CH648017A5 - CARBACYCLIN ANALOGA. - Google Patents

Description

The present invention relates specifically to new analogs of prostacyclin or PGI2. More particularly, the present invention relates to analogues of carbacyclin modified at the C-5 or C-9 position, e.g. C-5 inter-phenylene analogs of carbacyclin, 5-fluoro analogs of carbacyclin, 9/3 alkyl analogs of carbacyclin, C-6a, 9 tri-cyclic (cyclopropyl) analogs of carbacyclin and combinations thereof as well as new ones Benzene analogues thereof.

Prostacyclin is an endogenously produced compound in mammals and is structurally biosynthetically related to prostaglandins (PG's). Specifically, prostacyclin has the structure and carbon atom numbering of Formula 1 when the C-5,6 positions are unsaturated. For the sake of simplicity, prostacyclin is often simply referred to as “PGI2”. Carbacyclin, 6a-carba-PGI2 has the structure and the

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Carbon atom numbering given in Formula II when the C-5,6 positions are unsaturated. Likewise, for the sake of simplicity, carbacyclin is simply referred to as “CBA2”.

A stable, partially saturated derivative of PGI2 is PGIi or 5,6-dihydro-PGI2 when the C-5,6 positions are saturated, represented by the carbon atom numbering in Formula II when the C-5,6 positions are saturated . The corresponding 5,6-dihydro-CBA2 is CBAi, shown in Formula II.

As can be seen from formulas I and II, prostacyclin and carbacyclin can simply be named as derivatives of PGF-type compounds, e.g. PGF2a of Formula III. Accordingly, prostacyclin is simply named 9-deoxy-6,9-epoxy- (5Z) -5,6-didehydro-PGFi and carbacyclin is named 9-deoxy-6,9a-methano- (5E) -5,6 -didehydro-PGFi. For the description of prostacyclin and its structural identification, see Johnson, et. al., Prostaglandins 12: 915 (1976).

For simplicity, the new prostacyclin or carbacyclin analogues are referred to by the simple, species-recognized nomenclature system described by N.A. Nelson, J. Med. Chem. 17: 911 (1974) for prostaglandins. Accordingly, all new prostacyclin derivatives are referred to herein as 9-deoxy-PGF 1-like compounds, PGI2 derivatives, or preferably as CBAi or CBA2 derivatives.

In the formulas used herein, connections to a ring with dashed lines mean that the substituents are in the "alpha" (a) configuration, e.g. below the level of the said ring. Connections to a ring with a thick, solid line mean substituents in the "beta" (β) configuration, e.g. above the level of the said ring. The use of wavy lines (~) herein means attachment of the substituents in the alpha or beta configuration or a mixture of the alpha and beta configurations. Alternatively, wavy lines mean either an E or Z geometric isomeric configuration or the mixture thereof.

The hydroxy substituent on the C-15 in the side chain in the formulas used herein is in the S or R configuration as determined by the Cahn-Ingold-Prelog sequence rules, J.

Chem. Ed. 41: 16 (1964). See also [Nature 212: 38 (1966)] for the discussion of the stereochemistry of prostaglandins, which discussion is used with the new prostacyclin or carbacyclin analogues herein. The molecules of prostacyclin and carbacyclin each have different asymmetry centers and can therefore be in optically inactive form or in one of the two enantiomeric (optically active) forms, e.g. in the right-handed and in the left-handed form. As shown, the formula of PGI2 corresponds to that which is produced endogenously in mammals. In particular, attention is drawn to the stereochemical configuration at C-8 (a), C-9 (a), C-II (a) and C-12 (ß) of endogenously produced prostacyclin. The mirror image of the above formula for prostacyclin is the other enantiomer. The racemic form of prostacyclin contains an equal number of both enantiomeric molecules.

For simplicity, the reference to prostacyclin and carbacyclin refers to the optically active form thereof. Accordingly, the reference to prostacyclin refers to the form thereof which has the same absolute configuration as that obtained from mammals.

The term "prostacyclin-like" product as used herein refers to any cyclopentane derivative herein that is useful for at least one of the same pharmacological purposes for which prostacyclin is used. A formula as drawn herein and representing a prostacyclin-like product or an intermediate which is useful in the preparation thereof,

represents the particular stereoisomer of the prostacyclin-like product which is of the same relative stereochemical configuration as the prostacyclin obtained from mammals, or the particular stereoisomer of the intermediate which is useful in the preparation of the above stereoisomer of the prostacyclin-like product Product.

The term "prostacyclin analogs" or "carbacyclin analogs" means that stereoisomer of a prostacyclin-like product that is of the same relative stereochemical configuration as the prostacyclin obtained from mammals, or a mixture containing the stereoisomer and the enantiomers thereof. In particular, where a formula is used to represent the prostacyclin-like product herein, the term "prostacyclin analogs" or "carbacyclin analogs" refers to the compound having this formula or a mixture containing this compound and the enantiomer thereof .

Carbacyclin and closely related compounds are well known in the art. See Japanese Kokia 63,059 and 63,060, also summarized as Derwent Farmdoc CPI numbers 48154B / 26 and 48155B / 26. See also British published descriptions 2,012,265 and German Offenlegungsschrift 2,900,352, summarized as Derwent Farmdoc CPI numbers 54825B / 30. See also British published applications 2,017,699, 2,014,143 and 2,013,661.

The synthesis of carbacyclin and related compounds is dealt with in the chemical literature, see for example: Mortin, D.R., et al., J. Organic Chemistry, 44: 2880 (1979); Shibasaki, M., et al., Tetrahedron Letters, 433-436 (1979); Kojima, K., et al., Tetrahedron Letters, 3743-3746

(1978); Nicolaou, K.C., et al., J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie, A., et al., Tetrahedron Letters 2607-2610 (1979); Shibasaki, M., Chemistry Letters, 1299-1300 (1979), and Hayashi, M., Chem. Lett. 1437-40

(1979); and Li, Tsung-tee, "A Facile Synthesis of 9 (0) -Me-thano-prostacyclin", Abstract No. 378, (Organic Chemistry), and P.A. Aristoff, "Synthesis of 6a-Carbaprostacyclin I2", Abstract No. 236 (Organic Chemistry) both as “Abstract of Papere Part II)” at the second congress of the North American continent, San Francisco, California (Las Vegas, Nevada), USA, August 24-29, 1980.

7-Oxo and 7-Hydroxy-CBA2 compounds are apparently described in U.S. Patent No. 4,192,891. 19-Hydroxy-CBA2 compounds are described in U.S. Series No. 054,811, filed July 5, 1979. CBA2 aromatic Esters are described in U.S. Patent No. 4,180,657. 11-deoxy-A10 or An-CBA2 compounds are described in Japanese Ko-kai 77 / 24,865, published February 24, 1979.

The present description specifically provides:

a carbacyclin analog of formula X or XI;

where n is 1 or 2;

Li is a-R3: 0-R4, CX-R4: jS-R3> or a mixture of a-R3: / 3-R4 and a-R4: j3-R3, wherein

R3 and R4 are identical or different and denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 and R4 is fluorine only when the other is hydrogen or fluorine;

Mi is a-OH: ß-R $ or a-R $: ß-OH, where R5 is hydrogen or methyl;

R7 means

(1) -CraH: m-CH3, where m is an integer from 1 to 5 inclusive,

(2) Phenoxy optionally substituted with one, two or three substituents selected from the group consisting of

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Chlorine, fluorine, trifluoromethyl, (Ci-C3) alkyl and (Ci-C3) alkoxy, with the proviso that no more than two substituents are different from alkyl, with the further proviso that R7 is only phenoxy or a substituted phenoxy when R3 and R4 are hydrogen or methyl, these being the same or different,

(3) phenyl, benzyl, phenylethyl or phenylpropyl, optionally substituted on the aromatic ring by one, two or three substituents selected from the group consisting of chlorine, fluorine, trifluoromethyl, (Ci-C3) alkyl and (CrC3) alkoxy, with provided that no more than two substituents are different from alkyl,

(4) cis-CH = CH-CH2-CH3,

(5) - (CH2) 2-CH (OH) -CH3, or

(6) - (CH2) 3-CH = C (CH3) 2;

wherein

-C (Li) -R7 means taken together

(1) (C4-C7) cycloalkyl, optionally substituted with one to three (Ci-Cs) alkyl;

(2) 2- (2-furyl) ethyl,

(3) 2- (3-thienyl) ethoxy, or

(4) 3-thienyloxymethyl;

R8 represents hydroxy, hydroxymethyl or hydrogen;

Ris means hydrogen or fluorine;

R16 represents hydrogen or Ri6 and Rn taken together represent -CH2-;

Rn has the above meaning or means

(1) hydrogen or

(2) (C, -Ct) alkyl;

(1) R2o, R2i, R22, R23 and R24 all mean hydrogen, where R22 means either a-hydrogen or β-hydrogen,

(2) R20 means hydrogen, R2i and R22 taken together form a second valence bond between C-9 and C-6a, and R23 and R24 taken together form a second valence formation between C-8 and C-9 or both mean hydrogen, or

(3) R22> R23 and R24 all represent hydrogen, where R22 is either a-hydrogen or / 3-hydrogen, and

(a) R20 and R21 taken together mean oxo, or

(b) R20 is hydrogen and R2i is hydroxy and is a-hydroxy or ß-hydroxy;

Xi means

(1) -COORi, where Ri has the meaning of

(a) hydrogen,

(b) (C, -C12) alkyl,

(c) (C3-C10) cycloalkyl,

(d) (C7-CI2) aralkyl,

(e) phenyl, optionally substituted with one, two or three chlorine atoms or (Ci-C3) alkyl groups,

(f) Phenyl substituted in the para position by

(1) -NH-CO-R25,

(ii) -CO-R26,

(iii) -0-C0-Rj4, or

(iv) -CH = N-NH-CO-NH2, where R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2; R26 means methyl, phenyl, -NH2 or methoxy and R54 means phenyl or acetamidophenyl; including,

or

(g) a pharmacologically acceptable cation;

(2) -CH2OH,

(3) -COL4, where L4 has the meaning of

(a) Amino of the formula -NR5iR52, in which RS1 and R52 have the meaning of

(i) hydrogen,

(ii) (CrC12) alkyl,

(iii) (C3-Cio) cycloalkyl,

(iv) (C7-Ci2) aralkyl,

(v) phenyl, optionally substituted with one, two or three chlorine, (Ci-C3) alkyl, hydroxy, carboxy, (C2-C5) alkoxycarbonyl or nitro,

(vi) (C2-C;) carboxyalkyl,

(vii) (C2-C5) carbamoylalkyl,

(viii) (C2-C5) cyanoalkyl,

(ix) (C3-C6) acetylalkyl,

(x) (C7-Cn) benzoalkyl, optionally substituted by one, two or three chlorine, (Q-Cjialkyl, hydroxy, (Ci-C3) alkoxy, carboxy, (C2-C5) alkoxycarbonyl or nitro,

(xi) pyridyi, optionally substituted with one, two or three chlorine, (Ci-C3) alkyl, or (CrC3) alkoxy,

(xii) (C6-C9) pyridylalkyl, optionally substituted by one, two or three chlorine, (Ci-C3) alkyl, hydroxy or (CrC3) alkyl,

(xiii) (Ci-C4) hydroxyalkyI,

(xiv) (C1-C4) dihydroxyalkyl,

(xv) (CrC4) trihydroxyalkyl,

with the further proviso that no more than one of the radicals R51 and R52 is different from hydrogen or alkyl,

(b) cycloamino selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, hexamethylene lenimino, pyrrolino or 3,4-didehydropiperidinyl, optionally substituted by one or two (Ci-Ci2) alkyl having one to 12 carbon atoms inclusive,

(c) carbonylamino of the formula -NR53CORsi, in which R53 has the meaning of hydrogen or (Ci-C4) alkyl and Rji is not hydrogen, but otherwise as defined above,

(d) sulfonylamino of the formula -NR53S02R5i, in which R51 and R53 have the definitions given in (c),

(4) -CH2NL2L3, where L2 and L3 are hydrogen or (Ci-C4) alkyl, and the same or different, or the pharmacologically acceptable acid addition salts thereof, if Xi is -CH2NL2L3,

Yi is trans-CH = CH-, cis-CH = CH-, -CH2CH2- or -C = C-;

Zi is

(1) -CH2- (CH2) rC (R2) 2, in which R2 has the meaning of hydrogen or fluorine and f is zero, one, two or three,

(2) trans-CH2-CH = CH-,

(3) - (Ph) - (CH2) g-, where (Ph) is 1,2-, 1,3- or 1,4-phenylene and g is zero, one, two or three; with the general rule that

(1) Ris, R16 and R17 all only mean hydrogen if the meaning of - (Ph) - (CH2) g-, and

(2) Zj only means - (Ph) - (CH2) g- when Ri5 is hydrogen.

With respect to the divalent substituents described above (e.g. Li and Mi), these divalent residues are defined as a-Ri: ß-Rj, where R; represents the substituent of the divalent part in the alpha configuration with respect to the level of the C-8 to C-12 cyclopentane ring and Rj means the substituent of the divalent part in the beta configuration with reference to the level of the ring. Similarly, when Mi is defined as a-OH: / 3-R5, the hydroxyl group of the Mi part in the alpha configuration, e.g. as in PGI2 above, and the R5 substituent is in the beta configuration.

The content of carbon atoms in different parts containing carbon atoms is indicated by a prefix which specifies the minimum and maximum number of carbon atoms in the part, e.g. the prefix (Q-Cj) indicates a part of the whole number “i” up to and including the whole number “j” of carbon atoms. Accordingly, (Ci-C3) A1 kyl means an alkyl group of one to three carbon atoms inclusive or a methyl, ethyl, propyl, and isopropyl group.

Certain new prostacyclin analogs, e.g. Compounds of Formula X are all referred to herein as CBAi or CBA2 compounds

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fertilize refers to the substitution of methylene instead of oxa in the heterocyclic ring of prostacyclin. CBA2 compounds are those that have a double bond at C-5.6, while CBAi compounds are those that are saturated at C-5.6. Connections of forms? XIs are referred to as PGEi or as PGFi derivatives, as described hereinafter.

New compounds in which Zi has the meaning of (Ph) - (CH2) g) - are referred to as inter-o-, inter-m- or inter-p-phenylene, depending on whether the link between the io C-5 and the - (CH2) g part is ortho, meta or para.

For those compounds where g is zero, one, two or three, the carbacyclin analogs so described are further characterized as 2,3,4-trinor, 3,4-dinor or 4-nor compounds because in this case the xi-terminated side chain (not including phenylene) contains two, three or four carbon atoms instead of five carbon atoms contained in the PGh. The missing carbon atom or carbon atoms are referred to as the C-4 to C-2 positions. seeks so that the phenylene is attached to the C-5 and C-120 to C-3 positions. Accordingly, these compounds are referred to as 1,5, 2,5, 3,5 and 4,5-inter-phenylene CBA compounds when g is zero, one, two or three.

Those CBA analogues in which Zi has the meaning of -CH2 - (CH2) f-CF2- are characterized as «2,2-difluoro» - 25

Links. For those compounds where f is zero, two or three, the carbacyclin analogs so described are further characterized as 2-nor, 2a-homo or 2a, 2b-dihomo because in this case the Xi-terminated side chain is four, six or seven Contains carbon atoms instead of five carbon atoms contained in the CBA2. The missing carbon atom is considered at the C-2 position so that the C-1 carbon atom is connected to the C-3 position. The additional carbon atom or atoms are considered to be inserted between the C-2 and C-3 positions. Accordingly, these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 position to the C-3 position.

Those CBA analogues in which Zi has the meaning of trans - CH2-CH = CH- are referred to as "trans-2,3-didehydro-CBA" compounds.

The new compounds, in which n is 2, are further characterized as 7a-homo-CBA compounds, by virtue of the cy-clohexyl ring, which replaces the heterocyclic ring of prosta-cyclin. 45

Furthermore, the new compounds are referred to as 9j3-alkyl-CBA compounds when Rn represents an alkyl group.

If R] 6 and R! 7 taken together mean -CH2- (methylene), the new compounds are referred to as «6a / 3,9 | 3-methane-CBA» compounds, due to the methylene-so bridge between C-6a and C-9.

When R15 is fluorine, "5-fluoro-CBA" compounds are described.

The CBA analogues of formula XI, wherein R20. R21. R22. R23 and R24 are all hydrogen and Ra / 3 is hydrogen, ss are referred to as "9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7 - (r, 3 '-inter-phenylene) -PGFi »compounds referred. Corresponding compounds in which R22 is α-hydrogen are characterized as “9-deoxy-2 ', 9/3 methano-3-oxa-4,5,6-trinor-3,7- (r, 3'- inter-phenylene) -PGFi »compounds. CBA analogues, in which R20, R23 and R24 are all hydrogen and R2i and R22 taken together form a valence bond between C-9 and C-6a, are characterized as« 9-deoxo-2 ', 9-metheno-3-oxo-3,4,5-trinor-3,7- (r, 3'-inter-phenylene) -PGF (»Compounds. CBA analogues, in which R2o means hydrogen and R2) and R22 taken together form a second valence bond between C-9 and C-6a and R23 and R24 taken together form a second valence bond between C-7

and C-8 form, are characterized as «9-deoxo-2 ', 9 - metheno-3-oxa-3,4,5-trinor-3,7- (l', 3'-inter-phenylene) - 7,8-dide-hydro-PGEi »connections. The CBA analogs of formula XI, wherein R22, R23 and R24 are all hydrogen and R2o and R2i taken together are oxo, are characterized as "6a-oxo-9-deoxy-2 ', 9a-methano-3-oxa-4,5 , 6-trinor-3,7 - (l ', 3'-inter-phenylene) -PGFi »or« 6a-oxo-9-deoxy-2', 9 / 3- ^ nethano-3-oxa-4, 5,6-trinor-3,7- (P, 3'-inter-phenylene) -PGFi », depending on whether R22 is an a-hydrogen or a / 3-hydrogen. The CBA analogs of formula XI, wherein R20, R22, R23 and R24 are all hydrogen and R21 is a-hydroxy, are characterized as "6aa-hydroxy-9-deoxy-2 \ 9a-methano-3-oxa-4, 5,6-trinor-3,7- (l ', 3' -interphenylene) -PGFi 'or' 6aa-hydroxy-9-deoxy-2 ', 9/3-methano-3-oxa-4,5 , 6-trinor - 3,7- (l ', 3'-inter-propylene) -PGFi »compounds, depending on whether the radical R22 is an a-hydrogen or a / 3-hydrogen. Finally, CBA analogs of the formula XI, in which R20, R22, R23 and R24 are all hydrogen and R21 is β-hydroxy, are characterized as «6a / 3-hydroxy-9-deoxy-2'9 / 3-me-thano-3 -oxa-4,5,6-trinor-3,7- (l ', 3'-inter-phenylene) -PGFi »or« 6a £ -hydroxy-9-deoxy-2', 9a-methano-3- oxa-4,5,6-trinor-3,7 - (l ', 3'-inter-phenylene) -PGFi »compounds, depending on whether the radical R22 is a-hydrogen or a / 3-hydrogen. If Z4 has the meaning of - (CH2) f-CF2- and f is zero, the CBA analogues of the formula XI are additionally characterized as “2,2-difluoro” compounds. If f has the meaning of one, two or three, such compounds are additionally characterized as «2a-homo», «2a, 2b-dihomo» or «2a, 2b, 2c-trihomo» compounds.

When R5 represents a methyl group, all carbacyclin analogs are referred to as "15-methyl-CBA" compounds. Except for compounds in which Yi has the meaning of cis-CH = CH-, compounds in which the Mi part contains a hydroxyl group in the beta configuration are also referred to as “15-epi-CBA” compounds.

Compounds in which Yi has the meaning of cis-CH = CH- and in which the Mt part contains a hydroxyl group in the alpha configuration are referred to as “15-epi-CBA” compounds. For a description of this convention of nomenclature for identifying the C-15 epimers, see U.S. Patent No. 4,016,184, issued April 5, 1977, and particularly note columns 24-27 thereof.

Herein the new carbacyclin analogues, which contain - (CH2) 2, cis-CH = CH- or -C = C- as the Yi part, are correspondingly referred to as “13,14-dihydro”, “cis-13” or “13,14-Dide-hydro” connections.

If R7 denotes the straight-chain radical -CmH2m-CH3, in which m has been defined above, the compounds described in this way are referred to as "19.20-dinor", "20-nor", "20-methyl" or "20-ethyl" Connections designated when m has the meaning of one, two, four or five. If R7 is a branched chain radical of the formula -CmH2m-CH3, the compounds described in this way are referred to as “17-, 18-, 19- or 20-alkyl” or “17,17-, 17,18-, 17,19-, 17.20-, 18.18-, 18.19-, 18.20-, 19.19- or 19.20-dialkyl “compounds if m has the meaning of 4 or 5 and the unbranched part of the chain at least is n-butyl; e.g. «17,20-dimethyl) compounds are described if m has the meaning of 5- (l-methylpentyl).

When R7 is phenyl and neither R3 nor R4 is methyl, the compounds so described are referred to as "16-phenyl-17,18,19,20-tetranor" compounds. When R7 is a substituted phenyl, the corresponding compounds are referred to as "16- (substituted phenyl) -17,18,19,20-tetranor" compounds. If one and only one of the radicals R3 and R4 is a methyl group or if both radicals R3 and R4 each represent a methyl group, the corresponding compounds in which R7 is the Be

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has meaning as "16-phenyl or 16- (substituted phenyl) - 18,19,20-trinor" compounds or as "I6-methyl-16-phenyl- or 16- (substituted phenyl) -! 8,19, 20-trinor »connections called.

When R7 is benzyl, the compounds so described are referred to as "17-phenyi-18,19,20-.trinor" compounds. When R7 is substituted benzyl, the corresponding compounds are referred to as "17- (substituted phenyl) * 18,19,20-trinor" compounds.

When R7 is phenylethyl, the compounds so described are referred to as "18-phenyl-19,20-dinor" compounds. When R7 is substituted phenylethyl, the corresponding compounds are referred to as "18- (substituted pheny]) - 19,20-dinor" compounds.

When R7 is phenylpropyl, the compounds so described are described as "19-phenyl-20-nor" compounds. When R7 is a substituted phenylpropyl, the corresponding compounds are referred to as "19- (substituted phenyl) -20-nor" compounds.

If R7 has the meaning of phenoxy and neither R3 nor R »mean a methyl group, the compounds described in this way are referred to as« I6-phenoxy-17,18,19,20-tetranor »compounds. When R7 is a substituted phenoxy, the corresponding compounds are referred to as "16- (substituted phenoxy) -17,18,19,20-tetranor" compounds. If one and only one of the radicals R3 and R <denote a methyl group or if both radicals R3 and R4 each denote a methyl group, the corresponding compounds in which R7 has the definition given in this section are referred to as "16-phenoxy or 16- ( substituted phenoxy) -18,19,20-trinor »compounds or referred to as« 16-methyl-16-phenoxy- or 16- (sub-substituted phenoxy) -18, I9,20-trinor »compounds.

If R7 has the meaning of cis-CH = CH-CH ^ CHj, the compounds described in this way are referred to as “cis-17,18-didehydro” compounds.

If R7 has the meaning of - (CHJrCHtOHJ-CHj, the compounds described in this way are referred to as “19-hydroxy” compounds.

If R7 has the meaning of - (CH ^ -CH = C (CH3) 2), the compounds described in this way are referred to as «20-isopropylidene» compounds.

If -C (L]) - R7 has the meaning of an optionally substituted cycloalkyl, 2- (2-furyl) ethyl, 2- (3-thienyl) ethyl or 3-thienyloxymethyl, the compounds described in this way are classified as 15- Cycloalkyl-16,17,18,19,20-pentanor compounds, 17- (2-furyl) -18,19,20-trinor-CBA compounds, 17- (3-thienyl) -18,19,20-trinor compounds or 16- (3-thienyl) oxy-17,18,19,20-tetranor compounds.

If at least one of the radicals R3 and R4 is not hydrogen (except for the 16-phenoxy or 16-phenyl compounds discussed above), the "16-methyl" (one and only one of the radicals R3 and R4 means methyl), " 16,16-dimethyl »(R3 and R4 both mean methyl),« 16-fluorine »(R3 or R4 means fluorine),« 16,16-difluoro »(R3 and Rj both mean fluorine) compounds. In those compounds in which R3 and R4 are different, the prostaglandin analogs thus illustrated contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: «(16S)» and «(16R)». Furthermore, the C-16 epimer mixture “(16RS)” is described in this invention.

If Xi has the meaning of -CH2OH, the compounds described in this way are referred to as “2-decarboxy-2-hydroxymethyl” compounds.

If X | has the meaning of -CH2NL2L3, the compounds described in this way are referred to as “2-decarboxy-2-aminomethyl” or “2- (substituted amino) methyl” compounds.

When Xi has the meaning of -COL4, the new compounds are referred to herein as CBA-like amides. Furthermore, when Xi has the meaning of -COORi, the new compounds are referred to herein as CBA-like esters and CBA-like salts.

Examples of phenyl esters which are substituted in the para position (eg X | means -COORi, Ri is a p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p- (p-acetamidobenzamido) phenyl ester, p- (p -Benzamidobenzamido) phenyl ester, p-amidocarbonyl-aminophenyl ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonylphenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p- (p-acetamidobenzoyloxy) phenylbenzate benzyl ester and p-hydroxyl ester.

Examples of new amides herein (e.g. Xi means -COL4) include the following:

(1) Amides within the range of the alkylamino groups of the formula NR51R52 are methyl amide, ethyl amide, n-propyl amide, n-butyl amide, n-pentyl amide, n-hexyl amide, n-heptyl amide, n-octyl amide, n-nonyl amide , n-decylamide, n-undecyl amide and n-dodecylamide and isomeric forms thereof. Further examples are dimethyl amide, diethyl amide, di-n-propyl amide, di-n-butyl amide, methyl ethyl amide, methyl propyl amide, methyl butyl amide, ethyl propyl amide, ethyl butyl amide and propyl butyl amide. Amides within the range of cycloalkylamino are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide, 2-methylcyclopentylamide, 3-tert-butylcyclopentylamide, cyclohexylamide, 4-tert-butylcyclohexylamide , 3-isopropylcyclohexylamide, 2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclodecylamide, N-methyl-N-cyclo-butylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclo-hexylamide, N -Ethyl-N-cyclopentyiamide and N-ethyl-N-cyclo-hexylamide. Amides within the range of aralkylamino are benzylamide, 2-phenylethylamide and N-methyl-N-benzylamide. Amides within the range of substituted phenylamides are p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4- Dimethoxyanilide, 3,4,5-trimethoxyanilide, p-hydroxymethylanilide, p-methylanilide, m-methylanilide, p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonylanilide, p-carboxyanilide and o-hydroxyanilide. Amides within the range of carboxyalkylamino are carboxyethylamide, carboxypropylamide and carboxymethylamide and carboxybutyl amide. Amides within the range of carbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide and carbamoylbutylamide. Amides within the range of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyanopropylamide and cyanobutylamide. Amides within the range of acetylalkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide and acetylbutylamide. Amides within the range of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, benzoylpropylamide and benzoylbutylamide. Amides within the range of substituted benzoylalkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide, 2,4-dichloro-benzoylmethylamide, 2,4,6-trichlorobenzoylmethylamide, m-Ni-trobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxy-benzox 2,4-dimethoxybenzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide, p-hydroxymethylbenzoyl-methylamide, p-methylbenzoylmethylamide, m-methylbenzoyl-methylamide, p-ethylbenzoylmethylamide, t-butylbenzoylme-thylamide, p-carboxyethylamidomoymoylmethyl-benzoylmethylamide o-carboxybenzoylmethylamide, o-hydro-xybenzoylmethylamide, p-chlorobenzoylethylamide, m-chloro-benzoylethylamide, 2,4-dichlorobenzoylethylamide, 2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide, p-nitrobenzoyl-ethylamide, p-methoxy p-methoxybenzoyl-

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• hylamide, 2,4-dimethoxybenzoylethylamide, 3,4-trimethoxy-oenzoyiethylamide, p-hydroxymethylbenzoylethylamide, p-methyl-ethylbenzoylethylamide, m-methylbenzoylethylamide, p-ethyl-. cnzoylethylamide, t-butylbenzoylethylamide, p-carboxyben-xoylethylamide, m-methoxycarbonylbenzoylethylamide, o-carb-oxybenzoylethylamide, o-hydroxybenzoylethylamide, p-chloro-L> enzoyIpropyIamid, m-chlorobenzoylpropylamide, 2,4-dichloro-en-2-dichloro-2-yl-dichloro-2-yl, dichloro-2-yl-dichloro-2-yl-2-yl-2-yl 4,6-trichlorobenzoylpropylamide, m-nitro-t.enzoylpropylamide, n-nitrobenzoylpropylamide, p-methoxy-benzoylpropylamide, 2,4-dimethoxybenzoyipropylamide, 3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, Methylbenzoylpropylamide, p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide, p-carboxybenzoylpropylamide, m-methoxycarbonyl-benzoylpropylamide, o-carboxybenzoylpropylamide, o-hydroxy-benzoylpropylamide, p-chlorobutylamide, p-chlorobenzylamide, p-chlorobenzylamide 2,4,6-trichlorobenzoylbutylamide, m-nitrobenzoylbutylamide, p-nitrobenzoyl-dutylamide, p-methoxybenzoylbutylamide, 2,4-dimethoxy-benzoylbutylamide, 3,4,5-trimethoxybenzoylbutylamide, p-hy-hydroxymylbenzoylbutylamide butylamide, m-methylbenzoylbutylamide, p-ethylbenzoylbutylamide, m-methylbenzoylbutylamide, p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide, p-carboxybenzoylbutylamide, m-methoxycarbo-nylbenamidoyloxybenzoylbutylamide, Amides within the range of pyridylamino are a-pyridylamide, 0-pyridylamide and y-pyridylamide. Amides within the range of substituted pyridylamino are 4-methyl-a-pyridylamide, 4-methyl-ß-pyridylamide, 4-chloro-a-pyridyiamide and 4-chloro-ß-pyridylamide. Amides within the range of pyridylalkylamino are a-pyridylmethylamide, 0-pyridylmethylamide, 7-pyridyl-methylamide, a-pyridylethylamide, / 3-pyridylethylamide, 7-pyridylethylamide, a-pyridylpropylamide, / S-pyridylpropylamide, 7-pyridylpropylamide -Pyridylbutylamide, ß-pyridylbutylamide and 7-pyridylbutylamide. Amides within the range of substituted pyridylalkylamide are 4-methyl-a-pyridylmethyl 1-amide, 4-methyl-ß-pyridylmethylamide, 4-chloro-a-pyridylmethylamide, 4-chloro- / 3-pyridylmethylamide, 4-methyl- a-pyridyI-propylamide, 4-methyl-0-pyridylpropylamide, 4-chloro-a-pyridyl-propylamide, 4-chloro-j3-pyridylpropylamide, 4-methyl-or-pyridyl-butylamide, 4-methyl-ß-pyridylbutylamide, 4-chloro-or-pyridyl-butylamide, 4-chloro-ß-pyridylbutylamide and 4-chloro-7-pyridyl-butylamide. Amides within the range of hydroxyalkylamino are hydroxymethylamide, β-hydroxyethylamide, β-hydroxypropylamide, 7-hydroxypropylamide, 1- (hydroxymethyl) ethylamide, 1- (hydroxymethyl) propylamide, (2-hydroxymethyl) propylamide and aa -Dimethyl-hydroxyethylamide. Amides within the range of dihydroxyalkylamino are di-hydroxymethylamide, / 3,7-dihydroxypropylamide, 1 - (hydroxymethyl) 2-hydroxymethylamide, / 3,7-dihydroxybutylamide, β, 5-dihydroxybutylamide, 7,0-dihydroxybutylamide and 1, 1-bis (hydroxymethyl) ethylamide amides within the range of tri-hydroxyalkylamino are tris (hydroxymethyl) methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide.

(2) Amides within the range of cycloamino groups described above are pyrrolidyl amide, piperidyl amide, morpholinyl amide, hexamethyleneiminyl amide, piperazinyl amide, pyrrolinyl amide and 3,4-didehydropiperidyl amide.

(3) Amides within the range of carbonylamino of the formula -NR53COR51 are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide and benzylcarbonylamide.

(4) Amides within the range of sulfonylamino of formula -NR53SO2R51 are methylsulfonylamide, ethylsulfonylamide, phenylsulfonylamide, p-tolylsulfonylamide and benzylsulfonylamide.

Examples of an alkyl group with one to 12 inclusive

Carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyi, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and isomeric forms thereof.

Examples of a (C3-C10) cycloalkyl group which comprises an alkyl-substituted cycloalkyl are cyclopropyl,

2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethyl-cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2- Dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butyl-cyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropyl-cyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

Examples of a (C7-Ci2) aralkyl group are benzyl, 2-phenylethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl,

3-phenylbutyl, 2- (l-naphthylethyl) and 1- (2-naphthylmethyl).

Examples of phenyl which is substituted by 1 to 3

Chlorine or alkyl with 1 to 4 carbon atoms are p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6- • trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p -tert.-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl.

Examples of (Cs-C7) cycloalkyl, optionally substituted by (C | -C4) alkyl, are cyclobutyl, 1-propylcyclobutyl,

1-butylcyclobutyl, 1-pentylcyclobutyl, 2-methylcyclobutyl,

2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl,

2.3.4-Triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, l-methyl-3-propylcyclopentyl, 2-methyl-3 propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl,

4-butylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, 2,6-dimethyl-4-propylcyclohexyl and cycloheptyl.

