IE50968B1 - Carbacyclin analogues - Google Patents

Abstract

Compounds of the formula wherein Q<1> is hydrogen and Q<2> is alkyl or CH2OH, or Q<1> and Q<2> together form a second bond or -CH2-, Q<3> is blocked CH2OH or a blocked alkyl- terminated prostaglandin side-group or derivative, n is 1 or 2, and R18 is H or optionally blocked OH or CH2OH.

Description

Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PC's). For convenience is often referred to simply as PGI2.

Carbacyclin, 6a-carba-PGI2, is often referred to simply as CBA2''.

A stable, partially saturated, derivative of PGIj is PGI^ or 5,6-dihydro-PGI2. 5,6-Dihydro-CBA2 is CBA-^.

Prostacyclin and carbacyclin may be trivially 10 named as derivatives of PGF-type compounds, e.g. PGF2 .

Accordingly, prostacyclin is trivially named 9-deoxy-6,9aepoxy-(5Z)-5,6-didehydro-PGF^ and carbacyclin is named 9-deoxy-6,9a-methano-(5E)-5,6-didehydro-PGF^. For description of prostacyclin and its structural identificat· ion, see Johnson et al, Prostaglandins 12:915 (1976).

For convenience, the prostacyclin or carbacyclin analogues herein described will be referred to by the trivial, art-recognized system of nomenclature described by N.A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF1-type compounds, PGI2 derivatives, or preferably as CBAj or CBA2 derivatives.

In the formulas herein, broken line attachments to a ring indicate substituents in the alpha (a) configuration, i.e., below the plane of said ring. Heavy solid line attachments to a ring indicate substituents in the “beta (¢) configuration, i.e., above the plane of said ring. The use of wavy lines (~) herein will represent attachment of substituents in the alpha or beta configuration or attached in a mixture of alpha and beta configurations. Alternatively wavy lines will represent either an E or Z geometric isomeric configuration or the mixture thereof.

A side chain hydroxy at C-15 in the formulas 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 discussion of the stereochemistry of the prostaglandins which discussion applies to the novel prostacyclin or carbacyclin analogs herein. Molecules of prostacyclin and carbacyclin each have several centers of asymmetry and therefore can exist in optically inactive form or in either of two enantiomeric (optically active) forms, i.e., the dextrorotatory and 1aveorotatory forms. As drawn, the formula for PGI2 corresponds to that endogenously produced in the mannalian species. In particular, refer to the stereochemical configuration at C-8 ( For convenience, reference to prostacyclin and carbacyclin will refer to the optically active form thereof. Thus, with reference to prostacyclin, reference is made to the form thereof with the same absolute configuration as that obtained from the mammalian species.

The term prostacyclin-type product, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes for which prostacyclin is employed. A formula as drawn herein which depicts a prostacyclin-type product or an intermediate useful in the preparation thereof, represents that particular stereoisomer of the prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostacyclin type product.

The term “prostacyclin analog or “carbacyclin analog represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or a mixture comprising stereoisomer and the enan10 tiomers thereof. In particular, where a formula is used to depict a prostacyclin type product herein, the term prostacyclin analog or carbacyclin analog refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.

Carbacyclin and closely related compounds are known in the art.

See Japanese Kokia 63,059 and 63,060, also abstracted respectively as Derwent Farmdoc CPI Numbers 481546/26 and 48155B/26. See also British published specifications 2,012,265 and German Offenlungsschrift 2,900,352, abstracted as Derwent Farmdoc CPI Number 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 also reported in the chemical literature, as follows: Morton, D.R., et al., J. Organic Chemistry, 44:2880 (1979); Shibasaki, Μ., 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, Μ., Chemistry Letters, 1299-1300 (1979), and Hayashi, M., Chem. Lett. 1437-40 (1979); and Li, Tsung-tee, A Facile Synthesis of 9(0)-Methano-prostacyclin, Abstract No. 378, (Organic Chemistry), and P. A. Aristoff, Synthesis of 6aCarbaprostacyclin I2, Abstract No. 236 (Organic Chemistry) both at Abstract of Papers (Part II) Second Congress of the North American Continent, San Francisco, California (Las Vegas, Nevada), USA, 24-29 August 1980. 7-0xo and 7-hydroxy-CBA2 compounds are apparently disclosed in United States Patent 4,192,891. 19-Hydroxy-CBA2 compounds are disclosed in United States Serial No. 054,811, filed 5 July 1979. CBA2 aromatic esters are disclosed in US-A-4,180,657. 11-Deoxy-Δ - or a^-CBA2 compounds are described in JP-A-77/24,865, Published 24 February 1979 Novel compounds according so the present invention are of the formula wherein n is one or 2; wherein Lj is a-RaiB-Rg, a-Rg:B-R3, or a mixture of a-R3:B-Ri, and a-R^B-R^ wherein R3 and Rg are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and Rt, is fluoro only when the other is hydrogen or fluoro; wherein Mj is a-OH:B-Rs or o-RsiB-OH, wherein R5 is hydrogen or methyl; wherein R? is (1) CmH2|n*®H3· wherein m is an integer from one to 5, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (Cj-C^alkyl, or (C!-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R? is phenoxy or substituted phenoxy, only when R3 and Ru are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (Cj-C3)alkyl, or (C3-C3)alkoxy, with the proviso that not more than two substituents are other 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 is (1) (Ci,-C7)cycloalkyl optionally substituted by one to 3 (CL-C5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein R8 is hydroxy, hydroxymethyl, or hydrogen; wherein Rts is hydrogen or fluoro; wherein R18 is hydrogen and R-i? is hydrogen or alkyl or R^g and R^y taken together are -CHg-; wherein X1 is (1) -COORj, wherein Rj is hydrogen, (C1-C12)alkyl, (C3-C10)cycloalkyl, (C7-C12)aralkyl, phenyl, optionally substituted with one, 2 or 3 (b) (c) (d) (e) criioro or (Ci-C3)alkyl, (f) phenyl substituted in the para position by (i) -NH-C0-R25. (ii) -C0-R26, (iii) -O-CO-R54, or (iv) -CH»N-NH-CO-NH2 wherein R2j is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2; R2g is methyl, phenyl, -NH2, or methoxy; and R5<» is phenyl or acetamidophenyl; inclusive, or (g) a pharmacologically acceptable cation; (2) -CH2OH, (3) -COL,,, wherein LH is (a) amino of the formula -NR51R52, wherein R5i and R52 are chloro, nitro, (i) (ii) (iii) (iv) (v) {CrC3)a1kyl, hydrogen, (Ci-Ci2)alkyl, (C3-C10) cycloalkyl, (C7-Ci2)aralkyl, phenyl, optionally substituted with one, 2 or hydroxy, carboxy, (C2-C5)alkoxycarbonyl, or (vi) (C2-C5)carboxyalkyl, (vii) (C2-C5)carbamoylalkyl, (viii) (C2-Cs)cyanoalkyl, (ix) (C3-Cs)acetylalkyl, (x) (C7-Cll)benzoalkyl, optionally substituted by one, 2 or 3 chloro, (Ci-C3)alkyl, hydroxy, (Ci-C3)alkoxy, carboxy, (C2-Cs)alkoxycarbonyl, or nitro, (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (Ci-C3)alkyl, or (Ci-C3)alkoxy, (xii) (C6-C9)pyridyl alkyl optionally substituted by one, 2 or 3 chloro, (CrC3)alkyl, hydroxy, or (CrC3)alkyl, (xiii) (Ci-Cjhydroxyalkyl, (xiv) (Ci-C,,) di hydroxyalkyl, (xv) (Ci-Cijtrihydroxyalkyl, with the further proviso that not more than one of R51 and R52 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (Ci-Ci2)alkyl of one to 12 carbon atoms, (c) carbonyl amino of the formula -NR53COR51, wherein 5 R23 is hydrogen or (Ci-C4)alkyl and R51 is other than hydrogen, but otherwise as defined above, (d) sulfonyl amino of the formula -NR53S02R51, wherein R21 and R23 are as defined in (c), (4) -CH2NL2L3, wherein L2 and L3 are hydrogen or (Ci-C^.)10 alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when Xi is -CH2NL2L3, wherein Υχ is trans-CH=CH-, cis-CH=CH-, -CH2CH2-, or -CeC-; wherein Ζχ is (1) -CH2-(CH2)f-C(R2)2, wherein R2 is hydrogen or fluoro and 15 f is zero, one, 2, or 3, (2) trans-CH2-CH=CH-, or (3) -(Ph)-(CH2)g-, wherein (Ph) is 1,2-, 1,3-, or 1,4-phenylene and g is zero, one, 2, or 3; with the overall provisos that (1) R15, Ri6, and R17 are all hydrogen only when Ζχ is -{Ph)-(CHz)g-, and (2) Ζχ is -(Ph)-(CH2)g- only when Rx5 is hydrogen.

With regard to the divalent substitutents described above (e.g., Lx and Μχ), these divalent radicals are defined as a-R^B-Rj, wherein 25 Ri represents the substituent of the divalent moiety in the alpha configuration with respect to the plane of the C-8 to C-12 cyclopentane ring and Rj represents the substituent of the divalent moiety in the beta configuration with respect to the plane of the ring.

Accordingly, when Μχ is defined as a-0H:g-R5, the hydroxy of the Μχ 30 moiety is in the alpha configuration, i.e., as in PGI2 above, and the R5 substituent is in the beta configuration.

The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C^-Cj) indi35 cates a moiety of the integer i to the integer j carbon atoms, inclusive. Thus (Cx-C3)alkyl refers to alkyl of one to 3 carbon atoms, or methyl, ethyl, propyl, and isopropyl.

The novel prostacyclin analogs herein, i.e., formula X compounds, are all named as. CBA j or CBA2 compounds, respectively, by virtue of the substitution of methylene for oxa in the heterocyclic ring of prostacyclin and the substitution. CBAZ compounds are those exhibiting the olefinic double bond at C-5,6, while CBAj compounds are those saturated at C-5,6.

Novel compounds wherein Zx is (Ph)-(CH2)g are designated inter-ο-, inter-m-, or 1nter-p-phenylene depending on whether the attachment between C-5 and the -(CH2)g- moiety is ortho, meta, or para, respectively.

For those compounds wherein g is zero, one, 2 or 3, the carbacyclin analogs so described are further characterized as 2,3,4trinor-, 3,4-dinor-, or 4-nor, since in this event the Xj-terminated side chain contains (not including the phenylene) 2, 3, or 4 carbon atoms, respectively, in place of the five carbon atoms contained in PGI2. The missing carbon atom or atoms are considered to be at the C-4 to C-2 positions such that the phenylene is connected to the C-5 and C-l to C-3 positions. Accordingly these compounds are named as 1,5-, 2,5-, 3,5-, and 4,5-inter-phenylene-CBA compounds when g is zero, one, 2, or 3, respectively.

Those CBA analogs wherein Z3 is -CH2-(CH2)^-CF2- are characterized as “2,2-di fluoro- compounds. For those compounds wherein f is zero, 2, or 3, the carbacyclin analogs so described are further characterized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this event the Χχ-terminated side chain contains 4, 6, or 7 carbon atoms, respectively, in place of the five carbon atoms contained in CBA2. The missing carbon atom is considered to be at the C-2 position such that the C-l carbon atom is connected to the C-3 position. The additional carbon atom or atoms are considered as though they were 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 to the C-3 position.

Those CBA analogs wherein Z3 is trans-CH2-CH=CH- are described as trans-2,3-didehydro-CBA compounds.

Those novel compounds where n is 2 are further characterized as 7a-homo-CBA compounds by virtue of the cyclohexyl ring replacing the heterocyclic ring of prostacyclin.

Further, the novel compounds are named as 9g-alkyl-CBA compounds when R]7 is alkyl.

When R^g and Rp taken together are -CH2*(methylene), the novel compounds so described are 6ag,9B-methano-CBA compounds by virtue of the methylene bridge between C-6a and C-9.

When R, r is fluoro, “5-fluoro-CBA compounds are lb described.

When R5 is methyl, the carbacyclin analogs are all named as 15-methyl-CBA compounds. Further, except for compounds wherein Yj is cis-CHOH-, compounds wherein the Mj moiety contains an hydroxyl in the beta configuration are additionally named as lS-epi-CBA compounds.

For the compounds wherein Yi is cis-CH=CH-, then compounds wherein the Mj moiety contains an hydroxyl in the alpha configuration are named as “15-epi-CBA compounds. For a description of this convention of nomenclature for identifying C-15 epimers, see U.S. Patent 4,016,184, issued 5 April 1977, particularly columns 24-27 thereof.

The novel carbacyclin analogs herein which contain -(CH2)2-, cis-CH=CH-, or -C=C- as the Y; moiety, are accordingly referred to as 13,14-dihydro, cis-13, or ''13,14-didehydro compounds, respectively.

When R7 is straight chained -C mH2m -CH3, wherein m is as defined above, the compounds so described are named as 19,20-dinor, 20-nor, ''20-methyT' or 20-ethyl compounds when m is one, 2, 4 or 5, respectively. When R7 is branched chain -CmH2m-CH3, then the compounds so described are 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 when m is 4 or 5 and the unbranched portion of the chain is at least n-butyl, e.g., 17,20-dimethyl compounds are described when m is 5 (1-methylpentyl).

When R7 is phenyl and neither R3 nor Ru is methyl, the compounds so described are named as 16-phenyl-17,18,19,20-tetranor compounds. When R7 is substituted phenyl, the corresponding compounds are named as “16-(substituted phenyl )-17,18,19,20-tetranor compounds. When one and only one of R3 and Ri» is methyl or both R3 and R^ are methyl, then the corresponding compounds wherein R7 is as defined in this paragraph are named as 16-phenyl or 16-(substituted phenyl )-18,19,20-trinor compounds or 16-methyl-16-phenyl- or 16-(substituted phenyl)18.19.20- trinor compounds respectively.

When R7 is benzyl, the compounds so described are named as 1750968 phenyl-18,19,20-trinor compounds. When R7 is substituted benzyl, the corresponding compounds are named as 17-(substituted phenyl)18,19,20-trinor compounds.

When R7 is phenylethyl, the compounds so described are named as 5 18-phenyl-19,20-dinor compounds. When R7 is substituted phenylethyl, the corresponding compounds are named as 18-{substituted phenyl )-19,20-dinor compounds.

When R7 is phenylpropyl, the compounds so described are named as 19-phenyl-20-nor compounds. When R7 is substituted phenylpropyl the corresponding compounds are named as “19-(substituted phenyl)-2O-nor compounds.

When R7 is phenoxy and neither R3 nor R„ is methyl, the compounds so described are named as “16-phenoxy-17,18,19,20-tetranor compounds. When R7 is substituted phenoxy, the corresponding compounds are named as 16-(substituted phenoxy)-17,18,19,20-tetranor“ compounds. When one and only one of R3 and Rt, is methyl or both R3 and R^. are methyl, then the corresponding compounds wherein R7 is as defined in this paragraph are named as 16-phenoxy or 16-(substituted phenoxy)18.19.20- trinor compounds or 16-methyl-16-phenoxy- or 16-(substi20 tuted phenoxy)18,19,20-trinor compounds, respectively.

When R7 is cis-CH=CH-CH2CH3, the compounds so described are named as cis-17,18-didehydrou compounds.

When R7 is -(CH2)2-CH(OH)-CH3, the compounds so described are named as 19-hydroxy“ compounds.

When R7 is -(CH2)3-CH=C(CH3)2, the compounds so described are named as 20-isopropylidene compounds.

