Novel compounds of the following formula: ##STR1##

BACKGROUND OF THE INVENTION 
The present invention relates to novel compounds which are 9-substituted 
carbacyclin analogs, to processes for the preparation of said carbacyclin 
analogs and the use of said analogs as pharmacological agents or as 
intermediates for the preparation of compounds useful as pharmacological 
agents. This invention also relates to chemical intermediates for 
preparing the novel 9-substituted carbacyclin compounds described and 
claimed herein. 
Prostacyclin is an endogenously produced compound in mammalian species, 
being structurally and biosynthetically related to the prostaglandins 
(PG's). In particular, prostacyclin exhibits the structure and carbon atom 
numbering of formula I when the C-5,6 positions are unsaturated. For 
convenience, prostacyclin is often referred to simply as "PGI.sub.2 ". For 
description of prostacyclin and its structural identification, see 
Johnson, et al, Prostaglandins 12:915 (1976). Carbacyclin, 
6a-carba-PGI.sub.2, exhibits the structure and carbon atom numbering 
indicated in formula II when the C-5,6 positions are unsaturated. 
Likewise, for convenience, carbacyclin is referred to simply as "CBA.sub.2 
". 
A stable partially saturated derivative of PGI.sub.2 is PGI.sub.1 or 
5,6-dihydro-PGI.sub.2 when the C-5,6 positions are saturated, depicted 
with carbon atom numbering in formula I when the C-5,6 positions are 
saturated. The corresponding 5,6-dihydro-CBA.sub.2 is CBA.sub.1, depicted 
in formula II when the C-5,6 positions are saturated. 
A formula as drawn herein which depicts a prostacyclin-type product or an 
intermediate useful in the preparation thereof, represents that particular 
stereoisomer of the prostacyclin-type product which is of the same 
relative stereochemical configuration as prostacyclin obtained from 
mammalian tissues or the particular stereoisomer of the intermediate which 
is useful in preparing the above stereoisomer of the prostacyclin type 
product. As drawn, formula I corresponds to that of PGI.sub.2 endogenously 
produced in the mammalian species. In particular, refer to the 
stereochemical configuration at C-8 (.alpha.), C-9 (.alpha.), C-11 
(.alpha.) and C-12 (.beta.) of endogenously produced prostacyclin. The 
mirror image of the above formula for prostacyclin represents the other 
enantiomer. 
The term "prostacyclin analog" or "carbacyclin analog" represents that 
stereoisomer of a prostacyclin-type product which is of the same relative 
stereochemical configuration as prostacyclin obtained from mammalian 
tissues or a mixture comprising stereoisomer and the enantiomers thereof. 
In particular, where a formula is used to depict a prostacyclin type 
product herein, the term "prostacyclin analog" or "carbacyclin analog" 
refers to the compound of that formula or a mixture comprising that 
compound and the enantiomer thereof. 
PRIOR ART 
Carbacyclin and closely related compounds are known in the art. See 
Japanese Kokia Nos. 63,059 and 63,060, also abstracted respectively as 
Derwent Farmdoc CPI Numbers 48154B/26 and 48155B/26. See also British 
published specification No. 2,012,265 and German Offenlungsschrift No. 
2,900,352, abstracted as Derwent Farmdoc CPI Number 54825B/30. See also 
British published application Nos. 2,017,699 and 2,013,661 and U.S. Pat. 
No. 4,238,414. The synthesis of carbacyclin and related compounds is also 
reported in the chemical literature, as follows: Morton, D. R., et al, J. 
Org. Chem., 44:2880 (1979); Shibasaki, M., et al, Tetrahedron Lett., 
433-436 (1979); Kojima, K., et al, Tetrahedron Lett., 3743-3746 (1978); 
Nicolaou, K. C., et al, J. Chem. Soc., Chemical Communications, 1067-1068 
(1978); Sugie, A., et al, Tetrahedron Lett., 2607-2610 (1979); Shibasaki, 
M., Chem. Lett., 1299-1300 (1979), and Hayashi, M., Chem. Lett., 1437-40 
(1979); Aristoff, P. A., J. Org. Chem. 46, 1954-1957 (1981); Yamazaki, M., 
et al, Chem. Lett., 1245-1248 (1981); and Barco, A., et al, J. Org. Chem. 
45, 4776-4778 (1980); and Skuballa, W., et al, Angew, Chem., 93, 1080-1081 
(1981). 7-Oxo and 7-hydroxy-CBA.sub.2 compounds are apparently disclosed 
in U.S. Pat. No. 4,192,891. 19-Hydroxy-CBA.sub.2 compounds are disclosed 
in U.S. Ser. No. 054,811, filed July 5, 1979. CBA.sub.2 aromatic esters 
are disclosed in U.S. Pat. No. 4,180,657. 11-Deoxy-.DELTA..sup.10 - or 
.DELTA..sup.11 -CBA.sub.2 compounds are described in Japanese Kokai No. 
77/24,865, published Feb. 24, 1979. Related 9.beta.-substituted compounds 
are disclosed in U.S. Pat. Nos. 4,306,075 and 4,306,076. 
SUMMARY OF THE INVENTION 
The present invention consists of compounds of formula IV wherein D is 
##STR2## 
wherein R.sub.3 is hydrogen, methyl or acetyl; wherein Z is 
(1) --CH.sub.2 --(CH.sub.2).sub.f --C(R.sub.4).sub.2 -- wherein each 
R.sub.4 is the same and is hydrogen or fluoro, and f is zero, one, 2 or 3; 
(2) trans-CH.sub.2 --CH.dbd.CH--; or 
(3) --(Ph)--(CH.sub.2).sub.g -- wherein Ph is 1,2-, 1,3-, or 1,4-phenylene 
and g is zero, one, 2 or 3; 
wherein Q is 
(1) --COOR.sub.5, wherein R.sub.5 is 
(a) hydrogen, 
(b) (C.sub.1 -C.sub.12)alkyl, 
(c) (C.sub.3 -C.sub.10)cycloalkyl, 
(d) (C.sub.7 -C.sub.12)aralkyl, 
(e) phenyl optionally substituted with one, 2 or 3 chloro or (C.sub.1 
-C.sub.4)alkyl, 
(f) phenyl substituted in the para-position with --NHCOR.sub.6, 
--COR.sub.7, --OC(O)R.sub.8 or --CH.dbd.N--NHCONH.sub.2, wherein R.sub.6 
is methyl, phenyl, acetamidophenyl, benzamidophenyl or --NH.sub.2 ; 
R.sub.7 is methyl, phenyl, --NH.sub.2, or methoxy; and R.sub.8 is phenyl 
or acetamidophenyl; 
(g) phthalidyl, 
(h) 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-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.sub.2 OH; 
(3) --COL.sub.2, wherein L.sub.2 is 
(a) an amino group of the formula --NR.sub.9 R.sub.10 wherein R.sub.9 is 
hydrogen or (C.sub.1 -C.sub.12)alkyl and R.sub.10 is 
(i) hydrogen 
(ii) (C.sub.1 -C.sub.12)alkyl 
(iii) (C.sub.3 -C.sub.10)cycloalkyl, 
(iv) (C.sub.7 -C.sub.12)aralkyl 
(v) phenyl optionally substituted with one, 2 or 3 chloro, (C.sub.1 
-C.sub.3)alkyl, hydroxy, carboxy, (C.sub.2 -C.sub.5)alkoxycarbonyl, or 
nitro, 
(vi) (C.sub.2 -C.sub.5)carboxyalkyl, 
(vii) (C.sub.2 -C.sub.5)carbamoylalkyl, 
(viii) (C.sub.2 -C.sub.5)cyanoalkyl, 
(ix) (C.sub.3 -C.sub.6)acetylalkyl, 
(x) (C.sub.7 -C.sub.12)benzoylalkyl, optionally substituted by one, 2, or 3 
chloro, (C.sub.1 -C.sub.3)alkyl, hydroxy, (C.sub.1 -C.sub.3)alkoxy, 
carboxy, (C.sub.2 -C.sub.5)-alkoxycarbonyl, or nitro, 
(xi) pyridyl, optionally substituted by one, 2, or 3 chloro, (C.sub.1 
-C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, 
(xii) (C.sub.6 -C.sub.9)pyridylalkyl optionally substituted by one, 2, or 3 
chloro, (C.sub.1 -C.sub.3)alkyl, hydroxy, or (C.sub.1 -C.sub.3)alkyl, 
(xiii) (C.sub.1 -C.sub.4)hydroxyalkyl, 
(xiv) (C.sub.1 -C.sub.4)dihydroxyalkyl, 
(xv) (C.sub.1 -C.sub.4)trihydroxyalkyl; 
(b) cycloamine selected from the group consisting of pyrolidino, 
piperidino, morpholino, piperazino, hexamethyleneimino, pyrroline, or 
3,4-didehydropiperidinyl optionally substituted by one or 2 (C.sub.1 
-C.sub.12)alkyl; 
(c) carbonylamino of the formula --NR.sub.11 COR.sub.10, wherein R.sub.11 
is hydrogen or (C.sub.1 -C.sub.4)alkyl and R.sub.10 is other than 
hydrogen, but otherwise defined as above; 
(d) sulfonylamino of the formula --NR.sub.11 SO.sub.2 R.sub.10, wherein 
R.sub.11 and R.sub.10 are defined in (c); 
(4) --CH.sub.2 NL.sub.3 L.sub.4, wherein L.sub.3 and L.sub.4 are hydrogen 
or (C.sub.1 -C.sub.4)alkyl, being the same or different, or the 
pharmacologically acceptable acid addition salts thereof when Q is 
--CH.sub.2 NL.sub.3 L.sub.4 ; or 
(5) --CN; 
wherein s is the integer one or 2; 
wherein L is H,H; .alpha.-OR.sub.12,.beta.-H; .alpha.-H,.beta.-OR.sub.12 ; 
.alpha.-CH.sub.2 OR.sub.12,.beta.-H; .alpha.-H,.beta.-CH.sub.2 OR.sub.12 
wherein R.sub.12 is hydrogen or a hydroxyl protective group; 
wherein Y is trans --CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, 
or --C.tbd.C--; 
wherein M is .alpha.-OR.sub.12,.beta.-R.sub.14 ; 
.alpha.-R.sub.14,.beta.-OR.sub.12, wherein R.sub.12 is as defined above, 
and R.sub.14 is hydrogen or methyl; 
wherein L.sub.1 is .alpha.-R.sub.15,.beta.-R.sub.16 ; 
.alpha.-R.sub.16,.beta.-R.sub.15 ; or a mixture thereof wherein R.sub.15 
and R.sub.16 are hydrogen, methyl, or fluoro being the same or different 
with the proviso that one of R.sub.15 and R.sub.16 is fluoro only when the 
other of R.sub.15 and R.sub.16 is hydrogen or fluoro; 
wherein R.sub.17 is 
(1) --C.sub.m H.sub.2m CH.sub.3 wherein m is an integer of from one to 5, 
(2) phenoxy optionally substituted by one, 2, or 3 chloro, fluoro, 
trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, 
with the proviso that not more than two substituents are other than alkyl 
and with the proviso that R.sub.17 is phenoxy or substituted phenoxy, only 
when R.sub.15 and R.sub.16 are hydrogen or methyl, being the same or 
different; 
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on 
the aromatic ring by one, 2, or 3 chloro, fluoro, trifluoromethyl (C.sub.1 
-C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not 
more than two substituents are other than alkyl, 
(4) cis-CH.dbd.CH--CH.sub.2 CH.sub.3, 
(5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, 
(6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2, 
(7) 
##STR3## 
(8) 
##STR4## 
or (9) 
##STR5## 
or wherein 
##STR6## 
taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted 
by one to 3 (C.sub.1 -C.sub.5)alkyl, 
(2) 3-thienyloxymethyl, 
(3) 
##STR7## 
(4) --C.tbd.C--C.sub.q H.sub.2q CH.sub.3 wherein q is an integer of from 2 
to 6, or 
(5) --C.sub.p H.sub.2p CH.dbd.CH.sub.2 wherein p is an integer of from 3 to 
7; and individual optical isomers thereof. 
The compounds of Formulas A-2 and C-2 which are useful as intermediates in 
the preparation of the compounds of Formula IV, are also a part of the 
present invention. In the various formulas used herein the substituent 
groups L, Y, M, L.sub.1, R.sub.17, s D, Z, and Q have the same meanings as 
defined in Formula IV. The group L.sub.50 is H,H; .alpha.-OR,.beta.-H; 
.alpha.-H,.beta.-OR; .alpha.-CH.sub.2 OR.sub.1,.beta.-H; 
.alpha.-H,.beta.-CH.sub.2 OR wherein R has the same meaning as R.sub.12 
only R is not hydrogen. The group M.sub.x is .alpha.-OR,.beta.-R.sub.14 ', 
.alpha.-R.sub.14,.beta.-OR wherein R has the same meaning As R.sub.12 only 
R is not hydrogen; R.sub.14 is hydrogen or methyl. The group R.sub.13 is a 
hydroxyl protecting group as defined hereinafter. The group Q.sub.2 is the 
same as Q only Q.sub.2 is other than --CH.sub.2 OH. The group Z.sub.1 is 
the same as Z only Z.sub.1 is other than --(Ph)--(CH.sub.2).sub.g --. 
DETAILED DESCRIPTION OF INVENTION 
In naming the novel compounds of the present invention in general the 
art-recognized system of nomenclature described by N. A. Nelson, J. Med. 
Chem. 17:911 (1974) for prostaglandins is followed. As a matter of 
convenience, however, the novel carbacyclin derivatives herein are named 
as 6a-carba-prostaglandin I.sub.2 compounds. 
In the formulas herein, broken line attachments to a ring, i.e., ( ) 
indicate substituents in the "alpha" (.alpha.) configuration, i.e., below 
the plane of said ring. Heavy solid line attachments to a ring, i.e., ( ) 
indicate substituents in the "beta" (.beta.) configuration, i.e., above 
the plane of said ring. The use of wavy lines (.about.) herein will 
represent attachment of substituents in the alpha or beta configuration or 
attached in a mixture of alpha and beta configurations. Alternatively wavy 
lines will represent either an E or Z geometric isomeric configuration or 
the mixture thereof. Also, solid and dotted lines used together, as for 
example, in formulas I and II at C-5,6 positions indicates the presence of 
either a double bond or alternatively a single bond. 
A side chain hydroxy at C-15 in the formulas herein is in the S or R 
configuration as determined by the Cahn-Ingold-Prelog sequence rules, J. 
Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) for discussion of 
the stereochemistry of the prostaglandins which discussion applies to the 
novel carbacyclin analogs herein. 
With regard to the divalent groups described above, i.e., M, L and L.sub.1 
said divalent groups are defined in terms of an .alpha.-substituent and a 
.beta.-substituent which means that the .alpha.-substituent 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 .beta.-substituent is in the 
beta 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 L.sub.2 in the 
--COL.sub.2 substituent group the definition (C.sub.1 -C.sub.12)alkyl 
means that L.sub.2 can be an alkyl group having from one to 12 carbon 
atoms. Additionally, any moiety so defined includes straight chain or 
branched chain groups. Thus (C.sub.1 -C.sub.12)alkyl as set forth above 
includes straight or branched chain alkyl groups having from 1 to 12 
carbon atoms and as additional illustration, when L.sub.2 represents, for 
example, (C.sub.2 -C.sub.5)carboxyalkyl, the alkyl moiety thereof contains 
from 1 to 4 carbon atoms and is a straight chain or a branched chain alkyl 
group. 