Examples of substituted phenoxy, phenylmethyl, phenylethyl or phenylpropyl of the R7 part are (o-, m- or p-) tolyl, (o-, m- or p-) ethylphenyl, 4-ethyl-o-tolyl, 5-ethyl --m-tolyl, (o-, m- or p-) propylphenyl, 2-propyl- (m- or p-) tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, ( 2,3,4-,

2.3.5-, 2,3,6- or 2,4,5-) trimethylphenyl, (o-, m- or p-) fluorophenyl, 2-fluoro- (m- or p-) tolyl, 4-fluoro- 2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4- or 3,5-) difluorophenyl, (o-, m- or p-) chlorophenyl, 2- Chloro-p-tolyl, (3-, 4-, 5- or 6-) chloro-o-tolvl, 4 - chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5- -xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyl, 4-chloro-3-fluorophenyl, (3 or 4- ) Chloro-2-fluorophenyl, (o-, m- or p-) trifluoromethylphenyl, (o-, m- or p-) methoxyphenyl, (o-, m- or p-) ethoxyphenyl, (4- or 5-) Chloro-2-methoxy-phenyl, 2,4-dichloro- (4- or 6-) methylphenyl, (o-, m- or p-) tolyloxy, (o-, m-pder p-) ethylphenyloxy, 4-ethyl -o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m- or p-) propylphenoxy, 2-propyl- (m- or p-) tolyloxy, 4-isopropyl-2,6- xylyloxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-) trimethylphenoxy, (o-, m- or p-) fluorophenoxy, 2-fluoro- (m- or p-) to-lyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4 - or 3,5-) difluorophenoxy, (o-, m- or p-) chlorophenoxy, 2-chloro-p-tolyloxy, (3, 4, 5 or 6-) chloro-o-tolyloxy, 4-chloro-2-propyl-phenoxy, 2-isopropyl -chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyloxy, 4-chloro -3-fluorophenoxy, (3- or 4-) chloro-2-fluorophenoxy, (o-, m- or p-) trifluoromethylphenoxy, (o-, m- or p-) methoxvphen-oxy, (o-, m- or p-) ethoxyphenoxy, (4- or 5-) chloro-2-meth-oxyphenoxy, 2,4-dichloro- (5- or 6-) methylphenoxy, (o-, m- or p-) tolylmethyl, (o - m- or p-) ethylphenylmethyl, 4 - ethyl-o-tolylmethyl, 5-ethyl-m-tolylmethyl, (om- or p-) propylphenylmethyl, 2-propyl- (m- or p-) tolylmethyl, 4- isopropyl-2,6-xylyimethyl, 3-propyl-4-ethylphenylmethyl, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-) trimethylphenylmethyl, ( om-or

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p-) Fluorophenylmethyl, 2-fluoro- (m- or p-) toiylmethyl, 4-fluoro-2,5-xylylmethyl, (2,4-, 2,5-, 2,6-, 3,4- or 3,5-) di-fluorophenyl, (o-, m- or p-) chlorophenylmethyl, 2-chloro-p-tolylmethyl, (3,4,5 or 6-) chloro-o-tolylmethyl, 4-chloro 2 - propylphenylmethyl, 2-isopropyl-4-chlorophenylmethyl, 4 - chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, '2,6-, 3,4- or 3,5-) di-chlorophenylmethyl, 4-chloro-3-fluorophenylmethyl, (3- or 4-) chloro-2-fluorophenylmethyl, (o-, m- or p-) trifluoromethyl-phenylmethyl, (o-, m - or p-) methoxyphenylmethyl, (o-, m- or p-) ethoxyphenylmethyl, (4- or 5-) chloro-2-methoxyphenylmethyl and 2,4-dichloro- (4- or 6-) methoxyphenylmethyl.

The new CBA analogs disclosed herein produce certain prostacyclin-like pharmacological effects.

Accordingly, the new CBA analogs of formulas X and XI are used as agents in the study, prevention, control and treatment of diseases and other undesirable physiological conditions in mammals, especially humans, "valuable farm animals, pets, animals in zoological gardens and in laboratories - Animals (eg mice, rats, rabbits and monkeys). In particular, these compounds find valuable use as anti-thrombic agents, anti-ulcer agents and anti-asthma agents, as indicated below.

(a) Inhibition of platelet aggregation

These new CBA analogs described herein are valuable, if desired, for preventing platelet aggregation, for reducing or removing the adherence of platelets, or for preventing thrombus formation in mammals, including humans. For example, these compounds are useful for the treatment and prevention of myocardial infarctions, for the treatment and prevention of post-operative thrombosis, for the promotion of the opening of vascular grafts in surgery, for the treatment of peripheral vascular diseases and for the treatment of conditions such as atherosclerosis, arteriosclerosis , Blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is related to lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemia attacks and long-term prophylaxis following myocardial infarction and stroke. For these purposes, these compounds are administered systemically, for example intravenously, subcutaneously, intramuscularly and in the form of sterile implants for an extended duration of action. For rapid effectiveness, especially in emergency situations, the intravenous route of administration is preferred. Doses ranging from about 0.01 to about 10 mg per kg of body weight per day are used, the exact dose depending on the age, weight and general condition of the patient or animal and on the frequency and route of administration.

The preferred dosage form for these compounds is the oral dosage form using other non-parenteral routes (e.g. buccal, rectal, sublingual) similarly, with the parenteral routes preferred. The oral dosage forms are formulated in a conventional manner (tablets, capsules, etc.) and are administered 2-4 times a day. Doses in the range of about 0.05 to 100 mg per kg of body weight per day are effective.

The addition of these compounds to whole blood gives the possibility of in vitro applications such as the storage of whole blood to be used in heart-lung machines. In addition, whole blood containing these compounds can be passed through organs, e.g. Heart and kidney, which have been removed by a donor, prior to the transplant. These compounds are also useful in the manufacture of platelet-rich concentrates for the treatment of thrombocytopenia, chemotherapy, and radiation therapy. A dose of 0.001 to 1.0 pg per ml of whole blood is required for in vitro applications. For the treatment of peripheral vascular diseases, see U.S. Patent No. 4,103026.

(b) Reduction of gastric secretion

These new CBA analogs disclosed herein are also useful in mammals, including humans and certain farm animals, such as dogs and pigs, to reduce and control gastric secretion, reducing or avoiding gastrointestinal ulceration, and healing of such ulcers which already exist in the gastrointestinal tract is accelerated. For this purpose these compounds are injected 'or administered by infusion intravenously, subcutaneously or intramuscularly. The dose for an infusion ranges from about 0.1 ng to about 20 fig per kg body weight per minute, or the total daily dose for injection or infusion is about 0.01 to about 10 mg per kg body weight per day, where the exact dosage depends on the age, weight and general condition of the patient or animal, and on the frequency and route of administration.

However, these new compounds are preferably administered orally or by other non-parenteral routes. For oral use, 1 to 6 times daily administration in a dose range of approximately 1.0 to 100 mg per kg body weight per day is used. Once the ulcers have healed, the continued dosage required to prevent relapse is adjusted down until the patient or animal remains asymptomatic.

(c) NOSAC-induced injury inhibition

These new CBA analogs disclosed herein are also useful in reducing the undesirable gastrointestinal effects caused by the systemic administration of anti-inflammatory prostaglandin synthetase inhibitors. For this purpose, the prostaglandin derivatives and the anti-inflammatory prostaglandin synthetase inhibitor are administered together. See Partridge, et al., U.S. Patent No. 3,781,429 for a description of the fact that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents is inhibited in rats by the simultaneous oral administration of certain Prostaglandins. Accordingly, these new CBA analogs are useful, for example, for reducing the undesirable gastrointestinal effects resulting from the systemic administration of indomethacin, phenylbutazone and aspirin. These are substances that Partridge et al. specifically mentioned as non-steroidal, anti-inflammatory agents. These compounds are also known to be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, e.g. Indomethacin, aspirin, or phenylbutazone is administered by any route known in the art to alleviate inflammatory conditions, for example according to any dosage regimen and any known route of systemic administration.

(d) Bronchial dilation (anti-asthma)

These new analogs disclosed herein are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as mediator-induced bronchoconstriction inhibitors, such as SRS-A and histamine, which are released by cells activated by an antigen-antibody complex

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that are. Accordingly, these compounds control spasms and facilitate breathing in conditions such as bronchial bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, for example orally in the form of tablets, capsules or liquids; rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly, intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or nebulizer solutions; or by blowing in the form of powders. Dosages in the range of about 0.01 to 5 mg per kg of body weight are used 1 to 4 times a day, the exact dosage depending on the age, weight and general condition of the patient and on the frequency and route of administration. For the use indicated above, these CBA analogs can advantageously be combined with other anti-asthmatic agents, such as sympathomimetic agents (isoproterenol, phenylephrine, ephedrine, etc.); Xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by oral inhalation with conventional nebulizers or by oxygen aerosol formation, it is advantageous to provide the immediate active ingredient in dilute solution, preferably in concentrations of about one part of the drug to about 100 to 200 parts by weight of the total solution. Ordinary conventional additives can be used to stabilize these solutions or to create an isotonic medium, for example sodium chloride, sodium citrate, citric acid, sodium bisulfide and the like can be used. The provision of a self-propelling dosage unit for the administration of the active ingredient in aerosol form suitable for inhalation therapy of the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoromethane) together with a co-solvent such as Include ethanol, fragrance materials and stabilizers. Suitable agents for using the aerosol inhalation therapy technique are fully described, for example, in US Pat. No. 3,868,691.

If Xj has the meaning of -COORi, the new CBA analogs thus described are used for the purposes described above in the form of the free acid, in the form of the esters or in the form of pharmacologically acceptable salts. When the ester form is used, the ester is any of those which meet the above definition of Ri. However, it is preferred

that the ester is an alkyl group having 1 to 12 carbon atoms inclusive. Of the alkyl esters, the methyl and ethyl esters are particularly preferred because of the optimal absorption of the compound by the body or by the experimental animal system; straight chains of octyl, nonyl, decyl, undecyl and dodecyl are especially preferred for the extended effectiveness.

Pharmacologically acceptable salts of the new prostaglandin analogues of this invention for the purposes described above are those with pharmacologically acceptable metal cations, ammonia, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are those derived from the alkali metals, e.g. Lithium, sodium and potassium, and those derived from the alkaline earth metals. are, e.g. Magnesium and calcium, as well as those cationic forms of other metals, e.g. Aluminum, zinc and iron, which also fall within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, tri-isopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, 0-phenylethylamine, 0-phenylethylamine, 0-phenylethylamine , Diethylenetriamine, adamantylamine and the similar aliphatic, cycloaliphatic, araliphatic amines, which contain up to and including about 18 carbon atoms, as well as the heterocyclic amines, for example piperidine, morpholine, pyrrolidine, piperazln and lower alkyl derivatives thereof, for example 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, as well as amines containing water-soluble or hydrophilic groups, e.g. Mono-, di- and tri-ethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-l-butanol, 2-amino-2-ethyl-l, 3-propane-diol, 2-amino-2-methyl- l-propanol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amyIphenyI) -di-ethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine , Procain, and the like. Other valuable amine salts of the basic amino acid salts are, for example, lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

If X) has the meaning of -CH2NL2L3, the new CBA analogs so described are used for the purposes described above either in the form of the free base or in the form of the pharmacologically acceptable acid addition salts.

The acid addition salts of the 2-descarboxy-2-aminomethyl or 2- (substituted aminomethyl) -CBA analogs provided by this invention are, for example, the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, Benzenesulfonates, toluenesulfonates and the like, made by the reaction of the CBA analog with the stoichiometric amount of the acid, corresponding to the pharmacologically acceptable acid addition salt.

To achieve the optimal combination of biological activity specificity, conductivity and duration of activity, certain compounds within the scope of this invention are preferred.

It is preferred that in the Xi-terminated side chain of the inter-p-phenylene CBA compounds g means zero, that in inter-m-phenylene CBA compounds g means zero or one (preferably zero), and that in inter-o-phenylene-CBA compounds g means zero, one or two (preferably one). Inter-o-and inter-m-phenylene-CBA compounds, preferably inter-m-phenylene-CBA compounds, are preferred. In addition, when Zi is -CH2- (CH2> C (R2) 2, f is preferably one and R2 is preferably hydrogen. When Rn is (Ci-C4) alkyl, Rn is preferably methyl. if the C-12 side chain contains the residue -CmH2m ^ H3, it is preferred that m is 3, 4 or 5, most preferred is 3. When m is 5, more straight chain isomer forms are preferred, especially methyl "Substituted butyl. Further, when R7 is aromatic, it is preferred that R7 is phenoxy, phenyl or benzyl, including substituted forms thereof. For those compounds where R7 is substituted phenoxy or phenylalkyl, it is preferred that." only one or two substituents are selected from the group consisting of chlorine, fluorine or trifluoromethyl, and it is preferred for those compounds wherein R7 is aromatic that R3 and R4 both represent hydrogen.

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Most preferred for biological performance are CBA2 analogs of Formula X, which have the same C-5 isomeric configuration as CBA2 itself.

Especially preferred are those compounds which satisfy two or more of the above advantages. Furthermore, the above advantages are expressly intended to describe the preferred compounds within the scope of any generic formula of the new CBA analogs disclosed herein.

The following formula schemes describe new preferred processes for making new intermediates and the end products of the present invention. With reference to these formula schemes, the symbols g, n, Li, Mi, R7, Rg, R15, Rie, Rn, R20, R21, R22, R23 and R24, Xi, Y1 and Z! the meaning given above.

Mô is a-ORio: 18-R5 or a-Rs: 0-ORio, wherein R5 is hydrogen or methyl and Rio represents an acid hydrolyzable protecting group;

Ria means hydrogen, hydroxy, hydroxymethyl, -OR10 or -CH2OR10, where Rio means an acid hydrolyzable protecting group;

Ri6 and R47 taken together form a second valence bond between C-6a and C-9 or mean -CH2-;

R27 has the same meaning as R7, except that - (CH2) 2-CH (OH) -CH3 is replaced by - (CH2) -CH (ORi0) - CHj;

R32 represents hydrogen or R31, where R31 represents a hydroxyl hydrogen-replacing group;

R33 represents -CHO or -CH2OR32, wherein R32 has been defined above;

R47 has been defined or means above

(1) (C, -C4) alkyl or

(2) -CH2OH;

Z4 is -CH2- or - (CH2) f-CF2, where f is defined above.

R37 is the same as R47, but different from -CH2OH.

R38 means -OR3i, hydrogen or -CH2OR3i, where R3i is defined above.

R27 is the same as R7, except that the residue - (CH2) 2 - CH (OH) -CH3 has the meaning of - (CH2) 2-CH (ORi0) -CH3.

R37 is the same as Rn, but different from hydrogen.

Ac means acetyl.

Z2 is the same as Zi, but does not mean - (Ph) - (CH2) g-.

Z3 is the same as Zi, but does not mean trans-CH2-CH = CH-.

The protecting groups within the Rio area are any groups that replace a hydroxy hydrogen and are neither attacked nor reactive with the reagents used herein for transformations on a hydroxy group. The protective groups are then replaced by means of acidic hydrolysis with hydrogen in the preparation of the prostaglandin-like compounds. Various such protecting groups are known in the art, e.g. Tetrahydropyranyl and substituted tetrahydropyranyl. See, for example, E.J., Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XII Organic Synthesis, pages 51-79 (1969). These protecting groups, which have been found useful, include:

(a) tetrahydropyranyl;

(b) tetrahydrofuranyl;

(c) a group of the formula -C (ORn) (Ri2) -CH (Ri3) (Ri4), in which Rn has the meaning of alkyl from one to 18 carbon atoms inclusive, cycloalkyl from 3 to 10 carbon atoms inclusive, aralkyl from 7 to including 12 carbon atoms, phenyl or substituted phenyl with one to three alkyl radicals with one to four carbon atoms.

R12 and R] 3 have the meaning of alkyl from one to four carbon atoms, phenyl, substituted phenyl with one, two or three alkyl radicals with one to four carbon atoms, or, when R12 and R) 3 are taken together, to - (CHj) a - or when R12 and Ri3 have been taken together to - (CH2) b-0- (CH2) c, in which a is 3, 4 or 5 and b is 1, 2 or 3, and c is 1, 2 or 3, with the proviso that b plus c is 2, 3 or 4, with the further proviso that R12 and R) 3 can be the same or different, and

R14 has the meaning of hydrogen or phenyl; and

(d) Silyl groups corresponding to the radical R2g, as will be described hereinafter.

When the protecting group Rio is tetrahydropyranyl, the tetrahydropyranyl ether derivative is obtained from any hydroxy portion of the CBA-like intermediates by reaction of the hydroxy containing compound with 2,3-dihydropyran in an inert solvent, e.g. Dichloromethane, in the presence of an acidic condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran is used in a large stoichiometric excess, preferably in a 4 to 100 times stoichiometric amount. The reaction is usually complete in less than an hour at a temperature of 20-50 ° C.

When the protecting group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as described in the section above, instead of 2,3-dihydropyran.

When the protecting group is a radical of the formula -C (ORu) - (Ri2) -CH (Ri3) (R | 4), in which Rn, Ri2, Ri3 and R | 4 are defined above, a vinyl ether or an unsaturated cyclic or heterocyclic compound used, e.g. 1-cyclohexen-l-yl methyl ether or 5,6-dihydro-4-methoxy - 2H-pyran. See, for example, C.B. Reese, et al., J. American Chemical Society 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for the above dihydropyran.

R28 has the meaning of a silyl protective group of the formula -Si (Gi) 3. In some cases, such silylations are generalized by silylating all of the hydroxyl groups in a molecule, while in other cases they are selective by silylating one or more hydroxyl groups and leaving at least one other hydroxyl group untouched. For any of these silylations, the silyl groups include within the range of -Si (Gi) 3: trimethylsilyl, dimethylphenylsilyl, triphenylsilyl, t-butyldimethylsilyl or methylphenylbenzylsilyl. With respect to the rest Gi are examples of alkyl, methyl, ethyl, propyl, isobuty, butyl, sec-butyl, tert-butyl, pentyl and the like. Examples of aralkyl are benzyl, phenethyl, a-phenylethyl, 3-phenylpropyl, a-naphthylmethyl and 2- (a-naphthyl) ethyl. Examples of phenyl which is substituted with halogen or alkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl and 2,4 -Dichlor-3-methylphenyl.

These silyl groups are known in the art.

See, for example, Pierce "Silylation of Organic Compounds", Pierce Chemical Company, Rockford, III. (1968). If the silylated products in the following sections are intended to be chromatographically purified, then the use of silyl groups known to be unstable in chromatography (e.g. trimethylsilyl) should be avoided. Furthermore, when silyl groups are to be introduced selectively, silylating agents are used which are readily available and are known to be used in selective silylation. For example, t-butyldimethylsilyl group is used when selective introduction is required. Furthermore, when selectively hydrolyzing silyl groups

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if in the presence of protecting groups corresponding to the rest of Rio or acyl protecting groups, silyl groups are used which are readily available and which are known

that they are easily hydrolyzable with tetra-n-butylammonium fluoride. A particularly useful silyl group for this purpose is t-butyldimethylsilyl because other silyl groups (e.g. trimethylsilyl) are not used when selective introduction and / or hydrolysis is required.

The protecting groups, as defined by the rest of Rio, on the other hand, are removed by mild, acidic hydrolysis. For example, by reaction with (1) hydrochloric acid in methanol; (2) a mixture of acetic acid, water and tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran at temperatures below 55 ° C, the hydrolysis of the protective group is achieved.

R31 is a hydroxy hydrogen protecting group as indicated above. As such, the radical R31 can be an acyl protecting group corresponding to R9, an acid hydrolyzable protecting group corresponding to Rio, a silyl protecting group corresponding to R28, or an arylmethyl-hydroxy-hydrogen replacing group corresponding to R34.

Acyl protecting groups corresponding to R9 include:

(a) benzoyl;

(b) Benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms inclusive, or phenylalkyl of 7 to 12 carbon atoms inclusive, or nitro, with the proviso that no more than two substituents have a meaning other than alkyl, and that the Total number of carbon atoms in the substituents does not exceed 10 carbon atoms, with the further proviso that the substituents are the same or different;

(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms inclusive;

(d) naphthoyl;

(e) Naphthoyl substituted with one to 9 inclusive alkyl radicals containing one to 4 carbon atoms inclusive, phenylalkyl containing 7 to 10 carbon atoms inclusive, or nitro, with the proviso that no more than two substituents on one of the two connected aromatic rings are different from Alkyl, and that the total number of carbon atoms in the substituents on one of the two linked rings does not exceed 10 carbon atoms, with the further proviso that the different substituents are the same or different; or

(f) alkanoyl of 2 to 12 carbon atoms inclusive.

Processes which are generally known in the prior art are used in the preparation of these acyl derivatives from a hydroxy-containing compound. For example, an aromatic acid of formula R9OH, wherein R9 is defined above (e.g. benzoic acid) with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-toluenesulfonyl chloride or di-cyclohexylcarbodiimide, reacted; or alternatively an aromatic acid anhydride of formula (R «) OH, e.g. Benzoic anhydride used.

However, preferably the method described in section 1 above is carried out using the appropriate acyl halide, e.g. RçHal, in which shark has the meaning of chlorine, bromine or iodine. For example, benzoyl chloride is reacted with the hydroxyl-containing compound in the presence of a hydrogen chloride binder, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is carried out under a variety of conditions using methods well known in the art. Mild conditions are generally used: a temperature of 0-60 ° C when contacting the reactants in a liquid medium (e.g. in an excess of pyridine or in an inert solvent such as benzene, toluene or chloroform). The acylating agent is used either in the stoichiometric amount or in a substantial stoichiometric excess.

As examples of the radical R9 the following compounds 5 are available as acids (R9OH), (Rq ^ O or acylchloride (R9CI): benzoyl, substituted benzoyl, for example (2-, 3- or 4-) methyl-benzoyl, (2- , 3- or 4-) ethylbenzoyl, (2-, 3- or 4-) isopropyl-benzoyl, (2-, 3- or 4-) tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5- Dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethyl-10 benzoyl, pentamethylbenzoyl, phenyl (2-, 3- or 4-) toluyl, (2-, 3- or 4-) phenethylbenzoyl, (2-, 3- or 4-) nitrobenzoyl, (2,4-, 2,5- or 2,3-) dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6- phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl, 15 3-nitrol-2-phenethylbenzoyl; monoesterified phthaloyl, isophthaloyl or terephthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, e.g. (2- , 3-, 4-, 5-, 6- or 7-) methyl-l-naphthoyl, (2- or 4-) ethyl-l-naphthoyl, 2-isopropyl-l-naphthoyl, 4,5-dimethyl -l-naphthoyl, 6-isopropyl-4-methyl-20 -1-naphthoyl, 8-ben zyl-l-naphthoyl, (3-, 4-, 5 or 8-) nitro-l-naphthoyl, 4,5-dinitro-l-naphthoyl, (3-, 4-, 6-, 7 or 8 -) Methyl-1-naphthoyl, 4-ethyl-2-naphthoyl and (5- or 8-) nitro-2-naphthoyl and acetyl.

Benzoyl chloride, 4-nitro-benzoyl chloride, 25 3,5-dinitrobenzoyl chloride or the like can be used for this, e.g. R9CI compounds, corresponding to the above R9 groups. If the acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride, as is known in the art. It is preferred that the 30 R9OH, (R9) 20 or R9CI reactant not have large hindering substituents, e.g. tert-Butyl on both of the ring carbon atoms, which are adjacent to the carbonyl-bonded side.

The acyl protective groups, corresponding to the radical R9, are removed by deacylation. Alkali metal carbonate or hydroxide are effectively used at ambient temperature for this purpose. For example, potassium carbonate or hydroxide is advantageously used in aqueous methanol at a temperature of about 25 ° C.

40 R34 is defined as any arylmethyl group that replaces the hydroxyhydrogen in the intermediates in the manufacture of the various CBA analogs, which group is subsequently replaceable by hydrogen in the methods used to prepare them herein, and relate to the prostacyclin analogs, and wherein this group is stable with respect to the various reactions to which the R34-containing compounds are exposed and this residue is introduced and then removed by hydrogenolysis under conditions which give essentially 50 quantitative yields of desired products.

Examples of arylmethyl hydroxy-hydrogen replacing groups are

(a) benzyl;

(b) benzyl substituted by one to 5 alkyl of one to 55 including 4 carbon atoms, chlorine, bromine, iodine, fluorine,

Nitro, phenylalkyl having 7 to 12 carbon atoms inclusive, with the further proviso that the different substituents are the same or different;

(c) benzhydryl;

60 (d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms, chlorine, bromine, iodine, fluorine, nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the different substituents are the same or different on each of the aroma table rings;

(e) trityl;

(f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms, chlorine, bromine, iodine, fluorine,

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Nitro, phenylalkyl of 7 to 12 carbon atoms inclusive, with the further proviso that the different substituents are the same or different in each of the aromatic rings.

Such ether linkages to the hydroxy-containing compounds herein, especially the benzyl or substituted benzyl ether, are introduced by methods known in the art, e.g. by the reaction of the hydroxy containing compound with the benzyl or substituted benzyl halide (chlorine, bromine or iodine), according to the desired ether. This reaction takes place in the presence of a suitable condensing agent (e.g. silver oxide). The mixture is stirred and heated to a temperature of 50-80 ° C. Response times of 4 to 20 hours are usually sufficient.

With reference to Formula Scheme A, a method is provided wherein the known bicyclic lactone of Formula XXI is converted to the carbacyclin intermediate of Formula XXV, which is useful in the preparation of the CBA compounds of Formula X, wherein Rn is alkyl or Ri6 and Rn taken together mean methano or a second valence bond between C-6a and C-9. With reference to Formula Scheme A, the compound of Formula XXI is converted to the compound of Formula XXII by treatment with the anion of dimethyl methylphosphonate. Methods for such a reaction are known in the art. Compare e.g. Dauben, W.G., et al., JACS, 97: 4973 (1975), which describes a reaction of this type.

The lactol of formula XXII is converted to the diketone of formula XXIII by means of oxidation processes which are known in the prior art. For example, the Collins reagent or the Jones reagent is used in this oxidative conversion.

The diketone of formula XXIII is cyclized into the compound of formula XXIV by means of an intramolecular Horner-Emmons reaction. The chemical methodology for analog conversions is known in the art. Compare e.g. Piers, E., et al., Tetrahedron Letters, 3279 (1979) and Clark, R.D., et al., Synthetic Communications 5: 1 (1975).

The compound of formula XXIV is converted into the new compound of formula XXV, in which Ri6 is hydrogen and R37 is alkyl, by treatment with lithium dialkyl cuprate. The lithium dialkyl cuprate is made by conventional means, e.g. by reaction of anhydrous copper iodide in diethyl ether with an alkyl lithium in diethyl ether, and is then reacted with the compounds of the formula XXIV, for example in diethyl ether.

The compound of formula XXIV is converted to the new compound of formula XXV, wherein RI6 and R37 taken together mean methylene (-CH2-) by either of the following two methods. In the first method, the compound of formula XXV is prepared by treating the compound of formula XXIV with the anion of trimethyl oxosulfonium iodide. See, for example, E.J. Corey, et al., JACS 87: 1353 (1965). In this process, the anion is conveniently prepared by treating trimethyloxosulfonium iodide with sodium hydride.

In the second process, the compound of the formula XXIV is converted into the compound of the formula XXV, in which Ri6 and R37 taken together mean methylene, the compound of the formula XXIV first being converted into the corresponding hydroxymethyl compound of the formula XXVI by means of photochemical addition of methanoi (see eg GL Bundy, Tetr. Lett. 1957, 1975), after which the resulting hydroxymethyl compound is treated with an excess (for example two equivalents) of p-toluenesulfonyl chloride in a tertiary amine base in order to do this accordingly! To give tosylate of formula XXVII, and finally the resulting tosylate of formula XXVII is treated with a base (e.g. potassium t-butoxide) to give the cyclopropyl compound of formula XXV.

With respect to Formula Scheme B, a method is provided wherein a compound of Formula XXXI, prepared in accordance with the procedures of Formula Scheme A, is converted to the new CBA2 analogs of Formula XXXVI.

The compound of formula XXXI is converted to a compound of formula XXXVI using methods known in the art to produce carbacyclin. See e.g. the British published descriptions mentioned above. Alternatively, the compound of formula XXXI is reacted with a compound of formula XXXII, which are successively converted into the compounds of formulas XXXIII, XXXIV and XXXV.

The reaction of the compound of formula XXXI using the compound of formula XXXII is achieved by means of: methods known in the art. See, for example, Moersch, G.W., J. Organic Chemistry, 36: 1149 (1971) and Mulzer, J., et al., Tetrahedron Letters, 2949 (1978). The reactants of formula XXXII are known in the art or can be prepared using methods which are known in the art. See Example 4, which describes such a process for the preparation of a compound of formula XXXII.

The compound of formula XXXIII is then converted into the compound of formula XXXIV by means of decarboxylative dehydration. Methods for this reaction are known in the art. See, for example, Eschenmoser, A., et al., Helv. Chim. Acta. 58: 1450 (1975), Hara, S., et al., Tetrahedron Letters, 1545 (1975) and Mulzer, J., et al., Tetrahedron Letters, 2953 (1978) and 1909 (1979).

Finally, the compound of formula XXXV is prepared from the compound of formula XXXIV by means of selective desilylation. Such processes are known in the prior art and typically use tetra-n-butylammonium fluoride and tetrahydrofuran. See, for example, Corey, E.J., et al., JACS 94: 6190 (1972).

The compound of formula XXXV is converted to various acids, esters, amides and amines of formula XXXVI using methods that are known in the art. From this point of view, the methods which are contained in the British published descriptions mentioned above and which describe the preparation of carbacyclin analogs are particularly useful.

The compounds of the formula XXXVI are prepared from the compounds of the formula XXXV, for example, by oxidation to the corresponding carboxylic acid, followed by the hydrolysis of any protective groups at the C-11 or C-15 position of the molecule. Such carboxylic acids are then esterified using conventional means or they are amidized using conventional means. Such amides can then be reduced, for example, to the corresponding amines (X, means -CH2NL2L3) by means of reduction with lithium aluminum hydride. Compare the US PS. 4,073,808. When the primary alcohols corresponding to the formula XXXVI are prepared from the compound of the formula XXXV, such products are obtained directly by hydrolysis of any protective groups on the C-II or C-15. The hydrolysis is accomplished using the methods described above, e.g. mild, acidic conditions at elevated temperatures.

In Formula Scheme C, a process is presented in which the known compounds of the formula XLI are converted into the aldehydes of the formula XLIV, which in Formula-

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Scheme D can be used to make inter-phenylene-CBA2 compounds.

With reference to formula scheme C, the compound of formula XLII is prepared from the compounds of formula XLI by reduction. Conventional processes which are known in the prior art for converting the carboxylic acids into the corresponding primary alcohols are used. One of the extremely useful, conventional ways of doing this reduction is to use lithium aluminum hydride as a reducing agent, for example.

The compound of the formula XLIII is then prepared from the compound of the formula XLII by means of monosilylation. Specifically, compounds of formula XLIII are prepared wherein R28 represents a relatively stable silyl group, most preferably it means t-butyldimethylsilyl or phenyldimethylsilyl. Other silyl groups, especially trimethyl silyl (TMS), are not preferred for use in connection with the procedures outlined in Formula Scheme C.

The monosilylated derivatives of the formula XLIII are prepared from the compound of the formula XLII by reacting the compounds of the formula XLII with about an equal molar amount of the silylating agent. For example, when R28 is t-butyldimethylsilyl, a single equivalent of t-butyldimethylsilyl chloride is used for the conversion. Both monosilylated derivatives of the compound of the formula XLII are prepared accordingly, as are the bis-silylated derivatives of the compound of the formula XLII. The compound of formula XLIII is obtained from this product mixture by conventional methods, e.g. by means of column chromatography. Otherwise, the silylation takes place under conditions which are conventionally used for the silylation of hydroxyl groups. Compare also the discussion above.

The compound of the formula XLIV is then prepared from the compound of the formula XLIII by oxidation of the alcohol of the formula XLIII in the corresponding aldehyde. Conventional oxidizing agents are used, e.g. Manganese dioxide.

Formula Scheme D presents a process in which the known ketones of formula LI are converted to the inter-phenylene CBA2 analogs of formula LX, which are disclosed herein.

In accordance with Formula Scheme D, the compound of Formula LII is prepared from the compound of Formula LI by reducing the ketone of Formula LI to the corresponding secondary alcohol. This reduction takes place by means of conventional means using easily available reducing agents. Accordingly, sodium, potassium or lithium borohydride is usually used in this reduction.

The alcohol of the formula LII is then converted into the corresponding mesylate (methanesulfonate). Conventional methods are used to convert the alcohols to the corresponding mesylates. For example, the alcohol of formula LH is reacted with methanesulfonyl chloride in the presence of a tertiary amine (e.g. tri-ethylamine) in the preparation of the compound of formula LIII.

Other sulfonyl derivatives corresponding to the alcohol of formula LII can be used in place of the compound of formula LIII when converted to formula D. These other sulfonyl derivatives are preferably those derived from readily available sulfonylating agents, e.g. the corresponding sulfonyl chlorides. A particularly important alternative compound of formula LIII is tosylate (toluenesulfonate) corresponding to the compound of formula LII.

The compound of formula LIII or another corresponding sulfonate is converted into the compound of formula LIV by treatment with sodium, lithium or

Potassium thiophene oxide. The thiophene oxide is usually prepared just prior to conversion by mixing approximately equal molar amounts of thiophenol and base, e.g. Potassium t-butoxide.

This compound of the formula LIV is then oxidized into the corresponding compound of the formula LV by means of oxidation with an easily available oxidizing agent, such as, for example, m-chlorpenbenzoic acid.