When -C(Li)-R7 is optionally substituted cycloalkyl, 2-(2-furyl)ethyl, 2-(3-thienyl)ethyl, or 3-thienyloxymethyl, the compounds so described are respectively 15-cycloalkyl-16,17,18,19,20-pentanor cam30 pounds, 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.

When at least one of R3 and is not hydrogen then (except for the 16-phenoxy or 16-phenyl compounds discussed above) there are described the '‘16-methyl (one and only one of R3 and is methyl), '‘16,16-dimethyl (R3 and R,, are both methyl), 16-fluoro (R3 or Rt, is fluoro), 16,16-difluoro (R3 and Rt, are both fluoro) compounds. For those compounds wherein R3 and Rk are different, the prostaglandin analogs so represented contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: (16S)1' and *(16R)·'. Further, there is described by this invention the C-16 epimeric mixture: “(16RS).

When X! is -CH2OH, the compounds so described are named as 2-decarboxy-2-hydroxymethyl compounds.

When Xj is -CH2NL2L3, the compounds so described are named as 2-decarboxy-2-aminomethyl or “2-(substituted amino)methyl“ compounds.

When Xx is -COL,,, the novel compounds herein are named as CBAtype amides. Further, when X? is -COORi, the novel compounds herein are named as CBA-type esters and CBA-type salts.

Examples of phenyl esters substituted in the para position (i.e., Xi is -COORi, Ri is p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester, p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester, p-acetyl phenyl ester, p-benzylphenyl ester, p-amidocarbonylphenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde semicarbazone ester.

Examples of novel amides herein (i.e., Xi is -COLt,) include the following: (1) Amides within the scope of alkylamino groups of the formulaNR5iRs2 are methylamide, ethylamide, n-propylamide, n-butylamide, npentylamide, n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Further examples are dimethyl amide, diethylamide, di-npropylamide, di-n-butylamide, methyl ethyl amide, methyl propyl amide, methyl butyl amide, ethyl propyl amide, ethyl butyl amide, and propyl butylamide. Amides within the scope of cycloalkyl amino are cyclopropylamide, cyclobutyl amide, cyclopentyl amide, 2,3-dimethyl cyclopentylamide, 2,2-dimethylcyclopentylamide, 2-methylcyclopentyl amide, 3-tertbutylcyclopentyl amide, cyclohexyl amide, 4-tert-butylcyclohexyl amide, 3-isopropylcyclohexyl amide, 2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctyl amide, cyclononyl amide, cyclodecyl amide, N-methyl-Ncyclobutylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexy 1 amide, N-ethyl-N-cyclopentylamide, and N-ethyl-Ncyclohexylamide. Amides within the scope of aralkyl amino are benzyl amide, 2-phenyl968 ethyl amide, and N-methyl-N benzyl-amide. Amides within the scope of substituted phenylamide are p-chloroanilide, m-chloroanilide, 2,4dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimethoxyanilide, p-hydroxymethyl anilide, p-methylanilide, m-methyl anilide, p-ethylanilide, p-carboxyanilide, p-methoxycarbonyl anilide, p-carboxyanilide and o-hydroxyanilide. Amides within the scope of carboxyalkylami no are carboxyethyl amide, carboxypropyl amide and carboxymethyl amide, carboxybutyl amide. Amides within the scope of carbamoyl alkyl ami no are carbamoylmethylamide, carbamoyl ethyl amide, carbamoyl propyl amide, and carbamoyl butyl amide. Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyanopropylamide, and cyanobutylamide. Amides within the scope of acetylalkylamino are acetylmethylamide, acetyl ethyl amide, acetyl propyl amide, and acetyl butyl amide. Amides within the scope of benzoyl alkyl amino are benzoylmethylamide, benzoyl ethyl amide, benzoyl propyl amide, and benzoyl butyl amide. Amides within the scope of substituted benzoylalkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethyl amide, 2,4,6-tri chi orobenzoylmethyl amide, m-nitrobenzoylmethyl amide, p-nitrobenzoylmethyl amide, p-ntethoxybenzoylmethyl amide, 2,4-dimethoxy benzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide, p-hydroxymethylbenzoylmethylamide, pmethylbenzoylmethylamide, m-methylbenzoylmethylamide, p-ethylbenzoylmethyl ami de, p-carboxybenzoylmethylami de, m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethyl amide, o-hydroxybenzoylmethylamide, p-chlorobenzoylethyl amide, m-chlorobenzoyl ethyl amide, 2,4-dichlorobenzoylethyl amide, 2,4,6-trichlorobenzoyl ethyl amide, m-nitrobenzoylethyl amide, p-nitrobenzoylethyl amide, p-methoxybenzoylethyl amide, p-methoxybenzoylethyl amide, 2,4-dimethoxybenzoylethyl amide, 3,4,5trimethoxybenzoy1ethy1amide. D-hydroxymethylbenzoylethyl amide, p-methylbenzoyl ethyl amide, m-methylbenzoyl ethyl amide, p-ethylbenzoylethyl amide, p-carboxybenzoylethyl amide, m-methoxycarbonylbenzoyl ethyl amide, o-carboxybenzoylethyl amide, o-hydroxybenzoyl ethyl amide, p-chlorobenzoylpropylamide, m-chlorobenzoylpropyl amide, 2,4-dichlorobenzoylpropyl amide, 2,4,6-trichi orobenzoylpropyl amide, m-nitrobenzoylpropyl amide, p-nitrobenzoylpropyl amide, p-methoxybenzoylpropyl amide, 2,4-dimethoxybenzoylpropyl amide, 3,4,5-trimethoxybenzoylpropyl amide, p50968 hydroxymethyl benzoyl propyl amide, p-methylbenzoyl propyl amide, m-methylbenzoyl propyl amide, p-ethylbenzoyl propyl amide, p-carboxybenzoyl propyl amide, m-methoxycarbonylbenzoyl propyl amide, o-carboxybenzoylpropyl amide, o-hydroxybenzoylpropyl ami de, p-chlorobenzoylbutyl amide, m-chlorobenzoylbutyl amide, 2,4-dichl orobenzoylbutyl amide, 2,4,6-trichlorobenzoylbutylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylbutyl amide, p-methoxybenzoylbutyl amide, 2,4-dimethoxybenzoylbutyl-amide, 3,4,5-trimethoxybenzoylbutylamide, p-hydroxymethyl benzoyl butyl-amide, p-methylbenzoylbutyamide, m-methylbenzoyl butyl ami de, p-ethyl-benzoylbutyalmide, m-methylbenzoyl butyl amide, p-ethylbenzoyl butyl-amide, p-carboxybenzoylbutylamide, m-methoxycarbonylbenzoyl butyl amide, o-carboxybenzoyl butyl amide, o-hydroxybenzoylmethyl amide. Amides within the scope of pyridylamino are α-pyridylamide, B-pyridyl amide, and γ-pyridylamide. Amides within the scope of substituted pyridylamino are 4-methyl-a-pyridyl amide, 4-methyl-B-pyridyl amide, 4-chloro-apyridylamide, and 4-chloro-e-pyridylamide. Amides within the scope of pyridylalkyl amino are o-pyridylmethylamide, B-pyridylmethylamide, γ-pyridyl methyl amide, α-pyridylethyl amide, B-pyridylethyl amide, γ-pyridylethyl amide, α-pyridylpropyl amide, β-pyridylpropyl amide, γ-pyridylpropyl amide, α-pyridylbutyl amide, β-pyridylbutyl amide, and γ-pyridylbutylamide. Amides within the scope of substituted pyridylalkylamido are 4-methyl-a-pyridyl methyl amide, 4-methyl-B-pyridyImethyl amide, 4-chl oro-α-pyr idylmethyl amide, 4-chl orο-β-pyr idy1methyl amide, 4-methyl-a-pyridyl propyl amide, 4-methyl-β-pyridyl propyl amide, 4-chloro-a-pyridylpropyl amide, 4-chloro-B-pyridyl propyl amide, 4methyl-a-pyridylbutyl amide, 4-methyl-β-pyridylbutyl amide, 4-chloroa-pyridyl butyl amide, 4-chloro-B-pyridyl butyl amide, 4-chloro-ypyridylbutyl-amide. Amides within the scope of hydroxyalkyl ami no are hydroxymethyl amide, β-hydroxyethylamide, β-hydroxypropylamide, γ-hydroxypropylamide, 1-(hydroxymethyl)ethyl-amide, 1-(hydroxymethyl )propylamide, (2-hydroxymethyl)propyl amide, and a,a,-dimethyl-hydroxyethyl amide. Amides within the scope of dihydroxyal kylamino are di hydroxymethyl amide, β,γ-dihydroxypropylamide, l-(hydroxymethyl)2hydroxymethylamide, β,γ-dihydroxybutyl amide, β,fi-dihydroxybutyl - amide, γ,ί-dihydroxybutylamide, and l,l-bis(hydroxymethyl)ethyl amide. Amides within the scope of tri hydroxyalkyl ami no are tris(hydroxy-methyl )methylamide and l,3-dihydroxy-2-hydroxymethylpropyl amide. 968 (2) Amides within the scope of cycloamino groups described above are pyrrol idyl amide, piperidyl amide, morpholinylamide, hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydropiperidinylamide. (3) Amides within the scope of carbonylamino of the formula -NR53C0Rsl are methyl carbonyl amide, ethyl carbonyl amide, phenylcarbonylamide, and benzyl carbonyl amide. (4) Amides within the scope of sulfonylamino of the formula -NR53SO2R51 are methyl sulfonyl amide, ethylsufonylamide, phenylsulfonylamide, p-tolyl sulfonyl amide, benzyl sulfonyl amide.

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isomeric forms thereof.

Examples of (C3'C10)cycloalkyl which includes alkyT-substituted cycloalkyl, are cyclopropyl, 2-methylcycl0propyl, 2,2-dimethylcyclopropyl, 2,3-diethyl cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propyl cyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl , 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of (C7-C12)aralkyl are benzyl, 2-phenylethyl, 1- phenylethyl, 2-phenylpropyl, 4-phenyl butyl, 3-phenyl butyl, 2- (l-naphthylethyl), and l-(2-naphthylmethy1).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, 2,4dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, pethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of (Cs-C7)cycloalkyl optionally substituted by (C1-C5)alkyl are cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 1-pentylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3- propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethyl cyclopentyl, 3-ethyl cyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 1-methyl-3-propylcyclopentyl, 2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cycl0hexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4- ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 4-tert50968 butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, 2.6- dimethyl-4-propylcyclohexyl, and cycloheptyl.

Examples of substituted phenoxy, phenylmethyl, phenyl ethyl, or phenylpropyl of the R7 moiety are (ο-, m-, or p-)tolyi, (ο-, m-, or p-) ethyl phenyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (ο-, m-, or p-)propylphenyl, 2-propyl-(m- or p-)tolyl, 4-isopropyl-2,6-xylyl, 3propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethy1phenyl, (ο-, m-, or p-)fluorophenyl, 2-fluoro-(m- or p-)to1yl, 4fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-,m-, or p-)chl orophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propyl phenyl, 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, (ο-, m-, or p-)trifluoromethyl phenyl, (ο-, m-, or p-)methoxyphenyl, (ο-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxypheny1, 2,4dichloro-(4- or 6-)methylphenyl, (ο-, m-, or p-)tolyloxy, (ο-, m-, or p-)ethyl phenyloxy, 4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (ο-, m-, or p-) propyl phenoxy, 2-propyl-(m- or p-)tolyloxy, 4-isopropyl-2,6-xyly1oxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenoxy, (ο-, m-, or p-)fluorophenoxy, 2-fluoro-(m- or p-)tolyloxy, 4-f1uoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenoxy, (ο-, m-, or p-)-chlorophenoxy, 2-chloro-p-tolyl oxy, (3, 4, 5, or 6-)chloro-o-tolyloxy, 4-chloro-2-propyl phenoxy, 2-isopropyl-4-chl orophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2.6- , 3,4-, or 3,5-)dichlorophenyloxy, 4-chl oro-3-fluorophenoxy, (3or 4-)chloro-2-fluorophenoxy, (ο-, m-, or p-)trifluoromethyl phenoxy, (ο-, m-, or p-)methoxyphenoxy, (ο-, m-, or p-)ethoxyphenoxy, (4- or - )chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)methylphenoxy, (ο-, m-, or p-)tolylmethyl, (ο-, m-, or p-)ethyl phenyl methyl, 4-ethyl-otolylmethyl, 5-ethyl-m-tolylmethyl, (ο-, m-, or p-) propyl phenyl methyl, 2-propyl-(m- or p-)tolylmethy1, 4-isopropyl-2,6-xylylmethyl, 3propyl-4-ethylphenyl methyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethyl phenyl methyl, (ο-, m-, or p-)fluorophenylmethyl, 2-fluoro-(m- or p-)tolylmethyl, 4-fluoro-2,5-xylylmethy1, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dif1uorophenyl, (ο-, m-, or p-)chlorophenylmethyl, 2-chloro-ptolyl methyl , (3, 4, 5, or 6-)chloro-o-tolyl methyl, 4-chl oro-2-propylphenylmethyl, 2-isopropyl-4-chlorophenylmethyl, 4-chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichl orophenylmethyl, 509 68 4-chIoro-3-fluorophenylmethyl, (3- or 4-)ch1oro-2-fluorophenylmethyl, (ο-, m-, or p-)trifl uoromethyl phenyl methyl, (ο-, m-, or p-)methoxyphenylmethyl, (ο-, m-, or p-)ethoxyphenyl and (4- or 5-)chloro-2-methoxyphenylmethyl.

The novel CBA analogs disclosed herein produce certain prostacyclin-like pharmacological responses.

Accordingly, the novel formula X CBA analogues are used as agents in the study, prevention, control, and treatment of diseases, and other undesirable physiological conditions, in mammals, particularly humans, valuable domestic animals, pets, zoological specimens, and laboratory animals (e.g., mice, rats, rabbits and monkeys). In particular, these compounds have useful application as antithrombotic agents, anti-ulcer agents, and anti-asthma agents, as indicated below. (a) Platelet Aggregation Inhibition These novel CBA analogs disclosed herein are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, or to remove or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts -following surgery, to treat peripheral vascular diseases, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses of from 0.01 to 10 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of acton nistration.

The preferred dosage form for these compounds is oral, although other non-parenteral routes (e.g., buccal, rectal, sublingual) are likewise employed in preference to parenteral routes. Oral dosage forms are conventionally formulated (tablets, capsules) and administered 2-4 times daily. 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 provides in vitro applications such as storage of whole blood to be used in heart-lung machines. Additionally whole blood containing these compounds can be circulated through organs, e.g., heart and kidneys, which have been removed from a donor prior to transplant. They are also useful in preparing platelet rich concentrates for use in treating thrombocytopenia, chemotherapy, and radiation therapy. In vitro applications utilize a dose of 0.001-1.0 ug per ml of whole blood. For treatment of peripheral vascular diseases, see U.S. Patent 4,103,026. (b) Gastric Secretion Reduction These novel CBA analogs disclosed herein are also useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control gastric secretion, thereby to reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of from 0.1 pg to 20 ug per kg of body weight per minute, or in a total daily dose by injection or infusion in the range of from 0.01 to 10 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

Preferably, however, these novel compounds are administered orally or by other non-parenteral routes. As employed orally, one to 6 administrations daily in a dosage range of from 1.0 to 100 mg per kg of body weight per day is employed. Once healing of the ulcers has been accomplished the maintenance dosage required to prevent recurrence is adjusted downward so long as the patient or animals remains asymptomatic. (c) NOSAC-Induced Lesion Inhibition These novel CBA analogs disclosed herein are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are useful for that purpose by concomitant adminis50968 tration of the prostaglandin derivative and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge, et al., U.S. Patent No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins. Accordingly these novel CBA analogs herein are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge, et al. as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate inflammatory conditions, for example, in any dosage regimen and by any of the known routes of systemic administration. (d) Bronchodilation (Anti-asthma) These novel analogs disclosed herein are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediator-induced bronchoconstriction, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial bronchitis, bronchiectasis, pneumonia and emphysema. For these pur25 poses, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories, parenterally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of from 0.01 to 5 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these CBA analogs can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone). 50868 These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by the oral Inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentrations of about one part of medicament to fcora 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid or sodium bisulfite can be employed. For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Suitable means to employ the aerosol inhalation therapy technique are described fully in United States Patent 3,868,691, for example.