Novel compounds wherein Z is --(Ph)--(CH.sub.2).sub.g -- are designated 
inter-o-, inter-m-, or inter-p-phenylene depending on whether the 
attachment between C-5 and the --(CH.sub.2).sub.g -- moiety is ortho, 
meta, or para, respectively. For those compounds wherein g is zero, one or 
2, the carbacyclin analogs so described are further characterized as 
2,3,4-trinor-, 3,4-dinor-, or 4-nor, since in this event the Q-terminated 
side chain contains (not including the phenylene) 2, 3, or 4 carbon atoms, 
respectively, in place of the five carbon atoms contained in PGI.sub.2. 
The missing carbon atom or atoms are considered to be at the C-4 to C-2 
positions such that the phenylene is connected to the C-5 and C-1 to C-3 
positions. Accordingly these compounds are named as 1,5-, 2,5-, and 
3,5-inter-phenylene compounds when g is zero, one, or 2, respectively and 
when g is 3 the compounds are named as 4,5-inter-phenylene compounds. 
The compounds of Formula IV wherein Z is --CH.sub.2 --(CH.sub.2).sub.f 
--C(R.sub.4).sub.2 -- wherein R.sub.4 is fluoro are characterized as 
"2,2-difluoro-" compounds. For those compounds wherein f is zero, 2, or 3, 
the compounds so described are further characterized as 2-nor, 2a-homo, or 
2a,2b-dihomo, since in this event the Q-terminated side chain contains 4, 
6, or 7 carbon atoms, respectively, in place of the five carbon atoms 
contained in PGI.sub.2. The missing carbon atom is considered to be at the 
C-2 position such that the C-1 carbon atom is connected to the C-3 
position. The additional carbon atom or atoms are considered as though 
they were inserted between the C-2 and C-3 positions. Accordingly these 
additional carbon atoms are referred to as C-2a and C-2b, counting from 
the C-2 to the C-3 position. 
The compounds of Formula IV wherein Z is trans-CH.sub.2 --CH.dbd.CH-- are 
described as "trans-2,3-didehydro-CBA" compounds. 
Those novel compounds where s is 2 are further characterized as 7a-homo-CBA 
compounds by virtue of the cyclohexyl ring replacing the heterocyclic ring 
of prostacyclin. 
Further, all of the novel compounds of the present invention are 
substituted at the 9.beta.-position with a hydroxy group and are named as 
9.beta.-hydroxy compounds, or with a methoxy group and are named 
9.beta.-methoxy compounds, or with an acetoxy group and are named 
9.beta.-acetoxy compounds. 
When R.sub.14 is methyl, the carbacyclin analogs are all named as 
"15-methyl-" compounds. Further, except for compounds wherein Y is 
cis-CH.dbd.CH--, compounds wherein the M moiety contains an hydroxyl in 
the beta configuration are additionally named as "15-epi-" compounds. 
For the compounds wherein Y is cis-CH.dbd.CH--, then compounds wherein the 
M moiety contains an hydroxyl in the alpha configuration are named as 
"15-epi-" compounds. For a description of this convention of nomenclature 
for identifying C-15 epimers, see U.S. Pat. No. 4,016,184, issued Apr. 5, 
1977, particularly columns 24-27 thereof. 
The novel carbacyclin analogs herein which contain --(CH.sub.2).sub.2 --, 
cis-CH.dbd.CH--, or --C.tbd.C-- as the Y moiety, are accordingly referred 
to as "13,14-dihydro", "cis-13", or "13,14-didehydro" compounds, 
respectively. 
When R.sub.17 is straight chained --C.sub.m H.sub.2m --CH.sub.3, 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 R.sub.17 is branched chain --CH.sub.m 
H.sub.2m --CH.sub.3, then the compounds so described are "17-, 18-, 19-, 
or 20-alkyl" or "17,17-, 17,18-, -17,19-, 17,20-, 18,18-, 18,19-, 18,20-, 
19,19-, or 19,20-dialkyl" compounds when m is 4 or 5 and the unbranched 
portion of the chain is at least n-butyl, e.g., 17,20-dimethyl" compounds 
are described when m is 5 (1-methylpentyl). 
When R.sub.17 is phenyl and neither R.sub.15 nor R.sub.16 is methyl, the 
compounds so described are named as "16-phenyl-17,18,19,20-tetranor" 
compounds. When R.sub.17 is substituted phenyl, the corresponding 
compounds are named as "16-(substituted phenyl)-17,18,19,20-tetranor" 
compounds. When one and only one of R.sub.15 and R.sub.16 is methyl or 
both R.sub.15 and R.sub.16 are methyl, then the corresponding compounds 
wherein R.sub.17 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 R.sub.17 is benzyl, the compounds so described are named as 
"17-phenyl-18,19,20-trinor" compounds. When R.sub.17 is substituted 
benzyl, the corresponding compounds are named as "17-(substituted 
phenyl)-18,19,20-trinor" compounds. 
When R.sub.17 is phenylethyl, the compounds so described are named as 
"18-phenyl-19,20-dinor" compounds. When R.sub.17 is substituted 
phenylethyl, the corresponding compounds are named as "18-(substituted 
phenyl)-19,20-dinor" compounds. 
When R.sub.17 is phenylpropyl, the compounds so described are named as 
"19-phenyl-20-nor" compounds. When R.sub.17 is substituted phenylpropyl 
the corresponding compounds are named as "19-(substituted phenyl)-20-nor" 
compounds. 
When R.sub.17 is phenoxy and neither R.sub.15 nor R.sub.16 is methyl, the 
compounds so described are named as "16-phenoxy-17,18,19,20-tetranor" 
compounds. When R.sub.17 is substituted phenoxy, the corresponding 
compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" 
compounds. When one and only one of R.sub.15 and R.sub.16 is methyl or 
both R.sub.15 and R.sub.16 are methyl, then the corresponding compounds 
wherein R.sub.17 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)18,19,20-trinor" 
compounds, respectively. 
When R.sub.17 is cis-CH.dbd.CH--CH.sub.2 CH.sub.3, the compounds so 
described are named as "cis-17,18-didehydro" compounds. 
When R.sub.17 is --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, the compounds so 
described are named as "19-hydroxy" compounds. 
When R.sub.17 is --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2, the 
compounds so described are named as "20-isopropylidene" compounds. 
When R.sub.17 is 
##STR8## 
the compounds so described are named as 17(S),20-dimethyl compounds. 
When R.sub.17 is 2-furylmethyl or 3-thienylmethyl, i.e., 
##STR9## 
respectively the compounds so described are named as 
"17-(2-furyl)-18,19,20-trinor" compounds and 
"17-(3-thienyl)-18,19,20-trinor" compounds respectively. 
When 
##STR10## 
the compounds are named as "16-(R,S)methyl-18,19-tetradehydro" compounds. 
When --C(L.sub.1)--R.sub.17 is optionally substituted cycloalkyl or 
3-thienyloxymethyl, the compounds so described are named respectively 
15-cycloalkyl-16,17,18,19,20-pentanor compounds and 
16-(3-thienyl)oxy-17,18,19,20-tetranor compounds. The term 
3-thienyloxymethyl means the moiety having the structure: 
##STR11## 
When --C(L.sub.1)R.sub.17 is --C.tbd.C--C.sub.q H.sub.2q CH.sub.3 wherein q 
is an integer of from 2 to 6 the compounds so described are named as 
"16,17-tetradehydro", "16,17-tetradehydro-20-methyl", 
"16,17-tetradehydro-20-ethyl", "16,17-tetrahydro-20-n-propyl" and 
"16,17-tetrahydro-20-n-butyl" compounds as the integer as represented by q 
varies from 2 to 6 respectively. 
When --C(L.sub.1)R.sub.17 is --C.sub.p H.sub.2p CH.dbd.CH.sub.2 wherein p 
is an integer of from 3 to 7 the compounds so described are named as 
"19,20-didehydro", "19,20-didehydro-18a,18b-dihomo", 
"19,20-didehydro-18a,18b,18c-trihomo", 
"19,20-didehydro-18a,18b,18c,18d-tetrahomo" compounds as the integer 
represented by p varies from 3 to 7 respectively. 
When 
##STR12## 
the compounds so described are named as "16(R,S),20-dimethyl" compounds. 
When at least one of R.sub.15 and R.sub.16 is not hydrogen then (except for 
the 16-phenoxy or 16-phenyl compounds discussed above) there are described 
the "16-methyl" (one and only one of R.sub.15 and R.sub.16 is methyl), 
"16,16-dimethyl" (R.sub.15 and R.sub.16 are both methyl), "16-fluoro" (one 
and only one of R.sub.15 and R.sub.16 is fluoro), "16,16-difluoro" 
(R.sub.15 and R.sub.16 are both fluoro) compounds. For those compounds 
wherein R.sub.15 and R.sub.16 are different, the carbacyclin analogs so 
represented contain an asymmetric carbon atom at C-16. Accordingly, two 
epimeric configurations are possible: "(16S)" and "(16R)". Further, there 
is described by this invention the C-16 epimeric mixture: "(16RS)". 
When Q is --CH.sub.2 OH, the compounds so described are named as 
"2-decarboxy-2-hydroxymethyl" compounds. 
When Q is --CH.sub.2 NL.sub.3 L.sub.4, the compounds so described are named 
as "2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl" compounds. 
When Q is --COL.sub.2, the novel compounds herein are named as amides. 
Further, when Q is --COOR.sub.5 and R.sub.5 is other than hydrogen the 
novel compounds herein are named as esters and salts. 
When Q is CN the novel compounds herein are named as 2-decarboxy-2-cyano 
compounds. 
Examples of phenyl esters substituted in the para position (i.e., Q is 
--COOR.sub.5, R.sub.5 is p-substituted phenyl) include p-acetamidophenyl 
ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester, 
p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester, 
p-acetylphenyl ester, p-benzoylphenyl ester, p-aminocarbonylphenyl ester, 
p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, 
p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde 
semicarbazone ester. 
Examples of novel amides herein (i.e., Q is --COL.sub.2) include the 
following: 
(1) Amides within the scope of alkylamino groups of the formula --NR.sub.9 
R.sub.10 are methylamide, ethylamide, n-propylamide, isopropylamide, 
n-butylamide, n-pentylamide, tert-butylamide, neopentylamide, 
n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, 
n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Further 
examples are dimethylamide, diethylamide, di-n-propylamide, 
diisopropylamide, di-n-butylamide, methylethylamide, di-tert-butylamide, 
methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutylamide, 
and propylbutylamide. Amides within the scope of cycloalkylamino are 
cyclopropylamide, cyclobutylamide, cyclopentylamide, 
2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide, 
2-methylcyclopentylamide, 3-tertbutylcyclopentylamide, cyclohexylamide, 
4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, 
2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide, 
cyclononylamide, cyclodecylamide, 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 benzylamide, 2-phenylethylamide, and 
N-methyl-Nbenzyl-amide. Amides within the scope of substituted phenylamide 
are p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide, 
2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 
3,4-dimethoxyanilide, 3,4,5-trimethoxyanilide, p-hydroxymethylanilide, 
p-methylanilide, m-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, cyanopropylamide, and cyanobutylamide. 
Amides within the scope of acetylalkylamino are acetylmethylamide, 
acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within 
the scope of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, 
benzoylpropylamide, and benzoylbutylamide. Amides within the scope of 
substituted benzoylalkylamino are p-chlorobenzoylmethylamide, 
m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethylamide, 
2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, 
p-nitrobenzoylmethylamide, p-methoxybenzoylmethylamide, 2,4-dimethoxy 
benzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide, 
p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethylamide, 
m-methylbenzoylmethylamide, p-ethylbenzoylmethylamide, 
t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide, 
m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide, 
o-hydroxybenzoylmethylamide, p-chlorobenzoylethylamide, 
m-chlorobenzoylethylamide, 2,4-dichlorobenzoylethylamide, 
2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide, 
p-nitrobenzoylethylamide, p-methoxybenzoylethylamide, 
p-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide, 
3,4,5trimethoxybenzoylethylamide, p-hydroxymethylbenzoylethylamide, 
p-methylbenzoylethylamide, m-methylbenzoylethylamide, 
p-ethylbenzoylethylamide, t-butylbenzoylethylamide, 
p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide, 
o-carboxybenzoylethylamide, o-hydroxybenzoylethylamide, 
p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide, 
2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide, 
m-nitrobenzoylpropylamide, p-nitrobenzoylpropylamide, 
p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpropylamide, 
3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, 
p-methylbenzoylpropylamide, m-methylbenzoylpropylamide, 
p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide, 
p-carboxybenzoylpropylamide, m-methoxycarbonylbenzoylpropylamide, 
o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide, 
p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide, 
2,4-chlorobenzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide, 
m-nitrobenzoylmethylamide, p-nitrobenzoylbutylamide, 
p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutylamide, 
3,4,5-trimethoxybenzoylbutylamide, p-hydroxymethylbenzoylbutylamide, 
p-methylbenzoylbutyamide, m-methylbenzoylbutylamide, 
p-ethylbenzoylbutyalmide, m-methylbenzoylbutylamide, 
p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide, 
p-carboxybenzoylbutylamide, m-methoxycarbonylbenzoylbutylamide, 
o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide. Amides within the 
scope of pyridylamino are .alpha.-pyridylamide, .beta.-pyridylamide, and 
.gamma.-pyridylamide. Amides within the scope of substituted pyridylamino 
are 4-methyl-.alpha.-pyridylamide, 4-methyl-.beta.-pyridylamide, 
4-chloro-.alpha.-pyridylamide, and 4-chloro-.beta.-pyridylamide. Amides 
within the scope of pyridylalkylamino are .alpha.-pyridylmethylamide, 
.beta.-pyridylmethylamide, .gamma.-pyridylmethylamide, 
.alpha.-pyridylethylamide, .beta.-pyridylethylamide, 
.gamma.-pyridylethylamide, .alpha.-pyridylpropylamide, 
.beta.-pyridylpropylamide, .gamma.-pyridylpropylamide, 
.alpha.-pyridylbutylamide, .beta.-pyridylbutylamide, and 
.gamma.-pyridylbutylamide. Amides within the scope of substituted 
pyridylalkylamido are 4-methyl-.alpha.-pyridylmethylamide, 
4-methyl-.beta.-pyridylmethylamide, 4-chloro-.alpha.-pyridylmethylamide, 
4-chloro-.beta.-pyridylmethyl-amide, 4-methyl-.alpha.-pyridylpropylamide, 
4-methyl-.beta.-pyridylpropylamide, 4-chloro-.alpha.-pyridylpropylamide, 
4-chloro-.beta.-pyridylpropylamide, 4-methyl-.alpha.-pyridylbutylamide, 
4-methyl-.beta.-pyridylbutylamide, 4-chloro-.alpha.-pyridylbutylamide, 
4-chloro-.beta.-pyridylbutylamide, 4-chloro-.gamma.-pyridylbutylamide. 
