CA1215994A - Intermediates for benzopyran prostaglandin derivatives - Google Patents

Abstract

ABSTRACT

Intermediate compounds for preparing benzo-pyran prostaglandin derivatives of general formula:

(XIII) or (XIX) wherein Y is -CH2CH2, cis-CH=CH-, trans-CH=CH- or -C?C-;
R1 is =O, H:H, .alpha.-OR12:.beta.-H, .alpha.-H:.beta.-OR12, .alpha.-CH2OR12:.beta.-H or .alpha.-H:.beta.-CH2OR12, wherein R12 is H or an -OH-protecting group; M is .alpha.-OR12:.beta.-R14 or .alpha.-R14:.beta.-OR12, wherein R12 is as defined above and R14 is H or -CH3; L1 is .alpha.-R15:.beta.-R16, .alpha.-R16:.beta.-R15 or a mixture thereof, wherein R15 and R16, independently, are H, F or -CH3, with the proviso that one of R15 and R16 is F only when the other is not -CH3;
R17 is ; , when taken together, is (i)

Description

2~

This is a divisional application of copending application serial no. 420,222, filed January 25, 1983.

FIELD OF INVENTION

The present invention relates to novel benzopyran compounds which are prostaglandin derivatives, to processes for the preparaticn o~
said novel compounds and their use as pharmacological agents or as intermediates for the preparation of compounds useful as pharmacologi-cal agents. This invention also relates to chemical intermediates for preparing the novel benzopyran compounds described and claimed herein.
PRIOR ART
~ ~ 7 Related 6a methano compounds are described in U.S. Patent 4,306,075~ Also compounds having a 5-membered oxa containing ring are described in European Patent 24-943 (Derwent No. 19801D).
SUMMARY OF THE INVE _ IO
The parent application claims compounds of formula I
wherein R is -CH2- or -0-;
wherein Z is -CH2-~ -CH2CH2-; -CF2-; -CF2CH2-; or ~herein Z-R taken toyether is trans-CH=CH-CH2- or trans-CH=CH-;
wherein Q is (1) -COOR5, wherein R~ is ~a) hydrogen, (b) (C1-Cl2)alkyl, (c) (C3-C1O)cycloalkyl, (d) (C7-Cl2)aralkyl, (e) phenyl optionally subs~ituted with one, 2 or 3 chloro or (C1-C4)alkyl, (f) phenyl substituted in the para-position wi~h -NHCOR6, COR7, -OC(O)R8 or -CH=N-NHCON~ , wherein R6 is methyl, phenyl, acet-amidophenyl, benzamidophenyl or -NH2; R7 is methyl, phenyl, -NH2, or methoxy, and R~ is phenyl or acetamidophenyl;
(g)~phthalidyl, ~h) 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopro-pan-1-yl P-oxide, (i) 3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide, or (j) a pharmacologically acceptable cation;
(2) -CH~OH;

(3) -COL~, wherein L2 is (d) an amino group of the formula -NRgR1o wherein Rg is o i . ~ .
-2~ L~ 3993 - hydrogen or (Cl-Cl2)alkyl and Rlo is (i) hydrogen (ii) (C1-Cl2)alkyl (i i i ) (C3-ClO )cycl oal kyl, 5(iv) (C7-C12)aralkyl (v) phenyl op~ionally substituted with one, 2 or 3 chloro, (Cl-C3)alkyl, hydroxy, carboxy, (C2-Cs)alkoxycarbonyl, or nitro, (vi) (C2-Cs)carboxyalkyl, 10(V i i ) (C2-C5 )carbamoyl al kyl, (Vi i i ) (C~-C5 )cyanoalkyl, (ix ) (C3 -C6 )acetyl al kyl, (x) (C7-Cl2)benzoylalkyl, optionally substituted by one, 2, or 3 chloro, (~ -~ )alkyl, hydroxy, (Cl-C3)alkoxy, carboxy, (C2-Cs)-alkoxycarbonyl, or nitro, (xi) pyridyl, optionally subs~ituted by one, 2, or 3 chloro, (Cl-C3)alkyl, or ~C1-C3)alkoxy, (xii~ (C6-Cg)pyridylalkyl optionally subs~ituted by one, 2, or 3 chloro, (C1 C3)alkyl, hydroxy, or (Cl-C33alkyl, (xiii) (Cl-C4)hydroxyalkyl~
~xiv) (Cl-C4~dihydroxyalkyl, (XY ) (C l -C4 ~trihydroxyalkyl;
(b) cycloamino selected from the group consisting of pyro-lidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrroline, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (Cl-Cl~)alkyl;
(c) carbonylamino of the formula -NRllC0R1o, wherein Rll is hydrogen or (Cl-C4)alkyl and Rlo is other than hydrogen9 but o~herwise defined as above;
(d) sulfonylamino of the formula -NRllS0~Rlo, wherein R
and R~o are defined in (c);

(4) -CH2NL~L4, wherein L3 and L4 are hydrogen or (Cl-C4)alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when Q is -CH2NL~L4;
r5) CN; or Il (6) -CCH3, iOe.~ acetyl;
wherein Rl is oxo, i.e., =0; H,H; -0Rl2,~-H; a-H,~-0RI2;

3- ~ 2~
a-CH~OR12,~-H; -H,~-CH20R12 wherein R12 is hydrogen or a hydroxyl protective group; or wherein Y is trans -CH=CH-, cis-CH=CH-, -CH2CH2-, or -C_C-;
wherein M is ~-ORl2,~-Rl4; or -Rl4,~ ORl~, wherein R12 is as defined above, and Rl4 is hydrogen or methyl;
wherein L1 is ~-Rls~-Rl6; ~-R16,~-Rl5; or a mixture thereof ~herein Rl5 and R16 are hydrogen, methyl, or fluoro being the same or di~ferent with the proviso that one oF Rls and R16 is fluoro only when the other of Rl5 and Rl6 is hydrogen or fluoro;
wherein Rl7 iS
(lj -CmH2mCH3 wherein m is an integer of from one to 5, (2) phenoxy optionally substitu~ed by one, 2~ or 3 chloro, fluoro, trifluoromethyl, (Cl-C3)alkyl, or (Cl-C3)al~oxy, wi~h the proviso that not more than two substituents are othef than alkyl and with the proviso that Rl7 is phenoxy or substituted phenoxy~ only when Rls and Rl6 are hydrogen or methyl, being the same or different;
(3) phenyl, benzyl, phenylethyl, or phenylpropyl ~ptionally sub-stituted on the aromatic ring by one, 2, or 3 chlorog fluoro, tri-fluoromethyl (Cl-C3~alkyl, or (Cl-C3)alkoxy, with the proviso that not more than t~o substituents are other than alkyl, (4) cis-CH=CH-CH2CH3,

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

(6) -~CH2)3-CH=C(CH3)z,

(7) -C-CH~CH~CH2CH3, H

(8) -CH2 ~ 3 or

(9) -CH2 ~ , or wherein -C-Rl7 taken together is Ll (1~ (C4-C~)cyc10alkyl optionally substituted by one to 3 (Cl-Cs)-alkyl, (2~ 3-thienyloxymethyl, ~LX~

(3) -~H-C~2C-C-CH3, (4) -C-C-C H2qCH3 wherein q is an integer of from 2 to 6, or (5) -C H2 CH=CH2 wherein p is an integer of from 3 to 7;
and individual optical isomers thereof.
The compounds of general Formula I wherein R12 ls hydrogen possess useful pharmacological properties as defined in detail herein-below and phamacologically acceptable salts which may be formed with these compounds are a part of the present invention.
The compounds of Formulas II, XIII, XIX and XXII are useful as intermediates in the preparation of the compounds of Formula I, and in said formulas the substituent groups R, Z, Z-R, Y, Q, M, Ll, R17, ICI-R17 and Rl have the same meanings as defined in Ll 1 I and R is -CHO or -C~2OR12 wherein 12 The intermediates of Formulas II and XIII wherein R17 is _ 2 2 2 3 or wherein -IC-Rl7 taken together is Ll (a) -CH-CH2C--C-CH3 ~b) ~C_C~CqH2qCH3 wherein q is an integer of from 2 to 6, or (c) -C H2 CH=CH2 wherein p is an integer of from 3 to 7, are also a part of the present invention.
The intermediates of general formula XIII, wherein R17 and -C-R17 are as defined immediately above, and XIX are claimed in this application.
Ll DETAILED DESCRIPTION OF INVENTION
The compounds of the present invention are trivially named as derivatives of prostaglandin Fl using in general the art-recogni~ed system of nomenclature described by N.A. Nelson, J. Med.
Chem. 17:911 (1974) for prostaglandins.
In the formulas herein, broken line attachments to a ring, i.e., (---), indicate substituents in the "alpha" (~) configuration, i.e., below the plane of said ring. A heavy solid line attachment to a ring, i.e., ( _ ), indicates substituents in the "beta" (~) confi-guration, i.e., above the plane of said ring. The use of wavy lines (~) herein indicates attachment of substituents in the alpha or beta con-mab/

~ 5 ~2~L.~ 3993 figura~ion or attached in a mixture of alpha and beta sonfigurations.
Alternatively wavy lines will represent either an E or Z geometric isomeric configuration or the mixture thereo~.
A side chain hydroxy at C~15 in the formulas herein is in the S
or R configuration as determined by the Cahn-lngold-Prelog sequence rules, J~ Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) ~or discussion of the stereochemistry of the prostaglandins which discus-sion applies to ~he novel compounds described herein. With regard to the divalent groups described above, i.e~, Rl, M, and Ll said divalent groups are defined in terms of an a-substituent and a ~-substituent which means that ~he -subs~ituent of the divalent group is in the alpha configuration with respect to the plane of the C-8 to C-12 cyclopentane ring and the ~-substituent is in the be-ta configuration with respect to said cyclopentane ring~
The carbon atom content of various hydrocarbon containing groups is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety. For example, in defining the moiety L2 in the -COLz substituent group the definition (Cl-Cl2)alkyl means that L2 can be an alkyl group having from one to 12 carbon atoms. Addition-ally, any moiety so defined includes straight chain or branched chain groups. Thus (Cl-Cl2)alkyl as set forth above includes straight or branched chain alkyl groups having from 1 to 12 carbon atoms and as additional illustration, when L2 represents, for example, (C2-Cs)carb-oxyalkyl, the alkyl moiety thereof contains from 1 $o 4 carbon atoms an~ is a straight chdin or a branched chain alkyl group.
The compounds wherein-R is oxa, i.e 3 -O- and Z is -CH2- are named as 9 deoxy-2'3~-epoxy-3-oxa-4,5,6-trinor-3,7-(1',3'-interphen-ylene)-PGFl compounds. The compounds wherein each of R and Z is -CH2- are named as 9-deoxy-2',9~-epoxy-495,6-trinor-3,7~ 3'-inter-phenylene)-PGFl compounds. When Z is -CH2CH2- the compounds are further characterized as "2a-homo"~ When Z- is -CF2- the compounds are further characterized as "2,2-difluoro" compounds. And when Z is -CF2CH2- the compounds are further characterized as "2,2-difluoro-23-homo". When Z-R taken together is -CH=CH-CH2- the compounds are named 35 dS "2a-vinylidene" compounds. When 2-R is -CH=CH- the compounds are named as 2a-me~hinyl compounds.

~..

~- ~
-6~ L~ 3993 When Rl4 is methyl, the compounds are named as "15-methyl-" com-pounds. Further, except for compounds wherein Y is cis-CH=CH-, com-pounds wherein the M moiety contains an hydroxyl in the beta con-fig~
uration are additionally named as "15-epi-" compounds.
l~hen Y is cis-CH=CH-, and the M moiety contains an hydroxyl in the alpha configuration the compounds are named as "15-epi-" com-pounds. For a description of this convention o~ nomencla-ture for identifying C-15 epimers, see U.S. Patent 49016,184, issued April 5, 1977, particularly columns 24-27 thereof.
The compounds of Formula I 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 Rl7 is straight chained -CmH2m-CH3, wherein m is an integer of from one to 5, the compounds so described are named as "19,20-dinor"~ "20-nor", "20-methyl" or "20-ethyl" compounds when m is one, 2, 4 or 5, respectively. When Rl7 is branched chain -CmH2m-CH3, then the compounds so described are "17-, 18-, 19-, or 20-alkyl" or "17,17-, 17918-9 -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, eOg., 17,20-dimethyl" compounds are described when m is 5 (1-me~hylpentyl).
When 2l7 is phenyl and neither Rl5 nor Rl6 is methyl, the com-pounds so described are named as "16-phenyl-17~18,19,20-tetranor" com-pounds. When R17 i5 substituted phenyl, the corresponding compounds are named as "16-(subs~ituted phenyl)-17~18,19,20-tetranor" compounds.
When one and only one o~ R15 and R16 is methyl or both Rl5 ~nd R16 are methyl, then the corresponding compounds wherein Rl7 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 R17 is benzyl, the compounds so described are named as "17-phenyl-18,19,20-trinor" compounds. When R17 iS substituted benzyl, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor" compounds.
When Rl7 is phenylethyl, the compounds so described are named as "18-phenyl-19,20-dinor" compounds. When R1~ is subs-tituted phenyl-Pthyl, the corresponding compounds are named as "18-(substituted phenyl)-19,20-dinor" compounds.