When Xi is -COORi, the novel CBA analogs so described are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of Rp However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.

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

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminium, zinc, and iron are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines 508 68 are methylamine, dimethyl amine, trimethylamine, ethylamine, dibutylamine, tri isopropyl amine, N-methylhexyl amine, decyl amine, dodecylamine, allylamine, crotylamine, cyclopenty!amine, dicyclohexyl amine, benzylamine, dibenzylamine, a-phenylethylamine, g-phenyl ethyl amine, ethylenediamine, diethylenetriamine, adamantylamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereto, e.g., 1-methyl piperidine, 4-ethylmorpholine, 1-isopropyl pyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, as well as amines containing watersolubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyl diethanolamine, N-butylethanolamine, 2-amino-l-butanol, 2-amino-2-ethyl-l,3-propanediol, 2-amino-2-methyl-l-propanol, tris15 (hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine and procaine. Further useful amine salts of the basic amino acid salts, e.g., lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethyl ammonium, tetraethyl ammonium, benzyltrimethyl ammonium and phenyl triethyl ammonium.

When X! is -CH2NL2L3, the novel CBA analogs so described are used for the purposes described in either free base or pharmacologically acceptable acid addition salt form.

The acid addition salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted ami nomethyl)-CBA analogs provided by this invention are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzene30 sulfonates and toluenesulfonates, prepared by reacting the CBA analog with the stoichiometric amount of the acid corresponding to the pharmacologically acceptable acid addition salt.

To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of this invention are preferred.

It is preferred that in the X!-terminated side chain for interp-phenylene-CBA compounds, g be zero, for inter-m-phenylene-CBA compounds g be zero or one (especially zero), and for inter-o-phenyl ene CBA compounds g be zero, one, or 2 (especially one). lnter-o- and inter-m-phenylene-CBA compounds, especially inter-m-phenylene-CBA compounds are preferred. Moreover when Zj is -CH2-(CH2)pC(R2)2, f is preferably one and R2 is preferably hydrogen. When R17 is (0χ-(\)alkyl, R17 is preferably methyl. Further, when the C-12 side chain contains -CmH2|]fCH3» is preferred that m be 3, 4, or 5, most preferably 3. When m is 5, more straight chain isomeric forms are preferred, especially methyl-substituted butyl. Further, it is preferred that, when R7 is aromatic, R7 be phenoxy, phenyl, or benzyl, including substituted forms thereof. For those compounds wherein R7 is substituted phenoxy or phenylalkyl, it is preferred there be only one or 2 substituents selected from the group consisting of chloro, fluoro, or tri fl uoromethyl. Further, for those compounds wherein R7 is aromatic, it is preferred that R3 and Ru both be hydrogen.

Most expecially preferred to biological potency are formula X CBA2 analogs exhibiting the same C-5 isomeric configuraton as CBA2 itself.

Especially preferred are those compounds which satisfy two or more of the above preferences. Further, the above preferences are expressly intended to describe the preferred compounds within the scope of any generic formula of novel CBA analogs disclosed herein. The preparation of the novel compounds of this invention will now be described with reference to the Charts herein. In these Charts, g, n, Lp Mp Ry, Rg, R15, R]6. Rp. > Y-j and above. The other variables are defined as follows Ac is acetyl; Mg is a-0R10:e-R5 or a-R5:e-0R10 wherein are as defined Rg is hydrogen or methyl; R-jθ is an acid-hydrolysable blocking group; R is hydrogen, OH, CHgOH, 0R1Q or CH20R1Q wherein R]0 is as 18 defined above; R27 is the same as R? -(CHZ)2-CH(OR1O)-CH3; R28 except that -(CH2)2-CH(0H)-CH3 is a silyl protective group; is R31 is a hydroxy-hydrogen protective group; R37 is Cp4 alkyl; R^g is hydrogen, OR^ or CHgOR^i wherein R^ is as defined above; and Z2 is the same as Z^ but is not -(Ph)-CH2)g-.

Those protective groups within the scope of R^o are any group which replaces a hydroxy hydrogen and is neither attacked by nor is reactive to the reagents used in the transformations used herein as a hydroxy is and which is subsequently replaceable by acid hydrolysis with hydrogen in the preparation of the prostaglandin-type compounds. Several such protective groups are known in the art, e.g. tetrahydropyranyl and substituted tetrahydropyranyl. See for reference E.J. Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XII Organic Synthesis, pages 51-79 (1969). Those blocking groups which have been found useful include: (a) tetrahydropyranyl; (b) tetrahydrofuranyl; (c) a group of the formula -C(OR-j-j)(R^2)-CH(Ri3)(R^), wherein R,, is alkyl of one to 18 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, 20 aralkyl of 7 to 12 carbon atoms, phenyl or phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, wherein R^ and R^ are alkyl of one to 4 carbon atoms, phenyl, phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, or when and R^ are taken together -(CH2)a- or when Ri2 are R13 are taken together -(CH2)|j-O-(CH2) , wherein a is 3, 4, or 5 and b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, with the further proviso that R12 and R13 may be the same or different, and wherein is hydrogen or phenyl; and (d) silyl groups according to R28, as qualified hereinafter.

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

When the protective group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as described in the preceding paragraph, in place of the 2,3-dihydropyran.

When the protective group is of the formula -C(0Rli)(R12)-CH(R13)(R11(), wherein Rn, R12, Ri3, and Rllt are as defined above; a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1-cyclohexen-l-yl methyl ether, or 5,6-dihydro-4methoxy-2H-pyran is employed. See 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 dihydropyran above.

R28 is a silyl protective group of the formula -SifGjJj- In some cases, such silylations are general, in that they silylate all hydroxyls of a molecule, while in other cases they are selective, in that while one or more hydroxyls are silylated, at least one other hydroxyl remains unaffected. For any of these silylations, silyl groups within the scope of -Si(G1)3 include trimethylsilyl, dimethylphenylsilyl, tri phenyl si 1yl, t-butyldimethylsilyl, and methyl phenylbenzylsilyl. With regard to Gj, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl and phenyl.

Examples of aralkyl are benzyl, phenethyl, a-phenyl ethyl, 3-phenyl968 propyl, α-naphthylmethyl, and 2-(a-naphthy1 )ethyl. Examples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2methylphenyl, and 2,4-dichloro-3-methylphenyl.

These silyl groups are known in the art. See for example, Pierce Silylation of Organic Compounds, Pierce Chemical Company, Rockford, Ill. (1968). When silylated products of the charts below are intended to be subjected to chromatographic purification, then the use of silyl groups known to be unstable to chromatography (e.g. trimethylsilyl) is to be avoided. Further, when silyl groups are to be introduced selectively, silylating agents which are readily available and known to be useful in selective silylations are employed. For example, t-butyl dimethyl silyl groups are employed when selective introduction is required. Further, when silyl groups are to be selectively hydrolyzed in the presence of protective groups according to R10 or acyl protective groups, then the use of silyl groups which are readily available and known to be easily hydrolyzable with tetra-n-butylammonium fluoride are employed. A particularly useful silyl group for this purpose is t-butyldimethylsilyl, while other silyl groups (e.g. trimethylsilyl) are not employed when selective introduction and/or hydrolysis is required.

The protective groups as defined by R10 are 'otherwise 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., hydrolysis of the blocking group is achieved.

R31 is a hydroxy-hydrogen protective group, as indicated above. As such, R31 may be an acyl protective group according to Rg, an acid hydrolyzable protective group according to R10, a silyl protective group according to R2g, or an arylmethyl hydroxy hydrogen replacing group according to R31(.

Acyl protective groups according to Rg include: (a) benzoyl; (b) benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 12 carbon atoms, or nitro, with the proviso that not more than two substituents are 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 alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, or nitro, with the proviso that not more than two substituents on either of the fused aromatic rings are other than alkyl and that the total number of carbon atoms in the substituents on either of the fused aromatic rings does not exceed 10 carbon atoms, with the further proviso that the various substituents are the same or different; or (f) alkanoyl of 2 to 12 carbon atoms.

In preparing these acyl derivatives of a hydroxy-containing compound herein, methods generally known in the art are employed. Thus, for example, an aromatic acid of the formula R90H, wherein R9 is as defined above (e.g., benzoic acid), is reacted with the hydroxycontaining compound in the presence of a dehydrating agent, e.g. ptoluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively an anhydride of the aromatic acid of the formula (RgjOH, e.g., benzoic anhydride, is used.

Preferably, however, the process described in the above paragraph proceeds by use of the appropriate acyl halide, e.g., R9Hal, wherein Hal is chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the hydroxyl-contain!ng compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine or triethylamine. The reaction is carried out under a variety of conditions, using procedures generally known in the art. Generally mild conditions are employed: 0-60°C., contacting the reactants in a liquid medium (e.g., excess pyridine or an inert solvent such as benzene, toluene, or chloroform). The acylating agent is used either in stoichiometric amount or in substantial stoichiometric excess.

As examples of R9, the following compounds are available as acids (R9OH), (R9)20, or acyl chlorides (R9C1): benzoyl; substituted benzoyl, e.g., (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-, or 4-) isopropyl benzoyl, (2-, 3-, or 4-)tert-butylbenzoyl, s 09 68 2.4- dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)toluyl, (2-, 3-, or 4-)phenethyl benzoyl, (2-, 3-, or 4-}nitrobenzoyl, (2,4, 2.5- , or 2,3-)Hinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-di5 methyl-2-nitrobenzoyl, 2-nitro-6-phenylethyl benzoyl, 3-nitro-2phenethylbenzoyl, 2-nitro-6-phenethyl benzoyl, 3-nitro-2-phenethylbenzoyl; mono esterified phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 2-isopropyl10 1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-lnaphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-lnaphthoyl, 4,5-dinitro-l-naphthoyl, (3-, 4-, 6-, 7-, or 8-)methyl-l-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-)m'tro-2naphthoyl and acetyl.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. RgCl compounds corresponding to the above Rg 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 RgOH, (Rg)2O, or RgCl reactant does not have bulky hindering substituents, e.g. tert-butyl on both of the ring carbon atoms adjacent to the carbonyl attaching site.

The acyl protective groups, according to Rg, are removed by deacylation. Alkali metal carbonate or hydroxide are employed effec25 tively at ambient temperature for this purpose. For example, potassium carbonate or hydroxide in aqueous methanol at about 25° C is advantageously employed.

R34 is defined as any arylmethyl group which replaces the hydroxy hydrogen of the intermediates in the preparation of the various CBA analogs herein which is subsequently replaceable by hydrogen in the processes herein for preparation of these respective prostacyclin analogs, being stable with respect to the various reactions to which R3g-containing compounds are subjected and being introduced and subsequently removed by hydrogenolysis under conditions which yield substantially 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 4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the various substituents are the same or different; (c) benzhydryl; (d) benzhydryl substituted by one to 10 alkyl of one to carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the various substituents are the same or different on each of the aromatic rings; (e) trityl; (f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to carbon atoms, with the further proviso that the various substituents are the same or different on each of the aromatic rings.

The introduction of such ether linkages to the hydroxycontaining compounds herein, particularly the benzyl or substituted benzyl ether proceeds by methods known in the art, for example by reaction of the hydroxy-containing compound with the benzyl or substituted benzyl halide (chloride, bromide, or iodide) corresponding, co the desired ether. This reaction proceeds in the presence of an appropriate condensing agent (e.g. silver oxide). The mixture is stirred and heated to 50-80°C. Reaction times of 4 to 20 hours are ordinarily sufficient.

Starting materials for the processes of Charts A, C, E, F and G are described and claimed in British Patent Application No. 8319030 )(Serial No.

Starting materials for the processes of Charts D, G (formula CII) and I are described and claimed in British Patent Application No. 8319031 (Serial No. ).

With respect to Chart A, a method is provided whereby the formula 50S68 XXXI compound is transformed to the novel CBAg analogues of formula XXXVI.

The formula XXXI compound is transformed to the formula XXXVI compound by methods known in the art for preparing carbacyclin. See for example, British published applications referred to above. Alternatively, the formula XXXI compound is reacted with formula XXXII compound and thereby successively transformed to the formula XXXIII, fonnula XXXIV and fonnula XXXV compounds.

The reaction of the fonnula XXXI compound employing the formula 10 XXXII compound is accomplished by methods known in the art. See Moersch, G.W., J. Organic Chemistry, 36:1149 (1971) and Mulzer, J., et al., Tetrahedron Letters, 2949 (1978). The fonnula XXXII reactants are known in the art or are prepared by methods known in the art. Example 1 describes one such method of preparation of a formula XXXII compound.

The fonnula XXXIII compound is then transformed to the formula XXXIV compound by decarboxylative dehydration. Procedures for this reaction are known in the art. See Eschenmoser, A., et al., He1v. 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 fonnula XXXV compound is prepared from fonnula XXXIV compound by selective desilylation. Such procedures are known in the art and typically employ the use of tetra-n-butyl ammonium fluoride and tetrahydrofuran. See Corey, E.J., et al., JACS 94:6190 (1972).

The fonnula XXXV compound is transformed to various acids, esters, amides, and amines of a formula XXXVI by methods known in the art. Particularly useful in this regard are methods described in the aforementioned British published specifications describing the prepa30 ration of carbacyclin analogs.

The preparation of fonnula XXXVI compounds from the formula XXXV compounds proceeds by, for example, oxidation to the corresponding carboxylic acid, followed by hydrolysis of any protective groups at the C-ll or C-15 position of the molecule. Such carboxylic acids are then esterified by conventional means or amidized by conventional means. Such amides may, for example, then be reduced to corresponding amines (Xx is -CH2NL2L3 by reduction by lithium aluminum hydride. See U.S. Patent 4,073,808. In a preparation of the primary alcohols according to formula XXXVI from the fonnula XXXV compound, hydrolysis of any protective groups at C-ll or C-15 yields such products directly. Hydrolysis is accomplished by procedures described above, e.g., mild acidic conditions at elevated temperatures.

Chart B provides a method whereby the known fonnula XLI compounds are transformed to the fonnula XLIV aldehydes employed in Chart C in the preparation of inter-phenylene-CBA2 compounds therein.

With respect to Chart B, the fonnula XLII compound is prepared from the fonnula XLI compounds by reduction. Conventional methods known in the art for the transformation of carboxylic acids to corresponding primary alcohols are employed. For example, one extremely useful conventional means for this reduction is employing lithium aluminum hydride as a reducing agent.