The compound of formula LV is then condensed with the compound of formula XLIV, which has been prepared according to formula C, by first treating the compound of formula LV with a strong base, e.g. n-butyllithium to produce the corresponding anion of the compound of formula LV followed by treatment of the corresponding anion with the aldehyde of formula XLIV and finally treatment of the resulting adduct with acetic anhydride to give the acetyl compound of formula LVI surrender.

The compound of the formula LVI is then converted into the compound of the formula LVII by the reaction with a sodium amalgam. Methods with which the olefin of the formula LVII is formed from the compound of the formula LV are analogous to known methods which are described by Kocienski, PJ, et al., "Scope and Stereochemistry of an Olefin Synthesis from β-Hydroxysulphones", JCS Perkin I, 829-834 (1978).

The compound of the formula LVII is then converted into the compound of the formula LVIII by means of selective hydrolysis of the silyl group, corresponding to the radical R28. Conventional means for this hydrolysis are used, e.g. Tetra-n-butylammonium fluoride. See also the discussion above for a description of this hydrolysis.

The C-5 diastereomers of formula LVIII thus prepared are suitably purified into the (5-E) and (5-Z) isomeric forms. This conversion is done by conventional means, e.g. Column chromatography.

Then one of the (5E) or (5Z) isomers of the formula LVIII is converted into the carboxylic acid or into the ester of the formula LIX by means of conventional oxidation, optionally followed by esterification. A particularly suitable means for the oxidation is to use the Jones reagent, with other oxidizing agents also being used. The esterification is then carried out using methods which are described below.

Finally, the products of formula LX are made from the compound of formula LIX by first hydrolyzing the protecting groups under acidic conditions, e.g. Mixtures of water, tetrahydrofuran and acetic acid. The acids and esters of the formula LIX are then converted into various other C-1 derivatives by means of processes which are described below.

A particularly suitable means of producing the compound of the formula LX as a free carboxylic acid (Xi means -COOH) consists in cleaning the corresponding methyl ester, followed by saponification under basic conditions (for example treatment with potassium carbonate or sodium or potassium Hydroxide).

Formula Scheme E presents a process in which the known compound of formula LXI is converted to an intermediate of formula LXIII which is useful in the preparation of the new CBA2 analogs.

The procedures for the conversion of the compound of formula LXI into the compound of formula LXIII are analogous to those which describe in formula schemes A, B and D the conversion of the compound of formula XXI into the compounds of formula XXXVI and LX (e.g. corresponding to the conversion the compound of the formula LXI in Verbin5

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Formation of formula LXII in formula scheme A is the conversion of the compound of formula XXI into the compound of formula XXV and corresponding to the conversion of the compound of formula LXII into the compound of formula LXIII in formula scheme D is the conversion of formula LI into the compound of formula LX). For the sake of simplicity, the protective groups R31 and R38 can be the same or different, preferably such protective groups being different, the hydrolysis of a protective group corresponding to the radical R31 taking place in the presence of a protective group corresponding to the radical R38.

Finally, in Formula Scheme F, a process is provided in which the compound of Formula LXXI, prepared according to Formula Scheme E, is converted into the carbacyclin analogs of Formula LXXII, in accordance with the present invention. With reference to formula scheme F, the compound of the formula LXXI is converted into the compound of the formula LXXII by means of selective hydrolysis of the protective group corresponding to the radical R31. The compound of the formula LXXII is then converted into the compound of the formula LXXIII by means of processes which are known in the art, e.g. by oxidation of the primary alcohol of formula LXXII in the corresponding aldehyde, followed by Wittig oxylacylation of the aldehyde and reduction of the resulting ketone in the secondary or tertiary alcohol, corresponding to the remainder M |. For an example of the various conversions used according to formula scheme F, see, for example, formula scheme A (part VI) of US Pat. No. 4,107,427, issued August 15, 1978.

In formula scheme G, a method is provided, whereby the new intermediate of formula LXXXI, produced in accordance with formula scheme A, into the corresponding isomers of formulas LXXXVIII and LXXXIX of the new C-6a and / or C-9 substituted CBA2 analogues is transferred.

With reference to Formula Scheme G, the compound of Formula LXXXIII is prepared from the ketone of Formula LXXXI using Wittig a carboxyalkylation using a triphenylphosphonium compound of Formula LXXXII. The Wittig reaction is carried out under conventional reaction conditions for the production of prostaglandin-like substances. The compound of the formula LXXXIII is then optionally hydrolyzed to give the carboxylic acid products of the formula X, or it is used in the further conversions according to formula scheme G in the ester form.

The compound of formula LXXXIII thus prepared is then preferably separated directly into the C-5 isomers of formulas LXXXVIII and LXXXIX (e.g. by chromatographic means followed by the hydrolysis of any protecting groups at the C-II or C-15 position in the molecule)

or alternatively the compound is converted to the ester of formula LXXXIV using conventional esterification techniques, e.g. Treatment with ethereal diazomethane or by treatment with methyl iodide. The ester of formula LXXXIV is then reduced to the corresponding primary alcohol by reduction with a suitable reducing agent, e.g. Lithium aluminum hydride, by means of methods which are known in the prior art for the production of prostaglandin-like primary alcohols from the corresponding prostaglandin esters.

The compound of the formula LXXXV represents a particularly suitable intermediate for the simple separation of the C-5 diastereomers. Accordingly, the compound of formula LXXXV can be separated using conventional means for the separation of diastereomeric mixtures, e.g. Column chromatography, whereby compounds of the formulas LXXXVI and LXXXVII are obtained in isomeric, pure form. These primary alcohols are then converted in a suitable manner into the products of the formulas LXXXVIII and LXXXIX using processes which are described above. For the conversions of the compound of the formula XXXV into the compound of the formula XXXVI, reference is made to formula scheme B.

Formula Scheme H provides a process in which the 5-fluoro-CBA2 compounds of the formula XCVII are prepared from the CBA2 intermediates of the formula XCIII known in the art. See, for example, British Published Patent Application 2,014,143, specifically the discussion regarding step (b) of Formula Scheme A. This sulfoxamine of Formula XCI is converted to the fluorinated sulfoxamine of Formula XCII by first preparing an anion of the compound of Formula XCII, e.g. by treatment with n-butyllithium in hexane, after which the resulting anion is then treated with a fluorine source. Perchloryl fluoride (FC103) is particularly preferred as a fluorine source.

The compound of the formula XCII thus prepared and the known compound of the formula XCIII described above are subsequently used in the preparation of the compound of the formula XCIV by means of known processes. Reference is again made to step (b) in formula A of British published patent application 2,014,143.

The compound of formula XCIV thus prepared is then converted to the primary alcohol of formula XCV by hydrolysis under mild, acidic conditions (e.g. mixtures of acetic acid, water and tetrahydrofuran) as is known in the art. The primary alcohol of formula XCV is then oxidized to the corresponding carboxylic acid of formula XCVI using conventional means. For example, treatment with oxygen and an aqueous suspension of platinum oxide at ambient temperature and under pressure gives the carboxylic acid of the formula LXXVI. The compound of the formula XCVI is then converted into various products of the formula XCVII by derivatization or conversion of the carboxyl group of the compound of the formula XCVI.

The isomeric compounds of formula XCIV to formula XCVII are suitably separated at any step in the process according to formula H, but most suitable and preferred is the separation of the diastereomeric mixture of formula XCIV. Conventional means, e.g. Column chromatography are used in this separation.

An optional process is presented in formula scheme I, wherein the known compound of the formula CI is converted into the products of the formula CHI. With reference to Formula Scheme I, the compound of Formula XCII is prepared from the compound of Formula XCI by the method described in Formula Scheme H for the preparation of the compound of Formula XCVII from the compound of Formula XCIII. This CBA2 intermediate of formula CII is then converted to the compound of formula CIII using the procedures described in Formula Scheme F for the conversion of the compound of formula LXXI to the compound of formula LXXIII.

Formula Scheme J provides the preferred methods for the preparation of the CBA analogs of Formula X, wherein Zt has the meaning of trans-CH2-CH = CH-. Regarding formula scheme J, R | has a meaning other than hydrogen or a cation and is preferably a lower alkyl. The compound of formula CXIV is prepared from the compound of formula CXI by first preparing the a-phenylselenyl derivative thereof, followed by dehydrophenyl selenation to produce the a, | 3-unsaturated ester of formula CXIII. This ester is then released into the free

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Acid (Xj means -COOH) of the formula CXIV converted by means of saponification and this free acid is converted into various other compounds of the formula CXIV, as indicated in formula scheme H (see the conversion of the compound of the formula XCVI into the compound of the formula XCVII) .

Formula scheme K shows the preferred process, whereby the CBA intermediates of formula VI are prepared, wherein Zi has the meaning of trans-CH2-CH = CH-. With reference to Formula Scheme K, the compound of Formula CXXI is converted to the compound of Formula CXXIII using procedures analogous to those described in Formula Scheme J for the preparation of the compound of Formula CXIV from the compound of Formula CXI.

For a detailed description of the methodology used in Formula Schemes J-K, reference is made to the discussion in British Patent 2,014,143 and the references contained therein.

The formula schemes L-O provide methods • using CBA2 intermediates and analogs for the synthesis of the corresponding CBA intermediates and analogs.

Formula Scheme L provides the preferred process for the preparation of the CBA | intermediates of Formula VII, wherein Zi has the meaning of trans-CH 2-CH = CH- With reference to Formula Scheme L, the compound of formula CXXXI, which has been prepared like the compound of the formula CXXII in formula scheme K, reduced to the compound of the formula CXXXII using conventional methods. For a discussion of such processes and general methodologies for the conversion of CBAj intermediates and analogs into the corresponding CBAi intermediates and analogs, reference is made to British published patent application 2,017,699. For example, catalytic hydrogenation with conventional catalysts under atmospheric pressure is used.

Thereafter, this compound of the formula CXXXII is successively converted into the α, (3-unsaturated ester of the formula CXXXIII and into the CBA 1 intermediate of the formula CXXXIV by the methods described in formula schemes JK (e.g. how to convert the compound of the formula CXII into the corresponding compounds of formula XCIV and how the conversion of the compound of formula CXXII into the compound of formula CXXIII).

Otherwise, the CBAj intermediates of Formula VII are prepared in accordance with the procedure of Formula Scheme M, reducing the compound of Formula CXLI, prepared as described above, to the intermediates of Formula CXLII using techniques described in Formula Scheme L and in the references cited therein are described.

Formula scheme N describes the preparation of various CBAi analogs from the compounds of the formula CLI, which have been prepared in the formula schemes L and M. The methods used in Formula Scheme N are those described in Formula Scheme F above.

Finally, Formula Scheme O provides an alternative process for the preparation of the CBAi analogs of Formula CLXII directly from the CBA; Analogs of the formula CLXI are available. This conversion into formula scheme O takes place through the direct reduction of the compound of formula CLXI by means of methods which are described in formula scheme M and in the references cited therein. Formula scheme O represents a particularly suitable process for the preparation of CBAi analogs, in which Yi has the meaning of -CH2CH2-.

The CBA analogs of formula XI are prepared according to the procedures described in the formula schemes P-U. With reference to Formula Scheme P, the compound is the

Formula CLXXI is known in the art or can be prepared using methods known in the art. Compare, for example, US Pat. No. 4,181,789! This compound is suitably converted into the corresponding methylene compound of the formula CLXIII and into the hydroxymethyl compound of the formula CLXXIII by methods known in the art. Such methods are specifically and exquisitely described in U.S. Patents 4,012,467 and 4,060,534.

The compound of the formula CLXXIII thus prepared is then converted into the mesylate of the formula CLXXIV using methods which are known in the art, e.g. by reaction with methanesulfonyl chloride in a tertiary amine base. Alternatively, other sulfonated derivatives are prepared in accordance with the compound of formula CLXXIV, such as those described in connection with the compound of formula LIII in Formula Scheme D.

The mesylate (or other sulfonates) of the formula CLXXIV is then selectively hydrolyzed to give the phenol derivatives of the formula CLXXV. Selective hydrolysis of the R28 silyl ether groups in the presence of protected Ris or M6 hydroxyl groups is accomplished using methods described above, e.g. by using tetra-n-butylammonium fluoride by means of methods which are known in the prior art and are described above. The phenol derivative of the formula CLXXV is then cyclized to give the compounds of the formula CLXXVI. Cyclization is most conveniently carried out by treating the compound of formula XVI with base at elevated temperatures. For example, n-butyl lithium, sodium hydride or potassium hydride are suitably used at reflux temperatures in an organic solvent such as tetrahydrofuran or glyme.

The cyclized compound of the formula CLXXVI is then converted into the compound of the formula CLXXVII by o-carboxyalkylation. Methods are used which are known in the prior art, e.g. Process for the preparation of 3,7-inter-phenylene-PGF "compounds and corresponding phenolic intermediates. For example, the compound of the formula CLXXVII is prepared by the reaction of the compound of the formula CLXXVI with sodium hydride and the alkyl bromoalkanoate, corresponding to the group -Z4-COOR1 to be introduced into the molecule. The compound of the formula CLXXVIII is then prepared by removing the protective groups, e.g. by hydrolysis under mild, acidic conditions for the protecting groups, followed by conversion to various other C-1 derivatives by methods which are described below.

Formula Scheme Q provides a method of producing other CBA analogs of Formula XI in accordance with the present invention. In particular, compounds of the formula XI are prepared in which at least one of the radicals R2o, R21, R23 or R24 is not hydrogen. In accordance with Formula Scheme Q, the compound of Formula CLXXXI, see the discussion above regarding Formula Scheme P, is oxidized into the corresponding aldehyde of Formula CLXXXII using methods known in the art. For example, the Collins reagent is used in this oxidation. With regard to the conversion of one C-9 stereoisomer of the formula CLXXXI1I into the other stereoisomer, reference is made to the process in formula scheme R.

The aldehyde of the formula CLXXXII is then hydrolyzed into the corresponding phenol derivative of the formula CLXXXIII by means of processes which are described above for the preparation of the compound of the formula CLXXV from the compound of the formula CLXXIV in formula scheme P.

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The cyclization of the compound of the formula CLXXXIII into the corresponding compound of the formula CLXXXIV is then achieved by heating to reflux temperature in an organic solvent of the phenoxide anion of the compound of the formula CLXXXIII. For example, compare Casiraghi, G., et al., J.C.S. Perkin I, 2027 (1979). The C-9 isomers of the compound of formula CLXXXIV are suitably separated using conventional techniques, e.g. Column chromatography. The compound of the formula CLXXXIV is then converted into the compound of the formula CLXXXV by means of processes which are described in formula scheme P for the preparation of the compound of the formula CLXXVII from the compound of the formula CLXXVI. This alcohol is then oxidized into the corresponding ketone of the formula CLXXXVI (for example by means of processes which are described above for the preparation of the compound of the formula CLXXXII from the compound of the formula CLXXXI) or this alcohol is dehydrated to give the compound of the formula CLXXXVIII surrender. Such dehydrations take place by means of methods which are known in the prior art and first comprise the preparation of the corresponding mesylate from the compound of the formula CLXXXV, followed by treatment with a base.

The compounds of the formulas CLXXXVI or CLXXXVIII are then converted into the compounds of the formulas CLXXXVII or CLXXIX using methods which are described below.

Finally, the compound of formula CLXXXIX so prepared is dehydrogenated to give the compound of formula CXC by conventional means, e.g. by catalytic dehydrogenation (palladium on carbon catalyst) or by treatment with DDQ (2,3-dichloro-5,6-dicyano-l, 4-benzoquinone).

Formula Scheme R provides a process whereby the C-9 epimeric forms of the compounds are obtained which have been prepared according to Formula Scheme P. With reference to Formula Scheme R, the aldehyde of Formula CXCI, prepared like the compound of Formula CLXXXII in Formula Scheme Q, isomerized by treatment under mild, basic conditions [e.g. using an organic base such as 1,8-diazobicyclo [4,4,0] -undec - 7-ene in an organic solvent (e.g. methylene chloride)]. This 9/3 aldehyde is then reduced to the corresponding alcohol of the formula CXCIII by treatment with a suitable reducing agent, such as a borohydride reducing agent (e.g. sodium, lithium or potassium boron hydride). The alcohol of the formula CXCIII thus prepared is then converted into the corresponding 9/3-CBA analogs by means of processes which are described in formula scheme P, for example by converting the compound of the formula CLXXIII into the compound of the formula CLXXVIII.

If appropriate, the various CBA analogs of the formula XI, prepared according to the formula schemes P, Q and R, prepared using the process from formula scheme S. The process from formula scheme S uses the starting material of the formula CCI, which is described in formula scheme P, and which subsequently is converted into the compound of formula CCII, prepared in accordance with methods described for the preparation of the compound of formula CLXXVIII from the compound of formula CLXXI in formula P, the compounds of formulas CLXXXVII, CLXXXIX and CXC from the compound of formula CLXXXI in formula scheme Q and the compounds of formula CXCIV from the compound of formula CXCI in formula scheme R. The compound of formula CCII thus prepared is then converted to the compounds of formula CCIII by methods described hereinabove, e.g. by converting the compound of formula LXXI into the compound of formula LXXIII in formula F.

Formula Scheme T shows a preferred method, wherein the 9-deoxo-2 \ 9-methano-3-oxa-4,5,6-trinor-3,7- (1,3-inter-phenylene) -PGEi compounds of the Formula CCXIII can be produced. In accordance with Formula Scheme T, the compound of Formula CCX1, prepared like the compound of formula CLXXXIII in Formula Scheme Q, is treated with a methyl Gri-gnard reagent, methyl-magnesium bromide, and is refluxed in an organic solvent (e.g. Glyme) heated.

The compound of the formula CCXII thus prepared is then converted into the product of the formula CCXIII using the process which is described in formula scheme P for the preparation of the product of the formula CLXXVIII from the phenol intermediate of the formula CLXXVI.

A suitable process is provided in formula scheme U, wherein compounds of the formula XI, in which Yi has the meaning of trans-CH = CH-, the compound of the formula CCXXI from formula scheme U, are converted into the corresponding aldehyde intermediates of the formula CCXXII . This conversion is accomplished by ozonolysis using methods commonly known in the art.

The intermediate of formula CCXXII is then suitably converted to various products of formula XI (the compound of formula CCXXIII in formula U) using methods described above, e.g. by reacting the compound of formula CCXXII with the appropriate Wittig reagent, followed by reduction and hydrolysis. In accordance with the procedure described in Formula Scheme U, the C-12 side chains in various compounds of Formula CCXXI are suitably modified by the aldehyde intermediates of Formula CCXXII. As discussed above, the methods described herein result in multiple carboxylic acids (X] means -COORi and Ri means hydrogen) or esters or primary alcohols (Xi means -CH2OH).

When the alkyl ester has been obtained and when an acid is desired, saponification methods are used as are known in the art for PGF-like compounds.

When an acid has been prepared and an alkyl, cycloalkyl or aralkyl ester is desired, the esterification is advantageously carried out by interaction of the acid with the appropriate diazo hydrocarbon. For example, if diazomethane is used, the methyl ester is produced. A similar use of diazoethane, diazobutane and l-diazo-2-ethylhexane and diazodecane gives, for example, the ethyl, butyl and 2-ethylhexyl and decyl esters. Likewise, diazocyclohexane and phenyldiazomethane give the cyclohexyl and benzyl ester.

The esterification with diazo hydrocarbons is carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, preferably in the same or in a different inert diluent,

mixes. After the esterification reaction is complete, the solvent is removed by evaporation and the ester is purified, if desired, by conventional methods, preferably by chromatography. It is preferred that the contact of the acid reactant with the diazo hydrocarbon is no longer than necessary to achieve the desired esterification, preferably about one to about 10 minutes to avoid undesirable molecular changes. Diazo hydrocarbons are known in the art or can be made by methods known in the art. See for example

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Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Voi. 8, pages 389-394 (1954).

An alternative method for the alkyl, cycloalkyl or aralkyl esterification of the carboxy portion of the acid compounds involves transforming the free acid into the corresponding substituted ammonium salt, followed by interaction of this salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide and the like.

Various processes are available for the preparation of the phenyl or substituted phenyl esters within the scope of the invention from the corresponding aromatic alcohols and the free acid, with different yields and purity of the product.

With respect to the preparation of the phenyl, especially the p-substituted phenyl esters disclosed herein (eg Xi has the meaning of -COORi and Rj means p-substituted phenyl), such compounds are made by the method described in U.S. Patent No. 3,890,372. Accordingly, with the preferred method described herein, the p-substituted phenyl ester is prepared by first forming a mixed anhydride, especially according to the methods described below for the preparation of such anhydrides in the first step in the preparation of Amido and cycloamido derivatives.

This anhydride is then reacted with a solution of the phenol, corresponding to the p-substituted phenyl ester to be prepared. This reaction is preferably carried out in the presence of a tertiary amine such as pyridine. When the conversion is complete, the p-substituted phenyl ester is recovered using conventional techniques.

A preferred method for substituted phenyl esters is that disclosed in U.S. Patent 3,890,372, in which a mixed anhydride is reacted with a suitable phenol or naphthol. The anhydride is formed from the acid with isobutyl chloroformate in the presence of a tertiary amine.

Phenacyl-like esters are made from the acid using a phenacyl bromide, e.g. p-phenylphenacyl - bromide, in the presence of a tertiary amine. See, for example, U.S. Patent 3,984,454, German Offenlegungsschrift 2,235,693 and Derwent Farmdoc 16828X.

Carboxamides (X! Means -COL4) are produced using one of various amidation processes which are known in the prior art. See, for example, U.S. Patent 3,981,868, issued September 21, 1976 for a description of the preparation of the present amido and cycloamido derivatives of prostaglandin-like free acids, and U.S. Patent 3,954,741 describes the preparation of carbonylamido and sulfonyl-amido derivatives of prostaglandin-like free acids.

The preferred method by which the present amido and cycloamido derivatives of the acids are prepared involves first converting such free acids to the corresponding mixed acid anhydrides. In this process, the prostaglandin-like free acid is first neutralized with an equivalent of an amine base and then it is reacted with a slight stoichiometric excess of chloroformate, according to the mixed anhydride to be produced.

The preferred amine base for neutralization is tri-ethylamine, although other amines (e.g. pyridine, methyl diethylamine) can also be used. Also suitable is a readily available chloroformate for use in making the mixed anhydride isobutyl chloroformate.

The mixed anhydride is formed using conventional methods and, accordingly, the free acid is mixed with the tertiary amine base and chloroformate in a suitable solvent (e.g. aqueous tetrahydrofuran), the reaction proceeding at a temperature from -10 ° C to 20 ° C.

5 The mixed anhydride is then converted into the corresponding amido or cycloamido derivatives by reacting it with the amine which corresponds to the amide to be prepared. In the case where the simple amide (-NH2) is to be produced, the conversion is carried out by adding Ammo-10 niak. Accordingly, the corresponding amine (or ammonia) is contacted with the mixed anhydride at or about a temperature from -10 ° C to + 10 ° C until the reaction is complete.

The new amido or cycloamido derivative is then obtained from the reaction mixture using conventional techniques.

The carbonylamido and sulfonylamido derivatives of the PG-like compounds disclosed herein are also made by known methods. See, for example, US Pat. No. 3,954,741 for a description of the processes by which 20 such derivatives are made. In this known process, the acid is reacted with a carboxyacyl or sulfonyl isocyanate, corresponding to the carbonylamido or sulfonylamido derivative to be prepared.

In another, more preferred method, the sulfonylamido derivatives of the instant compounds are prepared by first preparing the PG-like mixed anhydride using the method described above for the preparation of the amido and cycloamido derivatives. The sodium salt of the corresponding sulfonamide is then reacted with the mixed anhydride and hexamethylphosphoramide. The pure PG-like sulfonylamido derivative is then obtained from the resulting reaction mixture using conventional techniques.

35 The sodium salt of the sulfonamide, corresponding to the sulfonylamido derivative to be prepared, is obtained by reacting the sulfonamide with alcoholic sodium methoxide. In a preferred process, methanolic sodium methoxide is reacted with an equal molar amount of Sul-40 fonamide. The sulfonamide salt is then reacted with the mixed anhydride, as described above, using about four equivalents of the sodium salt per equivalent of anhydride. Temperatures around 0 ° C are used as reaction temperatures.

The compounds according to the invention, produced by the new processes, in the form of the free acid, are converted into the pharmacologically acceptable salts by means of neutralization with suitable amounts of the corresponding inorganic or organic base; Examples of these correspond to the cations and amines listed above herein. These conversions are carried out by a variety of methods which are known in the art to be generally useful for the preparation of inorganic salts, e.g. Metal or ammonium salts. The choice of process depends in part on the solubility characteristics of the specific salt to be produced. In the case of the inorganic salts, it is usually suitable to dissolve an acid according to the invention in water which contains a stoichiometric amount of a hydroxide, carbonate or bicarbonate, corresponding to the desired inorganic salt. For example, the use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. By evaporating the water or by adding a water-miscible solvent of moderate polarity, e.g. a lower alkanol or a lower alkanone, the solid inorganic salt is obtained if this form is desired.

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To produce an amine salt, an acid according to the invention is dissolved in a suitable solvent with moderate or low polarity. Examples of the former solvent are ethanol, acetone and ethyl acetate. Examples of the latter solvent are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to this solution. If the resulting salt does not precipitate, it is usually obtained in solid form by evaporation.

If the amine is relatively volatile, any excess can be easily removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts in which the cation is quaternary ammonium are obtained by mixing an acid of the invention with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in aqueous solution, followed by evaporation of the water.

The present invention will be understood more fully by handling the following examples:

example 1

3-oxo-7a-tetrahydropyran-2-yloxy-6/3 [(3 'S) -3' -tetrahydro-pyran-2-yloxy-trans-l '-octenyl] bicyclo [3,3,0] - oct-l -en (Formula XXIV: Rig is tetrahydropyranyloxy;

Y is trans-CH = CH-, M6 is a-tetrahydropyranyloxy:

ß-H, L | is a-H: ß-H, Ri? is n-butyl and n is the integer one).

Compare formula scheme A.

A. To a stirred solution of 19 ml (170 mmol) of dimethyl methylphosphonate and 600 ml of dry tetrahydrofuran at a temperature of -78 ° C. and under an argon atmosphere, 110 ml (172 mmol) of a 1, 56 M solution of N-butyllithium in hexane was added. The resulting solution was stirred for 30 min at a temperature of -78 ° C, with 25.4 g of 3a, 5a - dihydroxy-2ß- (3a-hydroxy-trans-l-octenyl) -l a-cyclopentane-- Acetic acid lactone bis (tetrahydropyranyl) ether in 100 ml of dry tetrahydrofuran was added dropwise over an hour, and stirred for one hour at a temperature of -78 ° C and for four hours at room temperature. The reaction was then quenched by adding 10 ml of glacial acetic acid, diluted with 700 ml of saline, and extracted with diethyl ether (3 x 700 ml). The combined ethereal layers were washed with 200 ml of bicarbonate and 500 ml of saline and were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 37 g of the compound of formula XXII as an oily, white solid: 3-dimethyl-phosphonomethyl -3-hydroxy-2-oxy-7o: -tetrahydropyran-2-yl-oxy-6ß [(3'S) -3'-tetrahydropyran-2-yloxy-trans-r-octenyl] -bi-cyclo [3,3, 0] octane. Crystallization of the crude product from hexane and ether gave 22.1 g of the purified product of formula XXII. Silica gel DC. Rf = 0.22 in ethyl acetate. The melting range was 89-93 ° C. NMR absorptions were observed at 3.72 (doublet, J = 11Hz) and 3.83 (doublet,

J = 11Hz) S. Characteristic infrared absorption bands are 3340, 1250, 1185, 1130, 1075 and 1030 cm-1.

B. To a solution of 10.0 g of the product from Part A in 75 ml of acetone and with stirring under a nitrogen atmosphere at a temperature of -10 ° C was added 9.0 ml of Jones reagent over 30 minutes. The resulting suspension was stirred at a temperature of -10 ° C for 30 minutes and then quenched with 4 ml of 2-propanol. The solvents were decanted from the green residue and most of the acetone was removed under reduced pressure. The acetone concentrate was then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 8.2 g of the product of the formula XXIII: 2-descarboxy-6-desbu-tyl-6-dimethyIphosphonomethyl-6-keto-PGEi-II, 15-bis (tetra-hydropyranyl ether). Chromatography of the product of formula XXIII on 600 g of silica gel, eluting with 20% acetone in methylene chloride, gave 4.95 g of the pure product of formula XXIII. Silica gel DC.Rf (in 20% acetone in methylene chloride) = 0.22. Characteristic NMR absorptions were observed at 3.14 (doublet, J = 23Hz) and 3.80 (doublet, J = llHz), 5.4-5.8 (m) 5. Characteristic infrared absorption bands were observed at 1745, 1715, 1260, 1200, 1185, 1130, 1030, 970, 870 cm- '.

C. A suspension of 5.37 g of the product from Example 1, Part B, 1.33 g of anhydrous potassium carbonate and 5.37 g of 18-crown-6-ether in 200 ml of toluene was brought to a temperature of 75 ° C. for six Heated under a nitrogen atmosphere for hours, then cooled to a temperature of 0 ° C. and washed with 200 ml of saline, 200 ml of a 3: 1 water: common salt solution mixture and 200 ml of saline solution, and then dried over anhydrous sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was filtered through 50 g of silica gel, eluting with 250 ml of ethyl acetate, to give 3.9 g of the product of formula XXIV: 3-oxo-7a-tetrahydropyranyl-2 -yloxy-6/3 [(3 'S) -3' -tetrahydropyran-2-yl-trans-l'-octenyl] bicyclo [3,3,0] oct-l-ene. The crude product was chromatographed on 300 g of silica gel eluting with 60:40 hexane: ethyl acetate to give 2.39 g of the pure title product. Silica gel DC.Rf = 0.22 in 60:40 hexane: ethyl acetate. NMR absorptions were observed at 5.18-5.86 (m) and 5.94 (broad singlet) 5. Infrared absorption bands were observed at 1710 and 1632 cm-1.

According to the procedure of Example 1, but using the various 3a, 5a-hydroxy-2-substituted-la-cyclopentane-acetic acid-5-lactones of the formula XXI, all of the various corresponding compounds of the formula XXIV were prepared, in which n the Meaning of one.

Furthermore, all of the different compounds of the formula XXIV were prepared according to the process from Example 1, but using all of the various 3a, 5a-dihydroxy-2-substituted-la-cyclopentane-propionic acid-5-lactones of the formula XXI, in which n has the meaning of two.

Furthermore, according to the method of Example 1, but using all of the various 5a-hydroxy-2-substituted-la-cyclopentanalkanonic acid lactones of the formula XXI, all of the different compounds of the formula XXIV were prepared, in which rig is hydrogen. Finally, according to the method of Example 1, but using all of the various 3a-hydroxymethyl-5a-hydroxy-2-substituted-la-cyclopentanalkanonic acid lactones of the formula XXI, all of the different compounds of the formula XXIV were prepared, in which rig the Meaning of -CH2OR10.

Example 2

3-Oxo-8a-tetrahydropyran-2-yloxy-7ß [(3'S) -3'-tetrahydro-pyran-2-yloxy-trans-l '-octenyl] bicyclo [4,3,0] non-l-ene

(Formula XXIV: Rig, Yi, Mê, R7 are defined in Example 1 and n is the integer two).

Compare formula scheme A.

A. A solution of 2.05 ml (18.9 mmol) of dimethyl methyl phosphonate and 100 ml of dry tetrahydrofuran was stirred at a temperature of -78 ° C under a nitrogen atmosphere and added dropwise with 11.8 ml (18.9 mmol) of one 1.6

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molar solution of n-butyllithium in hexane. After stirring for 30 minutes at a temperature of -78 ° C, the resulting mixture was added dropwise with 4.25 g of 3a, 5a-dihydroxy-2 / 3- (3a-hydroxy-trans-1-octenyl) over 25 minutes ) -la-cyclopentane-propionic acid-6-lactone-II, 15-bis (tetra-hydropyranyl ether) in 30 ml of dry tetrahydrofuran. The resulting mixture was then stirred at a temperature of -78 ° C for one hour. The solution was then stirred at ambient temperature for two hours and quenched by adding 1.2 ml of acetic acid. The mixture was then added to 250 ml of saline and 200 ml of diethyl ether. The aqueous and organic layers were then separated and the aqueous layer was extracted twice with diethyl ether. The ethereal extracts were then washed with brine, dried over anhydrous sodium sulfate and concentrated to give 5.6 g of the crude compound of formula XXII as an oil: 3- (dimethylphosphonomethyl) -3-hydroxy-2-oxa-8a -tetrahydropyran-2-yl-oxy-7/3 [(3 'S) - 3'-tetrahydropyran-2-yIoxy-trans-l'-octenyI] bicyclo [4,3,0] -nonane. Chromatography on silica gel, eluting with 4: 1 ethyl acetate: acetone, gave 4.1 g of the purified product of formula XXII. Characteristic NMR absorptions were observed at 5.15-5.65 (multiplet) <5. Silica gel DC.Rf = 0.34 in 4: 1 ethyl acetate: acetone. Characteristic infrared absorption bands were observed at 3350, 1235 and 1030 cm-1.

B. A suspension of 3.42 g of chromium trioxide and 80 ml of methylene chloride was treated with 5.8 ml of pyridine, stirred at ambient temperature under a nitrogen atmosphere for 30 minutes and mixed with 3 scoops of dry diatomaceous earth. The resulting mixture was then treated with 3.52 g of the reaction product from Part A and 8 ml of dry dichloromethane, stirred for 30 min at ambient temperature under nitrogen, filtered through 30 g of silica gel (eluting with 200 ml of ethyl acetate and acetone, 2: 1) and concentrated under reduced pressure. Chromatography of the residue (3.73 g) on 120 g of silica gel, eluting with ethyl acetate and acetone (4: 1), gave 2.07 g of the product of formula XXIII: 2-descarboxy-5-despropyl-6-di -methylphosphonomethyl-5-keto-PGEi-l 1,15-bis (tetrahydro-pyranyl ether). Characteristic infrared absorption bands were observed at 1740 and 1715 cm-1.