7 ~ L5 ~3~ 3993 ~hen Rl7 is phenylpropyl, the compounds so described are named as "l9-?henyl-20-nor" compounds. When R17 is substituted phenylpropyl the corresponding compounds are named as "19-(substituted phenyl)-20 nor" compounds.
When Rl7 is phenoxy and neither Rl5 nor Rl6 is methyl 7 the corn-pounds so described are named as "16-phenoxy~17318,19,20-tetranor"
compounds. When Rl7 is substituted phenoxy, the correspondiny com-pounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor"
compounds. When one and only one of Rl5 and Rl6 is methyl or both Rls and Rl6 are methyl, then the corresponding compounds wherein Rl7 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-(substituted phenoxy)l8,19,20-trinor" compounds, respectively~
When Rl7 is cis-CH=CH-CH2CH3, the compounds so described are named as "cis-17,18-didehydro" compounds.
When Rl7 is -(CH2)2-CH(OH)-CH3, the compounds so described are named as "19-hydroxy" compounds.
When Rl7 is -(CH2)3-CH=C(CH3)2, the compounds so described are named as "20-isopropylidene" compounds.
When Rl7 is H
the compounds so described are named as 17(5),20-dimethyl compounds.
When Rl7 is 2-furylmethyl or 3-thienylmethyl, i.e., -CH2~ -CH2~3 respectiYely the compounds so described are named as "17-(2-furyl)-18,19,20-trinor" compounds and "17 (3-thienyl~-18,19,20-trinor" com-ponds respectively.
~H3 When -C(Ll)-Rl7 is -CH-CH2C_C-CH3, the compounds are named as "16-(R,S)methyl-18,19-tetradehydro" compounds.
When -C(Ll)-R17 is optionally substituted cycloalkyl or 3-thien-yloxymethyl, the compounds so described are named respectively 15-cycloalkyl-16,17,18,19,20-pentanor compounds and 16-(3-thienyl)oxy ~ 3993 17,18,1~,20-~etranor compounds. The term 3-thienylox~2thyl means the moi~ty having the structure:
-CH2 -~

S
When -C(Ll)R17 is ~C_C-CqH2qCH3 wherein q is an in~eger o~ from 2 to 6 the compounds so described are named as "16,17-~etradehydro", "16,17-tetradehydro-20-methyl", "16,17~tetradehydro-20-ethyl", "16,17-tetrahydro-20-n-propyl" dnd "16,17-tetrahydro-20-n-bu~yl" compounds as the integer as represented by q varies from 2 to 6 respectively.
When -C(Ll)Rl7 is -CpH2pCH=CH2 wherein p is an integer of from 3 to 7 the compounds so described are named as "19,2~-didehydro", "19,20-didehydro-18a,18b-dihomo", "19~20-didehydro-18a,18b,18c-tri-homo", "19,20-didehydro-18a,18b,18c,18d-tetrahomo" co~pounds as the integer represented by p varies from 3 to 7 respectivel~. When at least one of Rl5 and Rl6 is not hydrogen then ~exc-ept for the 16-phenoxy or 16-phenyl compounds discussed above) there are described the "16-methyl" (one and only one of Rl5 and Rl5 is methyl), "16,16-dimethyl" (Rls and Rl6 are both methyl), "16-fluoro" (one and only on~
of Rl5 and Rl6 is fluoro), "16,16-difluoro" (Rls and ~16 are both fluoro) compounds. For those compounds wherein R~5 and Rl6 are different, the carbacyclin analogs so represented contain an asymmet-ric carbon atom at C-16. Accordingly, two epimeric con~;igurations are possible: "(16S)" and "(16R)"~ Further, there is described by this invention the C-16 epimeric mixture: "(16RS)".
When Q is -CH20H, the compounds so described are n~med as "2-de-carboxy-2-hydroxymethyl" compounds.
When Q is -CH2NL3L4, the compounds so described are named as "2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl~ compounds.
When Q is -C0L2, the novel compounds herein ane named as amides.
Further, when Q is -COOR5 and Rs is other than hydrogen ~he novel com-pounds herein are named as esters and salts.
When Q is CN the novel compounds herein are named as 2-decarboxy 2-cyano compounds.
When Q is 9 ~ 3993 O
: -CCH3 the novel compounds herein are named as 2-decarboxy-2-acetyl com-pounds~
S Examples of phenyl esters substituted in the para position (i.e., Q is -COORs, Rs is p-substituted phenyl) include p~acetamidophenyl ester, p-benzamidophenyl ester, p-(p-acetamidobenzarnido)pherlyl ester, p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl

10 \

\

.

z~

ester, p-acetylphenyl ester, p-benzoylphenyl ester, p-aminocarbonyl-phenyl ester, p-methoxycarbonylphenyl ester9 p-benzoyloxyphenyl ester3 p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde serni-carbazone ester.
Examples of novel amides herein (i.e., Q is -COL2) include the following:
(1) Amides within the scope of alkylamino groups o~ the ~ormula-NRgRlo are methylamide, ethylamide, n-propylamide, isopropylamide, n-butylamidel n-pentylamide, tert-butylamide, neopentylamide, n-hexyl-amide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, n undecylamide, and n-dodecylamide, and isomeric ~orms thereof. Fur-ther examples are dimethylamide, diethylamide3 di-n-propylamide, di-isopropylamide, di-n-butylamide, methylethylamide, di-tert-butylamide, methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutyl-amide, and propylbutylamide. Amides within the scope of cycloalkyl-amino are cyclopropylamide, cyclobutylamide, cyclopentylamide~ 2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide, 2-methylcyclo-pentylamide, 3-tertbutylcyclopentylamide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, 2,2-dimethylcyclo-hexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclo-decylamide, N-methyl-N-cyclobutylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexylamide, N-ethyl N-cyclopentylamide~ and N-ethyl-N-cyclohexylamide. Amides within the scope of aralkylamino are benzyl-amide, 2-phenylethylamide, and N-methyl-N benzyl-amide. -Amides within the scope of substituted pheny1amide are p-chloroanilide, m-chloro-anilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide~ m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimeth-oxyanilide, p-hydroxymethylanilide~ p-methylanilide, m-methyl anilide, p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonyl anilide, p-carboxyanilide and o-hydroxyanilide. Amides within the - scope of carboxyalkylamino are carboxyethylamide, carboxypropylamide and carboxymethylamide, carboxybutylamide. Amides within the scope of carbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide. Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyano-propylamide, and cyanobutylamide. Amides within the scope of acetyl-alkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within the scope of benzoylalkylamino ~z~
_1l 3993 are benzoylmethylamide, benzoylethylamide, benzoylpropylamide, and - benzoylbutylamide. Amides within the scope of substituted benzoyl-alkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethyldmide, 2,4-dichlorobenzoylmethylamide, Z,4,6-trichlorobenzoylmethylamide, m-ni~robenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxybenz-oylme~hylamide, 2,4-dimethoxy benzoylmethylamide, 3,4,5-trimethoxy-benzoylmethylamide, p-hydroxymethylbenzoylmethylamide~ p-methylbenz-oylmethylamide, m-methylbenzoylmethylamide, p-e~hylbenzoylmethylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide, m-methoxy-carbonylbenzoylmethylamide, o-carboxybenzoylmethylamide, o-hydroxy-benzoylmethylamide, p-chlorobenzoylethylamide, m-chlorobenzoylethyl-amide~ 2,4-dichlorobenzoylethylamide, 2,4,6-trichlorobenzoylethyl-amide, m-nitrobenzoylethylamide, p-nitrobenzoylethylamide, p-meth-oxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxybenz-oylethylamide, 3,495trimethoxybenzoylethylamide~ p-hydroxymethylbenz-oylethylamide, p-methylbenzoylethylamide, m-methylbenzoylethylamide, p-ethylbenzoylethylamide, t-butylbenzoylethylamide 3 p-carboxybenzoyl-ethylamide, m-methoxycarbonylbenzoylethylamide, o-carboxybenzoyl-ethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide, 2~4-dichlorobenzoylpropylamide~ 2,4,6-- trichlorobenzoylpropylamide, m-nitrobenzoylpropylamide, p-nitrobenz-oylpropylamide, p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpro-pylamide, 3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoyl-propylamide, p-methylbenzoylpropylamide, m methylbenzoylpropylamide, p ethylbenzoylpropylamide, t-butylbenzoylpropylamide, p-carboxybenz-oylpropylamide, m-methoxycarbonylbenzoylpropylamide, o-carboxybenznyl-propylamide, o-hydroxybenzoylpropylamide, p-chlorobenzoylbu~ylamide, m-chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutylamide, 2,4,6-tri-chlorobenzoylbutylamide, m-nitrobenzoylmethylamide, p-nitrobenzoyl-butylamide, p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutyl-amide, 3,4,5-trimethoxybenzoylbutylamide, p-hydroxyme~hylbenzoylbutyl-amide 9 p-methylbenzoylbutyamide, m-methylbenzoylbutylamide 9 p-ethyl-benzoylbutyalmide, m-methylbenzoylbutylamide, p-ethylbenzoylbutyl-amide, t-butylbenzoylbutylamide~ p-carboxyben~oylbutylamide, m-meth-oxycarbonylbenzoylbutylamide, o carboxybenzoylbutylamide, o-hydroxy-benzoylmethylamide. Amides within the scope of pyridylamino are -pyridylamide, B-pyridylamide, and y-pyridylamide. Amides within the scope of substituted pyridylamino are 4-methyl--pyridylamide, -12- ~ 3993 4-methyl-~-pyridylamide, 4-chloro--pyridylamide, and 4-chloro-~-pyridylamide. Amides within the scope of pyridylalkylamino dre a-pyridylmethylamide~ ~-pyridylmethylamide, y-pyridylmethylamide, a-pyridylethylamide, ~ pyridylethylamide, y-pyridyle~hylamide, a-pyridylpropyldmide~ ~-pyridylpropylamide, y-pyridylpropylamide, a-pyridylbutylamide, ~-pyridylbutylamide, and y-pyridylbutylamide.
Amides within the scope of substitllted pyridylal~ylamido are 4-methyl--pyridylmethylamide, 4-methyl~-pyridylmethylamide, 4-chloro-a-pyridylmethylamide, 4-chloro-~-pyridylmethyl-amide, 4-methyl-a-pyridylpropylamide, 4-methyl-~-pyridylpropylamide, 4-chloro-a-pyridylpropylamide, 4-chloro-~-pyridylpropylamide, 4-methyl-a-pyridylbutylamide, 4-methyl-~-pyridylbutylamide, 4-chloro-~-pyridyl-butylamide, 4-chloro-~-pyridylbutylamide, 4-chl~ro-y-pyridylbutyl-amide. Amides within the scope of hydroxyalkylamino are hydroxy-methylamide, B-hydroxyethYlamide, ~-hydroxypropylamide, y-hydroxy-propylamide, l-(hydroxymethyl)ethyl-amide, l-(hydroxymethyl)propyl-amide~ (2-hydroxymethyl~propylamide, and a9~,-dimethyl-hydroxy-ethylamide. Amides within the scope of dihydroxyalkylamino are dihy-droxymethylamide, B,Y-dihydroxypropylamide, l-(hydroxymethyl)2-hydroxymethylamide, ~,y-dihydroxybutylamide, ~,~-dihydroxybutyl-amide, y,~-dihydroxybutylamide, and l,l-bis(hydroxymethyl)ethyiamide. Amides within the scope of trihydroxyalkylamino are tris~hydroxy-methyl)-methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide.
(2) Amides within the scope of cycloamino groups described abo~e are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethylene-iminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydro-piperidinylamide each of which may be optionally substituted with one or 2 straight or branched alkyl chains having from I to 12 carbon atoms.
(3) Amides within the scope of oarbonylamino of the formula -NRllCORlo are methylcarbonylamide, ethylcarbonylamide, phenylcar-bonylamide, and benzylcarbonylamide.
(4) Amides within the scope of sulfonylamino of the formula -NRllCORlo are methylsulfonylamide, ethylsufonylamide, phenylsulfonyl-amide, p-tolylsulfonylamide, benzylsulfonylamide.
Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ~r~ 3~

dodecyl, isomeric forms thereof.
Examples of (C3-ClO)cycloalkyl which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclo-propyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl 7 cyclobutyl~
2-methylcyclobutyl, 3-propylcyclobutyl, Z,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pen-tylcyclopentyl, 3-terk-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropyl-cyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, and cyclodecyl.
10Examples of (C7-Cl2)aralkyl are benzyl, 2-phenylethyl, l-phenyl-ethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthyl-ethyl), and l-(2-naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclsive, dre p-chlorophenyl, m-chlorophenyl, 274-dichlorophenyl, 2,4,6-trichlorophenyl 3 p-tolyl, m-tolyl, o-tolyl, p-- ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2methyl-phenyl, and 2,4-dichloro-3-methylphenyl.
Examples of (C4-C7)cycloal~yl optionally substituted by one to 3 (Cl-Cs)alkyl dre cyclobutyl, l-propylcyclobutyl, l-butylcyclobutyl, l-pentylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethyl-cyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl 9 cyclopentyl, 2,2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 1-methyl-3-propylcyclo-pentyl, 2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclo-hexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclo-hexyl, 2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl.
Examples of substituted phenoxy, phenyl, phenylmethyl, i.e., ~enzyl, phenylethyl, or phenylpropyl of the Rl7 moiety are (0-9 m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, to-, m-, or p-)propylphenyl, 2-propyl-(m- or p-3tolyl, 4-iso-propyl-2~6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-9 2 9 3 9 5- ~ 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p~)fluorophenyl, 2-fluoro-(m- or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)di-fluorophenyl, (o-,m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 296-~ 3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoromethylphenyl, (o-; m-, or p-)~
methoxyphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or ~-)chloro-2-meth-oxyphenyl, 294-dich10ro-(4- or 6-)methylphenyl, (o-, m-, or p-)tolyl~
oxy, (o-, m-, or p-)ethylphenyloxy, 4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m , or p~)propylphenoxy, 2-propyl-(m- or p-)tolylox~, 4-isopropyl-2,6-xylyloxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(m- or p-)tolyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenoxy, (o-, m-, or p-)-chlorophenoxy, 2-chloro-p-tolyloxy, (3, 4, 5, or 6-)chloro-o-tolyloxy, 4-chloro-2-pro-pylphenoxy, 2-isopropyl-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chioro-3-fluoro-phenoxy, (3- or 4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoro-methylphenoxy, (o-, m-, or p-)methoxyphenoxy, (o-, m-, or p-)ethoxy-phenoxy, (4- or 5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)-methylphenoxy, (o-, m-, or p-)tolylmethyl, (o-, m-, or p-)ethylphenyl methyl, 4-ethyl-o-tolylmethyl, 5-e-thyl-m-tolylmethyl~ (o-, m-, or p-)propylphenylmethyl, 2-propyl-(m- or p-)tolylmethyl, 4-isopropyl-2,6-xylylmethyl, 3-propyl-4-ethylphenylmethyl, (2,3,4-, 2,3,5-, 2,3,6-, or ~,4,5-)trimethylphenylmethyl, (o-, m-, or p-3fluorophenyl-methyl 9 2-~luoro-(m- or p-)tolylmethyl~ 4-fluoro-2,5-xylylme~hyl, ~2,4-, 2~5-, 2,6-, 3,4-, or 3,5-)difluorophenylmethyl, (o-, m-, or p-)tolylethyl, (o-, m-~ or-p-)ethylphenylethyl~ 4-ethyl-o-tolylethyl, 5-ethyl-m-tolylethyl, (o-, m-, or p-)propylphenylethyl, 2-propyl-(m-or p-)tolylethyl 7 4-isopropyl-2,6-xylylethyl, 3-propyl-4-ethylphenyl-ethyl, (2,3,4-, 2,3,5-9 2,3,6-, or 2,4,5-)trimethylphenylethyl, (o-, m-, or p-)fluorophenylethyl, 2-fluoro-(m- or p-)tolylethyl, 4-fluoro--2,5-xylylethyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenylethyl, (0-9 m-, or p-)chlorophenylmethyl, 2-ch10ro-p-tolylmethyl, (3, 4, 5, or 6-)chloro-o-tolylmethyl, 4-chloro-2-propylphenylmethyl~ 2~isopro-pyl-4-chlorophenylmethyl, 4-chloro-3,5~xylylmethyl~ (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylmethyl, 4-chloro-3-fluorophenyl-me~hyl, (3- or 4-~chloro-2-fluorophenylmethyl, (o-, m-, or p-)tri-fluoromethylphenylmethyl, (o-, m-, or p-)methoxyphenylmethyl, (o-, m~, or p-)ethoxyphenylmethyl, (4- or 5-~chloro-2-methoxyphenylmethyl, and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl, (o-, m-, sr p-)chloro-phenylpropyl, 2-chloro-p-tolylpropyl, (3, 4, 5, or 6-)chloro-o-tolyl--l5~ 33 ~ 3993 propyl, 4-chloro-2-propylphenylpropyl, 2-isopropyl-4-chlorophenyl-propyl, 4-chloro-3,5-xylylpropyl, (2,3-9 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylpropyl, 4-chloro-3-fluorophenylpropyl, (3- or ~-)-chloro-2-fluorophenylpropyl, (o-, m-, or p-)trifluoromethylphenylpro-pyl, (o-, m-, or p-)methoxyphenylpropyl, (o-, m-, or p-)ethoxyphenyl-propyl, (4- or 5-)chloro-2-methoxyphenylpropyl, and 294-dichloro-(4-or 6-)methoxyphenylpropyl.
The group -CmH2mCH3 wherein m is an integer of from one to 5 which R17 may be represents straight or branched alkylCl-Cs groups such as named hereinabove.
The terms phthalidyl; 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide; and 3-(5,5-di(hydroxymethyl~-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide; which Rs may represent in the -COORs group mean the following respective moieties (a), (b) and (c):