The fonnula XLIII compound is then prepared from the formula XLII compound by monosilylation. Particularly, fonnula XLIII compounds are prepared wherein R28 represents a relatively stable silyl group, most preferably being t-butyldimethylsilyl or phenyldimethylsilyl. Other silyl groups, particularly trimethyl-silyl (TMS) are not preferred for use in connection with the methods of Chart B· The fonnula XLIII monosilyl derivatives are prepared from the fonnula XLII compound by reacting the fonnula XLII compounds 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 employed in the transformation. Accordingly, there are prepared both monosilyl derivatives of the fonnula XLII compound as well as the bis-silyl derivatives corresponding to fonnula XLII. From this mixture of products, the fonnula XLIII compound is recovered by conventional means, e.g., column chromatography. Otherwise, the silylation proceeds under conditions conventionally employed for silylating hydroxyl groups. Refer to the discussion hereinabove.

The fonnula XLIV compound is then prepared from the fonnula XLIII compound by oxidation of the formula XLIII alcohol to the corresponding aldehyde. Conventional oxidizing agents are employed, e.g., manganese dioxide.

Chart C provides a method whereby the fonnula LI ketones are transformed to the formula LX inter-phenylene CBA2 analogues disclosed herein. 50868 In accordance with Chart C the formula LI I compound is prepared from the formula LI compound by reduction of the formula LI ketone to the corresponding secondary alcohol. This reduction proceeds by conventional means, employing readily available reducing agents.

Accordingly, sodium, potassium, or lithium borohydride is conveniently employed in this reduction.

Thereafter, the formula LII alcohol is transformed to the corresponding mesylate (methanesulfonate). Conventional methods for the transformation of alcohols to corresponding mesylates are employed.

Thus, the formula LI I alcohol is reacted with methane-sulfonyl chloride in the presence of a tertiary amine (e.g., tri-ethyl amine) in the preparation of the formula LIII compound.

Other sulfonyl derivatives corresponding to the formula LII alcohol may be employed in place of the formula LIII compound in the transformations of Chart C. These other sulfonyl derivatives are preferably those derived from readily available sulfonylating reagents, i.e., the corresponding sulfonyl chlorides. One especially important alternative to the formula LIII compound is the tosylate (toluenesulfonate) corresponding to the formula LII compound.

The formula LIII compound, or an alternate sulfonate corresponding thereto, is transformed to the formula LIV compound by treatment with sodium lithium or potassium thiophenoxide. The thiophenoxide is conveniently prepared just prior to the transformation by mixing approximately equal molar amounts of thiophenol and base, e.g., potassium t-butoxide.

This formula LIV compound is then oxidized to the corresponding formula LV compound by oxidation with a readily available oxidizing agent such as m-chloroperbenzoic acid.

The formula LV compound is then condensed with the formula XLIV 30 compound prepared according to Chart B by first treatment of the formula LV compound with a strong base, e.g., π-butyllithium, to generate the anion corresponding to the formula LV compound, treatment of the corresponding anion with the aldehyde of formula XLIV and finally treating the resulting adduct with acetic anhydride to yield the formula LVI acetyl compound.

The formula LVI compound is then transformed to the formula LVI I compound by reaction with a sodium amalgam. Methods by which the formula LVI I olefin is formed from the formula LV compound are analo50968 gous to known methods described by Kocienski, P.J., et al., Scope and Stereochemistry of an Olefin Synthesis from B-Hydroxysulphones, JCS Perkin I, 829-834 (1978).

The fonnula LVII compound is then transformed to the fonnula LVIII compound by selective hydrolysis of the silyl group according to R28. Conventional means for this hydrolysis are employed, e.g., tetra-n-butyl ammonium fluoride. Refer to the discussion above for a discription of this hydrolysis.

The formula LVIII C-5 diastereomers thusly prepared are conveniently purified into (5-E) and (5-Z) isomeric forms. This transformation proceeds by conventional means, e.g., column chromatography.

Thereafter either the (5E) or (5Z) isomer of formula LVIII is transformed to the fonnula LIX carboxylic acid or ester by conventional oxidation, followed by optional esterification. One especially convenient means of oxidation is employing the Jones reagent, although other oxidizing agents are employed. Esterification then oroceeds by methods hereinafter described.

Finally, the formula LX products are prepared from the fonnula LIX compound by first hydrolyzing the protective groups under acidic conditions, e.g., mixtures of water, tetrahydrofuran, and acetic acid. Thereafter, the fonnula LIX acids and esters are transformed to various other C-l derivatives by methods hereinafter described.

One especially convenient means of preparing the formula LX compound as a free carboxylic acid (Xi is -COOH), is by purification of the corresponding methyl ester, followed by saponification under basic conditions (e.g., the treatment with potassium carbonate or sodium or potassium hydroxide). 68 Chart D then provides a method whereby the formula LXXI compound is transformed to the formula LXXII carbacyclin analogues in accordance with the present invention. With respect to Chart D> the formula LXXI compound is transformed to the formula LXXII compound by selective hydrolysis of the protective group according to R31. Thereafter, the formula LXXII compound is transformed to formula LXXIII compound by methods known in the art, e.g., oxidation of the formula LXXII primary alcohol to the corresponding aldehyde, Wittig oxylacylating the aldehyde, and reduction of the resulting ketone to the secondary or tertiary alcohol corresponding to Μχ. For an example of the various transformations employed according to Chart D, see Chart A (part VI) of U.S. Patent 4,107,427, issued 15 August 1978.

Chart E provides a method wherebv the formula LXXXI intermediate is transformed to the formula LXXXVIII and LXXXIX isomers of the novel C-6a- and/or C-9-substituted C8AZ analogues.

With respect to Chart E, the formula LXXXIII compound is prepared from the formula LXXXI ketone by a Wittig ω-carboxyalkylation employing a formula LXXXII tri phenyl phosphonium compound. The Wittig reaction is undertaken under conventional reaction conditions for preparing prostaglandin-type substances. The formula LXXXIII compound is then optionally hydrolyzed to yield the formula X carboxylic acid products or employed in the further transformations of Chart E in ester form.

The formula LXXXIII compound thusly prepared is thereafter preferably separated directly into C-5 isomers of formulas LXXXVIII and LXXXIX (e.g., by chromatographic means followed by hydrolysis of any protective groups at C-ll or C-15 position of the molecule), or is alternatively transformed to the formula LXXXIV ester by conventional esterification techniques, e.g., ethereal diazomethane treatment or treatment with methyl iodide. The formula LXXXIV ester is then reduced to the corresponding primary alcohol by reduction with a suitable reducing agent, e.g., lithium aluminum hydride, by methods known in the art for preparing prostaglandin-type primary alcohols from corresponding prostaglandin esters.

The formula LXXXV compound represents an especially convenient intermediate for the facile separation of the C-5 diastereomers. Accordingly, the formula LXXXV compound may be separated by conventional means of separation of diastereomeric mixtures, e.g., column chromatography, whereby the formula LXXXVI and formula LXXXVII compounds are prepared in isomerically pure form. These primary alcohols are then conveniently transformed to the formula LXXXVIII and LXXXIX products by methods described above. Refer to the transformations of the formula XXXV compound to the formula XXXVI compound in Chart A.

Chart F provides a method whereby the formula XCVII 5-fluoro-CBA2 compounds are prepared from the formula XCIII CBA2 intermediates known in the art. See, for example, British Published Application 2,014,143, especially the discussion relative to step (b) of Chart A therein. This formula XCI sulfoximine is transformed to the formula XCII fluorinated sulfoximine by first generating an anion of the formula XCII compound, e.g., by treatment with n-butyllithium in hexane, and treating the resulting anion with a fluorine source. Particularly preferred as a source of fluorine is perchloryl fluoride (FC103).

The formula XCII compound thusly prepared and the known formula XCIII compound described above are then employed in the preparation of the formula XCIV compound by known methods. Refer again to step (b) of Chart A of British Published Application 2,014,143.

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

The C-5 isomers of the formula XCIV to formula XCVII compounds are conveniently separated at any step during the process of Chart F, but are most conveniently and preferably separated from the formula XCIV diastereomeric mixture. Conventional means, e.g., column chromatography, are employed in the separation.

Chart G provides an optional method whereby the known formula CI compound is transformed to the formula CIII products herein. With respect to Chart G, the formula XCII is prepared from the formula XCI compound by the procedure described in Chart F for the preparation of the formula XCVII compound from the formula XCIII compound. This formula CII CBA2 intermediate is then transformed to the formula CIII compound by the procedures described in Chart D for the transformation of the formula LXXI to the formula LXXIII compound.

Chart H provides the preferred methods for preparing the formula X CBA analogs wherein Zj is trans-CH2-CH=CH-. With respect to Chart H, Rt therein is other than hydrogen or a cation, preferably being lower alkyl. The formula CXIV is prepared from the formula CXI compound by first preparing the α-phenylselenyl derivative thereof, dehydrophenylselenizing, whereby the formula CXIII α,β-unsaturated ester is prepared. This ester is then transformed to the formula CXIV free acid (Xi is -COOH) by saponification and this free acid is transformed to the various other formula CXIV compounds as indicated in Chart F (refer to the transformation of the formula XCVI compound to the formula XCVII compound).

For a detailed description of the methodology employed in Chart J, refer to the discussion in British Patent No. 2 014 143, and references cited therein.

Charts I-J provide methods whereby CBA2 intermediates and analogues 30 are employed in the synthesis of corresponding CBA-j intermediates and analogues.

Chart N describes the preparation of the various CBA-j analogues from the formula CL I compounds. Procedures employed in Chart I are those described in Chart D above.

Finally, Chart J provides an alternative method for the preparation of the formula CLXII CBA1 analogues directly from formula CLXI CBA2 analogues. This transformation of Chart J proceeds by direct reduction of the formula CLXI. For a discussion of such methods, and general methodologies for transforming CBA2 intermediates and analogues to corresponding CBA1 intermediates and analogues, refer to GB-A-2 017 699. For example,catalytic hydrogenation with conventional catalysts under atmospheric pressure is employed. Chart J is an especially convenient method for the preparation of CBA-j analogues wherein Y} is -CH2-CH2-.

The processes herein described lead variously to carboxylic acids (X1 is -COOR.J and R-j is hydrogen) or to esters or primary alcohols (X} is -CHgOH). when the alkyl ester has been obtained and an acid is desired, saponification procedures, as known in the art for PGF-type compounds are employed.

When an acid has been prepared and an alkyl, cycloalkyl, or aralkyl ester is desired, esterification is advantageously accomplished by interaction of the acid with appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl ester is produced. Similar use of diazoethane, diazobutane, and 1-diazo-2-ethylhexane, and diazodecane, for example, gives the ethyl, butyl, and 2-ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexane and phenyl diazomethane yield cyclohexyl and benzyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about 10 min, to avoid undesired molecular changes. Oiazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for alkyl, cycloalkyl or aralkyl esterification of the carboxy moiety of the acid compounds comprises transformation of the free acid to the corresponding substituted ammonium salt, followed by interaction of that 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 methods are available for preparing phenyl or substituted phenyl esters within the scope of the invention from corresponding aromatic alcohols and the free acid, differing as to yield and purity of product.

With regard to the preparation of the phenyl, particularly p-substituted phenyl esters disclosed herein (i.e., Xj is -COORi and Rl is p-substituted phenyl), such compounds are prepared by the method described in U.S. Patent No. 3,890,372. Accordingly, by the preferred method described therein, the p-substituted phenyl ester is prepared first by forming a mixed anhydride, particularly following the procedures described below for preparing such anhydrides as 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 proceeds preferably in the presence of a tertiary amine, such as pyridine. When the conversion is complete, the p-substituted phenyl ester has been recovered by conventional techniques.

A preferred method for substituted phenyl esters is that disclosed in U.S. Patent No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed from the acid with isobutyl chi oroformate in the presence of a tertiary amine.

Phenacyl-type esters are prepared from the acid using a phenacyl bromide, for example p-phenylphenacyl bromide, in the presence of a tertiary amine. See, for example, U.S. Patent No. 3,984,454, German Offenlegungsschrift 2,535,693, and Derwent Farmdoc No. 16828X.

Carboxyamides (Xj is -COL^) are prepared by one of several amidation methods known in the prior art. See, for example, U.§. Patent No. 3,981,868, issued 21 September 1976 for a description of the preparation of the present amido and cycloamido derivatives of prostaglandin-type free acids and U.S. Patent No. 3,954,741 describing the preparation of carbonyl amido and sulfonylamido derivatives of prostaglandin-type free acids.

The preferred method by which the present amido and cycloamido derivatives of the acids are prepared is, first, by transformation of such free acids to corresponding mixed acid anhydrides. By this procedure, the prostaglandin-type free acid is first neutralized with an equivalent of an amine base, and thereafter reacted with a slight stoichiometric excess of a chloroformate corresponding to the mixed anhydride to be prepared.

The amine base preferred for neutralization is triethylamine, although other amines (e.g., pyridine, methyldiethylamine) are likewise employed. Further, a convenient, readily available chloroformate for use in the mixed anhydride production is isobutyl chi oroformate.

The mixed anhydride formation proceeds by conventional methods and accordingly the free acid is mixed with both the tertiary amine base and the chloroformate in a suitable solvent (e.g., aqueous tetrahydrofuran), allowing the reaction to proceed at -10°C to 20°-C.

Thereafter, the mixed anhydride is converted to the corresponding 5 amido or cycloamido derivatives by reaction with the amine corresponding to the amide to be prepared. In the case where the simple amide (-NH2) is to be prepared, the transformation proceeds by the addition of ammonia. Accordingly, the corresponding amine (or amnonia) is mixed with the mixed anhydride at or about -10 to +10°C, until the reaction is shown to be complete.

Thereafter, the novel amido or cycloamido derivative is recovered from the reaction mixture by conventional techniques.

The carbonyl amido and sulfonyl amido derivative of the presently disclosed PG-type compounds are likewise prepared by known methods.

See, for example, U.S. Patent No. 3,954,741 for description of the methods by which such derivatives are prepared. By this known method the acid is reacted with a carboxyacyl or sulfonyl isocyanate, corresponding to the carbonyl amido or sulfonyl amido derivative to be prepared.

By another, more preferred method the sul fonylamido derivatives of the present compounds are prepared by first generating the PG-type mixed anhydride, employing the method described above for the preparation of the amido and cycloamido derivatives. Thereafter, the sodium salt of the corresponding sulfonamide is reacted with the mixed anhy25 dride and hexamethylphosphoramide. The pure PG-type sulfonylamido derivative is then obtained from the resulting reaction mixture by conventional techniques.

The sodium salt of the sulfonamide corresponding to the sulfonylamido derivative to be prepared is generated by reacting the sulfonamide with alcoholic sodium methoxide. Thus, by a preferred method methanolic sodium methoxide is reacted with an equal molar amount of the sulfonamide. The sulfonamide salt is then reacted, as described above, with the mixed anhydride, using about four equivalents of the sodium salt per equivalent of anhydride. Reaction temperatures at or about 0°C are employed.

The compounds of this invention prepared by the processes of this invention, in free acid form, are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed hereinabove. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared, in the case of the inorganic salts, it is usually suitable to dissolve an acid of this invention in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, an acid of this invention is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that 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 easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

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

A pharmaceutical composition according to the invention comprises a compound of the invention in association with a physiologically acceptable excipient.

The following Examples illustrate how compounds of the 5 invention, and intermediates in their preparation, may be prepared.

With reference to certain starting materials, Examples I, II and III are respectively Examples 1, 3 and 4 of British Patent Application No. 8319030 (Serial No. ).

Example 1 lu 5-Carboxypentanoi, t-butyldimethylsilyl ether A solution of 4 g of sodium hydroxide in 100 ml of methanol and water (4:1) is treated with 10 ml of caprolactone and stirred at ambient temperature under a nitrogen atmosphere. After 20 hr, solvent is evaporated following addition of toluene, yielding 15 g of solid, crude 5-carboxypentanol.

