Note: Descriptions are shown in the official language in which they were submitted.
~L~5~
-- 1 ~
~he present in~enti~n iB concerneà with novel 5-
fl~oro-carbac~clin derivative~ with a process for
their man~act~rc and with their ~e as medicame~t~.
(5~)- and (5Z~-6a-carbaprostaglandin~I2 ~nalogues are
described in ~erm~n Offenlegungssc~ri~t 9peci~ications
~oa. 28 45 7709 29 00 35?, 29 02 4427 29 04 655,
2~ 09 0~8, ~0 48 906 and 29 12 4~9. The ~omenclature
~hich ie ~sea herein ~or the compo~da accordi~g to
the pre~ent invention i8 ba~ed on a propo~al b~ Norto~
~d ~roka~ (~. Or~. Chem. ~ , 22~0 ~lg79~ he
synthesis o~ the~e compo~d~ al~-ay6 prod~ce~ two
do~ble bond isomer~ ~hich are ch~r~cteri~ed b~ the
prefi~ ) or (5Z). ~he two i~omers of thi~ proto-
type are repre~ented ~y the following str~ctur21
~ormulae:
-- 7 --
~C0
,r
~0 0~
( 5:E)-6a--carbapro5tagl~n~ I2
co2~
/~
EO o~I
( 5Z )--6PL-ca~b~proBtagl~din I
It i~ kn~ from the very eætensive prior art
on pro~tac~clin~ and their analogues that this clas~
of ~ubstances 9 owing to their biological and ph~rma
c~l~gieal properties, iA 6uitable ~or the treatment of
m~mm~l8~ including h~man beings~ Their use as medica~
ment~ however) ~req~entl~ enco~nter~ dif~iculties,
~ince they have a period of action that i~ too 3hort
for therapeutic purpoae~O The aim of ~n~ structural
modification iæ to increa~e the period of action aR
1~ well as the ~electivity of the activity~
It ha~ no~ been io~nd that a longer period oi
actio~, a g~eater ~electivit~ and a~ improved actlvity
can be achieved b~ replacing the hydroge~ atom in *he
~-pD~itio~ o~ th~ carba~yclin~ b~ a fluor-ne ato~
~he compo~nds of the prese~t in~ention, as deiined
belo~9 have a hypoteneive and bro~chodilative action.
The~ are furthermore s~itable ~or va~odilztation, an~
the inhibition o~ thromboc~te aggregPtion and of ga8
t~ic acid ~ecretion~
~he pregent invention accord~ngly provide~ 5-
fluoro-carbacyclln derivatives o~ the general formula
I
:~L25i~93
~2 C~2 ~2 E~l
--
~ W-D-~,
-
in ~hich
~1 represent~ a --CH20l~ ~~? ~ or
L repre~er~t~ a gro~p of the f orm~
~ 2
in which :~2 repre~ents a hydrogen ato~lL, an
un~3ub~tituted or ~ubstit~ted all~yl, cycloalkyl
or a:r~l group J a -C:EI2~ aryl group in R:tlich the
a~;yl group may be ~ubstit~ted, or a hetero-
cyclic group, or O
~:L represellt~ a group o~ the ~ormula -~5
in which ~3 represent~ an acyl ~;roup derived
îrom an org~nic carbo~;ylic or 6ulphonic acid
contzi~ing up to 10 carbon ato~s, a h~droge~
_ 5
~P atom, an uns~bstit~ted or ~b~ti tu~*ed a~ 9
c srcl~alkgl or aryl group, a C~2-C-ar;yl group
in ~rhich the 2:~1 ~OUp may~ be ~ub~tit~t ed " or
a heterocyclic group, or
~ repre~ents a gro~p o~ the form~la
~ ~1
_~ I
( 0~ )~,,
in ~hich m repre~ent~ 1 or ~"
~epreBe~t~ ~L CEI2-~H2- ~ro~p, a tran~
gro~p or a -~ gr~up,
1() ~ represent~ a ~r~e or ~unctio~ll;y modi~ied
h~rdro~ymeth;ylene gro~p or a ~ree or ~:Lctio~ally
~3
modi~ied ~C- gro~p, the h~dro~l gro~p in
OH
each gro~p being in the a- or ~-position~
D repreaents a gro~p of the formula
--C--C~2
<
(~a~)n
in which n represent~ 17 2 or 3 and whioh may
be substituted by at lea~t one fluorine ato~,
or repreaent~ a bivalent ~liph~tic hydroc~rbo~
3~
group contalning up to 10 carbon atoms which may be substituted
by at least one fluorine atom, E represents a -C-C- group, R~
represents an unsubstituted or substituted aliphatic hydrocarbon,
cycloalkyl or aryl group, or a heterocyclic group, and R5
represents a free or functionally modified hydroxyl group, and
physiologically tolerable salts wlth bases of such compounds in
which Rl represents a group of the formula
C~
~ OR2
in which R2 represents a hydrogen atom.
It is to be understood herein that the general formula
I inlcudes both the (5E~- and ~5Z)- isomers.
As alkyl groups represented by R2 and R3 there come
into considera-tion straight-chain or branched-chain alkyl grops
containing from 1 to 10 carbon atoms.
