CS215149B2 - Method of making the 9-deoxy-9a-methylenisosters of the prostacycline - Google Patents

Abstract

A wide range of 9-methylene carbaprostacyclin analogs and homologs, and intermediates for them (~250), were prepd. from appropriate bicyclic precursors; racemic and optically active compds. were prepd. Thus, 1.1g Na- borohydride was treated with 11.6g bicyclo [3,3,0 octane-3,7-dione in 100mL ethanol and 100mL CH2CL2 to give 9.1g 7-hydroxy-bicyclo[3.3.0 octane-3-one, 0.065 mol. of which were treated with 12.8g dimethyl-tertiary-butylcyllyl chloride and 8.85g imidazole to give 2.85g 7-oxo-hydroxy-bicyclo[3.3.0 -octane-3-one-dimethyl tertiary-butylcyllyl ether and 11.8g 7-endo-hydroxy-bicyclo-[3.3.0 -octane-3-one-7-dimethyl-tertiary-butylcyllyl ether. The latter compd. in Me2CO3 was treated with Na-hydride to give I.

Description

The present invention relates to a process for the preparation of the B-1BOxy-.alpha.-methyleinsosteres of prostacyclin PGI2 of the formula

CH - _(CH-S О Щ) where mf ¹¹ ',, ΒΧ (CHH, ^CH A ^b t

H βγ-γ-’Η

^R 3c 5 ^{R 1} -c-ichuc-x-ichl

R-.

2.

W in which

R is a substituent selected from the group consisting of a) a free carboxyl group or esterified carboxyl group of the formula -COOR 9 wherein Rg represents Cj_i _two alkyl or alkenyl C2_i _2, b) a moiety of the formula -C (OR ') 3, wherein each substituent R c) a radical of the formula "CH 2 -R" in which R "represents a hydroxyl group or an alkoxy group of 2 to 7 carbon atoms, d) a group of the formula rZ —CON \

R b in which R _a and R _b is selected from the group consisting of hydrogen, alkyl having 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms and phenyl, e] a cyano group, f) a radical of formula NN E ^N N чыН -N

g) a group of formula - CHO, h) a radical of formula

X * -Ra

Z —CH

X-Rb * wherein each individual X 'is independently O or S and R _a ' and R _b ', which may be the same or different, are C 1 -C 6 alkyl or are taken together to form a straight or a branched alkylene chain having 2 to 6 carbon atoms,

D is a substituent from the group consisting of the radicals of the formulas --CH2 -

CH — OH, z

H H \ z

С — C (cis)

OF \

H \ /

C = C (trans)

OF \

H

-CsC-, \

c = o,

Z-O-, -S- and carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl, and the other is an atom hydrogen, hydroxyl, C 1 -C 6 alkoxy or phenyl (or naphthyl) - (C 1 -C 6) -, or R 1 and R 2, and independently of them, R 3 and R 1 together form an oxo group,

R 5 and R 6, which are the same or different, each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom, or R 5 and R 6 together with the carbon atom to which they are attached form a radical of the formula

С = СНг or

Z / ^X CH _Z

Y represents a group of formulas —CH2 —CH2—, —C = C—,

Z \ Z

C = C (trans)

OF \

H h z \ Z

C = C (cis)

Z in which Z represents a hydrogen atom or a halogen atom, and furthermore a group of formulas —NH — CO— and —NH — CH2—,

X denotes groups of formulas - (CH2j _ni - in which тз is zero or 1,

H H \ z C = C (cis), z \

H \ Z

C = C (trans)

OF \

H

-o-, —S—, and \

N — R _c ,

Wherein R _c is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkanoyl, one of R 1 and R 2 and independently of one of R 3 and R 4 is hydrogen, C 1 -C 6 alkyl 6

NR _c ; .

where R _c is as defined above, mi, rnz, ni and na, which may be the same or different, denote zero or an integer from 1 to 12 so that the sum of mi + ma or ni + n2 is less than or equal to 15; individually zero or an integer of 1 to 3 such that the sum of p + q is an integer of 1 to 6, and

R7 is a substituent selected from the group consisting of ' i is hydrogen, b'j alkyl group having 1 to 4 carbon atoms, a monocyclic C ₃ c'j _9cykloalkyl or cycloalkenyl, norbornyl or adamantyl group, or said groups substituted by at least one alkyl group having from 1 to 6 (d) a phenyl or naphthyl group optionally substituted by at least one halogen atom, a haloalkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 atoms a saturated or unsaturated 5- or 6-membered heteromonocyclic ring containing at least one heteroatom, which is an oxygen, sulfur or nitrogen atom and optionally substituted by at least one halogen atom, a (C1-C6) haloalkyl group, (C 1 -C 6) alkoxy, phenyl or (C 1 -C 6) alkyl group, as well as lactone and the pharmaceutically or veterinarily acceptable salts thereof.

The invention further includes lactones derived from compounds of formula I as well as pharmaceutically or veterinarily acceptable salts, optical antipodes, geometric isomers and diastereomers of compounds of formula I, and mixtures thereof.

In the formulas in the description of the present invention, dashed lines (-----) indicate that the substituents attached to them are in the--configuration, i.e. below the plane of the ring, in the case of bicyclo [(p + q + 1), 3.0j of the alkane system (composed of condensed rings A and B) in the end configuration and, in the case of the carbon side chain, in the S configuration.

Solid lines in the form of a wedge (), on the other hand, indicate that the substituents they attach to are in the β-configuration, ie above the plane of the ring, in the case of bicyclics (p + q + + 1), the 3.0-alkane system in the exo configuration and of the carbon chain in the R-configuration. Wavy line (>): denotes a substituent with undefined stoichiometry, the substituents thus attached may be in the α- or β-configuration for the ring, in the case of the bicycloalkane system in end or exoconfiguration and in the case of the carbon side chain in the R or S configuration.

The compounds of formula I: and derivatives thereof described in this invention have a cis linkage between the fused rings A and: B; the hydrogen atoms bound to the bicyclic system at the point of attachment of the rings are both attached from the outside of the two-plane angle formed by the planes of the rings in the natural configuration.

The carbon side chain on the cyclopentane ring A (ω-chain) is in the trans position relative to the Bav ring exo position relative to the bicyclic system.

For each compound of the invention, two geometric isomers are possible, due to the arrangement of the substituents on the double bond exocyclically bonded to ring B: the carbon chain bound to the double bond (chain a) may be either on the same side or on the opposite side of the chain cyclopentane ring A (ω chain). In the first case, the exocyclic double bond is defined as cis and in the second case trans. In the general formula I and in the other general formulas which follow, the symbol - indicates that both geometric isomers are covered by the formula, both individually and in mixtures.

The above substituent arrangements refer to natural compounds. Their enantiomers, which are also within the scope of this invention, exhibit opposite stereochemistry at all asymmetric centers than natural compounds. They are therefore mirror images of the latter substances and their names use the prefix “ent” for their precise identification. The designation d, 1 is used for mixtures containing equimolar amounts of natural compounds and corresponding enantiomers.

The alkyl, alkenyl, alkynyl and alkanoyloxy groups may have a branched or straight-running carbon chain: and may be optionally substituted with one or more halogen atoms, (C 1 -C 6) alkoxy groups and aryl groups, in particular phenyl groups.

The substituent R is preferably a free or esterified or in the form of a salt present carboxyl group.

C 1 -C 6 alkyl is preferably methyl, ethyl or propyl.

C 2 -C 7 alkoxy is preferably C 2 -C 6 alkanoyloxy, for example acetoxy, propionyloxy or benzoyloxy.

C 2 -C 6 -alkanoyl is preferably acetyl or propionyl.

The C 2 -C 6 alkylene radical is preferably an ethylene or propionyl group.

C 1 -C 6 alkoxy is preferably methoxy, ethoxy or propoxy.

The C 2 -C 10 alkenyl group is preferably a group of the formula - CH-CHR 5, wherein R 5 is a hydrogen atom or a branched or straight-chained C 1 -C 8 alkyl group, preferably a vinyl group.

The C 2 -C 10 alkynyl group preferably represents a group of the formula -C = C-R e, in which R 5 is as defined above, preferably an ethynyl group.

C 1 -C 6 haloalkyl is preferably C 1 -C 6 trihaloalkyl, especially trifluoromethyl.

When Z is halogen, it is preferably chlorine or bromine.

Preferably, the substituents R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and fluorine.

When R2 represents a C1-C4 alkyl group, it is preferably a methyl group.

If R denotes? aryl, preferably phenyl, α-naphthyl or β-naphthyl.

When R7 is a cycloaliphatic, it may be a mono-, bi- or tricyclic residue. In the case of a monocyclic radical, it is preferably a C 3 -C 9 cycloalkyl or cycloalkenyl group, for example cyclopantyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. In the case of a bicyclic radical, it is preferably a norbornyl group. In the case of a tricyclic residue, this is preferably an adamantyl group.

When R 7 denotes a cycloaliphatic moiety, it is preferred that it is the aforementioned monocycllialiphatic group.

When R 7 is a heterocyclic ring, it may be a mono- or bicyclic radical containing at least one of the nitrogen, sulfur and oxygen atoms as the heteroatom. However, it is preferred that the heterocycle is a monocyclic radical as defined above, in particular a tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl radical.

When R is an esterified carboxyl group of the formula —COOR @ 9, R @ 8 preferably represents an alkyl group having 1 to 12 carbon atoms, in particular a methyl, ethyl, propyl or heptyl group, or an alkenyl group having 2 to 12 carbon atoms, especially an allyl group.

The indices nu, mz, ni and p2 are each independently preferably zero, 1, 2 or 3.

Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) may be formed with both inorganic and organic acids and bases.

Hydrochloric, hydrobromic or sulfuric acids can be used as pharmaceutically or veterinarily suitable inorganic acids, and citric, fumaric, tartaric, malic, maleic, methanesulfonic or ethanesulfonic acids can be used as organic acids. Suitable inorganic bases include alkali metal hydroxides, alkaline earth metal hydroxides, zinc hydroxide or aluminum hydroxide. As suitable organic bases, various amines such as methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, phenylamine, dibylamine, dibylamine, dibylamine, dibylamine, phenylethylamine, ethylenediamine, diethylenetriamine and other similar aliphatic, aromatic and heterocyclic amines such as piperidine, morpholine, pyrrolidine or piperazine, as well as substituted derivatives thereof such as

1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine or 2-methylpiperidine, and hydrophilic amine derivatives such as mono-, di- and triethanolamine, 2-amino-2-butanol, 2- amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) aminomethane, N-phenylethanolamine, N- [p-tert. amylphenyl is diethanolamine, ephedrine or procaine, and .alpha.-amino acids such as lysine and arginine.

Preferred salts of the present invention include those compounds of formula I wherein R is a group of formula - COOR _d , wherein R _d is a pharmaceutically or veterinarily acceptable cation derived from any of the above bases.

In the description of the invention, compounds of formula I are referred to as bicyclo [(p + q + 1), 3,0] alkanes, or, more preferably, as prostacyclic acid derivatives, compounds of 20 carbon atoms of the formula

wherein the position of the oxygen atom is referred to as the 9a-position.

According to this nomenclature, the compound of formula (I) wherein p = q = 1 is a bicyclo [3.3.0] octane derivative or, more preferably, a 9α-deoxo-9α-methyleneprostacyclic acid derivative since the heteroatom at position 9a of the prostacyclic acid is replaced methylene group. The compound of formula (I) wherein p = 2 and q = 1 is a bicyclo [4.3.0] nonane derivative or, preferably 215149 thereof, a 9a-deoxy-9a, 9b-dimethyleneprostacyclic acid derivative, since the heteroatom at position 9a of the prostacyclic acid is replaced by two methylene groups. Analogously, a compound of formula I wherein p = 3 and q = 1 is a bicyclo [5.3.0] decane derivative or, more preferably, a 9α-deoxy-9a, 9b, 9c-trimethyleneprostacyclic acid.

Analogous prostacyclic acid derivatives of formula I wherein q = 2 or q = 3 are referred to as 7a-homo- or 7a, 7b-dihomoprostacyclicanoic acid derivatives and compounds of formula I wherein p or q is zero, are called derivatives. 9a-nor-methylene acid; or

7-nor-methyleneprostacyclic acid.

The same nomenclature [homo, dihomo, nor, dinor, etc.] is used to denote extensions (the former prefixes) or shortening (the latter prefixes) of α- and ω-chains by one, two or more carbon atoms, based on the original number of carbon atoms atoms of prostacyclic acid.

As an example of this nomenclature, the full name of the following two compounds Ia and Ib is given:

Hs.)

In the following and other compound names, t = trans and c = cis.

Compound 1a: 7-endo-hydroxy-6-exo- (3,5-hydroxy-oct-1'-enyl) -bicyclo [3.3.0] octyl-3 (5 *) -pent-S ? trans -enoic acid, or 5t, 13t-11a, 15S-dihydroxy-9? -deoxy-9? -methyleneprostacyclla-5,13-dienoic acid, compound Ib:

8-endo-hydroxy-7-oxo- (3'-thydroxy-5S-methyl-non-1'-yl) -bicyclo [4.3.0] nonyl-3 (6 '] -1'-oxo-4-enoic acid or Sc SSR-dihydroxy-ISSZO-dimethyl-.alpha.-deoxy-.alpha.-methylene-I.alpha.-dihomo-prostacycl-5-ene.

Preferred compounds of the invention are those compounds of formula (I) wherein R is a free or salt present carboxyl group, and R 2 is a straight or branched (C 1 -C 4) alkyl group, a phenyl group optionally substituted as described above, saturated monoheterocyclic or (C výhodně-Cο-C m-C m-C tetrahydr-C tetrahydr-C m,) radical (preferably a C výhodně,, ne, ne tetrahydr nebr ne tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr zbytek zbytek zbytek zbytek zbytek nebo nebo,,) radical, and in which the other substituents are as defined above.

Particularly preferred compounds of formula I are:

5c, 13t-11a ', 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycla-4,13-dienoic acid. 5c, 13t-11αα, 15R-dihydroxy-9α-deoxy tga-methyleneprstacycla-5,13-dienoic acid, 5α, 11α, 15S-dihdroxh-9α-deoxh-9α-inethyleneprstacycl-5-enoic acid and its 15R epimer, 5S-11a -dihydroxy-9a-deoxy9a-methyleneprostacycl-5-en-13-yne and its

15R epimer,

16S-methyl derivatives of the above acids and 20-methyl derivatives of the above acids, 5c, 13t-4-oxo-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid,

1,4-γ-lactone of 5c, 1β-1β, 1β, 1β, 5β-trihydroxy-9α-deoxy-9α-methyleneprostacycla-5,13-dienoic acid and its 4R epimer, sodium acid 5c, 13t-4S, 11a, 15S-trihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid and its 4R epimer, 5c, 13tHa, 15S-dihydroxy-9a-deoxy-9a-methylene-17-cyclohexyl -18,19,20-trinor-prostacycl-5,13-dienoic acid, 5c, 13t-llio, 15S-dihydroxy-9α-deoxy-9α-methylene-17-phenyl-18,19,20-trinor-prostacyclic -5.13-dienoic acid 5c _{1 1} 13 t-III ', 15S-dihydгoxy-9a-deoxyt9a-methylent17 (2'] -tetrahydrof furyl-8,19,22-trInoг-prostacykla-5,13-dienoic acid, 5c, 13t-αα, 15S-dihydroxy-9α-deoxy-9α-methylene-16-m-trifluoromethylphenoxy-17,18,19,22-tetraneprostacycla-5,13-dienoic acid, 5c, 13t-11a, 15 [S] -dihydroxy-9α-deoxy-9α-methylene-16-methyl-16-butoxy-18,19,22-trino-prostacycl-5,13-dienoic acid, 5c-11α, 15S-dihydroxy-6-deoxy-9α-methylene -16R-thiophene-prostacycl-5-ent-13-ynoic acid, 5t, 13t-11α, 15S-dihydroxy-9at-deoxy-9a-methyl nprostacyclla-5,13-dienoic acid, 5t, 13t-11α, 15R-dihydroxyt9a-deoxy-9a-Inethyleneprostacyclla-5,13-dienoic acid, 5t-11a, 15S-dihydroxy-9a-deoxy-N-methyleneprostacycl-5-enoic acid and its 15R epimer, 5t-11α, 15S-dihydroxy-.alpha.-deoxyt9a-Inethyleneprostacycl-5-en-13-ynoic acid and its 15R epimer,

16S-methyl derivatives of the above-mentioned acids and 20-methyl derivatives of the above-mentioned acids, 5t, 13t-4-oxo-11a ', 15S-dihydroxy-9a-deoxy-9a-nethyleneprostacyclla-5,13-dioic acid,

1,4-γ-α-acetoxy of 5-, lt-4S, 11α, 15α-trihydroxy-9α-deoxy-9α-methyleneprosacycla-5,13-dienoic acid and its 4R epimer, sodium salt 5t, 13t-4S, 11a 15S-trihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid and its 4R epimer, 5t, 13t-11a ₎ 15S-dihydroxy-9a-deoxy-9a-methylene-17-cyclohexyl-18,19, 20-trinOr-prosta-cycla-5,13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,22-: rinor-prosta-cycla-5, 1t-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-17 (2 ') -tetrahydrofuryl-18,19,22-tinor-prostacycl-5,1t-dienoic acid, 5t, 13t- na, 15S4ihydroxy-9a-deoxy-9a-methylene-16-m-trifluoromethylphenoxy-17,18,19,22-tettanor-prostacycl-5,1t-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy -9a-llethylene-1H-methyl-1β-butoxy-18,19,22-trinor-prostacycl-5,1t-denoic acid, 5t-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluoroprostacycl- 5ten-13-ynoic acid, 5c, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-nor-methyleneprostacycla-5,1 t-dienoic acid, 5c-11a, 15S-dihydroxy-.alpha.-deoxy-9.alpha.-nor-ethylene-20-methyl-lt, 14tdidehydropropyl-stacyk-5-ene-lt-ynoic acid, 5c, 13t-lla, 15S- dihydroxyt9a-deo.xyt -7-nor-methyleneprostacycla-5,1t-dienoic acid, 5c, 13t-11a, 15S-dihydroxy-9at-deoxy-7-nor-methylene-17-phenyl-18,19,20 -trmor-prostacycl-5,13-dienoic acid, 5c-11a, 15S-dihydroxy-9α-deoxy-7-nor-methylene-16S-fluoro-13,14-didehydroprostacycl-5-en-1-tartaric acid and its 16R-Fluoroisomer, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-1α, 9b-dimethylene-prostacyclla-5,1t-dienoic acid, 5a11a, 15S-dihydroxy-9a-deoxy yla, 9b-dimethylene-prostacycl- 5-en-1-tartaric acid, 5c, 13t-11a, 15S-dihydroxy-9a, deoxyt9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trinor Prostacyclla-5,13-dienoic acid 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacycl-5,13-dienoic acid, 5c, 13F11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene- 15-methylprostacyclla-5,13-dienoic acid, 5c, 13t-11a, 15S-dihydroxy-9, -deoxyt9a, 7a-homodimethylene-16S- 5'-methylisomer, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,18,11,22-ttt- anor-prostacyclla-5,1t-dienoic acid, 5c-11a, 15S-dihydroxy-.alpha.-deoxy-9a, 7a-homo-dimethyleneprostacycl-5-en-13-ynoic acid, 5c, 13t-11a, 15S-dihydroxy -9α-deoxy-1α, 9b, 7αomo-trimethylene-2-nor-prostacyclla-5,13-dienoic acid, 5t, 11t-11αα, 15S-dihydroxy-9α-deo-γ-9α-nor-methyleneprostacycl-5,1t- dienoic acid, 5t-11a ', 15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-1t, 14t-didehydroprostacycl-5-ene-1tamic acid, 5t, 11t-11α, 15S -droxy-9a-deoxy-7-nor-methyleneprostacycla-5,1t-dienoic acid, 5t, 14t-11a, 15S-dihydroxy-9a-deoxy-7-nor-methylene-17-phenyl-18,19,20- trinor-prostacycl-5,13-dienoic acid, 5t-11a, 15S-dihydroxy-9a-deoxy-7-nortmethylene-16S-fluoro-13,14-didehydroprostacycl-5-ene-1-tonic acid and its 16R-fluorisomer, acid 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-1α, 9b-dimethyleneprostacycla-5,1t-dienoic acid, 5t-11a, 15S-d hydroxy-9a-deoxy215149

-9a, 9b-dimethyleneprostacycl-5-ene-13-ynoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trifluoro-prostacycl- 5,13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacyclla-5,13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy- 9α, 7α-homo-dimethylene-15-methylprostacycla-5,13-dienoic acid, 5α, 13α-11α, 15α-dihydroxy-9α-deoxy-9α, 7α-homo-dimethylene-16S-methylprostacycl-5,13-dienoic acid and its 16R-methyl isomer, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-1H-phenoxy-17,18,19,20-tetranor Prostacyclla-5,13-dienoic acid , 5t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-en-13-ynoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b 7α-homo-trimethylene-2-nor-prostacyclla-5,13-diene as well as 11-deoxy derivatives, 11-epimers, 15R-hydroxy isomers and all enantiomers of the above compounds, as well as pharmaceutically or veterinarily acceptable salts thereof.