The above solid is suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to 0°C, treated with 35 g of imidazole, stirred for 15 min at 0°C and 15 min at ambient temperature, cooled to 0°C and treated with 39 g of t-butyl dimethyl silyl chloride. The resulting solution is then allowed to warm to ambient temperature under a nitrogen atmosphere. After 26 hr, the resulting solution is treated with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol, with stirring maintained under a nitrogen atmosphere. After 13 hr, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts are then washed with 1 N aqueous sodium hydroxide. The basic extracts are then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine, and extracted with ethyl acetate. The ethyl acetate extracts are then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 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) yields 14.8 g of 5-carboxypentanol, t-butyldimethyl silyl ether. NMR absorptions are observed at 0.05 (singlet) and 0.90 (singlet)4. Infrared absorptions are observed at 3000 (broad) and 1700 cm .

Following the procedure of Example 4, but employing each of the various lactones corresponding to the ω-carboxyalkanol compounds of formula XXXII there are prepared each of the various formula XXXII products.

Example 2 2-Decarboxy-2-(t-butyldimethyl silyloxy)methyl-5-carboxy-6-hydroxy-96-methyl-CBAi, ll,15-bis(tetrahydropyran)ether (Formula XXXIII: R28 is t-butyldimethylsilyl, Z2 is -(CH2)8-, n is 1, and Rj8, Ri8, R37, Μθ, Lj, and Ru are as defined in Example II).

Refer to Chart A.

A solution of 0.58 ml of dry di isopropyl amine and 20 ml of dry tetrahydrofuran at 0°C under an argon atmosphere is treated with 2.6 ml of 1.56 M n-butyllithium in hexane, stirred for 5 to 10 min at 0°C, treated with 0.50 g of the title product of Example 4 in 5 ml of tetrahydrofuran, stirred for 15 min at 0°C and 1 hr at ambient temperature, cooled to 0°C, treated with 0.91 g of the title product of Example II in 5 ml of tetrahydrofuran, and allowed to slowly warm to ambient temperature under an argon atmosphere. Thereafter, 130 ml of water and 20 ml of brine are added and the mixture extracted with diethyl ether. The ethereal extracts are then washed with 4 ml of 1 N aqueous hydrochloric acid and 150 ml of brine and dried over sodium sulfate, and concentrated under reduced pressure to yield title product.

Following the procedure of Example 2, but employing each of the various formula XXXI compounds described following Example 1, there are prepared each of the various formula XXXIII compounds wherein R28 is t-butyldimethylsilyl and Z2 is -(ch2)3-.

Example 3 2-Decarboxy-2-(t-butyldimethyl silyl oxy) methyl -98methyl-CBA2, 11,15-bis-(tetrahydropyranylether) (Formula XXXIV: R28, Z2. n, R18, M6, Li and R7 are as defined for Examples 1 and 5).

The reaction product of Example 2 (1.37 g) and 16 ml of methylene chloride is treated with 2.9 ml of dimethylformamide dineopentyl acetal, stirred for 3 hr at ambient temperature under nitrogen, added to 160 ml of ice water and 40 ml of brine, and extracted with diethyl ether. The ethereal extracts are then washed with 150 ml of sodium bicarbonate and 150 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product. Chromatography on 100 g of silica gel eluting with 10% ethyl acetate in hexane yields pure title product.

Following the procedure of Example 3 but employing each of the various formula XXXIII compounds described following Example 2, there are prepared each of the various corresponding formula XXXIV products wherein R28 is t-butyldimethylsilyl and Z2 is -(CH2)3-.

Example 4 2-Decarboxy-2-hydroxymethyl-9B-methyl-CBA2, 11,15bi s(tetrahydropyranyl)ether (Formula XXXV: Z2, n, Ri6, 2o R37. Ri8. Vi, Mg, Li, and R7 are as defined in Example2) Refer to Chart A A solution of 0.71 g of the title product of Example 3 and 16 ml of dry tetrahydrofuran at 0°C under a nitrogen atmosphere is treated with 3.2 ml of 0.75 molar tetra-n-butylammoniumfluoride and tetrahy25 drofuran. After allowing the reaction mixture to slowly warm to ambient temperature overnight with stirring, 150 ml of brine is added and the resulting mixture extracted with ethyl acetate. The ethyl acetate extracts are then washed with 0.5 N aqueous potassium bisulfate, 100 ml of sodium bicarbonate, and 100 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product. Filtering through 25 g of silica gel with 200 ml of ethyl acetate and hexane yields 0.61 g of further purified product. Chromatography on silica gel eluting with 35% ethyl acetate in hexane yields pure title product.

Following the procedure of Example 4, but employing each of the various formula XXXIV compounds described in and following Example 3, there are prepared each of the various formula XXXV compounds wherein Z2 is -(CH2)3Following the procedure of Examples 2 to 4, and employing the various starting materials described in and following these examples and each of the various formula XXXII compounds described in and following Example 1, there are prepared each of the various formula XXXV compounds.

Example 5 2-Decarboxy-2-hydroxymethyl-9e-methyl-CBA2 (Formula XXXVI: X3 is -CH2OH, Z2 is -(CH2)3-, R8 is hydroxy, Y3 is trans-CH»CH-, is <χ-ΟΗ:β-Η, L3 is α-Η:β-Η and R7 is n-butyl).

Refer to Chart A.

The title product of Example 4 (0.25 g) is combined with 9 ml of acetic acid, water and tetrahydrofuran (6:3:1) and heated to 37-40°C for two hr. Thereafter the resulting mixture is cooled and extracted with diethyl ether. The ethereal extracts are then washed with brine, dried over sodium sulfate and concentrated to yield crude title product. Chromatography on silica gel yields pure title product.

Following the procedure of Example 5, but employing each of the various formula XXXV primary alcohols described in and following Example 4 there are prepared each of the various corresponding formula XXXVI products wherein X3 is -CH2OH.

Example 6 o-(t-Butyldimethylsilyloxyethyl)benzaldehyde (Formula XLIV: R28 is t-butyldimethylsilyloxy and g is one).

Refer to Chart B.

A. To a mixture of 7.6 g of lithium aluminum hydride and 400 ml of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise with stirring 18 g of homophthalic acid (Aldrich Chemical Company) in 250 ml of dry tetrahydrofuran. Dropwise addition rate is adjusted such that mild reflux is maintained during the course of the exothermic reaction. The resulting mixture is then heated at reflux for 5 hr, cooled to 0eC, and 7.6 g of water in 50 ml of tetrahydrofuran is added dropwise with stirring. Thereafter 27 ml of 10% aqueous sodium hydroxide is added and the resulting mixture is stirred at ambient temperature for 20 min, filtered, and the filter solids washed with 150 ml of tetrahydrofuran. The filtrate and tetrahydrofuran wash are then concentrated under reduced pressure to yield 14.0 g of crude formula XXXII diol, 2-(o-hydroxymethylphenyl)ethanol.

Chromatography on 1.2 kg of silica gel, deactivated by addition of 240 ml of ethyl acetate, eluting with ethyl acetate, yields 13.5 g of formula XLII product. Melting range is 41.5-43°C.

B. To a solution of 13.5 g of the reaction product of Part A in 5 50 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 9.05 g of imidazole. The resulting solution is then cooled to -5°C and 13.9 g of t-butyl dimethyl silyl chloride is added. The resulting mixture is then maintained for 20 min and thereafter allowed to warm to ambient temperature. After 1 hr, the resulting mixture is then shaken with 500 ml of hexane and diethylether (2:1) and 250 ml of water and brine (1:1)· The organic layer is then washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a crude mixture of mono- and bis-silyl ethers corresponding to the starting material of Part A. This mixture of products is then chromatographed on 2 kg of silica gel, deactivated with 400 ml of ethyl acetate and eluted with 25% ethyl acetate and Skellysolve B to yield 6.82 g of formula XLIII product, o-(t-butyldimethylsilyloxyethyl)phenylmethanol. NMR absorptions are observed at 7.20-7.52, 4.57, 3.91 (t, J G.l), 2.93 (t, J 6.1), 0.82, and -0.085.

Silica gel TLC is 0.54 in 25% ethyl acetate and hexane.

C. A mixture of 5.0 g of the reaction product of Part R, 100 ml of trichloromethane, and 25 g of activated manganese dioxide (Mn02) is stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then added and the resulting mixture filtered through diatomaceous earth.

After washing filter solids with 200 ml of trichloromethane, the resulting filtrate and wash is then concentrated under reduced pressure to yield a residue containing title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and elution with 25% ethyl acetate and hexane yields 2.93 g of pure title product.

Silica gel TLC Rf is 0.74 in 25% ethyl acetate and hexane. NMR absorptions are observed at 10.34, 7.25-8.00, 3.89 (t, J 6.0), 3.27 (t, J 6.0), 0.83 and -0.095. The mass spectrum exhibits a peak at 265 (M+l) and other peaks of decreasing intensity at m/e 75, 207, 73, 133, 223, 208, 77, 177, 76 and 105.

Following the procedure described in Chart B, but employing each of the various formula XXXI acids, there is prepared each of the various corresponding formula XXXIV aldehydes wherein R29 is t-butyldimethylsilyl.

Example 7 m-(t-butyldimethylsilyloxymethyl)benzaldehyde (Formula XLIV: g is zero and R28 is t-butyldimethylsilyl).

Refer to Chart β.

A. To a solution of 10.0 g of m-(hydroxymethyl)phenylmethanol in ml of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 7.35 g imidazole. The resulting solution is then cooled to 0°C and 11.3 g of t-butyl dimethyl silyl is added. The resulting mixture is then stirred with cooling for 15 min and thereafter allowed to warm to ambient temperature. After 90 min, the resulting mixture is then shaken in 400 ml of hexane and diethyl ether (2:1) and 200 ml of water and brine (1:1). The organic layer is 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 yield a mixture of mono- and bis-t-butyl dimethyl silyloxy ether corresponding to the formula XXXII compound. This mixture of products is then chromatographed on 1.4 kg of silica gel, deactivated by addition of 280 ml of ethyl acetate and eluted with 25-40% ethyl acetate in hexane to yield 7.65 g of pure formula XLIII product, m-(t-butyldimethylsilyloxymethyl)phenylmethanol. Silica gel TLC Rf is 0.46 in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.25, 4.72, 4.60, 2.23, 0.92, and 0.09«. The mass spectrum exhibits a peak at 251 (M+-l) and other peaks of 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 of Part A and 100 ml of trichloromethane and 25 g of activated manganese dioxide (Mn02) is stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then added and the resulting mixture filtered through diatomaceous earth. The filter solids are washed with 200 ml of trichloromethane and the filtrate and trichloromethane wash are then concentrated under reduced pressure to yield 5.2 g of crude title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and elution with ethyl acetate and hexane (1:3) yields 3.65 g of pure title product. Silica gel TLC Rf is 0.46 in 10% ethyl acetate and hexane. NMR absorptions are observed at 10.00, 7.26-7.86, 4.81, 0.95, and 0.116.

Example .. 3-Phenylsulfonyl-7a-tetrahydropyran-2-yloxy-6s-C(3 'SIS'-tetrahydropyran-2-yloxy-trans-l '-octenyl]-bicyclo[3.3.0]octane (Formula LV: n is the integer one, Rig is tetrahydropyranyloxy, Y? is trans-CH=CH-, Με is a-tetrahydropyranyloxy:B-hydrogen, Li is a-hydrogen:S-hydrogen, Ri6 and R17 are both hydrogen, and R27 is n-butyl).

Refer to Chart C.

A. Sodium borohydride (0.38 g) is added with stirring to a solution of 2.90 g of 3-oxo-7a-tetrahydropyran-2-yloxy-6g-[(3’S)-3'tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo[3.3.0]octane in 25 ml of 95% aqueous ethanol. The resulting mixture is then stirred at ambient temperature for 20 min. Thereafter the resulting mixture is shaken in 100 ml of brine and 200 ml of ethyl acetate. The organic layer is then immediately washed in brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 2.94 g of formula LII alcohol: (3RS)-3-hydroxy-7a-tetrahydropyran-2-yloxy-6P15 [ (3' S) -3' -tetrahydropyran-2-yl oxy-trans-1 ‘-octenyllbicycl o[3.3.0]octane. Infrared absorptions are observed at 3600 and 3450 cm” and no carbonyl absorption. Silica gel TLC Rf is 0.63 and 0.67 in ethyl acetate and hexane (1:1).

B. To a solution of 2.9 g of the reaction product of Part A in ml of dry dichloromethane and 1.4 ml (1.02 g) of triethylamine at 0°C is added with stirring 0.57 ml (0.848 g) of methanesulfonyl chloride over 5 min. The resulting mixture is then stirred an additional 20 min and shaken with 160 ml of diethyl ether and 80 ml of cold (0°C) dilute aqueous hydrochloric acid. The organic layer is then washed successively in brine, dilute aqueous potassium bicarbonate, and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 3.5 g of crude formula LIII compound: (3RS)-3-hydroxy-7a-tetrahydropyran-2-yloxy-6g-[(3 ’S)-3‘-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane, 3-methylsulfon30 ate.

C. Thiophenol (1.13 ml, 1.21 g) is added to a mixture of 1.12 g of potassium t-butoxide in 15 ml of dry dimethylsulfoxide (DMSO) under a nitrogen atmosphere. To the solution of potassium thiophenoxide thus prepared is added 3.5 g of the reaction product of Part 3 in 8 ml of dimethylsulfoxide. The resulting mixture is then stirred at ambient temperature for 16 hr, whereupon additional potassium tbutoxide is added so as to transform the solution to a distinct yellow color. The resulting mixture is then stirred an additional 4 hr at ambient temperature, diluted with 100 ml of diethyl ether and 100 ml of hexane, washed with 5% aqueous potassium hydroxide (200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 5 g of a residue of crude formula LIV compound: 3-phenylthio-7-a-tetrahydropyran-2-yloxy-6s-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-l'-octenyl]bicyclo[3.3.0]octane. Chromatography on 300 g of silica gel, deactivated with 40 ml of diethyl ether and 40 ml of trichloromethane and eluted with 5% diethyl ether in trichloromethane yields 3.1 g of pure product. Silica gel TLC Rf is 0.75 in 10% ethyl acetate in dichloromethane.

D. To a solution of 3.1 g of the reaction product of Part C and 50 ml of dichloromethane at 0’C is added with stirring over 10 min 2.43 g of 85% m-chloroperbenzoic acid. The resulting mixture is then stirred at 0’C for 30 min, 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 yield 3.4 g of crude title product. Chromatography on 350 g of silica gel, deactivated with 70 ml of ethyl acetate and elution with 500 ml of 30-50% ethyl acetate in hexane yields 2.90 g of pure title product as a mixture of C-6 isomers. Silica gel TLC R^'s are 0.41, 0.45 and 0.48 in 30% ethyl acetate in hexane (stereoisomers). NMR absorptions are observed at 7.52-8.02, 5.30-5.67, 4.70, and 3.304.135.

Following the procedure of Example 8, each of the fonnula LI compounds is transformed to the corresponding formula LV 3-phenylsulfonyl compound.

Example 9 (5E)-2,5-inter-o-phenylene-3,4-dinor-C8A2 (Formula LX: X! is -COOH, g is one, n is one, R16 and R17 are hydrogen, R8 is hydroxy, Y3 is trans-CH=CH-, Mj is α-0Η:β-Η, Lr is a-H:b-H, and R7 is n-butyl), its methyl ester and the corresponding (5Z) isomers thereof.