Characteristic NMR absorptions were observed at 3.1 (doublet, J = 23Hz) and 3.8 (doublet, J = 11Hz) ô.

C. A suspension of 12 mg of 50% sodium hydride in mineral oil and 3 ml diglyme was stirred at a temperature of 0 ° C under an argon atmosphere. The suspension was then treated with 150 mg of the product from Part B in 3 ml of diglyme. After one hour the cooling bath was removed and the resulting solution was stirred at ambient temperature under argon. After a total of 20 hours from the addition of the reactant of Formula XXIII, the resulting solution was added to 30 ml of water and extracted with 90 ml of diethyl ether. The ethereal extract was washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg) and on 10 g silica gel chromatographies, eluting with hexane and ethyl acetate (1: 1). 15 mg of the compound of the formula XXIV were prepared accordingly: 3-oxo-8a-tetra-hydropyran-2-yloxy-7/3 [(3 'S) -3'-tetrahydropyran-2-yloxy-trans - r-octenyl ] bicyclo [4,3,0] non-l-ene. NMR absorptions were observed at 4.7 (broad singlet) and 5.3-6.0 (multiplet) 6. An IR absorption band was observed at 1670 cm-1.

Alternatively, the above compound of Formula XXIV was prepared as follows:

A solution of 150 mg of the product from Part B and 5 ml of dry tetrahydrofuran at a temperature of 0 ° C. under an argon atmosphere was added dropwise with 0.5 ml of 0.52 M potassium hydride and 18 crown 6-ether [Aldrich Chemical Co Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee, Wisconsin, page 133; Pedersen, J.C., JACS 92: 386 (1970)] in tetrahydrofuran (made from 800 mg of potassium hydride and 1.0 g of 18-crown-6-ether in 8.7 ml of dry tetrahydrofuran). After stirring for one hour at a temperature of 0 ° C under argon, the mixture was added with 30 ml of water, extracted with 90 ml of diethyl ether and the ethereal extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and on 9 g silica gel chromatographies, eluting with ethyl acetate and hexane. The product (40 mg) of the formula XXIV was obtained. Silica gel DC.Rf = 0.30 in ethyl acetate and hexane (1: 1).

Example 3

l / 3-methyl-3-oxo-7o: -tetrahydropyran-2-yloxy-6 / 3-

[(3'S) -3'-tetrahydropyran-2-yloxy-trans-l'-octenyl] bicyclo [3,3,0] octane (Formula XXV: RiS, Yi, M6, n, Li, R7

are as defined in Example 1, Ri6 means hydrogen and R37 means methyl).

Compare formula scheme A.

A suspension of 2.70 g of anhydrous copper iodide was stirred in 100 ml of anhydrous diethyl ether at a temperature of -20 ° C under an argon atmosphere and was added dropwise with 20.0 ml of a 1.4 M ethereal solution of methyl lithium. The resulting solution was then stirred for 15 minutes at a temperature of −20 ° C. and for 2.5 hours at a temperature of −20 ° C. with a solution of 2.00 g of the title product from Example 1 in 100 ml of anhydrous diethyl ether transferred. Stirring was continued for a further 1.5 hours at a temperature of -20 ° C and the resulting mixture was poured into 200 ml of 1 M aqueous ammonium chloride. The aqueous and organic layers were then separated and the aqueous layer was extracted with diethyl ether (400 ml). The combined organic extracts were then washed with 200 ml brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 2.4 g of the title product as a pale green oil, chromatography on 25 g silica gel, eluting with hexane in ethyl acetate ( 3: 1) gave 2.0 g of the title product as a colorless oil. Characteristic NMR absorptions (CDCI3) were observed at 1.18, 3.20-4.43, 4.70 and 5.2-5.9 b. Characteristic infrared absorption bands were observed at 1745, 1665, 1200, 1130, 1110, 1075, 1035, 1020, 980 and 870 cm- '. Silica gel DC.Rf = 0.26 in ethyl acetate and hexane (1: 3).

Using methods known in the art, each of the various new intermediates of Formula XXV was converted to a 9/3 methyl CBAi compound or a CBAi compound, using methods that are discussed hereinafter, or which are known from the British published descriptions 2,013,661, 2,014,143 and 2,017,699.

Example 4

5-carboxypentanol t-butyldimethylsilyl ether

A solution of 4 g of sodium hydroxide in 100 ml of methanol and water (4: 1) was mixed with 10 ml of caprolactone and stirred at ambient temperature under a nitrogen atmosphere. After 20 hours the solvent was removed and toluene was added to give 15 g of a solid, crude 5-carboxypentanol.

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The above solid was suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to a temperature of 0 ° C., mixed with 35 g of imidazole, stirred for 15 minutes at a temperature of 0 ° C. and for 15 minutes at ambient temperature , cooled to 0 ° C and mixed with 39 g of t-butyldimethylsilyl chloride. The resulting solution was then warmed to ambient temperature under a nitrogen atmosphere. After 26 hours, the resulting solution was added with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol while stirring was kept under a nitrogen atmosphere. After 13 hours, the suspension was acidified to a pH of 4 with 500 ml of 1 N aqueous hydrochloric acid, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts were then washed with 1 N aqueous sodium hydroxide. The basic extracts were then acidified to a pH of 4 with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 22.6 g of a yellow liquid: 5-carboxypentanol-t-butyldimethylsilyl ether. Chromatography on 800 g of silica gel, eluting with ethyl acetate and hexane (1: 9 to 1: 1), gave 14.8 g of 5-carboxypentanol t-butyldimethylsilyl ether. NMR absorptions were observed at 0.05 (singlet) and 0.90 (singlet) 5. Infrared absorption bands were observed at 3000 (broad) and 1700 cm-1.

According to the procedure of Example 4, but using all different lactones, corresponding to the cj-carboxy-alkanol compounds of the formula XXXII, all of the different products of the formula XXXII were produced.

Example 5

2-decarboxy-2- (t-butyldimethylsilyloxy) methyl-5-carboxy-6-hydroxy-9 | S-methyl-CBAi-l 1,15-bis (tetrahydropyran) ether (formula XXXIII: R28 is t-butyldimethylsilyl, Z2 is - (CH2) 3-, n is 1 and Ri6, Ris, R37, M6, Li and R4 are defined in Example 3).

Compare formula scheme B.

A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry tetrahydrofuran at a temperature of 0 ° C. under an argon atmosphere was mixed with 2.6 ml of a 1.56 M solution of n-butyllithium in hexane for 5-10 min. stirred at a temperature of 0 ° C., mixed with 0.50 g of the title product from Example 4 in 5 ml of tetrahydrofuran, stirred for 15 minutes at a temperature of 0 ° C. and for one hour at ambient temperature, to a temperature of 0 Cooled ° C, mixed with 0.91 g of the title product from Example 3 in 5 ml of tetrahydrofuran, and slowly warmed to ambient temperature under an argon atmosphere. Thereafter, 130 ml of water and 20 ml of saline were added and the mixture was extracted with diethyl ether. The ethereal extracts were then washed in 4 ml of 1N aqueous hydrochloric acid and 150 ml of brine and dried over sodium sulfate and concentrated under reduced pressure to give the title product.

Following the procedure of Example 5, but using all of the different compounds of formula XXXI described following Example 1, all of the different compounds of formula XXXIII were prepared in which R28 means t-butyldimethylsilyl and Z2 means - (CH2 ) 3-.

Example 6

2-Decarboxy-2- (t-butyldimethylsilyloxy) methyl-9 | 3-methyl-CBA2-ll, 15-bis (tetrahydropyranylether) (Formula XXXIV: R28, Z2, n, Rig, Y], M6i are Li and R7 defined in Examples 1 and 5).

The reaction product from Example 5 (1.37 g) and 16 ml of methylene chloride were mixed with 2.9 ml of dimethylformamide dineopentyl acetal, stirred for 3 hours at ambient temperature under nitrogen, added to 160 ml of ice water and 40 ml of saline and extracted with diethyl ether. The ethereal extracts were then washed with 150 ml sodium bicarbonate and 150 ml brine, dried over sodium sulfate and concentrated under reduced pressure to give the title product. Chromatography on 100 g of silica gel, eluting with 10% ethyl acetate in hexane, gave the pure title product.

Following the procedure of Example 6, but using all of the different compounds of formula XXXIII described following Example 5, all of the different compounds of formula XXXIV were prepared, in which R28 means t-butyldimethylsilyl and Z2 means - (CH2 ) 3-.

Example 7

2-decarboxy-2-hydroxymethyl-9ß-methyl-CBA2-l 1,15 - bis (tetrahydropyranyl) ether (formula XXXV: Z2, n, Ri6,

R37, Rig, Yi, M «, Li and R7 are defined in Examples 1 and 5).

Compare formula scheme B.

A solution of 0.71 g of the title product from Example 6 and 16 ml of dry tetrahydrofuran was treated at a temperature of 0 ° C. under a nitrogen atmosphere with 3.2 ml of a 0.75 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran. After the reaction mixture was warmed up slowly to ambient temperature, the mixture was stirred overnight, and then 150 ml of brine was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were then washed with 0.5N aqueous potassium bisulfate, 100 ml sodium bicarbonate and 100 ml brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude title product. Filtration through 25 g of silica gel with 200 ml of ethyl acetate and hexane gave 0.61 g of the further purified product. Chromatography on silica gel, eluting with 35% ethyl acetate in hexane, gave the pure title product.

According to the procedure of Example 7, but using all of the different compounds of the formula XXXIV described in and following Example 6, all of the different compounds of the formula XXXV were prepared in which Z2 has the meaning of - (CH2) 3-.

Following the procedure of Examples 5, 6 and 7, but using all of the various compounds of Formula XXXII described in and following Example 4, all of the various compounds of Formula XXXV were prepared using the various starting materials described in and following these examples, and all of the various compounds of Formula XXXII described in and following Example 4, all of the various compounds of Formula XXXV were prepared.

Example 8

2-decarboxy-2-hydroxymethyl-9/3-methyl-CBA2 (formula XXXVI: X, is -CH2OH, Z2 is - (CH2) j-,

R8 is hydroxy, Yi is trans-CH = CH-, Mi is a-OH: / 3-H, Li is a-H: ß-H and R7 is n-butyl).

Compare formula scheme B.

The title product from Example 7 (0.25 g) was combined with 9 ml of acetic acid, water and tetrahydrofuran (6: 3: 1) and heated to a temperature of 37-40 ° C. for 2 hours. The resulting mixture was then cooled and

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extracted with diethyl ether. The ethereal extracts were then washed with brine, dried over sodium sulfate and concentrated to give the crude title product. Chromatography on silica gel gave the pure title product.

Following the procedure of Example 7, but using all of the various primary alcohols of formula XXXV described in and following Example 7, all of the various corresponding products of formula XXXI were prepared, wherein Ri has the meaning of -CH2OH.

Example 9

o- (t-Butyldimethylsilyloxyethyl) benzaldehyde (Formula XLIV: R28 is t-butyldimethylsilyloxy and g means one).

Compare formula C.

A. To a mixture of 7.6 g of lithium aluminum hydride and 400 ml of dry tetrahydrofuran under a nitrogen atmosphere was added dropwise and with stirring 18 g of homophthalic acid (Aldrich Chemical Company) in 250 ml of dry tetrahydrofuran. The rate of addition of the drops was chosen to maintain mild reflux during the course of the exothermic reaction. The resulting mixture was then heated to reflux temperature for 5 hours, cooled to a temperature of 0 ° C, and 7.6 g of water in 50 ml of tetrahydrofuran were added dropwise with stirring. Then 27 ml of 10% aqueous sodium hydroxide were added and the resulting mixture was stirred at ambient temperature for 20 minutes, filtered and the filter solids were washed with 150 ml of tetrahydrofuran. The filtrate and tetrahydrofuran from the washing process were then concentrated under reduced pressure to give 14.0 g of the crude diol of formula XXXII: 2- (o-hydroxymethylphenyl) ethanol. Chromatography on 1.2 kg of silica gel, deactivated by the addition of 240 ml of ethyl acetate, eluting with ethyl acetate, gave 13.5 g of the product of the formula XLII. The melting range was 41.5-43 ° C.

B. 9.05 g of imidazole were added to a solution of 13.5 of the reaction product from Part A in 50 ml of dry tetrahydrofuran under a nitrogen atmosphere. The resulting solution was then cooled to a temperature of -5 ° C and 13.9 g of t-butyldimethylsilyl chloride was added. The resulting mixture was then kept at this temperature for 20 minutes and was then warmed to ambient temperature. After one hour the resulting mixture was shaken with 500 ml of hexane and diethyl ether (2: 1) and 250 ml of water and brine (1: 1). The organic layer was then washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a crude mixture of mono- and bis-silyl ethers corresponding to the starting material from Part A. This mixture was then added to 2 kg Silica gel chromatography, which was deactivated with 400 ml of ethyl acetate and eluting with 25% ethyl acetate and Skellysolve B to give 6.82 g of the product of formula XLIII: o- (t-butyldimethylsilyloxyethyl) phenylmethanol. NMR absorptions were observed at 7.20-7.52, 4.57, 3.91 (t, J = 6.1), 2.93 (t, J = 6.1), 0.82 and -0 , 08 5. silica gel DC.Rf = 0.54 in 25% ethyl acetate and hexane.

C. A mixture of 5.0 g of the reaction product from Part B, 100 ml of trichloromethane and 25 g of activated manganese dioxide (MnCh) was stirred at ambient temperature for four hours. Chloroform (100 ml) was then added and the resulting mixture was filtered through diatomaceous earth. After washing the filter solid with

The resulting filtrate and the washing liquid were concentrated under reduced pressure to 200 ml of trichloromethane to give a residue containing the title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate, eluting with 25% of ethyl acetate and hexane, gave 2.93 g of the pure title product. Silica gel DC.Rf = 0.74 in 25% ethyl acetate and hexane. NMR absorptions were observed at 10.34, 7.25-8.00, 3.89 (t, J = 6.0), 3.27 (t, J = 6.0), 0.83 and -0 , 09 5. The mass spectrum showed a peak at 265 (M +1) and further peaks with decreasing intensity at m / e 75, 207, 73, 133, 223, 208, 77, 177, 76 and 105.

According to the process described in formula scheme C, but using all of the different acids of formula XXXI, all of the various corresponding aldehydes of formula XXXIV were prepared, in which R ^ s has the meaning of t-butyldimethylsilyl.

Example 10

m- (t-Butyldimethylsilyloxymethyl) benzaldehyde

(Formula XLIV: g is zero and R28 is t-butyldimethylsilyl).

Compare formula C.

A. 7.35 g of imidazole were added with stirring to a solution of 10.0 g of m- (hydroxymethyl) phenyl-methanol in 40 ml of dry tetrahydrofuran under a nitrogen atmosphere. The resulting solution was then cooled to a temperature of 0 ° C. and 11.3 g of t-butyldimethylsilyl were added. The resulting mixture was then stirred with cooling for 15 minutes and was then warmed to ambient temperature. After 90 minutes, the resulting mixture was poured into 400 ml of hexane and diethyl ether (2: 1) and 200 ml of water and brine (1: 1). The organic layer was then washed successively with water and brine (1: 1, 300 ml) and brine (150 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a mixture of mono- and bis-t-butyldimethylsilyloxy ether result, according to the compound of formula XXXII. This mixture of products was then run on 1.4 kg of silica gel chromatography, which was deactivated by the addition of 280 ml of ethyl acetate, eluting with 25-40% ethyl acetate in hexane, to give 7.65 g of the pure product of the formula XLIII: m- (t-butyldimethylsilyloxymethyl) phenylmethanol. Silica gel DC.Rf = 0.46 in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.25, 4.72, 4.60, 2.23, 0.92 and 0.09 5. The mass spectrum showed a peak at 251 (M ± 1) and further peaks with decreasing intensity at m / e 235, 121, 195, 237, 105, 133, 75, 89, 236 and 119.

B. A mixture of 5.0 g of the reaction product from Part A and 100 ml of trichloromethane and 25 g of activated manganese dioxide (MnO;) was stirred at ambient temperature for 4 hours. Chloroform (100 ml) was then added and the resulting mixture was filtered with diatomaceous earth. The filter solids were washed with 200 ml of trichloromethane, and the filtrate and trichloromethane from the washing process were then concentrated under reduced pressure to give 5.2 g of the crude title product. Chromatography on 400 g silica gel, which with

80 ml of ethyl acetate was deactivated and eluting with ethyl acetate and hexane (1: 3) gave 3.65 g of the pure title product. Silica gel DC.Rf = 0.46 in 10% ethyl acetate and hexane. NMR absorptions were observed at 10.00, 7.26-7.86, 4.81, 0.95 and 0.11 5.

Example 11

3-phenylsulfonyl-7a-tetrahydropyran-2-yloxy-6/3 [(3'S) -3 '- tetrahydropyran-2-yloxy-trans-r-octenyl] bicyclo [3,3,0] octane

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(Formula LV: n means the integer one, Ris is tetrahydropyranyloxy, Y is trans-CH = CH-,

Mfi is a-tetrahydropyranyloxy: / 3-hydrogen, Li is a-hydrogen: - / 3-hydrogen, Ris and R) 7 both mean hydrogen, and R27 means n-butyl).

Compare Formula Scheme D.

A. Sodium borohydride (0.38 g) was stirred with a solution of 2.90 g of 3-oxo-7a-tetrahydropyran-2-yloxy-6/3 [(3'S) - 3'-tetrahydropyran-2-yloxy- trans-1 '-octenyl] bicyclo [3,3,0] octane in 25 ml of 95% aqueous ethanol. The resulting mixture was then stirred at ambient temperature for 20 minutes. The resulting mixture was then poured into 100 ml of saline and 200 ml of ethyl acetate. The organic layer was immediately washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2.94 g of the alcohol of formula LII: (3RS) -3-hydroxy-7a-tetrahydropyran-2-yloxy-6 / 3 [(3'S) -3'-tetrahydropyran-2-yloxy-trans-l'-octenyl] bicyclo [3,3,0] octane. Infrared absorption bands were observed at 3600 and 3450 cm-1 and no carbonyl absorption was present. Silica gel DC.Rf = 0.63 and 0.67 in ethyl acetate and hexane (1: 1).

B. To a solution of 2.9 g of the reaction product from part A in 25 ml of dry dichloromethane and 1.4 ml (1.02 g) of triethylamine at a temperature of 0 ° C., 0.57 ml (0.848 g) Methanesulfonyl chloride was added over 5 minutes. The resulting mixture was then stirred for a further 20 min. And shaken with 160 ml of diethyl ether and 80 ml of cold (0 ° C.) dilute, aqueous hydrochloric acid. The organic layer was then washed successively with brine, dilute aqueous potassium bicarbonate, and brine, dried over sodium sulfate and concentrated under reduced pressure to give 3.5 g of the crude compound of formula LIII: (3RS) -3-hydroxy -7a - tetrahydropyran-2-yloxy-6/3 [(3'S) -3'-tetrahydropyran-2-yloxy - trans-l'-octenyl] bicyclo [3,3,0] octane-3-methylsulfonate.

C. Thiophenol (1.13 ml, 1.21 g) was added to a mixture of 1.12 g of potassium t-butoxide in 15 ml of dry dimethyl sulfoxide (pMSO) under a nitrogen atmosphere. 3.5 g of the reaction product from Part B in 8 ml of dimethyl sulfoxide were added to the solution of potassium thiophene oxide thus prepared. The resulting mixture was then stirred at ambient temperature for 16 hours after which additional potassium t-butoxide was added, the solution taking on a clear, yellow color. The resulting mixture was then stirred at ambient temperature for a further 4 hours, diluted with 100 ml of diethyl ether and 100 ml of hexane, washed with 5% aqueous potassium hydroxide (200 ml) and with brine (200 ml), dried over magnesium sulfate and concentrated under reduced pressure to give 5 g of a residue from the crude compound of formula LIV: 3-phenylthio-7a-tetrahydropyran-2-yloxy-6/3 [(3'S) -3'-tetrahydropyran-2-yloxy-trans-r- octenyl] bicyclo [3,3,0] octane. Chromatography on 300 g of silica gel, which was deactivated with 40 ml of diethyl ether and 40 ml of trichloromethane and eluting with 5% diethyl ether in trichloromethane, gave 3.1 g of the pure product. Silica gel DC.Rf = 0.75 in 10% ethyl acetate in dichloromethane.

D. 2.43 g of 85% m-chloroperbenzoic acid were added to a solution of 3.1 g of the reaction product from Part C and 50 ml of dichloromethane at a temperature of 0 ° C. with stirring over the course of 10 minutes. The resulting mixture was then stirred at a temperature of 0 ° C for 30 minutes, diluted with 150 ml of dry ethyl ether, washed with ice-cold, dilute, aqueous potassium hydroxide and brine, dried over magnesium sulfate and concentrated under reduced pressure to 3.4 g of the raw title product. Chromatography on 350 g of silica gel which was deactivated with 70 ml of ethyl acetate and eluting with 500 ml of 30-50% ethyl acetate in hexane gave 2.90 g of the pure title product as a mixture of the C-6 isomers. Silica gel DC.Rf values = 0.41, 0.45 and 0.48 in 30% ethyl acetate in hexane (stereoisomers). NMR absorptions were observed at 7.52-8.02, 5.30-5.67, 4.70 and 3.30-4.13 ò.

According to the procedure of Example 11, each compound of Formula LI was converted to the corresponding 3-phenylsulfonyl compound of Formula LV.

Example 12

(5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2 (Formula LX: X | is -COOH, g is 1, n is 1, Ri «and Rn are

Is hydrogen, Rg is hydroxy, Y | is trans-CH = CH-, Mi is a-OH: / 3-H, Li is a-H: 3-H and R7 is n-butyl)

Methyl ester and the corresponding (5Z) isomers thereof.

Compare formula C.

A. To a solution of 1.26 g of the title product from Example 11 in 15 ml of dry tetrahydrofuran at a temperature of -78CC under a nitrogen atmosphere was added 1.48 ml of a 1.6 M solution of n-butyllithium in hexane with stirring added during 1 min. After 10 minutes, 0.66 g of the title product from Example 4 in 5 ml of dry tetrahydrofuran was added. After 45 minutes, 0.26 distilled acetic anhydride was added. Stirring was then continued at a temperature of -78 ° C for 3 hours and at ambient temperature for an additional 2 hours. The resulting mixture was then shaken with 120 ml of diethyl ether and

80 ml saturated, aqueous ammonium chloride. The organic layer was then washed with 15 ml of brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2.21 g of the product of formula LVI as a mixture of isomers: 3- [a-acetoxy-o- (t-butvldi- methyIsilyloxyethyl) -a-tolyl] -3-phenyIsulfonyI-7a- (tetrahydro-pyran-2-yl) oxy-6/3 [(3 'S) -3' - (tetrahydropyran-2-yl) oxy-trans-l -octenyl] bicyclo [3,3,0] octane. R2S. g, Rn, n, Rie, Yi, Mé, Li and R27 are defined in Examples 9 and 11. Silica gel DC.Rr range 0.30-0.53 (8 spots) (stereoisomers) in 25% ethyl acetate and hexane.

B. The mixture of the isomeric products from Part A (2.21 g) and 40 ml of methanol and 20 ml of ethyl acetate were stirred at a temperature of -20 ° C with chips of 5.6% sodium amalgam for 60 min after decanting the liquid was flushed with excess amalgam and solid by decanting using 200 ml of diethyl ether. The organic solutions were then combined, washed with brine, dried and concentrated under reduced pressure to give 1.8 g of crude 2-decarboxy-2- (t-butyldimethylsilyloxymethyl) -2,5-inter-o-phenylene-3 , 4-dinor-CBA2-11.15-bis (tetrahydropyranyl ether). Chromatography on 250 g of silica gel, which was deactivated with 50 ml of diethyl ether and eluting with 30% diethyl ether in hexane, gave 1.06 g of the pure product. Silica gel DC.Rr values at 0.49, 0.56 and 0.62 (stereoisomers) in 30% diethyl ether and hexane. NMR absorptions were observed at 7.20, 6.54, 5.22-5.80, 4.72, 3,384.16 and 2.74-3.00 Ô.

C. A solution of 1.06 g of the reaction product from Part B in 10 ml of dry tetrahydrofuran was treated with 3.2 ml of 0.75 N tetra-n-butylammonium fluoride in tetrahydrofuran at ambient temperature for 40 min. The resulting mixture was then diluted with 125 ml of diethyl ether. The resulting solution was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue of isomeric products of formula LVIII: (5E) - and (5Z) -

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-2-decarboxy-2-hydroxymethyl-2,5-inter-o-phenylene-3,4-dinor - CBA2-ll, 15-bis (tetrahydropyranyl ether). Chromatography on 100 g of silica gel which was deactivated with 20 ml of ethyl acetate and eluting with 25-50% ethyl acetate in hexane gave 0.40 g of the (5Z) isomer and 0.51 g of the (5E) isomer. For the (5Z) isomer, the silica gel DC.Rf values were 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.20, 6.51, 5.10-5.72, 4.69, 3.32-4.16 and 2.76-3.00 5. For the (5E) isomers were Silica gel DC.Rf values observed at 0.20 and 0.24 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.19, 6.50, 5.10-5.64, 4.70, 3.324.10 and 2.88-3.01 Ô.

D. To a solution of 400 mg of the (5Z) reaction product from Part C in 20 ml of dry acetone at a temperature of -50 ° C., 1.0 ml of Jones reagent was added with stirring (prepared as follows: 26.72 g of chromium trioxide in 23 ml of concentrated sulfuric acid, diluted with water to a volume of 100 ml). The resulting mixture was then heated to a temperature of -20 ° C over a period of 20 minutes and stirred at a temperature of -20C for 30 minutes. Excess Jones reagent was then destroyed by adding 0.5 ml of isopropanol. After 5 minutes, the reaction mixture was poured into 100 ml of ethyl acetate and 80 ml of brine, which contained 0.5 ml of concentrated hydrochloric acid. The organic layer was then washed twice in 50 ml of water containing a trace (10 drops) of concentrated hydrochloric acid, twice in 50 ml of water and in brine. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure to give 360 mg of crude (5Z) -2,5-inter-o-phenylene-3,4-dinor-CBA2-1,1,5-bis (tetrahydro- pyranyl ether), a compound of formula LIX. The crude compound of the formula LIX was then taken up in 30 ml of diethyl ether and extracted in a mixture of 15 ml of water and 5 ml of methanol, which contained a trace (10 drops) of 45% aqueous potassium hydroxide. The extraction was repeated six times until the acid was completely extracted from the ethereal solution. The aqueous extracts were then acidified to a pH of 2 and were extracted with ethyl acetate. The organic extract was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue from the pure title product. The silica gel DC. was a streak with an Rf of 0.50 in ethyl acetate and hexane (1: 1). The purified acid was then converted into the corresponding methyl ester by treatment with excess ethereal diazo-methane for 10 min. After this esterification, the resulting reaction mixture was taken up in ethyl acetate and washed with dilute, aqueous potassium hydroxide and brine. After drying and concentration to a residue, chromatography on 20 g of silica gel, which was deactivated with 4 ml of ethyl acetate, and eluting with 10% ethyl acetate in trichloromethane, 210 mg of (5Z) -2,5-inter-o- Phenylene-3,4-dinor-CBA; methyl ester - 11, 15-bis (tetrahydropyranyl ether). Silica gel DC.Rr values were 0.52, 0.56 and 0.60 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.20, 6.45, 5.34-5.78, 4.70, 3.68 and 3.304.28 6.

E. A mixture of 200 mg of the methyl ester from Part D, 5 ml of acetic acid, 2.5 ml of water and 1 ml of tetrahydrofuran was heated to a temperature of 40 ° C. and stirred for 4 hours. The resulting mixture was then diluted with 100 ml of ethyl acetate and was washed with a mixture of 6 g of 85% aqueous potassium hydroxide in 20 ml of water and 30 g of ice, further washed with brine (40 ml), dried over magnesium sulfate and concentrated under reduced pressure to give 180 mg of crude (5Z) -2,5-inter-o-phenylene-3,4-dinor-CBA2-methyl ester. Chromatography on 20 g of silica gel which was deactivated with 4 ml of ethyl acetate and eluting with 100 ml of 50% ethyl acetate in trichloromethane and with 100 ml of 50% acetone in trichloromethane gave 105 mg of the pure product. Silica gel DC.Rf = 0.57 in 40% acetone and trichloromethane and Rf = 0.52 in ethyl acetate. NMR absorptions were observed at 7.20, 6.43, 5.45-5.59, 3.65, 3.404.20 and 3.18 5. The mass spectrum of the bis-TMS derivative showed peaks with decreasing intensity at m / e 73, 75, 74, 147, 43, 129, 41, 45, 167, 59 and an M + -C5Hn peak at 485.2513.

F. To a solution of 105 mg of the reaction product from Part E in 5 ml of methanol and 2.5 ml of water under a nitrogen atmosphere was added 0.33 g of potassium carbonate. The resulting mixture was stirred at ambient temperature for 20 hours after which a small quantity (5 drops) of 45% aqueous potassium hydroxide was added. The resulting mixture was stirred at ambient temperature for an additional 4 hours. The mixture was then shaken with 100 ml of ethyl acetate and excess, cold, dilute, aqueous hydrochloric acid. The organic layer was then washed with brine, dried and concentrated under reduced pressure to give 100 mg of pure (5Z) -2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel DC.Rf = 0.56 in the A-IX solvent system (the organic phase of an equilibrated mixture of ethyl acetate, acetic acid, cyclohexane and water, 9: 2: 9: 10). The mass spectrum of the tris-TMS derivative showed peaks with decreasing intensity at m / e 73, 75, 129, 167, 74, 55, 69, 57, 147 and 45 and an M + -Ch2 peak at 599.3418.

G. According to the procedure from Part D, 510 mg of the (5E) reaction product from Part C was converted into 310 mg (5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2-ll, 15-bis (tetrahydropyranyl - ether), silica gel DC.Rf = 0.41 in 25% ethyl acetate and hexane, which contained 1% acetic acid, and 220 mg (5E) -2,5-inter-o - phenylene-3,4- dinor-CB A2-l 1,15-bis (tetrahydropyranyl ether) methyl ester, silica gel DC. RF values were 0.48, 0.51 and 0.56 (stereoisomers) converted to 25% ethyl acetate and hexane. NMR absorptions were observed at 7.20, 6.43, 5.26-5.64, 4.70, 3.65 and 3.304.10 ô.

H. According to the procedure from Part E, the reaction product from Part G (210 mg) was converted to 110 mg (5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2 methyl ester. Silica gel DC.Rf = 0.57 in 40% acetone and trichloromethane and Rf = 0.46 in ethyl acetate. NMR absorptions were observed at 7.22, 6.44, 5.32-5.47, 3.68, 3,504.08 and 3.10 5. The mass spectrum of the bis-TMS derivative showed peaks with decreasing intensity at m / e 73, 75, 129, 227, 167, 55, 57, 173, 74, 466 and an M + -CH3 peak at 541.3198.

I. Following the procedure of Part F, the reaction product from Part H (110 mg) was converted to 102 mg (5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel DC.Rf = 0.50 in the A-IX solvent system. The mass spectrum of the tris-TMS derivative showed peaks with decreasing intensity at m / e 73, 75, 167, 129, 524, 453, 285, 147, 434, 213 and an M + -CH3 peak at 599.3424.

Example 13

(5E) -1,5-inter-m-phenylene-2,3,4-trinor-CBA2, its methyl ester and the corresponding (5Z) isomers.

Compare Formula Scheme D.

A. According to the procedure of Example 12, Part A, a solution of 1.26 g of the title product from Example 6 and 0.62 g of the title product from Example 5 was converted into 2.3 g of the compound of formula LVI. Silica gel DC.Rf range 0.37-0.56 (7 spots) (stereoisomers) in 25% ethyl acetate in hexane.

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B. According to the procedure of Example 12, Part B, the reaction product from Part A (2.3 g) was transferred to 1.0 g of the isomeric compounds of formula LVII: (5E) and (5Z) -2 - decarboxy -2- (t-butyldimethylsilyloxymethyl) -l, 5-inter-m-phenylene-2,3,4-trinor-CB A; -l 1,15-bis (tetrahydropyranyl ether). Silica gel DC.Rf values at 0.47, 0.54 and 0.58 (stereoisomers) in 30% diethyl ether and hexane.

C. According to the procedure of Example 12, Part C, 1.0 g of the isomer mixture of the reaction product from Part B was dissolved in 0.51 g of (5Z) -2-decarboxy-2-hydroxymethyl-1,5-inter-m-phe -nylene-2,3,4-trinor-CBA2-l, 15-bis (tetrahydropyranyl ether) and 0.40 g (5E) -2-decarboxy-2-hydroxymethyl-l, 5-inter-m-phe -Nylene-2,3,4-trinor-CBA2-l, 15-bis (tetrahydropyranyl ether) converted. For the (SZ) isomer, the silica gel DC.Rf values were 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.18, 6.36, 5.19-5.65, 4.63, 4.58, 3,314.08 and 2.92 5. The silica gel was TLC for the (5E) isomer .Rf values 0.23 and 0.27 (stereoisomers) in 25to ethyl acetate and hexane. NMR absorptions were observed at 7.19, 6.37, 5.29-5.72, 4.67, 4.60, 3.30-4.17 and 2.78 5.