The compounds of formula (I) according to the invention are prepared by producing a compound of formula (IV),

(IV) wherein R '', тг, mi, p, q, R 1 'and R 2' are as defined above and D 'is selected from the group consisting of a "') - 0 -, b" ') - S -, c '' j is a group of the general formula \

NR _c ,

Wherein R _c is as defined above, d "') —CH = CH- (cis), e'" J —CH = CH (trans), f "') —C = C-, g"' J residue of the general formula

X'— R _a '

OF

-C, \ '- R _b ' wherein X ', R _a ' and R _b 'are as defined above, h''is a group of the general formula

CH ~~ OCOR ‘

In which R 'is as defined above, i'') the radical “CH21”, or D', R “'and - (CH2) m ₂ together form a group of formula i - c = o in which m ₂ has the meaning defined above , alkylated with a compound of formula V, z

^H O Rf, (V) in which E represents a group of the formula (СбН5) зР— or (R _e O) 2 P- (O) -, in which each individual R _e represents independently an alkyl group having 1 to 6 carbon atoms or a phenyl group Z, ni, R5, R6, X, nz and R7 are as defined above, and from the compound of formula VI obtained;

1S wherein R 1 ', ms, D 1, p, q, R ¹ , R ¹ , Z ¹ , n ¹ , R ⁵ , R e, X, P 2 and R 7 are as defined above, optionally protecting groups to give a compound of formula I wherein Y is -CH = CZ- (trans), Z is as defined above, and R3 and R4 together form an oxo group, and / or a compound of formula VI in which Z is hydrogen or a compound of formula of formula I wherein Y is -CH = CZ- (trans), Z is hydrogen and R3. and R 4 together form an oxo group, optionally reduced, to yield, after deprotection, a compound of formula I wherein Y is -CH 2 -CH 2 - and R 3 and R 4 together form an oxo group, and / or optionally a free-nucleophilic addition to the free carbonyl in the side ω-chain of a compound of formula VI or a compound of formula I wherein Y is -CH 2 -CH 2 - or -CH-CZ- (trans), Z is as defined above, and R 3 and R 4 together form an oxo group; after deprotection, a compound of formula I wherein Y is -CH 2 -CH 2 or -CH = CZ- (trans), Z is as defined above and one of R 3 and R 4 is hydroxyl and the other is atom hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or phenyl (or naphthyl) - (C 1 -C 6 alkyl), and a compound of the general formula o of formula I in which Y represents a group -CH 2 -S- or -CH = CZ- (trans), Z is as defined above, one of R 3 and R 4 represents a hydroxyl group and the other represents a hydrogen atom, an alkyl group having 1 to 2 6 carbon atoms, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl, phenyl (or naphthyl) - (C 1 -C 6) alkyl and all other hydroxyl groups present are protected as described above, is optionally etherified, and deprotected to give a compound of formula I wherein Y is -CH 2 -CH 2 - or -CH = C 2 - (trans), Z is as defined above and one of R 3 and R 4 is alkoxy (C 1 -C 6 or phenylphenyl or naphthyl) - (C 1 -C 6 alkoxy and the other is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 alkynyl and C 1 -C 6 alkenyl; or 10, optionally phenyl, or phenyl (or naphthyl) - (C 1-6) alkyl, and / or optionally a compound of formula I wherein Y is -CH = CZ- (trans), Z is halogen , one of R 3 and R 1 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl)

- (C 1 -C 6) alkyl and the other is hydroxyl, C 1 -C 6 alkoxy or phenyl (or naphthyl) - (C 1 -C 6) alkoxy, or R 3 and R 4 together form oxo, and the hydroxyl groups, oxo groups present and the carboxyl groups are either free or protected as described above, dehydrohalogenated, and after removal of any protecting groups present, a compound of formula I is obtained wherein Y is -C = C- and one of R 3 and R 4 is hydrogen, (C 1 -C 6) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl and the other is hydroxyl, alkoxy Or (1-6C) atoms or phenyl (or naphthyl) - (C 1-6) -alkyloxy, or R 3 and R 4 together form an oxo group, and / or optionally form a lactone; or an appropriate salt of a compound of formula I, and / or optionally preparing a free compound of formula I from a salt thereof, and / or optionally separating a mixture of isomeric compounds of formula I into the corresponding individual isomers.

When only one or more substituents are specified in the compounds of formula (I) as described above, all other substituents are as previously defined for formula (I).

As protecting groups for hydroxyl groups, ether or ester radicals which can be easily removed under mild conditions, for example by acid hydrolysis, can be used. Preferred protecting groups include silyl ethers, for example trialkylsilyl ethers, such as trimethyl, dimethyl tert-butyl, dimethylisopropyl or dimethylethylsilyl ethers, as well as acetal and enol ether residues, for example tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether or oxathianyl ether radicals, formulas,

in which Alk represents an alkyl group having 1 to 6 carbon atoms.

The ketones are preferably protected in the form of ketals or thioketals of the general formula

wherein X ', R _a ' and R _b 'are as defined above.

If desired, ether protecting groups can be removed from hydroxyl groups by mild acid hydrolysis, for example by treatment with mono- or polycarboxylic acids such as acetic, formic, citric, oxalic or tartaric acid in a suitable solvent such as water, acetone, tetrahydrofuran, dimethoxyethane or in a low molecular weight alcohol or by treatment with a sulfonic acid such as p-toluenesulfonic acid, in a low molecular weight alcohol such as anhydrous ethanol or methanol, or using a polystyrene-sulfonic type ion exchanger. For example, 0.1-0.25 N polycarboxylic acid (such as oxalic or citric acid) may be used in a suitable, low-miscible, water-miscible solvent, which can be easily removed under reduced pressure after completion of the reaction.

The silyl ether protecting groups may be selectively removed in the presence of other protecting groups by treatment with an F ^- ion in a suitable solvent such as tetrahydrofuran or dimethylformamide.

The ester protecting groups can be removed by the typical saponification methods described below.

The ketal and thioketal protecting groups of the ketones are generally removed substantially as acetal or thioacetal groups by mild acid hydrolysis under the conditions described above.

Thioketal and thioacetal protecting groups may be selectively removed in the presence of other protecting groups in the molecule, for example, by treating with mercuric chloride in aqueous acetone or acetonitrile or in a mixture of these solvents, in the presence of alkaline earth carbonates such as calcium or magnesium carbonate.

Optional reduction of a compound of formula VI in which Z is hydrogen or a compound of formula I in which Y is -CH = CZ- (trans), Z is hydrogen, and R3 and R4 together form an oxo group which leads After deprotection, the compound of formula I in which Y 'is -CHa-CHa and R3 and R4 together form an oxo group is preferably carried out in liquid ammonia, optionally in the presence of a cosolvent [e.g., an aliphatic alcohol such as tert-butanol or 2- (C 1 -C 4) alkylpropan-2-ol, or a cyclic ether such as tetrahydrofuran or dioxane] by treating with an excess of an alkali or alkaline earth metal such as: lithium, sodium, potassium or calcium. After the reaction, the excess metal decomposes; a weak acid such as ammonium chloride or sulfate or an aliphatic alcohol such as ethanol or propanol is used as the proton source to decompose. The reaction can be carried out at a temperature ranging from -70 ° C to the boiling point of the solvent used.

By nucleophilic addition to the carbonyl group in the side ω-chain of a compound of formula (VI) or a compound of formula (I) wherein Y is -CH 2 -CH 2 - or -CH = CZ- (trans), Z is as defined above and R1 and R4 form together with an oxo group, depending on the nucleophilic reagent used, a secondary or tertiary alcohol is obtained.

The secondary alcohol is preferably prepared by treatment with an alkali metal or alkaline earth metal borohydride (such as sodium, lithium, calcium or magnesium) or zinc borohydride; after removal of all of the protecting groups, a compound of formula (I) is obtained in which Y is --CH2 --CH2 - or --CH.dbd.CH-- (trans), Z is as defined above and one of R3 and R4 is hydrogen and the other is hydroxyl group. 0.5 to 6 moles of reducing agent per mole of carbonyl compound of formula (VI) or (I) is used and the reaction is carried out in an aqueous or non-aqueous solvent such as a linear or cyclic ether such as ethyl ether, tetrahydrofuran, dimethoxyethane or dioxane; or an aliphatic or aromatic hydrocarbon, such as n-heptane or benzene, or: a halogenated hydrocarbon, such as methylene chloride, or in a hydroxylated solvent such as methyl, ethyl or isopropyl alcohol, and also in mixtures of said solvents. The reaction may be carried out at a temperature in the range of -40 ° C to the boiling point of the solvent used, but preferably at a temperature of -25 to +25 ° C.

The tertiary alcohol is prepared by reaction with an organometallic derivative, and after removal of all of the protecting groups, a compound of formula I is obtained wherein Y is -CH 2 -CH 2 - or -CH = CZ- (trans), Z is as defined above and one R3 and R4 are C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl or phenyl (or naphthyl) - (C1-C8) alkyl, and the other represents a hydroxyl group. As organometallic reagent, magnesium organo compounds can be used, for example compounds of the formula R10MgHal (wherein R10 is C1 -C6 alkyl, C2 -C10 alkenyl, phenyl or phenyl (or naphthyl) - (C1-C6) an alkyl group, and Hal represents a halogen atom, preferably a chlorine or bromine atom), a lithium hydrate of the formula R10CuLi (in which R10 is as defined above), an organolithium compound of the formula R10Li (in which R10 is as defined above) or an alkali metal or metal acetylide of alkaline earths of the general formula (R11-C = C-) _n -M ^{n +} [in which n is 1 or 2 and Rn represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 8 carbon atoms, phenylphenyl or naphthyl) - (A) an alkyl group or an aryl group, in particular a phenyl group, and M denotes an alkali metal or an alkaline earth metal). The reaction of the carbonyl compound with one of said organometallic reagents is preferably carried out using 1.05 moles (or slightly more) of reagent per mole of carbonyl compound, in an anhydrous solvent such as an aprotic solvent such as dimethylformamide or hexamethylphosphoric triamide or linear a cyclic ether such as ethyl ether, tetrahydrofuran, anisole, dioxane or dimethoxyethane, or an aliphatic or aromatic hydrocarbon such as n-heptane, n-hexane, benzene or toluene. The reaction may be carried out at a temperature in the range of about -70 ° C to the boiling point of the solvent used, but preferably at a temperature in the range of -60 to +20 ° C.

The product of said nucleophilic addition is a mixture of epimeric S and R alcohols for both the secondary and the tertiary alcohol. Individual S and R alcohols of general formulas n

(R) in which R 8 denotes hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) ) may be separated by fractional crystallization or by the chromatographic procedures described above.

Optional etherification of said secondary and tertiary alcohols to give, after removal of all protecting groups, compounds of formula I wherein Y is -CH 2 -CH 2 - or -CH = CZ- (trans), Z is as defined above, and one of R 3 and R 4 is C 1 -C 6 alkoxy or phenyl (or naphthyl) - (C 1 -C 6) alkoxy and the other is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl , a (C 2 -C 10) alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl group, is carried out by treatment with a diazoalkane or an optionally substituted diazoalkane in the presence of a catalyst such as fluoroboric acid or boron trifluoride in an organic solvent, as in methylene chloride. Alternatively, the etherification of the hydroxyl group (either free or in the form of a salt thereof) may be carried out by treatment with an alkyl or arylalkyl halide in the presence of a base such as silver oxide in a suitable solvent such as dimethylsulfoxide or dimethylformamide.

Optional dehydrohalogenation of a compound of formula I wherein Y is -CH = CZ- (trans), Z is halogen and one of R 3 and R 4 is hydroxyl, C 1 -C 6 alkoxy, or phenyl (or naphthyl). (C 1 -C 6) alkoxy and the other is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenylphenyl or naphthyl) - (C 1 -C 6) an alkyl group, or R 3 and R 4 together form an oxo group, to the corresponding compound of formula I in which Y is - C = C - may be carried out by treatment with a dehydrohalogenating agent, preferably selected from the group consisting of the anion CH 3 -SO-CH 2 , Diazabicycloundecene, diazabicyclononene and alkali metal amides or alcoholates 1 to 5 moles, preferably 1.5 to 1.8 moles, of the dehydrohalogenation agent are used per mole of the compound of formula (I). The reagents and reaction are preferably carried out in an oxygen-free atmosphere, in an inert solvent such as dlmethylsulfoxide, dimethylformamide, hexamethyltriophosphoric triamide, a linear or cyclic ether, or an aliphatic or aromatic hydrocarbon, for example those mentioned above, in liquid ammonia or mixtures of said solvents, at a temperature ranging from -60 ° C to the boiling point of water. If liquid ammonia is not used as the reaction medium, the reaction is preferably carried out at room temperature.

It is expedient that said dehydrohalogenation of a compound of formula I in which Y is -CH = CZ- (trans) and Z is a halogen atom to the corresponding derivative of formula I in which Y is -C = C- is preceded by the previously described nucleophilic addition to the carbonyl followed by etherification of the alcohol obtained.

The following reactions are all carried out using standard procedures: optionally converting a compound of formula I to another compound of formula I, optionally preparing a lactone or salt, preparing a free compound of formula I from a salt thereof, and optionally separating the mixture of isomers into individual isomers.

For example, a compound of formula I wherein R 3 and R 4 are hydrogen may be prepared from a compound of formula I wherein one of R 3 and R 4 is hydrogen and the other is a hydroxyl group by preparing a tosylate from said alcohol by treatment with tosyl chloride in the presence of a base, and the tosylate obtained is reduced with either sodium borohydride or sodium cyanoborohydride in water, aqueous alcohol or dimethylformamide, or hydride. lithium aluminum in an anhydrous solvent such as ethyl ether or tetrahydrofuran at a temperature ranging from room temperature to the boiling point of the solvent used. Analogously, a compound of formula I wherein R 1 and R 2 are hydrogen may be prepared from the compound. of the general formula I, in which it denotes one. R 1 and R 2. R 2 is hydrogen and a second hydroxyl group, and a compound of formula I wherein D is -CH 2 - can be prepared from a compound of formula I wherein D is -CH 2 -;

CH-OH.

OF

A compound of formula I wherein R 3 and R 4 together form an oxo group can be prepared from a compound of formula I wherein one of R 5 and R 4 is hydrogen and the other is hydroxyl by selective oxidation with an excess of activated manganese dioxide in an inert, preferably a chlorinated solvent, such as methylene chloride or chloroform, at room temperature, or alternatively by treatment with 1.1 to 1.5. 1.2 mol equivalents of dichlorodicyanobenzoquinone in an inert solvent such as dioxane, benzene or mixtures thereof at a temperature in the range of 40 ° C to the boiling point of the solvent used.

By analogy, a compound of formula I wherein R 1 and R 2 together form an oxo group can be prepared from a compound of formula I wherein one of R 1 and R 2 is hydrogen and the other a hydroxyl group, and a compound of formula I wherein D is group \

C = O, Z can be prepared from a compound of formula I wherein D is \

CH-OH.

OF

If only one of several secondary alcohol functions is to be oxidized, the others must be protected as described above; upon completion of the reaction, the protecting groups are removed again.

A compound of formula I wherein one of R 1 and R 2 is C 1 -C 6 alkoxy or phenyl (or naphthyl) - (C 1 -C 6) alkoxy may be prepared from a compound of formula I wherein one of the substituents R 1 and R 2 denote a hydroxyl group, by etherification, in an analogous manner to that described for the preparation of compounds of formula I in which one of the substituents R 3 and R 4 denotes a hydroxyl group, again if only one of several secondary alcohol functions present is etherified others must be protected and the protecting groups removed again after the reaction is complete.

A compound of formula I wherein R is an esterified carboxyl group (e.g., C 1 -C 12 alkoxycarbonyl) can be prepared from a compound of formula I wherein R is a free carboxyl group by known standard procedures, for example by reaction with an appropriate alcohol, such as an aliphatic alcohol having 1 to 12 carbon atoms, in the presence of an acid catalyst such as p-toluenesulfonic acid, or alternatively by the action of a diazoalkane.

