 16-methyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-11,15-bis-THP ether obtained in 5 ml of methanol. The mercury compound thus produced is reduced in situ by the careful addition of 85 mg of sodium borohydride in small proportions. The methanolic solution is then decanted from the solid residue and concentrated.

   10 ml of 0.2N aqueous oxalic acid solution and 20 ml of acetone are added and the mixture obtained is kept at 50 ° C. for 12 hours. The organic solvents are removed under vacuum and the solution obtained is saturated with sodium sulfate and extracted with ethyl acetate. The organic phase is washed with 2 times 5 ml of 30% ammonium sulfate solution and 2.5 ml of water; after drying over NA, SO, it is evaporated to give a crude residue, which is purified on silica gel, using an eluent containing an increasing fraction of benzene methyl acetate to remove the isomers 6aH-6 (9a) oxide and 6ssH-6 (9a) oxide to give.

   From the above reaction with 16-m-chlorophenoxy- - 16-p-fluorophenoxy- and 16-m-trifluoromethylphenoxy-5c, 13t-9 a, 11 a, 15S-trihydroxy-20, 19, 18, 17-tetranor -prosta-5,13-dienoic acid methyl ester-11,15-bis-THP ether and the analog 17-phenyl-18, 19, 20 -trinor derivative are obtained:

  <Desc / Clms Page number 17>

   13t-11α, 15S-dihydroxy-6ssH-6 (9α) oxide 17-phenyl-20,19,18-trinor-prostenic acid methyl ester, [a] D = +280;
 EMI17.1
 ss H-6 (9 a) -oxide-16-m-chlorophenoxy-20, 19, 18, 17-tetranor-prostic acid obtained.



   Example 8: 0.12 g of 13t-11α, 15S-dihydroxy-6ssH-6 (9α) -oxid-prost-13-enoic acid methyl ester in 6 ml of methanol are reacted with 2 ml of a 0.5N aqueous solution of lithium hydrate . After 6 h the methanol is removed in vacuo. The residue is diluted with 2 ml of water and extracted with ethyl ether to remove neutral contaminants. The alkaline aqueous phase is acidified by treatment with 4 ml of 30% aqueous NaH2 PO 4 solution and extracted several times with ethyl ether. The latter combined ether extracts are washed with 2 x 1 ml of water and dried; Removal of the solvent gives 91 mg of 13t-lla, 15S-dihydroxy-6ssH-
 EMI17.2
 Saponification of the esters from the preceding examples to give the corresponding free acids.



   Example 9: 0.11 g IIIa, 15S-dihydroxy-6ssH-6 (9a) oxide-16S-methyl-prost-13-acid in methylene chloride is treated with 1.5 molar equivalents of diazomethane in methylene chloride.



  After 15 min the solvent is removed under vacuum and the residue is adsorbed on silica gel. Elution with ethyl ether / benzene (70:30) in the order gives 12 mg of lla-hydroxy-15S-methoxy-6ssH-6 (9α) -oxide-16S-methyl-prost-13-acidic acid methyl ester [[? ] D = +24 (EtOH)] and 78 mg 11a, 15S-dihydroxy-6ssH-6 (9α) - oxide-16S-methyl-prost-13-acidic acid methyl ester [[α] D = +21.5 (EtOH)].
 EMI17.3
 