Amides within the scope of hydroxyalkylamino are hydroxymethylamide, 
.beta.-hydroxyethylamide, .beta.-hydroxypropylamide, 
.gamma.-hydroxypropylamide, 1-(hydroxymethyl)ethyl-amide, 
1-(hydroxymethyl)propylamide, (2-hydroxymethyl)propylamide, and 
.alpha.,.alpha.,-dimethyl-hydroxyethylamide. Amides within the scope of 
dihydroxyalkylamino are dihydroxymethylamide, 
.beta.,.gamma.-dihydroxypropylamide, 
1-(hydroxymethyl)2-hydroxymethylamide, .beta.,.gamma.-dihydroxybutylamide, 
.beta.,.delta.-dihydroxybutyl-amide, .gamma.,.delta.-dihydroxybutylamide, 
and 1,1-bis(hydroxymethyl)ethylamide. 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 above are 
pyrrolidylamide, piperidylamide, morpholinylamide, 
hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and 
3,4-didehydropiperidinylamide each of which may be optionally substituted 
with one or 2 straight or branched alkyl chains having from 1 to 12 carbon 
atoms. 
(3) Amides within the scope of carbonylamino of the formula --NR.sub.11 
COR.sub.10 are methylcarbonylamide, ethylcarbonylamide, 
phenylcarbonylamide, and benzylcarbonylamide. 
(4) Amides within the scope of sulfonylamino of the formula --NR.sub.11 
COR.sub.10 are methylsulfonylamide, ethylsufonylamide, 
phenylsulfonylamide, 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, dodecyl, isomeric 
forms thereof. 
Examples of (C.sub.3 -C.sub.10)cycloalkyl which includes alkyl-substituted 
cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 
2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 
2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, 
cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 
3-tertbutylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 
3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, 
cyclononyl, and cyclodecyl. 
Examples of (C.sub.7 -C.sub.12)aralkyl are benzyl, 2-phenylethyl, 
1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 
2-(1-naphthylethyl), and 1-(2-naphthylmethyl). 
Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 
carbon atoms, inclsive, are p-chlorophenyl, m-chlorophenyl, 
2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, 
p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 
4-chloro-2methylphenyl, and 2,4-dichloro-3-methylphenyl. 
Examples of (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 
(C.sub.1 -C.sub.5)alkyl are cyclobutyl, 1-propylcyclobutyl, 
1-butylcyclobutyl, 1-pentylcyclobutyl, 2-methylcyclobutyl, 
2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 
2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 
3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 
3-tert-butylcyclopentyl, 1-methyl-3-propylcyclopentyl, 
2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 
3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 
4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 
4-tert-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, 
2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl. 
Examples of substituted phenoxy, phenyl, phenylmethyl, i.e., benzyl, 
phenylethyl, or phenylpropyl of the R.sub.17 moiety are (o-, m-, or 
p-)tolyl, (o-, m-, or p-)ethylphenyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, 
(o-, m-, or p-)propylphenyl, 2-propyl-(m- or p-)tolyl, 
4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 
2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(m- or 
p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)difluorophenyl, (o-,m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 
4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 
2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 
3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or 
4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoromethylphenyl, (o-, m-, 
or p-)methoxyphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 
5-)chloro-2-methoxyphenyl, 2,4-dichloro-(4- or 6-)methylphenyl, (o-, m-, 
or p-)tolyloxy, (o-, m-, or p-)ethylphenyloxy, 4-ethyl-o-tolyloxy, 
5-ethyl-m-tolyloxy, (o-, m-, or p-)propylphenoxy, 2-propyl-(m- or 
p-)tolyloxy, 4-isopropyl-2,6-xylyloxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 
2,3,5-, 2,3,6 -, or 2,4,5-)trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 
2-fluoro-(m- or p-)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-propylphenoxy, 2-isopropyl-4-chlorophenoxy, 
4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenyloxy, 4-chloro-3-fluorophenoxy, (3- or 
4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoromethylphenoxy, (o-, m-, 
or p-)methoxyphenoxy, (o-, m-, or p-)ethoxyphenoxy, (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-ethyl-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 2,4,5-)trimethylphenylmethyl, (o-, m-, or 
p-)fluorophenylmethyl, 2-fluoro-(m- or p-)tolylmethyl, 
4-fluoro-2,5-xylylmethyl, (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, 
4-isopropyl-2,6-xylylethyl, 3-propyl-4-ethylphenylethyl, (2,3,4-, 2,3,5-, 
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, (o-, m-, or p-)chlorophenylmethyl, 
2-chloro-p-tolylmethyl, (3, 4, 5, or 6-)chloro-o-tolylmethyl, 
4-chloro-2-propylphenylmethyl, 2-isopropyl-4-chlorophenylmethyl, 
4-chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenylmethyl, 4-chloro-3-fluorophenylmethyl, (3- or 
4-)chloro-2-fluorophenylmethyl, (o-, m-, or 
p-)trifluoromethylphenylmethyl, (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-, or 
p-)chlorophenylpropyl, 2-chloro-p-tolylpropyl, (3, 4, 5, or 
6-)chloro-o-tolylpropyl, 4-chloro-2-propylphenylpropyl, 
2-isopropyl-4-chlorophenylpropyl, 4-chloro-3,5-xylylpropyl, (2,3-, 2,4-, 
2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylpropyl, 
4-chloro-3-fluorophenylpropyl, (3- or 4-)chloro-2-fluorophenylpropyl, (o-, 
m-, or p-)trifluoromethylphenylpropyl, (o-, m-, or p-)methoxyphenylpropyl, 
(o-, m-, or p-)ethoxyphenylpropyl, (4- or 5-)chloro-2-methoxyphenylpropyl, 
and 2,4-dichloro-(4- or 6-)methoxyphenylpropyl. 
The group --C.sub.m H.sub.2m CH.sub.3 wherein m is an integer of from one 
to 5 which R.sub.17 may be represents straight or branched alkylC.sub.1 
-C.sub.5 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-y 
l P-oxide; which R.sub.5 may represent in the --COOR.sub.5 group mean the 
following respective moieties (a), (b) and (c): 
##STR13## 
As indicated hereinabove R.sub.12 is hydrogen or a protecting group. Those 
protective groups within the scope of R.sub.12 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 with hydrogen in the 
preparation of the carbacyclin-type compounds. Several such protective 
groups are known in the art, e.g., tetrahydropyranyl and substituted 
tetrahydropyranyl. See for reference E. J. Corey, Proceedings of the 
Robert A. Welch Foundation Conferences on Chemical Research, XII Organic 
Synthesis, pp. 51-79 (1969). Those blocking groups which have been found 
useful include: 
(a) tetrahydropyranyl; 
(b) tetrahydrofuranyl; 
(c) a group of the formula 
--C(OR.sub.24)(R.sub.18)--CH(R.sub.19)(R.sub.20), wherein R.sub.24 is 
alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon 
atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl or 
phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, 
inclusive, wherein R.sub.18 and R.sub.19 are alkyl of one to 4 carbon 
atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3 alkyl of one 
to 4 carbon atoms, inclusive, or when R.sub.18 and R.sub.19 are taken 
together --(CH.sub.2).sub.a -- or when R.sub.18 and R.sub.19 are taken 
together to form --(CH.sub.2).sub.b --O--(CH.sub.2).sub.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 4, with the further proviso that R.sub.18 and 
R.sub.19 may be the same or different, and wherein R.sub.20 is hydrogen or 
phenyl; and 
(d) silyl groups according to R.sub.21, as qualified hereinafter. 
When the protective group R.sub.12 is tetrahydropyranyl, the 
tetrahydropyranyl ether derivative of any hydroxy moieties of the CBA-type 
intermediates herein is obtained by reaction of the hydroxy-containing 
compound with 2,3-dihydropyran in an inert solvent, e.g., dichloromethane, 
in the presence of an acid condensing agent such as p-toluenesulfonic acid 
or pyridine hydrochloride. The dihydropyran is used in large 
stoichiometric excess, preferably 4 to 100 times the stoichiometric 
amount. The reaction is normally complete in less than an hour at 
20.degree.-50.degree. C. 
When the R.sub.12 protective group is tetrahydrofuranyl, 2,3-dihydrofuran 
is used, as described in the preceding paragraph, in place of the 
2,3-dihydropyran. 
When the R.sub.12 protective group is of the formula 
--C(OR.sub.24)(R.sub.18)--CH(R.sub.19)(R.sub.20), wherein R.sub.24, 
R.sub.18, R.sub.19, and R.sub.20 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. B. 
Reese, et al., J. American Chemical Society 89, 3366 (1967). The reaction 
conditions for such vinyl ethers and unsaturated compounds are similar to 
those for dihydropyran above. 
R.sub.21 is a silyl protective group of the formula --Si(G.sub.1).sub.3. In 
some cases, such silylations are general, in that they silylate all 
hydroxyls of a molecule, while in other cases they are selective, in that 
while one or more hydroxyls are silylated, at least one other hydroxyl 
remains unaffected. For any of these silylations, silyl groups within the 
scope of --Si(G.sub.1).sub.3 include trimethylsilyl, dimethylphenylsilyl, 
triphenylsilyl, t-butyldimethylsilyl, or methylphenylbenzylsilyl. With 
regard to G.sub.1, examples of alkyl are methyl, ethyl, propyl, isobutyl, 
butyl, sec-butyl, tert-butyl, pentyl, and the like. Examples of aralkyl 
are benzyl, phenethyl, .alpha.-phenylethyl, 3-phenylpropyl, 
.alpha.-naphthylmethyl, and 2-(.alpha.-naphthyl)ethyl. Examples of phenyl 
substituted with halo or alkyl are p-chlorophenyl, m-fluorophenyl, 
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, Rockford, Ill. 
(1968). When silylated products of the charts below are intended to be 
subjected to chromatographic purification, then the use of silyl groups 
known to be unstable to chromatography (e.g. trimethylsilyl) is to be 
avoided. Further, when silyl groups are to be introduced selectively, 
silylating agents which are readily available and known to be useful in 
selective silylations are employed. For example, t-butyldimethylsilyl 
groups are employed when selective introduction is required. Further, when 
silyl groups are to be selectively hydrolyzed in the presence of 
protective groups according to R.sub.12 or acyl protective groups, then 
the use of silyl groups which are readily available and known to be easily 
hydrolyzable with tetra-n-butylammonium fluoride are employed. A 
particularly useful silyl group for this purpose is t-butyldimethylsilyl, 
while other silyl groups (e.g. trimethylsilyl) are not employed when 
selective introduction and/or hydrolysis is required. 
The protective groups as defined by R.sub.12 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.degree. C., hydrolysis of the blocking group is 
achieved. 
R.sub.13 is a hydroxyl protective group, as indicated above. As such, 
R.sub.13 may be an acyl protective group according to R.sub.22 as defined 
below, an acid hydrolyzable protective group according to R.sub.12 as 
defined above, or a silyl protective group according to R.sub.21 as 
defined above. 
Acyl protective groups according to R.sub.22 include: 
(a) benzoyl; 
(b) benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms, 
inclusive, or phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro, 
with the proviso that more than two substituents are other than alkyl, and 
that the total number of carbon atoms in the substituents does not exceed 
10 carbon atoms, with the further proviso that the substituents are the 
same or different; 
(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms, 
inclusive; 
(d) naphthoyl; 
(e) naphthoyl substituted with one to 9, inclusive, alkyl of one to 4 
carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, 
or nitro, with the proviso that not more than two substituents on either 
of the fused aromatic rings are other than alkyl and that the total number 
of carbon atoms in the substituents on either of the fused aromatic rings 
does not exceed 10 carbon atoms, with the further proviso that the various 
substituents are the same or different; or 
(f) alkanoyl of 2 to 12 carbon atoms, inclusive. 
In preparing these acyl derivatives of a hydroxy-containing compound 
herein, methods generally known in the art are employed. Thus, for 
example, an aromatic acid of the formula R.sub.22 OH, wherein R.sub.22 is 
as defined above (e.g., R.sub.22 OH is benzoic acid), is reacted with the 
hydroxy-containing compound in the presence of a dehydrating agent, e.g. 
p-toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively an 
anhydride of the aromatic acid of the formula (R.sub.22)OH, e.g., benzoic 
anhydride, is used. 
Preferably, however, the process described in the above paragraph proceeds 
by use of the appropriate acyl halide, e.g., R.sub.22 Hal, wherein Hal is 
chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the 
hydroxyl-containing compound in the presence of a hydrogen chloride 
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: 0.degree.-60.degree. C., contacting the reactants in a liquid 
medium (e.g., excess pyridine or an inert solvent such as benzene, 
toluene, or chloroform). The acylating agent is used either in 
stoichiometric amount or in substantial stoichiometric excess. 
As examples of R.sub.22, the following compounds are available as acids 
(R.sub.22 OH), (R.sub.22).sub.2 O, or acyl chlorides (R.sub.22 Cl): 
benzoyl; substituted benzoyl, e.g., (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, 
or 4-)ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or 
4-)tertbutylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 
2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl (2-, 
3-, or 4-)toluyl, (2-, 3-, or 4-)phenethylbenzoyl, (2-, 3-, or 
4-)nitrobenzoyl, (2,4, 2,5-, or 2,3-)dinitrobenzoyl, 
2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 
2-nitro-6-phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 
2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterified 
phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted 
naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)methyl-1-naphthoyl, (2- or 
4-)ethyl- 1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 
6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 
8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (, 4-, 6-, 7-, or 
8-)-methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 
8-)nitro-2-naphthoyl and acetyl. 
There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl 
chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R.sub.22 Cl 
compounds corresponding to the above R.sub.22 groups. If the acyl chloride 
is not available, it is prepared from the corresponding acid and 
phosphorus pentachloride as is known in the art. It is preferred that the 
R.sub.22 OH, (R.sub.22).sub.2 O, or R.sub.22 Cl reactant does not have 
bulky hindering substituents, e.g. tert-butyl on both of the ring carbon 
atoms adjacent to the carbonyl attaching site. 
The acyl protective groups, according to R.sub.22, are removed by 
deacylation. Alkali metal carbonate or hydroxide are employed effectively 
at ambient temperature for this purpose. For example, potassium carbonate 
or hydroxide in aqueous methanol at about 25.degree. C. is advantageously 
employed. 
The novel CBA analogs disclosed herein wherein R.sub.12 is hydrogen produce 
certain prostacyclin-like pharmacological responses. 
Accordingly, the novel formula IV compounds wherein R.sub.12 is hydrogen 
are used as agents in the study, prevention, control, and treatment of 
diseases, and other undesirable physiological conditions, in mammals, 
particularly humans, valuable domestic animals, pets, zoological 
specimens, and laboratory animals (e.g., mice, rats, rabbits and monkeys). 
In particular, these compounds are useful as anti-ulcer agents and 
anti-asthma agents, and additionally the compounds wherein s is one are 
useful as antithrombotic agents as indicated below. 
(a) Platelet Aggregation Inhibition 
The compounds of formula IV wherein R.sub.12 is hydrogen, and s is one are 
useful whenever it is desired to inhibit platelet aggregation, to reduce 
the adhesive character of platelets, or to remove or prevent the formation 
of thrombi in mammals, including man. For example, these compounds are 
useful in the treatment and prevention of myocardial infracts, to treat 
and prevent post-operative thrombosis, to promote patency of vascular 
grafts following surgery, to treat peripheral vascular diseases, and to 
treat conditions such as atherosclerosis, arteriosclerosis, blood clotting 
defects due to lipemia, and other clinical conditions in which the 
underlying etiology is associated with lipid imbalance or hyperlipidemia. 
Other in vivo applications include geriatric patients to prevent cerebral 
ischemic attacks and long term prophylaxis following myocardial infarcts 
and strokes. For these purposes, these compounds are administered 
systemically, e.g., intravenously, subcutaneously, intramuscularly, and in 
the form of sterile implants for prolonged action. For rapid response, 
especially in emergency situations, the intravenous route of 
administration is preferred. 