Optionally, a compound of formula I wherein R is an esterified carboxyl group (e.g., C 1 -C 12 alkoxycarbonyl) can be converted to a compound of formula I wherein R is a free carboxyl group using standard saponification methods such as treatment with hydroxide an alkali metal or alkaline earth metal in water or aqueous alcohol, followed by acidification of the reaction mixture.

A compound of formula I wherein R is —CH2 —R “and R” is a hydroxyl group can be prepared from a compound of formula I wherein R is a free or esterified carboxyl group by reduction of the ester group with lithium aluminum hydride in ethyl ether or tetrahydrofuran at the boiling point of the reaction mixture.

Optionally, a compound of formula I wherein R is a free carboxyl group can be converted to a compound of formula I wherein R is a group of formula

Ra Z - CON \

R b and R _a and R _b are as defined above by treatment with an amine of the formula HNR _and R _b in the presence of a condensing agent, for example a carbodiimide such as dicyclohexylcarbodiimide. A compound of formula I wherein R is an ester of a carboxyl group can be converted to a compound of formula I wherein R is a group of formula

Ra Z — CON, \

Rb by heating with an amine of formula HNR _a R _b in a suitable organic solvent at reflux for 2-3 hours.

A compound of formula I wherein R is n-n

II can be prepared from a compound of formula I in which R is a carboxyl group by first converting the starting carboxylic acid to the corresponding acid halide (preferably chloride, for example by refluxing with thionyl chloride or oxalyl chloride in dichloroethane or dioxane to reflux) which is dehydrated to nitrile (for example in the presence of p-toluenesulfochloride in pyridine at 90 to 100 ° C) and the nitrol obtained is then reacted with sodium azide in the presence of ammonium chloride in dimethylformamide at a temperature ranging from room temperature to 10 ° C. This procedure converts the carboxyl group to a nitrile and a ~ C II group

XNH-N is preferably carried out on the starting material.

Alternatively, a compound of formula I in which R is a free or esterified carboxyl group can be converted to a compound of formula I in which R is —CHO using standard procedures, for example by first preparing the corresponding acid or ester from the corresponding compound chloride and this is then subjected to the Rosenmund reaction as described in Org. Reactions 4, 362 (1948).

A compound of formula I in which R is-C (OR ') 3 and R' is as defined above can be prepared from a compound of formula I in which R is a free or esterified carboxyl group by subsequently the compound is converted to the carboximidoester hydrochloride in a known manner and reacted with a suitable alcohol, as described, for example, in J. Amer. Chem. Soc. 64, 1827 (1942).

Acetalisation, for example the optional preparation of a compound of formula I in which R is a group of formula wherein X 'is O and R _a ' and R _b 'are as defined above, is effected by reacting the starting aldehyde either by reaction with an alcohol or glycol in the presence of a catalyst, such as p-toluenesulfonic acid or a sulfonated resin, in a suitable solvent which allows removal of the water formed by azeotropic distillation, or undergoes an exchange reaction with acetone dioxolane to remove the acetone formed, or into the reaction with an orthoester, in which the alcohol formed is distilled off. Acetal may also be prepared from the appropriate thioacetal by reaction with a suitable alcohol or glycol in the presence of a mercuric salt, preferably mercuric chloride, as an exchange catalyst, and an alkaline earth metal carbonate, in an inert solvent medium.

Thioacetalisation, for example the preparation of a compound of formula I wherein R is a group of formula

X'-R '

Z —CH,

From x'-R _b '(in which X' is a sulfur atom and R _a 'and R _b ' are as defined above), a compound of formula I in which R is -CHO is preferably carried out by the starting aldehyde is reacted with a mono- or dimercaptan such as methyl mercaptan, ethyl mercaptan, dithioethylene glycol (1,2-ethanedithiol) or dithiopropylene glycol (1,3-propanedithiol) in the presence of a catalyst such as boron trifluoride etherate in an inert solvent, preferably halogenated or aromatic solvent a hydrocarbon such as methylene chloride, chloroform, benzene or toluene.

The corresponding ketals or thioketals can be prepared from the starting ketals by the methods described above for the preparation of acetals and thioacetals.

The preparation of the lactones and salts from the compounds of the formula I as well as the preparation of the free compounds of the formula I from their salts are carried out by conventional methods.

The separation of the mixture of isomers of the formula I into the individual isomers is also carried out by conventional methods, for example by traction crystallization or chromatography.

Compounds of formula (IV) may be prepared by the method of forming a compound of formula (XVIII) ⁱⁿ J,

X‘-Ra ‘

Z - CH.

\

X‘-Rb ‘and 9 ') a radical of formula

X ‘- Ra‘

Z —CH,

X‘ — Rb ‘

(XV П I) in which p, q, R 1 and R 2 are as defined above and T denotes the protected aldehyde function of the general formula

X'-R _a '

Z - CH, \

X'-R _h 'wherein X', R _a ', R _b ' are as defined above, react with a compound of formula III

E —CH— (CH2) _m —D— (CH2jm —R “'(-) 1.2 (III) in which

D, mi and mz are as defined above, E represents a group of formula (C 6 H 8 P 6 - or (R 6 O 2 P -) (O i -), wherein each individual R c is independently C 1 -C 6 alkyl or phenyl and R "is selected from from the group consisting of a ") carboxy, either a free or esterified group of the formula: -COOR 9, wherein R 9 is C 1-12 alkyl or C 2-12 alkenyl, or carboxy in the form of the corresponding salt, b") a group of formula -C (OR ') 3; wherein R 'is as defined above, c') a group of the formula —CH2 —R'v in which Riv denotes an acyloxy group having 2 to 7 carbon atoms or a protecting group attached to a —CH2 — ether bond, d “) a group of the formula

Rt>, wherein R _a , R _b are as defined above, e ") a cyano group, f") a radical of the formula

-ch II

NH-N wherein X ', R _a ' and R _b 'are as defined above to give a compound of formula XIX,

1 (1

Hi

H

CH 2 CH 2 D- (CH + R 2)

CH (CHj ICHj

HH (XIX) wherein R "', m2, D, I, p, q, R', R 'and T have the abovementioned meaning, ^B] The compound of formula XIX is optionally converted to a compound of formula XX 0becného,

in which R ‘, mz, D‘, mi, p, q, Ri ‘, Rzi and T are as defined above, and then

(d) remove the protective groups of the aldehyde function present in T.

The reaction of a compound of formula XVIII with a compound of formula III is carried out using an excess of at least 1.1 mol equivalents of the compound of formula III per mole of the compound of formula XVIII. The reaction is preferably carried out in an inert solvent, for example a linear or cyclic ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, an aliphatic or aromatic hydrocarbon such as n-hexane, n-heptane, benzene or toluene, or a halogenated hydrocarbon, as in dichloromethane or carbon tetrachloride, as well as in mixtures of the solvents mentioned.

In the compounds of formula (III), when E is (CeH5) 3P-,

Dimethyl sulfoxide, hexamethylphosphoric triamide and other aprotic solvents can be used in alkylation in particular for alkylation. Dimethylsulfoxide provides dimethylsulfinylcarbanion by reaction with an alkali metal hydride, which can then form carbanions of the general formulas III from the corresponding phosphates and phosphonates; this solvent is therefore particularly advantageous since the carbanions of formula III can be prepared in situ.

The above reactions can be carried out at a reaction temperature ranging from freezing to the boiling point of water, but particularly preferably at room temperature. A mixture of two isomeric olefins of differing configuration (cis or trans) on the newly formed exocyclic double bond is obtained. The individual geometric isomers of formula (XIX) can be separated by traction crystallization or chromatography as described above.

The compound of formula (XIX) may optionally be converted to a compound of formula (XX) as described above for analogous reactions to compounds of formula (I). For example, a compound of formula (XX) in which D ‘denotes the group \

CH «wwwOCOR‘

Z (R‘ is as defined above), to prepare from a compound of formula XIX wherein D is \

CH> W (O) ^ I,

By conventional methods used to esterify alcohols. Also a compound of formula XX in which D ‘denotes a group

X ‘- Ra‘ \ Z c z \

X'-Rb '(X', R _a 'and Rb' are as defined above), can be prepared from a compound of formula XIX in which D is \

C = O,

By conventional ketalisation and thioketalisation procedures.

Aldehyde function protecting groups in compounds of formula XX may be removed by the methods described above, preferably by acid hydrolysis when the aldehyde is protected in the form of acetal, or by the action of mercuric chloride when protected in the form of thioioacetal. If the aldehyde function protecting group needs to be removed selectively in the presence of other protected carbonyl functions in the molecule, these latter functions need to be protected as acetals or ketals when the aldehyde is protected in the form of thioacetal or vice versa as thioacetals or thioketals when the aldehyde is protected in the form of acetal.

The compounds of the formula I exhibit the same pharmacological activity as the natural prostacyclin PGI2, but in comparison with PGI2, the compounds according to the invention are more advantageous for their greater stability at a pH in the range of 0 to 11, in particular at physiological pH; this causes the compounds of formula I to have a longer lasting and more constant biological activity. The reason for this greater stability is that the chemical structure of the compounds of formula I is different from that of natural prostacyclin. Due to . Since an oxygen atom is incorporated as a heteroatom in the natural prostacyclin 2-oxa-bicyclo [3.3.0] octane system, prostacyclin is an exocyclic enol ether and is therefore extremely sensitive to acids. The product of the reaction of prostacyclin with acids, 6-keto-PFG _kz , shows almost none of the activities characteristic of natural prostacyclin. In contrast, the compounds of formula I do not contain oxygen in the bicyclic system and are therefore not enol ethers. Since they are not as highly labile as natural derivatives, they can be administered orally.

In addition, those compounds of the general formula. I in which a triple bond is present at position 13,14 of the side ω-chain or in which a suitable protecting group, such as a C1-C6 alkyl group, or an electron-receptor group, for example a fluorine atom, is present near the hydroxyl group in at position 15 (R 3 or R 4 denotes a hydroxyl group), they are more resistant to metabolic degradation caused by enzymes (e.g. 15-PG dehydrogenase) than natural prostacyclin.

The pharmacological activities of natural prostacyclin are known. For example, by inhalation. administered prostacyclin prevents asthmatic patients from developing non-specifically induced (e.g., water fog or exertion) bronchoconstriction [see S.. Bianco et al., J. Res. Medical Science 6,256 (1978)]. When administered by infusion in humans, prostacyclin exhibits hypotensive and vasodilatory activity and also has anti-platelet and anti-platelet effects. [see Szekely et al., Pharm. Res. Comm. 10, 545 (19713)). Prostacyclin also has uterine stimulating effects in monkeys and women; Furthermore, prostacyclin exhibits luteolytic activity in experimental animals and has the ability to protect the gastric mucosa from ulceration induced in experimental animals, such as rats, NSAID215149

These include anti-inflammatory agents such as acetylsalicylic acid (ASA) or indomethacin.

In the case of natural prostacyclin, these activities are associated with a significant chemical instability of the substance which makes the substance unsuitable for pharmaceutical use. As mentioned above, the compounds of formula I have pharmacological effects similar to those of natural prostacyclin, but are free of undesirable chemical instabilities of PGI2.

The following table shows both the in vitro inhibitory activity on platelet aggregation induced by 10 μΜ ADP in platelet-rich plasma and the hypotensive activity in anesthetized rats of two compounds of the invention and PGI2:

Substance antiplatelet effect in vitro hypotensive effect

IC50 ng / ml relative activity i οοο ((2) 25 1,15 (3) 20 0,25 (1) PGI 2, (2) 5t, 13t-11a, 15S-dihydroxy-9α-deoxy-Oα-methyleneprostacycl- 5,13-dienoic acid, (3) 5t, 13t'llQ ', 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacyclla-5,13-dienoic acid,

IC 50 = concentration inhibiting 50% platelet aggregation.

The anti-ulcer activity of dl-5,13t-11a, 15S-dihydroxy-9α-deoxy-7-nor-methyleneprostacyclla-5,13-dienoic acid, when administered at doses producing the same antiplatelet effect, is about 10-fold higher.

Also, in vitro luteolytic efficacy in hamsters, when administered at doses producing the same antiplatelet effect, is about 5-fold higher for dl-5,13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17 -cyclohexyl-18,19,20-trinor-prostacycl-5,13-dienoic acid and 8-fold higher for 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17 , 18,19,22-tetranor-prostacycl-5,13-diene.

With regard to prostacyclin and prostaglandin activity, the compounds of formula I can be used in human and veterinary medicine where natural prostaglandins and prostacyclin are therapeutically indicated.

For example, the compounds of formula I can be used for the treatment of asthma due to their significant bronchodilator effect. In this application, the compounds of the invention may be administered in various ways: orally in the form of tablets, capsules and pills or in the form of solutions such as drops or syrups, rectally in the form of suppositories, intravenously, intramuscularly or subcutaneously, inhalation in aerosols or solutions using inhalers, or inhalation in the form of powders. A suitable dose in this indication is about 0.01 to 4 mg per kg, administered 1 to 4 times daily; the exact dose level will depend on the age, weight and condition of the patient as well as the route of administration.

In antiasthmatic applications, the compounds of formula (I) may be combined with other antiasthmatics, for example sympathomimetics such as isoproterenol, ephedrine and the like, with xanthine derivatives such as theophylline and aminophylline, and with corticosteroids such as prednisolone and ACTH.

Furthermore, the compounds of formula (I) possess oxytocic activity and can therefore be used in place of oxytocin for inducing labor or expulsion of the fetus, both in human and veterinary obstetrics. For such administration, the compounds of the invention are administered intravenously at a dose of about 0.01 µg / kg / min until delivery or orally.

The compounds of formula I also have luteolytic activity and can therefore be used to control fertility; their advantage is that they much less stimulate smooth muscle and do not have the side effects of natural prostaglandins such as vomiting and diarrhea.

Furthermore, the compounds of formula I have anti-ulcer activity and can be used to reduce and control gastric juice secretion in mammals. In this way, they reduce or eliminate the formation of gastrointestinal ulcers and accelerate the cure of ulcers already present in the gastrointestinal tract. In such cases, the compounds of the invention may be administered by intravenous infusion or by intravenous, subcutaneous or intramuscular injection. Doses ranging from 0.1 µg to 500 µg / kg / min are used for intravenous infusion. The total daily dose for both injection and infusion is of the order of 0.1 to 20 mg / kg, depending on the age, weight and condition of the patient or animal, and the route of administration.

However, as with natural prostacyclins, the most important property of the compounds of formula I is their anti-platelet anti-platelet activity, i.e., their ability to inhibit platelet aggregation, reduce their adherence, prevent blood clots and dissolve blood clots. This platelet anti-aggregation activity is also associated with coronary artery relaxation. . For this reason, the compounds of the invention are suitable for the prevention and treatment of myocardial infarction and, in general, for the treatment and prevention of thrombosis and for the treatment of other vascular diseases such as atherosclerosis, arteriosclerosis and especially dihyperlipidemia.

In these applications, the normal routes of administration, for example intravenous, subcutaneous, intramuscular and others, may be used. In sudden situations, intravenous administration is preferred, at doses ranging from 0.005 to 20 mg / kg / day, again depending on the age, weight and condition of the patient and the mode of administration.

As mentioned above, the compounds of formula (I) may be used in human and veterinary therapy for various routes of administration. They can be administered orally in the form of tablets, capsules, drops or syrups, rectally in the form of suppositories, parenterally in the form of solutions or suspensions administered subcutaneously or intramuscularly, by injection, preferably in sudden cases, by inhalation as aerosols or by inhalers as solutions, in the form of sterile protracted implants, or endovaginally, for example in the form of vaginal suppositories.

Pharmaceutical and veterinary preparations containing compounds of formula I may be prepared using conventional carriers and / or diluents. For example, for intravenous injection or infusion, sterile isotonized aqueous solutions are preferably prepared. For subcutaneous or intramuscular injections, sterile aqueous solutions or suspensions in aqueous or non-aqueous media are used. For sterile implants, sterile moldings or capsules of silicone rubber containing or impregnated with the active ingredient are used.

Water, gelatin, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycols, starch, gum arabic, tragacanth, acid can be used as suitable carriers and diluents for the preparation of said pharmaceutical preparations. alginates, alginates, lecithin, polysorbates, vegetable oils and the like.

By inhalation, the compounds of the invention may be administered by inhalers, using aqueous suspensions or solutions of the compounds of formula I, preferably in the form of their salts, for example the sodium salt. Alternatively, the compounds of formula I may be suspended or dissolved in one of the conventional liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, and filled with suitable pressure vessels such as aerosol cartridges. If the active substance is not soluble in the liquefied propellant gas, a cosolvent, for example ethanol, dipropylene glycol and / or a surfactant, must be added to prepare said type of pharmaceutical preparation.

The following abbreviations are used in the following examples: THP = tetrahydropyranyl, DMtB = dimethyl-tert-butyl, DIOX = 1,4-diox-2-enyl, THF = tetrahydrofuran, DMSO = dimethylsulfoxide, DIBA = diisobutylaluminum hydride and DMF = dlmethylformamide.

The process according to the invention is explained in more detail in the following non-limiting examples.

Example 1

To a solution of 11.6 g (8.4 x 10 ^-2 mol) of bicyclo [3.3.0] octane-3,7-dione in a mixture of 100 ml of methylene chloride with 100 ml of ethanol is added 1.1 g with stirring. (0.029 mol) sodium borohydride. The mixture is stirred at room temperature for 45 minutes, then the excess reducing agent is quenched by the slow addition of 20 ml of acetone and the solution is neutralized with 1.4 ml of acetic acid. The solvents were distilled off under reduced pressure, the residue was taken up in a mixture of water and methylene chloride, the organic layer was separated and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / ethyl ether 70:30), to give 9.1 g of 7-hydroxybicyclo [3.3.0] octan-3-one; IC (film) 3400, 1740 cm ^{@ 4} .

To a solution of the latter compound (0.065 mol) in 27 ml of anhydrous dimethylformamide was added 12.8 g of dimethyl tert-butylsilyl chloride and 8.85 g of imidazole and the mixture was heated at 60 ° C for 5 hours. After cooling, the reaction mixture was diluted with two volumes of water and the product was taken up in ethyl ether (3 x 40 ml and 2 x 20 ml). The combined ether extracts were washed with 5% sodium bicarbonate solution and then with water until neutral and the solvent was distilled off; 15.8 g (95% yield) of crude product is obtained. After chromatography on silica gel, 2.85 g of 7-exo-hydroxy-bicyclo [3.3.0] octan-3-one dimethyl tert-butylsilyl ether (mp 40-42 ° C) and 11.8 g of 7- 7-endo-hydroxy-bicyclo [3.3.0] octan-3-one dimethyl-tert-butylsilyl ether, mp 51-52 ° C.