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

 6ss-6 PATENT CLAIMS: 1. Process for the preparation of new and known bicyclic prostaglandins of the general formula  EMI17.4  wherein R (a) is a free or esterified carboxy group,  <Desc / Clms Page number 18>    EMI18.1    EMI18.2  at the different radicals R ', (c) a group of the -CHOH,  EMI18.3    EMI18.4    EMI18.5  (f) represents the radical -C = N, p is zero or an integer from 1 to 7, q is 1 or 2,  EMI 18.6    EMI18.7    EMI 18.8     -C6-alkoxy, aryl-C, -C6-alkoxyR 2 and Rs taken together form an oxo group, each of the same or different radicals R, and R represents hydrogen, C, -C6 alkyl or fluorine or R, and R4 together with  EMI 18.9  form each of the indices n which are the same or different from one another,  and n 2 means zero or an integer from 1 to 6, X stands for -O -, - S-or- (CH.) M - and the meaning of zero or 1 for m and  EMI18.10  (a ') hydrogen, (b') C1-C4-alkyl, (c ') a C 3 -Cg -cycloaliphatic radical which is optionally at least monosubstituted by C1-C6-alkyl and / or C1-C6-alkoxy, (d' ) optionally substituted by halogen, halogen-C1-C6-alkyl, C1-C6-alkyl and / or CI-C6- - alkoxy aryl or (e ') an optionally by halogen, halogen-C1-C6-alkyl, C1 -C6 alkyl and / or C1-C6-alkyl is at least monosubstituted saturated or unsaturated heterocyclic radical,  <Desc / Clms Page number 19>    EMI19.1    EMI19.2    EMI 19.3  hydrogenated with a mixed hydride with hydrazine or with tri- (n-butyl) tin hydride, whereupon, if desired, a compound of the general formula (I) in which R2 and Rs taken together form an oxo group and Y is the group - CH = CZa -, where Z2 corresponds to the above definition, to a compound of the formula ( I) is reduced, in which one of the radicals R2 and R s is hydrogen and the other is hydroxyl and Y is the group -CH = CZ2 -, where Z2 corresponds to the above definition, or if desired an obtained compound of the formula (I), in which R 2 and R s taken together form an oxo group and Y is the group -CH = CZ2, where Z2 corresponds to the above definition, into a compound of the formula (I) in which one of the radicals R2 and R5 is hydroxy and the other is C1-C6-alkyl, C2-C6 alkenyl.  C2-C4-alkynyl or aryl is converted and, if desired, a compound of the formula (I) obtained, in which one of the radicals R2 and Rs is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6 -Alkynyl or aryl and Y is the group -CH = CZ2-, where Z2 corresponds to the above definition, to a compound of formula (I), in which one of the radicals Rz and Rs CI -C6 -alkoxy  EMI 19.4  and / or, if desired, a compound of formula (I) wherein Y is -CH = CZ2- where Z2 is hydrogen is hydrogenated to a compound of formula (I) wherein Y is -CH2CH2- or, if desired, a compound of the formula (I) obtained in which Y is the group -CH = CZ2-, where Z2 is halogen, to a compound of the formula (I),  wherein Y is the group -CC-, is dehydrohalogenated or, if desired, a compound of formula (I) obtained, wherein R 2 and R 5 taken together form an oxo group and Y is the group -CH = CZz-, where Z2 is hydrogen, to one Compound of formula (I) wherein R2 and Rs taken together form an oxo group and Y is -CH2CH2- is hydrogenated, or if desired a resulting compound of formula (I) wherein Rz and Rs taken together form an oxo group and Y represents the group -CH = CZ2-, where Z2 is halogen, to a compound of formula (I), wherein R 2 and R s taken together form an oxo group and Y  EMI19.5  Formula (I), in which Ra and R s taken together form an oxo group, to give a compound of formula (I),  wherein one of R2 and Rs is hydrogen and the other is hydroxy, is reduced or, if desired, an obtained compound of formula (I), wherein R: and R s together form an oxo group, into a compound of formula (I), wherein one of the Radicals Ra and R 5 are hydroxy and the other is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, and, if desired, a compound of formula (I) obtained, wherein one of the radicals R2 and R, hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- - alkynyl or aryl, is etherified to a compound of formula (I) in which one of the radicals  <Desc / Clms Page number 20>    EMI20.1  Compound of formula (I) in which R represents an esterified carboxy group,  is saponified and / or if desired a compound of formula (I) obtained is converted into a salt and / or if desired a free compound of formula (I) is released from the salt obtained and / or if desired a mixture of isomers is split into the individual isomers.  