~ (a) 0~
o ~) O~ C~3 -CH2-CC~z-P~ ~ (b) o CH3 G O
ll il/ ~ /CH~OH
-CH2-C -CH2-P\ j~ (c ) As indicated hereinabove R12 is hydrogen or a protecting group.
Those protective groups within the scope o~ R12 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 hydrolysis ~ith hydrogen in the preparation of the compounds of the present invention. Sev-eral such protective groups are known in the art, e.g., tetrahydro-pyrany1 and substituted tetrahydropyranyl. See for reference E.JG
Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XII Organic Synthesis, pp. 51-79 (1969). Those -l6~ 3L~ 3~ 3993 blocking groups which have been found wseful include:
(a) tetrahydropyranyl;
(b) tetrahydrofuranyl;
- (c) a group of the formula ~C(OR2l,)(R~ CH(RIg)~R~), wherein R24 is alkyl of one ~o 18 carbon atoms, inclusive, cycl~alkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 car~on atoms, inclu-sive, phenyl or phenyl substituted with one to 3 a~k~l of one ~o 4 carbon atoms, inclusive, wherein R18 and R~9 are alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3 1 0 \ - --_ ~Z~ 4 -l7- 3993 alkyl of one to 4 carbon atoms, inclusive, or when Rl8 and Rlg are taken together -(CH2)a- or when Rl8 and Rlg are taken together to form -(CH2)b-0-(CH2)c, 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 ~l wi~h the further proviso that R1~ and Rlg may be the same or di~Ferent, and wherein R20 is hydrogen or phenyl;
(d) silyl groups according to R2l, as qualified hereinafter; and (e) an acyl protecting group suchas alkanoyl of from 2 to 12 carbon atoms.
When the protective group R12 is tetrahydropyranyl, the tetra-hydropyranyl 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., dichloro-methane, in the presence o~ an acid condensing agent such as p-tolu-enesulfonic acid or pyridine hydrochloride. The dihydropyran is used in large stoiohiometric excess, preferably 4 to 100 times the stoich-iometric amoun~. The reaction is normally complete in less than an hour at 20-~0C.
When the Rl2 protective group is tetrahydrofuranyl, 2,3-dihydro-~uran is used, as described in ~he preceding paragraph, in place ofthe 2~3-dihydropyran.
When the R12 protective group is of the formula -C~0224)(Rl8)-CH(Rlg)(R20)~ wherein R24, ~18~ ~19~ and R20 are as defined above; a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran is employed. See C.8. Reese, et al,, J. American Chemical Society 89, 3366 (1~67). The reac~ion conditions for such vinyl ethers and unsaturated co~pounds are similar to those for dihydropyran above.
R21 is a silyl protective group of the formula -Si(Gl~3. In some cases, such silylations are general, in that they silylate all hydroxyls of a molecule9 while in other cases they are selective, in that ~hile 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, dimethyl-phenylsilyl, triphenylsilyl, t-butyldimethylsilyl, or methylphenyl-benzylsilyl. With regard to Gl, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl, and the like.
~xamples of ar~lkyl are benzyl, phenethyl, ~-phenylethyl, 3-phenyl-~%~
-l8- 3g93 propyl~ -naphthylmethyl, and 2-(-naphthyl)ethyl. EY.amples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluoro-phenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, 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, ~okford, 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. tri-methylsilyl) 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-butyldimethylsilyl groups are employed when selective introduction is required. Further, when silyl groups are to be selec-tively hydrolyzed in the presence of protective groups according to R12 or acyl protective groups, then the use of silyl groups which are readily available and known to be easily hydrolyzable with te~ra-n-butylammonium fluoride are employed. A particularly useful silyl group for this purpose is t-butyldimethylsilyl 9 while other silyl groups (e.g. trimethylsilyl) are not employed when selective introduc-tion and/or hydrolysis is required.
The Rl2 protec~ive groups as defined by (a)to (d) above 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 CD
hydrolysis of the blocking group is achieved.
In preparing these acyl derivatives of a hydroxy-containing com-pound herein, methods generally known in the art are employed. Thus, for example9 a C2 to C12 alkanoic acid or ah -anhydride thereof is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-toluensulfonyl chloride or dicyclohexylcar-bodiimideO Preferably, however, the acyl protecting group is intro-duced by use of the appropriate acyl halide, e.g.l acetyl chloride, in the presence of a hydrogen halide scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is carried out under a variety of conditions, using procedures generally known in the art. Generally mild conditions are employed: O-GOC., contacting 2 ~

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 substantjal stoichiomet-ric excess.
The acyl protective groups, according to R12, are removed by deacylation. Alkali metal carbonate or hydroxide are employed effec-tively at ambient temperature for this purpose. For example~ potas-sium carbonate or hydroxide in aqueous methanol at ahout 25 C is advantageously employed4 The compounds of Formula I ~herein Rl2 i5 hydrogen produce cer-tain prostacyclin-like pharmacological responses. Accordingly~ the novel Formula I compounds wherein R12 is hydrogen are used as agents in the study, prevention, controlg and treatment o~ diseases, and other undesirable physiological conditions, in mammals, particularly humans, valuable domestic animals, pets, zoological s~ecimens, and laboratory animals (e~g., mice, rats, rabbits and monkeys). In particular, these compounds are useful as anti-ulcer agents and anti-asthma agents9 and as antithrombotic agents as indicated below. The compounds of Formula I wherein C(=Ll)Rl~ is -CH(CH3)CH2C--CCH3 are particularly useful in that said compounds possess an improved ratio of pla~elet aggregation to blood pressure lowering eff~cts.
(a) Platelet Aggregation Inhibition rhe compounds of Formula I wherein Rl2 is hydro~en are useful wheneYer it is desired to inhibit platelet aggregation, ~o 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 dis-eases, and to treat conditions such as atherosclerosis, arterioscler-osis, blood clotting defects due to lipemia, and other-clinical con-ditions in which the underlying etiology is associat~d with lipid imbalance or hyperlipidemia. Other in vivo appli~ations 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., intra-venously, subcutaneously, intramuscularly, and in the f~rm of sterile implants for prolonged action. For rapid response, especially in ` -20- ~ ~3L~3~ 3993 - emergency situations, the intravenous route of administration is pre-ferred.
The preferred dosage route for these compounds is oral, although other non-parenteral routes (e.g., buccal, rectal, sublingual) are 3 5 li~ewise employed in preference to parenteral routes. Oral dosage forms are conventionally formulated as, e.g., tablets or 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 in trea~ing the a~ore-described conditions associated with the inhibition of platelet aggre-lO gation. Doses in the range about 0.01 to about 10 mg per kg of body weight per day are preferred, the exact dose depending on the age~
weight, and condition of the patient or animal, and on the frequency and route of administration.
The addition of these compounds to whole blood provides in vitro l5 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 dl 50 useful in preparing platelet rich concentrates for use in treating thrombocyto-20 penia, chemotherapy, and radiation therapy. In vitro applications utilize a dose of 0.001-1.0 ~ per ml of whole blood. These com-pounds, i.e., the compounds of Formula I wherein R12 is hydrogen are useful in the treatment of peripheral vascular diseases, in ~he same manner as described in U.S. Patent 4,103,026.
(b) Gastric Secretion Reduction - Compounds of Formula I wherein R12 is hydrogen are useful in mam-mals, 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 pur-pose, these compounds are injected or infused intravenously, subcuta-neously, or intramuscularly in an infusion dose ran~e of about 0.1 ~9 to about 20 ~9 per kg of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.01 to about 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 2 ~

orally or by other non-parenteral routes. As employed orally, one to 6 administrations daily in a dosage range of about 1.0 to 100 mg per kg of body weight per day is employëd. Once healing of the ulcers has been accomplished the maintenance dosage required to prevent recur-rence is adjusted downward so long as the patient or animals remainsasymptomatic.
(c) NOSAC-Induced Lesion Inhibition Compounds of Formula I wherein Rl2 is hydrogen are also useful in reducing the undesirable gastrointestinal e~fects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are useful for that purpose by concomitant adminis-tration of said compounds of Formula I 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 of ~he E series. Accordingly these novel Formula I compounds are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of known prostaglandin synthetase inhibitors, e.g., indomethacin, phenylbuta~one, and aspi-rin* in the same manner as described by Partridge, et al, for the PGE
compounds in U.S. 3,781,429.
The anti-inflammatory synthetase inhibitor, for example, indome ~ thacin, aspirin, or phenylbuta~one is administered in any of the ways known in the art to alleviate an inflammatory conditions, for example, in any dosage regimen and by any of the known routes of systemic administration.
(d) Bronchodilation (Anti-asthma) The compounds of Formula I wherein R12 is hydrogen are also use-ful in the treatment of asthma. For example, these compounds are use-ful as bronchodilators or as inhibitors of mediator-induced broncho-constriction, 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 condi~ions such as bronchial bronchitis, bronchiectasis, pneumonia and emphysemaO For these pur-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 intramus-*trade mark -22~ 3L~ 3993 cularly9 with intravenous administration being preferred in emergency situations; by inhalation in the form of aero$ols or solutions for nebulizers; or by insufflation in the form of powder. Dsses in the range of about 0.01 to 5 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condi-tion of the patient and on the frequency and route o~ administration.
For the above use Formula I compounds can be combined advantageously with other anti-asthmatic agents, such as sympathornimetics (isopro-terenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theo-phylline and aminophylline); and corticosteroids (ACTH and prednisol-one).
Tle pharmacologically useful Formula I compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalationO For administration by the oral inhalation route with con-ventional nebulizers or by oxygen aerosolization it is convenient toprovide the instant active ingredient in dilute solution, preferably at concentrations of about one part of medicamen~ to from about 100 to 200 parts by wei~ht of total solution. Entirely conventional addi-tiYes may be employed to stabilize these solutions or to provide iso-tonic media, for example, sodium chloride, sodium citrate, citricacid, sodium bisulfite, and the like can be employed. For administra-tion as a self-propelled dosage unit for administering the active ingredient in aerosol ~orm suitable for inhalation therapy the compo-sition can comprise the active ingredient suspended in an inert pro-pellant (such as a mixture of dichlorodifluoromethane and dichloro-tetrafluoroethane) 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 Q is -COORs, the novel Formula I compounds 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 R5. However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. 0~ the alkyl esters, methyl and ethyl are especially preferred for op~imum 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 3L~ 3 ~

ac~ivity.
Pharmacologically acceptable salts of the novel compounds of Formula I for the purposes described above are those with p~armaco-logically acceptable metal cations, ammonia, amine cations, or quater-nary ammonium cations~ Illustrative pharmacological acceptabl~ cat-ions which R5 may represent are the following.
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., magnesiurn and calcium, although cationic forms of other metals, e.g., aluminum/ zinc, and iron are within the scope of this inventionO
Pharmacologically acceptable amine cations are those derived from primary~ secondary, and tertiary amines. Examples of suitable amines are methylamin2, dimethylamine, trimethylamine, ethylamine, dibutyl-amine, triisopropylamine, N-methylhexylamine, decylamine, dodecyl-amine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, ~-phenylethylamine, 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-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanol-amine, ethyldiethanolamine, N-butylethanolamine, 2~amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-(hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amyl-phenyl)-diethanolamine, galactamine, N-methylglycamine, N-methyl-glucosamine, ephedrine, phenylephrine, epinephrine, procaine9 and thelike. Further useful amine salts of the basic amino acid salts, e.g.3 lysine and arginine.
Examples of suitable pharmacologically acceptable quaternary ammonium ca~ions are tetramethylammonium, tetraethylammonium, benzyl-trimethylammonium, phenyl~riethylammonium, and the like When Q is -CH2NL3L4, the Formula I compounds so described are used for the purposes described in either free base or pharmacologi-cally acceptable dcid addition salt ~orm.