To a solution of the latter compound (11.8 g, 4.63 χ 10 ^-2 mol) in 295 mL of methyl carbonate (MezCl 3) was added cautiously 6.95 g of 80% sodium hydride under stirring, with the exclusion of water and an inert atmosphere. After completion of hydrogen evolution, the reaction mixture is heated at 75-80 ° C for 40 minutes. After cooling, the solution is diluted with two volumes of ethyl ether, 13 g of glacial acetic acid are carefully added dropwise, and then an aqueous buffer solution of pH 5.2 to 5.5 is added. The organic layer was separated, the aqueous portion was washed with ethyl ether, the combined organic extracts were dried over anhydrous sodium sulfate, and the solvent was distilled off. 12.82 g of crude d, 1-7-endo215149 are obtained

-hydroxy-bicyclo [3.3.0] octan-3-one-2-methoxycarbonyl-7-dimethyl-tert-butylsilyl ether (85 ° / oz theoretical 14.49 g yield), which after purification by column chromatography on silica gel [45] g / g (97: 3 hexane / ethyl ether) to give 10.81 g of pure product; Λ _max = 254 nm, ε = 7000.

Using the exo-isomer as starting material, 7-dimethyl-tert-butylsilyl ether d, 1-7-exo-hydroxy-bicyclo [3.3.0] octan-3-one-2-methoxycarbonyl ester was obtained in the same manner; _Λ = 254 nm, ε = 6500.

Example 2

To a solution of 7.5 gd, 1-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-methoxycarbonyl-7-dimethyl-tert-butylsilyl ether (DMtB-silyl ether) in 75 ml of dichloromethane and Ethanol (75 ml) was added with sodium borohydride (0.9 g) while cooling to -20 ^° C and stirring. The reaction mixture was stirred at room temperature for 15 minutes and then the excess reducing agent was quenched by the addition of 12 mL of acetone. The mixture is cooled to 0 ° C, 20 ml of 20% potassium dihydrogen phosphate are added, the solvents are distilled off under reduced pressure, and the aqueous solution is extracted several times with ethyl ether. The organic extracts were combined, washed with 5 ml of water and the solvent was distilled off. The residue is recrystallized from n-hexane to give 4.8 gd, l-3,7-endo-dihydroxy-bicyclo [3.3.0] octane-2-oxo-methoxycarbonyl-7-DMtB-silyl ether, m.p. 68-70. Deň: 32 ° C. The mother liquors are chromatographed on 25 g of silica gel, eluting with n-heptane / ethyl ether (90:10); an additional 2 g of product is obtained which is sufficiently pure and can be used for further work as such.

To a solution of 6 gd, l-3,7-endo-dihydroxy-bicyclo [3.3.0] octane-2-oxo-methoxycarbonyl-7-DMtB-silyl ether in 100 mL of 80:20 methanol / water was added 2 g of potassium hydroxide are added and the mixture is heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrated solution was acidified to pH

5.1 and the product is taken up in ethyl acetate. After distilling off the solvent from the combined organic extracts, 5.1 g of 7-DMtB-silyl ether d, l-3,7-endo-dihydroxy-2-carboxy-bicyclo [3.3.0] octane is obtained.

To a solution of the latter acid in 150 ml of acetonitrile was added 2.81 g of d- (+) - ephedrine, and the mixture was allowed to crystallize at room temperature for 4 hours. 2.9 g of salt are obtained, which after recrystallization twice from aeetonitrile yields 1.85 g of d- (+) - ephedrine salt of 7-DMtB-silyl ether (+) -3,7-endo-dihydroxy-2-exo-carboxy- bicyclo [3.3.0] octane, [α] _D = + 52 °. Combine all mother liquors, evaporate the solvent to dryness, dissolve the residue in water and add a solution of 0.68 g of sodium hydroxide in water; The d- (+) -Ephedrine is shaken into benzene, the solution of sodium acid in water is acidified to pH 5 and the product is taken up in ethyl acetate. The solvent is distilled off from the combined organic extracts, l-ephedrine is added to the residue dissolved in acetonitrile and the salt obtained is recrystallized several times; 2.3 g of (-) -3,7-endo-dihydroxy-2-exo-carboxy-bicyclo [3.3.0] octane-7-DMtB-silyl ether are obtained, [g] d = - 49+

Example 3

To a solution of 6.28 g of 7-DMtB-silyl ether d, l-3,7-endo-dihydroxy-2-exomethoxycarbonyl-bicyclo [3.3.0] octane in 30 ml of anhydrous methylene chloride is added 2.19 g (2, Of 3-dihydropyran and 39 mg of p-toluenesulfonic acid and the mixture was allowed to stand at room temperature for 3 hours, washed with 5% sodium bicarbonate solution (2 x 5 mL), and 8 g of 7-DMtB- silyl ether-3-THP-ether d, l-3,7-endo-dihydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octane, which is dried by dissolving in anhydrous benzene (2 x 15 ml) and evaporating The product obtained is dissolved in anhydrous ethyl ether and a solution of 0.6 g of lithium aluminum hydride in 40 ml of anhydrous ethyl ether is added dropwise with stirring over 15 minutes, the reaction mixture is stirred for a further 30 minutes and then the excess reducing agent is quenched by careful addition. 5 ml of acetone and then of ethyl ether saturated with water sodium sulfate, filtered and the solvent was distilled off to give 7.2 g of 7-DMtB-silyl ether-3-THP-ether d 1,1,1,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo 0.15 octane, M ⁺ 370 m / e.

In the same way, but using optically active starting materials, the following compounds are prepared:

7-DMtB-silyl ether-3-THP-ether nat-3,7-enclo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane; and

7-DMtB-silyl ether-3-THP-ether ent-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane.

When used in the above procedure, l, 4-dioxo-2-ene in place of 2,3-dihydropyran, there are obtained the corresponding 3- (2 ^<dioxo) ether.

Example 4

To a solution of 3.8 gd, l-3,7-endo-dihydroxy-bicyclo [3.3.0] octane-2-exo-methoxycarbonyl-7-DMtB-silyl ether in 40 ml benzene was first added 3.66 g of acid benzoic acid and 7.9 g of triphenylphosphine, and then, with stirring, a solution

5.30 g of ethyl azobiskarboxylate in 15 ml of benzene. The reaction mixture was stirred for 40 minutes and then washed successively with 2 N sulfuric acid (2 x 20 mL), sodium carbonate solution (3 x 15 mL), and then water to neutral. After distilling off the solvent, a mixture of 3-benzoate 7-DMtB-methyl ether d, 1-3-exo-7x: nododihydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octane was obtained, NMR: 3-endo [H] - 5.8 µm); 2-endo [H 3.32 order, d); CO2CH3 [3H,. 3.64 (J); 7-endo [H, 4.4 om], and 7sDMtB-silyl ether d, 1-7-endo-hydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] oct-3-ene, M + 296 m / E.

The crude reaction product was dissolved in anhydrous methanol and the solution was stirred with 0.5 g of anhydrous potassium carbonate for 3 hours. The solvent is evaporated to dryness, the residue is taken up in a mixture of ethyl acetate and a saturated aqueous solution of potassium dihydrogen phosphate, the organic phase is washed neutral and the solvent is distilled off. The residue is chromatographed on a silica gel column, eluting first with hexane and then with hexane / ethyl ether; it is obtained:

a) 1.01 g of 7sDMtB-silyl ether dj-endo-hydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octs-3-ene, which is dissolved in methanol, 0.3 g of 5% is added to the solution palladium on calcium carbonate and the mixture is hydrogenated at room temperature at atmospheric pressure; There was obtained 7-DMtB-dimethyl ether d, 1-7-endo-hydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octane, M + 298 m / e.

b] 2.01 g of 7-DMtB-silyl ether dSs3sO5S7s-endo-dihydroxy-2sexo-methoxycarbonyl-bicyclo [3.3.0] octane, [M + 300 m / e], which is saponified as described in Example 2, by treatment with 5 % of a solution of potassium carbonate in methanol / water 80:20, and the obtained 7, 6-β-16,14-d, l-3-exo-mendo-dihydroxy-bicyclo [3.3.0] octane-2-exo-carboxylic acid, it is divided into individual optical antipodes with the aid of [+) - and [-) -amphetamine.

The obtained 7-DMtB-silyl ether [+] -3-exo-7-endo-dihydroxy-bicyclo [3.3.0] octane-2-exo-carboxylic acid is converted to the corresponding methyl ester by treatment with an ethereal solution of diazomethane. The ester provides reaction with 2,3-dihydropyran followed by reduction with lithium aluminum hydride in 3-Ti 1 -IP-ethers-7-DMtB-silyl ether [+ 4-oxo-7-endo-dihydroxy-2-exo-hydroxymethyl] -bicyclo [ 3,3,0] octane, M + 370 m / e.

The [-] enantiomer and the racemic mixture were prepared in an analogous manner.

Example 1 a d 5

To a solution of 5 g of d, l-7-endOshydroxy-bicyclo 7-methyl-βγ1β-™ methyl ester | 3.3 g of octane-3-exo-carboxylic acid in 100 ml of aqueous methanol are added 2 g of potassium hydroxide and the mixture is heated to reflux. Methanol is distilled off under reduced pressure, and the solvent is extracted with water from the remaining aqueous potassium salt solution. impurities, the solution is acidified and the product is taken up in ethyl ether. The ether extracts were combined and the solvent was distilled off. 4.5 g of d, l-acid are obtained, which is separated into the optical antipodes by [+] - and [-) -ephedrine.

1.32 g of the obtained [-] -7-endo-hydroxy-bicyclo [3.3.0] octane-2-exo-carboxylic acid DMtB-methyl ether are dissolved in 20 ml of tetrahydrofuran and 10 ml of a 1 M borane solution in THF. The reaction mixture is allowed to stand at room temperature for 4 hours, then the excess reagent is quenched by the careful addition of 20 ml of 1.5 N sodium hydroxide and the solvent is distilled off under reduced pressure. The remaining aqueous solution was extracted with ethyl ether, the organic extracts were combined, washed neutral and the solvent was evaporated to dryness; 1.02 g of 7α-α-α-β-α-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane is obtained, M + 270 m / e.

The corresponding [+ 1] -isomer and the racemic mixture were prepared in an analogous manner.

Example 6

0.95 g of 2,3-dihydropyran and 20 mg of p-acetic acid are added to a solution of 2.7 g of 7-DMtB-dimethyl ether d, 1- 7-sulfonic acid-2-exo-hydroxymethyl-bicyclo] 3.3.0] octane in 20 ml of methylene chloride. toluene sulfone and the mixture was allowed to stand at room temperature for 3 hours. The solution was washed with 7% aqueous sodium bicarbonate and then water and the solvent was evaporated to dryness. Dissolve crude 7? -? -? 1? 16? -D, lsendo-hydroxys2-exo-tetrahydropyranyloxymethyl-bicyclo [3.3.0] octane [M + 354 m / e] in 15 mL THF, add 4.5 g to the solution tetrabutylammonium fluoride and the mixture was stirred for 10 hours. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel using a mixture of benzene and ethyl ether as eluent; is obtained

2.1 gd, 1-endo-hydroxy-2-exo-THP-oxymethyl-bicyclo [3.3.0] octane, IC [film] 3400, 1280 cm &^lt; -1 & gt ^; , M + 240 m / e.

To a solution of the latter product in 25 ml of acetone is added, with cooling, to -20 to -8 ° C, with stirring, within 15 minutes.

4.2 ml of 8% Jones reagent [solution of chromium trioxide in aqueous sulfuric acid] until a persistent slightly pink color is obtained. The mixture is stirred for an additional 14-20 minutes, then isopropyl alcohol (1.5 ml) is added and the green solution obtained is diluted with 6 volumes of benzene. The organic portion was washed with a 20% ammonium sulfate solution until neutral, the aqueous portions combined and re-extracted with benzene. The combined benzene extracts were dried and the solvent was distilled off; 1.82 gd, l-2-exosTHP-oxymethybicyclo [3.3.0] octan-7-one are obtained, IC [film] 1740, 1228 cm &^lt; ^-1 &gt;, M + 238 111/0.

The corresponding nat- and enant-isomers were prepared in an analogous manner.

Example 1 a d 7

To a solution of 6.76 g of 4-carboxybutyl-triphenylphosphonium bromide in 40 ml of DMSO was added dropwise a solution of 6.57 g of potassium tertiary butylate in 65 ml of DMSO with stirring and external cooling, at 20-22 ° C. The reaction mixture was diluted with an equal volume of water, acidified to pH 5 and extracted with ethyl ether. The aqueous fractions were set aside and the combined organic extracts were shaken several times with 0.5 N sodium hydroxide. The alkaline aqueous extracts were combined, acidified to pH 5 and the product was taken up in a 1: 1 mixture of ethyl ether and pentane. The combined organic extracts were concentrated to a small volume, an ethereal diazomethane solution was added to the concentrated solution until a persistent yellow coloration, and then the volatiles were distilled off. The residue is dissolved in 50 ml of acetone, 20 ml of a 2 N aqueous solution of oxalic acid are added to the solution, and the mixture is heated at 40 to 45 ° C for 8 hours. The acetone was distilled off under reduced pressure, the remaining aqueous phase was extracted with ethyl acetate and the solvent was distilled off from the combined organic extracts. The residue obtained is purified by chromatography on silica gel, eluting with ethyl ether; a mixture of d, 1-5-cis, trans- (2'-exo-hydroxymethyl-bicyclo [3.3.0] oct-7'-enyl) pentenoic acid methyl esters (1.75 g) was obtained. The mixture is separated into the individual isomers by high pressure liquid chromatography; the 5-trans-d, l and 5-cis-d, l-isomer is obtained. The latter isomer is 5-cis-η (20-12) -octano-12β-hydroxymethyl-9α-deoxy-9α-methylene-prostacycl-5-enoic acid methyl ester, NMR: 5H (1H, 5.15 dm) CO 2 CH 3 (3H, 3.67 dS), M + 252 m / e.

Using the above procedure but using one of the following Wittig reagents, 3-carboxypropyl-triphenylphosphonium bromide, 5-carboxypentyl-triphenylphosphonium bromide or 4-carboxy-2-oxabutyl-triphenylphosphonium bromide, instead of 4-carboxybutyl-triphenylphosphonium bromide, d, l-5-cis-η (20-12) -octan-2-nor-12β-hydroxymethyl-9α-deoxy-9α-methyleneprostacycl-5-enoic acid, M ⁺ 238 m / e, d, l -5-cis-α (20-12) -octan-2α-homo-12β-hydroxymethyl-9α-deoxy-9α-methyleneprostacycl-5-enoic acid, M ⁺ 266 m / e, d, 1- 5- cis-a) (20-12) octanor-3-oxa12? -hydroxymethyl-9.alpha.-deoxy-9.alpha.-methyleneprostacycl-5-ene, M ⁺ 254 m / e and also their 5-trans isomers and the individual nat- and enantantipods.

Example 8

To a solution of 7.16 g of 5-cis-ω (20-12-octanor-12/3-hydroxymethyl-9a-deoxy-9a-methyleneprostacycl-5-enoic acid methyl ester in 90 ml of a 75:25 mixture of benzene / dimethylsulphoxide) 8.9 g of dicyclohexylcarbodiimide and then 14.2 ml of pyridinium trifluoroacetate solution (prepared by adding 25 ml of benzene / DMSO 75: 25 to 1 ml of trifluoroacetic acid with 2 ml of pyridine) are added and the mixture is stirred for four hours, then diluted with 100 ml of benzene. A solution of 3 g of oxalic acid in water is added dropwise to the solution, the precipitated dicyclohexylurea is filtered off, the organic layer is separated, washed with water (3 x 6 ml) and concentrated to a small volume. (2-Oxo-heptyl) dimethylphosphonate sodium salt The above compound is prepared by dropwise adding, under stirring, under inert atmosphere, a solution of 7.58 g of (2-oxo-heptyl) dimethylphosphonate in 40 ml of anhydrous benzene to solution 1, 02 g of sodium hydride (80% dispersion in mineral oil), and the mixture is stirred until the evolution of hydrogen ceases. After the addition of the formyl derivative to the phosphonate sodium salt thus prepared, the mixture is stirred for 20 minutes. The reaction mixture is neutralized with a saturated aqueous solution of sodium dihydrogen phosphate, the organic fraction is separated, concentrated to a small volume and chromatographed on silica gel using cyclohexane / ethyl ether as eluent; 6.4 g of 5-cis-13-trans-9α-deoxy-9α-methylene-15-oxo-prostacyclla-5,13-dienoic acid methyl ester are obtained.

When starting from analogous 12/3-hydroxymethyl derivatives prepared as described in Example 7, methyl esters of the following acids are obtained:

5-cis-13-trans-9α-deoxy-9α-methylene-15-oxo-2-nor-prostacyclla-5,13-dienoic acid, M ⁺ 332 m / e, 5-cis-13-trans-9a -deoxy-9α-methylene-15-oxo-2a-homo-prostacycl-5,13-dienoic acid, M ⁺ 360 m / e, 5-cis-13-trans-9α-deoxy-9α-methylene-15-oxo 3-oxa-prostacycl-5,13-diene, M ⁺ 348 m / e and also their 5-trans geometric isomers, in the nat-, enanth-ad, 1-forms.

Example 1 a d 9

To a solution of 1.35 g of 2-exo-hydroxymethyl-7-endo-hydroxy-bicyclo [3.3.0] octane in 5 ml of pyridine is added dropwise with stirring and cooling to 5 to 8 ° C.

0.82 g of benzoyl chloride. The mixture was stirred at room temperature for 8 hours, then 2 N sulfuric acid was added and the solution was extracted with ethyl ether. After distilling off the solvent, 2-exo-benzoyloxymethyl-7-endo-hydroxy-bicyclo [3.3.0] octane 7-DMtB-silyl ether is obtained from which the silyl ether protecting group is removed by heating its solution in 20 ml of acetone by heating to reflux with 8 ml of 2 N oxalic acid. The acetone is distilled off under reduced pressure, the product is taken up in ether from the remaining aqueous solution and, after evaporation of the solvent, it is purified by chromatography on silica gel; 1.11 g of 2-exobenzoyloxymethyl-7-endo-hydroxy-bicyclo [3.3.0] octane, IC (film) 3420 cm @ ^{-1, is obtained} .

A solution of the latter compound in pyridine was added to a solution of 1 g of chromium trioxide in 10 ml of pyridine, and the mixture was stirred at room temperature for 6 hours. The solution is diluted with 20 ml of benzene, the solid is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in a mixture of 2 N sulfuric acid and benzene, the organic layer is washed with 2 N sulfuric acid and water until neutral and the solvent is distilled off; 0.98 g of 2-exo-benzoyloxymethyl-bicyclo [3.3.0] octan-7-one is obtained, IR (film) 1745, 1705 cm @ -1, M @ ⁺ 258 m / e.