2. The method according to claim 1 for the preparation of new bicyclic prostaglandins of the general formula  EMI20.2  wherein  EMI20.3    EMI20.4    EMI20.5  -C 12 alkyl group R 5 represents hydrogen or CI -C6 alkyl, each of the mutually identical or different radicals R 3 and R4 represents hydrogen, C, -Ce alkyl or fluorine, n 2 is zero or an integer from 1 to 6 means X is -O -, - S-or- (CH) -with the meaning of zero or 1 for m, and R e for (a ') hydrogen, (b') methyl, (c ') a C3-C9-cycloaliphatic radical which is optionally at least monosubstituted by C, -C s-alkyl and / or Ci-Ce-alkoxy, (d' ) optionally by halogen, trifluoromethyl,    Ct-Ce-alkyl and / or CI-C, - - alkoxy at least monosubstituted aryl or (e ') a saturated, optionally at least monosubstituted by halogen, trifluoromethyl, Cl-Ce-alkyl and / or C, -C s -alkoxy or unsaturated heterocyclic radical, where the side chain having the radical R and the hydrogen atom bonded to the same position are in the trans position with respect to one another, and of pharmaceutically or veterinary-useful salts and isomers of these compounds, characterized in that a compound of the general formula  <Desc / Clms Page number 21>    EMI21.1    EMI21.2  any protective groups present are split off and, if desired, a compound of the general formula (Ia) obtained    esterified with the meaning of a carboxy group for R and / or saponified a compound of the general formula (Ia) obtained with the meaning of an esterified carboxy group for R and / or an obtained compound of the general formula (Ia) with the meaning of a carboxy group for R in a Salt transferred and / or a mixture of diastereoisomers or a racemic mixture is separated into the components.  3. The method according to claim 1 for the preparation of new bicyclic prostaglandins of the general formula  EMI21.3  wherein  EMI21.4    EMI21.5    EMI21.6    EMI21.7    <Desc / Clms Page number 22>  d) one of the radicals R2 and R5 represents C2-C6-alkenyl, C2-C6-alkynyl or aryl or aryl- - C t-C -alkoxy,  EMI22.1    EMI22.2  and for the individual points a) to f) the respective other symbols in formula (Ib) have the meaning given for formula (I) in claim 1, and of pharmaceutically or veterinarily useful salts and isomers of these compounds, characterized in that a compound the general formula  EMI22.3  where Q is halogen or a group wv Hg (+) Z (-), where Z (-) OH (-)  or is an acid anion and taking into account points a) to f) above, R, p, q, Ri, Y, R2, Rs, Ra, Rt, n, nz, X and R s correspond to the above definition, e.g. B. with a mixed hydride, with hydrazine hydrate or with tri- (n-butyl) tin hydride, whereupon, if desired, a compound of general formula (Ib) obtained, wherein R: and R s taken together form an oxo group  EMI22.4  if a compound of the formula (Ib) obtained in which one of the radicals R 2 and R 5 is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl and Y is the group - CH = CZ2-, where Z2 corresponds to the above definition, to a compound of the formula (Ib), in which one of the radicals R:    and R3 is C1-C6-alkyl or Ar-Ci-Ce-alkoxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, and Y is -CH = CZ2, where Za corresponds to the above definition, is etherified and / or, if desired, a compound of the formula (Ib) obtained in which Y is the group - CH = CZt -, where Z is hydrogen  EMI22.5  is hydrohalogenated or, if desired, a resulting compound of formula (Ib) wherein R: and R: taken together form an oxo group and Y is -CH = CZ: -, where Za is hydrogen, to a compound of formula (Ib) wherein R:    and R s taken together  <Desc / Clms Page number 23>  Form an oxo group and Y is the group -CHzCH: -, is hydrogenated or, if desired, a compound of the formula (Ib) in which R2 and R 5 taken together form an oxo group and Y is the group -CH = CZ2 -, where Z2 is halogen , to a compound of formula (Ib) wherein R and R 5 taken together form an oxo group and Y is the group -CC- is dehydrohalogenated, and if desired a resulting compound of formula (Ib) wherein R2 and Rs taken together form an oxo group to a compound of formula (Ib), in which one of the radicals R2 and R 5 is hydrogen and the other is hydroxy,  or desired-  EMI23.1  and, if desired, a compound of formula (Ib) obtained, wherein one of R2 and R 5 is hydroxy and the other is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or aryl, to a compound of formula (Ib) is etherified, in which one of the radicals R2 and Rs is CI-C6- alkoxy or Ar-CI-Ci-alkoxy and the other hydrogen is C1-C6-alkyl C2-C6-alkenyl, C2-C5alkynyl or aryl and / or if desired, an obtained compound of formula (Ib) in which R represents a free carboxy group is esterified and / or a obtained compound of formula (Ib) in which R represents an esterified carboxy group is saponified and / or if desired a compound of formula ( Ib) converted into a salt and / or, if desired, a free compound of the formula (Ib)  released from the salt obtained and / or, if desired, an isomer mixture is split into the individual isomers.