The preferred dosage route for these compounds is oral, although other 
non-parenteral routes (e.g., buccal, rectal, sublingual) are likewise 
employed in preference to parenteral routes. Oral dosage forms are 
conventionally formulated 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 treating the aforedescribed conditions 
associated with the inhibition of platelet aggregation. 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 
applications such as storage of whole blood to be used in heart-lung 
machines. Additionally whole blood containing these compounds can be 
circulated through organs, e.g., heart and kidneys, which have been 
removed from a donor prior to transplant. They are also useful in 
preparing platelet rich concentrates for use in treating thrombocytopenia, 
chemotherapy, and radiation therapy. In vitro applications utilize a dose 
of 0.001-1.0 .mu.g per ml of whole blood. These compounds, i.e., the 
compounds of formula IV wherein R.sub.12 is hydrogen, and s is one are 
useful in the treatment of peripheral vascular diseases, in the same 
manner as described in U.S. Pat. No. 4,103,026. 
(b) Gastric Secretion Reduction 
Compounds of Formula IV wherein R.sub.12 is hydrogen are useful in mammals, 
including man and certain useful animals, e.g., dogs and pigs, to reduce 
and control gastric secretion, thereby to reduce or avoid gastrointestinal 
ulcer formation, and accelerate the healing of such ulcers already present 
in the gastrointestinal tract. For this purpose, these compounds are 
injected or infused intravenously, subcutaneously, or intramuscularly in 
an infusion dose range of about 0.1 .mu.g to about 20 .mu.g 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 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 employed. Once healing of the ulcers has been accomplished the 
maintenance dosage required to prevent recurrence is adjusted downward so 
long as the patient or animals remains asymptomatic. 
(c) NOSAC-Induced Lesion Inhibition 
Compounds of Formula IV wherein R.sub.12 is hydrogen are also useful in 
reducing the undesirable gastrointestinal effects resulting from systemic 
administration of anti-inflammatory prostaglandin synthetase inhibitors, 
and are useful for that purpose by concomitant administration of said 
compounds of Formula IV and the anti-inflammatory prostaglandin synthetase 
inhibitor. See Partridge, et al., U.S. Pat. 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 the E series. Accordingly 
these novel Formula IV compounds are useful, for example, in reducing the 
undesirable gastrointestinal effects resulting from systemic 
administration of known prostaglandin synthetase inhibitors, e.g., 
indomethacin, phenylbutazone, and aspirin, in the same manner as described 
by Partridge, et al, for the PGE compounds in U.S. Pat. No. 3,781,429. 
The anti-inflammatory synthetase inhibitor, for example, indomethacin, 
aspirin, or phenylbutazone 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 IV wherein R.sub.12 is hydrogen are also useful in 
the treatment of asthma. For example, these compounds are useful as 
bronchodilators or as inhibitors of mediator-induced bronchoconstriction, 
such as SRS-A, and histamine which are released from cells activated by an 
antigen-antibody complex. Thus, these compounds control spasm and 
facilitate breathing in conditions such as bronchial bronchitis, 
bronchiectasis, pneumonia and emphysema. For these purposes, these 
compounds are administered in a variety of dosage forms, e.g., orally in 
the form of tablets, capsules, or liquids; rectally in the form of 
suppositories, parenterally, subcutaneously, or intramuscularly, with 
intravenous administration being preferred in emergency situations; by 
inhalation in the form of aerosols or solutions for nebulizers; or by 
insufflation in the form of powder. Doses in the range of 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 condition of the patient and on the 
frequency and route of administration. For the above use Formula IV 
compounds can be combined advantageously with other anti-asthmatic agents, 
such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); 
xanthine derivatives (theophylline and aminophylline); and corticosteroids 
(ACTH and prednisolone). 
The pharmacologically useful Formula IV compounds are effectively 
administered to human asthma patients by oral inhalation or by aerosol 
inhalation. For administration by the oral inhalation route with 
conventional nebulizers or by oxygen aerosolization it is convenient to 
provide the instant active ingredient in dilute solution, preferably at 
concentrations of about one part of medicament to from about 100 to 200 
parts by weight of total solution. Entirely conventional additives may be 
employed to stabilize these solutions or to provide isotonic media, for 
example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, 
and the like can be employed. For administration as a self-propelled 
dosage unit for administering the active ingredient in aerosol form 
suitable for inhalation therapy the composition can comprise the active 
ingredient suspended in an inert propellant (such as a mixture of 
dichlorodifluoromethane and dichlorotetrafluoroethane) together with a 
co-solvent, such as ethanol, flavoring materials and stabilizers. Suitable 
means to employ the aerosol inhalation therapy technique are described 
fully in U.S. Pat. No. 3,868,691, for example. 
When Q is --COOR.sub.5, the novel Formula IV 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 R.sub.5. 
However, it is preferred that the ester be alkyl of one to 12 carbon 
atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially 
preferred for optimum absorption of the compound by the body or 
experimental animal system; and straight-chain octyl, nonyl, decyl, 
undecyl, and dodecyl are especially preferred for prolonged activity. 
Pharmacologically acceptable salts of the novel compounds of Formula IV for 
the purposes described above are those with pharmacologically acceptable 
metal cations, ammonia, amine cations, or quaternary ammonium cations. 
Illustrative pharmacological acceptable cations which R.sub.5 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., magnesium and calcium, although cationic forms of other 
metals, e.g., aluminum, zinc, and iron are within the scope of this 
invention. 
Pharmacologically acceptable amine cations are those derived from primary, 
secondary, and tertiary amines. Examples of suitable amines are 
methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, 
triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, 
allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, 
dibenzylamine, .alpha.-phenylethylamine, .beta.-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 
triethanolamine, 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-amylphenyl)-diethanolamine, galactamine, 
N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, 
epinephrine, procaine, and the like. Further useful amine salts of the 
basic amino acid salts, e.g., lysine and arginine. 
Examples of suitable pharmacologically acceptable quaternary ammonium 
cations are tetramethylammoniun, tetraethylammonium, 
benzyltrimethylammonium, phenyltriethylammonium, and the like. 
When Q is --CH.sub.2 NL.sub.3 L.sub.4, the Formula IV compounds so 
described are used for the purposes described in either free base or 
pharmacologically acceptable acid addition salt form. 
The acid addition salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted 
aminomethyl)-Formula IV compounds provided by this invention are, for 
example, the hydrochlorides, hydrobromides, hydriodides, sulfates, 
phosphates, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, 
benzenesulfonates, toluenesulfonates and the like, prepared by reacting 
the appropriate compound of Formula IV with the stoichiometric amount of 
the acid corresponding to the pharmacologically acceptable acid addition 
salt. 
The compounds of Formula IV wherein R.sub.12 is a hydroxyl protecting group 
are useful as intermediates to the compounds of Formula IV wherein 
R.sub.12 is hydrogen. 
To obtain the optimum combination of biological response specificity, 
potency, and duration of activity, certain compounds within the scope of 
this invention are preferred. Preferred compounds of the present invention 
are the CBA.sub.2 analogs, i.e., the compounds of Formula IV wherein the 
C-5,6 position is unsaturated, and of these compounds those wherein Y is 
--CH.sub.2 CH.sub.2 --, --C.tbd.C-- or trans-CH.dbd.CH-- and/or Q is 
--COOR.sub.5 or --COL.sub.2 are preferred especially when R.sub.5 is 
hydrogen, methyl, ethyl, or a pharmacologically acceptable cation such as 
sodium, and when each of R.sub.9 and R.sub.10 of the L.sub.2 substituent 
moiety is hydrogen. To further characterize the preferred embodiments of 
the present invention, compounds of Formula IV wherein R.sub.17 is 
--C.sub.m H.sub.2m CH.sub.3, benzyl, phenoxy, 3-thienylmethyl, or phenyl 
or wherein --C(L.sub.1)R.sub.17 taken together is cyclohexyl, 
3-thienyloxymethyl or 3-ethylcyclobutyl, or --CH(.about.CH.sub.3)CH.sub.2 
C.tbd.CCH.sub.3 are especially preferred. Also compounds wherein R.sub.17 
is C.sub. m H.sub.2m CH.sub.3 and each of R.sub.15 and R.sub.16, which 
make up the L.sub.1 substituent, are fluoro are especially preferred. 
Preferred for biological potency are formula IV CBA.sub.2 analogs 
exhibiting the same C-5 isomeric configuration as CBA.sub.2 itself. As is 
apparent from the foregoing as compounds satisfy more of the above 
preferences, said compounds are more preferred. 
The carbacyclin analogs of the present invention as represented by Formula 
IV are prepared by various procedures which are all generally known in the 
art. The charts provided herein are useful in illustrating the preparation 
of the compounds. 
As indicated hereinabove the hydroxyl groups at positions C-11 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 and 
is generally desirable or necessary during the preparation of the 
components. Although any of the various protecting groups described herein 
may be employed those preferred are tetrahydropyranyl (THP) and 
tert-butyldimethylsilyl. Particularly, THP is a preferred protecting group 
during the various reactions required to add the side chains and 
t-butyldimethylsilyl is a preferred group to employ during separation of 
the isomers. Of course it may be useful or desirable to utilize protecting 
groups which may be selectively hydrolyzed. Also, when R.sub.17 is 
--(CH.sub.2).sub.2 CH(OH)--CH.sub.3 the hydroxyl group at C-19 generally 
is protected by the same type of groups utilized to protect the C-11 and 
C-15 hydroxyl groups during the preparation of said compounds and 
subsequently deprotected by hydrolysis as described herein. 
Also, it will be apparent that in the preparation of the compounds the 5(E) 
and 5(Z) isomers generally may be separated when the C-11 and C-15 
hydroxyl groups are either protected or are unprotected. However, it has 
been found that protection of these hydroxyl groups with, e.g., 
tert-butyldimethyl silyl often facilitates clean separation of the isomers 
in high yield. Separation of the 5(E) and 5(Z) isomers is achieved by 
conventional means, typically column chromatography is employed. 
The compounds of Formula IV wherein Z is other than 
--(Ph)--(CH.sub.2).sub.g -- and D is cis-CH.dbd.CH-- or trans-CH.dbd.CH-- 
are prepared as depicted in Chart A hereof. An enone of Formula A-1 is 
epoxidized with alkaline hydrogen peroxide then reduced with aluminum 
amalgam by procedures known in the art, e.g., see G. L. Bundy, et al., J. 
Am. Chem. Soc. 94, 2122 (1972) to give the corresponding hydroxy 
substituted compound of Formula A-2 wherein R.sub.12 is hydrogen. The 
enones of Formula A-1 are known in the art or readily prepared by 
procedures known in the art as set forth hereinafter. 
In preparing the compounds of Formula A-4 from the compounds of Formula A-2 
the 1-position hydroxyl group is first protected by an R.sub.12 protecting 
group as defined hereinabove. The hydroxy protected A-2 compounds are 
treated with the dianion of Formula A-3 by methods known in the art. See, 
for example, G. W. Moersch, J. Org. Chem. 36, 1149 (1979) and J. Mulzer, 
et al., Tetrahedron Lett. 2949 (1978) to give compounds of Formula A-4. 
The dianion compounds are known in the art or are prepared by procedures 
known in the art. For example, see the illustrative procedure set forth in 
Example 2 hereof. The hydroxy acids of Formula A-4 are subjected to 
decarboxylative dehydration using dimethylformamide dineopentyl acetal by 
generally known procedures, e.g., see A. Eschenmoser, et al., Helv. Chim. 
Acta. 58 1450 (1975); S. Hara, et al., Tetrahedron Lett. 1545 (1975) and 
J. Mulzer, et al., Tetrahedron Lett. 2953 (1978) and 1909 (1979) to give 
compounds of Formula A-5 which are selectively hydrolyzed to remove the 
R.sub.12 protecting group at the C-9 position to give compounds of Formula 
A-6 wherein R.sub.3 is hydrogen. The 9.beta.-hydroxy compounds of Formula 
A-6 can be used to prepare the corresponding 9.beta.-methoxy and 
9.beta.-acetoxy compounds. By treating a 9.beta.-hydroxy compound of 
Formula A-6 with a base such as a metal hydride and methyl iodide one 
obtains the corresponding 9.beta.-methoxy compound of Formula A-6 wherein 
R.sub.3 is methyl. By treating a 9.beta.-hydroxy compound of Formula A-6 
with acetic anhydride using dimethylaminopyridine as a catalyst one 
obtains the corresponding 9.beta.-acetoxy compound of Formula A-6 wherein 
R.sub.3 is acetyl. The chemistry employed to prepare the 9.beta.-methoxy 
and 9.beta.-acetoxy compounds from the 9.beta.-hydroxy derivatives is well 
known in the art. The compounds of Formula A-6 can be hydrolyzed to remove 
the various protecting groups at position C-1 and which may be present at 
positions C-11, C-15 and C-19 to give the compounds of A-7. Or, the 
R.sub.12 silyl protecting group in compounds of Formula A-6 can be 
selectively hydrolyzed, e.g., by fluoride mediated hydrolysis to give 
compounds corresponding to those of A-6 only wherein R.sub.21 is replaced 
by hydrogen. These C-1 deprotected compounds corresponding to Formula A-6 
are used to prepare the compounds of Formula A-7 wherein Q.sub.2 is the 
same as Q except it is other than --CH.sub.2 OH. The Formula A-6 compounds 
can be oxidized, e.g., using Jones reagent or platinum oxide/oxygen 
oxidation (J. Fried and J. C. Sih, Tetrahedron Lett. 1973, 3899), to the 
corresponding carboxylic acid which in turn can be converted to the esters 
and amides of Formula A-8 by conventional means. The C-1 position alcohols 
corresponding to A-6 also can be oxidized to the corresponding 
carboxaldehyde which upon treatment with a salt of hydroxylamine gives the 
oxime which is dehydrated to give the nitrile, i.e., the compounds of 
Formula A-8 wherein Q.sup.2 is CN. These conversions are all carried out 
by procedures generally known in the art. See, for example, the 
aforementioned British specifications which describe the synthesis of 
various carbacyclin compounds, and in particular G. B. No. 2,013,661. The 
amide also can be reduced to the corresponding amines, i.e., compounds of 
Formula A-8 wherein Q.sup.2 is --CH.sub.2 L.sub.3 L.sub.4 by using, e.g., 
lithium aluminum hydride. See U.S. Pat. No. 4,073,808. During the 
conversion of the C-1 position alcohols corresponding to Formula A-6 to 
the various other C-1 position derivatives as represented by Formula A-8, 
the C-11 and C-15 hydroxyl groups and when present the C-19 hydroxyl 
groups are protected as described herein which groups can ultimately be 
deprotected by hydrolysis as generally described hereinbefore. 
The 5(E) and 5(Z) isomers can be separated using either the compound of 
Formulas A-6, A-7 or A-8. 