A solution of the latter in 5 ml of anhydrous THF is added to a solution of (2-oxo-5-trimethoxypentyl) dimethylphosphonate, prepared by dropwise addition of a suspension of 0.23 g of 80% sodium hydride in THF, to a solution of 2.12 g (2- oxo-5-trimethoxypentyl) dimethylphosphonate in 6 mL of anhydrous THF. The mixture was stirred for 10 hours, then neutralized with 15% potassium dibasic phosphate solution, THF was distilled off under reduced pressure, and the aqueous solution was taken up in ethyl ether. The combined ether extracts are concentrated and the solution is chromatographed on silica gel, eluting with hexane / ethyl ether. 1.1 g of 2'-benzoyloxymethyl-bicyclo [3.3.0] oct-7-enyl-1,1,1-trimethoxypent-5-en-4-one or 12-p-benzoyloxymethyl- orthomethyl ester is obtained. ω (20-12) -octanor-4-oxo-9α-deoxy-9α-methyleneprostacycl-5-ene (M ⁺ 416 m / e), in the form of a mixture of 5-cis- and 5-trans-olefins to be separated high pressure liquid chromatography.

The orthoesters obtained are converted into the corresponding methyl esters by treatment with aqueous methanol in the presence of sulfuric acid. Reaction of 0.3 g of the methyl ester with 0.25 ml of 1,3-ethanedithiol in methylene chloride and in the presence of a catalytic amount of boron trifluoride etherate for 15 minutes at 0 ° C affords the methyl ester of 12H-benzoyl-oxymethyl-ω (20-12). ) -octanol-4,4-ethylenedithio-9a-deoxy-9a-methyleneprostacycl-5-ene, M ⁺ 446 m / e.

Example 10

A solution of 0.8 g of methyl ester 12/340

-benzoyloxymethyl-ω (20-12) -octanor-4-oxo-9α-deoxy-9α-methyleneprostacycl-5-ene in 10 ml of methanol was selectively debenzoylated by treatment with 0.15 g of anhydrous potassium carbonate with stirring. The solvent is distilled off, the residue is taken up in a mixture of 15% aqueous potassium dihydrogen phosphate solution with methylene chloride and the organic phase is evaporated to dryness. The obtained 12β-hydroxymethyl-ω (20-12) -octanor-4-oxo-9α-deoxy-9α-methyleneprostacycl-5-enoic acid methyl ester (M ⁺ 266 m / e) is dissolved in a mixture of 10 ml of methylene chloride with 10 90 ml of ethanol are added to the solution cooled to -20 DEG C. and 90 mg of sodium borohydride are added and the mixture is stirred for two hours. Excess reducing agent was quenched by addition of 15% aqueous acetic acid, the solvents were evaporated and the residue was chromatographed on silica gel using ethyl ether as eluent. 0.21 g of 12/3-hydroxymethyl-1- (20-12) -octanor-4S-hydroxy-9a-deoxy-9a-methyleneprostacycl-5-enoic acid methyl ester (M ⁺ 268 m / e) is obtained and 13 g of the corresponding 4R-hydroxy isomer, M ⁺ 268 m / e.

The individual isomers are then saponified by treatment with a 19% solution of potassium carbonate in 20% aqueous methanol; acidification and removal of the product into ethyl acetate gave 0.18 g of 12H-hydroxymethyl-ω (20-12) -octanor-4S-hydroxy-9α-deoxy-9α-methyleneprostacycl-5- (1,4-γ-lactone) 1,4-γ-lactone. ene (M ⁺ 236 m / e) and 0.11 g of the corresponding 4R-isomer (M ⁺ 236 m / e). Oxidation of said lactones as described in Example 8 affords the corresponding 12β-formyl derivatives.

Example 11

0.28 g of 4,4-ethylenedithio-12 (S-benzoyloxymethyl- (20-12) -octano-9a-deoxy-9a-methyleneprostacycl-5-enoic acid methyl ester) is selectively debenzoylated by methanolysis in anhydrous methanol in the presence of potassium carbonate to give the corresponding 12β-hydroxymethyl derivative, which is oxidized to the aldehyde as described in Example 8 to give the corresponding 12β-formyl derivative.

A solution of 0.12 g of the latter compound in benzene was treated as described in Example 8 with a phosphonate prepared from 0.177 g of (2-oxo-3,3-dlmethylheptyl) dimethylphosphonate and 20 mg of 80% sodium hydride; 5,13t-16,16-dimethyl-4,4-dithioethylenedioxy-15-oxo-9α-deoxy-9α-methyleneprostacycl-5,13- _dienoic acid methyl ester, _{λ =} 228 nm, ε = 9200, M ⁺ 464 me.

In an analogous manner, but using (4-cyclohexyl-2-oxobutyl) dimethylphosphonate as phosphonate and 4S-lactone, prepared as described in Example 10, as the aldehyde component, 1,4-.beta.-lactone 5, 1,3 is obtained. t-4S-hydroxy-15-oxo-9α-deoxy-9α-methylene-17-cyclohexyl-18,19,20215149

-trinor-pro) stacycl-5,13-diene (M + 370 m / e). Similarly, using. . (3-Phenoxy-2-oxopropyl) -dimethylphosphonate prepares 5,13t-4S-hydroxy-15-oxo-9α-deoxy-9α-methylene-17,18,19,29-tetranor-16 1,4-γ-lactone -phenoxyprostacycl-5,13-diene, M + 366 m / e.

Example 12

Using (2-oxo-3S-methylheptyl) dimethylphosphonate or (2-oxo-3S-fluorolieptyl) -dimethylphosphonate as. phosphonates and 1,4-χ-lactone of 12S-formyl-γ (20- + 12) -octanor-4R-hydroxy-9α-deoxy-9α-methyleneprostacycl-5-enoic acid as the aldehyde are obtained as described in Examples 8 and 11 :

5,13t-4R-hydroxy-15-oxo-9α-deoxy-9α-methylene-16S-methylprostacyclla-5,13-dlenic acid (M + 344 m / e), and

5,13t-4R-Hydroxy-15β-oxo-9α-deoxy-9α-methylene-16S-fluoroprostacyclla-5,13-dienoic acid 1,4-γ-lactone, M + 348 m / e.

Example 13

To the methyl ester solution. 5c, 13t-15-oxo-9.alpha.-deoxy-9.alpha.-methyleneprostacycla-5,13-dienoic acid (0.7 g) in a mixture of 7 ml. of methylene chloride and 7 ml. of ethanol are added, while cooling to -20 DEG C., 38 mg of sodium borohydride. The reaction mixture is stirred for 20 minutes and then the excess reducing agent is quenched by the addition of 2 ml of acetone and 2.5 ml of a 20% aqueous sodium dihydrate solution. The solution was concentrated under reduced pressure, the aqueous concentrate was extracted with methylene chloride, and the solvent was distilled off from the combined extracts. The residue is chromatographed on silica gel, eluting with ethyl ether, to give 0.32 g of 5c methyl ester, 13t-15s-hydroxy-9a-deoxy-9a-methylenepostostycycla-5,13-dienoic acid (5Z [a] _D = + 26 °, 5E (cD = = + 86 ° MeOH), M + 348m / e, and 0.26g of the corresponding 15R-somer, (5Z [α] d = + 22 °, 5E Md = + 54 ° MeOH), M + 348 m / e.

By the same procedure, methyl esters of the following acids are obtained by reducing the 15-oxo derivatives prepared by the methods described in Examples 8, 11 and 12:

5-cis, 13-trans-9α-deoxy-9α-methylene-15S-hydroxy-2-nor-prostacyclla-5,13-dienoic acid, M + 334 m / e, 5-cis-13-frans-9a -oxy-9.alpha.-methylene-15S-hydroxy-2a-homo-prostacyclla-5,13-dioic acid, M + 362 m / e, S (R) -3- (13-trans) -sulfonic acid. 9-Dioxo-9α-methylene-15S-hydroxy-3-oxaprostacyl ^, cyclo-5,13-dienoic acid, M + 350 m / e, 5-cis-13-rans 9α-deoxy-9α- methylene-4,4-dithioethylenedioxy-15S-hydroxyprostacyclla-5,13-dienoic acid, M + 438 m / e, and 1,4-lactones of the following acids:

5c, 13t-9a-deoxy-9a-methylene-4S, 15S-dihydroxy-17-cyclohexyl-18,19,20-ω-frinor-prostacyclla-5,13-eenoic acid,

M + - H 2 O 354 m / e, 5c, 13t-9α-deoxy-9α-methylene-4S, 15S-dihydroxy-16-phenoxy-η 7,18,19,20-N-tertanor-prostacycl-5-dienoic acid , M + - H2O 350 m / e, 5c, 13t-9a-deoxy-9a-methylene-4R, 15S-dihydroxy-166-methylprostacyclla-5,13-dienoic acid, M + - H2O 328 m / e, 5c, 13t -9? -Eoxy-9? -Methylene-4R, 15S-dihydroxy-16S- (4R, 4R, 4R, 4S, 5R, 5,13-diene, M @ ⁺ - H @ ⁺ 332 m) and also their 5-trans geometric isomers in the nat-, enant-ad, 1-forms.

Example 14

To a solution of 0.35 g of 5c, 13-tert-15-oxo-9a-deyleneprostacycl-5,13-dienoic acid methyl ester in 10 ml of 2: 1 ethyl ether-toluene was cooled to -30 ° C with stirring. 5 ml of a 5% solution of methylmagnesium iodide in ethyl ether is added. The reaction mixture was stirred for 4 hours, then allowed to warm to 0 ° C and a 20% aqueous ammonium chloride solution was added. The organic layer was separated, washed with water, sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, 0.1 ml of pyridine was added and the solvent was distilled off under reduced pressure; a mixture of 15S- and 15R-alcohol is obtained. Separation on silica gel, after addition. using a mixture of ethyl ether and isopropyl ether in an 80:20 ratio, 0.1 g of the methyl ester is obtained. 5c, 13t-15S-hydroxy-9.alpha.-deoxy-9.alpha.-methylene-15-methylprostacyclla-5,13-dienoic acid (M @ + - H2 O 344 m / e) and 0.1 g of the corresponding 15R-somer.

Example 15

Using the same starting material as in Example 14, but in anhydrous tetrahydrofuran, reaction with 8 mL of a 0.3 M solution by silica gel chromatography, silica gel chromatography, 5c, 13t-15-ethynyl-15-S methyl ester -hydroxy-9.alpha.-deoxy-9.alpha.-methyleneprstacycla-5,13-diene, [.alpha.] D = + 26 DEG MeOH, and its respective 15R4 isomer.

Analogously using a 0.3 M solution of vinylmagnesium bromide, methyl 5c, 13t-15-β-methyl-5α-η 5 -silyl (β-hydroxy-9α-dc215149 oxy-9α-methyleneprostacycl-5,13-dienoic acid) was obtained. [ _Α ] _D = + 19 °, and its 15R-isomer.

Example 16

To a solution of 5c, 13t-9a-methylene-4R, 15S-dihydroxy-16S-methylprostacyclla-5,13-dienoic acid 1,4-γ-lactone (0.26 g) in methylene chloride was stirred at -10 with stirring and cooling. to -8 ° C was added 0.3 mL of boron trifluoride etherate (1.2 x 10 ⁴ M in anhydrous methylene chloride) followed by a 5% solution of diazomethane in methylene chloride until a persistent yellow color. The solution was washed with 5% aqueous sodium bicarbonate solution and then with water until neutral, the solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (3 g). 0.21 g of 15-methyl ether is obtained

5c, 13t-9a-Deoxy-9a-methylene-4R, 15S-dihydroxy-16S-methylprostacyclla-5,13-dienoic acid 1,4-γ-lactone, M ⁺ 360 m / e.

Example 17

To a solution of 1.05 gd, 1-2-exo-hydroxymethyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane in 8 mL of 75: benzene / DMSO 0.89 g of dicyclohexylcarbodiimide is added followed by 1.42 ml of a solution of pyridinium trifluoroacetate with stirring. The mixture is stirred for 3 hours, then 20 ml of benzene is added and the excess carbodiimide is quenched by dropwise addition of a solution of 0.13 g of oxalic acid in 3.8 ml of water. The benzene fraction was separated, washed neutral and concentrated to a small volume under reduced pressure; a solution of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane (non-isolated compound) is obtained.

D, l-nata enantioformyl derivatives can be prepared by this process.

In the same way, but using 7-exo-hydroxy-bicyclo [3.3.0] octan-3-one, 7-dimethyl-tert-butylsilyl ether, prepared as described in Examples 1, 2 and 3, 2-exo- formyl-3-endo-THP-oxy-7-exo-DMB-silyloxy-bicyclo [3.3.0] octane.

Example 1 a d 18

To a solution of 0.45 g of 5,13t-4-oxo-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid trimethyl orthoester ( _λmax = 244 nm, ε = 9850) in 6 ml of methanol 1.2 ml of 0.2 N aqueous oxalic acid was added and the mixture was heated under reflux for 2 hours. The methanol was distilled off under reduced pressure and the aqueous solution was shaken with ethyl ether; evaporation of the solvent gave 0.42 g of the corresponding methyl ester.

A solution of the latter ester in 6 ml of anhydrous ethyl ether was added dropwise to the 0.1 M zinc borohydride solution (10 ml) with stirring. The mixture was stirred for one hour at room temperature, then the excess reducing agent was quenched with 2 N sulfuric acid, the organic layer was separated and washed until neutral. After distilling off the solvent, 0.4 g of 5,131-4 (S, R), 11a, 15S-trihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid methyl ester is obtained. The mixture of isomers is separated by chromatography on silica gel, eluting with a mixture of ethyl ether and ethyl acetate. 0.11 g of methyl 5,13t-4S, 11a, 15S-trihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid methyl ester, IR (film) 3400 cm-1 (broad), M ⁺ -2 are obtained. H2O 344 m / e, and 0.14 g of 4R-epimeric methyl ester.

To a solution of the latter compound in 5 ml of methanol was added 0.05 g of lithium hydroxide and 0.3 ml of water, and the mixture was stirred at room temperature for 6 hours. After distilling off the methanol under reduced pressure, acidifying the remaining aqueous solution to pH 5.6 and rapidly extracting with ethyl acetate, 5.13t-4R, 11a, 15S-trihydroxy-9α-deoxy-9α-methyleneprostacycla-5,13-dienoic acid was obtained. Treatment of 0.5 parts of polystyrenesulfonic resin (in H ⁺ form) with an ethyl acetate solution of the latter compound, with stirring, yields quantitatively the 1,4-t-lactone of 5,13t-4R-11a, 15S-trihydroxy-9a-deoxy- 9a-methyleneprostacycl-5,13-diene, mp 51-52 ° C, M ⁺ - H ² O 330 m / e.

The 4S-epimeric χ-lactone was prepared in an analogous manner.

Example 19

To a solution of 0.8 g of 11,15-bis-THP-ether of 5,13t-4-oxo-11a, 15S-dihydroxy-20-methyl-9α-deoxy-9α-methyleneprostacyclla-5,13-dienoic acid trimethyl orthosterone in 20 50 ml of methylene chloride / ethanol are added, while cooling to -20 ° C, 50 mg of sodium borohydride. The reaction mixture is stirred for 30 minutes, then the excess reducing agent is quenched by the addition of 2 ml of acetone and 5 ml of saturated sodium dihydrogen phosphate solution. The methylene chloride and ethanol were distilled off under reduced pressure, the remaining aqueous solution was repeatedly shaken with ethyl ether, the organic extracts were combined, dried and the solvent was evaporated. 0.75 g of 5,13t-4 (S, R), 11,15-bis-THP-ether of trimethyl orthoester of 11,15-bis-THP-ether, 11 ', 15S-trihydroxy-20-methyl-9α-deoxy-9α-methyleneprostacyclla-5,13 -dienové.

Said crude product is dissolved in

2.2 ml of methanesulfochloride and the reaction mixture was allowed to stand overnight at room temperature. It is then partitioned between ice-cooled 2 N sulfuric acid and ethyl ether, the organic extracts are combined, shaken with brine, dried and the solvent is distilled off at low temperature; 11,15-bis-THP ether, 5,13t-4 (S, R), 11,15-bis-THP-ether, 4'-mesylate, 11β, 15β-trihydroxy-20-methyl-9α-deoxy-9α-methyleneprostacycl-5,13- dienové.

The product was dissolved in anhydrous ether without further purification and a solution of 50 mg of lithium aluminum hydride in ethyl ether was added. The mixture was stirred at room temperature for 2 hours and heated to reflux for 1 hour. The reaction was quenched by addition of 2 mL ethyl acetate and then wet ether. After drying over anhydrous sodium sulphate and distilling off the ethyl ether, 0.5 g of crude 11,15-bis-THP-ether of trimethyl orthoester 5,13t-11a, 15S-dihydroxy-20-methyl-9a-deoxy-9a-methyleneprostacyclla-5, 13-diene.

The product was dissolved in 12 ml of methanol, 4 ml of 0.3 N aqueous oxalic acid was added, and the mixture was heated to reflux. After customary work-up, 0.2 g of 5,13t-11?, 15 (S) -dihydroxy-20-methyl-9? -Deoxy? 9? -Methylenepr; ostacyclla-5,13-dienoic acid methyl ester is obtained,

M ^{+ -} H ² O 360 m / e, M ⁺ - H ² O - C ² H 4 O 302 m / e. Liquid chromatography showed that the product consisted mainly of the trans-isomer (85%), the corresponding cis-isomer being 15%.

In an analogous manner, 5t, 11a, 15S-dihydroxy-9α-deoxy-9α-methylene acid is obtained [NMR (CDCl 3) δ ppm:

0.90 (H, t);

4.00 (1 H, m),

4.40 (1H, t);

5.30 (1H, t)] and its 5c-isomer [NMR (CDCl 3) δ ppm:

0.90 (3 H, t),

4.00 (1H, m),

4.40 (1 H, t),

5.27 (1H, t)] as well as 5t-11a, 15R-dihydroxy-9α-deoxy-9α-methylene 20-methylprostacycl-5-ene-13-ynoic acid [NMR (CDCl3) δ ppm:

0.90 (3 H, t),

4.00 [1 H, m),

4.39 (1 H, t),

5.30 (1H, t) j and its 5c-isomer [NMR (CDCl3) δ ppm:

0.90 (3 H, t),

4.00 (1H, m),

4.40 (1 H, t),

5.28 (1 H, t)].