, , The acid addi-tion salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted aminomethyl)-Formula I compounds provided by this invention are, for example, the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates, methane-sulEonates, ethanesulfona-tes, benzenesulfona-tes, -toluenesul~onates and the like, prepared by reacting the appropriate compound oE Formula I
with the stoichiometric amount of ~he acid corresponding to the pharrn-acologically acceptable acid addition salt.
The compounds of Formula I wherein R12 is a protectiny group are useful as intermediates to the compounds of Formula I wherein ~12 is hydrogen.
To obtain -the optimum combination of biological response specifi-city, potency, and duration of activity, certain compounds within the scope of this invention are preferred. Preferred compounds of the present invention are those of Formula I wherein Y is -CH2C~2-, -C_C-or trans-C~=CH- and/or Q is -COORs or -COL2 are preferred especially when R5 is hydrogen, methyl, ethyl, or a pharmacologically acceptable cation such as sodium, and when each of Rg and Rlo of the L2 substit-uent moiety is hydrogen. Also preferred are compounds of Formula I
wherein R17 is ~Cm~2mCH3~ benzyl, phenoxy, 3-thienylmethyl, or phenyl or wherein -C(Ll)R17 taken together is cyclohexyl, 3-thienyloxymethyl or 3-ethylcyclobutyl, or -CH(~CH3)C~2C-CC~3 are especially preferred.
Also compounds wherein R17 is Cm~2mCH3 and each of Rls and Rl6, which make up the Ll substituent, are fluoro are preferred. Of these pre-ferred comPounds those wherein Z is -C~2- are more preferred and com-pounds wherein R is -0-, i.e., oxa, are most preferred. Also compounds wherein Rl and M are ~-ORl2,~-~ wherein R12 is hydrogen are more preferred.
As indicated hereinabove the hydroxyl groups at positions C-ll and C-15 of the compounds of the present invention may be protected by various groups generally employed in the art and protection of the hydroxyl functions is generally desirable or necessary during the preparation of the compounds. Although any of the various protecting groups described herein may be employed those preferred are tetra-hydropyranyl (T~P)~ tetrahydrofuranyl (T~F), and tert-butyldimethyl-silyl or tert-butyldiphenylsilyl. Of course it may be useful or desirable to utilize protecting groups which may be selectively hydro-lyzed. Also, when R}7 is -(C~2)2CH(O~) C~3 the hydroxyl group at C-l9 ye/jb ,L - -~z~

generally is protected by the same type of groups utilized to protect the C-ll and C-15 hydroxyl groups during the preparation of said com-pounds dnd subsequen~ly deprotected by hydrolysis as described herein.
The preparation of the compounds of Formula I is depicted in Charts A, B and C hereof. Chart A depicts the preparation o, the compounds of Formula I wherein R is -CH~-. In Char-t A the various substituent groups Rl, Y, M, LI, R17, and Rl2 have the meanings defined in Formula l; the group Z' is -CH2-, -CH2CH2, CF2-, or -CF~CH2-; the group Q' is the same as Q is Formula only Q' is other than -CH20H; and W nas the meaning defined in Chart A.
By the general procedures of D. R. Morton dnd J. L. Thompson, J.
Org. Chem. 439 2102 (1978) a 2-methylenecyclopentanone of Formula II
is added at low temperature, e.g., -40 to -80 C, to a cuprate reagent derived from the treatment of a compound of Formula III with t-butyl-lithium, copper iodide, and a trialkylphosphine, such as, tri-n-butyl-phosphine to giYe a methoxy substituted interphenylene-cyclopentanone of Formula IV. The cyclopentanone of Formula IV is reduced to the corresponding cyclopentanol by generally known-procedures, e.g., using a hydride reducing agent, such as, sodium borohydride in methanol or ethanol, after which the interphenylene methyl ether is hydrolyzed to the corresponding phenol by generally known means, e.g., by using a lithium dlkylsulfide, e.g., butyl mercaptide in hexamethylphosphoram-ide by the general procedures described by S. C. Welch and A.S.C.P.
Rao, Tetrahedron Lett. 505 (1977) to give the compounds of Formula V.
The me~hyl ether may also be hydrolyzed using lithium diphenylphos-phide in, e.g.~ tetrahydrofuran according to the procedure of R. E.
Ireland, et al., J. Am. Chem. Soc. 95, 7829 (1973). Intramolecular cyclization of the phenol of Formula V to the benzopyran derivative of Formula VI is achieYed using a trisubstituted phosphine, e.g., tri-phenyl phosphine and diethyl azodicarboxylate which is an adaptationof the procedure of Bittner, Chem. Ind. (London), 281 ~1975) and Manhas, J. Chem. Soc. Perkin Trans. 1, 461 (1975). The primary alco-hol Rl~ protecting group and any protecting group which may be present at positions C-ll, C-15 or C-19 are removed by hydrolysis as generally described hereinbefore to give compounds of Formula VII. The alcoh~ls of Formula VII are useful to derive the corresponding compounds wherein the C~1 position substituent is other than -CH20H. During such C-1 position conversions it is generally desirable to have any -26- ~ 2 ~ 3993 hydroxy groups at C-11, C-15 or C-19 protected with Rl~ groups by pro-cedures described hereinabove.
Oxidation of the primary alcohol of Formula VII to the C-1 carb-oxylic acid of Formula VIII may be achieved by using platinum and ox~-gen by generally known procedures. Alternatively the primary alcoholof Formula VII may be selectively protected with a silyl protecting group, e.g., by treatment with one equivalen~ of t-butyldimethylsilyl chloride and any secondary alcohol which may be present at positions C-11, C-15 and C-19 is then protected with an R1~ group other than a silyl protecting group, e.g., acetyl after which the silyl ether is hydrolyzed with fluoride ion and the resulting primary alcohol oxi-dized to the C-1 carboxy using Jones reasent by known procedures.
Following the oxidation step any secondary alcohol protecting groups are removed by hydrolysis. The thus obtained C-1 carboxylic acids of Formula ~III can ~e converted to the various esters and amides as d2fined in Formula I, and the amides carl be reduced to the correspond-ing amines, i.e., compounds wherein Q' is -CHzNL3L4, by using lithium aluminum hydride as generally described in U.S. 4,073,808.
Also, the alcohols of Formula VII can be oxidized to the corre-sponding carboxaldehyde which upon treatment with a salt of hydroxyl-amine gives the oxime which is dehydrated to give the nitrile, i.e., Formula YIII compounds wherein Q' is -CN, The C-1 nitril?s of Formula VIII may also be obtained by dehydration of the corresponding amide.
By treatment of the nitrile with methyl li~hium or a methyl Grignard the corresponding imine is obtained which is hydrolyzed with aqueous acid to the C-1 acetyl, i.e., Q' is O
Il CH3-C-.
Also the acetyl derivatives are obtained by treating the C-1 carbox-aldehyde with methyl lithium or methyl Grignard followed by oxidation using~ e.gO~ Jones or Collins reagents. The various conversions at-the C-1 position to obtain the compounds of Formula YIII are all known in ~he art. See, e.g~, G.B. 2,013,661.
The compounds of Formula VIII wherein Z' is -CH2- or -CH2CH2- and Q' is a carboxylic acid ester, e.g., a lower alkyl ester such as the methyl ester, are useful in the preparation of the compounds of For-mula I wherein -Z-R- taken together is trans-CH=CH- or trdns-CH=CHCH2-as depicted in Chart B wherein Ph is phenyl, s is zero or one and W' ~23L~ 9~
` -27- 3993 has the meaning defined in Chart B. The C-l acid ester of Formula IX
is treated with lithium amide base and phenylselenyl chloride to give the corresponding ~-phenylselenyl derivatives (Formula X) which are converted to the trans-vinyl derivatiYes (Formula XI) by, e.g., the general procedures described in G . B . 2, 017, 699 . The compounds of Formula XI can be converted to the C-1 free acids, i.e., Formula XII where Q is -COOH, from which other esters or amides and in turn amines and nitriles can be formed as generally described herein-above in connection with the preparation of the compounds of Formula 10 VIII in Chart A. The C-l carboxylic acids of Formula XII also can be reduced to the corresponding alcohol, i.e., Q is -CHzOH, by, for exam-ple, refluxing with lithium aluminum hydride in an ether solvent. The alcohol thus obtained can be utilized to prepare the corresponding nitrile via the oxime and the C-l acetyl derivatiYes as described hereinabove in reference to compounds o~ Formula VIII~
The preparation of the compounds of Formula I wherein R is -O- is depicted in Chart C hereof. In Chart C, the groups R~ Y, M, Ll, Rl7, Q-and Rl2 have the meanings defined in Formula I, Z' and alkyl are defined below and W2 is as defined in Chart C. The phenol of Formula 20 XIII is treated with one equivalent of base, e.g., sodium hydride and an appropriate alkyl halo alkanoate, e.g., alkyl bromo alkanoate of the formula BrZ'-COOalkyl wherein alkyl has, e.g., from 1 to 4 carbon atoms and is straight or branched and Z' is -CH2-, -C~2CH2-, -CF2-, or -CH2CF2- to give the ~-carboxyalkyl ether of Formula XIV which can be used to prepare the corresponding compounds depicted by Formula XV
wherein the C-l position group is other than a lower alkyl carboxyl-ate, i.e., Q is as defined in Formula I. These various conversions at the C-1 position are carried out in the same manner as described here inabove in relation to the compounds of Formula ~III in Chart A and as noted hereinbe~ore during such conversions it may ~e useful to have any hydroxyl groups at C-ll, C-15 or C-l9 protected by an Rl2 group which may ultimately be removed by means described hereinabove.
The C-l alcohol compounds of Formula YII wherein ~' is -CH2- may be used to prepare the C-l carboxylic acids of Formula VIII wherein Z' is -CH2CH2-. The Formu1a VII primary alcohol is selectively activated with a leaving group, i.e., is converted to the mesylate or tosylate by treatment with one equivalent of methanesulfonyl chloride or p-toluenesulfonyl chloride at lower tempera-tures by generally known proce~ures. Treatrnent with sodium cyanide or potassium cyanide ât elevated temperatures in a dipolar aprotic solvent results in dis-placernent of the tosylate or mesylate group to gi~e ~he corresponding C-1 nitrile derivative. Hydroxide hydrolysis of the nikrile b~ proce-dures known in the art gives the Formula VIII compounds wtlerein Q'is COOH and Z' is -CH2CH2-.
~ e compounds of Formula XIII in Chart C are prepared in a manner analogous to that described in Chart A for the preparation of the com-pounds of Formula 'II. By substituting a compound of Formula XVI (see Formula Chart) for compounds of Formula III in Chart A and following the procedure therein described for the preparation of Formula VI com-pounds one obtains compounds of Formula XVII (Chart C) which are hydrolyzed by ~luoride mediated or acid hydrolysis to the compounds of Formula XIII by generally known procedures. 3 In preparing the compounds of Formula III (see Chart A) wherein Z' is -CH2- or -CH2CH2-, 6-allyl-2-bromophenol 9 which is a known com-pound and is obtained according to the procedure of C. D. Hurd and C.
N. Webb, J. ~n. Chem. Soc. 941 (1936), is alkylated using methyl iodide by generally known procedures to give the corresponding methyl ether, i~e., the compound depicted as Formula D-1 in Chart D hereof.
By hydroboration-oxidation of the D-1 olefin by treatment with a hin-dered borane follo~ed by oxidation with hydrogen peroxide and hydrox-ide by generally known procedures ~he alcohol of D-2 is obtained which is converted to the protected alcohol, D-3, wherein Rl2 has the mean-ing~defined in Formula I by procedures described herein. The alcoholof D-2 can be used to obtain Formula III compounds wherein Z' is CH2CH2- by activation of the alcohol with a leaving groupS e.g., R13 is rnesyl or tosyl by treatment with methanesulfonyl chloride or p-toluenesulfonyl chloride followed by cyanide displacement by treat-ment with sodium cyanide or potassium cyanide in a dipolar aproticsolvent at elevated temperatures to give the compound of D-5. Hydrox-ide hydrolysis of the nitrile by generally known procedures gives the acid of D-6 which is reduced to the alcohol ~D-7) using, e.g., lithium aluminum hydride or diborane. The alcohol is then protected as described hereinbefore with an R12 protecting group.
The compounds of Formula III wherein Z' is -CF2- or -CF2CH2- are prepared as depicted in Chart E. By oxidizing l-allyl-3-brorno-2-meth-oxybenzene (E-1) using, e.g., ozone followed by dimethyl sulfide work-~23~

up or by using methyl periodate one obtains the aldehyde E-3 ~"herein u is the integer one. By hydroboration-oxidation of the olefin E-l by treatment with a hindered borane, such as 9-borobicyc10nonane7 followed by treatment with hydrogen peroxide and hydroxide one abtains 3-bromo-2-methoxyphenylpropanol of E-2. The E-2 alcohol is oxidized to the aldehyde of E-3 wherein u is the integer 2 by standard proce-dures, e~g., using Collins or Jones reagent. Dithiane addition to the aldehydes of E-4 is accomplished by treatment with lithium di-thiane according to the general procedure of D. Seebach and E. J. Corey, J.
Org. Chem. 40, 231 (1975) to give compounds of E-4 which are oxidized using Jones or Collins reagents by standard procedures to the ketone of E-5. Dithiane hydrolysis of the E-5 ketone gives the oxalyl deriv-ative E-6. Dithiane hydrolysis is achieved for example by treatment with silver nitrate in aqueous ethanol according to the procedure of C. A. Reece, et a1., Tetrahedron 24, 4249 (1968) or by treatment with N-chlorosuccinimide and silver nitra~e in acetonitrile and water according to the procedure of E. J~ Corey, et al., J. Org. Chem. 36, 3553 (1971). Mild oxidation using silver nitrate or air oxidation of the oxalyl derivative gives the 2-ketoalkanoic acid of E-7 which is esterified by well known procedures., e.g., treatment with an acidic lower alkanol, such as, methanol, or by treatment with diazomethane to give E-8 compounds. The ester of E-8 is fluorinated using diethyl-aminosulfurtrifluoride by the general procedure of W. J. Middleton, et al., J. Org. Chem., 45, 2883 (1980) to give the 2,2-difluoroalkanoic acid es~er of E-9. The difluoro E-9 compound is reduced to the alco-hol using, e.g., diisobutyl aluminum hydride by standard procedures after which the alcohol is protected with an R12 protecting group by means described hereinbefore.
The compounds of Formula XVI are prepared by treating the olefin of Formula D-l (See Chart D) with base, e.g., potassium t-butoxide in t-butanol to give acompound of Formula D-9. A compound of formula D-9 is then ozoni2ed for example with ozone followed by dimethyl sulfide work-up or by treatment with methyl periodate by well known procedures to give 3-bro~o-2-methoxybenzaldehyde which is treated with a peracid, such as peracetic acid or perbenzoic acid or is treated with hydrogen peroxide followed by treatment with hydroxide, such as sodium or potassium hydroxide or potassium carbonate in a lower alkanol under ~he conditions of a Baeyer-Villiger reaction to give 3-~romo-2-meth-~z~

oxyphenol which is converted to a suitable OR;2 protected derivative by means described hereinbe~ore, e.g., by treatment with dihydropyran in acid to give the compound of Formula XVI.
The 2-bromo-2-me~hoxyphenol obtained above also can be treated with a base, e.g., sodium hydride and a protect2d ~-halo, e.g,, bromo, alkanol of the formula BrCH2(CH~)s-CH20Rl2 wherein s is zero or one and R12 has the meaning defined hereinbefore to give a compound o~
Formula XVIII which when substi~uted for the compounds of Formula lII
in Chart A and the procedures defined therein ~or the preparatîon of compounds of Formulas VII and VIII are ~ollowed results in compounds of Formula I wherein R is oxa and Z is -CH2- or -CH2CH2-.
The compound of Formula XVIII wherein s is zero can also be pre-pared by treating 3-bromo-2-methoxyphenol with methyl bromoacetate to give 3-bromo-2-methoxyphenoxyacetic acid methyl ester which is reduced ~o the alcohol using, e.g., diisobutylaluminum hydride with subsequent ?rotection of ~he alcohol with an RIz protecting group as generally described hereinbefore.
The compounds of Formula XVI may additionally be prepared by pro-tecting 2-methoxyphenol with an R12 protecting group followed by treating with an alkyl lithium, e.g., n-butyllithium in hexane and tetramethylethylenediamine and quenching with bromine by the ~eneral procedures of G. Schill and E. Logeman, Chem. Ber. 106, 2910 (1973).
The compounds of Formula II are known in the art or are prepared by procedures generally known in the art. For example, the prepara-tion~ of many of the compounds of~Formula II is descrlbed in U.S.
4,181,798 and in particular in columns 7, 8 and 13-15. The stirring materials used in preparing the compounds of Formula II are prepared as depicted in Chart F~ Compounds of Formula F-1 wherein R1 has the meaning de~ined in Formula I, which compounds are known in the art, are treated with the anion of an alkyl phasphonate of Formula F-2 wherein alkyl is a lower alkyl group such as methyl, ethyl, or n-propyl, and L1 and Rl7 have the meanings defined in Formula I, under the conditions of a Wittig reaction tn give a ketone intermediate corresponding to Formula F-3 wherein l~5 ls the group trans-CH=CH-C-C-Rl7 li 11 O Ll which is then reduced by dissolving metal hydride reduction to the ~-.'' '. ' ~