The compounds of Formula IV wherein D is cis-CH.dbd.CH-- or 
trans-CH.dbd.CH-- and wherein Z is --(Ph)--(CH.sub.2).sub.q -- are 
prepared as follows reference being made to Chart B. The ketones of 
Formula A-2 are reduced by conventional means using, for example, a 
borohydride reducing agent such as sodium, potassium or lithium 
borohydride, to the corresponding alcohol. The alcohol is converted to a 
sulfonate derivative, typically a methanesulfonate or toluenesulfonate by 
treatment with methanesulfonyl chloride or toluenesulfonyl chloride in the 
presence of a tertiary amine such as triethylamine. The sulfonate 
derivative is treated with sodium, lithium or potassium thiophenoxide to 
give the compounds of Formula B-1. The thiophenoxide is preferably 
prepared by reacting equal molar amounts of thiophenol and a base such as 
potassium tertiary butoxide just prior to reaction with the sulfonate. The 
compounds of Formula B-1 are oxidized to the corresponding phenylsulfonate 
using, e.g., m-chloroperbenzoic acid then treated with a strong base such 
as n-butyllithium to generate the corresponding anion. The anion is 
treated with an aldehyde of Formula B-2 and the resulting adduct is 
treated with acetic anhydride to give compounds of Formula B-3. The 
compounds of Formula B-3 are treated with sodium amalgam by procedures 
analogous to those described by P. J. Kocienski, et al., "Scope and 
Stereochemistry of an Olefin Synthesis from .beta.-Hydroxysulphones", JCS 
Perkin I, 829-834 (1978) and are selectively hydrolyzed to remove the 
hydroxyl protecting group at the C-9 position to give the olefins of 
Formula B-4 wherein R.sub.3 is hydrogen. The 9.beta.-hydroxy derivatives 
of Formula B-4 can be used to prepare the corresponding 9.beta.-methoxy 
and 9.beta.-acetoxy derivatives to give compounds of Formula B-4 wherein 
R.sub.3 is methyl or acetyl by procedures described hereinabove in 
connection with the preparation of the compounds of Formula A-6. The 
compounds of Formula B-4 are used to prepare the products of Formula B-5. 
The various hydroxyl groups are protected in such a manner to permit 
selective hydrolysis to give ultimately the deprotected products of 
Formula B-5. The R.sub.21 silyl protecting group is conveniently removed 
via fluoride mediated hydrolysis using, e.g., tetrabutyl ammonium fluoride 
to give the C-1 position alcohols of Formula B-5 which are utilized to 
prepare the corresponding carboxylic acids, esters, amides, amines and 
nitriles of Formula B-5 by the same general procedures as described 
hereinabove in reference to the preparation of compounds of Formula A-8. 
The 5(E) and 5(Z) isomers can be separated conveniently using the alcohol 
corresponding to Formula B-4 and the various C-9, C-11, C-15 and C-19 
hydroxyl protecting groups which may be present are removed by mild acid 
hydrolysis using, e.g., mixtures of water, tetrahydrofuran and acetic 
acid. 
The compounds of Formula B-2 are prepared using known bis-acids of the 
formula 
##STR14## 
wherein g is zero, one, 2 or 3, which are reduced to the corresponding 
diol by conventional procedures, e.g., by using lithium aluminum hydride. 
About equal molar amounts of the diol and a silylating reagent of R.sub.21 
are combined thereby preferentially silylating the alkanol hydroxyl 
although some di-silylated compound is produced. The mono-silylated 
compounds of the formula 
##STR15## 
are oxidized to the aldehydes of Formula B-2 by conventional means, e.g., 
using manganese dioxide. See U.S. Pat. No. 4,306,075. 
The compounds of Formula IV may also be prepared as depicted in Chart C 
hereof. When a compound of C-1, which compounds are known in the art or 
are readily prepared by means known in the art, is substituted for and 
treated in the same manner as the compounds of Formula A-1 in Chart A 
Compounds of Formula C-2 are obtained. When compounds of Formula C-2 are 
substituted for and treated in the same manner as compounds of Formula A-2 
in each of Charts A and B compounds of Formula C-3 are obtained which may 
be converted to the various C-1 position analogs of Formula C-4 by the 
general procedures described hereinabove for conversion of compounds of 
Formula A-6 to A-7. When R.sub.3 in Formula C-3 is hydrogen it is 
preferred that the C-9 hydroxy group is protected by a hydroxy protecting 
group as defined by R.sub.12 hereinabove. 
Also, the compounds of Formulas C-3 and C-4 can be reduced to the 
corresponding 5,6-dihydro derivatives of Formula V by known procedures, 
e.g., as generally described in U.K. application G.B. No. 2,017,699. For 
example, the reduction may be achieved by a standard hydrogenation in the 
presence of a catalyst such as palladium on charcoal or platinum dioxide 
in a lower alkanol such as methanol or ethanol. 
The intermediates of Formulas C-3, C-4 and V are utilized in preparing the 
compounds of Formula IV by procedures which are also useful in preparing 
compounds of Formula A-1 (Chart A). Initially the intermediates of 
Formulas C-3, C-4 and V are hydrolyzed to remove the R.sub.13 protecting 
group thus giving the primary alcohol derivatives which are oxidized to 
the corresponding aldehyde by conventional procedures, e.g., under the 
conditions of a Collins reaction, to give compounds of Formulas C-5, C-6 
and VII. To prepare compounds of Formula A-1 one utilizes aldehydes of 
Formula VI which are obtained by oxidation of the corresponding "C-12 
position" substituted alcohol by conventional procedures. The alcohols are 
known in the art or are readily prepared by procedures known in the art. 
The aldehydes of Formulas C-5, C-6, VI and VII are then treated as 
described hereinbelow, wherein for purposes of convenience only the 
chemical transformations which occur at the "C-12 position" of said 
compounds are depicted. When R.sub.3 in Formulas C-5, C-6 and C-7 is 
hydrogen it is preferred that the C-9 hydroxy group is protected by a 
hydroxy protecting group as defined by R.sub.12 hereinabove. 
The "C-12" aldehydes are subjected to a Wittig reaction with the anion of 
an alkyl phosphonate derivative of the formula 
##STR16## 
which is obtained by addition of the anion of dialkylmethylphosphonate, 
i.e., 
##STR17## 
with an ester of the formula 
##STR18## 
by procedures known in the art, wherein R.sub.17 and L.sub.1 have the same 
meanings defined in Formula IV, to give the corresponding ketone 
intermediates wherein W is the group 
##STR19## 
The ketone intermediate is then reduced by dissolving metal hydride 
reduction to the .alpha.- or .beta.-alcohol as defined by M in Formula I 
to give compounds corresponding to Formulas C-5, C-6, VI and VII only 
wherein W is the group 
##STR20## 
wherein M.sub.1 is .alpha.-OH,.beta.-H or .alpha.-H,.beta.-OH and wherein 
L.sub.1 and R.sub.17 have the meanings defined in Formula I. The thus 
obtained trans-vinyl compounds can be hydrogenated to give compounds 
corresponding to Formulas C-5, C-6, VI and VII only wherein W is the group 
##STR21## 
or can be halogenated followed by tetradehydrohalogenation to give the 
corresponding compounds wherein W is the group 
##STR22## 
Hydrogenation of the thus obtained acetylene containing compounds with a 
Lindlar catalyst gives the corresponding cis-vinyl compounds, i.e., 
compounds corresponding to Formulas C-5, C-6, VI or VII only wherein W is 
the group 
##STR23## 
The compounds of Formula A-1 and IV are also prepared by treating a 
compound of Formula C-5, C-6, VI or VII with a phosphine of the formula 
(alkyl).sub.3 -P.dbd.CHCHO under the conditions of a Wittig reaction to 
give the corresponding compounds wherein W is a trans-vinyl aldehyde group 
of the formula trans-CH.dbd.CHCHO which is reduced to the corresponding 
trans-vinyl alcohol, i.e., Formula C-5, C-6, VI or VII wherein W is 
trans-CH.dbd.CHCH.sub.2 OH. The trans-vinyl alcohol can be hydrogenated to 
give the corresponding compounds wherein W is the group --CH.sub.2 
CH.sub.2 CH.sub.2 OH, or the trans-vinyl alcohol can be halogenated then 
tetradehydrohalogenated to give the corresponding acetylene alcohol, i.e., 
compounds of Formula C-5, C-6, VI or VII wherein W is the group 
--C.tbd.CCH.sub.2 OH. Hydrogenation of the acetylene alcohol with a 
Lindlar catalyst gives the corresponding cis-vinyl alcohols, i.e., 
compounds wherein W is the group cis-CH.dbd.CHCH.sub.2 OH. 
The thus obtained alcohols, i.e., compounds of Formula C-5, C-6, VI or VII 
only wherein W is trans-CH.dbd.CHCH.sub.2 OH, --CH.sub.2 CH.sub.2 CH.sub.2 
OH, --C.tbd.CH.sub.2 OH or cis-CH.dbd.CHCH.sub.2 OH are oxidized to the 
corresponding aldehydes then treated with a Grignard reagent of the 
formula halo MgCpH.sub.2 pCH.dbd.CH.sub.2, wherein halo is a halogen or an 
alkyl lithium of the formula LiCpH.sub.2 pCH.dbd.CH.sub.2, or an acetylide 
anion of the formula --C.tbd.CCpH.sub.2 pCH.sub.3 or an anion of the 
formula 
##STR24## 
to give the corresponding compounds of Formula wherein W is 
##STR25## 
wherein Y, L.sub.1 and R.sub.17 have the meanings defined in Formula I and 
M.sub.1 is a-OH,.beta.-H or .alpha.-H,.beta.-OH. The C-15 hydroxyl group 
can be protected as required with an R.sub.12 group as described 
hereinbefore. 
To prepare compounds of Formula A-1 or IV wherein R.sub.14 of the M 
substituent group is --CH.sub.3 the corresponding C-15 alcohol derivatives 
are oxidized to the corresponding C-15 ketone then treated with methyl 
lithium or a methyl Grignard by procedures known in the art. 
Removal of protecting groups which may be present at positions C-9 or C-11 
is achieved by hydrolysis as generally described hereinabove. 
Upon completion of the above-described "C-12 position" transformations with 
respect to the compounds of Formula VI the resulting lactone derivatives 
are converted to the compounds of Formula A-1 via lactol and diketone 
phosphonate derivatives in a manner analogous to that described in U.S. 
Pat. No. 4,306,075 in reference to Chart A thereof. 
A preferred method of preparing the CBA.sub.1 compounds of Formula IV 
wherein Z is trans-CH.sub.2 CH.dbd.CH-- is to utilize the appropriate 
intermediates of Formula C-6 wherein Z is --CH.sub.2 --(CH.sub.2).sub.f 
--C(R.sub.4).sub.2 -- wherein f is one and R.sub.4 is hydrogen and wherein 
Q.sup.2 is a carboxylic acid ester, preferably the methyl ester which 
derivatives are referred to herein as the butanoic acid esters. The 
butanoic acid ester derivatives are treated with lithium amide base and 
phenylselenyl chloride to give the corresponding .alpha.-phenylselenyl 
derivatives which are reduced by, e.g., general procedures described in 
U.K. Application GB No. 2,017,699 to give the 5,6-dihydro intermediates. 
The 5,6-dihydro intermediates are dehydrophenylselenized by treatment with 
hydrogen peroxide to give intermediates corresponding to Formula C-6 
wherein Z is --CH.sub.2 CH.dbd.CH.sub.2, Q.sup.2 is a carboxylic acid 
ester and the carbon atoms at positions 5 and 6 are saturated, which 
intermediates can be converted to the corresponding derivatives wherein 
the terminal C-1 position corresponds to Q as defined herein by the 
general procedures described hereinabove in connection with the 
preparation of compounds of Formula B-5 in Chart B. These 5,6-dihydro 
intermediates are then converted to the CBA.sub.1 compounds of Formula IV 
wherein Z is --CH.sub.2 CH.dbd.CH-- by treatment in a manner analogous to 
that described hereinabove in connection with the conversion of Formula 
C-6 to CBA.sub.2 compounds of Formula IV. 
When the alkyl ester has been obtained and an acid is desired, 
saponification procedures, as known in the art for PGF-type compounds are 
employed. 
When an acid has been prepared and an alkyl, cycloalkyl, or aralkyl ester 
is desired, esterification is advantageously accomplished by interaction 
of the acid with appropriate diazohydrocarbon. For example, when 
diazomethane is used, the methyl ester is produced. Similar use of 
diazoethane, diazobutane, and 1-diazo-2-ethylhexane, and diazodecane, for 
example, gives the ethyl, butyl, and 2-ethylhexyl and decyl esters, 
respectively. Similarly, diazocyclohexane and phenyldiazomethane yield 
cyclohexyl and benzyl esters, respectively. 
Esterification with diazohydrocarbons is carried out by mixing a solution 
of the diazohydrocarbon in a suitable inert solvent, preferably diethyl 
ether, with the acd reactant, advantageously in the same or a different 
inert diluent. After the esterification reaction is complete the solvent 
is removed by evaporation, and the ester purified if desired by 
conventional methods, preferably by chromatography. It is preferred that 
contact of the acid reactants with the diazohydrocarbon be no longer than 
necessary to effect the desired esterification, preferably about one to 
about 10 minutes, to avoid undesired molecular changes. Diazohydrocarbons 
are known in the art or can be prepared by methods known in the art. See, 
for example, Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., 
Vol. 8, pp. 389-394 (1954). 
An alternative method for alkyl, cycloalkyl or aralkyl esterification of 
the carboxy moiety of the acid compounds comprises transformation of the 
free acid to the corresponding substituted ammonium salt, followed by 
interaction of that salt with an alkyl iodide. Examples of suitable 
iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, 
tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, 
phenethyl iodide, and the like. 
Various methods are available for preparing phenyl or substituted phenyl 
esters within the scope of the invention from corresponding aromatic 
alcohols and the free acid, differing as to yield and purity of product. 
With regard to the preparation of the phenyl, particularly p-substituted 
phenyl esters disclosed herein (i.e., Q is --COOR.sub.5 and R.sub.5 is 
p-substituted phenyl), such compounds are prepared by the method described 
in U.S. Pat. No. 3,890,372. Accordingly, by the preferred method described 
therein, the p-substituted phenyl ester is prepared first by forming a 
mixed anhydride, particularly following the procedures described below for 
preparing such anhydrides as the first step in the preparation of amido 
and cycloamido derivatives. 
This anhydride is then reacted with a solution of the phenol corresponding 
to the p-substituted phenyl ester to be prepared. This reaction proceeds 
preferably in the presence of a tertiary amine, such as pyridine. When the 
conversion is complete, the p-substituted phenyl ester has been recovered 
by conventional techniques. 
A preferred method for substituted phenyl esters is that disclosed in U.S. 
Pat. No. 3,890,372 in which a mixed anhydride is reacted with an 
appropriate phenol or naphthol. The anhydride is formed from the acid with 
isobutylchloroformate in the presence of a tertiary amine. 
Phenacyl-type esters are prepared from the acid using a phenacyl bromide, 
for example p-phenylphenacyl bromide, in the presence of a tertiary amine. 
See, for example, U.S. Pat. No. 3,984,454, German Offenlegungsschrift No. 
2,535,693, and Derwent Farmdoc No. 16828X. 
The phthalidyl esters are obtained by treating the corresponding acid with 
a phthalidyl halide such as the bromide in, e.g., dimethylformamide in the 
presence of an amine base. The phosphoranyl esters are obtained by 
treating the corresponding acid with a 1-halo derivative, e.g., the 
1-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 the presence of an organic amine. 
Carboxyamides (Q is --COL.sub.2) are prepared by one of several amidation 
methods known in the prior art. See, for example, U.S. Pat. No. 3,981,868, 
issued Sept. 21, 1976, for a description of the preparation of the present 
amido and cycloamido derivatives of prostaglandin-type free acids and U.S. 
Pat. No. 3,954,741 describing the preparation of carbonylamido and 
sulfonylamido derivatives of prostaglandin-type free acids. 