Example 20

To a solution of 0.37 g of 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid methyl ester in 10 ml of benzene is added 250 mg of 2,3-dichloro-5,6-dicyanobenzoquinone and the mixture was heated at 50 ° C for 8 hours. The precipitate formed is filtered off and the benzene solution is chromatographed on a short column of alumina; 0.29 g of 5c, 13t-11a-hydroxy-15-oxo-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid methyl ester, M ⁺ 362, M + - H2O 344 m / e, was obtained.

1.2 ml of a 1M solution of methyl magnesium bromide in ethyl ether are added to a solution of the latter in ethyl ether-toluene, while cooling to -20 ^° C. The mixture was stirred for 2.5 hours at -20 ° ^C, then quenched with ammonium chloride solution, the organic layer was separated and the solution concentrated to a small volume. Purification by silica gel chromatography eluting with ethyl ether-ethyl acetate gave 0.1 g of 5c, 13t-11a, 15S-dihydroxy-15-methyl-9α-deoxy-9α-methyleneprostacycl-5,13-, methyl ester. diene, M H2 O 360 m / e, and 0.072 g of the corresponding 15R-hydroxyepimer.

Example 21

To a solution of 2.2 g of 3-endo-hydroxy-bicyclo [3.3.0] octan-7-one in 100 ml of anhydrous benzene was added 4 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid (monohydrate) and the mixture was The mixture was heated at reflux for 12 hours while distilling off the water formed in the reaction. Pyridine (0.25 ml) was added to the solution, the mixture was cooled and washed with water, sodium bicarbonate solution and water. After distilling off the solvent, 2.32 g of 3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, 7,7-ethylenedioxide; IC (film) 3450 cm ^-1 and no absorption at 1745 cm ^-1 .

4.1 ml of Jones reagent was added to a solution of the product in 40 ml of acetone under cooling to -5 ° C. The mixture is stirred for 20 minutes at -5 ° C, then the excess oxidant is quenched by addition of 4 ml of isopropyl alcohol, 150 ml of benzene is added and the benzene solution is washed sequentially with 20% ammonium sulfate solution, water, 5% sodium bicarbonate solution and water. After distilling off the solvent, 2.1 g are obtained

D, 1-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethyl ester, 7,7-ethylenedioxide, m.p. 40-42 ° C.

This compound is reacted with methylcarboinate as described in Example 1 to give d, 1-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethyl ester, 7,7-ethylenedioxide, A _max. = 254 nm, ε = 7000.

A solution of the latter in a mixture of 20 ml of methylene chloride with 20 ml of ethanol was reduced as described in Example 2 by treatment with sodium borohydride at -20 ° C to give 1.72 g of 7,7-ethylenedioxide d, 1-exo-methoxycarbonyl. -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one; IC (film) 3400, 1720 cm ^-1 .

To a solution of the latter compound (1.57 g) in 3 ml of dimethylformamide was added 1.3 g of methyl-1,5-dimethyl-1511-dimethyl-0.81 g and 0.885 g of imidazole and the mixture was allowed to stand for 5 hours at 0 ° C. Under cooling, water is added to the reaction mixture and the solution is worked up in the usual manner; 2.3 g of 7,7-ethylenedioxide d, l-2-exo-methoxycarbonyl-S-endo-hydroxy-bicyclo [3.3.0] octan-7-one, 3-dimethyl-tert-butylsilyl ether; IR (film) 1710 cm ^-1 .

Subsequent reduction of this product with lithium aluminum hydride in anhydrous ethyl ether as described in Example 3 affords quantitative 3-dimethyl-tert-butylsilyl ether 1,1,1-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo [3,3,0] octan-7-ol; IC (film) 3400 cm ^-1 .

Example 22

Using the method described in Example 21, but using dithioethylene glycol instead of ethylene glycol, the corresponding 7,7-ethylene-dithio analog was prepared.

Example 23

To a solution of 2-exo-bromo-3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one in benzene was added ethylene glycol (15 mL) and p-toluenesulfonic acid (0.9 g), and the mixture was stirred at room temperature. The mixture is heated at reflux for 12 hours while distilling off the water formed in the reaction. Pyridine (0.6 mL) was added to the reaction mixture, the solution was cooled to room temperature, washed with water, 2.5% aqueous sodium bicarbonate solution and water, and dried. Some benzene (100 mL) was distilled off under reduced pressure, tributyltin hydride (41 g) was added to the concentrated solution under nitrogen and the mixture was heated at 55 ° C for 8 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous sodium dihydrogen phosphate solution, dried and the solvent was evaporated to dryness. Purification on a silica gel column (240 g), eluting with benzene / ethyl ether as eluent, gave 14.9 g of 3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one-6,6- ethylenedi dioxide; Ir (film 34fi0 cm ^"1, M ⁺ 242 m / e as the trimethylsilyl ether.

Example 24

To a solution of 3-endo-hydroxy-bicyclo [3.2.0] heptan-e-one-E-ethylenedioxide (1.2.75 g) in a mixture of benzene 340 mL) with DMSO (11.2 mL) was added dicyclohexylcarbodiimide with stirring. (46.35 g), pyridine (5.9 g) and trifluoroacetic acid (5.4 g). The reaction mixture was stirred for 6 hours then diluted with benzene (600 mL) and water (50 mL), the precipitated dicyclohexylurea was filtered off, the organic portion was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off; There was obtained bicyclo [3.2.0] heptane-3,6-dione-6,6-diethylenedioxide, IC (film) 1742 cm &^lt; -1 & gt ^; , M ⁺ 16-8 m / c.

A solution of the crude product thus obtained in dimethyl carbonate (70 ml) was added to a suspension of sodium hydride (80% dispersion in mineral oil, 4 g) and the mixture was stirred at room temperature until hydrogen evolution had ceased and heated for 40 min. Mp 75-80 ° C. After cooling, the reaction mixture was diluted with benzene (350 mL), acidified with acetic acid (8.4 g), the solution was washed with water, dried and the solvent was evaporated to dryness. A mixture of (1: 1) d, 1-bicyclo [3.2.0] heptane-3,6-dione-2-methoxycarbonyl-6,6-ethylene oxide is obtained, M ⁺ 226 m / c (p = 0). , q = 1) ad, 1-bicyclo [3.2.0] heptane-3,6-dione-4-methoxycarbonyl-6,6-ethylenedioxide, M ⁺ 226; m / e (p = 1, q = 0) ), which is separated into its individual isomers by chromatography on silica gel (free of Fe ²⁺ and Fe ³⁺ ions), eluting with a mixture of hexane and ethyl ether.

Example 25

Using the procedure described in Example 24, by oxidation of 14.85 g of 3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, 13.9 g of bicyclo [4] were obtained. , 3,0] nonane-3,7-dione-7,7-ethylenedioxide, IC (film) 1740 cm ^-1 , M ⁺ 196 m / e, from which 4.2 gd, 1-bicyclo [4] are obtained by carboimethoxylation. , 3,0] nonane-3,7-di-2-methoxycarbonyl-7,7-ethylenedioxide, M ⁺ 254 m / e (p = 1, q = 2) and 4.8 gd, 1-bicyclo [4, 3,0] nano-3,7-dione-4-methoxycarbonyl-7,7-ethylenedioxide, also named d, 1-bicyclo [4,3,0] nonane-3,8-dione-2 -methoxycarbonyl-8,8-ethylenedioxide (p = 2, q = 1), M ¹ - 254 m / e.

Example 26

A solution of bicyclo [4.3.0] non-7-en-3-ene (90 grams) in dimethyl carbonate (350 mL) was added to a suspension of sodium hydride (80% dispersion in mineral oil, 42 g) in dimethyl carbonate (with stirring). 550 ml). The mixture was stirred until hydrogen evolution had ceased and then heated to 75-80 ° C for 4.5 hours. After cooling the reaction simulation to room temperature, benzene (2.7 L) was added and the solution was washed with a 25% aqueous solution of sodium hydrogen phosphate to distill off the solvent to give bicyclo [4.3.0] non-7-en-3-one. -2-carboxymethyl ester (91 g), λ _max 252 nm, ε = 8200,

Sodium borohydride (14.4 g) was added to a solution of the latter in a mixture of methylene chloride (1200 mL) and ethanol (120-0 mL) with stirring and cooling to -20 ° C. The mixture was stirred for 30 minutes at -20 ° C, then acidified cautiously with acetic acid (23 mL), warmed to room temperature, and the solvents were distilled off under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, dried and the solvent was distilled off under reduced pressure.

The obtained d, 1-bicyclo [4.3.0] non-7-ene-3-endo-hydroxy-2-exo-carboxylic acid methyl ester, M + 268 m / e as trimethylsilyl ether (64 g), was dissolved in anhydrous tetrahydrofunane (THF), 2,3-dihydropyran (Bg) and p-toluenesulfonic acid (0.63 g) were added to the solution, and the mixture was allowed to stand at room temperature for 3 hours. The solution was neutralized with pyridine (0.4 g) and, while cooling to 0 ° C and stirring, a 1.2 M solution of bonan in tetrahydrofuran was added over 45 minutes. The simes were stirred for an additional 1 hour at 0 ° C, then the remaining hydride was decomposed with water, the resulting borane oxidized with vigorous stirring and external cooling □ 0 to -5 to 0 ° C by slowly adding 110 ml of 3 M sodium hydroxide solution and 110 ml. ml of 30% hydrogen peroxide. The reaction mixture was diluted with benzene (2 L), the benzene layer was separated, and the aqueous portion was extracted with benzene (2 x 50 mL). The organic extracts were combined, washed successively with 1% sodium carbonate solution, saturated sodium sulfite solution and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvents, a crude mixture of 7- and 8-hydroxy compounds is obtained which is obtained. divides by column chroimatography. Silica gel (300 g), eluting with ethyl ether. There was obtained d, 1-bicyclo [4.3.0] nonane-3-endo, 7H-dlhydroxy-2-exo-methoxycarbonyl-3-THP-ether (24 g), M + 370 m / e as timethylsilyl ether, 1-bicyclo [4.3.0] nonane-3-endo, 8 H -dihydroxy-2-exo-methoxycarbonyl-4-THP-ether (27 g), M + 370 m / e as trimethylsilyl ether.

To a solution of 7 H -hydroxy alcohol (24 g) in anhydrous DMF (30 mL) was added dimethyl t-butylsilyl chloride (15.8 g) and imidazole (8.85 g) and the mixture was heated at 60 ° C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (90 mL) and the product was taken up in ethyl ether. The organic extracts were combined, washed with water, and the solvent was distilled off; There was obtained d, 1-bicyclo [4.3.0] nonane-3-endo, 7 &apos; -dihydroxy-2-exo-methoxycarbonyl-3-THP-ether-7-DMtB-silyl ether, M + 412 m / e.

To a solution of the latter compound in anhydrous toluene (220 mL) was added a solution of 1.4 M DIBA in toluene with cooling over -70 ° C with stirring. The mixture was stirred at -70 to -60 ° C for 2 hours, then the excess hydride was quenched by the addition of a 2M solution of isopropyl alcohol in toluene and allowed to warm to room temperature. To the solution was added 30% aqueous sodium dihydrogen phosphate solution followed by anhydrous sodium sulfate (50 g), the mixture was filtered and the organic portion was washed with water. After distilling off the solvent under reduced pressure, d, 1-bicyclo [4.3.0] nonan-13-eno, 7H-dihydroxyl-2-oxo-formyl-13-THP-ether-17-DMtB-silyl ether (p = 2, q = 1) was obtained, M + 382 m / e.

Using the same procedure, but starting from the 8α-hydroxy compound as the starting material, d-bicyclo [4,3.0] nonan-13-endo, 8-dihydroxyl-2-oxo-methoxycarbonyl-3-THP-ether-8-DMtB-Siyl ether, M + 412 m / ead, 1-bicyclo kl o [4,3,2] nonane-3-endo, 8'-dihydroxy2lexOformyl-3-THPlether8 · DMtB-silyl ether, M + 382 m / e.

Example 27

In the manner described in Example 1, 30 g

2-acetoxyperhydroazultin-6-one, also referred to as 3-endolhydroxylbicyclo [5.3.0] decan-18,103,113-acetate (and obtainable by the method described by DK Banerje et al. In Indian J. Chem. 10, 1, 1972) , was converted to the corresponding ethylene dioxide (29.1 g). The compound is saponified by treatment with a 2% solution of potassium carbonate in aqueous methanol and the resulting 3-endolhydroxylbicyclo [5.3.0] decanilone8,8-ethylenedioxide is oxidized as described in Example 2. The ketone obtained is reacted with dimethyl carbonate (see procedure described above). in Example 2) and converted to β-bicyclo [2.2.1] decane-4-dione-2-methoxycarbonyl-18,8-ethyltin dioxide (21.2 g), λ max 254 nm, ε = 7000.

Example 28

The ethylenedioxides of bicyclo-keto esters obtained as described in Examples 24, 25 and 27 are reduced as follows:

To a solution of bicyclo-o-ketoester ethylene dioxide (2.5 x 10 -2 mol) in methylene chloride / ethanol (1: 1, 150 ml) was added portionwise with stirring and cooling to -20 ° C sodium borohydride (0.9 g). and the mixture was stirred for an additional 30 minutes at -20 ° C. Excess hydride was quenched by the addition of acetone (12 mL), then the reaction mixture was allowed to warm to room temperature and a -20% aqueous potassium dihydrogenphosphate solution was added. After distilling off, the residue was diluted with water (20 ml) and the product was taken up in methylene chloride. The organic extracts were combined, washed with water until neutral, dried and the solvent was distilled off. The residue was dissolved in absolute methanol (20 ml), sodium methoxide (0.54 g) was added and the mixture was allowed to stand at room temperature for 12 hours. After acidification with acetic acid (0.59 g), the solvents were distilled off and the residue was taken up in methylene chloride. About 0.22.10-2 moles of the following ethylenedioxides of bicyclo / 3-hydroxy esters are obtained:

d, l13-endolhydroxylbicyclo [3.2.0] heptan-6-one-2-exo-methoxycarbonyl-1, 6,6-ethylthio-dioxide, M + 300 m / e as trimethylsilyl ether, d, l13-endolhydroxylbicyclo [3,2,0] heptane 6-on-4-exo-methoxycarbonyl-6,6-ethylenedioxide, which may also be named dj-4-ω-hydroxy-γ-bicyclo [3.2.0] heptan-4-one-ε-methoxymethylcarbonyl-7 M + 300 m / e as trimethylsilyltetrtr, d, l-3-endo-hydroxylbicyclo [4.3.0] nonan-7-one-2-exo-methoxycarbonyl-7,7215149

-ethylenedioxide, M + 328 m / e as trimethylsilyl ether, d, 1-3-endo-hydroxybicyclo [4.3.0] nonan-8-one-2-exo-methoxycarbonyl-8,8-ethylenedioxide, M + 328 m / e as trimethylsilyl ether, d, 1-3-endo-hydroxy-bicyclo [5.3.0] decan-8-one-2-exo-methoxycarbonyl-8,8-ethylenedioxide, M + 342 m / e as trimethylsilyl ether.

Next, 2. · 10 ^"2 mole each of the above compounds dissolved in anhydrous methylene chloride · [25 ml) and treated with 2,3-dihydropyran [2 · g) and p-toluenesulfonic acid (38 mg, 2.10 ^-4 mol) and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched by addition of pyridine (0.1 mL) and the solvents were distilled off under reduced pressure. The corresponding 3-THP-ethers are obtained and can be used for further work without any purification.

Example 29

The 3-endo-hydroxy-2-exo-carboxymethyl esters and their 3-THP-ethers obtained as described in Example 28 are reduced to the corresponding 2-exo-hydroxymethyl-derivatives as follows:

A solution of 2.10 ~ 2 _m ol competent / 3-ketoester (either an alcohol or 3-THP eeheru) in anhydrous ethyl ether (25 ml) was added dropwise to a suspension of lithium aluminum hydride (0.4 g) in anhydrous ethyl ether (50 ml) . The reaction mixture was stirred for 30 minutes, then the excess hydride was quenched by the addition of acetone (5 mL) and water-saturated ethyl ether. Anhydrous magnesium sulfate (12 g) was added to the suspension, the mixture was filtered and the solvent was evaporated to dryness.

The following 3-endo-hydroxy-2-exo-hydroxymethyl compounds are prepared as follows:

-bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide, M + 342 m / e,

-bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, M + 342 m / e,

-bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, M + 370 m / e,

-bicyclo [4.3.0] non-8-one-8,8-ethylenedioxide, M + 370 m / e,

-bicyclo [5.3.0] decan-8-one +, 8-ethyl] -endioxide, M + 384 m / e (everywhere as bis-trimethylsilyktber), and their 3-endo-hydroxy-THP-ethers, as in both in racemic and optically active form (nat, ent) when using the optically active material obtained by resolution of the racemic starting materials.

Example 30

To a solution of 3-endo-hydroxy-2-exo-hydroxymethyl-bicyclo [5.3.0] decan-9-one-8,8-ethylenedioxide (5 g, 2.10 ² mol) in methanol (20 mL) was added water (2 ml) and p-toluenesulfonic acid (0.3 g) were added and the mixture was heated under reflux for 2 hours. The solvents were distilled off under reduced pressure and the crude free ketone was purified by filtration through a short column of silica gel.

A solution of the obtained 3-endo-hydroxy-2-exo-hydroxymethyl-bicyclo [5.3.0] decan-8-one (4.7 g) in anhydrous DMSO (17 mL) is reacted with an ylide prepared by heating a tertiary solution. potassium butoxide (27 g) in DMSO (280 mL) with 3-carboxypropylphosphonium bromide at 40 cc for 5 hours. The reaction mixture was diluted with water (300 mL) and the triphenylphosphoxide was removed by extraction with ethyl ether / benzene (80:20). The organic extracts were discarded, the aqueous alkaline portion was acidified to pH 5 and the product was repeatedly extracted into ethyl ether (8 x 200 mL) and then into ethyl ether: ethyl acetate 3: 1 (5 x 100 mL). The combined organic extracts were dried, concentrated to a small volume, and an ethereal solution of diazomethane was added to the concentrated solution (100 mL). After evaporation of the solvents, the corresponding methyl ether is obtained.

The crude product was purified by silica gel chromatography (100 g), eluting with ethyl acetate. 4.1 g of methyl ester of 1 (Z, E) and (2Ck> 12) octanol-12 H -hydroxymethyl-11α-hydroxy-9a-deoxy-9a, 9b, 7-homo-trimethylene-2-nor-prostacyclic acid are obtained. -5-ene, M + 426 m / e as a bis solution of the latter compound in anhydrous DMF [12 mL] was added dimethyl tert-butylsilyl chloride (2.2 g) and imidazole (1.55 g) and allowed to stand 24 hours at 15 ° C. After addition of water (24 ml), the product is taken up in ethyl ether and purified by chromatography on silica gel using a mixture of cyclohexane and ethyl ether as eluent; There was thus obtained 12'-DMtB-silyloxymethyl ester (4.31 g, 80%), M + 396 m / e.