-3l- 3993 or ~-alcohol as defined by M in Formula I to giYe compounds of Formula F-3 wherein ~5 is the group trans-CH=CH-C~C-Rl7 Il 11 Ml Ll wherein M1 is ~-OH,~-H or ~ -OH and wherein L1 and R17 have the meanings defined in Formula I. The thus obtained trans-vinyl com-pounds can be hydrogenated to give corresponding compounds o~ Formula F-3 wherein W5 is the group -CH2CH2C C-P~17

11 11 Ml Ll or can be halogenated followed by tetradehydrohalogenation to give the corresponding compounds of Formula F-3 wherein 1~5 is the group Il 11 Ml Ll Hydrogen2tion of the ~hus obtained ace~ylene containing compounds with a Lindlar catalyst give the corresponding cis-vinyl compounds, i.e., Formula F-3 wherein Ws is the group cis-CH=CHC - C-R17 Il 11 The compounds of Formula F-3 are also prepared by treating a com-pound of Formula F-l with a phosphine of the formula (alkyl)3-P=CHCHO
under the conditions of a Wittig reaction to give the corresponding compounds of Formula F-3 wherein W5 iS trans-vinyl aldehyde group of the formula trans-CH=CHCHO which is reduced to the corresponding trans-vinyl alcohol, i.e., Formula F-3 wherein W5 iS trans-CH=CHCH20H.
The trans-vinyl alcohol can be hydrogenated to give Formula F-3 compounds wherein W5 is the group -CHzCH2CH20H, or the trans-vinyl alcohol can be halogenated then tetradehydrohalogenated to give the correspnding acetylene alcohol, iOe., compounds of Formula F-3 wherein W5 is the group -C_CCH20H. Hydrogenation of the acetylene alcohol wi~h a Lindlar catalys~ gives the corresponding cis-vinyl alcohols, i.e~, Formula F-3 compounds wherein W5 is the group cis-CH=CHCH20HO
The thus obtained alcohols, i.e., compounds of Formula F-3 wherein W5 is trans-CH=CHCH20H, -CH2CH~CH20H, -C-CCH20H or cis-CH=CHCH20H are oxidized to the corresponding aldehydes then treated with a Grignard reagent of the formula halo MgCpH~pCH=CH2, wherein halo is a halogen or an alkyl lithium of the formula LiCpH~pCH-CH2, or -32 ~Z15~ 3993 an acetylide anion of the formula -C_CCpH~PCH;~ or an anion of the fcrmula LiCHCH2C-CCH3 to give compounds of Formula F-1 wherein Ws is -Y-C--C-Rl~
Il 11 M; L1 wherein Y, Ll and Rl7 have the meanings defined in Formula I and Ml is 10 s:~-OH ~-H or a-H ,~s-OH.
To prepare compounds of Formula F-3 wherein R14 oF the M substit-uent group is -CH3 the corresponding C-15 alcohol derivatives are oxi-dized to the corresponding C-15 ketone then ~reated with methyl lith-ium or a methyl Grignard by procedures known in the art.
The compounds of Formula F-2 are prepared by addition of the anion of a dialkyl methyl phosphonate of the formula O
(alkyl-0-)2-P-CH2 wherein alkyl is, e.g., methyl, ethyl, propyl or butyl with an ester of the formula i CH3Occ-Rl7 wherein Ll and R17 have the meanings defined in Formula--I by proce-dures well known in the art.
The compounds of Formula ~ wherein R is oxa can also be prepared utilizing a compound of Formula XIX as depicted in Chart G. Wherein R1 has the meaning defined in Formula I, R33 is -CH0 or -CH20R12, and R12 is a protecting group as defined hereinbefore. By substituting a compound of Formula XIX for compounds of Formula XIII in Chart C and following the procedure described for preparing compounds of Formula XIY from the compounds of Formula XIII one obtains the compounds of Formula XX wherein R1 and R33 are defined above and Z' is -CH~-, -CH2CH2-, -CF2-~ or -CF2CH~-. It may be useful to protect the phenol hydroxy and the primary alcohol selectively. For example, the phenol may be protected wi~h a silyl group or defined by R2l and the alcohol with ~HP or some other R;~ protecting group other than a silyl group.

The compounds of Formula XX are then converted to the compounds of Formula XXI which are ~hen converted to the compounds of XXII by the same general procedures described nereinabove for the preparation of compounds of Formula F-3 and X'~, respective1y~
The compounds of Formula XXII wherein R33 is CH0 are also useful in preparing the compounds oF Formula I. The compounds of Formula XXII are converted to the compounds of Formula I by the same general procedures described hereinabove for the preparation of the compounds o~ Formula F-3. The compounds of Formula XXII wherein R33 is ~CH20~l2 are useful in making conversions of the various XXII C-l groups repre-sented by Q.
The compounds of Formula XIX and Formula XX wherein R33 is -CH0 are prepared by ozonolysis, e.g.~ ozone treatment followed by dimethyl sulfide work-up, of compounds of Formula XVII and Formula I respect-ively wherein in each the group Y is -CH=CH-. Reduction of the com-pounds of Formula XIX and XX wherein R33 is -CHU by, e.g., use of sodium borohydride gives the corresponding primary alcohol which can be protected with an R12 group by procedures described hereinbefore.
When the alkyl ester has been obtained and an acid is desired, saponification procedures, as known in the art for P&F-type compounds are employed.
When an acid has been prepared and an alkyl 9 cycloalkyl, or aralkyl ester is desired, esterification is advantageously accom-plished 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 l-diazo-2-ethylhexane, and diazodecane, for example, gives the ethyl, buty1, and 2-ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexane and phenyldiazomethane yield cyclohexyl and benzyl esters, respectively.

\

-34~ 3993 Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a sui~able inert solvent, prefer-ably diethyl ether, with the acd reactant; adv~ntageously in the same or d different iner~ 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 diazohydro-carbon be no longer than necessary to effect the desired esterifica-tion, preferably about one toabout 10 minutes, toavoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reac-tions, ~ohn Wiley and Sons, Inc,, New York, N.Y., Vol. 8, pp. 389-394 11954) .
An alternative method for alkyl, cycloalkyl or aralkyl esterifi-cation of the carboxy moiety of the acid compounds comprises trans-formation 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, cyclo-pentyl iodide, benzyl iodide, phenethyl iodide, and the like.
Yarious methods are available for preparing phenyl or substituted phenyl esters within the scope of the invention from corresponding aromatic alcohols and the free acid, differiny as to yield and purity of product.
With regard to the preparation of the phenyl, particularly p-sub-stituted phenyl esters disclosed herein (i.e.~ Q is -COORs and Rs is p-substituted phenyl), such compounds are prepared by the method described in U.S. Patent No. 3,8gO,372. Accordingly, by the preferred method described therein, the p-substituted phenyl ester is prepared first by forming a mixed anhydride, particularly following the proce-dures 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 complete9 the p-substituted phenyl ester has been recovered by conventional techniques.
A preferred method for substituted phenyl esters is that dis-_35 3L2 ~ 3993 closed in U.S. Patent t~o. 3,~90,3~2 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed from the acid with isobutylchloroformate in the presence of a tertiary amine.
Phenacyl-type esters are prepared from the acid using a phenac~l bromide, for example p-phenylphenacyl bromide, in the presence of a tertiary amine. See, for exa~ple, U~S. Patent No. 3,984,454, German Offenlegungsschrift 2,535,693, and Derwent Farmdoc ~lo. 16828X.
The phthalidyl esters are obtained by treating the corresponding acid with a phthalidyl halide such as the bromide in, e.g., dimethyl-formamide in the presence of an amine base. The phosphoranyl esters are obtained by treating the corresponding acid with a l-halo deriva-tive, e.g., the l-chloro derivative of 3-(5,5-di(hydroxymethyl~-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide and 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide in, e.g., acetonitrile in thP presence of an organic amine.
Carboxyamides (Q is -COL~) are prepared by one of several amida-tion methods known in the prior art. See9 for example, U.S. Patent ~o. 3,981,868, issued September 21, 1976, for a description of the preparation of the present amido and cycloamido derivatives of prosta-glandin-type free acids and U.SO Patent No. 3,954,741 describiny the preparation of carbonylamido and sulfonylamido derivatives of prosta-glandin-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 pro-cedure, the carbacyclin-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 like-wise emp10yed~ Further, a convenient, readily available chloroformate for use ir. the mixed anhydride production is isobutyl chloroformate.
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 sui~able solvent (e.g., aqueous tetra-hydrofuran), dllowing the reaction to proceed at -10 C to 20 C.

2~L~
~36- 3993 Thereafter, the mixed anhydride is converted to the corresponding amido or cycloamido derivatives by reaction with the amine correspond-ing to the amide tobe 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 ammonia) 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 ~echniques.
The carbonylamido and sulfonylamido derivative of the presen~ly disclosed carbacyclin compounds are likewise prepared by known meth-ods~ 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 carbonylamido or sulfonylamido derivative to be prepared.
By another, more preferred method the sul~onylamido derivatives o~ the present compounds are prepared by first generating the PG-type mixed anhydride, employing the method described above for the prepara-tion of ~he amido and cycloamido derivatives. Thereafter, the sodium salt o~ the corresponding sulfonamide is reacted with the mixed anhydride and hexamethylphosphoramide. The pure carbacyclin sulfonyl-amido derivative is then obtained from the resulting reaction mixture by conventional techniques.
The sodium salt of the sulfonamide corresponding to the sulfonyl-amido derivative to be prepared is generated by reacting the sulfon-amide with alcoholic sodium methoxide. Thus, by a preferred method methanolic sodium methoxide is reacted with an equal molar amount of the sul~ona~ide. The sulfonamide salt is then reacted, as described above, with the mixed anhydride, using about four equivalents of the sodium salt per equivalent o~ anhydride. Reaction temperatures at or about 0 C are employed.
The compounds of this invention prepared by the processes o~ this invention, in ~ree acid form9 are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples o~ 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 2~L~ 3993 generally useful for the preparation if inorganic, i.e., me~al or ammonium saltsO The choice of procedure depends in part upon the solubility characteristics of the par~icular salt to be prepared. In the case of the inorganic sal~s, 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 inor-ganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt.
Evapora~ion 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 former are ethanol, acetone, and ethyl acetate. Examples of the lat-ter 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 pre ferred 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.
-.

-38- ~L~L~ 3993 Example 1 (a) 6-Allyl-2-bromo-phenol A deyassed solution of 0-bromophenol (404 g, 2.6 ml, 23.34 ~mol) in acetone-(30 ml) is treated at ambien~ temperature under an inert atmosphere with allyl bromide (3.39 g, 2.42 ml, 28.Q mmol) and anhydrous potassium carbonate (5.48 9, 39.68 mmol)~ The resultiny yellow suspension is stirred at reflux for 3 hours, cooled and fil-tered. The filtrate is concentrated in vacuo, then partitioned between diethyl ether and cold water. The layers are separated ~nd the aqueous layer extracted with diethyl ether. The ether extract is washed with saturated sodium bicarbonate, then twice with brine, dried over magnesium sulfate, filtered and concentrated to give 5.46 9 of yellow oil.
The crude product is distilled dt 0.82 mm and collected at 73-75 C to give l-allyloxy-2-bromobenzene as a colorless oil.
Degassed l-allyloxy-2-bromobenzene (3.34 9, 25.68 mmol) is stirred under nitrogen while being heated at 210-223 C for 2 hours.
The reaction is cooled to -5 C, diluted with ether and extracted with lN sodium hydroxide (2 x 20 ml). The alkaline (aqueous~ layer is acidified with cold, lN hydrochloric acid and extracted with ether (3 x 100 ml~. The acidic ether extract is washed with brine ~Z x 100 ml), dried over magnesium sulfate, filtered and concentrated to gi~e 2.16 g of brown oil.
The cru~e product is distilled at 0O78 mm at 74-90 C (oven tem-perature) to give 1.96 9 of the title product~
TLC (Silica Gel GF): -Rf = 0.20 in hexane; Rf = 0.43 in ethy1 acetate/hexane.

(b) 3-Allyl-2-methoxy-1-bromobenzene A solution of 6-allyl-2-bromophenol (4.84 9, 22072 mmol) in dry t-butyl alcohol (11.5 ml) and dry glyme (28 ml) is added to a suspen-sion of potassium t-butoxide (2~65 9, 23.63 mmol) in dry t-butyl a1cohol (24 ml) at ambient temperature under an inert atmosphere. The resulting greenish yellow suspension is treated with methyl iodide (5 ml) and stirred for 3.5 hours. The reaction gradually turns from yellow to light brown, and a precipitate forms within 30 minutes.
After 3.5 hours, the reaction is diluted with cold water (200 ml~ and extracted with diethyl ether (3 x 175 ml). The organic extract is washed wi~h brine (2 x 200 ml), dried over magnesium sulfate, filtered a~d concentrated to sive 4.16 9 of brown oil.
The crude product is chromatographed on basic alumin~ eluting with 2% ethyl acetate in hexane to give 3.72 g of brown oil.
Distillation of the product dt 80-90 C (oven ternperature) at 0.21 mm gives 3.58 g of 2-allyl-6-bromoanisole.
TLC (Silica Gel GF): Rf ~ 0.53 in 5% ethyl acetate/hexane.

~c) 2-Methoxy-3-C3'-(hydroxypropyl)~_1-bromobenzene A degassed solution of 2-allyl-6-bromoanisole (3.53 9, 15.5 mmol) in dry tetrahydro~uran (225 ml) is cooled to 0 C under an inert atmosphere and treated with 0.5M 9-borobicyclo[3.301]nonane in tetrahydrofuran (50 ml)0 ~e resulting colorless solution is stirred for 1 hour at 0 C and is permitted to warm to ambient temperature slowly overnight. After 18 hours the solution is cooled to 0 C, treated with 30% hydrogen peroxide (21 ml) fol lowed by 3N potassium hydroxide (aqueous, 21 ml). There is effervescence upon the addition of hydro~en peroxide9 and the colorless solution becomes turbid upon the addition of potassium hydroxide. The resulting suspension is stirred for 30 minutes at 0 C then for 2 hours while warming to ambient temperature. The suspension is poured into ice-cold brine (300 ml) and extracted with ethyl acetate (3 x 200 ml). The combined ethyl acetate extrac~s are washed with brine ~300 ml), dried over magnesium sulfate, filtered and concentrated to a brown oil (8.3 9).
The crude product is chromatographed on 610 9 of silica gel in 25 ethyl acetate in hexane. The column is elu~ed with 6 liters of 25%
ethyl acetate in hexane and 2 liters of 50% ethyl acetate in hexane to give 2~86 9 of the title product.
TLC (Silica Gel GF)- R~ = 0.08 in 20% ethyl acetatethexane; Rf =
0.11 in 25% ethyl acetate/hexane.