D. According to the procedure of Example 12, Part D, 510 mg of the (SZ) reaction product from Part C became 310 mg (5Z) -1,5-inter-m-phenylene-2,3,4-trinor-CBA2 -l 1,15-bis (tetra-hydropyranyl ether) and 240 mg (5Z) -l, 5-inter-m-phenylene - 2,3,4-trinor-CBA2-methyl-ester-l 1,15-bis (tetrahydropyranyl ether) converted. The silica gel gave DC for the acid. a streak with an Rf of about 0.54 in 50% ethyl acetate and hexane. For the methyl ester, the silica gel DC.Rf values were 0.58, 0.63 and 0.68 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.28-8.00, 6.40, 5.13-5.73, 4.71, 3.89 and 3.28-4.08 5.

E. According to the procedure of Example 12, Part E, 240 mg of the methyl ester product from Part D was dissolved in 140 mg (5Z) - 1,5-inter-m-phenylene-2,3,4-trinor-CBA2- converted to methyl ester. Silica gel DC.Rf = 0.49 in ethyl acetate. NMR absorptions were observed at 7.28-7.93, 6.40, 5.34-5.48, 3.88 and 3.32 5. The mass spectrum of the bis-TMS derivative showed peaks with decreasing intensity at m / e 83, 85, 73, 47, 213, 75, 129, 48, 87, 88 and an M + -CH3 peak at 527.2996.

F. A solution of 0.20 g of 85% potassium hydroxide in 2 ml of water was added to a solution of 140 mg of the reaction product from Part E in 6 ml of methanol and under a nitrogen atmosphere. The resulting mixture was then stirred at ambient temperature for 7 hours, shaken with 200 ml of ethyl acetate and excess cold, dilute, aqueous hydrochloric acid. The organic layer was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 110 mg of pure (5Z) -1,5-inter-m-phenylene-2,3,4-trinor-CBA2. Silica gel DC.Rf = 0.60 in the A-IX solvent system. The mass spectrum of the tris-TMS derivative showed peaks with decreasing intensity at m / e 73, 271, 394, 129, 420, 510, 75, 147, 32, 74 and an M + -CH3 peak at 585.3234.

G. According to the procedure of Example 12, Part D, 400 mg of the (5E) reaction product from Part C was converted into 260 mg (5E) -1,5-inter-m-phenylene-2,3,4-trinor-CBA2 -l 1,15-bis (tetra-hydropyranyl ether) and 190 mg (5E) -l, 5-inter-m-phenylene - 2,3,4-trinor-CBA2-methyl ester-ll, 15-bis (tetrahydropyranyl- ether) converted. The silica gel showed DC for the acid. a streak with an Rf of about 0.36 in 50% ethyl acetate and hexane. For the methyl ester, the silica gel was DC.Rf values of 0.50, 0.53 and 0.57 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions were observed at 7.38-7.95, 6.42, 5.13-5.75, 4.68, 3.89 and 3.30-4.09 5.

H. According to the procedure of Example 12, Part E, 190 mg of the reaction product from Part G was converted into 81 mg (5E) -1.5-

-inter-m-phenylene-2,3,4-trinor-CBA2-methyl ester converted. Silica gel DC.Rf = 0.51 in ethyl acetate. NMR absorptions were observed at 7.30-7.93, 6.43, 5.45-5.59, 3.89, 3.50-4.14 and 3.09 5. The mass spectrum of the bis-TMS- Derivates showed peaks with decreasing intensity at m / e 73, 213, 129, 75, 83, 452, 173, 85, 262, 362 and an M + -CH3 peak at 527.2996.

I. According to the procedure of Example 13, Part F, 81 mg of the reaction product from Part H was converted into 65 mg (5E) -1.5 - inter-m-phenylene-2,3,4-trinor-CBA2. Silica gel DC.Rf = 0.60 in the A-IX solvent system. The mass spectrum of the tris-TMS derivative showed peaks with decreasing intensity at m / e 73, 271, 394, 75, 510, 129, 420, 147, 173, 395 and an M + -CH3 peak at 585.3227.

Following the procedure of Examples 12-13, but using all of the different compounds of Formula LV described in and following Example 11, in all different compounds of Formula XLIV described in and following Examples 9 and 10, all were of the various compounds of formula L in the form of the free acid or in the form of the methyl ester.

Example 14

9/3-methyl-CB A2-methyl-ester-l 1,15-bis (tetrahydropyranylether) (formula LXXXIV: Ri6 is hydrogen,

R37 is methyl, Z2 is - (CH2) 3 - and R18, Y |, M6, Li and R7

are defined in Example 3) and the corresponding (5E) and (5Z) free acids (formula LXXXIII).

Compare formula scheme G.

A. A suspension of 57% sodium hydride in mineral oil (1.90 g) was washed with hexane and 130 ml of dry dimethyl sulfoxide (DMSO) was added. The resulting suspension was heated to a temperature of 65 ° C for 1 hour under a nitrogen atmosphere and the resulting solution was cooled to a temperature of 15 ° C and added dropwise over 15 minutes with 10.0 g of 4-carboxybutyltri-phenyl-phosphonium. bromide added. The resulting orange solution was stirred for 15 minutes at a temperature of 10 ° C. and then dropwise for 15 minutes with a solution of 2.12 g of the title product from Example 3 in

20 ml of dry DMSO added. The resulting solution was then stirred at ambient temperature under a nitrogen atmosphere for 60 hours, treated with 15 ml of water, stirred for 30 minutes at ambient temperature, poured into 200 ml of ice water and 100 ml of brine, acidified with 1N aqueous hydrochloric acid and with 900 ml of diethyl ether extracted. The ethereal extracts were washed with 1 liter of water and 200 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give 4.8 of a yellow oil, namely the carboxylic acid of formula LXXXIII.

B. The product of formula LXXXIII and 42 ml of diisopropylethylamine in 120 ml of acetonitrile were treated at a temperature of 10 ° C under a nitrogen atmosphere with 15 ml of methyl iodide and slowly warmed to ambient temperature. The resulting suspension was then stirred for 16 hours, treated with 3.0 ml of methyl iodide, stirred for a further 2 hours, mixed with 500 ml of saline and extracted with 1 liter of ethyl acetate. The organic extracts were washed with 250 ml of 0.5N potassium bisulfate, 250 ml of saturated aqueous sodium bicarbonate and 250 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a solid residue. The residue was then chromatographed on 500 g of silica gel, eluting with 8% acetone in hexane to give 2.25 g of the title product of formula LXXXIV. NMR absorptions (CDC13) were

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observed at 0.9, 1.05, 1.08, 3.66, 3.02-4.35, 4.70 and 4.95 5. Infrared absorption bands were observed at 1730, 1670, 1645, 1200, 1165 , 1135, 1080, 1035, 1020, 980 and 870 cm "1- silica gel DC.Rf = 0.46 in ethyl acetate and hexane (1: 3) and Rf = 0.26 in ethyl acetate and hexane (1: 6).

C. Alternatively, the isomeric reaction products of formula LXXXIII from Part A were separated into the (5E) and (5Z) free acids title products by chromatography on silica gel washed with acid, eluting with 10-30% ethyl acetate in hexane.

According to the procedure of Example 9, but using all of the different ketones of the formula LXXXI instead of the product from Example 3, all of the different methyl esters of the formula LXXXIV were prepared, in which Z2 has the end of - (CT ^ -.

Furthermore, according to the method of Example 14, but using an aj-carboxytriphenylphosphonium compound of the formula LXXXII, in which Z2 has a meaning other than - (CH2) 3-, each of the different ketones of the formula LXXXI in the corresponding ester of the formula LXXXIV transferred, in which Z2 has a different meaning than - (CH2) 3-.

Example 15

(5Z) -2-Decarboxy-2-hydroxymethyl-9/3-methyl-CBA2 - 11, 15-bis (tetrahydropyranyl ether) (Formula LXXXVI: Ri6> R37 »Z2, Rig, Mê, Li and R7 are in Example 14 defines) and its (5E) isomer (formula LXXXVII).

Compare formula scheme G.

A suspension of 0.16 g of lithium aluminum hydride in 45 ml of dry tetrahydrofuran at a temperature of 0 ° C. under a nitrogen atmosphere was added dropwise to 1.98 g of the title product from Example 14 in 15 ml of dry tetrahydrofuran. The resulting suspension was stirred at a temperature of 0 ° C. for 1 hour and then at ambient temperature for 1 hour. The resulting mixture was then cooled to a temperature of 0 ° C, quenched by the addition of 0.16 ml of water and 0.16 ml of 15% aqueous sodium hydroxide. After stirring at ambient temperature for 1 hour, a mixture was obtained after treatment with magnesium sulfate and filtration through diatomaceous earth and rinsing with diethyl ether, which was concentrated under reduced pressure. The resulting product, 0.25 g, was chromatographed on 180 g of silica gel, eluting with 30% ethyl acetate in hexane, to give 1.03 g of the product of formula LXXXVII and 1.06 g of the product of formula LXXXVI.

For the product of the formula LXXXVI, NMR absorptions (CDCI3) were observed at 0.90, 1.09, 3.2-4.4, 4.72, 5.0-5.9 5. Infrared absorption bands were observed at 3470, 1760 , 1200, 1135, 1120, 1075, 1035, 1020 and 980 cm -'-. Silica gel DC.Rf = 0.29 in ethyl acetate and hexane (35:65). For the product of the formula LXXXVII, NMR absorptions (CDClj) were observed at 0.90, 1.05, 3.2-4.4, 4.64.95, 5.05-5.97 Ô. Infrared absorption bands were observed at 3470, 1670, 1200, 1125, 1110, 1080, 1035, 1020 and 985 cm "1. silica gel DC.Rf = 0.36 in ethyl acetate and hexane (35:65).

All primary alcohols of the formula LXXXVI and the formula LXXXVII were prepared in accordance with the procedure of Example 15, but using all of the various esters of the formula LXXXIV, described following Example 14.

Example 16

(5Z) -9 / 3-methyl-CBA2-methyl ester (formula LXXXVIII:

Xj is -COOCH3, Rs is hydroxy, Mi is a-OH: 0-H and

Ri6, Rn, Li, R7, Yi and Z2 are defined in Example 15).

Compare formula scheme G.

A. A solution of the title product of the formula LXXXVI from Example 15 in 38 ml of acetone at a temperature of −20 ° C. under a nitrogen atmosphere was prepared for 5 minutes with 1.9 ml of Jones reagent (prepared by dissolving 133.6 g of chromium trioxide in 115 ml of concentrated sulfuric acid and with dilution with water to a volume of 500 ml), stirred for 2 hours at a temperature of −20 ° C., quenched by the addition of 2.3 ml of isopropanol, during 40 min stirred at a temperature of -20 ° C with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 600 ml of brine, dried over sodium sulfate and concentrated under reduced pressure, giving 1.01 g of carboxylic acid corresponding to the primary alcohol of formula LXXXVI as one pale green oil was obtained.

B. 4.1 ml of diisopropylethylamine and 1.5 ml of methyl iodide were added to a solution of the product from Part A in 11 ml of acetonitrile at a temperature of 15 ° C. under a nitrogen atmosphere. The resulting suspension was then stirred at ambient temperature for 17 hours, mixed with 0.3 ml of methyl iodide, stirred for 2 hours at ambient temperature, diluted with 50 ml of brine, extracted with 100 ml of ethyl acetate, with 50 ml of 0.5 M potassium bisulfate, Washed 50 ml aqueous sodium bicarbonate and 50 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.02 g of the methyl ester, corresponding to the carboxylic acid product from Part A.

C. A solution of the product from Part B in 56 ml of a mixture of tetrahydrofuran, water and acetic acid (1: 2: 4) was heated to a temperature of 45 ° C under a nitrogen atmosphere for 3 hours, cooled, diluted with 200 ml of saline and extracted with 400 ml of diethyl acetate. The organic extracts were then with

Washed 600 ml of saturated aqueous sodium bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.9 g of the crude title product as a yellow oil. Chromatography on 100 g of silica gel, eluting with hexane and ethyl acetate (3: 7), gave 0.39 g of the pure title product as a colorless oil. NMR absorptions (CDC13) were observed at 0.89, 1.08, 3.5-4.35, 3.66, 5.0-5.7 ô. Infrared absorption bands were observed at 3360, 1740, 1670, 1455, 1435, 1370, 1240, 1225, 1195, 1170, 1075, 1020 and 970 cm ~ '. Silica gel DC.Rf = 0.22 in ethyl acetate and hexane (7: 3).

According to the procedure of Example 16, but using all of the different compounds of the formula LXXXVI, described following Example 15, all of the different 9/3 methyl CBA2 compounds of the formula LXXXVIII were prepared, in which Xi has the meaning of - COOR ,.

Example 17

(5E) -9 / 3-methyl-CBA2-methyl ester (formula LXXXIX: Ri6> Rn, Xi, Z2, Ra, R], Mi, Li and R7 are defined in Example 16).

Compare formula scheme G.

A. According to the procedure of Example 16, Part A, 0.60 g of the product of formula LXXXVII from Example 15 was converted to the carboxylic acid, corresponding to the primary alcohol of formula LXXXVII, to give 0.66 g of a green oil.

B. According to the procedure of Example 16, Part B, the product from Part A (0.66 g) above was converted to the methyl ester, corresponding to the carboxylic acid product from Part A, with 0.58 g of a yellow oil.

C. According to the procedure from Example 16, Part C, was

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the product from Part B above (0.58 g) was transferred to 0.25 g of the title product to give a colorless oil. NMR absorptions (CDCI3) were observed at 0.90, 1.05, 3.30, 3.66, 3.75-4.25, 5.0-5.7 b. Infrared absorptions were observed at 3360, 1740, 1670, 1455, 1435, 1250, 1225, 1195, 1170, 1075, 1020 and 970 cm-1. Silica gel DC.Rf = 0.22 in ethyl acetate and hexane (3: 7).

According to the method from Example 17, but using all of the different compounds of the formula LXXXVII, described following Example 15, all of the different products of the formula LXXXIX were prepared, in which X] has the meaning of -COOCH3.

Example 18 (5Z) -9 / 3-methyl-CBA2.

A solution of 0.28 g of the title product from Example 16 in 8 ml of methanol was stirred at ambient temperature under a nitrogen atmosphere and 1 ml of 8 M aqueous sodium hydroxide was added. The resulting yellow solution was then stirred for 5 hours at ambient temperature under a nitrogen atmosphere, diluted with 90 ml of ice and brine, acidified to pH 2 with 1N hydrochloric acid, extracted with 360 ml of ethyl acetate, washed with 120 ml of brine, Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.25 g of the crude title product. Chromatography on 30 g of silica gel, extracting with the A-IX solvent system (the organic phase of an equilibrated mixture of ethyl acetate, acetic acid, cyclohexane and water 9: 2: 5: 10), gave 0.235 g of the pure title product as a colorless oil. NMR absorptions (CDCI3) were observed at 0.89, 1.08, 3.5-4.35, 5.0-5.7, 6.05 b. Infrared absorption bands were observed at 3340, 2660, 1710, 1240, 1205, 1175, 1130, 1075, 1055, 1020 and 970 cm - '/ silica gel DC.Rf = 0.25 in the A-IX solvent system.

According to the procedure of Example 18, all of the various methyl esters, prepared according to Example 16, were converted into the corresponding carboxylic acids.

Example 19 (5E) -9 / 3-methyl-CBA2.

According to the procedure of Example 18, 0.25 g of the title product from Example 17 was transferred to 0.21 g of the title product, whereby a colorless oil was obtained. NMR absorptions (CDCI3) were observed at 0.90, 1.06, 3.5-4.3, 5.0-5.7 and 5.93 b. Infrared absorption bands were observed at 3340, 2660, 1710, 1300, 1240, 1175, 1130, 1075, 1055, 1020 and 970 cm "1st silica gel DC.Rf = 0.27 in the A-IX solvent system.

All of the various carboxylic acids corresponding to the formulas LXXXVIII and LXXXIX, where Xj has the meaning of -COOH, can be prepared from the corresponding reaction products of the formula LXXXIII by means of acid hydrolysis of the tetrahydropyranyl ether protective groups on C-11 and C-15. [The (5Z) reaction products of the formula LXXXIII from Example 14, Part C, give the products of the formula LXXXVIII; and the (5E) reaction products of the formula LXXXIII from Example 14, Part C, give the products of the formula LXXXIX.]

According to the procedure of Example 19 but using all of the various methyl esters of the formula LXXXIX, described following Example 17, all of the various corresponding carboxylic acids were prepared.

Example 20

2 / 3- (t-butyldimethylsilyloxymethyl) -5 / 3-methyl-7-

-oxo-3a-tetrahydropyran-2-yl-oxv-bicyclo [3,3,0] octane

(Formula LXII: n is the integer one, R3] means t-butyldimethylsilyl and R38 is tetrahydropyranyloxy).

Compare formula scheme E.

A. A solution of 40.6 g of 3a-benzyloxy-5a-hydroxy-2j3-hydroxymethyl-la-cyclopentanacetic acid-ci) lactone in 250 ml of dimethylformamide was stirred with a temperature of 0 ° C under a nitrogen atmosphere with 25 g Imidazole in 28 g of t-butyldimethylsilyl chloride. The resulting solution was then stirred for 67 hours at ambient temperature, mixed with 500 ml of water, extracted three times with 500 ml portions of diethyl ether, washed with 500 ml of 10% aqueous potassium bisulfate, 500 ml of aqueous sodium bicarbonate and 500 ml of brine, dried over sodium sulfate and under concentrated under reduced pressure to give 59.9 g of 3a-benzoyloxy-5a-hydroxy-2 / 3- (t-butyldimethylsilyloxyme-thylj-la-cyclopentanacetic acid-co-lactone as a white solid. NMR absorption (CDC13) was obtained observed at 0.06, 0.91, 2.1-3.12, 3.74, 4.94-5.54, 7.24-7.67 and 7.9-8.2 Ô. Infrared absorption bands were observed at 1780, 1720, 1600, 1585, 1490, 1270, 1255, 1180, 1115, 1100, 1070, 1050, 830, 790 and 710 cm "1. silica gel DC.Rf = 0.20 in ethyl acetate and hexane (1 : 4).

B. A solution of 59.1 g of the reaction product from Part A and 500 ml of absolute methanol was mixed with 35 ml of a 25% solution of sodium methoxide and methanol while stirring at ambient temperature under a nitrogen atmosphere. The resulting reaction mixture was then stirred at ambient temperature for 90 minutes and quenched by the addition of 9.5 ml of glacial acetic acid. The methanol was removed under reduced pressure and the resulting residue was diluted with 500 ml of saturated aqueous sodium bicarbonate. The resulting mixture was then extracted with two 500 ml portions of ethyl acetate, washed with 300 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give 58 g of an oily solid, crude 3a , 5a-Dihydroxy-2 / 3- (t-butyldimethylsilyloxymethyl) - la-cyclopentanacetic acid-w-lactone. This crude product was then chromatographed on 800 g of silica gel, eluting with 20-75% ethyl acetate in hexane, and the pure title product was obtained as a white crystalline solid. The melting range was 60.5 ° C to 62 ° C. NMR absorptions (CDC13) were observed at 0.06, 0.90, 1.7-3.0, 3.67, 3.9-4.4 and 4.7-5.13 b. Silica gel DC.Rf = 0.3 in 50% ethyl acetate in hexane.

C. A solution of 37.3 g of the reaction product from Part B in 400 ml of methylene chloride was mixed with 18 ml of dihydropyran and 0.14 g of pyridine hydrochloride while stirring at a temperature of 0 ° C. under a nitrogen atmosphere. The solution obtained was stirred at ambient temperature for 13 hours, a further 3 ml of dihydropyran and 30 mg of pyridine hydrochloride were added, and the mixture was stirred for a further 4 hours, washed with two 400 ml portions of saturated, aqueous sodium bicarbonate and 400 ml of saline,

Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 49 g of a pale yellow oil, namely crude 5 <x-hydroxy-3a-tetrahydropyran-2-yloxy - 2 / 3- (t-butyldimethylsilyloxymethyl) -la-cyclopentanacetic acid- -oj-lactone. Chromatography on 800 g of silica gel, eluting with 0-75% ethyl acetate in hexane, gave 37 g of the pure product as a colorless oil. NMR absorptions (CDCI3) were observed at 0.05, 0.90, 1.62, 2.0-3.0,

3.6, 3.2-4.4, 4.67 and 4.8-5.2 b. Infrared absorption bands

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were observed at 1789, 1255, 1175, 1160, 1116, 1080, 1035, 1020, 1005, 975, 835 and 775 cm "1. silica gel DC.Rf = 0.25 in hexane and ethyl acetate (2: 1).

D. A solution of 28 ml of dimethyl methylphosphonate in 800 ml of dry tetrahydrofuran at a temperature of -70 ° C under a nitrogen atmosphere was treated with 160 ml of 1.56 M n-butyllithium in hexane and for 30 minutes at a temperature of -70 ° C stirred. The resulting mixture, kept at a temperature of -70 ° C., was then added dropwise over 30 minutes with 41.7 g of the reaction product from part C in 200 ml of tetrahydrofuran. The resulting solution was then stirred at a temperature of -70 ° C for one hour, warmed, stirred for a further 2.5 hours at ambient temperature, quenched by the addition of 14 ml of glacial acetic acid, emptied in 1 liter of saline, with three 700 ml Portions of diethyl ether extracted, washed with 500 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 63 g of a yellow oil, namely crude. 6j3- (t-butyldimethylsilyloxymethyl) -3-dimethyl-phosphono-methyl-3-hydroxy-2-oxa-7a-tetrahydropyranyloxy-bicyclo [3,3,0] octane. Chromatography on 800 g of silica gel, eluting with 50-75% ethyl acetate in hexane, gave 44.2 g of the pure title product as a colorless oil. NMR absorption (CDC13) was observed at 0.05, 0.89, 1.23-3.02, 2.2-4.37, 4.70 and 4.99 5. Infrared absorption bands were observed at 3380, 1255, 2235, 11220, 1050, 1035, 835 and 775 cm-1. Silica gel DC.Rf = 0.25 in ethyl acetate.

E. A suspension of 29.2 g of chromium trioxide in 700 ml of methylene chloride was quickly mixed with 50 ml of pyridine while stirring at ambient temperature under a nitrogen atmosphere, treated with dry diatomaceous earth, stirred for 5 minutes and then with 23.8 g of the title product from part D in 60 ml of methylene chloride. The resulting suspension was then stirred for 45 minutes at ambient temperature under a nitrogen atmosphere and filtered through 300 g of silica gel, eluting with 2 liters of ethyl acetate in acetone (2: 1). After concentration under reduced pressure, 24 g of a brown, yellow oil, namely crude 3 / J- (t-butyldimethylsilyloxymethyl) -2a :-( 2'-dimethylphosphonomethyl-2'-oxoethyl) -4ü: -tetrahydropyranyloxy- pentanon. High pressure liquid chromatography of 12 g of the crude product on silica gel, eluting with 20% acetone in methylene chloride, gave 4.54 g of the pure product as a colorless oil. NMR absorption (CDC13)

were observed at 0.05, 0.88, 2.8-4.5, 3.77 and 4.86 5. Infrared absorptions were observed at 1745, 1715, 1255, 1130, 1115, 1060, 1025, 835, 810 and 775 cm- '. Silica gel DC.Rf

• = 0.27 in 20% acetone in methylene chloride and Rf = 0.3 in ethyl acetate.

F. A degassed suspension of 0.52 g of the reaction product from Part E, 0.15 g of anhydrous potassium carbonate and 0.59 g of 18-crown-6-ether in 20 ml of toluene was under at a temperature of 75 ° C for 6 hours stirred in a nitrogen atmosphere and then cooled to a temperature of 0 ° C. The resulting solution was then washed successively with 20 ml of brine, a solution of 15 ml of water and 5 ml of brine, and 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to give a brown residue, namely crude 6β-t-butylimethylsilyloxymethyl 7oi-tetrahydropyran-2-yl-oxybicyclo [3,3,0] oct-l-en-2-one, which was filtered through 7 g of silica gel, eluting with hexane and ethyl acetate (70 ml, 1: 1) to give 0.31 g of the product as an oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml / minute flow rate) on silica gel eluting with hexane and ethyl acetate (3: 1) gave 0.20 g of the pure product as a colorless oil. NMR

Absorbances (CDCI3) of the trimethylsilyl derivative were observed at 0.06, 0.90, 1.20-3.20, 3.20-4.85 and 5.85-6.0 5. Infrared absorption bands were observed at 1710, 1630, 1250, 1130, 1115, 1075, 1030, 965, 870, 835, 810, 775 cm "1. Silica gel DC.Rf = 0.34 in hexane and ethyl acetate (2: 1).

G. A suspension of 0.35 g of anhydrous copper iodide in 12 ml of anhydrous diethyl ether was added dropwise with 2.0 ml of 1.4 M methyl lithium at a temperature of 20 ° C. under an argon atmosphere. The resulting solution was then stirred at a temperature of -20 ° C for 15 minutes, at a temperature of -20 ° C dropwise for 1.5 hours with a solution of 0.22 g of the reaction product from Part F in 12 ml of anhydrous Diethyl ether added. The resulting suspension was then stirred at a temperature of −20 ° C. for 2 hours, poured into 50 ml of 1 M aqueous ammonium chloride, extracted with 150 ml of diethyl ether, washed with 50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, to give 0.23 g of the crude title product as a pale yellow oil. Chromatography on 30 g of silica gel, eluting with ethyl acetate in hexane (1: 4), gave 0.22 g of the pure title product as a colorless oil. NMR absorption (CDCI3) was observed at 0.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4 and 4.63 5. Infrared absorption bands were observed at 1745, 1255, 1135, 1110, 1095, 1075, 1035, 1020, 835 and 775 cm- '. Silica gel DC.Rf = 0.32 in ethyl acetate in hexane (1: 4).

Example 21

N-methyl- (l-fluoro-5-tetrahydropyranyloxypentyl) phenyl sulfoximine (Formula XCII: Z2 is - (CH2) 32- and R10 is tetrahydropyranyl.)

Compare formula scheme H.

Diisopropylamine (0.59 g) was dissolved in 21 ml of tetrahydrofuran and the resulting mixture was cooled to a temperature of -78 ° C with stirring under an atmosphere of argon. Then triphenylmethane was added, which served as an indicator, and a solution of n-butyllithium and hexane was added dropwise until the resulting mixture turned pink in color. After stirring for a further 75 minutes, the resulting mixture was treated with 1.50 g of N-methyl- (5-tetrahydropyranyloxypentyl) phenylsulfoximine, dissolved in 6 ml of dry tetrahydrofuran. The resulting mixture was then stirred for a further 30 minutes at a temperature of -78 ° C. Excess perchloryl fluoride (FCIO3) was then blown through the solution for 4-5 minutes, during which time an argon stream was also blown through the mixture for safety reasons. The resulting mixture was then stirred for a further 90 minutes at a temperature of -78 ° C and then the reaction was quenched by the addition of 5% aqueous sodium bicarbonate. After equilibrating the reaction mixture to ambient temperature, the mixture was diluted with additional 5% aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.64 g of a yellow oil. Chromatography on silica gel columns in a series, eluting with ethyl acetate and hexane (1: 1), gave 0.18 g of the title product of formula XCII as a mixture of diastereomers. Silica gel DC.Rf values in ethyl acetate and hexane (1: 1) were 0.54 (less polar isomer) and 0.45 (more polar isomer). NMR absorptions (CDCI3) for the less polar isomer were observed at 1.2-2.12, 3.65, 3.68, 3.1-4.1, 4.4-4.8, 5.5 and 7.4-8.1 ô. NMR absorption (CDC13) for the more polar isomer was

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the. observed at 1.5-2.20, 3.63, 3.1-4.1, 4.45-4.65, 5.27 and 7.4-8.1 p.

Following the procedure of Example 21, but using all different phenylsulfoxamines of formula XCI, all different corresponding fluorinated phenylsulfoxamines of formula XCII were prepared.

Example 22

5-fluoro-2-decarboxy-2-hydroxymethyl-CBA2-l, ll, 15-tris (tetrahydropyranyl ether). (Formula XCIV: R16 and Rn are both hydrogen, Rio is tetrahydropyranyl, Z2 means - (CH2) 3-, n is the whole number, RJ8 means tetrahydro-

pyranyloxy, Yi is trans-CH = CH-, Mç is a-tetrahydro-pyranyloxy: / 3-hydrogen, R3 and R4 of the Lp part both mean hydrogen, and R7 is n-butyl).

Compare formula scheme H.

Diisopropylamine (164 mg) and triphenylmethane (1.5 mg) were dissolved in 4 ml of dry tetrahydrofuran and the resulting solution was cooled to a temperature of -78 ° C under a nitrogen atmosphere. A solution of n-butyllythium and hexane was added until a pale pink color was obtained. This solution was then stirred for a further 80 minutes. Then 0.488 g of the title product from Example 21 in 4 ml of dry tetrahydrofuran was added dropwise. Then 608 mg of 7-oxo-3o: -tetrahydropyran-2-yloxy-2 | 3 - [(3 ', S) -3'-tetrahy-dropyran-2-yloxy-trans - ^' - octenyl] bicyclo [ 3.3.0] octane (formula XCIII: Ri6, marginal n, R18, Yi, M6, Lj and R7 are defined for the title product) in 4 ml of tetrahydrofuran added to the reaction mixture. After 4 minutes, the resulting mixture was quenched by the addition of saturated aqueous ammonium chloride, and then ethyl acetate was added to the reaction mixture, which was kept at a temperature of -78 ° C. The resulting mixture was warmed until solids precipitated. Additional ethyl acetate was then added and the reaction mixture was extracted with brine. The ethyl acetate layer was then dried over sodium sulfate and concentrated under reduced pressure.

An aluminum amalgam was then prepared by reacting 0.31 g of 20 mesh aluminum with 2.5 ml of aqueous mercury chloride, followed by washing with ethyl acetate and diethyl ether. The residue from the ethyl acetate layer (described in the previous section) was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to a temperature of 0 ° C. This cooled solution was then treated with aluminum amalgam, 2 ml of water and 1 ml of glacial acetic acid. The resulting mixture was then stirred at a temperature of 0 ° C for 2 hours and at a temperature of 20 ° C for 16 hours. The reaction mixture was then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer was washed with 5% aqueous sodium bicarbonate and saturated saline, dried over sodium sulfate and concentrated under reduced pressure to give 0.96 g of an oily residue. Chromatography on 100 g of silica gel and eluting with 500 ml of 15% ethyl acetate in mixed hexanes, 500 ml of 25% ethyl acetate in mixed hexanes, 300 ml of 50% ethyl acetate in mixed hexanes, and 800 ml of 50% acetone in methylene chloride, with 20 ml fractions a less polar isomer in fractions 22-26 (80 mg) and a more polar isomer in fractions 30-36 (74 mg). These isomers represent the C-5 diastereomers of the product of formula XCIV. The less polar isomer showed NMR absorptions (CDC13) at 0.65-2.65, 3.15-4.15, 4.35-4.75 and 5.25-5.75 5. For the more polar isomer, NMR absorptions (CDC13) were observed at 0.6-2.65, 3.10-4.15, 4.40-4.7 and 5.2 -5.7 5. silica gel DC.Rp value for the less polar isomer i; t 0.66 and de Rr value for the more polar isomer is 0.57 in ethyl acetate and mixed hexanes (3: 7).

Following the procedure of Example 22, but using all of the various ketones of formula XCIII, all of the various intermediates of formula XCIV were obtained, wherein Z2 has the meaning of - (CH2) 3-.

Furthermore, all different products of the formula XCIV were prepared from the various ketones of the formula XCIII, in which Z2 has a meaning other than - (22), but with replacement of all different fluorinated phenylsulfoximines, described after example 21. CH2) 3-.

Example 23

5-fluoro-2-decarboxy-2-hydroxymethyl-CBA2- (more polar

Isomers) (Formula XCV: R16, R17, Z2, n, R8, Mi, Lj and R7 have the same meaning as in Example 17).

Compare formula scheme H.

The title product from Example 22 (74 mg) was dissolved in 2 ml of a mixture of tetrahydrofuran, water and glacial acetic acid (2: 2: 1) and the resulting mixture was stirred under a nitrogen atmosphere. The reaction mixture was kept at ambient temperature for 17 hours, then it was heated to a temperature of 40 ° C. for 7 hours and finally it was kept at a temperature of 23 ° C. for a further 24 hours. The resulting mixture was then diluted with ethyl acetate, washed with 5% aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 52 mg of the crude title product. Chromatography on silica gel, eluting with acetone and methylene chloride (60:40), gave 19 mg of the pure title product. NMR absorptions (CDC13) were observed at 0.6-2.60, 2.60-3.30, 3.30-4.14, 5.1-5.9 5. 13C NMR absorptions (CDCI3) were observed at 135.8, 133.0, 117.5 (d, J = 18Hz), 77.4, 73.3, 62.6, 57.6, 46.4, 41.1, 38.0, 37.2, 36.2 (d, J = 5Hz), 31.9, 31.8, 31.2, 29.5 (d, J = 29), 25.2, 22.5, 14.0. Silica gel DC.Rf = 0.280 in acetone and methylene chloride (1: 1).

Example 24

5-fluoro-2-decarboxy-2-hydroxymethyl-CBA2 (less polar isomers).

In accordance with the procedure of Example 23, 85 mg of the less polar title product from Example 22 were converted into 25 mg of the pure title product. NMR absorptions (CDC13) were observed at 0.5-2.5, 3.1-4.75 and 5.05-5.8 5. 13C NMR absorptions (CDC13) were observed at 137.0, 132 , 6, 77.0, 73.6, 62.3, 57.4, 45.5, 41.6, 36.9, 36.5, 34.4 (d, J = 3, lHz), 32, 5 (d, J = 5.4Hz), 31.8, 31.7, 29.2 (d, J = 28.9Hz), 25.4, 22.6, 22.4 and 14.0 5. silica gel DC.Rf = 0.33 in acetone and methylene chloride.

According to the process from Examples 23 and 24, but using the various diastereomeric products described after Example 22, all of the various diastereomers were prepared in accordance with the formula XCV.