The preferred method by which the present amido and cycloamido derivatives 
of the acids are prepared is, first, by transformation of such free acids 
to corresponding mixed acid anhydrides. By this procedure, the 
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 likewise employed. 
Further, a convenient, readily available chloroformate for use in 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 suitable solvent (e.g., aqueous tetrahydrofuran), 
allowing the reaction to proceed at -10.degree. C. to 20.degree. C. 
Thereafter, the mixed anhydride is converted to the corresponding amido or 
cycloamido derivatives by reaction with the amine corresponding to the 
amide to be prepared. In the case where the simple amide (--NH.sub.2) 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.degree. to +10.degree. C., until the reaction is 
shown to be complete. 
Thereafter, the novel amido or cycloamido derivative is recovered from the 
reaction mixture by conventional techniques. 
The carbonylamido and sulfonylamido derivative of the presently disclosed 
carbacyclin compounds are likewise prepared by known methods. See, for 
example, U.S. Pat. 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 sulfonylamido derivatives of the 
present compounds are prepared by first generating the PG-type mixed 
anhydride, employing the method described above for the preparation of the 
amido and cycloamido derivatives. Thereafter, the sodium salt of the 
corresponding sulfonamide is reacted with the mixed anhydride and 
hexamethylphosphoramide. The pure carbacyclin sulfonylamido derivative is 
then obtained from the resulting reaction mixture by conventional 
techniques. 
The sodium salt of the sulfonamide corresponding to the sulfonylamido 
derivative to be prepared is generated by reacting the sulfonamide with 
alcoholic sodium methoxide. Thus, by a preferred method methanolic sodium 
methoxide is reacted with an equal molar amount of the sulfonamide. The 
sulfonamide salt is then reacted, as described above, with the mixed 
anhydride, using about four equivalents of the sodium salt per equivalent 
of anhydride. Reaction temparatures at or about 0.degree. C. are employed. 
The compounds of this invention prepared by the processes of this 
invention, in free acid form, are transformed to pharmacologically 
acceptable salts by neutralization with appropriate amounts of the 
corresponding inorganic or organic base, examples of which correspond to 
the cations and amines listed hereinabove. These transformations are 
carried out by a variety of procedures known in the art to be generally 
useful for the preparation if inorganic, i.e., metal or ammonium salts. 
The choice of procedure depends in part upon the solubility 
characteristics of the particular salt to be prepared. In the case of the 
inorganic salts, it is usually suitable to dissolve an acid of this 
invention in water containing the stoichiometric amount of a hydroxide, 
carbonate, or bicarbonate corresponding to the inorganic salt desired. For 
example, such use of sodium hydroxide, sodium carbonate, or sodium 
bicarbonate gives a solution of the sodium salt. Evaporation of the water 
or addition of a water-miscible solvent of moderate polarity, for example, 
a lower alkanol or a lower alkanone, gives the solid inorganic salt if 
that form is desired. 
To produce an amine salt, an acid of this invention is dissolved in a 
suitable solvent of either moderate or low polarity. Examples of the 
former are ethanol, acetone, and ethyl acetate. Examples of the former are 
ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl 
ether and benzene. At least a stoichiometric amount of the amine 
corresponding to the desired cation is then added to that solution. If the 
resulting salt does not precipitate, it is usually obtained in solid form 
by evaporation. If the amine is relatively volatile, any excess can easily 
be removed by evaporation. It is preferred to use stoichiometric amounts 
of the less volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing an 
acid of this invention with the stoichiometric amount of the corresponding 
quaternary ammonium hydroxide in water solution, followed by evaporation 
of the water.

EXAMPLE 1 
(a) 
3-Oxo-7.alpha.-tetrahydropyran-2-yloxy-6.beta.[(3'S)-tetrahydropyran-2-ylo 
xy-trans-1'-octenyl]-bicyclo-[3.3.0]oct-1-ene-1,2-oxide 
A solution of 11.69 g (27.0 mmol) of 
3-oxo-7.alpha.-tetrahydropyran-2-yloxy-6.beta.[(3'S)-3'-tetrahydropyran-2- 
yloxy-trans-1'-octenyl]-bicyclo-[3.3.0]oct-1-ene, 20 ml of 30% hydrogen 
peroxide, and 200 ml of isopropanol was cooled to -40.degree. C. This 
solution was treated dropwise with 25 ml of 3N lithium hydroxide reagent 
over 10 minutes and the resulting solution was allowed to warm between 
-25.degree. to 20.degree. C. and stirred for 2 hours. An additional 2 ml 
of 3N lithium hydroxide reagent was added followed by 5 ml of 30% hydrogen 
peroxide. While maintaining the temperature between -25.degree. to 
-20.degree. C. the reaction was stirred in additional 2 hours. The 
reaction mixture was neutralized to pH 7 by the addition of 10% sodium 
bisulfate. Iso-propanol was removed under reduced pressure and the 
concentrate was diluted with water and ethyl acetate. Solid sodium 
bisulfite was added (until bubbling ceased) to remove excess 
hydrogenperoxide (addition of ice was necessary to moderate the exothermic 
reaction). The mixture was extracted with ethyl acetate (500 ml) and the 
organic phase was washed with brine, dried over anhydrous magnesium 
sulfate, filtered, and concentrated in vacuo to give the crude product as 
a yellow oil. This material was chromatographed on 1 kg silica gel-60 
(63-200.mu.), eluting with hexane-acetone (8:1) to give the title 
compound. 
NMR (CDCl.sub.3, TMS) .delta.: 5.92-5.15 (m, 2H, --CH.dbd.CH--), 4.67 
(broad s, 2H, --O--CH--O--), 3.33-2.12 (m, 6H, --CH.sub.2 --O--, 
--CH--O--), and 3.26 (s, 1H, 
##STR26## 
Infrared (film) .nu.max: 2930, 2860, 1740, 1435, 1200, 1125, 1070, 1020, 
970, 865, and 815 cm.sup.-1. 
TLC (Silica gel GF): Rf 0.44 in hexane-ethyl acetate (2:1). 
(b) 
5.beta.-Hydroxy-7-oxo-3.alpha.-tetrahydropyran-2-yloxy-2.beta.-[(3'S)-3'-t 
etrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo-[3.3.0]-octane 
Twenty grams of aluminum turnings (20 mesh) were washed with 100 ml of 
ether followed by 100 ml of methanol. A saturated solution of mercuric 
chloride (100 ml) was added to the washed aluminum, swirled, and decanted 
when vigorous hydrogen evolution was evident. This amalgam was then washed 
with methanol (2.times.100 ml) followed by ether (100 ml). A solution of 
3-oxo-7.alpha.-tetrahydropyran-2-yloxy-6.beta.[(3'S)-tetrahydropyran-2-ylo 
xy-trans-1'-octenyl]-bicyclo-[3.3.0]-oct-1-ene-1,2-oxide (9.91 g, 22.1 
mmol) in 200 ml of ether was added in one portion to the amalgam. Methanol 
(20 ml) and water (2 9.beta.were added and the resulting mixture was 
stirred for 2 hours at room temperature. The mixture was filtered and the 
residue was washed with ethyl acetate. The combined filtrates were 
concentrated in vacuo to give 10.04 g of crude product as a colorless oil. 
This material was chromatographed on 1.2 kg of silica gel-60 (63-200.mu.) 
eluting with hexane-acetone and concentrated in vacuo to give the title 
compound. 
NMR (CDCl.sub.3, TMS) .delta.: 5.90-5.11 (m, 2H, --CH.dbd.CH--), 4.62 
(broad S, 2H, --O--CH--O--), 4.37-3.25 (m, 6H, --CH--O--, --CH.sub.2 
--O--), 2.52 (s, 2H, --C--CH.sub.2 --CO--). 
Infrared: .nu.max (film): 3430, 2930, 2860, 1740, 1465, 1450, 1435, 1385, 
1350, 1260, 1195, 1100, 1070, 1015, 970, 905, 865, and 815 cm.sup.-1. 
TLC (Silica gel GF): Rf 0.41 in hexane-acetone (2:1). 
(c) 5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-hydroxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether) 
(1) A round-bottomed flask equipped with a magnetic stirring bar was 
charged with 11.0 g (24.4 mmol) of [1'-octenyl]-bicyclo-[3.3.0]-octane and 
48.8 ml of 1,1,1,3,3,3-hexamethyldisilazane-trimethylchlorosilane-pyridine 
(6:3:10) at room temperature under a nitrogen atmosphere. The mixture was 
stirred at room temperature for 10 minutes and the excess reagent was 
removed by blowing with nitrogen stream. The concentrate (including a 
white ppt) was diluted with toluene and the mixture was filtered through a 
layer of Celite. The filtrate was concentrated in vacuo to give a light 
yellow oil. 
(2) A 3-neck, round-bottomed flask equipped with a magnetic stirring bar, a 
dropping funnel and a gas inlet tube was dried and flushed with nitrogen. 
The flask was charged with 8.2 g (80.5 mmol) of diisopropylamine and 183 
ml of tetrahydrofuran (THF). The solution was cooled to 
0.degree.-5.degree. C. and 47.2 ml (73.2 mmol) n-butyllithium in hexane 
(1.55M) was added dropwise over 5 minutes via dropping funnel. To this 
mixture a solution of 9.0 g (36.6 mmol) 
6-(dimethyl-t-butylsilyloxy)-hexanoic acid in 61 ml of THF was added over 
5 minutes. After stirring an additional 10 minutes, the ice-water bath was 
removed and the mixture was stirred at room temperature. The solution was 
cooled again to 0.degree.-5.degree. C. and the yellow oil obtained in step 
(1) dissolved in 61 ml of THF was added over 5 minutes. The ice-water bath 
was again removed and the solution was stirred at room temperature for 2 
hours. The mixture was quenched with saturated ammonium chloride and THF 
was removed under reduced pressure. The concentrate was carefully 
acidified with cold 10% sodium bisulfate and extracted with ether 
(2.times.1 liter). The ether layer was washed with water (.times.4) and 
brine. After drying over anhydrous magnesium sulfate, the solution was 
filtered through a layer of Celite and the filtrate was concentrated in 
vacuo to give a crude adduct as an oil, Rf 0.08-0.33 in hexane-ethyl 
acetate (5:1). 
(3) The crude oil obtained in step (2) was dissolved in a solution of 28.2 
g (122.0 mmol) of dimethylformamide-dineopentylacetal (DMF-DNPA) and 183 
ml of chloroform. The flask was equipped with a magnetic stirring bar, a 
reflux condenser and a nitrogen inlet tube. The solution was stirred at 
room temperature overnight (16 hours) and at 65.degree. C. for 8 hours 
under a nitrogen atmosphere. Chloroform was then removed under reduced 
pressure and the concentrate was extracted with ether (1 liter). The ether 
layer was washed with water, cold 10% sodium bisulfate, 1N sodium 
hydroxide, brine, and dried over anhydrous magnesium sulfate. Activated 
charcoal was added to decolorize the deep brown color. Filtration and 
concentration in vacuo gave a brown oil, Rf=0.78 in hexane-ethyl acetate 
(2:1). 
(4) The oil obtained in step (3) was then dissolved in a mixture containing 
6.7 g (48.8 mmol) of potassium carbonate and 488 ml of methanol-water 
(9:1). The mixture was stirred at room temperature for 18 hours. TLC 
analysis showed the reaction to be completed. Methanol was removed under 
reduced pressure and the concentrate was extracted with ether (1 liter). 
The ether layer was washed with water, brine, and dried over anhydrous 
magnesium sulfate. Filtration and concentration gave a brown oil. HPLC, 
using 2.times.324 g silica gel-60 (40-63.mu., E. Merck), packed in two 
Michel-Miller columns, eluting with hexaneacetone, afforded the title 
compound as a pale yellow oil. 
NMR (CDCL.sub.3, TMS) .delta.: 5.86-5.13 (m, 3H, --CH.dbd.CH--), 4.80-4.60 
(m, 2H, --O--CH--O--), 4.32-3.34 (m and t, 8H, --CH--O--, --CH.sub.2 
--O--), 0.88 (s and t, 12H, --Si--t--Bu, and CH.sub.3). 
IR (film) .nu.max: 3400, 2930, 2850, 2730, 1660, 1630, 1460, 1440, 1380, 
1350, 1255, 1200, 1180, 1025, 980, 905, 870, 840, 810, and 780 cm.sup.-1. 
TLC (Silica gel GF): Rf 0.25 in hexane-acetone (3:1). 
(d) 5(E and 
Z)-2-Decarboxy-2-hydroxymethyl-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 1.9 g (3.0 mmol) of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxy)-methyl-9.beta.-hydroxy-6a-carba 
-prostaglandin I.sub.2, 11,15-bis(tetrahydropyranyl ether), 6 ml of 1N HCl, 
and 24 ml of iso-propano.degree.l. The mixture was stirred at room 
temperature for 24 hours. The solution was then neutralized with saturated 
sodium bicarbonate to pH 7 and iso-propanol was removed under reduced 
pressure. The concentrate was extracted with ethyl acetate (2.times.1 
liter). The organic phase was washed with brine and dried over anhydrous 
magnesium sulfate. Filtration and concentration afforded a yellow oil. 
HPLC, using 324 g silica gel-60 (40-63.mu., E. Merck), eluting with 
methylene chloride-acetone-ethanol (10:10:1), and taking 40 ml fractions, 
gave two major products with very similar polarity. The less polar 
component contained mostly the E isomer. The more polar component 
contained mostly the Z isomer. Crystallization of the less polar component 
from ethyl acetate gave a white solid (m.p. 131.degree.-132.degree. C., 
406.2 mg, pure E isomer). The mother liquor of this crystallization was 
combined with the more polar component and repurified by HPLC using the 
same condition as described above. Fractions 64-71 (40.0 mg) gave mostly 
the E isomer, fractions 72-80 (95.5 mg) gave the mixture of E and Z 
isomers, and fractions 81-112 (311.3 mg) gave pure Z isomer as an oil. 
E isomer: 
NMR (CD.sub.3 OD, TMS) .delta.: 5.82-5.18 (m, 3H, --CH.dbd.CH--), 4.20-3.70 
(m, 2H, --CH--O--), 3.55 (t, 2H, --CH.sub.2 O), 2.45 (broad s, 2H, 
--CH.sub.2 --C.dbd.C--). 
IR (film) .nu.max: 3350, 2950, 2930, 2860, 1640, 1440, 1290, 1070, 1020, 
970, and 640 cm.sup.-1. 
TLC (Silica gel GF): Rf 0.35 in methylene chloride-acetone-ethanol 
(10:20:1). 
Z isomer: 
NMR and IR were very similar to those of E iosmer. 
TLC (Silica gel GF): Rf 0.31 in methylene chloride-acetone-ethanol 
(10:20:1). 
EXAMPLE 2 
6-(t-Butyldimethylsilyloxy)hexanoic Acid 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 22.8 g (0.2 mol) of .epsilon.-caprolactone, 8.8 g (0.22 mol) of 
sodium hydroxide and 200 ml of methanol-water (4:1). The yellow solution 
was stirred at room temperature under a nitrogen atmosphere for 24 hours. 