The product was dissolved in pyridine (10 mL), acetic anhydride (5 mL) was added and the mixture was allowed to react for 12 hours at room temperature. Hydrolysis of DMtB-slyyloxy-skins with p-toluenesulfonic acid in aqueous methanol yields 5 (Z, E) -w- (20- + 12) -octanor-12/1-hydroyymethyl-1-hydroxy-9a-methyl ester 11-acetate. -deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacycl-B-ene, (M + 324 m / e). Preparative high pressure liquid chromatography (using an HPLC instrument with eluent control by refractive index) on silica gel, coupled with 3% silver nitrate, eluting with methylene chloride / ethyl215149 acetate) gave the individual mixture of geometric isomers to yield 5c- and 5t - isomers.

Using the same procedure, but using 3-endo-hydroxy-bichklo [4.3.0] n -nan-J-one-Z-exo-methoxycarbonyl-7,7-ethylenedioxide, disperse the appropriate pedhdrazulene derivative using 4-carboxybutylphosphonium bromide. instead of said 3-carboxy-5-propyl compound, 5 [Ζ, Ε) -ω- (20-12) -octanor-12β-hydroxymethyl-11 (1-hydroxy-9α-deoxy-9α, 7α) -acetate is prepared. -hino-dimethylethylprostacycl-5-ene, (Μ ⁴

324 m / e) and its individual 5c and 5t geometric isomers.

Example 31

From the 2-hexyloxymethyl-THP-ethes prepared as described in Example 29 and from the 12/3-hydroxymethyl-t-acetates described in Example 30, the following aldehydes were prepared by the following oxidation reaction:

The rrztrku hhdroxhmethylsloučeniny (2nd. 10 ^_3 MRL) in benzene with DMSO (75: 25, 6 ml] was gradually added dicyklohexylkadbodiimid (0.64 g), pyridine (0.1 mL] and -riflurrrctová acid. The reaction mixture was stirred for 4.5 heroes, then diluted with benzene (20 mL) and water (10 mL) and stirred for an additional 30 minutes .The precipitated dicyclohexylurea was filtered off, the organic filtrate was washed with water until neutral and concentrated to 10 mL. with the solution of aldehydes in anhydrous benzene:

3-endo-THP-oxy-2-exo-butyl-bicyclo [3.2.0] hepan-6-one, 6-ethylenedioxide, [M + -102] 180 m / e,

3-endo-THP-oxy-2-exo-γ-γ-β-β-ω [3,2,0] heptan-7-one-7,7-ethanedioxide, [Μ + - 102] 180 m / E,

3-endo-THP-oxy-2-oxo-butyl-bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, [M + -102] 208 m / e,

3-endo-THP-oxy-2-exo-oryl-bicyclo [4.3.0] nonanthanone-8,8-ethylenedioxide, [M + -102] 208 m / e,

3-endo-THP-oxy-2- (4-oxo-4-methyl-bicyclo) -4- [5,3,0] decan-8-one-8,8-ethylenedioxide, [M + -102] 229 m / e,

11- (4 (5-Z, E) or 5c, 5t-w (20-12) octan-12,15-formyl-11a-hydroxydo-9a-deoxy-9a); , 9b, 7-homottrimethylene-2-chloro-postacycl-5-ene, M + 322 m / e,

11-Acetyl methyl ester 5 (Z, E] and 5c, St-ω (20-12) -Μ-πορ-4-isopropyl-111-1 ^ 1'0x1-91-600x1-91,714101110M + 322 m /E.

The compounds are used without further purification in the subsequent Wig-Horner reaction.

Example 32

A solution of (2-oxo-heptyldimethylphosphonate (0.49 g) in benzene (6 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in mineral oil, 66 mg, 2.2, 10 ^-3 mol) in stirring. benzene (15 mL) and stirred for an additional 45 minutes before adding a solution of 2.10-3 mol of 5ΐ-ω (20-12) octanor-12 / ifyryl-11a-hydroxyl-9-aldehyde 11-acetate methyl ester. -9a, 9b, 7a-homo-trimethylene-2-nitro-pros-5-enoic acid in benzene (10 mL) The reaction mixture was stirred for an additional hour, then quenched by the addition of acetic acid solution (132 mg) in benzene. benzene (5 ml), the organic portion was washed with water until neutral, dried and the solvent was distilled off The residue (1.2 g) was chromatographed on silica gel (10 g) using cyclohexane / e-chelate as eluent; There was obtained 5t, 13t-11c-hydroxydo-15-oxo-9a-de-oxa, 9b, 7alpha-methylene-2-nor-prostacycl-5,13-thiene (11-acetate methyl ester) for the first time ( 0.76 g), Amax

228 nm, ε = 9800, M + 418, M + - CH 3 CO 2 H 358 m / e.

Using the above procedure but using the other aldehydes described in Example 31, the following α, β-unsaturated ketones are prepared:

11 acetá- the methyl ester 5ο ERU, 13Μ1ι hhddoxht15-oxo-9atdeoxy-9a, 9b, 7athomo tгimethylen-2-nortprostacyk.la-5,13-diene and _having x 228 nm, ε = 9900, and the mixture corresponding to 5 (Z @ +), M + 418, M @ + --CH3CO2H 358 m / e,

11-Acetyl 5ϊ, 13ϊ-1ι-hyddoxht15toxo-9a-deoxy 99a, 7α-homotdimethylene pdOstacyclla-5,13-dienoic acid methyl ester, Amax

229 nm, ε = 10,000, and the corresponding 5c and 5 (Z, E) -isomed, M + 418, M + —CH 3 CO 2 H 358 m / e, followed by 2 ^ 0 - ^^ 0-0 ^ -4 / -trans -enyl) -3-endo-hydroxyTHP-ethers:

bicyclo [3.2.0] heptane-6-thiol-6,6-ethylenedioxide, [M + - -102] 276 m / e, bicyclo [3.2.0] hepan-7-one 7,7-e-heptide Dioxide, [M + - 102] 276 m / e, Bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, (M + - 102) 304 m / e, Bicyclo [4.3, O] nonan-B-one .beta.-ethylenedioxide, [M @ + -102] 304 m / e and bicyclof 5,3,0] decal-8-one, 8,8-ethylenedioxide, [M @ + -102] 318 m / e.

Example 33

To 5t, 13t215149 methyl ester solution

-11a-hydroxy-15-oxo-9a-deoxy-9a, 7a4iomo-dimethyleneprostacycla-5,13-diene (0.4g) in 2: 1 ethyl ether-toluene (12ml) was stirred and cooled to - A 30% methylmagnesium iodide (5 mL) ethereal solution (5 mL) was added at 30 ° C, and the reaction mixture was stirred for an additional 4 hours, then allowed to warm to 0 ° C, quench with excess 20% aqueous ammonium chloride solution. The residue was dissolved in anhydrous methanol (10 ml) and stirred for 2 hours with anhydrous potassium carbonate (0.1 g). The solvent was distilled off under reduced pressure and the crude residue was partitioned between ethyl acetate and 20% aqueous sodium dihydrogen phosphate solution, the organic portion was concentrated to a small volume after usual work-up and the solution was chromatographed on silica gel (20 g) using ethyl ether-isoprop. ethyl ether (80:20) as eluent to give 5t, 13t-11a, 15S-dihydroxy-15-methyl-9α-deoxy-9α, 7α-homo-dimethyleneprostacyclla-5,13-dienoic acid methyl ester, M ⁺ 392 m (e) (0.1 g) and its 15R-isomer (0.085 g), respectively.

The following compounds are also prepared by this procedure:

5t, 13t-11a, 15S-dihydroxy-15-methyl-9α-deoxy-9a, 9b, 7α-homo-trimethylene-2-nor-prostacyclla-5,13-dienoic acid methyl ester (M ⁺ 392 m / e) and its 15R-epimer. The free acids are obtained by heating solutions of the methyl esters in methanol / water 80:20 to reflux in the presence of 2% potassium carbonate. The solvent was distilled off under reduced pressure and the residue was partitioned between ethyl ether and water. From the organic portion, the product is extracted into 0.5% potassium carbonate, the combined alkaline portions are acidified to pH 6 and the acid is taken up in ethyl ether. The combined organic extracts were washed, dried over anhydrous magnesium sulfate, and evaporated to give the free acids.

Example 34

Using the procedure described in Example 33, but using ethinylmagnesium bromide, vinylmagnesium bromide or ethylmagnesium bromide in place of methylmagnesium iodide, the corresponding 15-ethynyl, 15-vinyl and 15-ethylprostacyladienic acids were obtained.

Example 35

Using the α, β-unsaturated ketones described in Example 32 as starting materials, the corresponding secondary allyl alcohols were obtained as follows: A solution of α, β-unsaturated ketone (2.10 ^-3 mol) in anhydrous ethyl ether (20 mL) was added to the reaction. with stirring, over 30 minutes, dropwise to a solution of 0.25 M zinc borohydride in anhydrous ether (48 ml) and the mixture was stirred for a further 2 hours. Excess hydride was decomposed by addition of saturated sodium chloride solution, the organic layer was separated, washed to neutral reaction, dried over anhydrous sodium sulfate and the solvent was distilled off. The mixture of isomers obtained, after separation by HPLC, (methylene chloride / ethyl acetate), gave:

11-acetate methyl ester 5c 13 t-lla, 15S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimsthylen-2-nor-5,13-prostacykla-diene (M ^h 420 m / e) and its 5 (Z, E) - and 5t geometric isomers,

5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylenepostacycl-5,13-dienoic acid 11-acetate methyl ester (M + 420 m / e) and its 5 (Z, E) and 5c geometric isomers;

and the following 2-exo- (3S-hydroxy-oct-1'-trans-enyl) -3-endo-THP-oxyderivatives of compounds:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide, M + 380 m / e, bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, M ⁺ 380 m / e, bicyclo [4.3.0] nonane-Z-on-ZJ-ethylenedioxide, M + 408 m / e, bicyclo [4.3.0] nonane-8-on-8,8-ethylenedioxide, M ⁺ 408 m / e, and the following 3 endo-THP-oxyderivatives:

2-exo- (2 ^{<3'S bromo-4-hydroxy-£} R-fluoro-oct-Γ-trans-enyl) bicyclo [3,2,0] heptan-7-one-7,7-ethylendioxidu M ⁺ 476.477 m / e,

2-exo- ^(2-bromo-£ 3'S 4'S-hydroxy-oct-fluoro-Γ-trans-enyl) bicyclo [3,2,0] heptan-7-one-7,7-ethylendioxidu, M ⁺ 476 478 m / e

2-exo- (2'-bromo-3'S-hydroxy-non-1'-trans-enyl) -bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide, M ⁺ 472, 474 m /E,

2-exo- (3 ^{T-hydroxy-non-l-trans-enyl)} bicyclo [3.2.0] heptan-6-one 6,6-ethylendioxidu, M + 394 m / e.

2-exo- (3'S-hydroxy-5'-phenyl-pent-l ^{t-trans-enyl)} bicyclo [3,2,0] heptan-7-one-7,7-ethylendioxidu, M ⁺ 414,

2-exo- (2'-bromo-3 &apos; -hydroxy-oct-l-trans-enyl) bicyclo [4.3.0] nonan-7-one-7,7-ethylendioxidu, M ^h 486 488 m /E,

2-exo- (3S-liydroxy-4S-methyl-oct-1-215149)

-trans-enyl) -bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, M ⁺ 422 m / e,

2-exo- (3'S-hydroxy-4'R-methyl-oct-1'-trans-enyl) -bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, M ⁺ 422 m / e ,

5c, 13t-11a, 15R-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacyclla-5,13-dienoic acid methyl ester 11-acetate (M ⁺ 420 m / e) and its 5 (Z, E) and 5t geometric isomers,

5t, 13t-11a, 15R-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacycla-5,13-dienoic acid methyl ester 11-acetate (M ⁴ 420 m / e) and its 5 (Z, E) and 5c geometric isomers, and the following 2-exo- (3'R-hydroxy-oct-1'-trans-enyl) -3-endo-THP-oxyderivatives of compounds:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide, M + 380 m / e, bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, M ⁴ 380 m (e) bicyclo [4.3.0] nonan-7-on-7,7-ethylenedioxide, M ⁴ 408 m / e, bicyclo [4.3.0] nonan-8-on-8,8-ethylenedioxide, M ⁴ 408 m / e, and the following 3-endo-THP-oxyderivatives of the compounds:

2-exo- (2'-bromo-3'R-hydroxy-4'Rfluoro-oct-1'-trans-enyl) -bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide m ^4476, 478 m / e.

2-exo- (2'-bromo-3'R-hydroxy-4'Sfluoro-oct-1'-trans-enyl) -bicyclof 3,2,0] heptan-7-one-7,7-ethylenedioxide, M ⁴ 476 478 m / e

2-exo- (2'-bromo-3'R-hydroxy-non-l-trans-enyl) bicyclo [3.2.0] heptan-6-one 6,6-ethylendioxidy, M ^4472, 474 m / e

2-exo- (3'R-hydroxy-non-l-trans-enyl) bicyclo [3.2.0] heptan-6-one 6,6-ethylendioxidu M ⁴³⁹⁴ m / e,

2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-enyl) -bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, M ⁴ 414 m /E,

2-exo- (2'-bromo-3'R-hydroxy-oct-l-trans-enyl) bicyclo [4.3.0] nonan-7-one-7,7-ethylendioxidu, M ^4486, 487 m / e,

2-exo - ^ 'R ^ S-hydroxy-oct-uiethyl t-trans eiiyl) bicyclo [4.3.0] nonan-7-one-7,7-ethylendioxidu M ^4,422 m / e

2-exo - ^ 'R ^ R-hydroxy-methyl-oct-R-trans-enyl) bicyclo [4.3.0] nonan-7-one-7,7-ethylendioxidu M ^4,422 m / e.

Example 36

The individual 11-acetates of the methyl esters of prostacyclenoic acids are converted to 11-hydroxymethyl esters by transesterification in anhydrous methanol in the presence of anhydrous potassium carbonate (0.5 mol equivalents) and to the free 11-hydroxy acids by treatment with potassium carbonate in 80% aqueous methanol.

Example 37

To a solution of 5t, 13t-11a, 15Sdihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-15-methylprostacyclla-5,13-dienoic acid methyl ester (0.39 g) in benzene / DMSO 75:25 (6 mL) Dicyclohexylcarbodiimide (0.32 g), pyridine (0.044 ml) and trifluoroacetic acid (0.022 ml) were added sequentially with stirring. After 5 hours, the reaction mixture was diluted with benzene (20 mL) and an aqueous solution (10 mL) of oxalic acid (1.2 g) was added. The mixture was stirred for 20 minutes, then the precipitated urea was filtered off and the organic filtrate was washed until neutral. After drying and evaporation of the solvent, the residue is chromatographed on silica gel (4 g), eluting with ethyl ether. 0.26 g of methyl 5t, 13t-11-oxo-15S-hydroxy-9a-deoxy-9a, 7a-homo-dimethylene-15-methyl-prostacyclla-5,13-dienoic acid methyl ester (M ⁴ 390 m / e) is obtained. ), which is hydrolyzed with 2% aqueous potassium carbonate solution to the free acid.

Example 38

To a solution of bicyclo [4.3.0] nonan-7-en-3-one (11.42 g) in ethanol (80 mL) was added portionwise sodium borohydride (2.5 g) with stirring. The mixture was stirred for an additional 2 hours, then acidified with acetic acid (5 mL) and the solvents were distilled off. The residue was partitioned between water and methylene chloride, the organic layer was separated and the solvent was evaporated to dryness. To a solution of the obtained bicyclo [4.3.0] non-7-en-3-ol (11 g) in anhydrous DMF was added dimethyl tert-butylsilyl chloride (15.6 g) and midazole (10.85 g) successively, and the mixture was heated at 60 ° C for 6 hours. The solution was cooled, diluted with water (66 mL), the product was extracted thoroughly with ethyl ether, and the ether extract was worked up in the usual manner. The obtained bicyclo [4.3.0] non-7-en-3-ol-3-DMtB-silyl ether (19.1 g) was dissolved in anhydrous THF (100 mL) and the solution was cooled and stirred under stirring. 1 N borane in THF (75 mL) was added at 0 ° C. The reaction mixture was stirred at 25 ° C for 2 hours and then 1 N sodium hydroxide solution (25 mL) and 30% hydrogen peroxide (25 mL) were added. The mixture was heated at 60 ° C for 2 h, then cooled, diluted with benzene (400 mL), the organics separated, washed with 1% sodium carbonate solution, saturated sodium chloride solution, dried and the solvent was distilled off. The obtained crude bicyclo [4.3.0] nonane-7 (8) ξ 3-dihydroxy-3-DMtB-silyl ether (20.39) was dissolved in a 75: 25 mixture of benzene and DMSO (150 mL) and the solution was Dicyclohexylcarbodiimide (16 9), pyridine (2 mL) and trifluoroacetic acid (1 mL) were added sequentially. After 5 hours, the reaction mixture was diluted with benzene (400 mL), water (50 mL) and a solution of oxalic acid (69) in water (75 mL) were added, and after stirring for 30 minutes the urea precipitate was filtered off. The organic layer was separated from the filtrate, washed with water until neutral and the solvent was distilled off. The obtained bicyclo [4.3.0] nonan-7 (8) -one-3-o-DMtB-silyl ether (18.25 9) was dissolved in methanol (60 ml) and 1.8 9 acid was added to the solution. p-toluenesulfonic acid and the mixture was allowed to stand for 12 hours. Then pyridine (1.959) was added, the solvent was evaporated to dryness and the residue was chromatographed on silica gel using a mixture of ethyl ether and ethyl acetate as eluent; to give bicyclo [4.3.0] nonan-7 (8) -one-3-ol (10 9).

To a solution of the latter compound in benzene (50 mL) was added anhydrous ethylene glycol (5.29) and p-toluenesulfonic acid (0.62%) and the mixture was heated to boiling to distill off the water formed. After 14 hours, pyridine (2 mL) was added, the solution was cooled, washed with water, 2% sodium carbonate solution and saturated sodium chloride solution until neutral. After distilling off the solvents, bicyclo [4.3.0] nonan-7 (8) was obtained. -one-3-hydroxy-7,7-8,8) -ethylenedloxide, oil, IC (film) 3400 cm -1, M + 198 m / e.