-- 6 --
:
for e~ample methyl, ethyl9 propyl, isopropyl~ butyl~
lBObUt~l, tert.-butyl, pen~ opent~l~ neopen~
heptyl, hegyl ~nd dec~l group~
~he alkyl group8 represented by ~2 and ~ ma~
if desired, be ~ub~tituted by one or more substitne~ts
~elected from haloge~ atoma, hydro~yl ~ro~ps, Cl-C4-
alko~ group8, optional-~ eub~ituted C6-C10-aryl
group~, di-(cl-c4-alkyl)-amino ~roup~ z~d tri-~Cl C~-
alkyl)-ammoni~m gro~pa. Such alkyl groups that are
mono-sub~tit~ted ~re preferred.
~ 8 ~ub~tit~e~t~ there may be ~entioned~ for
e~a~ple, ~luori~e, c~lorine ~d bromine ato~s ~nd
phenyl, dimethylamino, diethylamino, methox~ and
etho~y gro~p80
~s p~eferred unsub~tit~ted and æubstitu~ed alkyl
gro~ps represented by R~ and ~ there ~ay be mention~d
tho~e containing ~rom 1 to 4 carbon 2t~6 1n e~ch
al~yl ~roup or part, respecti~ely, f or eælmple methyl,
ethyl, propyl~ dimethylami~oprop~ obu~l and
butyl group~.
As aryl ~ro~ps represented b~ R2 ~nd ~3 -there
come into co~sideration both ~ubstituted and U118~b-
stituted ar~l gro~p~, for e~ample phen~ naphthyl
a~d 2-n2phthyl ~roup8, each oi which m2y be substit~ted
by from 1 to 3 halogen atoms, a phenyl ~roup, from 1
to 3 aIkyl groups each contP~ning from 1 -to 4 carbon
Ptoms, a chloromethgl, fluoro~ethyl, trifluoromethylD
3~
carbo~yl or h~àro~yl gro~p or a~ alko~ gr~up contai
ing irom 1 to 4 c~rbon atoms. The ~ub~i~entR ~r~
preferabl~ in the ~- a~d 4-po~i-tio~s ol the phen~l
ring, ~uch æubstituents being, for eYample7 ~luorine,
chlorl~e, al~o~ and trifluoromethyl; a hydro~yl
aubstituent is preferably in the 4-position.
The cyclo~lkyl groups represented b~ ~2 and
m~.y contain from ~ to 10, but preferably 5 or 69
carbon atoms i n the ring, ~he ringa may be ~ùb;
stit~ted b~ one or more al~yl groups each containi~g
~rom 1 to 4 carbon atom~. ~here may be mentio~ed~
for e~ample9 c~clopenty~, cyclo~e~l, meth~lcycl~-
he~l and adama~tyl grGUp9~ -
~ heteroc~clic grO~pB represented by ~2 and
there come into conside~ti~n 5- znd 6-mem~ered
heteroc~cles that contain at least 1 hetero atom,
preferably sele~ted ~rom nitrogen, o~ygen a~d sulphur
atom~. ~here ~P~ be mentio~ed inter alia, ~or e~-
ample, 2-~uryl, ~-iuryl, 2 thienyl, ~ t~ienvl1 2-
p~ridyl, ~-pyridyl and 4-pyridyl ~ oups.
The aryl groups in the -~E2-C-zryl groups re-
presented by ~2 ZrLQ ~ m~ ~e phenyl, l-naphthyl ~nd
2-naphth~l ~roups, each of which may be substitute~
by ro~ 1 to 3 Cl-C4-zlko~y groups, ~rom 1 to 3
hzlogen atoms7 for exam~le ~, Cl or .Br, or ~rom 1 to
3 phen~l gr~ups,each of ~hich may in turn be sub-
stituted by from 1 to ~ h~loge~ atoms, for e~ample
~, Cl or ~r, or from 1 to ~ Cl-C4-alko~y ~roup~.
Preferred are mo~osubstit~tion~ ~ith phenyl9 Cl-C2-
alko~ chlorine or bromine.
h~ acyl groups repreaented b~ ~ there come
into coneideration physiologicPlly tolerable acyl
gro~p9 . Preferred acyl groupR are tho~e o~ organic
ca:rbo~lic acid~ and sulphonic acid~ cont ~ g ~rom
1 to 10 carbon atom~ belo~gin~ to the ~liphatic~
c~rcloaliphatic, aroEIlatic ~ aroE~tic-a:!iphztic and
10 heteroc ~clic ~erie~. lhese ~ cids may be ~aturated
or un~atura-ted arla/~r mono ~ di~ or pol~basic and/or
un~ubstitute~ or ~ubs~it~ted 1~ the customa~y m~nnerD
There may be me~tio~ed as e~a~ples of the sub~tit~ents
C~ alkyl gro~ps, hy~ro2yl gro~pæ, C~ ælk~y
groups) oxo gr~up~ amino ~roups and h~o~en atoms
(~, Cl, Br)~
~ he h~dro~yl groups represe~ted b~ R5 and each
oi the hydro~yl group~ in the h~dro~ containi~g
gro~ps represe~ted b~ ~ ma~ be ~unctio~Pl 1~ modified,
for e~ample b~ etheri~icetion or esteri~ication,
it bein~ posEible ~or the free or modi~ied h~droxyl
groups in the groups represented by W to be i~ the
a- or ~-po~i-tio~; ~ree h~dro~yl groups ~re pre-
ferred.