Refer to Chart B.

A. To a solution of 1.26 g of the title product of Example 8 in 15 ml of dry tetrahydrofuran at -78°C under a nitrogen atmosphere is added dropwise with stirring 1.48 ml of 1.6 M n-butyllithium in hexane over 1 min. After 10 min 0.66 g of title product of Example 4 in 5 ml of dry tetrahydrofuran is added. After 45 min 0.26 ml of distilled acetic anhydride is added. Stirring is then continued at -78°C for 3 hr and at ambient temperature for an additional 2 hr. The resulting mixture is then shaken with 120 ml of diethyl ether and 80 ml of saturated aqueous ammonium chloride. The organic layer is then washed with 15 ml of brine, dried over magnesium sulfate, and concen5 trated under reduced pressure to yield 2.21 g of formula LVI product as a mixture of isomers: 3-[a-acetoxy-o-(t-butyldimethylsilyloxyethyl )-a-tolyl]-3-phenylsulfonyl -7a-(tetrahydropyran-2-yl)oxy-6B[ (3' S) -31 - (tetrahydropyran-2-yl )oxy-trans-l' -octenyl]bicycl o[3.3.03octane. R28, 9. Ri7> n, Ria> Υι> Με· Li, and R27 are defined in Examples 9 and 11. Silica gel TLC R^ range is 0.30-0.53 (8 spots) (stereoisomers) in 25% ethyl acetate and hexane. 8. The mixture of isomeric products of Part A (2.21 g) and 40 ml of methanol and 20 ml of ethyl acetate is stirred at -20°C with chips of 5.5% sodium amalgam for 60 min. After decanting liquid, excess amalgam and solids are rinsed by decantation employing 200 ml of diethyl ether. The organic solutions are then combined, washed with brine, dried, and concentrated under reduced pressure to yield 1.8 g of crude 2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-2,5-inter-ophenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether). Chroma20 tography on 250 g of silica gel, deactivated with 50 ml of diethyl ether and eluted with 30% diethyl ether in hexane yields 1.06 g of pure product. Silica gel TLC R^'s are 0.49, 0.56, and 0.62 (stereoisomers) in 30% diethyl ether and hexane. NMR absorptions are observed at 7.20, 6.54, 5.22-5.80, 4.72, 3.38-4.16 and 2.74-3.005.

C. A solution of 1.06 g of the reaction product of Part B in 10 ml of dry tetrahydrofuran is treated with 3.2 ml of 0.75 N tetra-nbutylammoniurn fluoride in tetrahydrofuran at ambient temperature for 40 min. The resulting mixture is then diluted with 125 ml of diethyl ether. The resulting solution is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a residue of isomeric formula LVIII products: (5E)- and (5Z)-2-decarboxy-2-hydroxymethyl-2,5-i nter-o-phenylene-3,4-di nor-CBA2, 11,15-bi s(tetrahydropyranyl ether). Chromatography on 100 g of silica gel, deactivated with 20 ml of ethyl acetate and eluted with 25-50% ethyl acetate in hexane yields 0.40 g of (5Z) isomer and 0.51 g of (5E) isomer. For the (5Z) isomer silica gel TLC R^'s are 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.51, 5.10-5.72, 4.69, 3.32-4.16, and 2.76-3.005.

For the (5E) isomer silica gel TLC Rf's are 0.20 and 0.24 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.19 , 6.50 , 5.10-5.64 , 4.70 , 3.32-4.10, and 2.88-3.016.

D. To a solution of 400 mg of the (5Z) reaction product of Part C in 20 ml of dry acetone at -50eC is added with stirring 1.0 ml of Jones reagent (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 is then allowed to warm to -20°C over a 20 min period and stirred at -20eC for 30 min. Excess Jones reagent is then destroyed by addition of 0.5 ml of isopropanol. After 5 m1n the reaction mixture is then shaken in 100 ml of ethyl acetate and 80 ml of brine containing 0.5 ml of concentrated hydrochloric acid. The organic layer is 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 layer is then dried over magnesium sulfate and concentrated under reduced pressure to yield 360 mg of crude (5Z)-2,5-inter-o-phenylene-3,4-dinor-C8A2, 11,15-bis(tetrahydropyranyl ether), a formula LIX compound. Crude formula LIX compound is then taken up in 30 ml of diethyl ether and extracted in the mixture of 15 ml of water and 5 ml of methanol containing a trace amount (10 drops) of 45% aqueous potassium hydroxide. The extraction is repeated 6 times, until the acid is completely extracted from the ethereal solution. The aqueous extracts are then acidified to pH2 and extracted with ethyl acetate. The organic extract is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a residue of pure title product. Silica gel TLC is a streak to about Rf 0.50 in ethyl acetate and hexane (1:1). Purified acid is then converted to the corresponding ethyl ester by treatment with excess ethereal diazomethane for 10 min. Following esterification, the resulting reaction mixture is treated with ethyl acetate and washed with dilute aqueous potassium hydroxide and brine. After drying and concentrating to a residue, chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 10% ethyl acetate in trichloromethane yields 210 mg of (5Z)-2,5-inter-ophenylene-3,4-dinor-CBA2, methyl ester, 11,15-bis(tetrahydropyranyl ether). Silica gel TLC Rf's are 0.52, 0.56, and 0.60 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.45, 5.34-5.78, 4.70, 3.68, and 3.30-4.286. Ε. A mixture of 200 mg of methyl ester of Part D, 5 ml of acetic acid, 2.5 ml of water, and 1 ml of tetrahydrofuran is heated to 40°C and stirred for 4 hr. The resulting mixture is then diluted with 100 ml of ethyl acetate and washed with a mixture of 6 g of 85% aqueous potassium hydroxide in 20 ml of water and 30 g of ice, washed with brine (40 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 180 mg of crude (5Z)-2,5-inter-o-phenylene3,4-dinor-CBA2, methyl ester. Chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 100 ml of 50% ethyl acetate in trichloromethane and 100 ml of 50% acetone in trichloromethane yields 105 mg of pure product. Silica gel TLC Rf is 0.57 in 40% acetone and trichloromethane and 0.52 in ethyl acetate. NMR absorptions are observed at 7.20, 6.43, 5.45-5.59, 3.65, 3.404.20, and 3.184. The mass spectrum of the bis TMS derivative exhibits peaks of 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 of Part E in 5 ml of methanol and 2.5 ml of water under a nitrogen atmosphere is added 0.33 g of potassium carbonate. The resulting mixture is stirred at ambient temperature for 20 hr whereupon a small quantity (5 drops) of 45% aqueous potassium hydroxide is added. The resulting mixture is stirred for an additional 4 hr at ambient temperature. Thereupon the mixture is shaken with 100 ml of ethyl acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried, and concentrated under reduced pressure to yield 100 mg of pure (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel TLC is 0.56 in the A-IX solvent system (the organic phase of an equillibrated mixture of ethyl acetate, acetic acid, cyclohexane, and water, 9:2:9:10). The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 129, 167, 74, 55, 69, 57, 147, and 45 and an M+-CH3 peak at 599.3418.

G. Following the procedure of Part D, 510 mg of the (5E) reaction product of Part C is transformed to 310 mg of (5E)-2,5i nter-o-phenylene-3,4-dinor-CBA2, 11,15-bi s(tetrahydropyranyl ether).

Silica gel TLC Rf is 0.41 in 25% ethyl acetate and hexane con-taining 1% acetic acid, and 220 mg of (5E)-2,5-inter-o-phenylene-3,4-dinorCBA2, ll,15-bis(tetrahydropyranyl ether)methy1 ester. Silica gel TLC Rf's are 0.48, 0.51, and 0.56 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.43, 5.26-5.64, 4.70, 3.65, and 3.30-4.106.

H. Following the procedure of Part E, the reaction product of Part G (210 mg) is transformed to 110 mg of (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2, methyl ester. Silica gel TLC Rf is 0.57 in 40% acetone and trichloromethane and 0.46 in ethyl acetate. NMR absorptions are observed at 7.22, 6.44, 5.32-5.47, 3.68, 3.50-4.08, and 3.105. The mass spectrum of the bis TMS derivative exhibits peaks of 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 of Part H (110 mg) is transformed to 102 mg of (5E)-2,5-inter-ophenylene-3,4-dinor-CBA2. Silica gel TLC Rf is 0.50 in the A-IX solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 167, 129, 524, 453, 285, 147, 434, 213, and an M+-CH3 peak at 599.3424.

Example 10 (5E)-l,5-inter-m-phenylene-2,3,4-trinor-CBA2, its methyl ester, and the corresponding (5Z) isomers.

Refer to Chart C.

A. Following the procedure of Example 9, Part A, a solution of I. 26 g of the title product of Example 3 and 0.62 g of the title product of Example 2 are transformed to 2.3 g of formula LVI compound. Silica gel TLC Rf range is 0.37-0.56 (7 spots)(stereoisomers) in 25% ethyl acetate in hexane.

B. Following the procedure of Example 9, Part B, the reaction product of Part A (2.3 g) is transformed to 1.0 g of isomeric formula LVII compounds: (5E)- and (5Z)-2-decarboxy-2-(t-butyldimethyl silyl oxymethyl)-l,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetrahydropyranyl ether). Silica gel TLC Rf's are 0.47, 0.54 and 0.58 (stereoisomers) in 30% diethyl ether and hexane.

C. Following the procedure of Example 9, Part C, 1.0 g of the isomerically mixed reaction product of Part B is transformed to 0.51 g of (5Z)-2-decarboxy-2-hydroxymethy1-l,5-inter-m-phenylene-2,3,4trinor-CBA2, 11,15-bis(tetrahydropyranyl ether) and 0.40 g of (5E)2-decarboxy-2-hydroxymethy1 -1,5-inter-m-phenyl ene-2,3,4-tr i nor-CBA2, II, 15-bis(tetrahydropyranyl ether). For the (5Z)-isomer, silica gel TLC Rf's are 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.18, 6.36, 5.19-5.65, 4.63, 4.58, 3.31-4.08, and 2.924. For the (5E)-isomer, silica gel TLC R^'s are 0.23 and 0.27 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.19, 5.37, 5.29-5.72, 4.67, 4.60, 3.304.17, and 2.786.

D. Following the procedure of Example 9, Part D, 510 mg of the (5Z) reaction product of Part C is transformed to 310 mg of (5Z)-1,5i nter-m-phenylene-2,3,4-tri nor-CBA2, 11,15-bi s(tetrahydropyranyl ether) and 240 mg of (5Z)-l,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester, ll,15-bis(tetrahydropyranyl ether). For the acid, sili10 ca gel TLC streak to about Rf 0.54 in 50% ethyl acetate and hexane. For the methyl ester, silica gel TLC R^'s are 0.58 , 0.63, and 0.68 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.28-8.00 , 6.40 , 5.13-5.73 , 4.71, 3.89, and 3.28-4.086.

E. Following the procedure of Example 9, Part E, 240 mg of the methyl ester product of Part D is transformed to 140 mg of (5ZJ-1.5inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC Rf is 0.49 in ethyl acetate. NMR absorptions are observed at 7.28-7.93, 6.40, 5.34-5.48, 3.88, and 3.326. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 83, 85, 73, 47, 213, 75, 129, 48, 87, 77, and an M+-CH3 peak at 527.2996.

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

G. Following the procedure of Example 9, Part 0, 400 mg of the (5E) reaction product of Part C is transformed to 260 mg of (5E)1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetrahydropyranyl ether) and 190 mg of (5E)-l,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester, ll,15-bis(tetrahydropyranyl ether). For the acid silica gel TLC streak to about Rf 0.36 in 50% ethyl acetate and hexane. Ror the methyl ester, silica gel TLC Rf's are 0.50, 0.53, and 0.57 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.38-7.95, 6.42, 5.13-5.75, 4.68, 3.89, and 3.30-4.095.

H. Following the procedure of Example 9, Part E, 190 mg of the reaction product of Part G is transformed to 81 mg of (5E)-l,5-interm-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC R^ is 0.51 in ethyl acetate. NMR absorptions are observed at 7.30-7.93, 6.43, 5.45-5.59, 3.89, 3.50-4.14, and 3.095. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing Intensity at m/e 73, 213, 129, 75, 83, 452, 173, 85, 262, 362, and an M+-CH3 peak at 527.2996.

I. Following the procedure of Example 10, Part F, 81 mg of the reaction product of Part H is transformed to 65 mg of (5E)-l,5-interm-phenylene-2,3,4-trinor-CBA2. Silica gel TLC Rf is 0.60 in the A-IX solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of 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 9-10, but employing each of the various formula LV compounds described in and following Example8 in each of the various formula XLIV described in and following Examples 6 and 7, there are prepared each of the various formula L compounds in free acid or methyl ester form.

Example 11 9g-methyl-CSA2, methyl ester, ll,15-bis(tetrahydropyranyl ether) (Formula LXXXIV: Rl6 is hydrogen, R37 is methyl, Z2 is -(CH2)3- and Rl8, Yx, M6, Lx, and R7 are as defined in Example II)and the corresponding (5E) and (5Z) free acids (Fonnula LXXXIII).

Refer to Chart E.

A. A suspension of 57% sodium hydride in mineral oil (1.90 g) is washed with hexane and treated with 130 ml of dry dimethyl sulfoxide (DMSO). The resulting suspension is heated at 65°C for 1 hr under a nitrogen atmosphere and the resulting solution cooled to- 15°C and treated dropwise over 15 min with 10.0 g of 4-carboxybutyltri phenylphosphonium bromide. The resulting orange solution is stirred for 15 min at 10°C and then treated dropwise over 15 min with a solution of 2.12 g of the title product of Example II in 20 ml of dry DMSO. The resulting solution is then stirred at ambient temperature under a nitrogen atmosphere for 60 hr, treated with 15 ml of water, stirred for 30 min at ambient temperature, added to 200 ml of ice water and 100 ml of brine, acidified with 1 N aqueous hydrochloric acid, and extracted with 900 ml of diethyl ether. The ethereal extracts are then washed with 1 ι of water and 200 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.8 g of a yellow oil, the formula LXXXIII carboxylic acid.

B. The formula LXXXIII product and 42 ml of di isopropyl ethyl amine in 120 ml of acetonitrile at 10°C under a nitrogen atmosphere is treated with 15 ml of methyl iodide and allowed to warm slowly to ambient temperature. The resulting suspension is then stirred for 16 hr, treated with 3.0 ml of methyl iodide, stirred for an additional 2 hr, added to 500 ml of brine, and extracted with 1 litre of ethyl acetate. The organic extracts are then washed with 250 ml of 0.5 N potassium bisul fate, 250 ml of saturated aqueous sodium bicarbonate, 250 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a solid residue. The residue is then chromatographed on 500 g silica gel, eluting with 8Ϊ acetone in hexane to yield 2.25 g of title formula LXXXIV product.

NMR absorptions (CDC13) are observed at 0.9, 1.05, 1.08, 3.66, 3.02-4.35, 4.70, and 4.955. Infrared absorptions are observed at 1730, 1670, 1645, 1200, 1165, 1135, 1080, 1035, 1020, 980, and 870 cm' . Silica gel TLC Rf is 0.46 in ethyl acetate and hexane (1:3) and 0.26 in ethyl acetate and hexane (1:6).

C. Alternatively the isomeric formula LXXXIII reaction products of Part A are separated into the (5E) and (5Z) title free acid pro25 ducts by chromatograhpy on acid washed silica gel eluting with 10-30? ethyl acetate in hexane.