-(d) 2-Methoxy-3-~3'-(tètrahydropyranyloxypropyl~
bromobenzene A degassed solution of 2-methoxy-3-[3'-(hydroxypropyl~]-1-bromo-benzene (2.78 9, 11.67 mmol) in methylene chloride (30 ml) is treated at ambien~ temperature under an inert atmosphere with dihydropyran (10 ml, 110 mmoles) followed by saturated pyridinehydrochloride/methylene chloride (1.2 ml~. The resulting solution is permitted to stir for 18 hours, diluted with methylene chloride (150 ml) and washed with satu-

12~

rated sodium bicarbonate (aqueous, 150 ml). The aqueous wash is extracted with methylene chloride (150 ml), and the organics are washed wi~h brine (150 ml), dried over magnesium sulfate, filtered and concentrated to 6.42 of amber oil. The crude product is chromato~
graphed on 57D g of silica gel in 10% ethyl acetate in hexane. The column is eluted with 2 liters each of 10% and 15% ethyl acetate in hexane to give 3.66 9 of the title compound.
NMR (CDC13, ~S) ~: 1.33-2.10 (m, 8H), 2.75 (t, 2H), 3.25-4.03 (m, 4H), 3.80 (s, 3H), 4.53 (m, lH), 6.73-7.45 (m, 3H).
Infrared (filnl): 3354, 2998, 2940, 2870, 2826~ 1565, 1466, 1452, 1~21, 1292, 1254, 1227, 1170, 1125, 1083, 1059, 1039, 1004, 919, 798, 777, 753 cm~l.
TLC (Silica Gel GF): R~ = 0.20 in 10% ethyl acetate/hexane; R~ =
0.34 in 15% ethyl acetate/hexane. 5 Example 2 2-Decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-meth-oxy-1',3'-interphenylene~-PGEl, 2,11,15-tris(tetra-hydropyranyl ether) Solution II: A 100-ml, three-neck, round-bottomed flask, equipped with magnetic stirrer, serum stoppers and a nitrogen-vacuum connection, is charged with anhydrous diethyl ether (20 ml). The ether is alternately degassed and flushed with nitrogen (3 x), then cooled to _78D C under nitrogen and treated with 2.1M t-butyliithium in pentane (4.33 ml).
Solution III: A 50-ml, three-neck, round-bottomed flask, equipped with magnetic s~irrer, serum stoppers and a nitrogen-vacuum connection, is charged with anhydrous diethyl ether (23 ml) and 2-methoxy-3-[3'-(tetrahydropyranyloxy)propyl]-1-bromobenzene (1~50 9, 4.55 mmol), and the resulting solution is alternately degassed and flushed with nitrogen (3 x). The solution is cooled to -78 C and stirred under nitrogen at that temperature for 5 minutes then trans-ferred via double-tipped needle to a solution II at -78 C to give a white suspension which is stirred for 1.75 hours at -78 C.
Solution I: A 250-ml, three-neck, round-bottomed ~lask3 equipped with magnetic stirrer, serum stopper and nitrogen-vacuum connection, is charged with anhydrous diethyl ether (50 ml) and cuprous iodide (0~417 g, 2.18 mmol~. The resulting suspension is alternately degassed and flushed with nitrogen (3 x), then treated at ambient temperature under nitroger) with tri-n-butylphosphine (0.58 ml, 2.29 -41- 39'~
mmol). The re3ction is stirred for 1 hour dt ambient temperature, ~nd the cuprous iodide gradually goes into solution. The resulting grey-ish solution is cooled to -78 C and treated with solution 1ll (at -78 C) via double-tipped needle wi~h posi~ive argon pressure. rne addition requires about 15 minutes, and the resul-ting grey suspension is stirred vigorously for an addi~ion 45 rninutes at -78 C.
The 500-ml, one-neck, round-bottomed flas~ which is used to con-centrate the 2-methylene-4a-hydrox~-3~-[(3'S)-3'-hydroxy-trans-1'-octenyl cyclopentanone 4,3'-bis-tetrahydropyranyl ether is equipped with a magnetic stirring bar, serum stopper and a nitrogen-vacuum connection. The ~lask charged with 2-methylene-4-hydroxy-3~-[(3'5)-3'-hydroxy-trans-1'-octenyl cyclopentanone 493'-bis-tetrahydropyranyl ether (0.37 9~ 0.91 mmol) is charged with anhydrous diethyl ether (25 ml). ~e resulting solution is alternately degassed and flushed with nitrogen (3 x), cooled to -78 C and added to the above cuprate mix-ture (with vigorous stirring at -78 C~ via a double-tipped needle with positive nitrogen pressure. The addition requires Z0 minutes, and the reaction mixture is then stirred at 78 C for an additional 45 minutes. The resulting greyish-brown reaction mixture is transferred via a lJ8-inch O.D. Teflon*cannula into a rapidly stirred solution of 7.6~ acetic acid/diethyl ether (100 ml) which has been precooled to -60 C. After the transfer is completed, the organics are washed with brine ~2 x 150 ml), aqueous saturated sodium bicarbonate (3 x 150 ml), and brine (150 ml), dried over magnesium sulfate, filtered and concen-~5 trated to 3.82 9 o~ yellow oil. The crude product is chromatogrdphed on silica gel (220 9) in 15% ethyl acetate/Skellysolve B* The column is eluted with 1.6 liters of 15~9 1.2 liters o~ 25~, and 1.75 liters of 35% ethyl acetate/Skellysolve B to give 0.46 9 of the title com-pound.
NMR (CDCl3, TMS) ~: 0.88 (t, 3H), 1.02-3.12 ~m~, 3.22-4.12 ~m, 10~)t 3.67 (s, 3H), 4.38~4r73 (m, 3H), 5.17-5.60 (m, 2H), 6.80-7.23 (m, 3H).
Infrared (Film): 2941, 2870, 1745, 1467, 1455, 1440, 1365, 1323, lZ60, 1200, 1135, 1121, 1077, 971, 908, 869, 767 cm~l.
TLC (Si1ica Gel GF): Rf = 0.18 in 25% ethyl acetate/hexane.
2-Decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7 (2'-meth oxy-1',3'-interphenylene)-PGFl~, 2,11,15-tris(tetra hydropyranyl ether) and *trade mark ' -42~ 3993 2-Decarboxy-2-h~droxymethyl-4,5,6-trinor-3,7-(2'meth-oxy-1',3'-interphenylene)-PGF1~, 2,11,15-tris(tetra-hydropyranyl ether) Degassed absolute methanol (7 ml) is cooled to -40~ C and treated under an inert atmosphere with sodium borohydride (0.083 9, 2~18 mmol). To the resulting suspension, a solution of the cornpound from Example 2 (0.43 g, 0.66 mmol) in methylene chloride (5 ml) is added.
The reaction mixture is stirred for 75 minutes at -30 to -25 C, poured into ice-cold brine (60 ml) and extracted with ethyl acetate (3 x 60 ml~. rne organic extracts are washed with brine (2 x 60 ml), dried over magnesium sulfate, filtered and concentrated to a yellow oil (0.51 g). The crude product is chromatographed on si1ica gel (60 9~ in 30% ethyl acetate/Skellysolve B*to give 0.263 9 of the PGF
tit'le compound and 0.179 g of the PGF1~ title compound.
PGF1~ deriv.:
NMR (CDCl~, TMS) ~: 0.90 (t, 3H), 1.12-3.09 (m), 3.28-4.33 (m, 11H), 3.77 (s, 3H), 4.53-4O90 (m, 3H), 5.37-5.93 (m, 2H), 6.93-7.23 (m, 3H).
Infrared (film): 3455, 2930, 2865, 1465, 1455, 1440, 1350, 1320, 1255, 1200, 1180, 1135, 1116, 1075, 1035, 1015, 985, 970, 865 cm~
TLC ~Silica Gel GF): Rf = 0.10 in 35~ ethyl acetate/hexane.
PGFi deri1.:
NMR (CDCl~, TMS) ~: 0.90 (m, 3H~, 1.12-3.07 (m), 3.27-4.30 (m, 12H), 3.78 (s, 3H), 4,30-4.83 (m~ 3H), 5.40-5.80 (m, 2H), 6.87-7.20 (m, 3H).
Infrared (~ilm): 3475, 2930, 2860, 1465, 1450, 1435, 1350, 1320, 1255, 1200, 1180, 1135, 1070, 1030, 1015, 970, 905, 865, 810, 767 cm TLC (Silica Gel GF): Rf = 0.24 in 35% ethyl acetate/hexane.
~ 2-Decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-hydr-oxy-1',3'-interphenylene)-PGF1'~, 2,11,15-tris(tetra hydropyranyl ether) Degassed hexamethylphosphoric triamide (H~lPA) (8 ml) is treated at ambient temperature under an inert atmosphere with butyl mercaptan (0.33 ml). The resulting solution is cooled via ice-bath and treated dropwise with n butyllithium (1.75 ml of 1.6M solution). rne result-ing solution is stirred for a few minutes with cooling, is permitted to warm to room temperature and treated with a solution of the PGF

* T r a d e Mar k _43 ~ ~3L~ 3993 compound of Example 3 above (0.179 9, 0.17 mmol) in dry H~PA (4 ml).
The resulting yellow solution is heated at 100 ~ S C for 2.5 hours, cooled and poured into cold3 0.2M aqueous HCl (130 ml)~ The aqueous suspension is extracted with ethyl acetate (3 x 80 ml3, and the com-bined ethyl acetate extracts are washed with brine (3 x 130 ml), dried over magnesium sulfate, filtered and concentrated to a yello~ oil.
The crude product is chromatographed on silica gel in 30% ethyl ace-tate/hexane to give 0.144 9 o~ the title compound.
NMR (CDCl~, TMS) ~: 0.87 (t, 3H), 1.10-3.17 (m~, 3.20-4.27 (m, 11H), 4.43-4 88 (m, 3H), 5.30-5.87 (m, 2H), 6.60-7.00 (m, 3H), 7.17 (bs, lH).
Infrared (film): 3370, 2930, 2870, 1595, 1465, 1440, 13759 1355, 1325, 1265, 1240, 1200, 1140, 1118, 1075, 1035, 1025, 975, 910, 875, 815, 765 cm~l.
TLC (Silica Gel GF): Rf = 0.18 in 50% ethyl acetate/hexane; R~ =
0.08 in 35~ ethyl acetate/hexane.
Example 5 2-Decarboxy-9-deoxy-2'-9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl, 2,11,15-tris-(tetrahydropyranyl ether) A degassed solution o~ the compound of Example 4 above (0.082 9, 0.127 mmol) in dry dioxane (4 ml~ is treated at ambient temperature under an inert atmosphere with triphenylphosphine (0.10 9~ 0.381 mmol) and diethylazodicarboxylate (63.2 ~l, 0.381 mmol)~ The pale yellow solution is stirred for 2 hours at ambient temperature, diluted with anhydrous diethyl ether (10 ml) and stirred for 15 minutes and the reaction is concentrated in vacuo. The crude product is chromato-graphed on silica gel in 20% ethyl acetate/hexane to give 0.071 9 of the title compound.
NMR (CDCl3, TMS) ~: 0.90 (t, 3H), 1.07-3.07 (m, 36H), 3.23-4.22 (m, 10H), 4.38 (m, lH), 4.50-4.80 (m, 3H), 5.27-5.77 (m, 2H), 6.65-7.17 (m, 3H~.
Infrared (film): 3025, 2940, 2870, 1595, 1465, 1445, 1385, 1355, 1327, 1263, 1203, 1187, 1160, 1135, 1120, 1073, 1030~ 975s 910, 870, 818, 765, 748 cm~l.
TLC (Silica Gel Gf): R~ = 0.72 in 50~ ethyl acetate/hexane; ~f =
0.49 in 35% e~hyl acetate/hexane.
Example 6 2-Decarboxy-9-deoxy-2',9a-epoxy-2-hydroxymethyl-4,5,6 trinor-3,7-(1',3'-interphenylene)-PGFl -44- ~ 2 ~ 3993 A solution of the compound of Example 5 above (0.071 9, 0.113 mmolJ in acetic acid (1.8 ml), water (0.9 ml), and tetrahydro~uran (0.45 ml) is reacted at 45 C for 2~25 hours, cooled to ambient temperature, and diluted with ice-cold brine (90 ml). The aqueous suspension is extracted with ethyl acetate (3 x 65 ml), and the organics are washed with water (2 x 90 ml) and brine (2 x 90 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The residue is azeotroped with toluene to remove any acetic acid. The crude product is chromatographed on silica gel (~5 9) in 4% methanol/
ethyl acetate to give 0.034 of the title compound, m.p. 114-116 C.
NMR (CDCl~ 0.90 (t, 3H), 1.08-3.25 (m, 21H), 3.40-3.70 (m, 2H), 3.77-4.20 (m, 2H~, 4.37 (bs~ lH), 5.40~5.67 (m, 2H~, 6.77-7.13 (m, 3H)D
Mass Spec (tri-TMS derivative~: Calculated for C32H5~045i~:
590.3643. Found: 590.3662. M/e 575, 519, 500, 429, 410, 339, 314, 26i, 237, 221, 199, 173, 147, 129, 73.
TLC (Silica Gel GF): Rf = 0.14 in ethyl acetate.
Example 7 9-Deoxy-2'-9a,epoxy-4,536-trinor-3,7-(1',3'-inter phenylene)-PGr 1 To a three-neck, round-bottomed flask (50 ml), equipped with a magnetic stirring bar and serum stoppers, platinum oxide (0.065 9) and water (8 ml) are added. The resulting brown suspension is degassed and flushed with nitrogen (3 x) then evacuated and purged with hydro-gen. rhe suspension is reduced at atmospheric pressure for about 20 minutes un~il suspension turns blac~O The system is evacuated and flushed with nitrogen (3 x) then stirred under nitrogen atmosphere for 10 minutes. The suspension is evacuated and flushed with nitrogen and removed.
The flask is equipped with a reflux condenser, a gas inlet tube (adjusted so that the tip of the tube is be1Ow the surface of the sol-vent), and a nitrogen connection-. Oxygen gas is bubbled through the inlet tube and sodium bicarbonate (0.125 9, 1.49 mmol) is added. The suspension becomes grey, and the triol, i~e., the compound from Exam-ple 6 ~bove, (0.055 9, 0.15 mmol) in 50~ acetone/water (16 ml) is added. The suspension becomes an emulsion immediately upon the addi-tion of the triol and the mixture is stirred vigorously at 60 C (bath temperature) for 3.25 hours while the oxygen gas is bubbled throu~h.
The reaction is cooled to ambient temperature, ice is added, and the _ 45 _ ~2~
reaction is neutralized with 10% (aqueous) potassium bisulfate ~m til pE~ -5 to 6. The suspension is diluted with acetone (200 ml) and filtered through celite. The filter cake is washed with acetone and the combined filtrate is concentrated in vacuo. The concen-trate is acidified with 10% potassium bisulfate and ex-trac-ted with e-thyl ace-tate (3 x 100 ml). The organics are washed with brine ~2 x 100 ml), dried over magnesium sulfate, fil-tered and concentrated to an off-white solid. The crude product is recrystallized frorn ether-hexane to give 25 mg of off-white crystalline ti-tle product, m.p. 135-137 C.
NMR (CDC13~ TMS) ~: 0.90 (t, 3H), 1.08-3.50 (m), 3.55-4.70 (m), 5.30-5.60 (m, 2H), 6.55-7.15 (m, 3H).
Mass Spec (tris-TMS deriv.): Calculated for C32H56OsSi3:
604.3435. Found: 604.3444. M/e 589, 533, 514, 443, 424, 353, 275, 263, 217, 173, 161, 147, 129.
Example 8 (a) 2-Decarboxy-9-deoxy-2',9a-epoxy-2-tosyloxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl A solution of 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl (0.22 g, 0.59 mmol) in dry pyridine (9 ml) is cooled to 0 C under an inert atmosphere and treated with p-toluenesulfonyl chloride (0.126 g, 0.65 mmol). The resulting solution is stirred for 15 minutes at 0 and is allowed to react for three days at 4 C, di~uted with ice-cold brine (200 ml) and extracted with ethyl acetate (3 x 150 ml). me organics are washed with O.lM aqueous hydrochloric acid (3 x 200 ml), saturated aqueous sodium bicarbonate (2 x 200 ml), and brine (2 x 200 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel in 80~ ethyl acetate/hexane to give 0.056 g of the title product.
NMR (CDC13, TMS) ~: 0.90 (t, 3H), 1.07-3.37 (m, 24H), 2.43 (s, 3H), 3.70-4.23 (m, 4H), 4.37 (m, lH), 5.43-5.67 (m, 2H), 6.70-7.07 (m, 3H), 7.40 (D, 2H), 7.83 (D, 2H).
Infrared (film): 3360, 2930, 2855, 1647, 1598, 1495, 1457, 1355, 1245, 1213, 1173, 1100, 1070, 1020, 970, 937, 890, 837, 815, 670 cm~l.
TLC (silica gel GF): Rf = 0.58 in ethyl acetate.