Methanol-water was removed under reduced pressure. Toluene azeotrope was 
used to remove water. The resulting solid mass was broken up and ground to 
a fine powder. This powder was heated with 72.0 g (0.48 mol) of 
t-butyldimethylchlorosilane, 65.3 g (0.96 mol) of imidazole, and 200 ml of 
dimethylformamide. The mixture was stirred at room temperature under a 
nitrogen atmosphere for 16 hours. Water (20 ml) was added to this mixture, 
stirred for 5 minutes, and was diluted with 800 ml of water. The mixture 
was extracted with 1 liter of hexane-ether (1:1). The aqueous layer was 
extracted once more with 1 liter of ether. The combined organic phase was 
washed with water (.times.2), brine, and dried over anhydrous magnesium 
sulfate. Filtration and concentration afforded a light yellow oil. This 
oil was then stirred in a mixture of 27.6 g (0.2 mol) potassium carbonate 
and 200 mL of methanol-water (4:1). After 3 hours, methanol was removed 
under reduced pressure. The concentrate was acidified with cold 10% sodium 
bisulfate until pH 3-5 and the mixture was extracted ether (2.times.1 
liter). The ether layer was washed with water (.times.3), brine and dried 
over anhydrous sodium sulfate. Filtration and concentration afforded the 
crude product. Column chromatography, using 1 Kg CC-4 silica gel, eluting 
with Skelly B-EtOAc (10:1), gave a pale yellow oil which solidified in the 
freezer. 
EXAMPLE 3 
(5E)-9.beta.-Hydroxy-6a-carba-prostaglandin I.sub.2 
A 3-neck round-bottomed flask equipped with a magnetic stirring bar was 
charged with 323.4 mg of platinum oxide and 23.8 ml of water. The brown 
suspension was stirred under hydrogen atmosphere using hydrogenation 
apparatus at room temperature for one hour. The catalyst turned black and 
coagulated. The flask was then purged thoroughly with nitrogen and 
attached with a reflux condenser and a gas inlet tube. The tip of the tube 
was placed below the surface of the solution. Nitrogen was bubbled through 
while the mixture was being stirred. After 10 minutes, nitrogen was 
replaced by oxygen. To this mixture, 709.2 mg of sodium bicarbonate and 
10.6 ml of water was added. This was followed by addition of 300 mg (0.851 
mmol) of 
5(E)-2-decarboxy-2-methyloxy-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2 in 10.6 ml of acetone. The mixture was heated at 60.degree. C. 
(bath temperature) while stirring and bubbling of oxygen continued. The 
mixture was acidifed with 10% sodium bisulfate (to pH 5.about.6), diluted 
with about 1 liter of acetone and the mixture was filtered through a layer 
of Celite. The filtrate was concentrated under reduced pressure. The 
concentrate was saturated with sodium chloride and extracted with ethyl 
acetate (1 liter). The organic phase was washed with brine (.times.4) and 
dried over anhydrous sodium sulfate. Filtration and concentration gave a 
crude oil which was purified by HPLC using CC-4 silica gel (52.5 g was 
packed in a Michel-Miller column). Eluting with methylene chloride-acetone 
(1:1) and concentrating in vacuo gave the title compound as an oil. 
NMR (CD.sub.3 OD, TMS) .delta.: 5.72-5.12 (m, 3H, --CH.dbd.CH--), 4.24-3.60 
(m, 2H, --CH--O--). 
Infrared (film) .nu.max: 1710, 1030, and 970 cm.sup.-1. 
TLC (Silica gel GF): Rf 0.38 in chloroform-methanol-acetic acid (10:1:1). 
EXAMPLE 4 
(5Z)-9.beta.-Hydroxy-6a-carba-prostaglandin I.sub.2 
Exactly the same procedure as described in Example 3 was followed. Using 
242.5 mg of platinum oxide in 17.8 ml of water, adding 531.9 mg of sodium 
bicarbonate as well as 225 mg (0.638 mmol) of 
5(Z)-2-decarboxy-2-methyloxy-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2 and 15.9 ml acetone-water (1:1). The crude product was purified by 
HPLC using 52.5 g CC-4 silica gel. Eluting with methylene chloride-acetone 
(2:1), and concentrating in vacuo gave the title compound as an oil. 
NMR (CD.sub.3 OD, TMS): Identical with that of Example 3 except peaks 
around .delta. 2.6-1.7. 
Infrared: Identical with that of Example 3. 
TLC (Silica gel GF): RF 0.35 in chloroform-methanol-acetic acid (10:1:1). 
EXAMPLE 5 
5(E and 
Z)-2-Decarboxy-2-hydroxymethyl-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2, 11,15-bis(tetrahydropyranyl ether) 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 381.0 mg (0.6 mmol) of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxy)-methyl-9.beta.-hydroxy-6a-carba 
-prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether), 1.6 ml of 
tetra-n-butylammonium fluoride in THF (0.75M) and 3.2 ml of THF. The 
mixture was stirred at room temperature under a nitrogen atmosphere for 18 
hours. THF was removed under reduced pressure and the concentrate was 
treated with water and extracted with ether. The organic phase was washed 
with water, 10% sodium bisulfate, saturated sodium bicarbonate, brine, and 
dried over anhydrous magnesium sulfate. Filtration and concentration in 
vacuo gave a light yellow oil. HPLC, using 166 g silica gel (40-63.mu.), 
eluting with hexane-acetone (3:1), and taking 15 ml fractions, afforded 
the following products: The less polar component, Rf 0.43 in 
hexane-acetone (3:2), was assigned as E isomer and the more polar 
component, Rf 0.39 in the same solvent, was assigned as Z isomer. In 
addition there was obtained a mixture of E and Z isomers. 
NMR (CDCl.sub.3, TMS) (for both E and Z isomers) .delta.: 5.86-5.08 (m, 3H, 
--CH.dbd.CH--, .dbd.CH--), 4.82-4.54 (m, 2H, --O--CH--O--), 4.34-3.28 (m 
and t, --CH--O--, --CH.sub.2 --O). 
IR (film) (for both E and Z isomers) .nu.max: 3400, 2930, 2850, 1440, 1350, 
1260, 1200, 1180, 1120, 1020, 980, 910, and 810 cm.sup.-1. 
EXAMPLE 6 
When in the procedure of Example 1(a) 
(3'S)-7.alpha.-tetrahydropyran-2-yloxy-6.beta.-[3'-tetrahydro-2-yloxyoctan 
yl]bicyclo[3.3.0]octen-3-one or 
(3'S)-7.alpha.-tetrahydropyran-2-yloxy-6.beta.-[3'-tetrahydro-2-yloxy-1'-o 
ctynyl]bicyclo[3.3.0]octen-3-one is substituted for 
3-oxo-(3'S)-7.alpha.-tetrahydropyran-2-yloxy-6.beta.-[3'-tetrahydropyran-2 
-yloxy-trans-1'-octenyl]-bicyclo[3.3.0]oct-1-ene and the general procedure 
of Example 1(a) and 1(b) is otherwise followed one obtains respectively 
5.beta.-hydroxy-7-oxo-3.alpha.-tetrahydropyran-2-yloxy-2.beta.[(3'S)-3'-te 
trahydropyran-2-yloxy-trans-1'-octanyl]bicyclo[3.3.0]octane and 
5.beta.-hydroxy-7-oxo-3.alpha.-tetrahydropyran-2-yloxy-2.beta.[(3'S)-3'-te 
trahydropyran-2-yloxy-trans-1'-octynyl]bicyclo[3.3.0]octane, and when each 
of these compounds so obtained is substituted for 
5.beta.-hydroxy-7-oxo-3.alpha.-tetrahydropyran-2 
-yloxy-2.beta.-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo- 
[3.3.0]octane in Example 1(c) and the procedure of Example 1(c) and 1(d) is 
followed one obtains respectively the 5E and 5Z isomers of 
2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-13,14-dihydro-6a-carba-prostag 
landin I.sub.2 and 
2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-13,14-didehydrota-carba-prosta 
glandin I.sub.2. 
EXAMPLE 7 
When 
(5Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-13,14-dihydro-6a-carba-pr 
ostaglandin I.sub.2 or 
(5Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-13,14-didehydro-ta-carba- 
prostaglandin I.sub.2 is substituted for 
(5E)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2 in the procedure of Example 3 the following are obtained: 
(5Z)-9.beta.-hydroxy-13,14-dihydro-6a-carba-prostaglandin I.sub.2 and 
(5Z)-9.beta.-hydroxy-13,14-didehydro-6a-carba-prostaglandin I.sub.2. 
EXAMPLE 8 
5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-methoxy-6a-carba- 
PGI.sub.2, 11,15-bis(tetrahydropyranyl ether) 
A two-neck round-bottomed flask equipped with a magnetic stirring bar, a 
dropping funnel, and a gas inlet tube under a nitrogen atmosphere was 
charged with 576 mg (12 mmol) of sodium hydride (50% active). The hydride 
was washed twice with dry hexane and the powder was suspended in 20 ml of 
DMF. 5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-hydroxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether) (1.9 g, 3 mmol) 
dissolved in 5 ml of dimethylformamide was added. The resulting mixture 
was stirred at room temperature for one hour. To this mixture 1.7 g (12 
mmol) of methyl iodide dissolved in 5 ml of DMF was added dropwise via 
dropping funnel over 30 minutes. The mixture was stirred at room 
temperature for 18 hours. The mixture was quenched with saturated ammonium 
chloride and extracted with ether. The ether layer was washed with water, 
10% sodium bisulfate, saturated sodium bicarbonate, brine, and dried over 
anhydrous magnesium sulfate. Filtration and concentration gave a brown 
oil. HPLC, using 324 g of silica gel-60 (40-63.mu.), eluting with 
hexane-acetone (20:1), and taking 40 ml fractions, afforded 1.6 g (fr. 
16-63, 82%) of the title compound as an oil. 
NMR (CDCl.sub.3, TMS) .delta.: 5.8-5.1 (m, 3H, --CH.dbd.CH--), 4.80-4.58 
(m, 2H, --O--CH--O--), 4.24-3.30 (m and 5, 8H, --CH--O--, --CH.sub.2 
--O--), 3.20, 3.18 (s, 3H, --OCH.sub.3). 
Infrared (film) .nu.max: 2930, 2850, 1460, 1440, 1360, 1350, 1260, 1200, 
1100, 1020, 975, 900, 870, 840, 820, and 780 cm.sup.-1. 
TLC (Silica gel GF) Rf 0.40 in hexane-acetone (3:1). 
EXAMPLE 9 
5(E and Z)-2-Decarboxy-2-methyloxy-9.beta.-methoxy-6a-carba-prostaglandin 
I.sub.2 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 1.4 g (2.2 mmol) of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-methoxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis(tetrahydropyranyl ether), 6.6 ml of 1N 
HCl, and 26.4 ml of iso-propanol. The mixture was stirred at room 
temperature for 24 hours. Saturated sodium bicarbonate was added until pH 
7 and iso-propanol was removed under reduced pressure. The concentrate was 
extracted with ethyl acetate. The organic layer was washed with brine and 
dried over anhydrous magnesium sulfate. Filtration and concentration 
afforded an oil. HPLC, using two HPLC columns attached in a series (324 g 
and 166 g silica gel-60, 40-63.mu.), eluting with methylene 
chloride-acetone-methanol (20:20:1), and taking 40 ml fractions gave two 
major products with very similar TLC mobility. Fractions 23-27 (344.0 mg) 
gave mostly E-isomer and fractions 58-85 (382.5 mg) gave mostly Z-isomer. 
Repurification of each isomer by the same HPLC condition afforded pure E 
and Z isomers. 
E isomer: 
NMR (CDCl.sub.3, TMS) .delta.: 5.68-5.05 (m, 3H, --CH.dbd.CH--), 4.20-3.60 
(m, 7H, --CH--O--, --CH.sub.2 O--), 3.22 (s, 3H, --OCH.sub.3). 
Infrared (film) .nu.max: 3350, 2960, 2930, 2850, 1640, 1460, 1300, 1260, 
1060, and 970 cm.sup.-1. 
TLC (Silica gel GF) Rf 0.42 in methylene chloride-acetone-methanol 
(10:10:1). 
Z isomer: 
NMR and IR were similar to those of E isomer. 
TLC (Silica gel GF) Rf 0.40 in methylene chloride-acetone-methanol 
(10:10:1). 
EXAMPLE 10 
(5Z)-9.beta.-Methoxy-6a-carba-prostaglandin I.sub.2 
The same procedure as described in Example 3 was followed. Using 363.0 mg 
of platinum oxide in 26.8 ml of water, adding 795.9 mg of sodium 
bicarbonate as well as 350.0 mg (0.955 mmol) of 
(5Z)-2-decarboxy-2-methyloxy-9.beta.-methoxy-6a-carba-prostaglandin 
I.sub.2 and 23.9 ml of acetone-water (1:1). The crude product obtained was 
then purified by HPLC using CC-4 silica gel, eluting with methylene 
chloride-acetone (2:1), and taking 30 ml fractions. The fractions 
homogeneous by TLC were combined and concentrated in vacuo to give 302.0 
mg (83.2%) of pure (5Z)-9.beta.-methoxy-6a-carba-prostaglandin I.sub.2. 
NMR (CDCl.sub.3, TMS) .delta.: 5.75-5.08 (m, 3H, --CH.dbd.CH--), 4.2-3.5 
(m, 2H, --CH--O--), 3.20 (s, 3H, --OCH.sub.3), 2.42 (s, 2H, --CH.sub.2 
--C.dbd.C). 
Infrared (film) .nu.max: 1710, 1060, and 970 cm.sup.-1. 
High Resolution Mass Spectrum (as TMS derivative): Calc'd for C.sub.3 
OH.sub.57 O.sub.5 Si.sub.3 (M.sup.+ --CH.sub.3): 581.3514. Found: 
581.3502. 
TLC (Silica gel GF) Rf 0.29 in chloroform-methanol-acetic acid (20:1:1). 
EXAMPLE 11 
5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-acetoxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether) 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 1.9 g (3.0 mmol) of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-hydroxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether), 3.0 ml of 
acetic anhydride and 3.0 ml of pyridine. To this mixture 76 mg of 
diethylaminopyridine was added. The solution turned yellow in color. After 
stirring at room temperature for 2 hours the mixture was cooled to 
0.degree.-5.degree. C. and -0.6 ml of water was added. The mixture was 
stirred for 10 minutes and then extracted with ether. The etherlayer was 
washed with 10% sodium bisulfate, water, saturated sodium bicarbonate, 
brine and dried over anhydrous magnesium sulfate. Filtration and 
concentration gave a yellow oil (2.0 g). 
NMR (CDCl.sub.3, TMS) showed a singlet at .delta.2.00 indicating 
--OCOCH.sub.3. 
Infrared (film) showed .nu.max 1740 cm.sup.-1. 
TLC (Silica gel GF) showed Rf 0.5 in hexane-acetone (5:1). 
EXAMPLE 12 
5(E and Z)-2-Decarboxy-2-methyloxy-9.beta.-acetoxy-6a-carba-prostaglandin 
I.sub.2 
A round-bottomed flask equipped with a magnetic stirring bar was charged 
with 2.0 g (3.0 mmol) of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxy)methyl-9.beta.-acetoxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether), 9 ml of 1N HCL 
and 36 ml of iso-propanol. The mixture was stirred at room temperature for 
24 hours. Saturated sodium bicarbonate was added until the mixture was 
about pH 7 and iso-propanol was removed under reduced pressure. The 
concentrate was saturated with sodium chloride and extracted with ethyl 
acetate. The organic layer was washed with brine and dried over anhydrous 
magnesium sulfate. Filtration and concentration gave a light yellow oil. 