Example 25

5-fluoro-CBA2- (more polar isomer) (Formula LXXVI: Z2, n, Rg, Yi, Mi, Li and R7 are defined in Example 23).

Compare formula scheme H.

The platinum oxide catalyst was prepared by suspending 46 mg of 85% platinum oxide in 9 ml of water and hydration

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the resulting mixture at ambient temperature and under pressure for 34 minutes. 58 mg of sodium bicarbonate and 18 mg of the title product from Example 23, dissolved in 2 ml of acetone, were added to this suspension. The resulting mixture was then heated to a temperature of 60 ° C. and oxygen was bubbled through for 80 minutes. The reaction mixture was then filtered through diatomaceous earth and the filter cake was washed in water. The filtrate was then acidified to a pH of 4 with 5% aqueous hydrogen sulfate and extracted with ethyl acetate. The organic extracts were then dried over magnesium sulfate and concentrated under reduced pressure to give 21 mg of the pure title product. NMR absorptions (CDCI3) were observed at 0.6-2.8, 3.0-4.2 and 4.65-5.8 5. 13C NMR absorptions (CDCI3) were observed at 176.9, 135 , 5, 133.2, 118.5, (d, J = 17.5Hz), 77.7, 73.5, 57.3, 46.5, 41.0, 38.2, 37.0, 36 , 2 (d, J = 4.8Hz), 32.3, 31.7, 31.1 (d, J = 13.5Hz), 28.5 (d, J = 28.3Hz), 25.2, 22.6, 21.0 and 14.0 6. silica gel DC.Rf = 0.39 in A-IX solvent system.

Example 26 5-Fiuor-CBA2 (less polar isomer).

According to the procedure of Example 25, 24 mg of the title product from Example 24 were converted into 23 mg of the pure title product. NMR absorptions (CDCI3) were observed at 0.6-2.9, 3.3-4.2, 5.0-6.0 ò. I3C NMR absorptions (CDCI3) were observed at 176.8, 135.4, 132.9, 118.3 (d, J = 18.2Hz), 77.6, 73.4, 57.2, 46, 3, 41.2, 37.8, 36.8, 34.6 (d, J = 2.7Hz), 32.8, 32.4, 31.7, 28.7 (d, J = 28.4Hz ), 25.2, 22.6, 21.1 and 14.0 5. DC.Rf = 0.50 in the A-IX solvent system.

The reaction products from Examples 25-26 were obtained as diastereomer mixtures of the (5E) and (5Z) geometric isomers. These geometric isomers have been characterized herein as “less polar” and “more polar” isomers based on DC migration. The isomers of these 5-fluoro-CBA2 compounds correspond to (5E) and (5Z) geometric isomers of CBA2 itself. Based on the relative biological activities, the more polar 5-fluoro-CBA2 isomer gave more potent pharmacological effects and on this basis it was able to the (5Z) structure can be assigned based on pharmacological considerations only. However, the 13C NMR data indicate that the more polar isomer corresponds to the (5E) structure of the 5-fluor-CBA2 compound.

According to the procedure of Examples 25-26, all of the various 5-fluoro-CBA2 diastoeromers of the formula XCVI were prepared from the starting materials which are described in connection with Example 24.

Furthermore, according to the methods known in the prior art, all the different 5-fluoro-CBA2 compounds described in and following Examples 24-25 were converted into the corresponding 5-fluoro-CBA2 analogs the formula XCVII transferred.

Example 27 (5Z) -9 / 3-methyl-CBA2-adamantylamine salt.

The title product from Example 18 (54 mg), (5Z) -9 / 3-methyl-CBA2, in 6 ml of diethyl ether was mixed with 23 mg of adamantylamine. After 10 minutes, the precipitate formed, which was then stirred for 12 hours, decanted off and concentrated under reduced pressure to give 68 mg of a solid, namely the pure title product. The melting range was 110-114 ° C.

Example 28 (5Z) -9 / 3-methyl-CBA2 calcium salt hydrate.

The title product from Example 18 (0.96 g), 9j8-methyl- (5Z) - CBA2, calcium oxide (0.064 g), freshly boiled water (9.2 ml) and distilled tetrahydrofuran (6 ml) were combined and opened heated to a temperature of 50 ° C under a nitrogen atmosphere and stirred for 20 min. The resulting mixture was then filtered, washed with tetrahydrofuran and concentrated under reduced pressure to give a residue. The residue was then dissolved in tetrahydrofuran (10 ml) and concentrated eight times to give an off-white foam. This foam was then dissolved in 6 ml of tetrahydrofuran and added dropwise to anhydrous diethyl ether (95 ml). The resulting suspension was then stirred for 15 minutes at ambient temperature under a nitrogen atmosphere and filtered. The filter cake was then washed with anhydrous diethyl ether and dried for 20 hours under reduced pressure at ambient temperature to give 0.686 g of the title product. The melting range was 101-108 ° C. After atmospheric equilibration, the melting range was 80-117 ° C. Infrared absorption bands were observed at 3330, 1670, 1555, 1455, 1345, 1310, 1270, 1075, 1020 and 970 cm -

Example 29

8a-Hydroxy-7 / 3- (3o: -hydroxy-trans-l-octenyl) -tricyclo [4,3, l] -nonan-4-one-8,3'-bis (tetrahydropyranyl ether) (Formula XXV :

Ris, Yi, Mg, Li, R27 and n are defined in Example 1, Ri6 and R37 taken together mean -CH2-).

Compare formula scheme A.

A. The title product of formula XXIV from Example 1 (4.0 g) and benzophenone (2 g) in one liter of methanol were photolyzed for 3 hours (3500 A lamp) while argon was bubbled through the solution. The methanol was then removed by concentrating under reduced pressure and the residue was chromatographed on 600 g of silica gel, eluting with a mixture ranging from ethyl acetate in hexane (1: 3) to 100% ethyl acetate. The compound of formula XXVI, namely 1/3-hydroxymethyl-7a-hydroxy-6 / 3- (6'a-hydroxy-trans-r-octe-nyl) bicyclo [3,3,0] octan-3-one -7.3 '- (tetrahydropyranylether) was obtained as a white solid (3.45 g). Crystallization from ethyl acetate in hexane gave a white solid with a melting range of 65-70 ° C. NMR absorptions (CDCI3) were observed at 0.89, 1.17-2.90, 2.92-4.40, 4.69 and 5.24-5.77 ô. Infrared absorption bands were observed at 3420, 1730, 1200, 1110, 1070, 1040, 1020 and 970 cm- '. Silica gel DC.Rf = 0.29 in hexane and ethyl acetate (1: 4).

B. A solution of 0.6 g of the reaction product from Part A and 0.49 g of p-toluenesulfonyl chloride in 30 ml of pyridine was cooled to a temperature of 0 ° C. under argon for 70 hours, poured into 100 ml of ice, with 300 ml Diluted water and extracted with diethyl ether (800 ml). The ethereal extracts were then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure and chromatographed, eluting with 50% to 80% hexane in ethyl acetate to give 0.49 g of the compound of formula XXVII, namely 3-oxo -7a-tetrahydropyran

-2-yloxy-6 / H (3's) -3'-tetrahydropyran-2-yloxy-trans-r-octenyl] - 1/3 (p-toluenesulfonyl) oxymethyl-bicyclo [3,3,0] octane , which was obtained as a colorless oil. NMR absorptions (CDCI3) were observed at 0.88, 1.06-2.9, 2.45, 31.7-4.35, 4.52-4.83, 5.2-5.8, 7 , 37 and 7.81 6. Infrared absorption bands were observed at 1740, 1600, 1360, 1200, 1190, 1175, 1130, 1110,

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1075, 1035, 1020, 970 and 820 cm "1. Silica gel DC.Rr = 0.45 or 0.26 in ethyl acetate and hexane (1: 1 or 1: 2).

C. A degassed solution of 0.49 g of the reaction product from Part B and 1 ml of t-butanol in 50 ml of dry tetrahydrofuran was treated with 0.8 ml of 1.7 M potassium t at a temperature of 0 ° C. under an argon atmosphere. treated butoxide in tetrahydrofuran. After 5 minutes the reaction was warmed and the resulting brown solution was stirred at ambient temperature for 3 hours. Then 90 ml of saline was added and the mixture was extracted with 270 ml of ethyl acetate. The ethyl acetate extracts were then washed with 100 ml of saturated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 0.37 g of a brown oil, and chromatographed on 40 g of silica gel, with hexane and ethyl acetate (2: 1) was eluted to give 0.32 g of the pure title product of Formula XXV as a colorless oil.

D. Alternatively, a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 g of trimethyloxosulfonium iodide was treated dropwise with 6 ml of dimethyl sulfoxide under a nitrogen atmosphere. The resulting gray slurry was then stirred at ambient temperature for 20 minutes, 2.03 g of the title product from Example 1 in 4 ml of dry dimethyl sulfoxide was added, and the mixture was stirred at ambient temperature for 2 hours. The stirring was then continued for 1 hour at a temperature of 50 ° C., the reaction product was cooled and diluted with 200 ml of water and then extracted with three 100 ml portions of diethyl ether. The combined ethereal extracts were then washed with 200 ml of water and with 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a brown oil, and chromatographed on 250 g of silica gel, using ethyl acetate and hexane (1: 2) was eluted, and 453 mg of the pure title product were obtained.

E. For the title product, prepared according to Part C or Part D above, NMR absorptions (CDC13) were observed at 0.25-2.75, 3.15-4.39, 4.68 and 5.2-5, 8 5. Infrared absorption bands were observed at 1725, 1665, 1135, 1080, 1040, 1020 and 980 cm-1. The mass spectrum showed a molecular ion at 446 and the silica gel DC.Rr value in ethyl acetate and hexane was 0.30.

Example 30

(5Z) and (5E) -6a / 3.9 / 3-methano-CBA (formula X: Xi is -COOH, Zi is - (CH2) 3-, R15 is hydrogen, Ri6 and Rn taken together are methano, n is one, Rg is hydroxy, Y, is trans-CH = CH-, Mi is a-OH: ß-R, Li is aH: / 3-H, R7 is n-butyl and the C-5, C-6 positions are unsaturated.

Compare formula scheme G.

A. A suspension of 452 mg of 57% sodium hydride in mineral oil and 30 ml of dimethyl sulfoxide was heated to a temperature of 65 ° C for 1 hour under a nitrogen atmosphere, cooled to a temperature of 17 ° C and then for 15 minutes at 2.39 g of 4-carboxybutyl-triphenylphosphonium bromide were added. The resulting red solution was then stirred for 15 minutes at a temperature of 17-20 ° C., a solution of 716 mg of the title product from Example 29 and 6 ml of dry dimethyl sulfoxide was added, and the mixture was stirred at a temperature of 40 ° C. for 43 hours , cooled to a temperature of 0 ° C, treated with 3.5 ml of water, stirred for 30 minutes at a temperature of 0 ° C, added in 75 ml of water and brine (2: 1), acidified with 1N aqueous hydrochloric acid and then extracted with 225 ml of diethyl ether. The ethereal extracts were then washed with 375 ml of water and 75 ml of brine, dried over magnesium sulfate, concentrated under reduced pressure and chromatographed on 150 g of silica gel washed with acid, eluting with 10-25% ethyl acetate in hexane, to give 290 mg (5Z) -6a / 3-9 | 3-metha-no-CBA2-ll, 15-bis (tetrahydropyranylether), 70 mg (5E) -6a / 3, -9 / 3-methano-CBA2-l l, 15 bis (tetrahydropyranyl ether) and 400 mg of a mixture of (5E) and (5Z) isomers of the formula LXXXIII. Rechromatography of the mixture of isomers on 150 g of silica gel washed with acid gave a further 50 mg of the (5E) isomer and 180 mg of the (5Z) isomer.

For the (5Z) isomer, NMR absorptions (CDC13) were observed at 0.5-2.85, 3.22-4.4, 4.70, 4.9-5.75 and 10.1 5. Infrared Absorption bands were observed at 3600-3000 (a broad band), 1740, 1710, 1240, 1210, 1135, 1080, 1035, 1020, 980 and 870 cm-1. Silica gel DC.Rf = 0.27 in hexane, ethyl acetate and acetic acid (64: 34: 1). For the (5E) isomer, NMR absorptions were observed at 0.40-2.70, 3.2-4.4, 4.70, 5.0-5.8 and 8.82 6. Infrared absorption bands were observed at 3600-3000, 1740, 1719, 1460, 1445, 1200, 1135, 1075, 1035, 1020 and 980 cm "1. silica gel DC.Rf = 0.32 in hexane, ethyl acetate and acetic acid (65: 34: 1).

B. A solution of 446 mg of the (5Z) reaction product from Part A in 44 ml of acetic acid, water and tetrahydrofuran (6: 3: 2) was heated to a temperature of 45 ° C under a nitrogen atmosphere for 3 hours, cooled and in 200 added ml of saline, extracted with 160 ml of ethyl acetate in hexane (3: 2), washed with 500 ml of brine, extracted with 120 ml of ethyl acetate and hexane (3: 2),

Dried over sodium sulfate, concentrated under reduced pressure to give 0.38 g of a yellow oil, and chromatographed on 60 g of silica gel washed with acid, eluting with 70% ethyl acetate in hexane, to give 170 mg of the pure (5Z) title product as one to give colorless oil. NMR absorptions were observed at 0.5-2.90, 0.89, 4.05, 4.85-5.8 and 6.13 5. Infrared absorption bands were observed at 3360, 2260, 1710, 1245, 1240 , 1075, 1025 and 970 cm-1. The mass spectrum of the tris-trimethylsilyl derivative showed a high resolution peak at 578.3653. Silica gel DC.Rf = 0.30 in the A-IX solvent system (the organic phase of an equilibrated mixture of ethyl acetate, acetic acid, cyclohexane and water; 9: 2: 5: 10).

C. According to the procedure of Part B above, 90 mg of the (5E) reaction product from Part A was converted into 46 mg of the (5E) title product, which was obtained as a colorless oil. NMR absorptions were observed at 4.40-2.8, 0.89, 4.06 and 5.0-5.85 5. Infrared absorption bands were observed at 3340, 2630, 1710, 1070 and 970 cm-1. The mass spectrum showed a high resolution peak at 578.3664. Silicagel DC.Rf = 0.32 in the A-IX solvent system.

According to the process of Examples 27-29, all of the various products of the formula X, in which Ri6 and Rn are methano, were prepared from the corresponding reactants of the formula LXXXI from formula G

Accordingly, the above examples provide methods of making all of the various CBA analogs of Formula X according to the invention.

Example 31

9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGFia (formula XI: Xi is COOH, R20, R21, R23 and R24 all represent hydrogen, Z4 is -CH2-, R22 is / 3-hydrogen, Rg, Xi, Mi, Li and R7 are defined in Example 8) and the corresponding methyl ester (Xi means -COOCH3).

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Compare formula scheme P.

A. A solution of methyl-phenyl-N-methyl-sulfoximine (3.39 g) in dry tetrahydrofuran (60 ml) was alternately degassed and purged with nitrogen, cooled to a temperature of -78 ° C and added dropwise over 7 min 2.8 M methyl magnesium cnloride (7.16 ml) was added. The resulting solution was stirred at a temperature of -78 ° C for 30 minutes and then at a temperature of 0 ° C for 15 minutes. The reaction mixture was cooled to a temperature of -78 ° C. and with a solution of 3-oxal-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGEi-3- (t- Bu-tyldimethylsilyl ether) -1 1,15-bis (tetrahydropyranyl ether) (6.05 g), a compound of the formula CLXXI, in dry tetrahydrofuran (35 ml). The resulting mixture was stirred for 1.75 hours while the temperature was raised from -78 ° C to 0 ° C, and then stirred at a temperature of 0 ° C for 1 hour. The reaction mixture was then diluted with brine (170 ml) and extracted with diethyl ether. The ethereal extracts were then washed successively with saline (170 ml), 0.5 M aqueous potassium bisulfate (170 ml), saturated aqueous sodium bicarbonate (170 ml) and brine (170 ml), dried over magnesium sulfate, filtered and concentrated to a yellow oil (8.0 g), namely 9 - [(N-methyl) -phenylsulfoximinmethyl] -3-oxa-l, 2,4,5,6-penta-nor-3,7-inter-m- phenylene PGFi-3- (t-butyldimethylsilyl ether) - 11, 15-bis (tetrahydropyranyl ether). A degassed solution of 9 - [(N-methyl) -phenylsulfoximinmethyl] -3-oxa-l, 2,4,5,6-penta-nor-3,7-inter-m-phenylene-PGFr3- (t-butyldimethylsilyl ether ) - 11, 15-bis (tetrahydropyranylether) (8.0 g) in tetrahydrofuran (150 ml) was cooled to a temperature of 0 ° C., treated with 50% acetic acid / water (45 ml) and then immediately with aluminum amalgam Nitrogen added. "(The aluminum amalgam was produced from 8.0 g of aluminum with a mesh size of 20, which with 170 ml of di-

■ ethyl ether and 340 ml of methanol was washed, and 8.03 g of mercury chloride in 275 ml of water, 170 ml of methanol and 170 ml of diethyl ether.)

The resulting black suspension was stirred for 1.75 hours, during which the reaction temperature was slowly raised from 0 ° C. to 15 ° C. and then lowered to 0 ° C., ethyl acetate (210 ml) was added and the mixture was stirred for a further 30 minutes stirred at a temperature of 0 ° C. The suspension was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The combined filtrate was then washed with brine (300 ml), 0.5 M aqueous potassium sulfate (300 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (300 ml). wash, dried, filtered and concentrated to a yellow oil, the crude compound of formula CLXXII (6.03 g), namely 9-deoxy-9-methylene-3-oxa-l, 2,4,5,6-pentanor- 3,7-inter-m-phenylene PGF i-3- (t-butyldimethylsilyl ether) -l 1,15-bis (tetrahydropyranyl ether). The crude product was combined with that from a repeated preparation to give 10.1 g of the product of formula CLXXII, which was chromatographed on silica gel, eluting with 5% ethyl acetate in Skel-lysolve B (SSB, isomeric hexanes) , around 6.93 g of 9-deoxy-9-methylene-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-3- (t- butyldimethylsilyl ether) -ll, 15-bis (tetrahydro-pyranyl ether) to give. NMR absorptions were observed at 4.52-5.12 and 6.53-7.30 5. Infrared absorption bands were observed at 1600 and 1655 cm-1. Silica gel DC.Rf = 0.39 in 10% ethyl acetate in hexane.

B. A degassed solution of 9-deoxy-9-methylene-3-oxa - 1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-3- (t-butyldime- thylsilyl ether) -ll, 15-bis (tetrahydropyrany! ether), the reaction product from part A, (1.33 g) in dry tetrahydrofuran (70 ml) was cooled to a temperature of 0 ° C. and under nitrogen with 0 , 5 M 9-borabicyclo [3,3, 1] nonane (14 ml) was added dropwise over 5 min. The colorless solution was stirred at a temperature of 0 ° C for 4.5 hours, and 30% hydrogen peroxide (6 ml) was added, followed by the addition of 3 N potassium hydroxide (6 ml). The resulting suspension was stirred for a further 30 minutes at a temperature of 0 ° C. and for 75 minutes while warming to room temperature. The reaction mixture was placed in a separatory funnel, diluted with brine (300 ml) and ethyl acetate (300 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (600 ml). The organic extracts were washed with brine (6 ml), dried, filtered and concentrated to the product of the formula CLXXII, a colorless oil (3.3 g), namely 9-deoxy-9a- (hydroxymethyl) -3-oxa-1,2 , 4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-3- (t-butyldimethylsilyl ether) -11.15-bis- (tetrahydropyranyl ether). The crude product of formula CLXXIII was chromatographed on silica gel (300 g) eluting with 35% ethyl acetate in hexane to give 1.26 g of 9-deoxy-9a- (hydroxymethyl) -3-oxa-1,2. 4,5,6-pentanor - 3,7-inter-m-phenylene-PGFi-3- (t-butyldimethylsilyl ether) - 11, 15-bis (tetrahydropyranyl ether) as a colorless oil. NMR absorptions were observed at 4.73, 5.12-5.70, 6.52-7.23 ô. Infrared absorption bands were observed at 3480 and 1670 cm-1. Silica gel DC.Rf = 0.21 in 35% ethyl acetate in hexane.

C. A degassed solution of 9-deoxy-9a-hydroxymethyl-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-3- (t-bu- tyldimethylsilyl ether) -l 1,15-bis (tetrahydropyranyl ether) (2.01 g), the reaction product from Part B, in dry methylene chloride (45 ml) was cooled to a temperature of -5 ° C under nitrogen and with Triethylamine (0.72 ml) was added, followed by the addition of methanesulfonyl chloride (0.76 ml). The resulting solution was stirred at a temperature of -5 ° C for 5 minutes and then for 75 minutes while warming to ambient temperature. The reaction solution was poured onto ice and the resulting mixture was stirred for a few minutes and then placed in a separatory funnel and partitioned between diethyl ether and brine. The layers were separated and the aqueous layer was extracted with ether (400 ml). The organic layer was washed with brine (200 ml) and saturated aqueous sodium bicarbonate (400 ml), dried, filtered and concentrated to a product of formula CLXXIV, a colorless oil (2.69 g), namely 9-deoxy-9o: -mesyloxymethyl-3-oxa-l, 2,4,5,6-pentanor-3,7-in-ter-m-phenylene-PGFi-3- (t-butylidimethylsilyl ether) -l 1,15-bis ( te-trahydropyranyl ether). This product (2.69 g) was chromatographed on silica gel (185 g), eluting with 25% ethyl acetate in Skellysolve B, to give 1.99 g of 9-deoxy-9a-mesyloxy methy 1-3 -oxa- 1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-3- (t-butyldimethylsilyl ether) -ll, 15-bis (tetrahydro-pyranyl ether). NMR absorptions were observed at 2.95, 4.70, 5.20-5.70 and 6.52-7.22 5. silica gel DC.Rf = 0.30 in 35% ethyl acetate in hexane.

D. A degassed solution of 9-deoxy-9a-mesyloxymethyl-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF | -3- (t-bu -tylmethylsilyl ether) -l 1,15-bis (tetrahydropyranyl ether) (0.971 g), the reaction product from part C, in dry tetrahydrofuran (35 ml) was cooled to a temperature of 0 ° C. and under nitrogen with 0. 75 M tetrabutylammonium fluoride (2.6 ml) was added. The resulting amber solution was stirred at a temperature of 0-5 ° C for 2.5 hours and partitioned between ethyl acetate (150 ml) and brine (150 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (300 ml). The organic layer was then washed with 0.5 M aqueous ammonium chloride (150 ml), saturated aqueous sodium bicar-

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bonate (300 ml) and brine (150 ml), dried, filtered and concentrated to give 0.82 g of the product of formula CLXXV, namely 9-deoxy-9a-mesyloxy-methyl-3-oxa-1,2 , 4,5,6-pentanor-3,7-inter-m-phenylene-PGFr-III, 15-bis (tetrahydropyranyl ether). An infrared absorption band was observed at 3330 cm-1, silica gel DC.Rr = 0.37 in 50% ethyl acetate in hexane.

E. A degassed solution of 9-deoxy-9a-mesyloxymethyl-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFi-l 1,15-bis- (tetrahydropyranyl ether) (0.82 g), the reaction product from Part D, was cooled to a temperature of -40 ° C under argon and 57% sodium hydride (0.67 g) was added. The resulting suspension was then stirred for 40 minutes at a temperature of -40 ° C and then for 15 minutes at a temperature of 0 ° C. The suspension was stirred for a further 20 min while warming to room temperature and then stirred under reflux for 2.5 hours. The reaction mixture was then cooled to a temperature of 10 ° C., diluted with ice-cold saline (200 ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extracts were then washed with brine (300 ml), dried, filtered and concentrated to give 0.72 g of the crude product of the formula CLXXVI. The crude product was chromatographed on silica gel (175 g), eluting with 25% ethyl acetate in Skellysol-ve B, to give 0.49 g of 9-deoxy-2 ', 9a-me-thano-3-oxa-1 , 2,4,5,6-pentanor-3,7- (l ', 3' -interphenylene) - PGFi-1 l, 15-bis (tetrahydropyranyl ether). NMR absorptions were observed at 4.77, 5.32-6.03 and 6.52-7.22 5. Infrared absorption bands were observed at 3340 and 1670 cm-1. Silica gel DC.Rf = 0.56 in 35% ethyl acetate in hexane.

F. A degassed solution of 9-deoxy-2 \ 9o! -Methano-3 - oxa-l, 2,4,5,6-pentanor-3,7- (l ', 3'-inter-phenylene) - PGFi-ll, 15 - bis (tetrahydropyranyl ether) (0.47 g), the reaction product from part E, in dry glyme (15 ml) was cooled to a temperature of 0 ° C. and, under nitrogen, with methyl bromine -acetate (0.26 ml), followed by the addition of a 57% sodium hydride suspension (0.136 g). Following a violent effervescence, a white precipitate was formed. The resulting suspension was stirred at a temperature of 0-5 ° C for 2.5 hours, diluted with ice-cold saline (200 ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extracts were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated to a pale yellow oil (0.62 g), a compound of formula CLXXVII, namely 9-deoxy-2 ', 9a-methano-3-oxa --4,5,6-trinor-3,7- (l ', 3' -interphenylene) -PGFi-methyl ester-l 1,15 - bis (tetrahydropyranyl ether). Infrared absorption bands were observed at 1765 and 1740 cm-1.

G. A solution of 9-deoxy-2 ', 9-methano-3-oxa-4,5,6-trinor-3,7- (l', 3'-inter-phenylene) -PGFrmethyl-ester-l 1,15-bis (tetrahydropyranyl ether) (0.62 g), the reaction product from Part F, in acetic acid (15 ml), water (7.5 ml) and tetrahydrofuran (5 ml) was at a temperature of 45 ° C under nitrogen for 2.75 hours, cooled and diluted with ice-cold saline (200 ml). The resulting suspension was extracted with ethyl acetate (400 ml) and the organic extracts were washed with brine (400 ml), saturated aqueous sodium bicarbonate (600 ml) and brine (200 ml). The ethyl acetate extracts were then dried over magnesium sulfate, filtered and concentrated to give 0.44 g of a pale yellow oil.

This crude product was chromatographed on silica gel (60 g), eluting with 50% ethyl acetate in Skellysolve B, to give 0.37 g of a product which was crystallized and which gave 0.216 g of the title product.

namely 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3' - inter-pheny] en) -PGFi-methyl-ester. The melting range was 82-84 ° C. NMR absorptions were observed at 3.77, 4.62, 5.42-5.63 and 6.53-7.25 ô. Infrared absorption bands were observed at 3520, 3400 and 1735 cm-1. Silica gel DC.Rf = 0.30 in 35% acetone in methylene chloride.

H. A solution of 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGFrmethyl-ester (0, 15 g), the reaction product from part G, in 5% potassium hydroxide in

9: 1 methanol-water (5.5 ml) was stirred at a temperature of 0 ° C under nitrogen. The solution immediately became cloudy and a precipitate formed within 5 min. The reaction mixture was then stirred for 1 hour at a temperature of 0 ° C., diluted with ice-cold saline (90 ml), acidified with 1N hydrochloric acid and with ethyl acetate (180 ml) extracted. The ethyl acetate extract was then washed with brine (270 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a waxy semi-solid (0.131 g) which crystallized to give 0.105 g of the title product, namely 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGF]. The melting range was 131-133 ° C. NMR absorptions were observed at 4.68, 5.48-5.72, 6.68-7.22 6. Infrared absorption bands were observed at 3460, 3280, 1735, 1720 and 1700 cm "1.

I. The dose at which the title compounds should be administered to achieve their effect, primarily to prevent platelet aggregation or to lower blood pressure, will vary according to the effectiveness of the particular compound being studied. When administered orally, the compounds exhibit a desired effect in humans at a dose of about 0.05 to about 50 mg / kg orally, preferably from about 0.1 to about 5 mg / kg. The compounds 9-deoxy-2 ', 9o: -methano-3-oxa-4,5,6-trinor-3,7- (l', 3 '--interphenylene) -PGFi-methyl-ester, one Rat administered orally at a dose of 1 mg / kg lowered the blood pressure by 44 mm Hg. After 52 minutes the blood pressure was still 14 mm lower. Intravenous dosages for the desired effect are from about 1 to about 500 ng / kg / min. in humans, preferably from about 10 to about 100 ng / kg / min.

Example 32

9-deoxy-2 ', 9o: -methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -16,16-difluoro-PGFi (formula XI : Xj is -COOH, Li is a-fluorine: / 3-fluorine, R20, R21.R23 and R24 all mean hydrogen, Z4 is -CH2-, R22 is / 3-hydrogen, Rg, Yj, Mj and R7 are in Example 8 defined) and the corresponding methyl ester (Xi means -COOCH3).

Compare formula scheme P.

A. Diethyl ether (55 ml) tri-n-butylphosphine (2.28 g) and copper iodide (2.13 g) were combined with stirring and the resulting mixture was alternately degassed and purged with nitrogen at a temperature of 25 ° C for 1 hour. The resulting solution was then cooled to a temperature of -78 ° C and was referred to herein as Solution 32-1. Then 60 ml of anhydrous di. ethyl ether and 6.47 g m-bromo-phenol-t-butyldimethylsilyl ether combined and the resulting solution was alternately degassed and purged with nitrogen and cooled to a temperature of -78 ° C. After cooling, the resulting mixture was treated with 44.16 ml of a 1.02 M solution of 6-butyllithium in n-pentane. This reaction mixture was then stirred at a temperature of -78 ° C for 1 hour and hereinafter referred to as solution 32-11. Solution 32-11 was then stirred with solution 32-1 under a stick 5 for 15 minutes

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given atmosphere. The resulting solution changed color from clear to yellow, to orange-brown, to brown. The resulting mixture was then stirred at a temperature of -78 ° C for 30 minutes and referred to as solution 32-111. 4a-Hydroxy-3 / 3- (4 ', 4'-di-fluoro-3' o: -hydroxy-trans-r-octenyl) -2-methylene-cyclopentanone-4,3'-bis (tetrahydropyranyl -2-yl ether), 4 g, Example 25 of US Pat. No. 4,181,798, and 38 ml of anhydrous dry ethyl ether combined with stirring and the resulting mixture was alternately degassed and flushed with nitrogen and then to a temperature of -78 ° C cooled. The resulting solution was referred to herein as Solution 32-IV. Solution 32-IV was then added to solution 32-111 with vigorous stirring for 25 minutes at a temperature of -78 ° C under a nitrogen atmosphere. The reaction mixture was then stirred at a temperature of -78 ° C for 30 minutes and then added to 100 ml of 8% glacial acetic acid in diethyl ether (-40 ° C) with vigorous stirring and under a nitrogen atmosphere. The resulting mixture was then diluted with brine and extracted with diethyl ether. The ethereal extracts were then washed with aqueous potassium bicarbonate in brine, dried over sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel, eluting with 20% ethyl acetate in Skellysolve B, to give 5.56 g of the pure compound of formula CLXXI: 16.16 - difluoro-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-PGEr -3- (t-butyldimethylsilyl ether) -l 1, 15- bis (tetrahydropyranyl-2-yl ether). NMR absorptions (CDC13) were observed at 0.18, 3.1-5.0, 5.67, 6.52-6.88 and 6.88-7.2 5. Infrared absorption bands were observed at 1745, 1600, 1585, 1490, 1275, 1260, 1200, 1155, 1125, 1075, 1035, 1025, 975, 840 and 780 cm-1. Silica gel DC.Rf = 0.36 and 0.41 in 25% ethyl acetate in Skellysolve B. Silica gel DC.Rf = 0.5 in 5% acetone in methylene chloride.

B. According to the procedure of Example 31, Part A, 3.47 g of the reaction product from Part A of this example was converted into 2.98 g of the product of formula CLXXII, a colorless oil, namely 9-deoxy-9-methylene-3 -oxa-l, 2,4,5,6 - pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFi-3- (t-butylsilyl ether) -ll, 15- bis (tetrahydropyranyl ether). NMR absorptions were observed at 0.17, 0.97, 1.0-3.2, 3.2-4.4.4.4-5.0, 5.3-6.0 and 6.4- 7.3 S. Infrared absorption bands were observed at 1655, 1605, 1585, 1485, 1275, 1260, 1200, 1144, 1125, 1080, 1025, 970, 870 and 780- '. Silica gel DC.Rf = 0.31 and 0.36 in 10% ethyl acetate in hexane.

C. According to the procedure of Example 31, Part B, 2.83 g of the reaction product from Part B of this example was converted to 2.5 g of the product of formula CLXXIII, a colorless oil, namely 9-deoxy-9a- (hydroxymethyl ) -3-oxa-

-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-l 6,16-difluoro-PGF r -3- (butyldimethylsilyl ether) -l 1,15-bis (tetrahydropyranyl- ether). NMR absorptions (CDC13) were observed at 0.18, 0.98, 1.15-3.0, 3.0-4.5, 4.5-5.0, 5.3-5.9 and 6 , 4-7.3 5. Infrared absorption bands were observed at 3460, 1670, 1600, 1585, 1485, 1275, 1260, 1160, 1135, 1125, 1075, 1025, 975, 840 and 780 cm-1. Silica gel DC.Rf = 0.28 in 35% ethyl acetate in hexane.

D. According to the procedure of Example 31, Part C, the reaction product from Part C of this example (2.29 g) was converted into 1.83 g of the product of formula CLXXIV, a colorless oil, namely 9-deoxy-9a mesyloxymethyl-3-oxa - l, 2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFi - 3- (t-butyldimethylsilyl ether) -l 1 , 15-bis (tetrahydropyranyl ether). NMR absorptions were observed at 0.18, 0.98, 1.15-2.85, 2.95, 3.11-4.5, 4.5-5.0, 5.2-5.9 and 6.5-7.4 &. Infrared absorption bands were observed at 2930, 2860, 1605, 1590, 1490, 1465, 1440, 1360, 1275, 1200, 1175, 1120,

1025, 975 and 840 cm-1. Silica gel DC.Rf = 0.28 in 30% ethyl acetate and hexane.