(b) 2-Decarboxy-2-cyanomethyl-9-deoxy-2',9a-epoxy-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl A solution of the product of l(a) above (0.12 g,0.23 mmol) in ye/jb , -46- ~Z3L~ 4 3993 dry dimethylformamide (8m1) is treated at ambient temperature under an inert atmosphere with sodium cyanide (0.034 9, 0.7 mmol). The reaction is stirred at 60-65 C for 3.25 hours, cooled and diluted with ice-cold brine (100 ml). The resulting suspension is extracted with ethyl acetate (3 x 100 ml), and the organics are washed with brine (3 x 100 mlj, dried over magnesium sulfate, filtered and concentrated ~o a solid (0.088 9), m.p. 110-112 C.
NMR (CDC13, TMS) ~: (0.90, t, 3H), 1.08-3.13 (m), 4.03 (m), 4.41 (m, 1H), 5.20-5.60 (m, 2H), 6.60-7.06 (m, 3H).
Infrared (mull): 3449, 2870, 2855, 2246, 1673, 1595, 1463, 1438, 1425, 1377, 1354, 1333, 131g, 1245, 123~, 1210, 1204, 1114, 1091, 1077, 1065, 970, 963, 759, 740 cm~l.
TLC (silica gel GF): Rf = 0 53 in ethyl acetate.

(C~ 9-Deoxy-2',9~-epoxy-2a-homo-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl A solution of the product of l(b) above (0.088 9, 0.23 mmol-~heory) in methanol (4 ml) is treated at ambient temperature ~ith 25~
potassium hydroxide/water (2 ml). The resulting solution is stirred for 18 hours at 90-95 C, cooled to ambient temperature and diluted with 0.2M hydrochloric acid (100 ml). The resulting suspension is extracted with ethyl acetate (3 x 100 ml), and the organics are washed withbrine (3 x lOOml), dried over magnesium sulfate, filtered and con-centrated to give a yellow semi solid.
The crude product is chromatographed on silica gel in ethyl ace-tate to give a white solid which is recrystallized from ether-hexane to give 0.058 9 of the title co~pound, m.p. 150-152 C.
NMR (CDCl3, IMS) ~: 0.89 (t, 3), 1.06-3.13 (m, 20H), 3.53-4.18 (m, 2H), 4.33 (m~ lH), 4.80 (m, 3H), 5.35-5.63 (m, 2H~, 6.53-7.08 (m, 3~)-lnfrared (mull-): 3426, 3038, 3019, 29599 2870, 2856, 1716, 14b3, 1433, 1~21, 1409, 1377, 1356, 1350, 1340, 1335, 1317, 1257, 1243, 1208, 1187, 1121, 972, 918, 7639 737 cm~l.
TLC (silica gel GF): R~ = 0.00-0.20 in e~hyl acetate. Rf = 0.41 in the organic phase of 9:2:5:10 EtOAc-HOAc-water-cyclohexane~
Exampl e 9 When in the procedure of Example 2 one substitutes -47- gLZ ~ 3993 2-methylene-4~-hydroxy-3~-~(3'S)-3'-hydroxyoctanyl]c~clo-pentanone 4,3'-bis(tetrahydropyranyl ether~, 2-methylene 4~-hydroxy-3~-~(3'S)-3'-hydroxy-1-octynyl]
cyclopentanone 4,3' bis(tetrahydropyranyl ether), 2-methylene-4~-hydroxy-3~-C(3'5)-3'-hydroxy-1-methyl-oc~-6-yn-1-enyl~cyclopentanone 4,3'-bis(tetrahydropyranyl ether), 2-methylene-4-hydroxy-3~-[(3'S)-3'-hydroxy-4'-phenyl-1-butenylJcyclopentanone 4,3'-bis(tetrahydropyranyl ether), 2-methylene-4a-hydroxy-3~-[~3'S)-3'-hydroxy-3'-phenoxy-1-propenyl]cyclopentanone 4,3'-bis(tetrahydropyranyl ether), 2 methylene-4-hydroxy-3~-[(3'S)-3'-hydroxy-4'-(3-thienyl)-l-butenyl]cyclopentanone 4,3'-bis(tetrahydropyranyl ether), 2-methylene-4~-hydroxy-3~-~(3'S)-3'-hydroxy-3'-phenyl)-1-propenyl]cyclopentanone 4,3'-bis(tetrahydropyranyl ether), 2-methylene-4~-hydroxy-3~-C(3'S)-3'-hydroxy-3'-cyclohexyl-1-propenyl]cyc10pentanone 4,3'-bis(tetrahydropyranyl ether), 2-methylene-4~-hydroxy-3B-~(3'S)-3'-hydroxy-4'-(3-thienyl-oxy)-1-butenyl~cyclopentanone 4,3'-bis(tetrahydropyranyl ether), or 2-methylene-4~-hydroxy-3~-~(3'5)-3' hydroxy-3'-(2-ethyl-cyclobutyl~-l-propenyl]cyclopentanone 4,3'-bis(tetrahydro-pyranyl ether) which are prepared as generally described in Examples 1, 2, 3 and 4 of U.S. 4,181,798 for 2-methylene-4~-hydroxy-3~-C(3'S)-3'-hydroxy-trans-l'-octenyl]cyclopentanone 4,3'-bis(tetrahydropyranyl ether)in Solution 1 and follows the procedure of Example 2 the following compounds are ., .

-48~ L~ 3993 obtained:

2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-13,14-dihydro-PGE1, 2,11,15-tris(tetrahyclropyranyl ether), 2-decarboxy 2 hydroxymethyl-4,5,6 trinor-3~7-(2'-methoxy-1',3'-interphenylene)_l3,14-dehydro-PGEl, 2,11,15-- tris(tetrahydropyranyl ether), 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-t2'-methoxy-1',3'-interphenylenej-16-methyl-18,19-tetradehydro-PGEl, 2,11,15-tris(tetrahydropyranyl ether), 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-17,18,19,20-tetranor-16-phenyl-PGEl, 2,11jl5-tris(tetrahydropyranyl ether), 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-16,17,18,19,20-pentanor-15-phenoxy-PGEl, 2,11,15-tris(tetrahydropyranyl ether), 2-decarboxy-2~hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-17,18,19,20-tetranor-16-~3-thienyl)-?S PGE1, 2,11~15-tris(tetrahydropyranyl ether~, 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-337-(2'-methoxy-1',3'-interphenylene)-16,17,18,19,2Q-pentanor 15-phenyl-PGEl, 2,11,15-tris(tetrahydropyranyl ether), 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3~7-(2'-~ethoxy-1',3'-interphenylene)~16,17,1~3,19920-pentanor-15-cyclo-hexyl-PGEl, 2,11~15-tris~tetrahydropyranyl ether~, 2rdecarboxy-2-hydroxy~ethyl-4~5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-17,18,19,20-tetranor-16-~2-thienyl-oxy~-PGEl, 2311,15-tris(tetrahydropyranyl ether), and - 49 ~
2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-16,17,18,19,20-pentanor-15-(2-ethyl-cyclobutyl~-PGEl~ 2,11,15-tris(tetrahydropyranyl ether).

Example 10 When one substitutes appropria-te amounts of each o~ -the PGEl com-pounds of Example 9 for 2~decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-in-terphenylene)-PGEl, 2,11,15-tris(te-trahydrop~ranyl ether) in Example 3 one obtains the respective PGEl~ and PGF1~3 com-pounds wherein the lower side chain correspond to the PGEl compounds of Exampl.e 9, when the thus ob-tained PGFl~ compounds are substituted for 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3,7-(2'-methoxy-1',3'-interphenylene)-PGFl~ in the procedure of Exarnple 4 one obtains the corresponding 2-decarboxy-2-hydroxyrnethyl-4~5~6-trinor-3/7-(2l-hydroxy-1',3'-interphenylene)-PGFI3, 2,11,15-tris(tetrahydxopyranyl ether) derivatives wherein the lower side chain corresponds ~o that of the PGEl compounds of Example 9. When the thus obtained 2'-hydroxy-1',3'-interphenylene derivatives are substituted ~or the compound of Example 4 in the procedure of Example 5 one obtains the following com-pounds.

2-decarboxy-9-deoxy-2', 9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydro-PGFl, 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9-deoxy-2', 9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dehydro-PGFl, 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-16-methyl-18,19-tetrade-hydro-pGFl~ 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-17,18,19,20-tetranor-16-phenyl-PGFl, 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl--4,5,6-ye/jb 1 ~ ~

~ _50_ 3LZ~L5~ 3993 trinor-3,7-(1',3'-in~erphenylene)-16,17,1B,19,20-pentanor-15-phenoxy-PGFl, 2,11,15~tris-(te~rahydropyranyl ether~, 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene) 17,18,19,20-tetranor-16-(3-thienyl3-PGFl, 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9 deoxy-2',9a-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-16,17,18,19,20-pentanor-15-phenyl-PGFl, 2,11,15-tris-(tetrahydropyranyl ether), 2-decarboxy-9-deoxy-2',9-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-16,17,18,19,20-pentanor-15-cyclohexyl-PGFl, 2,11,15-tris-(tetrahydropyranyl ether~, 2-decarboxy-9-deoxy-2',9a-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylenc)-17,18,19,20-tetranor-16-(2-thienyloxy)-PGFl, 2,11,15-tris-(tetrahydropyranyl ether~, dnd 2-decarboxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6-trinor-3,7-(1',3'-interphenylene)-16,17,18,19,20-pentanor-15-(2-ethylcyclobutyl)-PGFl, 2,11,15-tris-(tetrahydropyranyl ether).

When the thus obtained above named PGFl compounds are substituted for the compound of Example 5 in the procedure of Example 6 the corre-sponding hydroxy deprotected products are obtained all of which are converted to the corresponding C-l carboxylic acid derivative when substituteJ for the compound of Example 6 in the procedure of Example 7.
Example 11 .