~s ether and ac~l ~roups for these ~u~ctio~ally
modif~ed hydroxyl groups there come into consi.deratio~
-- 10 ~
th~se th~t are kno~n to a per~on ~killed ~n the artO
Pre~erred ~re ether gro~p~ th~t can re~dily be Yplit
o~ or e~ample tetrahydropyrzn~l, tebrah~dro~ranyl~
~-etho~yethyl, trimethylsilyl~ dimethyl-tert.-butyl-
silyl a~d tribenzylsilyl groupa,
As acyl group~ there come into consideratio~those ~entioned above ~or ~ ; the follo~ing ~a~ be
mentioned b~ way o~ e~ample, namel~ acet~l~ propion~l,
but~r~l and benzoyl group~O
aliph2tic hydrocarbon gro~ps repre~ented by ~4
there come into con~ideration strai~h~-chain a~d
branched chai~, saturated ~d ~atur~ted Plipha~ic
hydroc~rbon gro~pa~ but pre~erably sat~rated group~,
that i8 al~yl group6, containi~g ~p to 10~ e~peci~lly
up to 73 carbo~ ato3~, which may, i~ desired, be
substit~ted b~ optionall~ ~ubstit~ted a~yl group~.
~here ma~ be mentio~ed, f~r example, ~eth~l, ethyl,
propyl, butyl, isob~tyl, tert,-but~19 pentyl, he~yl,
heptyl, octyl, butenyl, isobu*enyl~ propenyl; pen-
tenyl, he~en~l7 ben~yl and ~-chlorobe~z~l grOUp8o
The cycloalk~l &roup~ represented b~ R4 may ccn-
tain ~ro~ 3 t~ 10, b~t preferably fro~ 3 to 6, c~rbon
atoms in the ri~gD The ri~gs may be substituted by
one or more alkyl group~ each contai~ing ~rom 1 to 4
carbon atoms. ~here may be ~entioned, ~or e~ample 9
cyclopropyl~ cyclobutyl~ c~clopentyl, cyclohe~yl,
me~hyl-cyclohe~yl and a~amantyl group~0
3~
~ ~ub~tit~ted and ~nsubstituted aryl groupq
represented b~ ~ there come into conEide~atio~? ~or
e~ple, phenyl, l-naphthyl a~d 2-naphthyl ~roup~,
each of ~hich may be subs-tituted by .~rom 1 to 3
halogen atoms9 a phen~l group, ~rom 1 to ~ alkyl
group~ each contain ~ from 1 to 4 carbon atoms, ~r
a ch-oromethyl, fluorometh~l~ trifluorome~hyl, car-
bo~yl, ~l-C4-Plko~y or hydro~yl ~roup. ~he substi-
tution i8 preferabl~ in the 3D and 4-positionE o~
the phe~yl rt~, such ~ubstituents bei~g~ for eæample,
fluori~e~ chlor~ ne ~ Cl-C4-alko~y and trlfl~oro-
~eth~l; a h~dro~yl ~bqtit~ent i3 preferably ln the
4 pos~io~.
As he~eroc~clic gro~p~ repre6ented b~ ~4 there
come i~to considerat~on 5- Pnd 6-me~bered hetero-
c~cles that contain at lea~t 1 hetero atom9 preferabl~
~elected L~om nitrogen, oxygen and sulphur atom~.
There ma~ be mentioned ln r alia7 for example~ 2-
fur~l, 2-thienyl, 2-pyridyl, ~-pyridvl, 4-pyridyl,
3-~uryl æ~d 3~thien~1 group~0
~ the bivalent al~phatic hydrocæ~bon gro~ps
represented b~ D there come into con~iaeration
straight-chain and branched-chain, 6&turated and
un~aturated bivalent aliphatic hydroczrbon groups
containing up to 10 czrbon atoms, the straight-c~ain,
saturated ~roups (that i9 strai~ht-cha n alkylene
groups) containing 1 to 10, pre~e~abl~ 1 tD 5, carbon
atoms, and the branched-chain~ saturated groups (that is
branched-chain alkylene groups) and unsaturated groups containiny
2 to 10, preferably 2 to 5, carbon atoms; all such groups may, if
desired, be substituted by at least one :Eluorine atom. There may
be mentioned, for example, methylene, fluoromethylene, ethylene,
1,2-propylene, ethylethylene, trimethylene, tetramethylene,
pentamethylene, 1-methyltetramethylene and l-methyltrimethylene
groups.
There are suitable for the formatlon of salts with the
free aicds (R2 =H) those inorganic and organic bases that are
already known to a person skilled in the art for the formation of
physiologically tolerable salts. There may be metnioned, for
example, alkali metal hydroxides, for example sodlum and
potassium hydroxide, alkaline earth metal hydroxides, for example
calcium hydroxide, ammonia and amines, for example ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine, morpholine
and tris-(hydroxymethyl)-methylamine.
The present invention also provides a process for the
manufacture of the 5-fluoro-carbacyclln dPrivatives of the
present invention of the general formula I and physiologically
tolerable salts with bases of such compounds in which R
represents a group of formula
-C~
\ ~2
3~ in which R2 represents a hydrogen atom, wherein the silyloxy
group in a compound of the general formula II
lcE~z-cEl2-cH2-c~2~ s~
CF \ b
~ ~1~
:
- 12 ~ (II),
~-W-D_E_~4
in which R4, R5, A, w, D and ~ have the meanings glven above and
R8, Rg and Rlo each represents a Cl-C10- alkyl group or an aryl
group, i5 converted into a free hydroxyl group, and then, iE
desired, in any sequence,
~0
- 13 -
,,~`.