Following the procedure of Example 6, but employing each of the various formula LXXXI ketones in place of the Example II product, there are prepared each of the various formula LXXXIV methyl esters wherein Z2 is -(CH2)3-.

Further following the procedure of Example 11, but employing a formula LXXXII ω-carboxytriphenylphosphoniurn compound wherein Z2 is other than -(CH2)3-, each of the various formula LXXXI ketones is transformed to corresponding formula LXXXIV ester wherein Z2 is other than -(CH2)3-.

Example 12 (5Z)-2-Decarboxy-2-hydroxymethyl -9g-methyl -CBA2, ll,15-bis(tetrahydropyranyl ether) (Formula LXXXVI: Rls, r37> Z2, R18, Μθ, Lj, and R7 are as defined in Example Π) and Its (5E) isomer (formula LXXXVII).

Refer to Chart E.

A suspension of 0.16 g of lithium aluminum hydride in 45 ml of dry tetrahydrofuran at 0°C under a nitrogen atmosphere is treated dropwise with 1.98 g of the title product of Example Π in 15 ml of dry tetrahydrofuran. The resulting suspension is stirred for 1 hr at 0°C and thereafter for 1 hr at ambient temperature. The resulting mixture is then cooled to 0°C, quenched by addition of 0.16 ml of water, 0.16 ml of 15% aqueous sodium hydroxide. After stirring for 1 hr at ambient temperature, treatment with magnesium sulfate and filtration with diatomaceous earth, rinsing with diethyl ether, yields a mixture which is concentrated under reduced pressure. The resulting product, 0.25 g, is chromatographed on 180 g of silica gel, eluting with 30% ethyl acetate in hexane to yield 1.03 g of formula LXXXVII product and 1.06 g of formula LXXXVI product. For the formula LXXXVI product NMR absorptions (COC13) are observed at 0.90, 1.09, 3.2-4.4, 4.72, 5.0-5.94. Infrared absorptions are observed at 3470, 1760, 1200, 1135, 1120, 1075, 1035, 1020, and 980 cm1. Silica gel TLC Rf is 0.29 in ethyl acetate and hexane (35:65). For the formula LXXXVII product NMR absorptions (CDCl3) are observed at 0.90, .1.05, 3.2-4.4, 4.6-4.95, 5.05-5.974. Infrared absorptions are observed at 3470, 1670, 1200, 1125, 1110, 1080, 1035, 1020, and 985 cm . Silica gel TLC Rf is 0.36 in ethyl acetate and hexane (35:65).

Following the procedure of Example 12, but employing each of the various formula LXXXIV esters described following Example Π, there are prepared each of the respective formula LXXXVI and formula LXXXVII primary alcohols.

Example 13 (5Z)-9g-methyl-CBA2, methyl ester (Formula LXXXVIII: Xj^ is -COOCH3, Rg is hydroxy, Mj is α-0Η:β-Η, and Ri6, R17, Li, R7, Yi, and Z2 are as defined in Example 15).

Refer to Chart E.

A. A solution of the formula LXXXVI title product of Example 12 in 38 ml of acetone at -20°C under a nitrogen atmosphere is treated over 5 min with 1.9 ml of Jones reagent (prepared by dissolving 133.6 g of chromium trioxide in 115 ml concentrated sulfuric acid and diluting with water to a volume of 500 ml), stirred for 2 hr at -20°C, quenched by addition of 2.3 ml of isopropanol, stirred for 40 min at -20°C, diluted with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 600 ml of trine, dried over sodium sulfate, and concentrated under reduced pressure to yield 1.01 g carboxylic acid corresponding to the formula LXXXVI primary alcohol as a pale green oil.

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

C. A solution of the product of Part 8 in 56 ml of a mixture of tetrahydrofuran, water, and acetic acid (1:2:4). is heated to 45°C under a nitrogen atmosphere for 3 hr, cooled, diluted with 200 ml of brine, and extracted with 400 ml of diethyl acetate. The organic extracts are then washed with 600 ml of saturated aqueous sodium bicarbonate and 400 ml of brine, dj-ied over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.9 g of crude title product as a yellow oil. Chromatographing on 100 g of silica gel, eluting with hexane and ethyl acetate (3:7) yields 0.39 g of pure title product as a colorless oil. NMR absorptions (CDC13) are observed at 0.89, 1.08, 3.5-4.35, 3.66, 5.0-5.76. Infrared absorptions are observed at 3360, 1740, 1670, 1455, 1435, 1370, 1240, 1225, 1195, 1170, 1075, 1020, and 970 cm-1. Silica gel TLC Rf is 0.22 in ethyl acetate and hexane (7:3).

Following the procedure of Example 13, but employing each of the various formula LXXXVI compounds described following Example 12, there are prepared each of the various formula LXXXVIII 9g-methyl-CBA2 compounds wherein Xt is -COORj.

Example 14 (5E )-98-methyl-CBA2, methyl ester (Formula LXXXIX: Ri6. Ri7. Xi» Z2, R8i Ri, Mi, Li, and R7 are as defined in Example 13).

Refer to Chart E.

A. Following the procedure of Example 13, Part A, 0.60 g of the formula LXXXVII product of Example 12 is transformed to the carboxylic acid corresponding to the formula LXXXVII primary alcohol, yielding 0.66 g of a green oil.

B. Following the procedure of Example 13, Part B, the product of Part A above (0.66 g) is transformed to the methyl ester corresponding to the carboxylic acid product of Part A, yielding 0.58 g of a yellow oil.

C. Following the procedure of Example 13, Part C, the product of Part B above (0.58 g) is transformed to 0.25 g of title product as a colorless oil. NMR absorptions (CDCl3) are observed at 0.90, 1.05, 3.30, 3.66, 3.75-4.25, 5.0-5.74. Infrared absorptions are observed at 3360, 1740, 1670, 1455, 1435, 1250, 1225, 1195, 1170, 1075, 1020, and 970 cm . Silica gel TLC Rf is 0.22 in ethyl acetate and hexane (3:7).

Following the procedure of Example 14, but employing each of the various formula LXXXVII compounds described following Example 12, there are prepared each of the various formula LXXXIX products wherein Xj is -COOCHj.

Example 15 (5Z)-9g-methyl-CBA2.

A solution of 0.28 g of the title product of Example 13 in 8 ml of methanol is stirred at ambient temperature under a nitrogen atmosphere and treated with 1 ml of 8 M aqueous sodium hydroxide. The resulting yellow solution is then stirred for 5 hr at ambient temperature under a nitrogen atmosphere, diluted with 90 ml of ice and brine, acidified to pH2 with 1 N 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 yield 0.25 g of crude title product. Chromatography on 30 g of silica gel, eluting with the A-IX solvent system (the organic phase of an equillibrated mixture of ethyl acetate, acetic acid, cyclohexane, and water, 9:2:5:10), yields 0.235 g of pure title product as a colorless oil. NMR absorptions (CDC13) are observed at 0.89, 1.08, 3,5-4.35, 5.0-5.7, 6.054. Infrared absorptions are observed at 3340, 2660, 1710, 1240, 1205, 1175, 1130, 1075, 1055, 1020, and 970 cm'1. Silica gel TLC Rf is 0.25 in the A-IX solvent system.

Following the procedure of Example 15 each of the various methyl esters prepared following Example 13 is transformed to the corresponding carboxylic acid.

Example 16 (5E)-98-methyl-CBA2.

Foliowing the procedure of Example 15, 0.25 g of the title product of Example 14 is transformed to 0.21 g of title product as a colorless oil. NMR absorptions (COC13) are observed at 0.90, 1.06, 3.5-4.3, 5.0-5.7, and 5.936. Infrared absorptions are observed at 3340, 2660, 1710, 1300, 1240, 1175, 1130, 1075, 1055, 1020, and 970 cm' . Silica gel TLC Rf is 0.27 in the A-IX solvent system.

Each of the various carboxylic acids corresponding to LXXXVIII and LXXXIX wherein X! is -COOH- can be prepared from the corresponding formula LXXXIII reaction products by acid hydrolysis of the tetrahydropyranyl ether protecting groups of C-ll and C-15. [The (5Z) LXXXIII reaction products from Example 11, Part C go to formula LXXXVIII products; and the (5E) LXXXIII reaction products from Example 11, Part C go to formula LXXXIX products.] Following the procedure of Example 16, but employing each of the various formula LXXXIX methyl esters described following Example 14, there are prepared each of the various corresponding carboxylic acids.

Example 17 N-methyl-(1-f1uoro-5-tetrahydropyranyloxypentyl)phenyl sulfoximine (Formula XCII: is -(CHg)^- ar|d Rjq is tetrahydropyranyl.

Refer to Chart F.

Di isopropylamine (0.59 g) is dissolved in 21 ml of tetrahydrofuran and the resulting mixture cooled to -78°C with stirring under an argon atmosphere. Thereafter triphenylmethane is added, for use as an indicator, and a solution of n-butyllithium and hexane is added dropwise until the resulting mixture attains a pink color. After stirring for an additional 75 min, the resulting mixture is treated with 1.50 g of N-methy1-(5-tetrahydropyranyloxypenty1)-pheny1sulfoximine dissolved in 6 ml of dry tetrahydrofuran. The resulting mixture is then stirred for an additional 30 min at -78°C. Thereafter excess perchloryl fluoride (FC103) is bubbled through the solution for 4-5 min, during which time a stream of argon is also bubbled through the mixture for safety reasons. The resulting mixture is then stirred at additional 90 min at -78°C and then the reaction is quenched by addition of 5Ϊ aqueous sodium bicarbonate. After equilibration of the reaction mixture to ambient temperature, the mixture is diluted with additional 5% aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts are then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 1.64 g of a yellow oil. Chromatography on silica gel columns in a series, eluting with ethyl acetate and hexane (1:1) yields 0.18 g of the formula XCII title product as a mixture of diastereomers. Silica gel TLC R^ in ethyl acetate and hexane (1:1) are 0.54 (less polar isomer) and 0.45 (more polar isomer). NMR absorptions (CDCl3) for the less polar isomer are 1.2-2.15, 3.65, 3.68, 3.1-4.1, 4.4-4.8, 5.5, and 7.4-8.15. NMR absorptions (COC13) for the more polar isomer are 1.15-2.20, 3.63, 3.1-4.1, 4.45-4.65, 5.27, and 7.4-8.15.

Following the procedure of Example 17, but employing each of the various formula XCI phenylsulfoxamines, there are prepared each of the various corresponding formula XCII fluorinated phenyl sulfoxamines. Example 18 5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2, 1,11,15tris(tetrahydropyranyl ether). (Formula XCIV: R16 and Rp are both hydrogen, R10 is tetrahydropyranyl, Z2 is -(CH2)3-, π is the integer one, R18 is tetrahydropyranyloxy, is trans-CH=CH-, M6 is a~tetrahydropyranyloxy:8-hydrogen, R3 and R^ of the Lj moiety are both hydrogen, and R7 is n-butyl).

Refer to Chart F.

Di isopropyl amine (164 mg) and tri phenyl methane (1.5 mg) are dissolved in 4 ml of dry tetrahydrofuran and the resulting solution is cooled to -78°C under a nitrogen atmosphere. A solution of n-butyllithium and hexane is added until a faint pink color is attained. 68 This solution is then stirred an additional 80 min. Thereafter, 0.488 g of the title product of Example 17 in 4 ml of dry tetrahydrofuran is added dropwise. Thereafter 608 mg of 7-oxo-3a-tetrahydropyran-2-yloxy-2g-[(31S)-31 -tetrahydropyran-2-yloxy-trans-11-octenyl] bi cyclo5 [3.3.0]octane (Formula XCIII: Rlfi, R17, n, R18, Yj, M6, L1? and R7 are as defined for the title product) in 4 ml of tetrahydrofuran is added to the reaction mixture. After 4 min, the resulting mixture is quenched by addition of saturated aqueous ammonium chloride and ethyl acetate is thereafter added to the reaction mixture, which is main10 tained at -78°C. The resulting mixture is then allowed to warm until solids separate. Thereupon additional ethyl acetate is added, the reaction extracted with brine. The ethyl acetate layer is then dried over sodium sulfate and concentrated under reduced pressure.

An aluminum amalgam is then prepared by reacting 0.31 g of 20 mesh aluminum with 2.5 ml of aqueous mercuric chloride followed by washing with ethyl acetate and diethyl ether. The residue from the ethyl acetate layer (described in the preceeding paragraph) is dissolved in 5 ml of tetrahydrofuran and the solution cooled to 0°C. This cooled solution is then treated with aluminum amalgam, 2 ml of water, and 1 ml of glacial acetic acid. The resulting mixture is then stirred for 2 hr at 0°C and 16 hr at 20°C. The reaction is then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer is then washed with 5% aqueous sodium bicarbanate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 0.96 g as an oily residue. Chromatographing over 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 m! of 50% ethyl acetate in mixed hexanes, and 800 ml of 50% acetone in methylene chloride, taking 20 ml fractions, yields 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 formula XCIV product. For the less polar isomer, NMR absorptions (COC13) are observed at 0.65-2.65, 3.15-4.15, 4.35-4.75, and 5.25-5.755. For the more polar isomer, NMR absorptions (CDC13) are observed at 0.6-2.65, 3.10-4.15, 4.40-4.7, and 5.2-5.75. Silica gel TLC Rf for the less polar isomer is 0.66 and for the more polar isomer is 0.57 in ethyl acetate and mixed hexanes (3:7).

Following the procedure of Example 18, but employing each of the various formula XCIII ketones, there are obtained each of the various formula XCIV intermediates wherein Z2 is -(CH2)3-.

Further following the procedure of Example 18, but substituting each of the various fluorinated phenylsulfoximines described following Example 17, there are prepared from the various formula XCIII ketones each of the various formula XCIV products wherein Z2 is other than -(CH2)3~.

Example 19 5-Fluoro-2-Decarboxy-2-hydroxymethyl-CBA2 (more polar isomer) (Formula XCV: R16, R17, Z2, n, R8, Lj, and R7 are as defined in Example 14).

Refer to Chart F.

The title product of Example 18 (74 mg) is dissolved in 2 ml of a mixture of tetrahydrofuran, water, and glacial acetic acid (2:2:1) and the resulting mixture stirred under a nitrogen atmosphere. The reaction mixture is maintained at ambient temperature for 17 hr, thereafter at 40°C for 7 hr, and finally at 23°C for an additional 24 hr. The resulting mixture is then diluted with ethyl acetate, washed with 5% aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 52 mg of crude title product. Chromatography over silica gel, eluting with acetone and methylene chloride (60:40) yields 19 mg of pure title product. NMR absorptions (CDC13) are observed at 0.6-2.60, 2.60-3.30, 3.30-4.15, 5.1-5.94. 13C-NMR absorptions (COC13) are 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=5 Hz), 31.9, 31.8, 31.2, 29.5 (d J=29Hz), 25.2, 22.5, 14.04. Silica gel TLC Rf is 0.280 in acetone and methylene chloride (1:1).

Example 20 5-Fluoro-2-decarboxy-2-hydroxymethy1-CBA2 (less polar i somer) Following the procedure of Example 19, 85 mg of less polar title product of Example 18 are transformed to 25 mg of pure title product.

NMR absorptions (CDC13) are observed at 0.5-2.5, 3.1-4.75, and 5.0513 .84. C-NMR absorptions (COC13) are 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=3.1Hz), 32.5 (d J=5.4Hz), 31.8, 31.7, 29.2 (d J=28.9Hz), 25.4, 22.6, 22.4, and 14.04. Silica gel TLC R^ is 0.33 in acetone and methylene chloride.