Example 39

Saponification of d, l-3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide-2-exo-carboxylic acid methyl ester (4.5 g) with 2% potassium carbonate solution in 80% aqueous methanol, the corresponding free acid is obtained [4,2]. To a solution of said free acid (4.29) in acetonitrile (120 mL) was added d- (+) -ephedrine (2.3.9) and the mixture was allowed to stand at room temperature for 4 hours. The precipitated salt (2.8 9) is recrystallized again from acetonitrile; 2.15 9 d- (+) -ephedrinium salt of ethylene acid [+ J-bicyclo] [4,3,0] nonan-8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo is obtained -carboxylic. All mother liquors were combined, the solvent was distilled off, the residue was dissolved in water and the solution basified with 1 N sodium hydroxide to pH 12-13; The d- (+) - ephedrine is taken up in ether, the alkaline aqueous phase is acidified to pH 5 and taken up in ethyl acetate. The solvent is distilled off from the combined organic extracts, the residue is dissolved in acetononitrile and the above cleavage procedure is repeated using (-) - ephedrine; (-) - bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxld-3-endo-hydroxy-2-exo-carboxylic acid 1- (-) - ephedrinium salt is obtained. Each of said salts is individually dissolved in water, basified with sodium hydroxide, the optically active base is regenerated by shaking into ether, the aqueous alkaline portion is acidified to pH 5 to 5.1 and the optically active acid is extracted into ethyl acetate. (+) -Bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid and (-) -bicyclo [4.3, O) nonan-8-one) 8,8-ethylenediidine-3-endo-hydroxy-2-exo-carboxylic acid.

The optically active acids are converted to the corresponding methyl esters by treatment with diazomethane.

Example 40

A solution of 26 9 d, 1-endo-hydroxy-bicyclo [4.3.0] nonane-2-exo-methoxycarbonyl-7-one-7,7-ethylenedioxide in acetone (100 mL) was heated to reflux. with 2 N sulfuric acid (20 mL) for 4 hours. The acetone was distilled off under reduced pressure and the aqueous portion was extracted with ethyl acetate. The combined organic extracts are washed until neutral, dried and the solvent distilled off; 21.29 d, l-3-endo-hydroxy oxybicyclo [4.3.0] nonan-2-exo-methoxycarbonyl-7-one is obtained. To a solution of the obtained ketone in anhydrous acetononitrile (250 mL) was added d-1-phenyl-1-ethylamine (12.1.9), and then 50 mL of solvent was distilled slowly over 30 minutes. The mixture was slowly cooled to room temperature and the precipitated Schiff base was filtered off; 12.12 of 9 (+) -3-endo-hydroxy-7,7- (1'-phenyl-1'-ethylidenimino) -2-exo-methoxycarbonyl-bicyclo [4,3,0] nonane is obtained. The mother liquors are further concentrated to yield 69% of racemic material. Further concentration of the mother liquors up to 80 ml yields 11.42 9 (-) -endoxyhydroxy-7,7- (1'-phenyl-Pethylidenimino) -2-exo-methoxycarbonyl-bicyclo [4.3, 0] nonane.

The Schiff bases obtained are each resolved separately into an optically active ketone by dissolving in methanolic 2 N sulfuric acid (200 mL) and refluxing the solution for 2 hours. The solvent was distilled off under reduced pressure, the product was taken up in ethyl acetate, and the combined organic extracts were washed to neutral pressure. It is obtained

8.1. 9 (+) -3-Endo-hydroxy-bicyclo [4.3.0-nonanane] -2-oxo-methoxycarbonyl-7-one; and

7.2 9 (-) -3-endo-hydroxy-bicyclo [4.3.0] nonan-2-exo-methoxycarbonyl-7-one.

In this way, all of the bicyclo [beta] -hydroxy-carboxylic acid ester ethylenedioxides described in Example 28 after &lt; 151 &gt;

(+) - Bicyclo [3.2.0] heptan-6-one-2-exo-carboxymethyl ester, (+) - bicyclo [3.2.0] heptan-7-one-2-exo-carboxymethyl ester, [+ (+) -bicyclo [4.3.0] nonan-8-on-2-exo-carboxymethyl ester, (+) -bicyclo [4,3.0] nonan-8-on-2-exo-carboxymethyl ester 5,3,0] Decan-8-one-2-exo-carboxymethyl ester, (-) -bicyclo [3,2,0] heptan-6-one-2-exo-carboxymethyl ester, (-) -bicyclo [3] , 2,0] heptan-7-one-2-exo-carboxymethyl ester, (-) -bicyclo [4.3.0] nonan-7-one-2-exo-carboxymethyl ester, (-) -bicyclo [4.3.0] (-) - bicyclo [5.3.0] decan-8-one-2-exo-carboxymethyl ester, O] nonan-8-one-2-exo-carboxymethyl ester.

In the manner described in Example 27, the above-mentioned ketones were converted to the corresponding ethylenedioxides

Example 41

Dicyclohexylcarbodiimide (12.7 g), pyridine (1.65 mL) and trifluoroacetic acid (0.83 mL) were added sequentially to the 3-THP solution while stirring and external cooling to maintain the reaction temperature at 20-22 ^° C. of 2-exo-hydroxymethyl-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, 7,7-ethylenedioxide ether, in benzene / DMSO 75/25 (80 mL). The reaction mixture was diluted with benzene (50 mL), filtered, washed with water until neutral and dried over sodium sulfate. The solvents were evaporated to a small volume (30 ml) and this solution was added with stirring to a solution of sodium phosphonate prepared by adding a solution of 2-oxo-octyl-dimethylphosphonate (10.8 g) in benzene (30 ml) to a suspension of 80% sodium hydride ( 1.35 g) in benzene (125 mL). After 15 minutes, the reaction is complete and the reaction mixture is heated with acetic acid (6 mL), washed with water until neutral, dried over sodium sulfate. The solvent is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel. Using n-hexane with ethyl acetate (80:20) as eluent, 2-exo (3'-oxo-non-1'-trans-1'-enyl) 3THP-ether 7,7-ethylenedioxide is obtained as a yellow oil. 3-endo-hydroxy-bicyclo [3.3.0] octan-7-one (12.7 g), IC (neat) in cm ^-1 :

2970 1690 1670 1625

NMR (CDCl3)?

0.88 (3 H, t),

4.60-4.75 (1H, m), 6.18--6.20 (1H, d), 6.79-6.89 (1H, dd).

To a solution of this compound in dry pyridine (100 mL) was added pyridine bromide hydrobromide (24 g) with stirring. After 1.30 h, the mixture was diluted with 30% aqueous sodium dihydrogen phosphate solution (500 mL) and extracted with ethyl acetate. The organic extracts were combined and washed until neutral, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified on silica gel (eluent hexane / ethyl ether 80:20) to give 2-exo- (2'-bromo-3'-oxo-non-1'-trans- 3-THP-ether 7,7-ethylenedioxide). r-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one (13 g), IC (neat) in cm ^-1 : 2940, 1685, 1610. The obtained bromoketone solution (12, 6 g) in methanol (32 ml) is added dropwise to a solution of sodium borohydride (4.2 g) in methanol (65 ml) cooled to -20 ° C. Reduction is complete in 1 hour. The reaction mixture was then diluted with an excess of 30% aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate and the solvents evaporated to dryness in vacuo. The residue (12 g) was dissolved in acetone (100 ml) and then treated with 1N aqueous oxalic acid solution (50 ml) for 12 hours at 40 ° C. After removal of acetone at 50 ° C under vacuum, the aqueous suspension was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated and the residue was chromatographed on silica gel. Using n-hexane with ethyl acetate (50:50), the following keto alcohols were obtained:

2-exo- (2'-bromo-3'R-hydroxy-non-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one ( 3 (g) a

2-exo- (2'-bromo-3'S-hydroxy-non-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one (4, 2 g).

Under an inert gas (N2) atmosphere, to a solution of potassium tertiary butylate (18 g) in anhydrous DMSO (180 mL) was added 4-carboxybutyltriphenylphosphonium bromide (32.4).

g) to form a red ylide solution. Then, after 5 minutes, add a solution of the above 3‘S alcohol (4.2 g). The reaction mixture is kept under an inert gas atmosphere for 15 hours with stirring at room temperature. The reaction mixture was diluted with an excess of 30% aqueous sodium dihydrogen phosphate solution (350350 mL) and extracted with ethyl ether (50 mL short). The ethereal extracts were combined, washed with brine (15 ml) and then extracted with 1N sodium hydroxide solution (5 times 15 ml) and water until the washings were neutral. The basic extracts were combined and acidified to pH and then extracted with ethyl ether (3 x 30, 1 x 15, 1 x 10). These organic extracts were combined, washed with brine, dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel using acetic acid ether (100: 0.5) as the eluent to give 5Z-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-ene acid -13-yne (1.21 g), NMR (CDCl 3) δ ppm: 0.90 (3H, t),

4.00 (1 H, m),

4.40 (1 H, t),

5.27 (1 H, t);

and 5E-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-ene-13-ynoic acid (1.84 g), IR (neat (cm ^-1 )): 3350, 2115, 1705;

NMR (CF 3 CO 2 D) δ:

0.9 (3H, t);

4.00 (1 H, m),

4.40 (1 H, t),

5.30 (1 H, t),

6.38 (3 H, m).

In an analogous manner, but using the 3'R alcohol as the starting material obtained after Wittig reaction with 4-carboxybutyl-triphenylphosphonium bromide and chromatographic separation on SiO 2 'using ethyl ether with acetic acid (99.5: 0.5), these compounds are obtained in order :

5Z-11a, 15R-Dihydroxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-en-13-ynoic acid (0.4 g), NMR (CDCl 3) δ ppm: 0.90 (3H, t) ,

4.00 (1 H, m),

4.40 (1 H, t),

5.28 (1H, t) and 5E-111aR-Dihydroxy-9a-deoxy-9a-methylene-20-methylprostan-4-yl-4-en-13-ynoic acid (0) 8 g) 1 H NMR (CDCl 3) δ ppm:

0.90 (3 H, t),

4.00 (1 H, m),

4.39 (1 H, t),

5.30 (1 H, t).

Example 42

Using the procedure described in Example 41 but substituting 2-oxo-nonyl dimethylphosphonate instead of 2-oxo-alkyl dimethylphosphonate, the following compounds were obtained:

5Z-11a, 15S-dihydroxy-9α-deoxy-9almethylene-20-ethylprostacycl-5-en-13-ynoic acid, m / e 358 (M + - H 2 O), 340 (M + - 2 H 2 O); NMR (CDCl3):

0.88 (3 H, t),

2.37 (2 H, t),

3.98 (1 H, m),

4.40 (1 H, t),

5.30 (1H, broad t),

5.98 (3H, broad);

5E-11α, 15S-dihydroxy-9α-deoxyl9α-methylene-20-ethylprostacycl-5-ene-13l-acid, m / e 358 (M + - H 2 O), 340 (M + - 2 H 2 O), NMR ( CDC13):

0.88 (3 H, t),

2.36 (2 H, t),

3.98 (1 H, m),

4.39 (1 H, t),

5.30 (1H, broad t),

5.62 (3H, broad), and their 15R epimers:

5Z-11a, 15R-dihydroxy-9α-deoxy-9α-methylene-20-ethylprostacycl-5-ene-13-ynoic acid, m / e 358 (M ⁺ - H 2 O), 340 (M ^{+ -} 2 H 2 O) and 'acid 5E-11a, 15R-dihydroxy-9α-deoxy-9almethylene-20-ethylprostacycl-5-ene-13-yne, m / e 358 (M + - H 2 O, 340 (M + - 2 H 2 O)).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of the 9-deoxy-9α-methyl-1-lysers of prostacyclin PGI 2 of formula I, wherein: R is a substituent selected from the group consisting of a) a free carboxyl group or an esterified carboxyl group of formula —COOR9 wherein R9 is C1-4 alkyl or C2-12 alkenyl, b] a group of formula —C (OR ') 3 wherein each individual substituent R' denotes independently C1-C6alkyl or phenyl, cj is a group of the formula “CH2-R” in which R 'is a hydroxyl or alkoxy group of 2 to 7 carbon atoms, dj a group of the formula From —CON \ R b wherein R a and R _b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl and phenyl, e) cyano, f is a radical of formula -C N-N II ⁴ N-NH gj -CHO, h) a radical of formula X‘-Ra ‘ Z —ch, OF X'-Rb 'wherein each individual X' is independently O or S, and R _a 'and R _b ', which are the same or different, are C 1 -C 6 alkyl or are taken together to form a straight or a branched alkylene chain having 2 to 6 carbon atoms, D is a substituent selected from the group consisting of -CH 2 -, -; CH — OH, OF Η H \ Z C = C (cis), z \ H \ z C = C (trans) 66 — CsC-, \ c = o, OF -0-, —S—, and \ N-Rc, Z wherein R _c is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkanoyl, one of R 1, R 2, and independently of one of R 3, R 1 is hydrogen, C 1 -C 6 alkyl (C 6 -C 6 alkenyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenylphenyl or naphthyl) - (C 1 -C 6) alkyl and the other is hydrogen, hydroxyl, C 1 -C 6 alkoxy carbon atoms or phenyl or naphthyl) - (C 1 -C 6) alkoxy, or R 1 and R 2, and independently of them R 3 and R 6, together form an oxo group, R 5 and R 6, which are the same or different, each represent a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a halogen atom, or R 5 and R 6 together with the carbon atom to which they are attached form a radical of formula C = CH 2 or OF Y represents a group of formulas —CH2 —CH2—, —C = C—, Z \ Z C = C (trans) OF \ H H Z \ Z C = C (cis) Wherein Z represents a hydrogen atom or a halogen atom, and furthermore a group of formulas —NH —CO— and —NH-CH2-, X denotes groups of formulas H - _(CH2) M3- wherein m3 is zero or 1, Η H \ Z O = C (cis) OF \ H \ Z C = C (trans) OF \ H -0-, -S- or N-R _c, wherein R _c is as defined above, mi, mz, m, on which are the same or different, are zero or an integer 1: to 12 and the sum mi + mg or m + P 2 is less than or equal to 15, and p and q are each zero or an integer from 1 to 3, the sum of p + q being an integer from 1 to 6, and R 7 is a substituent selected from the group consisting of a ') a hydrogen atom, b') a (C 1 -C 4) alkyl group, c ') a monocyclic C _3-9 cycloalkyl or cycloalkenyl, norbornyl or adamantyl group optionally substituted with at least one C 1-6 alkyl group (d) a phenyl or naphthyl group optionally substituted by at least one halogen atom, a haloalkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 atoms e ') a saturated or unsaturated 5- or 6-membered heteromonocyclic ring containing at least one heteroatom which is an oxygen, sulfur or nitrogen atom and optionally substituted by at least one halogen atom, a (C1-C6) haloalkyl group, an alkoxy group C 1 -C 6 -alkyl, phenyl or C 1 -C 6 -alkyl, as well as lactones The compounds of formula (I) as well as their pharmaceutically or veterinarily acceptable salts are characterized in that the compound of formula (IV) wherein R '', mz, mi, p, q, R 1 'and R 2' are as defined above. , and D 'is selected from the group consisting of a'') -, -, b', -, -, c '') - NR _c , In which R _c is as defined above, (d '') —CH = CH- (cis), e '') —CH = CH- (trans), (f '') —CeC-, g “') formulas X'-R _a ' X'-R _b 'wherein X', R a 'and R _b' are as defined above, h '') a group of formula \ ch ocor ‘, In which R 'is as defined above, i'') —CH 2 -, or D', R '' and (CH ₂ ) m ₂ together form a group of the general formula -Cl ·! - (Four) tr> wherein it is as defined above, alkylated with a compound of formula V wherein E is a group of formula (C6H5) sP- or (Re0) 2P- (O) -, wherein each individual R e is independently an alkyl group of 1 to 6 carbon atoms or phenyl, Z, ni, Rs, R6, X, on, Rz are as defined above, and from the obtained compound of formula VI, (CH _z) -CX- (C ^ ^H (V) wherein R ' mz, D ', mi, p, q, R 1', R 2 ', Z, ni, R 5, R 6, X, n 2, R 7 are as defined above, optionally deprotecting to give a compound of formula I, wherein Y is -CH = CZ- (trans), Z is as defined above, and R 3 and R 4 together form an oxo group, and / or a compound of formula VI wherein Z is hydrogen or a compound of formula I, wherein Y represents —CH = CZ-- (trans), Z is hydrogen and R3 and R4 together form an oxo group, optionally reduced, and are obtained after deprotection h groups, a compound of formula I wherein Y is -CH 2 -CH 2 - and R 3 and R 4 together form an oxo group and / or optionally nucleophilic addition to the free carbonyl in the side ω-chain of a compound of formula VI or a compound of formula I wherein Y is -CH 2 -CH 2 - or -CH = CZ (trans), Z is as defined above, and R 3 and R 4 together form an oxo group, to give, after deprotection, a compound of formula I wherein Y Z is as defined above and one of R 3 and R 4 'is hydroxyl and the other is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl C 2 -C 10 alkynyl, C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6 alkyl), and a compound of formula I wherein Y is -CH 2 -CH 2 - or -CH = CZ— ( Z is as defined above, one of R 3 and R 4 is hydroxyl and the other is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl , phenyl, phenyl (or naphthyl) - (C 1 -C 6 alkyl) and all other hydroxyl groups present are protected as described above, optionally etherified, and, after deprotection, to give a compound of formula I wherein Y is a group of 70 - CH2-CH2- or -CH = CZ- (trans) Z is as defined above and one of R3 and R4 is C1-C6 alkoxy or phenylphenyl or naphthyl) - (C1-C6) alkoxy and the other is hydrogen , (C 1 -C 6) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl and / or optionally a compound of formula I wherein Y is -CH = CZ- (trans), Z is halogen, one of R 3 and R 4 is hydrogen, C 1 -C 6 alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl, and the other is hydroxyl, (C 1 -C 6) alkoxy or phenyl ( or naphthyl) - (C 1 -C 6) alkoxy, or R 3 and R 4 together form an oxo group, and any hydroxy, oxo or carboxyl groups present are either free or protected as described above, dehydrohalogenated, and after removal of any protecting groups present, a compound of formula (I) wherein Y is -C CC C and one of R3 and R4 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms; C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl) - (C 1 -C 6) alkyl and the other is hydroxyl, C 1 -C 6 alkoxy or phenyl (or naphthyl) - ( C 1 -C 6) alkoxy, or R 3 and R 4 together form an oxo group, and / or optionally convert a compound of formula I to a lactone or a corresponding salt, and / or optionally prepare a free compound of formula I from a salt thereof, and / or the mixture of isomeric compounds of formula I is separated into the corresponding individual isomers.