. ~,
~4
any re~ultln$ i~omers a~e sep2xated ~d/or -the
hydro~meth~l ~ro~p i~ the 2-position is o~idiaed to
form a carbox~l group (~ = C~O~ and/or any fUn5-
tionally ~odi~ied hydro~yl ~ro~p is converted into a
~ree hydroxyl ~roup and/or an~ ~ree hydro~l group
i~ esterified or etheri~ied and/or ~n~ free carbox~l
group i~ esterified or converted into 2 gro~p 0~ the
formula
~\ I
(~ ~ )m
10 ~ representing 1 or 2, and/or any result~n~ cGmpo~nd
conta; ~ing an e~teri~ied carbo~yl gro~p is converted
into the corre~ponding ~ree acid or a phy~iologic~lly
toler~ble 6alt thereo~ with a base and/or ~ny re~lt~
i~g compou~d containing a free czrbo~l group is con-
verted into an amide tOereo~ (the amide containi~g agroup of the formulz -C~ haYi~g the meaning
give~ ~bove) or a phyaiologically tolerable Balt
thereo~ with a ba~e.
Each step in the proces6 of the pre6e~nt invention
may be carried o~t ~ n 2 m~nner known ~er se.
1~ desired, any free hydro~l groups ~n ~ atarting
materiPl of the general for~ula II ma~ be protected
before the converBion of the ~ilylo~y group into a
hydroxyl group,
The s~mbols R8 9 ~ ænd ~10 mPy h2~e the same o~
different mean~gs, ~he Cl ic-Plkyl ~oups repre--
sented by these s~mbol~ may have a ~tr2ight or br~nched
chain O
The sil~l ether ~roups in the com~ound~ of the
gener~l ~or~la II ma~ be split o~i by meanR of a
reagent known to be ~uitable for thi~ purpose, for
e~ample ~ith a tetraalkylammo~ium fluoride~ pre~er-
ably tetr~b~tylammonium ~luoride5 or ~-th an alkali
1~ metal fl~oride or P.lkaline earth metal ~luoride in an
i~ert sol~ent~ fo~ example tet~ahydro~ran, dieth~l
ether, dio:i:an, dimetho~yethane, methylene ::hloride,
dime thyl~or~de or di~eth;yl sulpho~iae, at tempera
t~res oi bet~een 0C and 80C? preferably :~r~m 20~
15 to 45~
~ he optional oxidation of the l-hydro:~l gro~p
ma~ be ca~Tied o~t in accordance ~ith 2 method kno~rn
to a person skilled ~ the art, ~here mPy be ~ed
~s o~ldising agents, for exam?le, pyricini~m di-
20 chromate (Tetrahedron :Letters, ~Z2- 399~ 3 Jone8
reagent (J~, Chem. Sec. ~, 2555~ or ~latinumJ
o~gen ~Adv. in Carbohydrate Chem. ~-7`, 169 (1962)]
or Collins o~iàation and subseq~ent Jones o~id~tion.
The o~idation with pyridini~m dic~romate is
czrried o~t at temperat~res of from 0C to 100C 9
preferabl~ ~rom 20C to 40C 9 i~ a sol~ent that i~
-- 16 -
inert with respe ct to the o:~di~ agent " f or e:~:amp l e
dimeth;~l~orm~de 1,
The o:~idation wi~h ~o:~eB rea~gent i~ car:rled o~t
at ~emperat~re~ oi ~rom ~40~C to ~4C~C, preferabl;y
5 from 0C to 30~C 9 in acetone a~ solvent .
~ he o~ idation ~ith pla~ /o~:ygen i8 carried
o~t at temperat~re~ of fro~ 0C to 60C 9 preferably
from 20C to 40C, in a ~ol~ent ~hat i~ ine:~t w~th
respoct to the o~idis~g agent, ~or s~mple ethyl
10 acetate .
The h;ydrolysi~ o~ the carb~c;~clin eSteT~ t~ fo~
the corre~po~ding free aclde or 6alts thereoi ~ay b~
carried o~t ic accordance ~ith ~ethoda kn~n ~o a
person skilled i~ the art~ ~or e~ample ~i*h ba~ic
catal~t~.
~ he i~trod~ctio~ of a~ eoter gro~p ~o iorm a
compo~ o~ the ge~ersl formRla I in ~hich ~ repre;
~ent~ C ~ ~ when ~2 represents an al~yl group con~
taining fro~ 1 tQ 10 carbon atoms, m~ be carried o~t
i~ accordance with methods k~o~n to a per~on skilled
i~ the art~ The czrbo~y~compou~ds are, for e~ample~
reacted with diazohydroc~rbon~ in a mPnner known
~r se. ~he e~terific~tio~ wi-th diazoh~drocæ~bons
iB cPrried VUt 9 for example, by mixin~ a ~olution o~
the diazoh~droc2rbon in an inert ~olvent, preferabl~
in diethyl ether, with the carbo~y-compGund in the
~ 17
saale or ~ a di~ere:Qt inert ~ol~ent, ~or e~cample
meth~le~e chlor~de. When the reaction ~as bee:r~ com~
pleted, ~hich ta~ea ~rom 1 to 30 ~iIl~te~, the solven-t
iB removed and the eater iB p~ri~ied i~ the cu~tvmar;y
5 ma~erO Diazoal~a~es are ei ther ~:no~n or ca:~ be pre-
pared accordi ng to kno~ll methods [Prg. }3eaction~,
vol. 8" pagea 389-~94 (19543~. 0
The i~troduction OI an e~ter group -CaEL2 repre-
~ented by ~ when }~2 repr~sent~ a ~u~atitllted or an
nnQubætit~ted ar~l groupg may be carried oll~ acsordi~Lg
to ~ethods kno~n to a perBO~ ~killed in the art, ~or
e~ample, the carbox~-c~mpDu~ds are reacted ~n ~ inert
solve~t ~ith the corre~pond~ ng hydro~y ~yl co~p~nd~
in the pre~ence o~ dic~clohe~yl carb~di~;de and ~f
a 8uitable ba~e~ ~or e~a~ple pyrid' e ~r triethyl-
~ e. A3 ~olvents there c~me ~ to co~sideration
methylene chloride~ ethylene chloride~ chloroform~
ethyl acet~te and tetrah~dro~ran, b~t pre~erably
chlorciormO ~he reac~ion i c~rried out at tempera
2Q turee of bet~een -30 C and ~50C, b~t preferably at
+lO~C. 0
~ he introductiD~ of the ester gro~p - COR2
repre~ented by ~ can also be carried ou~ by reacting
the carbo~ylate Pnion ~-ith the corresponding alkyl
~alide oO w-h~lok0tone (for e~ample of the form~la
~al-C~2-C-~r9 in which ~r repre~ent~ phenyl or di~
phenyl each o~ ~h.ich ma~ be s~b~tit~ted by Cl~C
jl3~
-- 1~
al~o~y ~r chlo~e or bromine ) .