Following the procedure of Examples 19 and 20, but employing the various diastereomeric products described following Example 18, there are prepared each of the various diastereomers corresponding to formula XCV.

Example ?i 5-fluoro-CBA2 (more polar isomer) (Formula LXXVI: Z2, n, R8, Yx, Μχ, Lj, and R7 are as defined in Example 19).

Refer to Chart F.

The platinum oxide catalyst is prepared by suspending 46 mg of 85% platinum oxide in 9 ml of water and hydrogenating the resulting mixture at ambient temperature and pressure for 34 min. To this suspension is added 58 mg of sodium bicarbonate and 18 mg of the title product of Example 19 dissolved in 2 ml of acetone. The resulting mixture is then warmed to 60°C and oxygen bubbled therethrough for 80 min. The reaction mixture is then filtered through diatomaceous earth and the filter cake washed in water. The filtrate is then acidified to pH4 with 5% aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The organic extracts are then dried over magnesium sulfate and concentrated under reduced pressure to yield 21 mg of pure title product. NMR absorptions (CDC13) are observed at 0.6-2.8, 3.0-4.2, and 4.65-5.86. I3C-NMR absorptions (CDC13) are observed at 176.9, 135.5, 133.2, 118.5 (d 3=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 3=13.5Hz), 28.5 (d J=28.3Hz), 25.2, 22.6, 21.0, and 14.06. Si-lica gel TLC Rf is 0.39 in the A-IX solvent system.

Example 22 5-F1uoro-CSA2 (less polar isomer).

Following the procedure of Example 21, 24 mg of the title product of Example 20 yields 23 mg of pure title product. NMR absorptions (CDC13) are observed at 0.6-2.9, 3.3-4.2, 5.0-6.06. C-NMR absorptions (CDCI3) are 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 14.06. TLC Rf is 0.50 in the A-IX solvent system.

The reaction products of Examples 21-22 are obtained as diastereomeric mixtures of (5E) and (5Z) geometric isomers. These geometric isomers are characterized herein as less polar and more polar'1 isomers based on TLC motilities. The isomers of these 5-fluoro-CBA2 compounds correspond to the (5E) and (5Z) geometric isomers of CBA2 itself. On the basis of relative biological activities, the more polar 5-fluoro-CBA2 isomer yields more potent pharmacological effects and on this basis could be assigned the (5Z) structure based on phar13 macoiogical considerations alone. However, the C-NMR data suggests the more polar isomer corresponds to the (5E) structure of the -fl uoro-CBAj, compound.

Following the procedure of Examples 21-22, there are prepared each of the various formula XCVI 5-fluoro-CBA2 diastereomers from the starting materials described following Example 20.

Further following the procedures known in the art, each of the various 5-fluoro-CBA2 compounds described in and following Examples 21-22 is transformed to the corresponding formula XCVII 5-fluoro-CBA2 analogs.

Example 23 (5Z)-9e-methyl-CBA2 adamantylamine salt The title product of Example 15 (54 mg), (5Z)-9R-methyl-CBA2 in ml of diethyl ether is combined with 23 mg of adamantylamine. After 10 min the precipitate forms which is thereafter stirred for 12 hr, decanted, and concentrated under reduced pressure to yield 68 mg of a solid, pure title product. Melting range is 110-114°C.

Example 24 (5Z)-9p-methyl-CBA2, calcium salt hydrate.

The title product of Example 15 (0.95 g), 9&-methyl-(5Z)-CBA2, calcium oxide (0.064 g), freshly boiled water (9.2 ml), and distilled tetrahydrofuran (6 ml), are combined by heating to 50°C under a nitrogen atmosphere with stirring for 20 min. The resulting mixture is then filtered, washed with tetrahydrofuran, and concentrated under reduced pressure to yield a residue. The residue is then dissolved in tetrahydrofuran (10 ml) and concentrated 8 times to yield a creamcolored foam. This foam is then dissolved in 6 ml of tetrahydrofuran which is dripped into anhydrous diethyl ether (95 ml). The resulting suspension is then stirred for 15 min at ambient temperature under a nitrogen atmosphere and filtered. The filter cake is then washed with anhydrous diethyl ether and dried for 20 hr under reduced pressure at ambient temperature to yield 0.686 g of title product. Melting range is 101-108°C. Following atmospheric equilibration melting range is 80-117°C. Infrared absorptions are observed at 3330, 1670, 1555, 1455, 1345, 1310, 1270, 1075, 1020, 970 cm'l.

Example 25 (5Z) and (5E)-6ae,9B-methano-C8A2 (Formula X: Xt is -COOH, Zt is -(CH2)3-, R1S is hydrogen, Rl6 and R17 taken together are methane, n is one, Rg is hydroxy, is trans-CH=CH-, Mi is ο-ΟΗ:β-Η, Li is ο-Η:β-Η, R7 is n-butyl, and the C-5, C-6 positions are unsaturated).

Refer to Chart E.

A. A suspension of 452 mg of 57% sodium hydride in mineral oil and 30 ml of di methyl sulfoxide is heated to 65°C for 1 hr under a nitrogen atmosphere, cooled to 17°C and thereafter treated over 15 min with 2.39 g of 4-carboxybuthyltriphenylphosphonium bromide. The resulting red solution is then stirred for 15 min at 17-20eC, treated with a solution of 716 mg of the title product of Example III, 6 ml of dry dimethylsulfoxide, stirred for 43 hr at 40°C, cooled to 0°C, treated with 3.5 ml of water, stirred for 30 min at 0°C, added to 75 ml of water and brine (2:1), acidified with one N aqueous hydrochloric acid, and extracted with 225 ml of diethyl ether. The ethereal extracts are 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 acid-washed silica gel eluting with 10-25% ethyl acetate in hexane to yield 290 mg of (5Z)-6ae,9B-methano-CBA2, 11,15-bis(tetrahydropyranyl ether), 70 mg of (5E)-6as,9e-methano-CBA2, ll,15-bis(tetrahydropyranyl ether), and 400 mg of a mixture of (5E) and (5Z) formula LXXXIII isomers. Rechromatographing the isomeric mixture on 150 g of acid-washed silica gel yields an additional 50 mg of (5E) isomer and 180 mg of (5Z) isomer.

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

B. A solution of 446 mg of the (5Z) reaction product of Part A in 44 ml of acetic acid, water, and tetrahydrofuran (6:3:2) is heated at 45°C under a nitrogen atmosphere for 3 hr, cooled, added to 200 ml of brine, 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, yielding 0.38 g of a yellow oil and chromatographed on 60 g of acid washed silica gel eluting with 70% ethyl acetate in hexane to yield 170 mg of pure (5Z) title product as a colorless oil. NMR absorptions are observed at 0.5-2.90, 0.89, 4.05, 4.B5-5.8, and 6.136. infrared absorptions are observed at 3360, 2260, 1710, 1245, 1240, 1075, 1025, and 970 cm1. The mass spectrum for the tris-trimethylsilyl derivative exhibits a high resolution peak at 578.3653. Silica gel TLC Rf is 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. Following the procedure of Part B above 90 mg of the (5E) reaction product of Part A is converted to 45 mg of (5E) title product as a colorless oil. NMR absorptions are observed at 4.40-2.8, 0.89, 4.06, and 5.0-5.85 ό. Infrared absorptions are observed at 3340, 2630, 1710, 1070, 970 cm'1. The mass spectrum exhibits a high resolution peak at 578.3664. Silica gel TLC Rg is 0.32 in the A-IX solvent system.

Following the procedure of Examples 23-25, each of the various formula X products is prepared wherein R16 and R17 are methano from the corresponding formula LXXXI reactants of Chart E.

Accordingly, the above examples provide methods for preparing each of the various formula X CBA analogs of the present invention. Ψ To XXXVI I LiOC-CH-Z2-CH2OR2a I Li To XXXIV XXXI XXXII CHART A (continued) -Υ,-C—C-Rv II II Mn Li XXXIV XXXV XXXVI CHART Β COOH CH2OH (CH2)g-C00H (CH2)g-CH2OH (CH2)g-CH2OR2e XLI XLII XLIII CH2OH CHO (CH2)g-CH2-OR28 XLIV CHART C Ψ Ψ R-is Ψ To LIV CHART c (continued) From LIII Ψ LVI To LVIII LVII CHART C (continued) From LVII Ψ Υ-,-C—c-r7 n a Mi L, I Rg CHART 0 V LXXI LXXII LXXIII CHART Ε LXXXI LXXXII LXXXIII LXXXIV From LXXXIV CHART E (continued) Z2-CH20H Rl6 ' R37 R18 HOH2C-Za (CH2)n Ύι-C-C-R27 H 1 Me L, LXXXV Z2-CH~0H CHART F Mi Li V To XCVI CHART F (continued) From XCV XCVI XCVII Rl 6 ' Rl7 Ζ2-Χι (CH2)n I •Υ-,-C—C-R: π n Mt Lt chi CHART Η CXI CXII \ / Η ___COORi ’ Ρ—Ρ CXIII CXIV CHART I R3S V CHART J CLXI CLXII 1. A compound of the formula

Claims (10)

1. CLAIMS R. R, '8 wherein n is one or 2; either Rj or R^ is independently selected from hydrogen methyl and fluorine, provided that CR^R^ is not CFMe, and R 7 is C 26 alkyl, cis-CH = CH-CHg-CHg, -(CH 2 ) 2 -CHOH-CH 3 , -(CH 2 ) 3 -CH = C(CH 3 ) 2 or optionally ring-substituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring substituents (no more than 2 of which are alkyl) independently 10 selected from chlorine, fluorine, trifluoromethyl, C-j_ 3 alkyl and . C p3 alkoxy, provided that neither R 3 nor R^ is fluorine when Ry is optionally substituted phenoxy; or CRjR^-Ry is 2-(2-furyl)ethyl,
2. 2-(3-thienyl)ethoxy,
3. 3-thienyloxymethyl, or C^_ 7 cycloalkyl optionally carrying up to 3 15 g alkyl substituents; is a-0H:B-Rg or B-R g : a-OH and R g is hydrogen or methyl; Y^ is trans-CH = CH-, cis-CH = CH-, -CH 2 CH 2 or -C s C-; R g is H, OH or CHgOH; Rp is hydrogen or C·^ alkyl; Z ] is -(CH 2 ) f+2 -, -(CH 2 ) f+1 -CF 2 -, trans-CH, - CH = CH- °i -Ph-(CH 2 ) f - in which f is zero, 1, 2 or 3 and Ph 1s 1,2 , 1,3- or 1,
4. 4-phenylene; provided that R^g is hydrogen when Z 1 is -Ph-(CH 2 ) f - and that, if R-jg and Rp are each hydrogen, Z 1 is -Ph-(CH 2 ) f -; and X 1 is COOR, CH 2 0H, CH 2 NL 2 L 3 or C0L 4 ; in which R-j is hydrogen, a pharmacologically acceptable cation, C l-12 C 3-10 c ycloalkyl, C 7 _-| 2 aralkyl, phenyl optionally substituted up to 3 times by chlorine atoms or C-|_ 4 alkyl radicals, or phenyl substituted in the para-position by -NHC0R 25 , -COR 2g , benzoyloxy, acetamidobenzoyloxy or -CH = N-NH-C0NH 2 in which R 2g is methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH 2 and R 2g is methyl, methoxy, phenyl or -NH 2 ; L ? and L 3 are independnetly selected from hydrogen and Cp 4 alkyl; and L 4 is -NR 27 R 28 , -NR 2 gCOR 2 y, -NR 2g SO 2 R£ 7 or cycloamino selected from pyrroiidino, piperidino, morpholine, piperazino, hexamethyleneimino, pyrrolino and 3,4-didehydropiperidinyl optionally substituted by one or 2 C-|.| 2 a^y 1 radicals, in which R27 is hydrogen, C^_12 alkyl, C3_-|Q cycloalkyl, C 7-12 aralkyl, phenyl optionally substituted by up to 3 substituents selected from chlorine, Cp3 alkyl, hydroxy, carboxy, (C-|_ 4 alkoxy)carbonyl and nitro, carboxy (Cp 4 alkyl), carbamoyl (Chalky!), cyano (Cp 4 alkyl), acetyl (C^ alkyl), benzo(C.|_ 4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, C^_ 3 alkyl, hydroxy, C^_ 3 alkoxy, carboxy, (Cp 4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to 3 substituents selected from chlorine, C 13 alkyl and C^_ 3 alkoxy, pyridyl(C.,_ 4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, C^g alkyl and hydroxy, or mono-, di- or tri-hydroxyfC^ alkyl), R 2 7 is R 27 other than hydrogen, R 2g is hydrogen or C^_^ 2 alkyl, and R 2 g is hydrogen or C^_ 4 alkyl; or a pharmacologically acceptable acid addition salt thereof when X-j is ch 2 nl 2 l 3 . 2. A compound of the fonnula «8 wherein Rg, R 4 , R 7 , R g) R lg , Mp n, Xp Y ] and Z ] 5 are as defined in claim i, provided that, if R 15 is hydrogen, Z^ is -Ph-(CH 2 ) f - as defined in claim 1; or a pharmacologically acceptable acid addition salt thereof when X 1 is CH 2 NL 2 L 3 . 3. A compound of the formula wherein Rg, R^, 87. Rg> R-jg» 7’ Mp η» Xp Yj and Z-j are as defined in claim 1, provided that R^g is hydrogen when Z-| is -Ph-(CH 2 ) f - and that, if R lg and Rp are each hydrogen, ly is -PH-(CH 2 )f-; or a pharmacologically acceptable acid addition salt thereof when X-| is C^Nl^L-j. wherein R 3 , R^, R 7 , R g , R lg , Mp n, X-| and Z.j are as defined in claim 1, provided that, if R^g is hydrogen, ly is -PH-(CH 2 )^.- as defined in claim 1; or a pharmacologically acceptable acid addition salt thereof 15 when is CH 2 NL 2 Lg. 4. 5. (5E)-
5. 5-Fluoro-CBA 2 or its methyl ester. 5. 6. (5Z)-5-Fluoro-CBA 2 or its methyl ester.
6. 6. 7. (5E)-5-Fltioro-7a-homo-CBA2 or its methyl ester.
7. 7. 8. (5Z)-5-Fluoro-7a-homo-CBA2 or its methyl ester.
8. 8. 9. (5E)-3,4-Di nor-2,5-i nter-o-phenylene-CBAg. 5 10. (5Z)-3,4-Dinor-2,5-inter-o-pheny1ene-CBA2. 11. (5E)-2,3,4-Trinoi-1,5-inter-m-phenylene-CBA 2 . 12. (5Z)-2,3,4-Tri nor-1,5-i nter-m-phenylene-CBA 2 . 13. (5E)-3,4-Di nor-2,5-i nter-o-phenylene-7a-homo-CBA2. 14. (5Z)-3,4-Di nor-2,5-i nter-o-phenylene-7a-homo-CBA 2 .
9. 9. 10 15. (5E)-2,3,4-Trinor-l,5-inter-m-phenylene-7a-homo-CBA2. 16. (5Z)-2,3,4-Trinor-l,5-inter-m-phenylene-7a-homo-CBA2· 17. (5E)-9p-methyl-CBA2 or its methyl ester. 18. (5Z)-9B-methyl-CBA2 or its methyl ester. 19. (5E)-6ag,9B-methano-CBA2 or its methyl ester.
10. 10. 15 20. (5Z)-6aB,9B-methano-CBA 2 or its methyl ester. 21. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.