E. According to the procedure of Example 31, Part D, 1.7 g of the reaction product from Part D of this example was transferred to 1.6 g of the product of formula CLXXV, a yellow oil, namely 9-deoxy-a-mesyloxymethyl -3-oxa-l, 2,4, -5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGF il 1,15 - bis (tetrahydropyranyl ether). Silica gel DC.Rf = 0.34 in ethyl acetate and hexane (1: 1).

io F. According to the procedure of Example 31, Part E, 1.52 g of the reaction product from Part D of this example was converted to 0.83 g of the product of the formula CLXXVI, a white foam, namely 9-deoxy-2 ', 9a-methano-3-oxa - l, 2,4,5,6-pentanor-3,7- (r, 3'-inter-phenylene) -16,16-difluoro-15 -PGFi-ll, 15- bis (tetrahydropyranyl ether). NMR absorbances were observed at 0.95, 1.05-2.95, 3.5-5.0, 5.3-6.0 and 6.5-7.2 5. Infrared absorption bands were observed at 3350 , 2930, 1670, 1615, 1590, 1465, 1280, 1200, 1120, 1070 and 975 cm-1. The mass spectrum showed peaks at 534, 451, 446, 20 402 and 348. Silica gel DC.Rf = 0.26 in ethyl acetate and hexane (1: 3) and Rf = 0.40 in acetone and methylene chloride (1:19).

G. According to the procedure of Example 31, Part F, 0.80 g of the reaction product from Part F of this example was converted to 1.06 g of the product of formula CLXXVII, one

2j colorless oil, namely 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-tri-nor-3,7- (r, 3'-inter-phenylene) -16,16-difluoro -PGFi-methyl-ester - ll, 15-bis (tetrahydropyranyl ether). Silica gel DC.Rf = 0.44 in 5% acetone and methylene chloride.

H. According to the procedure of Example 31, Part G, 301.0 g of the reaction product from Part G of this example was converted to 0.62 g of the crystalline methyl ester title product, a white solid of the formula CLXXVIII. Recrystallization from hexane in diethyl ether gave a material with a melting range of 93-95 ° C. NMR absorptions were observed at 0.95, 1.10-2.90, 2.90-4.8, 5.4-5.8 and 6.4-7.3 5. Infrared absorption bands were observed observed at 3560, 3400, 1765, 1750, 1735, 1720, 1675, 1605, 1585, 1270, 1215, 1205, 1120, 1105, 1080, 1010, 970 and 770 cm-1. The mass spectrum of the bis-trimethylsilyl derivative showed a 40 high resolution peak at 582.2997. Silica gel DC.Rf = 0.35 in hexane and ethyl acetate (1: 4).

In accordance with the procedure of Example 31, Part H, the reaction product from Part H of this Example (0.25 g) was converted to the carboxylic acid title product (158 mg), a crystalline solid. The melting range was 128-130 ° C. NMR absorptions (COCI3) were observed at 0.9, 1.3-3.0, 3.0-4.6, 4.68, 4.8-5.5, 6.5-6.9, 5 , 5-5.9 and 6.6-7.3 6. Infrared absorption bands were observed at 3570, 3480, 3370, 3220, 2800, 1740, 1720, 1605, 1585, 1235, 1210, 1125, 50 1105, 1080 , 1000 and 970 cm-1. The mass spectrum for the tris-trimethylsilyl derivative showed a high resolution peak at 640.3232. Silica gel DC.Rf = 0.18 in the A-IX solvent system.

According to the procedure of Examples 31 and 32, all 55 of the different products of the formula CLXXVIII in the form of the free acid or in the form of the esters were prepared from the corresponding reactants of the formula CLXXI.

The compounds of the formula CLXXVIII, in which Yi is unsaturated, (trans- or cis-CH = CH-) are converted into the corresponding compounds of the formula CLXXVIII, in which Y is saturated (-CH2CH2-), by hydrogenation, such as is carried out in the following:

Example 33

65

9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (l', 3 '-inter-phenylene) -13,14-dihydro-PGF, (formula XI: X, is COOH, Y,

is -CH2CH2-, R20, R21. R23 and R24 are all hydrogen,

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Z4 is -CHr, R22 is / 3-hydrogen, R8, Mi, Li and R7 are defined in Example 8) and the corresponding methyl ester (Xi is -COOCH3).

A. A solution of the methyl ester title product from Example 31 (0.341 g) in ethyl acetate (35 ml) was hydrogenated at ambient temperature with 5% palladium on carbon under atmospheric pressure. The resulting suspension was then stirred for 70 minutes under a hydrogen uptake of 20 ml (atmospheric pressure). The resulting suspension was then filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The combined filtrate was then concentrated under reduced pressure to give a colorless oil which was chromatographed on silica gel eluting with ethyl acetate in Skellysolve B to give 0.306 g of the title product (methyl ester), a colorless oil. NMR absorptions (CDCI3) were observed at 0.9, 1.07-1.23, 3.3-4.03, 3.77, 4.62, 6.52-7.27 Ô. Infrared absorption bands were observed at 3350, 2930, 2855, 1760, 1740, 1605, 1585, 1467, 1435, 1275, 1205, 1120, 1080, 1025 and 775 cm-1. Silica gel DC.Rf = 0.54 in ethyl acetate.

B. Following the procedure of Example 31, Part H, the title product from Part A of this example (0.177 g) was converted to 0.23 g of the title product (free acid) to give a solid. Recrystallization from ethyl acetate in hexane gave 0.096 g of a product with a melting range of 121-123 ° C. The mass spectrum of the tris-trimethylsilyl derivatives showed a high-resolution peak at 606.3553 and further peaks at 591-535, 516, 427, 426, 275, 274, 173 and 157. Silica gel DC.Rf = 0.27 in A- IX solvent system.

Example 34

9-deoxy-2 ', 9/3-methano-3-oxa-4,5,6-trinor-3,7- (l', 3 '-interphenylene) -PGFi (formula XI: Xi is COOH , R20, r21, r22 and R24 are all hydrogen, Z4 is -CH2-, R22 is a-hydrogen,

RS, Yi, Mi, Li and R7 are defined in Example 8) and the corresponding methyl ester (Xi is -COOCH3).

Compare formula schemes Q and R.

A. A solution of 0.82 g of the reaction product from Example 31, Part B, in 16 ml of methylene chloride was stirred at ambient temperature and under a nitrogen atmosphere and mixed with diatomaceous earth and 26 ml of Collins reagent, which was prepared from 2.5 ml Pyridine and 1.55 g chromium trioxide in 50 ml methylene chloride. The resulting suspension was then stirred for 35 minutes at ambient temperature under a nitrogen atmosphere and filtered through 30 g of silica gel, eluting with 150 ml of ethyl acetate. Concentration under reduced pressure gave 0.90 g of a pale yellow oil. Chromatography on 85 g of silica gel, eluting with 20% ethyl acetate in Skellysolve B, gave 0.644 g of the pure aldehyde of the formula CLXXXII, a colorless oil, namely 9-deoxy-9a-formyl-3-oxa-l, 2.4 , 5,6-pen-tanor-3,7-inter-m-phenylene-PGEi-3- (t-butyldimethylsilyl ether) - 11,15-bis (tetrahydropyranyl ether). NMR absorptions were observed at 0.18, 0.88, 0.98, 1.13-3.08, 3.23-4.35, 4.73, 5.25-5.75, 6.57- 7.37 and 9.88 ô. Infrared absorption bands were observed at 2730, 1720, 1600, 1585, 1485, 1275, 1260, 1075, 1035, 1030, 1020, 975 and 840 cm-1. Silica gel DC.Rf = 0.47 in ethyl acetate and hexane (1: 3).

B. A degassed solution of 1.5 g of the reaction product from Part A and 0.36 ml of l, 8-diazobicyclo [5,4,0] undec-7-ene in 150 ml of methylene chloride was stirred for 40 hours at ambient temperature under a Nitrogen atmosphere stirred, washed with 100 ml ice cold 0.15 M aqueous potassium bisulfate, 100 ml saturated aqueous sodium carbonate and 100 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.5 g of the product of formula CXCII as a yellow oil to give, namely 9-deoxy-9/3-formyl-3-oxa-l, 2,4,5,6-pentanor-3,7-inter-phenylene-PGF i-3- (t-butyl idimethylsilyl -ether) -11.15-bis (tetrahydropyranyl ether). NMR absorptions (cdci3) were observed at 0.18, 0.89, 0.98, 1.1-3.2, 3.2-4.4, 4.68, 5.2-5.8, 6 , 58-7.4 and 9.22 5. Infrared absorption bands were observed at 1725, 1600, 1585, 1485, 1440, 1275, 1260, 1200, 1160, 1130, 1075, 1035, 1020, 975, 870 and 840 cm -1. Silica gel DC.Rf = 0.24 in ethyl acetate and hexane (1: 3).

C. A solution of 1.5 g of the reaction product from Part B in 40 ml of methanol was admixed with 400 mg of sodium borohydride with stirring at a temperature of 20 ° C. under a nitrogen atmosphere for several minutes, at a temperature of 20 ° for 20 minutes C was stirred. The resulting mixture was then added to a cold solution of 200 ml of saline and 32 ml of 0.1 M aqueous potassium sulfate, extracted with 600 ml of ethyl acetate, washed with 200 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over anhydrous magnesium sulfate, under reduced pressure The pressure was concentrated and the residue was chromatographed on 200 g of silica gel, eluting with 35% ethyl acetate in hexane, and 1.37 g of the product of the formula CLCIII were obtained as a colorless oil, namely 9-deoxy-9/3-hydroxymethyl-3- oxa-l, 2,4,5,6-pentanor-3,7-inter-m-phenylene - PGFi-3- (t-butyldimethylsilyl ether) -l 1,15- (tetrahydropyranyl ether). NMR absorptions (CDCI3) were observed at 0.17, 0.88, 0.99, 1.1-3.0, 3.0-4.35, 4.7, 5.25-5.85 and 6 , 5-7.4 S. Infrared absorption bands were observed at 3460, 1665, 1605, 1685, 1490, 1275, 1260, 1200, 1160, 1135, 1115, 1075, 1020, 1005, 975, 840 and 780 cm "1 Silica gel DC.Rf = 0.20 in 35% ethyl acetate in hexane.

D. A degassed solution of 1.32 g of the reaction product from Part B in 0.47 ml of triethylamine and 30 ml of methylene chloride was mixed with 0.5 ml of methanesulfonyl chloride at a temperature of 20 ° C. under a nitrogen atmosphere, for 5 min Stirred temperature of 0 ° C, heated to a temperature of 20 ° C for 90 min, poured into 50 g of ice, diluted with 150 ml of saline, extracted with 450 ml of diethyl ether, washed with 150 ml of brine and 300 ml of saturated aqueous sodium bicarbonate , dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give an oil, and filtered through 70 g of silica gel, eluting with 30% ethyl acetate in hexane, to give 1.47 g of the mesylate corresponding to the starting material, e.g. the 9/3 analogue of the formula CLXXIV. Silica gel DC.Rf = 0.23 in 30% ethyl acetate in hexane.

E. A degassed solution of 1.47 g of the reaction product from Part D and 50 ml of dry tetrahydrofuran at a temperature of 0 ° C. under a nitrogen atmosphere was treated with 3.9 ml of 0.45 M tetra-n-butylammonium fluoride. The resulting solution was then stirred at a temperature of 0 ° C. for 4 hours, a further 0.5 ml of tetra-n-butylammonium fluoride was added, and the mixture was stirred at a temperature of 0 ° C. for 30 minutes, diluted with 150 ml of saline solution , extracted with 450 ml of ethyl acetate, washed successively with 150 ml of 0.5 M aqueous ammonium chloride, 300 ml of saturated aqueous sodium bicarbonate and 150 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.3 g of a yellow oil , the phenol, according to the starting material, e.g. the 9/3 isomer of the compound of formula CLXXV. Silica gel DC.Rf = 0.11 in 35% ethyl acetate in hexane.

F. A degassed solution of 1.3 g of the reaction product from Part E in 75 ml of dry glyme at a temperature of -40 ° C under a nitrogen atmosphere was added with 90 mg of 57% sodium hydride dispersion in mineral oil, at temperatures of -40 to -30 ° C for 40 min, stirred at a temperature of 0 ° C for 15 min, with ambient

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The temperature was stirred for 15 min, warmed and refluxed for 5 hours, cooled to ambient temperature, added to 200 ml of ice-cold glyme, extracted with 450 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous sodium sulfate and chromatographed on 175 g of silica gel , eluting with 25% ethyl acetate in hexane to give 0.61 g of the 9β-isomer corresponding to the compound of formula CLXXVI as a viscous oil. NMR absorptions were observed at 0.90, 1.07-3.1, 3.1-4.4, 4.75, 5.33-6.16 and 6.5-7.2 5. Infrared absorption bands were observed at 3340, 1665, 1610, 1585, 1500, 1465, 1135, 1110, 1075, 1020 and 980 cm "1. silica gel DC.Rf = 0.26 in 25% ethyl acetate in hexane and Rf = 0.23 in 5 % Acetone in methylene chloride.

G. A solution of 0.50 g of the reaction product from Part F in 28 ml of methyl bromoacetate in 16 ml of dry glyme at a temperature of 0 ° C. under an argon atmosphere was mixed with 0.14 g of a 57% mineral oil dispersion of sodium hydride. The resulting suspension was then stirred for 2.5 hours at a temperature of 0 ° C, quenched with 200 ml of cold saline, extracted with 460 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to 0 , 68 g of an oil, the 9/3 isomers corresponding to the compound of formula CLXXVII.

H. A solution of the reaction product from Part G (0.68 g) in 5 ml of tetrahydrofuran, 7.5 ml of water and 15 ml of acetic acid was heated to a temperature of 45 ° C. for 2.5 hours, cooled, with 200 ml of saline diluted, extracted with 400 ml of ethyl acetate, washed with 400 ml of brine, washed with 200 ml of saturated aqueous sodium bicarbonate and with 200 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give an oil which was chromatographed on 75 g of silica gel eluting with 30% hexane in ethyl acetate to 100% ethyl acetate to give 0.32 g of the title methyl ester as a white foam. Crystallization from warm diethyl ether in hexane gave 0.23 g of the pure ester product as a white solid. The melting range was 85-87 ° C. NMR absorptions (CDCI3) were observed at 0.90, 1.07-2.9, 2.9-4.5, 4.61, 5.4-5.8 and 6.38-7.34 Ô. Infrared absorption bands were observed at 3520, 3420, 1735, 1720, 1605, 1580, 1300, 1240, 1210, 1110, 1085, 1050, 1010, 970, 760, 720 and 710 cm ~ The mass spectrum of the bis-tri-methylsilyl- Derivates showed a high resolution peak at 546.3182. Silica gel DC.Rf = 0.14 in 30% ethyl acetate in hexane.

I. Following the procedure of Example 31, Part H, the title product from Part H (158 mg) was converted to the title free acid (129 mg) and a white solid was obtained. The melting range was 150-154 ° C. NMR absorptions were observed at 0.90, 1.07-3.5, 3.85-4.35, 4.70, 5.09-5.9 and 6.5-7.3 5. Infrared absorption bands were observed at 3380, 2640, 2560, 1730, 1605, 1580, 1260, 1230, 1115, 1050, 1025, 970 and 770 cm-1.

All of the various compounds of formula XI were prepared according to the procedure of Example 34, where R22 is α-hydrogen. Furthermore, according to the method of Example 33, the various 9 (3-methano isomers of Example 34 and the corresponding compounds of the formula XI, where Yi has the meaning of ice- or trans-CH = CH-, were converted into the corresponding 13,14-dihydro- PGFi connections hydrogenated.

Example 35

9-deoxo-2 ', 9-methano-3-oxa-4,5,6, -trinor-3,7- (r, 3'-inter-phenylene) -PGEi- (formula XI: Xi is COOH, R20, r21, r23 and R24 are all hydrogen, Z4 is -CH; -, R21 and R22 taken together form a valence bond, Rg, Yi, Mi, Li and R7 are defined in Example 8) and the corresponding methyl ester (X, is - COOCH3).

Compare formula scheme T.

A. A degassed solution of the reaction product from Example 34, Part A (1.68 g) in dry tetrahydrofuran (50 ml) was cooled to a temperature of 0 ° C. and under a nitrogen atmosphere with 0.75 M tetrabutylammonium fluoride (4.37 ml) are added. The resulting solution was then stirred at a temperature of 0 ° C for 2 hours, diluted with brine (300 ml), extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.3 g of a Oil. The oil was chromatographed on silica gel (160 g) eluting with 25% ethyl acetate in Skellysolve B to give 1.21 g of the compound of formula CCXI, namely 9-deoxy-9a-formyl-l, 2.4. 5,6-pentanor - 3,7-inter-m-phenylene-PGEi-II, 15-bis (tetrahydropyranyl ether). NMR absorptions (CDC13) were observed at 0.88, 1.13-3.15, 3.27-4.47, 4.71, 6.10, 6.53-7.41, 9.27 5. Infrared absorption bands were observed at 3345, 2930, 2860, 2720, 1735, 1715, 1605, 1595, 1585, 1485, 1450, 1370, 1350, 1255, 1235 and 970 cm-1. Silica gel DC.Rf = 0.12 in 25% ethyl acetate and hexane and Rf = 0.39 in 50% ethyl acetate in hexane.

B. A degassed solution of 0.28 g of the reaction product from Part A in 33 ml of glyme was brought to a temperature of

-40 ° C cooled under argon and mixed with 2.95 N methyl magnesium chloride in tetrahydrofuran (0.2 ml). The reaction mixture was stirred at a temperature of -40 ° C for 15 minutes, stirred at a temperature of 0 ° C for 5 minutes, warmed to ambient temperature, stirred at reflux for 115 hours under an argon atmosphere, cooled, with diluted ice-cold saline (150 ml), extracted with ethyl acetate (300 ml), washed with brine (300 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure to give 0.31 g of an oil, and chromatographed on silica gel, eluting with 25% ethyl acetate in Skellysolve B to give 0.16 g of the compound of formula CCXII, namely 9-deoxy-2 ', 9-methano-3-oxa-l, 2,4,5,6 -pentanor-3,7- (l ', 3'-inter-phenylene) - PGE] -ll, 15-bis (tetrahydropyranyl ether). The mass spectrum of the trimethylsilyl derivative showed a molecular peak at 568 and further peaks at 466, 382, 364, 314, 297, 267, 255, 243, 230, 270, 153 and 85. Silica gel DC.Rf = 0.25 in 25% ethyl acetate in hexane and Rf = 0.58 in 50% ethyl acetate in hexane.

C. A degassed solution of the reaction product from Part C (0.16 g) in dry glyme (5 ml) was cooled to a temperature of -5 ° C and methyl bromoacetate (0.04 ml) was added under a nitrogen atmosphere. The resulting solution was then treated with 50% sodium hydride dispersion in mineral oil (0.16 g). A precipitate formed within 5 min and the resulting suspension was stirred at a temperature of 0 ° C for 1.5 hours, diluted with brine (100 ml), extracted with ethyl acetate (240 ml), with brine (100 ml) washed, dried over magnesium sulfate, filtered, concentrated to a brown residue, which solidified on cooling, and on

25 g of silica gel was chromatographed, eluting with 20% ethyl acetate in Skellysolve B, and 0.136 g of the bis (tetrahydropyanyl ether) compound of the formula CCXIII: 9-de-oxy-2 ', 9-methano-3 was obtained -oxa-4,5,6-trinor-3,7- (l, 3-inter-phenylene) - PGEi-methyl-ester-1 l, 15-bis (tetrahydropyranyl ether). The melting range was 81-83 ° C. The mass spectrum showed peaks at 366, 384, 364, 297, 247, 230, 215, 149 and 85. Silica gel DC.Rf = 0.45 in 5% acetone in methylene chloride.

D. A solution of the reaction product from Part C (0.12 g)

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in tetrahydrofuran (1 ml), water (2 ml) and acetic acid (4 ml) was heated to a temperature of 45 ° C under a nitrogen atmosphere for 2.25 hours, cooled and partitioned between brine (100 ml) in ethyl acetate (90 ml ). The layers were separated and the aqueous layer was extracted with ethyl acetate (160 ml). The organic layers were then washed successively with brine (100 ml), water (100 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (200 ml), dried over magnesium sulfate, filtered, concentrated to give 0.97 g of a solid to give, and chromatographed on 30 g of silica gel, eluting with 85% ethyl acetate in hexane. , and 0.083 g of the white, crystalline title product of the formula CCXIII was obtained in the form of the methyl ester. Recrystallization from diethyl ether in hexane gave 0.056 g of the pure methyl ester title product. The melting range was 96 to 98 ° C. NMR absorptions (CDCI3) were observed at 0.94, 3.86, 3.92-4.28, 4.72, 5.58-5.86 and 6.62-7.18 ô. Infrared absorption bands were observed at 3420, 1765, 1665, 1600, 1575, 1465, 1440, 1275, 1215, 1190, 1105, 1085, 970 and 770 cm-1. The mass spectrum of the trimethylsilyl derivative showed a molecular ion at 554 and further peaks at 454, 383, 365, 364, 230, 229, 225. Silica gel DC.Rf = 0.41 in ethyl acetate.

E. According to the procedure of Example 31, Part H, the reaction product from Part D (0.19 g) was converted to 76 mg of the crystalline title product in the form of the free acid. The melting range was 150-152 ° C. NMR absorptions (CDCI3) were observed at 0.91, 1.2-3.48, 3.88-4.15, 4.70, 5.62-4.66 and 6.63-7.11 5. The mass spectrum of the trimethylsilyl derivative showed a high resolution peak at 602.3251 and further peaks at 512, 422, 287, 225, 174 and 173. Silica gel DC.Rf = 0.23 in the A-IX solvent system.

Example 36

9-deoxy-2,, 9a-methano-3-oxa-4,5,6,13,14,15,16,17,18,19,20 - undecanor-3,7- (l ', 3' -inter-phenylene) -12-formyl-P GF1 -methyl ester (formula CCXXII: X! is -COOCH3, Z4 is -CH2-, r20, r21 and R23 are hydrogen, R22 means ß-hydrogen and R] 8 has the meaning of tetrahydropyran-2-yl-oxy).

Compare formula scheme U.

Ozone was bubbled through a solution of 0.72 g of the reaction product from Example 31, Part F, in 50 ml of absolute methanol at a temperature of -78 ° C for 5 minutes. Thereafter, oxygen was bubbled through the resulting solution for 5 minutes, and 16 ml of dimethyl sulfide was added to the solution. After standing at a temperature of 0 ° C for 16 hours under a nitrogen atmosphere and for 2 to 1/2 hours at ambient temperature, the solution was diluted with 200 ml of ethyl acetate, washed successively with 100 ml of brine, 100 ml of saturated aqueous sodium bicarbonate and 100 ml of brine , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 175 g of silica gel, eluting with 35% ethyl acetate in hexane, to give 367 mg of the title product as a colorless oil. NMR absorptions (CDCI3) were observed at 1.0-3.0, 3.1-4.5, 3.63, 6.45-7.34 and 9.77 ô. The mass spectrum showed peaks at 388 and 304. Silica gel DC.Rf = 0.19 and 0.22 in 25% and 30% ethyl acetate in hexane.

Example 37

9-deoxy-2 ', 9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7 - (r, 3'-inter-phenylene) -PGFi (formula XI: Xi, Z4, Rs, R20, R2i, r22, R23 »R24, Y], Mi and Li are defined in Example 31 and R7 has the meaning of n-pentyl) its methyl ester (Zj has the

Meaning of -COOCH3), its 15-epimer (M, is a-H: ß-OH) and the 15-emipere methyl ester (Mi is a-H: ß-OH and Zi is -COOCI-I3).

Compare formula scheme U.

A. A suspension of 56 mg of a 57% sodium hydride dispersion in mineral oil and 4 ml of tetrahydrofuran at a temperature of 0 ° C. under a nitrogen atmosphere was treated with a solution of 286 mg of dimethyl-2-octylphosphonate in 4 ml of tetrahydrofuran for 5 min stirred at a temperature of 0 ° C, stirred for 1 hour at ambient temperature, cooled to a temperature of 0 ° C, mixed with a solution of 0.39 g of the title product from Example 36 and 4 ml of tetrahydrofuran, for 2 to 1/2 Stirred for one hour at ambient temperature, cooled to a temperature of 0 ° C, added to a solution of 40 ml of ethyl acetate containing a few drops of acetic acid, extracted with 120 ml of ethyl acetate, washed with 30 ml of saturated aqueous sodium bicarbonate, with 30 ml Washed brine, dried over anhydrous sodium sulfate, concentrated to an oil under reduced pressure, and chromatographed on 60 g of silica gel, with 25% ethyl acetate in hexane was eluted to obtain 0.42 g of a colorless oil, namely

9,15-dideoxy-l 5-keto-2 ', 9-methano-20-methyl-4,5,6-trinor-3,7 - (r, 3'-inter-phenylene) -PGFi-methyl- ester-ll-tetrahydropyranyl - ether. NMR absorptions were observed at 0.89, 1.05-3.0, 3.5-4.37, 4.62 and 5.97-7.30 S. The mass spectrum showed peaks at 414, 396, 323, 311 and 301. Silica gel DC.Rf = 0.26 in 25% ethyl acetate in hexane.

B. A degassed solution of 42 mg of sodium borohydride and 4 ml of absolute methanol at a temperature of -30 ° C. under a nitrogen atmosphere was added dropwise to a solution of 391 mg of the title reaction product from Part A in 0.3 ml of methylene chloride and 3 ml of methanol, Stirred for 1 to 1/2 hour at a temperature of -30 ° C, quenched by carefully adding 0.2 ml of glacial acetic acid, with

Dilute 70 ml of brine, extract with 210 ml of ethyl acetate, wash with 70 ml of saturated aqueous sodium bicarbonate, wash with 70 ml of brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give 0.42 g of a colorless oil, and add 60 g of silica gel was chromatographed, eluting with 40% ethyl acetate in hexane, and 0.36 g of an epimeric mixture of the C-15 alcohols was obtained. Silica gel DC.Rf = 0.20 in 40% ethyl acetate in hexane.

C. A solution of the reaction product from part B above in 3 ml of tetrahydrofuran, 4.5 ml of water and 9 ml of acetic acid was heated to a temperature of 45 ° C. under a nitrogen atmosphere for 2.5 hours, cooled, washed with 100 ml of saline, extracted with 200 ml of ethyl acetate, washed with 100 ml of brine, washed with 300 ml of saturated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to a yellow oil and on

Chromatograph 60 g of silica gel eluting with 20% ethyl acetate in methylene chloride to give 96 mg of 9-de-oxy-2 ', 9a-methano-20-methyl-3-oxa-4,5,6-trinor-3 , 7- (1,3-inter-phenylene) -15-epi-PGFi-methyl ester as a colorless oil and 159 mg of 9-deoxy-2 ', 9a-methano-20-methyl-3-oxa-4 , 5,6-trinor - 3,7- (1,3-inter-phenylene) -PGFi-methyl-ester as a white solid. The recrystallization of the 15a-hydroxy compound from warm hexane in diethyl ether gave 140 mg of a white solid. The melting range was 79-82 ° C. NMR absorptions were observed for the titanium product methyl ester at 0.92, 1.08-3.0, 3.38-4.5, 4.64, 5.33-5.70 and 6.5-7 , 4 8. The mass spectrum of the trimethylsilyl derivative showed a high resolution peak at 560.3375. Silica gel DC.Rf = 0.19 in 20% ethyl acetate in methylene chloride and Rf = 0.31 in 20% He5

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xan in ethyl acetate. NMR absorptions (CDC13) were observed for the 15-epi compound at 0.89, 1.07-3.0, 3.7-4.33, 4.63, 5.5-5.8 and 6, 55-7.37 5. Infrared absorption bands were observed at 3360, 1765, 1750, 1735, 1605, 1585, 1470, 1440, 1205, 1120, 1080, 970 and 770 cm-1. The mass spectrum of the trimethylsilyl derivative showed a high-resolution peak at 560.3385. Silica gel DC.Rf = 0.35 in 20% acetone and methylene chloride and Rf = 0.45 in 20% hexane and ethyl acetate.

D. According to the procedure of Example 31, Part H, the 15a-hydroxy title product from Part C (94 mg) was converted into the 9-des-10 oxy-2 ', 9o: -methano-20-methyl-3-oxa -4,5,6-trinor-3,7- (1,3-inter-phenylene) -PGFi transferred, the free acid of the title product, a white solid, 81 mg. The melting range was 144-146 ° C. NMR absorptions (CD3COCD3) were observed at 0.8, 1.05-2.9, 3.2-4.4, 4.65, 5.38-5.56 and 6.6-7.2 5. The mass spectrum of the trimethylsilyl derivative showed a high resolution peak at 618.3576. Silica gel DC.Rr = 0.14 in the A-IX solvent system.

E. Furthermore, according to the procedure of Example 31,

Part H, the 15 epi title product from Part C (93 mg) into the .20 9-deoxy-2 ', 9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7 - (l, 3 - inter-phenylene) -15-epi-PGF! transferred, a white solid, 72 mg. The melting range was 105-108 ° C. NMR absorptions (CD3COCD3) were observed at 0.90, 1.05-2.9, 3.2-4.3, 4.71, 5.0-5.84 and 6.5-7.34 Ô. Silica gel DC.Rf = 0.19 25 in the A-IX solvent system.