l`he introduction o~ the ~2~ cazoli:ELe gro~p
~--I
-C\
~ C~[2 )~a
represented by ~ be car:ried out ~ accord~nce
5 ~ith the proceeees de~cribed in GermPn O~:fenleg~ng~
BC~i~t Specification~ No~ 30 47 759, 31 15 997 Pnd
~1 45 8~0. :i?or e:~ample, the carboxy-compo~nd~ are
converted ~to the ~2--o:~azoli~le~ in the pre~e~ce o:~
the correspondirlg amin~ cohol ~ith the ~e o~ a
10 tertiar~ pho~phirle ~ e~peciall~ triphen;yl phc~sphir~e,
i~ the pre~ence o~ a hal~compovlld7 eQpecially, for
e~ ple, carbo~ tetrachloride, and a tertia~y ba~e~
pref erabl~ trieth ~la~irLe or D:B33 ~,
~he carbac;yclin àerivatives of the general f ormula
15 I ~n ~hich :E~2 represen~ a h;srdrogen atom ~a~ be co~
~erted into ~alt3 b;y ~eutralisatio~ ~nth ~u~table
amount~ of the appropria~e i~LorgarLic ba~es. l?or
e~ample, ~hen the appropriate acid iB dis~o~ved in
~ater containiDg the 3toichiometric a~:oun~ of the
20 ba~e 3 the ~olid i~org~ic salt is obtai~ed after
evaporati~ag olf the ~zter or aIter adàing a w2ter-
miscible ~olvent, for e~ample alcohol or acetoILe~
~ he ma~u~act~re vf the amine 8altB ma~ be carried
out in a c~6tomar;y manner. ~or this ~rpose the
~:~5~i~3~
~ 19 --
carbacyclin ~cid i~, ~or example~ diasolved in a
6uitable ~olvent, ~or e~ample ethanol 9 acetone, di-
ethyl ether or benzene, and at least the stoichi~;
metric amount o~ the amine i8 added to thiB sol~tionO
In this way the sPlt i~ u~u21ly obtained in a 601id
form or is isolated in the customa.ry m~nner a~ter
evaporation of the solve~t.
~ he ~nctional modification ~f free hyhro~yl
groups may be carried o~t according to methods knoun
to a person ~ki~led ~ n the art. For the introduction
of ether protect~ng gro~ps, a reaction i~ carried out
~ith, for eza~ple9 dihydrop~ra~ ln meth~lene chloride
or chloroform ~ing an acidic co~de~satio~ agent~
for e~ample p-toluenes~lpho ic acid. ~he dihydr~-
pyran 1~ used ~n e~ce~ preferzbly in an amo~nt thatiB ~rom 4 to 10 timea the amo~t theoreticall~ requir~
The reactio~ i~ nor~ally oo~plete at 0C to ~0C a~ter
15 to 30 mi nutes .
The i~troduction of ac~l protectin~ groups ma~
be carried o~t by reacti~g 2 compo~d of the ge~eral
fo~mula I in a manner kno~n per ~e with ~ carbo~ylic
acid deriv~tive, inter alia, for e~ample, an acid
chloride or acid anhydrideO
~he liberation of P fu~ctio~all~ modiiied h~
dro~yl group to ~orm the compounds of the general
~orm~la I conta1 ni ~g free hydrox~l group~ ma~ be
33
- 20 --
carried o~ aceordIng to known ~eth~ds. ~or example 9
ether protectlng group~ are split ofi ~ an ~q~eo~s
~olutio~ o~ an organic acid, inter a~ or exæmple,
acetic acid or propionic acid9 or i~ a~ aq~eouR
solution o~ Pn inorg~nic acid, ~or e~aeple h~drochloric
acid. To improve ~ol~bilit~, a water-mi~cible inert
organic solvent i~ advantageo~sly added. Suitable
organic solventQ ære, for e~ample, alcohol~ ~or
e~ample ~ethanol and ethanol, a~d ethersr for e~amp~e
d~metho~ethane, diox~ a~d tetrahydro~ura~. ~etra~
hydro~ran is pre~erably ~ea~ The ~plitting of~ i8
carried o~t preferably at temperatureE o~ be~een
2~C and 80C~
Siyl ether protecting gro~p~ are ~plit Of iJ
~or e~ample~ ~ith tetræbut~lam~oniu~ fluoride.