The crude oil was subjected to HPLC, using two silica gel-60 (40-63.mu.) 
columns (324 g and 321 g) attached in a series, eluting with ethyl 
acetate-methanol (20:5:1), and taking 30 ml fractions. Fractions 82-96 
(540.4 mg) gave E-isomer and fractions 58-84 (577.0 mg) gave Z-isomer. 
E isomer: 
NMR (CDCl.sub.3, TMS) .delta.: 5.68-5.04 (m, 3H, --CH.dbd.CH--), 4.20 
(broad s, 3H, --OH), 4.02-3.60 (m, 2H, --CH--O--), 3.54 (t, 2H, --CH.sub.2 
--O--), 2.00 (s, 3H, --O--CO--CH.sub.3). 
Infrared (film) .nu.max 3400, 2940, 2870, 1730, 1440, 1370, 1240, 1070, 
1020, 970, and 905 cm.sup.-1. 
TLC (Silica gel GF) Rf 0.35 in ethyl acetate-hexane-methanol (20:5:1). 
Z isomer: 
NMR and IR were very similar to those of E isomer, Rf 0.33 in the same 
solvent systems. 
EXAMPLE 13 
(5E)-9.beta.-Acetoxy-6a-carba-prostaglandin I.sub.2 
The same procedure as described earlier in Example 3 was followed. Using 
380.0 mg of platinum oxide in 28 ml of water, adding 833.3 mg of sodium 
bicarbonate as well as 394.5 mg (1.0 mmol) of 
(5E)-2-decarboxy-2-methyloxy-9.beta.-acetoxy-6a-carba-prostaglandin 
I.sub.2 and 25 ml of acetone-water (1:1). The crude product obtained was 
then purified by HPLC using 52.5 g CC-4 silica gel, eluting with methylene 
chloride-acetone (2:1), and taking 30 ml fractions. The fractions 
homogeneous by TLC were combined and concentrated in vacuo to give 280.2 
mg (58.5% of pure (5E)-9.beta.-acetoxy-6a-carba-prostaglandin I.sub.2 
(oil). 
NMR (CDCl.sub.3, TMS) .delta.: 5.68-5.04 (m, 3H, --CH.dbd.CH--), 5.10 
(broad s, 3H, --CO.sub.2 H, --OH), 4.20-3.70 (m, 2H, --CH--O--), 2.00 (s, 
3H, --OCOCH.sub.3). 
Infrared (film) .nu.max 3600-2400, 1730, 1710, 1440, 1370, 1240, 1080, 
1020, and 970 cm.sup.-1. 
TLC (Silica gel GF) Rf 0.32 in chloroform-methanol-acetic acid (20:1:1). 
EXAMPLE 14 
(a) 1-Bromo-2-butyne 
To a stirred solution of 2-butyne-1-ol (10.0 g, 0.143 mol) in 30 ml of 
ether at 0.degree. C. is added pyridine (4.84 g, 0.06 mol, 0.43 eq) at 
once followed by careful dropwise addition of phosphorous tribromide (26.3 
g, 0.097 mol, 0.68 eq) over a 30 minute period. An additional 10 ml of 
ether was added to facilitate stirring and the contents warmed to reflux 
for 2 hous. The reaction mixture is cooled in ice bath, treated cautiously 
with 70 ml of ice water and extracted with ether (2.times.150 ml). The 
combined ether extracts are washed with saturated brine (2.times.25 ml), 
the combined aqueous washings extracted with ether (1.times.50 ml) and the 
combined organic extracts dried over anhydrous sodium sulfate. The 
filtrate is concentrated on a rotary evaporator while keeping the water 
bath temperature less than 10.degree. C. Twice the contents are diluted 
with 100 ml of pentane and reconcentrated as before. The heterogenous 
looking oil is dissolved in 300 ml of pentane, dried over anhydrous 
magnesium sulfate and reconcentrated as before to obtain 11.0 g (58%) of 
1-bromo-2-butyne. 
(b) 2-Methyl-4-hexynoic acid 
Diisopropylamine (26.0 g, 0. 257 mmol, 3.1 eq) in 130 ml of tetrahydrofuran 
initially at -50.degree. C. is treated dropwise with n-butyllithium (98.8 
ml, 1.6M, 0.158 mol, 1.9 eq) over an 8 minute period while allowing the 
temperature to rise to -25.degree. C. After 5 minutes longer at 
-20.degree. C., the reaction mixture is treated dropwise with a mixture of 
hexamethylphosphoramide (17.8 g, 0.099 mol, 1.2 eq) and propionic acid 
(6.14 g, 0.083 mol, 1.0 eq) over a 7 minute period while the temperature 
rises to 0.degree. C. Following addition the reaction mixture is warmed to 
room temperature and maintained there for 35 minutes. The contents are 
then cooled to 0.degree. C. in an ice bath, treated dropwise over a 12 
minute period with 1-bromo-2-butyne (11.0 g, 0.083 mol, 1.0 eq) in 8 ml of 
tetrahydrofuran. The temperature, which rises to 16.degree. C. during 
addition, is allowed to warm to room temperature thereafter where it is 
maintained for 2 hours. The contents are carefully poured into 300 ml of 
10% HCl with stirring (exothermic) followed by 500 ml of ether-pentane 
(1:1). The organic layer is separated and the aqueous phase extracted 2 
more times with etherpentane (1:1) giving 1800 ml of total extract volume. 
The combined extracts are washed with water 2.times.60 ml) and the 
combined organic extracts are dried over anhydrous sodium sulfate, 
magnesium sulfate and concentrated at reduced pressure to provide 11.1 g 
(over theory) of 2-methyl-4-hexynoic acid which is converted to the methyl 
ester by treatment with methyl iodide. 
(c) 3-Methyl-2-oxo-hept-5-yne phosphonic acid dimethyl ester 
A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml 
of tetrahydrofuran is cooled to -78.degree. C. and treated dropwise with 
n-butyllithium (113 ml, 181.24 mmol), 1.6M in hexane) over a 25-minute 
period. The mixture is stirred an additional 30 minutes at -78.degree. C., 
then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 
51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The 
contents are stirred for another 3 hours at 31 78.degree. C. and then 17 
hours at ambient temperature. The reaction mixture is cooled to 8.degree. 
C., treated with 14 ml of acetic acid, stirred at ambient temperature for 
30 minutes, then concentrated in vacuo. The residue is treated with 100 ml 
of saturated brine and 100 ml of ice water to form a slurry and extracted 
3 times with ether (1400 ml total) and once with 250 ml of ethyl 
acetate-ether (1:1). The combined organic extracts are washed with 
saturated brine (2.times.75 ml), the combined aqueous washings extracted 
with ethyl acetate-ether (1:1, 1.times.100 ml) and dried over anhydrous 
sodium sulfate, and concentrated at reduced pressure. Vacuum distillation 
gives 10.21 g of the title product, m.p. 121.degree.-125.degree. C., 0.15 
mmHg. 
EXAMPLE 15 
5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-13,14,15, 
16,17,18,19,20-octanor-12.beta.-(benzyloxymethyl)-6a-carba-prostaglandin 
I.sub.2, 11-tetrahydropyranyl ether 
When in the procedure of Example 1(a) 
6.beta.-[(benzyloxy)methyl]-7a-(tetrahydropyran-2-yloxy)-bicyclo[3.3.0]oct 
en-3-one is substituted for 
3-oxo-7.alpha.-(tetrahydropyran-2-yloxy)-6.beta.-[(3'S)-3'-tetrahydropyran 
-2-yloxy-trans-1'-octenyl]-bicyclo[3.3.0]oct-1-ene and the general 
procedure of Example 1(a) and 1(b) is followed one obtains 
6.beta.-(benzyloxymethyl)-7.alpha.-(tetrahydropyran-2-yloxy)-1.beta.-(hydr 
oxy)-bicyclo[3.3.0]octan-3-one. When this compound is substituted for 
5.beta.-hydroxy-7-oxo-3.alpha.-tetrahydropyran-2-yloxy-2.beta.-[(3'S)-3'-t 
etrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane in Example 
1(c) and the procedure of Example 1(c) is followed one obtains the title 
compound. 
EXAMPLE 16 
5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-13,14,15, 
16,17,18,19,20-octanor-12.beta.-hydroxymethyl-6a-carba-prostaglandin 
I.sub.2, 11-tetrahydropyranyl ether 
Liquid ammonia (100 ml) is distilled into a solution of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-13,14,15, 
16,17,18,19,20-octanor-12.beta.-(benzyloxymethyl)-6a-carba-prostaglandin 
I.sub.2, 11-tetrahydropyranyl ether (5.4 g, 10 mmol) in 100 ml of 
tetrahydrofuran and 2.0 ml of t-butyl-alcohol at 3150.degree. C. utilizing 
a dry ice-acetone trap. The temperature is maintained at about -40.degree. 
C. while freshly scraped lithium wire (4 inches) is added in small pieces 
until the mixture is turned blue. After stirring the mixture for 30 
minutes solid ammonium chloride is added to quench excess lithium. The 
disappearance of blue color indicates the stoppage of reaction. A nitrogen 
stream is swept through the flask to expel the excess ammonia. The solid 
resdue is treated with 100 ml of saturated ammonium chloride and extracted 
with ethyl acetate. The organic phase is washed with brine and dried over 
anhydrous magnesium sulfate. Filtration and concentration in vacuo afford 
the title compound. 
EXAMPLE 17 
(a) 5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-13,14,15, 
16,17,18,19,20-octanor-12.beta.-formyl-6a-carba-prostaglandin I.sub.2, 
11-tetrahydropyranyl ether 
Collins oxidation, known in the art, of 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-13,14,15, 
16,17,18,19,20-octanor-12.beta.-hydroxymethyl-6a-carba-prostaglandin 
I.sub.2, 11-tetrahydropyranyl ether, the title compound of Example 16, 
gives the title compound. 
(b) 5(E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-15-keto-1 
6(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandin I.sub.2, 
11-tetrahydropyranyl ether 
Thallium ethoxide (634 mg, 2.55 mmol) in 10 ml of benzene at 0.degree. C. 
in a round-bottomed flask is treated with 
dimethyl-2-oxo-3-methyl-5-heptynyl phosphonate (613 mg, 2.64 mmol) in 2.5 
ml of benzene. After stirring for 50 minutes at 0.degree. to 10.degree. 
C., the title compound in Example 17(a) (889 mg, 1.96 mmol) in 5 mL of 
benzene is added at once to mixture at 0.degree. C. After stirring the 
mixture at room temperature for one hour, the mixture is again cooled to 
0.degree. C., quenched with 0.5 ml of acetic acid followed by addition of 
aqueous potassium iodide to precipitate the thallium as a yellow salt. The 
contents are diluted with ether, stirred at room temperature and filtered 
through a pad of Celite. The organic phase is washed with ice water, 
saturated sodium bicarbonate, brine, and dried over anhydrous magnesium 
sulfate. Chromatographic purification gives the 17(b) title compound. 
(c) 5 (E and 
Z)-2-Decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-15(R,S)-1 
6-methyl-18,19-tetradehydro-6a-carba-prostaglandin I.sub.2, 
11-tetrahydropyranyl ether 
A round-bottomed flask equipped with a magnetic stirring bar is charged 
with 0.55 g (1.0 mmol) of the title compound in Example 17(b) and 10 ml of 
methanol. The solution is cooled to -20.degree. to -15.degree. C. and 
sodium borohydride (76 mg, 2 mmol) is added. The mixture is stirred for 
one hour and quenched with saturated ammonium chloride. Methanol is 
removed under reduced pressure and the residue is extracted with ethyl 
acetate. The organic phase is washed with brine and dried over anhydrous 
magnesium sulfate. Chromatographic separation resolves the 15(R) and 15(S) 
isomers. 
EXAMPLE 18 
(a) 5(E and 
Z)-2-Decarboxy-2-hydroxymethyl-9.beta.-hydroxy-16(R,S)-16-methyl-18,19-tet 
radehydro-6a-carba-prostaglandin I.sub.2 
When in the procedure of Example 1(d) 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-16(R,S)-1 
6-methyl-18,19-tetradehydro-6a-carba-prostaglandin I.sub.2, 
11-tetrahydropyranyl ether is substituted for 5(E and 
Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-9.beta.-hydroxy-6a-carba- 
prostaglandin I.sub.2, 11,15-bis-(tetrahydropyranyl ether), one obtains the 
title compound. As in the case of Example 1(d), the (5E) and (5Z) isomers 
are resolved by the chromatographic separation. 
(b) 
9.beta.-Hydroxy-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandi 
n I.sub.2 
When in the procedure of Example 3 
(5Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-16(R,S)-16-methyl-18,19-t 
etradehydro-6a-carba-prostaglandin I.sub.2 is substituted for 
(5E)-2-decarboxy-2-methyl-oxy-9.beta.-hydroxy-6a-carba-prostaglandin 
I.sub.2 one obtains the title compound after the chromatographic 
purification. 
EXAMPLE 19 
When in the procedure of Example 17(b) each of the following phosphonates 
is substituted for dimethyl-2-oxo-3-methyl-5-heptynyl phosphonate and the 
procedures of Examples 17(b), 17(c) and 18 are followed one ultimately 
obtains the 9.beta.-hydroxy products listed below: 
dimethyl-2-oxo-3-phenylpropyl phosphonate; 
dimethyl-2-oxo-4-phenylbutyl phosphonate; 
dimethyl-2-oxo-3-phenoxypropyl phosphonate; 
dimethyl-2-oxo-4-(3-thienyl)butyl phosphonate; 
dimethyl-2-cyclohexyl-2-oxoethyl phosphonate; 
dimethyl-2-oxo-3-(3-thienyloxy)propyl phosphonate; or 
dimethyl-2-oxo-2-(3-ethylcyclobutyl)ethyl phosphonate; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-16-phenyl-17,18,19,20-tetra 
nor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-17-phenyl-18,19,20-trinor-6 
a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-16-phenoxy-17,18,19,20-tetr 
anor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-17-(3-thienyl)-18,19,20-tri 
nor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-15-cyclohexyl-16,17,18,19,2 
0-pentanor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-16-(3-thienyloxy)-17,18,19, 
20-tetranor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-2-decarboxy-2-hydroxymethyl-9.beta.-hydroxy-15-(3-ethylcyclobutyl)-16,1 
7,18,19,20-pentanor-6a-carba-prostaglandin I.sub.2 ; 
5(E and 
Z)-9.beta.-hydroxy-16-phenyl-17,18,19,20-tetranor-6a-carba-prostaglandin 
I.sub.2 ; 
5(E and Z)-9.beta.-hydroxy-17-phenyl-18,19,20-trinor-6a-carba-prostaglandin 
I.sub.2 ; 
5(E and 
Z)-9.beta.-hydroxy-16-phenoxy-17,18,19,20-tetranor-6a-carba-prostaglandin 
I.sub.2 ; 
5-(E and 
Z)-9.beta.-hydroxy-17-(3-thienyl)-18,19,20-trinor-6a-carba-prostaglandin 
I.sub.2 ; 
5(E and 
Z)-9.beta.-hydroxy-15-cyclohexyl-16,17,18,19,20-pentanor-6a-carba-prostagl 
andin I.sub.2 ; 
5(E and 
Z)-9.beta.-hydroxy-16-(3-thienyl-oxy)-17,18,19,20-tetranor-6a-carba-prosta 
glandin I.sub.2 ; 
5(E and 
Z)-9.beta.-hydroxy-15-(3-ethylcyclobutyl)-16,17,18,19,20-pentanor-6a-carba 
-prostaglandin I.sub.2 ; 
##STR27##