According to the procedures of Examples 36 and 37, the C-12 side chains were substituted according to the procedure of Formula Scheme U for all of the different compounds of Formula XI. 30th

The following compounds were thus prepared in accordance with the processes described above: (5E) -90-methyl-CBAi compounds, (5Z) -9 / 3-methyl-CBA2 compounds,

(5E) -5-fluoro-9/3-methyl-CBA2 compounds, 35

(5Z) -5-fluoro-9 | 3-methyl-CBA2 compounds, (5E) -5-fluoro-CBA2 compounds, (5Z) -5-fluoro-CBA2 compounds,

(5E) -9 / 3-methyl-2,5-inter-o-phenylene-3,4-dinor-CB A2 compounds,

(5Z) -9 / 3-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds,

(5E) -90-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds,

(5E) -90-methyl-1,5-inter-o-phenylene-3,4,5-trinor-CBA2 compounds,

(5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5Z) -2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5E ) -l, 5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, (5Z) -l, 5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, so 2,2-difluoro- (5E) -9 | 3-methyl-CBA2 compounds, 2,2-difluoro- (5Z) -90-methyl-CBA2 compounds, 2,2,5-trifluoro- (5E) -9 / 3-methyl-CBAi compounds, 2,2,5-trifluoro (5Z) -9 / 3-methyl-CBA2 compounds, 2,2,5-trifluoro (5E) -CBA2 compounds, 55

2,2,5-trifluoro (5Z) -CBA2 compounds, 2,2-difluoro- (5E) -9 | 3-methyl-2,5-inter-o-phenylene-3,4-dinor - CBA2 -Links,

2,2-difluoro- (5Z) -9 / 3-methyl-2,5-inter-o-phenylene-3,4-dinor - CBAj compounds, 60

2,2-difluoro- (5E) -9jS-methyl-1,5-inter-o-phenylene-2,3,4-tri-nor-CBA2 compounds,

2,2-difluoro- (5E) -9 (3-methyl-1,5-inter-o-phenylene-3,4,5-tri-nor-CBA2 compounds,

2,2-difluoro- (5E) -2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds,

2,2-difluoro- (5Z) -2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds,

2,2-difluoro- (5E) -1,5-inter-m-phenylene-2,3,4-trinor-CBA2 - compounds,

2,2-difluoro- (5Z) -l, 5-inter-m-phenylene-2,3,4-trinor-CBA2 - compounds,

trans-2,3-didehydro- (5E) -90-methyl-CBA2 compounds, trans-2,3-didehydro- (5Z) -9 / 3-methyl-CBA2 compounds, trans-2,3-didehydro- (5E) -5-fluoro-9j3-methyl-CBA2 compounds,

trans-2,3-didehydro- (5Z) -5-fluoro-9/3-methyl-CBA2 compounds,

trans-2,3-didehydro- (5E) -5-fluoro-CBA2 compounds, trans-2,3-didehydro- (5Z) -5-fluoro-CBA2 compounds, trans-2,3-didehydro- (5E ) -9 (3-methyl-2,5-inter-o-phenylene - 3,4-dinor-CBA2 compounds,

trans-2,3-didehydro- (5Z) -9 / 3-methyl-2,5-inter-o-phenylene - 3,4-dinor-CBA2 compounds,

trans-2,3-didehydro- (5E) -9j3-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds,

trans-2,3-didehydro- (5E) -9 / 3-methyl-l, 5-inter-o-phenylene - 3,4,5-trinor-CB A2 compounds,

trans-2,3-didehydro- (5E) -2,5-inter-o-phenylene-3,4-dinor - CB A2 compounds,

trans-2,3-didehydro- (5Z) -2,5-inter-o-phenylene-3,4-dinor - CB A? compounds,

trans-2,3-didehydro- (5E) -l, 5-inter-m-phenylene-2,3,4-trinor - CB A2 compounds,

trans-2,3-didehydro- (5Z) -l, 5-inter-m-phenylene-2,3,4-trinor - CBA2 compounds,

9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGF r compounds,

9-deoxy-2 ', 9/3-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGF t compounds,

9-deoxy-2 ', 9-metheno-3-oxa-3,4,5-trinor-3,7- (r, 3'-inter-phenylene) -7,8-didehydro-PGEi compounds,

9-deoxy-2 ', 9-metheno-3-oxa-3,4,5-trinor-3,7- (r, 3'-inter-phenylene) -PGEi compounds,

6a-oxo-9-deoxy-2 ', 9o: -methano-3-oxa-4,5,6-trinor-3,7 - (l', 3'-inter-phenylene) -PGFi compounds,

6a-oxo-9-deoxy-2 ', 9/3-methano-3-oxa-4,5,6-trinor-3,7 - (r, 3'-inter-phenylene) -PGFi compounds,

6aa-hydroxy-9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor - 3,7- (1', 3 '-interphenylene) -PGF 1 compounds,

6aa-Hydroxy-9-deoxy-2 ', 9/3-methano-3-oxa-4,5,6-trinor - 3,7- (l', 3 '-interphenylene) -PGF [compounds ,

6a0-hydroxy-9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor - 3,7- (r, 3'-inter-phenylene) -PGFi compounds, and

6a / 3-hydroxy-9-deoxy-2 ', 9/3-methano-3-oxa-4,5,6-trinor - 3,7- (l', 3 '-interphenylene) -PGFi- Links,

in the form of the free acid or in the form of the methyl esters which have the following side chain substituents:

15-cyclohexyl-16,17,18,19,20-pentanor-; 17- (2-furyl) -18,19,20-trinor-;

16- (3-thienyl) oxy-17,18,19,20-tetranor-;

17- (3-thienyl) -18,19,20-trinor-;

15-methyl-;

16-methyl-;

15,16-dimethyl-;

16,16-dimethyl-;

17,20-dimethyl-;

16-fluoro;

15-methyl-16-fluoro;

16,16-difluoro-;

15-methyl-l 6,16-difluoro-;

17-phenyl-18,19,20-trinor-; 17- (m-trifluoromethylphenyl) -18,19,20-trinor-; 17- (m-chlorophenyl) -18,19,20-trinor-;

17- (p-fluorophenyl) -l 8,19,20-trinor-;

39

648 017

15-methyl-17-phenyl-18,19,20-trinor-;

16-methyl-l 7-phenyl-l 8,19,20-trinor-;

16,16-dimethyl-l 7-phenyl-l 8,19,20-trinor-; 16-fluoro-17-phenyl-l 8,19,20-trinor-;

16,16-difluoro-17-phenyl-18,19,20-trinor-; 16-phenyl-17,18,19,20-tetranor-;

15-methyl-16-phenyl-17,18,19,20-tetranor-;

16- (m-trifluoromethylphenyl) -l 7,18,19,20-tetranor-; 16- (m-chlorophenyl) -17,18,19,20-tetranor-;

16- (p-fluorophenyl) -17,18,19,20-tetranor-; 16-phenyl-18,19,20-trinor-;

15-methyl-16-phenyl-18,19,20-trinor-;

16-methyl-16-phenyl-18,19,20-trinor-; 15,16-dimethyl-16-phenyl-l 8,19,20-trinor-;

16-phenoxy-l 7,18,19,20-tetranor-;

15-methyl-16-phenoxy-17,18,19,20-tetranor-;

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-; 16- (m-chlorophenoxy) -17,18,19,20-tetranor-; 16- (p-fluorophenoxy) -17,18,19,20-tetranor-; 16-phenoxy-18,19,20-trinor-;

15-methyl-16-phenoxy-18,19,20-trinor-;

16-methyl-16-phenoxy-l 8,19,20-trinor-;

15,16-dimethyl-1 6-phenoxy-18,19,20-trinor-; 13,14-didehydro-;

15-cyclohexyl-16,17,18,19,20-pentanor-13,14-didehydro-;

17- (2-furyl) -18,19,20-trinor-13,14-didehydro-;

16- (3-thienyl) oxy-l 7,18,19,20-tetranor-13,14-didehydro-;

17- (3-thienyl-l 8,19,20-trinor-l 3,14-didehydro-;

15-methyl-13,14-didehydro-;

16-methyl-13,14-didehydro-;

15,16-dimethyl-l 3,14-didehydro-; 16,16-dimethyl-13,14-didehydro-;

17,20-dimethyl-13,14-didehydro-;

16-fluoro-13,14-didehydro-;

15-methyl-16-fluoro-l 3,14-didehydro-; 16,16-difluoro-13,14-didehydro-;

15-methyl-16,16-difluoro-l 3,14-didehydro-;

17-phenyl-18,19,20-trinor-l 3,14-didehydro-;

17- (m-trifluoromethylphenyl) -l 8,19,20-trinor-l 3,14-dide-iidro-;

17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-; 17- (p-fluorophenyl) -18,19,20-trinor-13, l 4-didehydro-;

15-methyl-17 ^ phenyl-18,19,20-trinor-13,14-didehydro-;

16-methyl-l 7-pheny 1-18,19,20-trinor-13,14-didehydro-;

16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16-fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16-phenyl-17,18,19,20-tetranor-13,14-didehydro-;

15-methyl-16-phenyl-17-18,19,20-tetranor-13,14-didehydro-;

16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14-didehydro-;

16- (m-chlorophenyl) -17,18,19,20-tetranor-l 3,14-didehydro-; 16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-didehydro-; 16-phenyl-18,19,20-trinor-13,14-didehydro-;

15-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;

16-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;

15,16-dimethyl-16-phenyl-18,19,20-trinor-13,14-didehydro-; 16-phenoxy-17,18,19,20-tetranor-l 3,14-didehydro-;

15-methyl-16-phenoxy-17,18,19,20-tetranor-l 3,14-dide-îydro-;

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-didehydro-;

16- (m-chlorophenoxy) -l 7,18,19,20-tetranor-13,14-dide-îydro-;

16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-; 16-phenoxy-18,19,20-trinor-13,14-didehydro-;

15-methyl-16-phenoxy-18,19,20-trinor-l 3,14-didehydro-;

16-methyl-l 6-phenoxy-18,19,20-trinor-13,14-didehydro-;

15,16-dimethyl-16-phenoxy-l 8,19,20-trinor-13,14-didehydro-;

13,14-dihydro-;

15-cyclohexyl-16,17,18,19,20-pentanor-l 3,14-dihydro-; 17- (2-furyl) -18,19,20-trinor-13,14-dihydro-;

16- (3-thienyl) oxy-17,18,19,20-tetranor-13,14-dihydro-;

17- (3-thienyl) -18,19,20-trinor-l 3,14-dihydro-;

15-methyl-13,14-dihydro-;

16-methyl-l 3,14-dihydro-;

15,16-dimethyl-13,14-dihydro-;

16,16-dimethyl-l 3,14-dihydro-; 17,20-dimethyl-13,14-dihydro-;

16-fluoro-13,14-dihydro-;

15-methyl-1 6-fluoro-13,14-dihydro-; •

16,16-difluoro-l 3,14-dihydro-;

15-methyl-16,16-difluoro-l 3,14-dihydro-;

17-phenyl-l 8,19,20-trinor-l 3,14-dihydro-;

17- (m-trifluoromethylphenyl) -l 8,19,20-trinor-l 3,14-dihydro-;

17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-; 17- (p-fluorophenyl) -18,19,20-trinor-l 3,14-dihydro-;

15-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 16,16-dimethyl-17-phenyl-18,19,20-trinor-l 3,14-dihydro-; 16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-difluoro-17-phenyl-l 8,19,20-trinor-13,14-dihydro-; 16-phenyl-17,18,19,20-tetranor-13,14-dihydro-;

15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-;

16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14 - dihydro-;

16- (m-chlorophenyl) -17,18,19,20-tetranor-l 3,14-dihydro-; 16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro-; 16-phenyl-18,19,20-trinor-l 3,14-dihydro-;

15-methyl-l 6-phenyl-l 8,19,20-trinor-l 3,14-dihydro-;

16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-; 15,16-dimethyl-1 6-phenyl-18,19,20-trinor-13,14-dihydro-; 16-phenoxy-l 7,18,19,20-tetranor-13,14-dihydro-;

15-methyl-16-phenoxy-17,18,19,20-tetranor-l 3,14-dihydro-;

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14 - dihydro-;

16- (m-chlorophenoxy) -l 7,18,19,20-tetranor-13,14-dihydro-; 16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-; 16-phenoxy-18,19,20-trinor-13,14-dihydro-;

15-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

16-methyl-l 6-phenoxy-l 8,19,20-trinor-l 3,14-dihydro-;

15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-; 13-cis;

15-cyclohexyl-16,17,18,19,20-pentanor-13-ice-;

17- (2-furyl) -18,19,20-trinor-13-cis;

16- (3-thienyl) oxy-17,18,19,20-tetranor-l 3-cis;

17- (3-thienyl) -18,19,20-trinor-13-cis;

15-methyl-13-cis;

16-methyl-13-cis;

15,16-dimethyl-13-cis;

16,16-dimethyl-13-cis;

17,20-dimethyl-13-cis;

16-FIuor-13-cis;

15-methyl-16-fluoro-13-cis;

16,16-difluoro-13-cis;

15-methyl-l 6,16-difluoro-l 3-cis;

17-pheny 1-18,19,20-trinor-13-ice-; 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13-cis; 17- (m-chlorophenyl) -18,19,20-trinor-l 3-cis; 17- (p-fluorophenyl) -18,19,20-trinor-13-cis;

15-methyl-17-phenyl-18,19,20-trinor-13-cis;

16-methyl-17-phenyl-18,19,20-trinor-13-cis; 16,16-dimethyl-17-phenyl-18,19,20-trinor-13-cis; 16-fluoro-17-phenyl-18,19,20-trinor-13-cis;

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

648 017

16,16-difluoro-17-phenyl-18,19,2Q-trinor-13-cis; 16-phenyl-17,18,19,20-tetra-13-cis;

15-methyl-16-phenyI-17,18,19,20-tetranor-13-cis;

16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13-cis; 1 ó- (m-chlorophenyl) -17,18,19,20-tetranor-l 3-cis; 16- (p-fluorophenyl) -17,18,19,20-tetranor-13-cis; 16-phenyl-18,19,20-trinor-13-cis;

15-methyl-16-phenyl-18,19,20-trinor-13-cis;

16-methyl-1 6-phenyl-18,19,20-trinor-13-cis; 15,16-dimethyl-16-phenyl-18,19,20-trinor-13-cis; 16-phenoxy-17,18,19,20-tetranor-13-cis;

15-methyl-16-phenoxy-17,18,19,20-tetranor-13-cis;

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-cis; 16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-cis; 16- (p-fluorophenoxy) -17,18,19,20-tetranor-13-cis; 16- (Phenoxy-18,19,20-trinor-13-cis;

15-methyl-16-phenoxy-18,19,20-trmor-13-cis;

16-methyl-16-phenoxy-18,19,20-trinor-13-cis; and 15,16-dimethyl-16-phenoxy-18,19,20-trinor-13-cis.

Formulas

COOH

0 \ \

9

8th

17th

15

19th

16

ÌS

20th

J1

COOH

ea

\

/

13

17th

15

19th

"1"

16

"la

<11

HO

COOH

12)

13

15

17th

19th

16

Ì8

20th

«31.

Formulas (continued)

0

63

\ /

Ria

0

6a

Rl6

\

/

ch2or

Ria

15

Ï

18th

CH ^ sJ-Zì-X.,

—S ^ \ CH =) n Rl7— (

\ z ^ ch2or32 I

Ri 8

40

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Formulas (continued)

41

Formula scheme A

648 017

1-Z.-0-O

Ra% / \ R

r2, X—

r22-T r "R24

R33

t

R-1S

HO

»10

Y1-C-R27

I! L

M6 Li

Ri 5 — Zi -X-i

(CH2) n

\ J ^ Yl-C-C-Rv r II II

M-i L-j

VIII 10

Y1-C-C-R7

II II Mi Li

25th

IX

35

X 40

60

XI

0 (, ch2) "

XXI

'18

V

Y1 -C —C-R27 1 1

Me Li

0

II

, P (0CH3) 2

HO

H:

r '(ch2) "

XXII

Ria

Y-J-C-C-R ii ii Me U

27th

V

0 0

* "(Ch2) n-c-ch2-p (och3)

X / ^ - Yn-c — C-R27 «Il H

Me U

XXIII

Ri 8

(CH2) n 1

Y1 -C — C-R27 ii »M6 Li

XXIV

after XXV

according to XXVI

648 017 42

Formula scheme A (continued) Formula scheme B

43

Formula scheme B (continued)

Formula scheme C

from

XXXIII

(CHa} "

V

Za-CH20R28

Yi-C-C-R27

H #

M6 Ln

Yi-C-C-R27

Il H

Mß Ln xxxiv

20th

XXXV

40

(CH2) g-C00H

COOH

V

(CH2) g-CH20H

CH20H

M /

(CHa) g-CH2ORaa

CH20H

7

V

■ Za-X,

(CHaJn

Y-i-C-C-R7 n u Mi Li

50

55

XXXVI

60

M /

(CH2) g-CH2-0R28

CHO

648 017 44

Formula scheme D

O

V

Rl6 Ri 7

OH

'(CHaJn

C-R

»18th

Y -, - C 0 II Me Li

27th

LII

LUI

n 8

V

according to LIV

45 '

Formula scheme D (continued)

648 017

From LIII

R

16

Nk

(^ 2) n Rl7 <—4— (

LIV

Rl6 Rl7

S ° 2 - (^) (CH2) n

LV

S> ^ Yl-c-C-R27

T n g

Rl8

n «M6 Lt

R-JB

V

according to LVIII

yi-c c-r27

n n Me Li

LVI

LVII

648 017

Formula scheme D (continued)

46

Formula scheme E

by LVII

V

ch2) g-ch20h

Yi -C-C-R27 I 1 ms l-i

V

(ch2) g-c00rn f (ch2) n \ 7

o '

• »18th

yn-c — c-r27 b s m6 l,

V

(CHajg-Xi

LVIII

30th

35

LIX

40

45

LX

0

x

0 (CHa) n

ch2or31

r38

R16 R17

V

(chajn

1

ch20r3i

I.

r38

V

Rl6 Rl7

(/ ch2) n ch20r

2UI \ 31

* 38

LXI

LXII

LXIII

47

648 017

Formula scheme F

Formula scheme G

Zi-Xr

'(CHa) n ch2or

2U (% 31

ch2oh

'38

Y-c-c-r7 i ii ii

Re Mn L-,

(ch2) n

LXXI

lxxxi

25th

LXXII

LXXIII so

18th

y-i-c-c-r27 n t m6 ln

Br ° G ^

©

p = ch-z2-cooh lxxxii z2-cooh

(ch2) n

LXXXIII

y i -c-c-r27 i s m6 ln z2-cooch3

(ch2) n

LXXXIV

y i -c-c-r27

p b m6 l,

and LXXXIV

after lxxxv

648 017

. 48

Formula scheme G (continued)

By LXXXIV

z2-ch2oh

ìch2) n

»Yn-c — c-r27 n ii m6 l.

LXXXV

H0H2C-Z2 H

(CHa) n

LXXXVI

Yi-C-C-R27 n ii Mß Li

V

Xi-Z2 H

Rl6 Rl7

(CH = jn

LXXXVIII

Yi-C-C-R7 h o

Wed Ln

'16

kr .z2-ch2oh

(CH2) n

Tl.

V ^ Yn-

LXXXVII

Ria c-c-r27

II II

. m6 ln

V

H Z2-Xn

: CH2jn

LXXXIX

Yn-C-C-R.

Rr MI Li

49

Formula scheme H

648 017

CH2-CH2-Z2-CH2OR10

XCI

V

-CH (F) -CH2-Z2-CH20Rio

XCII

V

p ^ Z2-CH20Rno

'(CHa) n

XCIV

Yt-C-C-R27

n n M6 Ln

'(CHa) n

XCIII

Y1-C- ■ C-R27 B «Ms Li

F ^ Z2-CH20H

'(CHa) n

XCV

Yn-C-C-R7 II «Mi Ln

648 017

Formula scheme H (continued)

50

Formula scheme I

By XCV

V

I; .Z2-C00H

(CH2) n

■ yi-c-c-r7 u a m-, left

Z2-X-,

(CH2) n

Y-i-C-C-R7 * u

Mi L-i xcvi

20th

25th

30th

XCVII 40

45

ch, 0r

2 ^ 31

(CHa) n /

ch20r31

V

ci

CII

50

yn-c-c-ra

H U Mi Ln cm

51

Formula scheme J

Formula scheme K

RiL. f CH2-CH2CH2-C00R1

Ri 6 Rl7

(CH2} n

Yi-C-C-r7 n n Mi Li

V PhSe

^ ch2-ch2-ch-coori

Rl6 Rl7

'(CH2) n yn-c-c-r7

b h Mi Li

\ | / H ^ .COORi v C = C

1f \ ^ CH.

Rl6 Rl7

H

'(CH2) n yi-c — c-r7 u b Mi Li d / c = c ^.

rl5 .ch2 ^ h

Ri e— (CH2) n

Ri 7 '

yi-c-c-r7 b a i mi l,

CXI io

35

CXIII

50

CXIV

ri c cli2-ch2-ch2-c00r1

Ti

R16 Rl7

(CH2) n /

CHaORsi

R38

N /

PhS

cxn r->? ^ ch2-ch2-ch-coori

30 Bl6 Ri 7

((CHaJn ch2or31

R38

ch2or31

i

648 017

52

Formula scheme L

Formula scheme M

PhSe S

R->? ^ CHa-CHa-CH-COORì

Rie Rl7 '

(CHa) n

CXXXI

CHAOR

2Uf \ 3i

»38

Rl6

^ 17

V

PhSe

CH (Ri5) -CHa-CH2-CH-COORi

(CHa) n

R x

CXXXII

CHAOR

2ur \ 31

R38

V

H. ^ COOR, C = C

CH (Rn5) -CH2 <- ^ H

30th

35

40

Rie —T (CH2) n

CXXXIII

CHAOR

a * JK3n

R '

• »38

R

16

»17th

M // Xi

V C = C

CH (R15) -CHa ^ ^ H

(CHa) n

CXXXIV

ch2or31

»38

Ris ^ Z3-Xi

Rl6

Rl7

(CH2) n ch2or31

I.

R38

R16 Rl7

V

CH (Ri5) -Z3-XI V (CH2) n

CHaORs1

R

38

Ri 6

R17

Formula scheme N

C (Ri5) ~ Zi-Xi

CHAOR

2 <Jf \ 31

R38

V

CH (R15) -Zn-Xi

RI .- <- (CHa) n Rl7 — i— (

Vi-C-C-R7 B D Mi li

CXLI

CXLII

CLI

CLII

53

Formula scheme O

Formula scheme P

Yn-C-C-R7 s and Mn Ln

Rl6 Rl7

N /

CH (RnS) -Zi-Xn

(CH2) n /

Yn-C-C-R7

II

Mn Ln

CLXI

CLXII

45

28

CHoOH

Yn-C-C-R27 il n Mß Ln

V

p Yn-C C-R27

Kna n "

M6 Ln

V

Y n -C-C-R27 Il u

Me Ln

55

M /

according to CLXXIV

54

Wrong «P ^ nsazmì

By CLXXIII

CH2OSO2CH3 OR28

Me Li

CH2OSO2CH3

CLXXV

'' Yi-C -— C-Rav RlS 1 "'

Me ^

CLXXIV

CLXXVI

Yl_C — C-R27 ««

Me Li

Y -C — C- ^ 7 tl «

Mn U

CLXXVIII

O-ZurCOOR-

CLXXVII

C-Rz?

. 55 648 017

Formula scheme Q

V

CLXXXV

/ Y-C-C-R27

K18 II II

m6 u

H/

.according to CLXXXVI

according to CLXXXVIII

i

648 017

56

Formula scheme Q (continued)

By CLXXXV

Y -j -C C-R27 H II-Me Li

CLXXXVII

Yt-C-C-R7 Il II Mi Li

R1S "Y-i-C-C-R27 M6 Li y

o-z.-x.

CLXXXIX

Y, -C — C-R7 Il II Mi Li

57

648 017

Formula scheme R

Formula scheme S

Yi -C — C-R27 u u Me Li

OR28

/ Yn-C C-R27

Ris II ||

Me Ln

CH20H v

28

P Y1 -C C R27

* 18 II II

Me L,

Xn-Zu-0

CXCI

20th

CXCII

25th

30th

CXCIII

45

50

CXCIV 60

CHoOR;

V

Xn-Z ^ -0

H2OR31

Xi-Zu-0

CCI

CCII

CCIII

648 017

Formula scheme T

58

Formula scheme U

ris r y-i-c-c-r27 Il II m6 h xi-z * -0

Yi-C-C-R7 h u Mi Li ccxi

. 20th

ccxii

30th

35

45

ccxiii

50

Xi-Za-o c-C-R7

n n Me Li

V

c-r7

ccxxi ccxxii ccxxiil

Claims (3)

648 017 2nd PATENT CLAIMS 1. A carbacyclin analog of formula X or XI: 15 > ie Rr Ra • 20 ■ 22 wherein n is 1 or 2; Li means a-R3: β-Rt, a-R4: β-R3, or a mixture of a-R3: / 3-R4 and aR »: β-R3, where R3 and R4 have the meaning of hydrogen, methyl or Fluorine, and are the same or different, with the proviso that one of the radicals R3 and R »is only fluorine if the other radical is hydrogen or fluorine; Mt means a-OH: / 3-R5 or a-R5: / 3-OH, where R5 has the meaning of hydrogen or methyl; R7 has the meaning of (1) -CmH2m-CH3, where m is an integer from 1 to 5 inclusive, (2) Phenoxy, optionally substituted with 1, 2 or 3 chlorine, fluorine, trifluoromethyl, (Ci-C3) alkyl or (Ci-C3) alkoxy, with the proviso that no more than two substituents have a meaning other than Alkyl, with the proviso that R7 is phenoxy or a substituted phenoxy only when R3 and R4 are hydrogen or methyl and are identical or different, (3) phenyl, benzyl, phenylethyl or phenylpropyl, optionally substituted on the aromatic ring by 1, 2 or 3 chlorine, fluorine, trifluoromethyl, (Cj-C3) alkyl or (CrC3) alk-oxy, with the proviso that no more than two substituents have a different meaning than alkyl, (4) cis-CH = CH-CH2-CH3, (5) - (CH2) 2-CH (OH) -CH3, or (6) - (CH2) 3-CH = C (CH3) 2; wherein -C (Li) -R7 taken together has the meaning of (1) (C4-C7) cycloalkyl optionally substituted with 1 to 3 (C, -C5) alkyl; (2) 2- (2-furyl) ethyl, (3) 2- (3-thienyl) ethoxy, or (4) 3-thienyloxymethyl; Rg has the meaning of hydroxy, hydroxymethyl or hydrogen; Ris has the meaning of hydrogen or fluorine; Ri6 has the meaning of hydrogen or R | 6 and Rn taken together mean -CH2-; Ri7 is defined or means above (1) hydrogen or (2) (C, -C4) alkyl; wherein (1) R20, R2i, R22. R23 and Rm all represent hydrogen and R22 represents either a-hydrogen or β-hydrogen, (2) R2o means hydrogen, R21 and Ra taken together form a second valence formation between C-9 and C-6a, and R23 and R24 taken together form a second valence formation between C-8 and C-9 or both mean hydrogen, or (3) R22, R23 and R24 are all hydrogen, where R22 is either a-hydrogen or β-hydrogen, and (a) R2o and R2J taken together mean oxo, or (b) R2o is hydrogen and R2i is hydroxy and is either a-hydroxy or ß-hydroxy; Xi has the meaning of (1) -COORi, where Rj has the meaning of (a) hydrogen, (b) (C, -C12) alkyl, (c) (C3-Cio) cycloalkyl, (d) (C7-C12) aralkyl, (e) phenyl, optionally substituted with 1, 2 or 3 chlorine or (Ci-C3) alkyl, (f) Phenyl substituted in the para position by (1) -NH-CO-R25, (Ü) -CO-R2S, (iii) -0-C0-Rj4, or (iv) -CH = N-NH-CO-NH2, where R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2; R26 represents methyl, phenyl, -NH2 or methoxy; and R54 represents phenyl or acetamidophenyl; including, or (g) a pharmacologically acceptable cation; (2) -CH2OH, (3) -COL4, where L4 has the meaning of (a) Amino of the formula -NR51Rj2, wherein R51 and RJ2 have the meaning of (i) hydrogen, (ii) (C1-C12) alkyl, (iii) (C3-Clo) cycloalkyl, (iv) (C7-Ci2) aralkyl, (v) phenyl, optionally substituted with 1, 2 or 3 chlorine, (CrC3) alkyl, hydroxy, carboxy, (C2-Cs) alkoxycarbonyl or nitro, (vi) (C2-C5) carboxyalkyl, (vii) (C2-C5) carbamoylalkyl, (viii) (C2-C5) cyanoalkyl, (ix) (C3-C6) acetylalkyl, (x) (C7-Cn) benzoalkyl, optionally substituted with 1, 2 or 3 chlorine, (C] -C3) alkyl, hydroxy, (CrC3) alkoxy, carboxy, (C2-C5) alkoxycarbonyl or nitro, (xi) pyridyl, optionally substituted with 1, 2 or 3 chlorine, (CrC3) alkyl, or (Ci-C3) alkoxy, (xii) (C6-C9) pyridylalkyl, optionally substituted with 1, 2 or 3 chlorine, (Ci-C3) alkyl, hydroxy or (C1-C3) alkyl, (xiii) (Ci-C4) hydroxyalkyl, (xiv) (Ci-C4) dihydroxyalkyl, (xv) (Ci-C4) trihydroxyalkyl, with the further proviso that no more than one of the radicals Rsi and R52 has a meaning other than hydrogen or alkyl, (b) Cycloamino, selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyl-lenimino, pyrrolino or 3,4-didehydropiperidinyl, optionally substituted with 1 or 2 (Ci-C | 2) alkyls with 1 to 12 inclusive Carbon atoms, (c) Carbonylamino of the formula -NR53COR51, in which R53 has the meaning of hydrogen or (Ci-Gj) alkyl and RS1 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 648 017 has a different meaning than hydrogen, but is otherwise as defined above, (d) sulfonylamino of the formula -NR33SO2R51, in which R51 and Rj3 have the same meaning as given in (c), (4) -CH2NL2L3, where L2 and L3 are the. Are hydrogen or (C1-C4) alkyl, and are the same or different, or the pharmacologically acceptable acid addition salts thereof, if Xi is -CH2NL2L3, Yi means trans-CH = CH-, cis-CH = CH-, -CH2CH2- or • CsC-; Zi has the meaning of (1) -CH2- (CH2) f-C (R2) 2, in which R2 has the meaning of hydrogen or fluorine and f is 0, 1, 2 or 3, (2) trans-CH2-CH = CH-, (3) - (Ph) - (CH2) g-, where (Ph) has the meaning of 1,2-, 1,3- or 1,4-phenylene and g means 0.1, 2 or 3; with the . above all applicable stipulation that (1) R15, R16 and Rn all only mean hydrogen if Zi has the meaning of - (Ph) - (CH2) g-, and that: (2) Zi only then - (Ph) - (CH2) g- means if R13 water. is fabric. 2. A carbacyclin analog of formula X according to claim 1 selected from the group consisting of Valeric acid-5-fluoro-5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -2 (1H) -pentalenylidene] -, (3aS- [2E, 3a, 4oi- ( IE, 3R *), 5 / 3.6aa] J Valeric acid-5-fluoro-5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -2 (lH) -pentalenylidene] -, (3aS- [2Z, 3a, 4o ;-( lE, 3R *), 5ß, 6aa]} Valeric acid 5-fluoro-5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -2 (lH) -pentalenylidene] -, methyl ester, (3aS-j - [2E, 3a, 4a (IE, 3R *), 5 / 3.6ao;] J I valeric acid 5-fluoro-5- [hexahydro-5-hydroxy-4- (3-hy: droxy-l-octenyl) -2 (1H) -pentalenylidene] -, methyl ester, (3aS- ■ - [2Z, 3a, 4a (lE, 3R *), 5 / 3.6aa]) Valeric acid 5-fluoro-5- [octahydro-5-hydroxy-l- (3-hy-; hydroxy-l-octenyl) -5H-inden-5-ylidene] -, [lS- [la (lE, 3R * ), 2 / 3,3ao:, - 5E, 7aa]) : V aleric acid-5-fluoro-5- [octahydro-5-hydroxy-l- (3-hy- droxy-l-octenyl) -5H-inden-3-ylidene] -, [lS- [la (lE, 3R *), 2 / 3.3aa, -5Z, 7aof] J V aleric acid-5-fluoro-5 - [octahydro-5-hydroxy-1 - (3-hy- Droxy-l-octenyl) -5H-inden-5-ylidene] -, methyl ester, (IS- [la- (IE, 3R »), 20.3aa, 5E7aa]) : Valeric acid 5-fluoro-5- [octahydro-5-hydroxy-l- (3-hydroxy-l-octenyl) -5H-inden-5-ylidene] -, methyl ester, jlS- [la- (lE, 3R *), 2j3,3aa, 5Z, 7aa]) Benzene acetic acid-2 - ([hexahydro-5-hydroxy-4- (3-hydroxy-1-octenyl) -2 (lH) -pentalenylidene] [- methylene) -, (3aS- [2E, 3aa, 4a- (lE , 3R *), 5 / 3.6aa]] Benzene acetic acid-2 - [[hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -2 (lH) -pentalenylidene]? Methylene} -, 13aS-l2Z, 3aa, 4a- (lE, 3R * ), 50.6aa] j Benzoic acid-3 - ([hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -2 (lH) -pentalenylidene] [jmethyIen) -, (3aS- [2E, 3acc, 4a- (lE, 3R *), 5 / 3.6aa]) Benzoic acid-3 - {[hexahydro-5-hydroxy-4- (3-hydroxy-1-octenyl) -2 (1 H) -pentalenylidene] - methylene] -, {3aS- [2Z, 3ao:, 4Q: - (lE, 3R *), 5j3,6aa]) Benzolacetic acid-2 - ([octahydro-5-hydroxy-l- (3-hydroxy - l-octenylJ-SH-inden-S-ylidenlf-methylenj-, | lS- [la (lE, 3R *), - 2 / î, 3aa, 5E, 7aa] | Benzolacetic acid-2-i [octahydro-5-hydroxy-l- (3-hydroxy-l-octenyl) -5H-inden-5-ylidene] - methylene} -, jlS- [la (IE, 3R *), -2j3,3aa, 5Z, 7aor] j Benzoic acid-3-j [octahydro-5-hydroxy-l- (3-hydroxy-1-octenyl) -5H-inden-5-ylidene] ^ methylenl-, [1 S- [1 a (1 E, 3R * ), - 2j3,3ao:, 5E, 7aa]) Benzoic acid 3-f [octahydro-5-hydroxy-1- (3-hydroxy-1-octenyl) -5H-inden-5-ylidene] Qmethylene | -, JIS- [la (IE, 3R *), -2ß , 3ao:, 5Z, 7ao!] J Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) -6a-methyl-2 (lH) -pentalenylidene] -, (3aS- [2E, 3aa, 4a- (lE, 3R *), 5 / 3.6a a]) Valeric acid-5- [hexahydro-5-hydroxy-4- (3-hydroxy-1 -octenyl) -6a-methyl-2 (lH) -pentalenylidene] -, (3aS- [2Z, 3ao:, 4Q :( lE, 3R »), 5i3,6aa]} Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-1-octenyl) -6a-methyl-2 (1H) -pentalenylidene] -, methyl ester, (3aR - [2E, 3aa, 4a ( le, 3S *), 5 / 3.6aa]) Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-1-octenyl) -6a-methyl-2 (1H) -pentalenylidene] -, methyl ester, (3aR - [2Z, 3aa, 4a ( IE, 3S *), 5 / 3.6aa] j Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-1-octenyl) cyclopropa [c] pentalen-2 (3H) -ylidene] -, [laS- (laa, 2E, -3ass, 4 / 3.5a, 6aR *)] Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-1 - octenyl) cyclopropa [c] pentalen-2 (3H) -ylidene] -, [laS- (lao:, 2Z, -3a / 3,4j8,5a, 6aR *)] Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) cyclopropa [c] pentalen-2 (3H) -ylidene] -, methyl ester, [1 aS- (l aa, 2E, 3 a / 3.4 / 3.5a, 6aR *)] Valeric acid 5- [hexahydro-5-hydroxy-4- (3-hydroxy-l-octenyl) cyclopropa [c] pentalen-2 (3H) -ylidene] -, methyl ester, [laS- (laa, 2Z, 3a | 8.4 / 3.5a, 6aR *)]. 3. A carbacyclin analog of formula XI according to claim 1 selected from the group consisting of 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGF rmethyl ester, 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGFi, 9-deoxy-16,16-difluoro-2 ', 9a-methano-3-oxa-4,5,6-trinor - 3,7- (r, 3'-inter-phenylene) -PGFi or the methyl ester thereof , 9-deoxy-l 3,14-dihydro-2 ', 9a-methano-3-oxa-4,5,6-trinor - 3,7- (r, 3'-inter-phenylene) -PGFi or the methyl ester from that, 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGF ramid, 15 (R) -9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7 - (r, 3'-inter-phenylene) -PGFi or the methyl ester thereof, 9-deoxy-2 ', 9-metheno-3-oxa-4,5,6-trinor-3,7- (l', 3 '-interphenylene) -PGFi or the methyl ester thereof, 9-deoxy-7,8-didehydro-2 ', 9-metheno-3-oxa-4,5,6-trinor - 3,7- (r, 3'-inter-phenylene) -PGFi or the methyl ester thereof , 9-deoxy-2 ', 9-hydroxymetheno-3-oxa-4,5,6-trinor-3,7 - (l', 3'-inter-phenylene) -PGFi or the methyl ester thereof, 9-deoxy-2 ', 9a-carbonyl-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGFi or the methyl ester thereof, or 9-deoxy-2 ', 9a-methano-3-oxa-4,5,6-trinor-3,7- (r, 3'-inter-phenylene) -PGDi.