S~itable ~olve~t~ are, ~or e~.~mple, te~rah~dro~uran;
dieth~l ether, dio~an and methylene chloride~ ~he
~plitting of~ i8 preierabl~ carried out at temperatures
of between 0C and ~0C.
The h~droly6is of acylox~ groupa i 8 carried out~
for example, ~ith alkali met~l carbonzteP or hydrox-
ide~ or alkaline ePrth metal carbo~tes or h~dro~ide~
i~ an alcohol or in zn aqueous sol~tio~ o~ an alcohol.
As alcohols there come into consideration ali-
phatic alcohols, for e~ample methanol, eth~nol znd
butanol, 'out pre~erabl~ metha~ol. ~s ~lk21i metal
~5~
carbonates a~d h~dro~ides there may be me~tioned
potas~ium and ~odium s~lts, b~t the potaa i~ ealts
are h~wever preferred. Suit~ble Plk~l~ne earth ~etal
cP~rbonates and h~droxides are, ~or e~ample, calcium
carbonate, calci~m hydro~ide and barium carbonat~
~he reaction is carried ou~ at -10C ~o 70C ? but
pref erably at 25C .
The introduction of n Pmide group to form 2 com-
polmd o~ the general fo~ la I ~ n ~hich E~ repreE~ents
10 -C~R~ be carried o~t accordi~g to ~ethc~ds kllo~
to a per~on s~llled in the art.. ~?or e ~ mple~ th~
carbo~ylic acid~ of t~e general ~orm~la I (~ = H3
are fir~t of all conYerted ~ the pre~ence o~ a tertia~y
~m~ne7 for e~a~ple ~r~ethylamine~ ~ato the mi~ed an-
hydride ~ith chloroformic acid i~obutyl e~ter. ~heanh~dride i~ then reacted ~ith an al~al~ metal ~alt
o~ the corre~ponding am~àe ~r ~ith ammonia (~hen ~ -
~) in Pn inert solvent or ~o~ent mi~tGre 9 ior e~ample
tetrahydrof~rPn, dimetho~eth~ne, dimethyl~orm~mide or
he~amethylphoaphoric acld triamide, ~t temperatnre~
of between -~0C and +60C, prefer2bly at ~ro~ 0C to
~0C
Another possible method ~or the introduction of
an amide ~roup -C ~ represented by ~ comprise~
reacting a l-carbo~ylic acid of the general for~ula I
(~2 ~ ~), in ~hich, ~hen necessary9 free h~dro~l
- 22 -
~roup~ are i~termediately protected, ~ith a compo~nd
o~ the general form~la ~II
0 = C =
i~ ~hich ~ ha~ the ~ea~I~g give~ above~
~he reaction ol the compound of the general
formula I (~2 = ~) with an isoc~aDate of the general
formula III 1~ optionally carried cut ~ith the addition
of a tertiary ~ e, ~or e~ample triethylami~e ~r
pyridine. The reaction can ~e carried out without
a 201vent or in an inert ~ol~e~, preierably aceto-
~itrile~ tetrahydr~ura~, acetone, d~metk~lacetamidey
~eth~lene chloride, die~h~l ether or toluene9 at
temper~t~res of bet~een -80C to 100C, preferably
at from ~C to 3~C.
~hen the st~rting material contain~ hydro~yl
gro~ps i the prost~ne group, the~ these ~ydroxyl
grOUp8 ~1BO take part in the reaction~ ~hu~ the
finall~ desired end pr~d~cts are those co~taini~g ~ree
hydro~l groups in t~e prostane group, the star~i~g
mæterials ~sed are ad~antageously those i~ ~nich the~e
hydro~l gro~ps are i~ter~ediatel~ protected b~ ether
or ac~l groups that are prefera~l~ capable o~ being
readil~ split off.
~he compound6 ol the general form~la II ~sed as
~tarting materials may be man~factured, for e~ample7
23 -
by ~eacting in a ~a~ner kno~n ~er ~e ~ aldeh~de of
the ~ormula IV (~erman Offenlegungssch~i~t Speeifica-
tio~ No~ 2B 45~ 770)
X
( r~ )
s ~ 0
5 with a phosphonate o* the general lor~la V
C~O O O
\ 11 11
/ 2 C - D - ~ - R4 (~)
C~O
in ~hich D, ~ and ~ h~ve the me~n~ng~ given abo~e,
i~ the pre~ence of a deprotonat~ng age~t, for e~ample
80dium hydride or pot2ssium ter~-buto~ide, to ~orES a
ketone of the general forrnula Vl (~ r, addi-
tion~l ly, in the presence of a bromin2tIng agent,
~or example ~-brom~sRccil:Li~de, to fo:r~ a k:etone o~
t.he general f o~mllla VI (~ 3r~
I I
O O
X
(VI) .
C--D~
OC~
A~ter red~Lctioll of the :~eto gro~p with z~c boIv-
5 hydride or ~odi~ boroh~dride, or reaction with a~
alkyl mag~esium bromide or a lithi~ ~kyl~ and sub--
seque:~t ep~mer separation9 compo~d6 of the generPl
f orm~la VII
O~<
~` (VII~
C E[=C:~-W-~R4
0-~
2 5 ~ 2~ 0
are ob tai ned.