When 2-methoxy-3-[3'-(tetrahydropyrdnyloxypropoxy]-1-bromo-benzene, prepared from 3-bromo-2-methoxyphenoxyacetic acid methyl ester, is substituted for 2-methoxy-3-~3'-(tetrahydropyranyloxypro-pylJ-l-bromobenzene in the procedure o~ Example 2, one obtains. 2-decarboxy-2-hydroxymethyl-4,5,6-trinor-3-oxa-3,7-(2'~me~hoxy 1',3'-interphenylene)-PGE1, 2,11,15-tris~tetrahydropyranyl ether) which when substituted for the compound of Example 2 in the procedure of Example -51~ 3993 3 gives the corresponding PGFI~ and PGFl~ compounds~ When the thus obtained PGFl~ compound is substituted for the PGFl~ compound of Exam-ple 3 in the procedure of Example 4 one ob-tains 2 decarboxy-2-hydroxy-methyl-4,5,6-trinor-3-oxa-3,7- (2 '-hydroxy-1',3'-interphenylene~-PGFl~, 5 2, 11, 15-tris(tetrahydropyranyl ether) which ~Ihen substi~uted for the compound of Examp1e 4 in ~he procedure of Example 5 gives 2-decarb-oxy-9-deoxy-2',9~-epoxy-2-hydroxymethyl-4,5,6~trinor~3-oxa-3~7- (1 ',3 '-interphenylene)-PGFl, 2, 11, 15-tris(tetrahydropyranyl ether) which is deprotected by the procedure of Example 6 to give 2-decarboxy-9-10 deoxy-2',9a-epoxy-2-hydroxymethyl-4,5,6-trinor-3-oxa-3,7- (1 ' 93 '-inter-phenylene)-PGFl which can be oxidized to the corresponding C-1 carb-oxylic acid by the procedure of Example 7 to give 9-deoxy-2',9c--epoxy-4,5,6-trinor-3-oxa-3,7- (1',3 '-interphenylene)-PGFl-Example 12 When one substitutes 2-methoxy-3-~2 'j2 '-difluoro-3 '- (tetrahydro--pyranyloxypropyl ]-l-bromobenzene, prepared as depicted in Chart E, for 2-methoxy-3-[3'-tetrahydropyranyloxypropyl]-1-bromobenzene in the pro-cedure of Example 2 and substitutes the product thus obtained for Example 2 in the procedure of Example 3 and continues the sequence as described in Exampl e 11 through Exampl e 6 one obtains 2-decarboxy-2-deoxy-2 ',9~-epoxy-2-hydroxymethyl-2,2-difluoro-4,5,6-trinor-3,7-(1',3 '-interphenylene)-PGFl which can be oxidized to the corresponding C-l carboxylic acid derivative by the procedure of Example 7.
Example 13 When 2-methoxy-3-tetrahydropyranyloxy-1-bromoben~ene is substi-tuted for 2-methoxy-3-[3 '- (tetrahydropyranyloxypropyl)]-l bromobenzene in the procedure of Example 2, one obtains 1,2,4,5,6~pentanor-3-oxa-3,7- (2 '-methoxy-1',3 '-interphenylene)-PGEl, 3,11,15-tris (tetrahydro-pyranyl ether) which when substituted for the compound of Example 2 in 30 the procedure of Example 3 gives the corresponding PGFl and PGF
compounds. When the thus obtained PGFl~ compound is substituted for the PGFl~ compound of Example 3 in the procedure of Example 4 one obtains 1,2,4,5,6-pentanor-3-oxa-3,7- (2'-hydroxy-1',3 '-interphenyl-ene)-PGFl~, 3,11,15-tris (tetrahydropyranyl ether~ which when substi-35 tuted for the compound of Example 4 in the procedure of Example 5gives 9-deoxy-2',9-epoxy-1,2,4,5,6-pentanor-3-oxa-3,7- (1',3 '-inter-phenylene)-PGFl, 3,11,15-tris (tetrahydropyranyl ether) which is depro-tected by the procedure of Example 6 to give 9-deoxy-2',9-epoxy-- 52- ~Z~L~g~ 3993 1,2,~L,5,6-pentanor-3-oxa-3,7- (1',3 '-interphenylene)-PGFl. Treatment of 9-deoxy-2',9~-epoxy-1,2,4,5,6-pentanor-3-oxa-3,7- (1 '-,3 '-inter-phenylene)-PGrl with one equivalent of sodium hydride and one equiYa-lent of methylbromoacetate in glyme at 0 C for several hours ~ollowed 5 by partitioning between ethyl acetate and brine followed by remo~/al of solvents (i.e., ethyl acetate and glyme) affords 9-deo~-2 ',9~-epoxy-3-oxa-4,5,6-trinor-3,7- (1 ',3 '-interphenylene)-PGFl, methyl es~cer.
Hydrolysis of 9-deoxy-2 ',9~-epoxy-3-oxa-4,5,6-trinor-3,7- (1',3 '-inter-phenylene)-PGFl, meth~yl ester with 5% potassium hydroxide in 9:1 10 methanol/water at room temperature for several hours followed by acid-ification and extraction into ethyl acetate followed by removal of solvent affords 9 deoxy-2',9c~-epoxy-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenyl ene)-PGFl.
Example 14 A solution of 3.0 9 of 6-allyl-2-bromophenol (from Example 1 (a)) in 17 ml dry glyme is adde~ to 1.65 9 potassium t-butoxide in 22 ml t-butanol. The resulting suspension is treated with 3.2 ml methyl iodide and stirred overnight at room temperature~ diluted with water, and extracted into ether. The sol vents are removed in vacuo and ~he 20 residue chromatographed on basic alumina ~o give (after disti'lation at 0.45 mm at 113 C) 1.76 9 of 2-bromo-6-(1'-propenyl)-anisole (TLC
Rf 0.62 in 5% ethyl acetate in hexane).
A solution of 0.38 9 of the above 2-bromo-6-(1'-propenyl)-arisole in 55 ml of methanol at -78 C is treated with ozone for 8 minutes, 25 then treated with 24 ml dimethylsulfide and let stand at 0 C over-night, diluted with ethyl acetate, and washed with brine, saturated aqueous sodium bicarbonate, and brine. The solvents are removed in vacuo to give l-bromo-6-formyl-anisole (TLC Rf 0.39 in 10~ ethyl ace-tate in hexanol).
A solution of 0.037 9 1-bromo-6-formyl anisole in 1 ml methylene chloride is treated with 0.54 sodium dibasic phosphate and 1.3 m1 tri-fluoroperacetic acid, stirred overnight, treated with 10~ aqueous sodium carbonate (5 ml) and 5 ml diethyl ether, stirred for 1.5 hours, and partitioned between water and ether. The ether portion is 35 extracted with lN aqueous sodium hydroxide, the hydroxide extracts acidified and then extracted with ether. Concentration of the ether extracts affords 3-bromo-2-methoxyphenol.
Treatment of 3-bromo-2-methoxyphenol with dihydropyran and an -53- ~ 3~ 3~93 acid catalyst as described herein affords 2-me~hoxy-3-tetrahydropyran-yloxy-l-bromobenzene.
Example 15 A solution of 0.25 9 of 9-deoxy-2',9~-epoxy-~,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl, 0.45 m1 diisoprop~lethylamine, and 0~82 ml methyl iodide in 7.5 ml acetonitrile is stirred at room ternperature overnight, diluted with e~hyl acetate, washed with 5% aqueous s~dium sulfite and then with brine. Removal of solvents from the ethyl ace-tate extract affords 0.23 g of 9-deoxy-2',9~-epoxy-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFl, methyl ester which is disso1ved in 4 ml dimethylformamide and treated with 0.345 9 t-butyldimethylsilyl chloride and 0.31 9 of imidazole, then stirred at room temperature overnight, diluted with ice-cold brine and extracted with ethyl ace-tate. Concentration of the ethyl acetate extract ~ollowed by chroma-tography on silica gel affords 0.32 9 of 9-deoxy-2',9a-epoxy-4,5,6-trinor-3,7-(1',3' interphenylene)-PGFl, methyl ester, 11,15-bis(i-butyldimethyl silyl ether) (TLC Rf at 0.71 in 20~ ethyl acetate/hex-ane).
A solution of 0.23 9 of N-isopropylcyclohexylamine in 5 ml of dry tetrahydrofuran at -78 C under an inert atmosphere is treated with 1.18 ml of 1.3M n-butyllithium in hexane, stirred at -78 C for 15 minutes, treated with .32 9 of 9-deoxy-2',9~-epoxy-4t5,6-trinor-3,7-(1',3'-interphenylene)-PGFl, methyl ester, 11,15-bis(t-butyldimethyl silyl ether) in 4 ml of tetrahydrofuran, stirred for 45 minutes at -78 C, treated with 0.32 9 of dipheny1 diselenide in 4 ml of tetra-hydrofuran, stirred for one hour at -78 C, warmed to room tempera-ture, quenched with ammonium chloride solution, and extracted with diethyl ether. Chromatography on silica gel affords 0.17 9 o~ the corresponding 2-selenophenyl derivative~ which is dissolved in 5 ml of methylene chloride, treated with 0.17 ml of 3C% aqueous hydrogen - peroxide and 0.6 ml of water, stirred at room temperature for one hour, diluted with methylene chloride, and washed with saturated aqueous sodium bicarbonate and brine. Removal of solvents followed by chromatography affords 9-deoxy-2',9~-epoxy-2,3- dehydro-4, 5, 6-trinor-3,7-(1',3'-interphenylene)-PGFl, methyl ester, 11,15-bis(t-butyldi-methyl ether), which when treated with tetra-n-butylarnmonium fluoride in tetrahydrofuran (as described herein to remove silyl protecting groups at C-ll and C-15) followed by 5~O potassium hydroxide in 9:1 . .

1 2 1 5 9~4 5~ 3993 methanol-water hydrolysis of the methyl ester affords 9-deoxy-2',9-epoxy-2, ~ dehydro-4,5,6-trinor-3,7-(l',3'-interphe~ylene)-PGF~.

~Zl~

FûRMULA CHAR T

S ~,C;C-21~

Q-Z-R Formul a Br~ OR12 Formul a XVI

V OCH2( CH2) s-CH20Rl 2 Formula XVIII

~O~`cs~ Formula XXII
Q-Z-R

i ~ -56- :~2~ 4 3993 CHART A

~CH2 \ Y-C-C-R17 Formula II

~Br`~--CHa-Z'-CH20R12Formula III

\ /

CH2-Z ' -CH20R12 Y-C-C-R17 Formula IV
R,M L

\~ OH
~ CH2-Z ' -CH20R,2 Y-c-c-Rl7 Formula V
Il 11 11 R, M L

Y- C-C- R1 7 F~rmul a-CH20R1 2 l~ j~ O "~ VI I -CH20H

W-Z ' -CH2 - -57- ~Z~9~ 3993 CHART S

H3COCCHzCHz(CH2)s-W' Formula lX

0 ~SePh H3COCCHCH2(CH2)S-W' Formula X
,1 H3cûc~c=c(cH2)s-w Formula XI

H
Q-C=C-( CH2~ -W ' Formul a XI I

W' is Y- C-C-R.~7 ~ ~11 .Z~ 3993 CHAR T C

S ~ C~R, o~` Formul a XI I I
HO

\ / Y-C-C-R~7 ~/~//~< M L1 Formula W2 ~\ '"~Rl XxVv -Z'-COOalkyl r59-- 3993 CIIART D

W4-CH2CH=CH2 > W4-CH=CH-CH3 ~ Formula D-l Formula D-9 W4-CH2CH2CH20H > W4-CH2CH2CH20R12 ¦ Formula D-2 Formula D-3 ~
W4-CH~CH2CH20Rl 3 ¦ Formula D-4 ¦ Formula D-5 \1/ , Wl4-CH2CH2CH~COOH
Formula D-6 \ /

Formula D-7 Formula D-8 Br W4 iS ~

-60- :~23~ L 3g93 CHART E

W4-CH2CH2=CH2 -->W4-CH2CH2CH20H
Formula E-l / Forrnula E-2 \1/ ,o, ~
W4-(CH2)U-CH
Formul a E-3 \ / OH S F F
W4- CH2) u CH~ ~W4- ( CH2) u-C-CH20R1 2 S Formula E-ll lS Formul a E-4 / ~

\ / O S FF
W4- ( CH2) U~c < ~ W4- ( CH2) U-C-CH20H
S Formula E-10 Formul a E-5 25W4-(CH2)U-C-CH W4-(CHz)u-C-COOalkyl Formul a E-6 \ Formul a E-9 \ / O 00 W4-(CH2)U-CCOOH -_ W4-(CH2)u-C-COal kyl Forrrula E-7 Formula E-8 W4 i B r~
~ .

-61- ~23L5~ 39g3 ~ll I
~ i ~<~

~ Formula F-l R

(al kyl -0- )2-P-CH~--C-C-R17 Formul a F-2 J~, ' ~~- W5 Formula F-3 R

3~

s lZ~

CHART G

Formula XIX

.

1 5 ~ ~33 ~ ~R, al kyl OOC-~ ' -O
,.

\ /
Y-C-_-2,, ~ Ll l~ I~R, Formul a XXI

W -~ -O
Formula w6 XXI-COOal kyl XXIIQ

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing an intermediate compound, for preparing benzopyran prostaglandin derivatives, having a general formula selected from:

(XIII) and (XIX) wherein for the compound of general formula (XIII):
Y represents a group selected from -CH2CH2-, cis-CH=CH-, trans-CH=CH- and -C?C-;
R1 represents a group selected from =O, H:H, .alpha.-OR12: .beta.-H, .alpha.-H: .beta.-OR12, .alpha.-CH2OR12: .beta.-H and .alpha.-H: .beta.-CH2OR12,wherein R12 represents a group selected from H and an -OH-protecting group;
M represents a group selected from .alpha.-OR12: .beta.-R14 and .alpha.-R14: .beta.-OR12, wherein R12 is as defined above and R14 represents a group selected from H and -CH3;
L1 represents a group selected from .alpha.-R15: .beta.-R16, .alpha.-R16:

Claim 1 contd. 2 .alpha.-R15 and a mixture thereof, wherein R15 and R16, independently, represent a group selected from H, F and -CH3, with the proviso that one of R15 and R16 represents F only when the other does not represent -CH3; and R17 represents -CH2CH2CH2CH3; or , when taken together, represent a group selected from:
(i) , (ii) -C?CCqH2qCH3, wherein q is an integer of from 2 to 6, and (iii) -CpH2pCH=CH2, wherein p is an interger of from 3 to 7; and wherein for the compound of general formula (XIX):
R1 and R12 are as defined above for the compound of general formula (XIII); and R33 represents a group selected from -CHO and -CH2OR12, wherein R12 is as defined above;
said process comprising:
for the compound of general formula (XIII):
(a) a 2-methylenecyclopentanone of general formula:

(IIa) Claim 1 contd. 3 wherein L1, R17 and Y are as defined above, Mx represents a group selected frsm .alpha.-OR'12: .beta.-R14 and .beta.-OR'12: .alpha.-R14 and R'1 is as defined above for R1 with the exception that each R12 is R'12, wherein R14 is as defined above and R'12 is as defined above for R12 other than H, is added at low temperature to a cuprate reagent derived from the treatment of a compound of general formula:

( XVIa) wherein R"12 is an -OH-protecting group different from R'12, with t-butyl lithium, copper iodide and a trialkylphosphine to produce a compound of general formula:

wherein L1, Mx, R'1, R"12, R17 and Y are as defined above;
(b) reducing the product of step ta) to the corresponding cyclopentanol and selectively hydrolyzing the resultant compound to produce a compound of general formula:


1. Claim 1 cont. 4 wherein L1, Mx, R'1, R"12, R17 and Y are as defined above;
   and (c) intramolecularly cyclizing, with a trisubstituted phosphine and diethyl azodicarboxylate, the product of step (b) and removing the R"12 protecting group, by selective hydrolysis, to produce a compound of general formula:
   
   wherein L1, Mx, R'1, R17 and Y are as defined above; or (d) when needed, hydrolyzing the Mx and R'1 groups of the product of step (c) to produce the desired compound of general formula (XIII), wherein R12, for M and R1, are H;
   and for the compound of general formula (XIX):
   (e) effecting an ozonolysis reaction with a compound of general formula:
   
   wherein L1, M, R'1, R'12 and R17 are as defined above, to produce a compound of general formula:
   
   wherein R'1 and R'12 are as defined above; or (f) reducing the product of step (e) with sodium boro-hydride to produce a compound of general formula:
   
   wherein R'1 and R'12 are as defined above; or (g) when needed, hydrolizing the R'1 and/or R'12 groups of the product of step (f) to produce the desired compound of general formula (XIX), wherein R12, and/or R12 for R1, are H; or (h) when required, converting the -CH2OH group of the product of step (g) to a -CH2OR'12 group, wherein R'12 is as defined above;
   wherein said process is adapted to prepare all possible optical isomers of the compound of general formula (XIII) or (XIX) singly or in combination.
2. 2. An intermediate compound, for preparing benzopyran prostaglandin derivatives, having a general formula selected from (XIII) and (XIX) as defined in claim 1, when prepared by the process defined in claim 1 or an obvious chemical equivalent thereof.
3. 3. The process of claim 1, wherein steps (a) to (d) are effected.
4. 4. An intermediate compound, for preparing benzopyran prostaglandin derivatives, of general formula (XIII) as defined in claim 1, when prepared by the process defined in claim 3 or an obvious chemical equivalent thereof.
5. 5. The process of claim 1, wherein steps (e) to (h) are effected.
6. 6. An intermediate compound, for preparing benzopyran prostaglandin derivatives, of general formula (XIX) as defined in claim 1, when prepared by the process defined in claim 5 or an obvious chemical equivalent thereof.