~ drol~ie of the e~ter group9 for e~mpls ~ith
potas~ium carbonate in methanol, and ~ptional h~dro-
genatio~ of the double bond or option~l etherifica-
5 tion with di~ydropyran a~ld ~ubseq~ent removal, i~neces~ar~7 of h~droge~ bromide with9 for e~mple,
potas6i~m tert.~buto~ide in dime~h~ lpho~ide,
ketal ~plitting with aqueous acetic acid and option~l
functionPl ~dification o~ ~ree hydro~l gro~ps, ior
10 -e~ample by etheri~ication with dihydropyran~ yield~
2 keto~e Df the general io~m~la ~III
~ ...
~ (VIII).
'~
~ D~
-
The reaction of the ketone of the general ~orm~la
YIII with a carba~ion produced iro~ ~n ester of the
general formula IX
/~
Rll~)C~ C~2~L2~2C~2os~
~10
26 ~ 3~
in ~hlch ~ , ~9 an~ ~ ~ have the meanings given above
and ~ ~epresent~ an alkyl group containing fro~ 1
v~ ~ carbon 2tomB~ and lithium dil~opr~pyl~mide, a~ter
hydroly~is with~ for e~ample, a~ alc~holic potas~i~m
hydro~ide solution~ yields an acid of the general
formula ~
/~
-~20~ 9
~2 Rlo
~IO()C~
~0~
.~
.
~-W-D-~-R~
~5
Dehydrzting decarbo~ylation of the h~droxycar-
bo~ylic acid of the general form~la ~ ~ith dimetk~
~or~amide acet2te or with an arylsulpho~ic acid
chloride and pyridine and ~ubseqnent '~hermal treat
ment of the i~termediate ~-lactone ~ields the ~-
fluoro-olefin o~ the general form~la II.
The manufact~re of the phosphona~es of the
~eneral form~la V may be carrled o~t in a m~nner .
m ~ se by reacting the an:Lon of meth;ylpho~phorlic
acid dimeth;srl e~ter ~it~ an e3 ter o~ the genera:L
~ormul~
~2
5 ir- ~hich D, :~ ~Ld 1~4 have t~Le meaning~ ~i~en abo~e
and ~ L2 represe:nts a:~ al:~yl gro~p conta~ing ~ro~ 1 to
5 carbon ato~ns, ~hich can, i:e de~iredl, be c3btai:~ed
~rom the co~Tespo ding malonic acid e~ter by ~la-
tivn with a ~ide o~ the ge~eral ~02~a ~
~ tXII),
i~ ~hich Eal repre~ent~ a ~hlorine or bromine ato~,
a~ ~ub~equent decarbalXo~ylatio~. The e~ter o~ the
general formula Xl can als~7 i~ desi~ed, be obtained
fro~L a c~rbo~ ic zcid of the ge:~eral fo~ La ~II
~ C-D (~III) "
i~ which D has the meaning give~ abo~e, by al~ylation
with the halide of the general formula ~II and ~b-
seq~ent esteriflcQtionO
The manufactare of t~e fluoroesters of the genera
-- 2~3 --
~o~nnla I~ be carried out in a manner known ~ 9e
b~ eelective sil;ylation of 194-b~tanediol arld ~I:Lb~e
q~en~ oxidation ~ith, f or e:~ample, t:~ollins reagent or
p~rid~ ni~m dichrom~Lte to form a:~ aldeh~de of the
5 gener~l formlala XIV
0,~ /~3
c~2~c:a2os~ v3.
~o
~ter a:cL 018f~ nPtion reactlon with pho~pho~
~luoroRcetic acid tri-( Cl-C5-alk;yl) e~ter and ~ubse-
q~e~t catal~tic h;ydrogenat~on t~e ester o:f the genera:l
0 :~o~ iB obtainedO
The ne~ compound~ of the pre~e~t invention have
a hypoten6ive and bronchodilative actio~ The~ ~re
f~rt~ermore ~uitable for the i~hibition ol thro~boc~te
aggregat~on~ Conseq~ently, the novel c~rbac~clin
deri~atives of the general formula I anà the afore
said ph~siologicall~ tolerable ealt~ ar~ ~al~able
pharmaceutical active substance~. Purthermore, as
co~pared ~ith corre~ponding prostaglandins~ wh~lst
having a ~i~ilar 6pectrum o~ activity, they have a
kigher speci~icity and, above all, z ~ubstantlall~
more prol~nged activity~ In comp2rison ~ith P~I2 the~
are distinguished b~ a greater ~tabilit~. The high
- ~9 ~
ti~sue ~pecificit~ of the novel compo~nd~ of ~he
preserLt inventio~ demo~s trated by inve~tiga~io~s
carri ed o~t on smooth muscular orgarL~, s~ch as, for
e~ample, on the ileum of g~ea pig8 or on ~he is~
5 lated trachea o~ rabbitR, where a sub~tantiall~ lo~er
degree o~ atim~lation i~ observed than when natural
pro~taglandi~a of the ~ - or :F-t~pe are admini~
tered.
~he :~o~el carbac;yclin a~alogae3 po~E~es~ the
1~) propertie3 t;ypical o:e prostacycl~ n~ 9 2nd m~y accor
dingly be ~ed, for e~a~ple7 for the red~ctio~ of
peripheral arterial and coronar~ va~culær re~istance 9
i~h;bitio~ o~ thromboc~te a~gregatio~ and b~eaki~g ~p
of platelet thr~mbi, m~ocardial cytoprotectio~ and~
1~ therewith~ lo~eri~g oi the systemic blood pre~s~re
~-ithout aimultaneo~el~ red~cing cardia~ output and
coronary ~lood ~lo~; they ay be ~sed for the treat-
ment oi a stroke, prophyla~i~ znd therapy of coronary
he~rt disease~, coronary thrombo~es 9 cardiac lnfærct,
~0 peripheral arter~ di~eaaes, arteri~3clerosi~ and
thrombosi~ proph~la~i~ and therap~ of i~chae~ic
attacks of the central nervous system~ therap~ of
shock, inhibition of bronchoco~striction, inhibition
of ga~tric ~cid ~ecretion, cytoprotec~ion of the gas-
tric and i~testinal mucosa, an~ c~toprotection in thelive~ and i the pancrea~; they also pos~e~s anti~
~llergic propert~es9 and may be ~sed for the red~ctio~
~f p~lmonary vascular resistance and of p~lmonar~
blood pre~sure, stimulatio~ o~ the blood flo~ thr~$h
the kid~e~s, ma7 be ~sed instead o~ heparin or a~ ~n
adjuvant ln the dial~sis of haemo~iltration, and ma~
be nsed in~er alia ~or the preservation o~ blood
plasma ~upplies 9 e~pecially Or blood platelet supplie~,
inhibitio~ of labour p~in~, treatment o~ to~aemia in
pregnancy and ~or increa~ing cerebral blo~d flo~ In
1~ ~dditio~, the novel carbac~clin derivative~ have anti-
proliferati~e Pnd anti-diarrhoeagenic propertie~
~he carbac~clina o~ the pre~e~t in~entio~ can also
be used in combination with other acti~e sub~ta~ces,
for e~mple ~ith ~-blockeræ, diuretics or phosphone
diesterase in~ibitors~
~he dosage of the new componnds ~ irom 1 to 150
~g/k ~ day when admi~istered to h~man Patients c ~hen
~sed uith 2 pharmaceuticall~ acceptable carrier, the
~nit do~e ~or the carrier is ~rom 0.01 to 100 mg~
~hen a~ini~tered b~ intravenous injection to
con~cio~ hypertonic rats in doses o~ 5, 20 and 100
~ kg of body weight, the compo~nd~ of the present
in~ention e~hibit a more pronounced h~potensive action
and a more prolonged action than P OE 2 ~nd PG~2, with
out causing diPrrhoea li~e P OE2 or causing cardiac
arrhythmia like PG~ ~
-- 31 --
Whe~ admi istered b~ in .raveno~s injection to
~arcoti~ed rabbits, the co~Lpo~ds of the preaer~t inven-
tion, in comparison with P&~ and PG~2~ e:~:hihit a more
prono~ced a:nd cor~siderably longer las.,i~g reductio
5 ~ n blood press~re ~ithout other ~mooth m~3cular org~na
or organ ~unctio~s be~g af`fected~,
~ he present invention accordi ngly further provides
a compound of the present inven tion7 for use as a
medica~ent~
The pre~ent inventio~ rther provides a pharma~
ceutical pre~aration ~hich Compri~eB a compo~nd o~ the-
prese~t in~ention7 in ad~l~ture ~r co~ cti~n ~ith a
pharmaceutic~ suitæble carrierO ~e preparatio~
may be in a form suitable ~or ~se as h~pote~sives.
The prepPr2tions ~ay ~f co~rse contain one or m~r~
compo~nd~ of the present inventio~; znd may ~-ontain
the cus~omary a~iliaries that are no~ally ~sed in
g~le~ic 1 pharmasy.
he preparations of the present invention may be
~0 in a for~ s~itable ~or parenteral or oral administra
tion.
The preparations ~uitable ~or parenteral ad~i niS-
tration may be ~n the form of sterile, aqueou~ or oi~y
solutions suitable for injection.
2~ The prepærations suitable for or~ ministr~tion
msy be in the form o~, for e~ample 7 table*s, dragées
or cap~ules.
- ~2 -
The followi~g ~amples illustrate the in~entio~;
am~
¦5Z)-(16R5)-5-~luor~-16-methyl-18,1~19,19-tetra-
dehydro-6a-carbaprostaglandin-I2
0.93 g of tetrabut~lammoni~m fl~o~id~ was added
to a solutio~ o~ 960 mg of (5~92)-(1~3)-2-descarbo~-
5-fluoro-16-meth~1-2-(dimetkyl-tert.-b~tyl sil~lo~y-
methyl3-18,18,19,19-tetradeh~dro-6a-cæ~baprostaglan-
d~n-I2 11,15-bie-(tetrahydropyranyl ether) i~ ~0 ~1
o~ tetr~h~drof~ran and the ~ho~e was EtIrred for 6
hours at 2~C. ~he ~hole ~a~ then dil~ted with ether,
~hakèn three time~ ~ith ~ater, dried ~Yer mag~e~i~m
sulphate a~d concentrated by e~aporatio~ ~ ~acuo.
The re3id~e ~B chromatographed over ~il iC8 gel ~ith
he~ane/ether (~+23. ~here wa~ obtai~ed, as the less
pol~r component, ~60 mg of (5~)-(16~S~-2-de~carbo~y
5-fluor~-2 hydro~methyl-16~methyl-la,l8,19,19-
tetradeh~dro~6a-c&rbaprostagl&ndin-I2 ~1~15-bis
(tetrah~dropyran~l ether) ~nd, as the -ore polar
component, ~80 mg of (5~)-(16RS)-2-de~carbo~y-5-
iluor~-2-hydro~ethyl-16-~ethyl-18,18,19,1g-tetra-
dehydr~-6a-caIbaprostagl~din-I2 11,15-bi~-(-tetr~
hydrop~ran~l ether).
IR (C~Cl~): 3650, 2930, 2865, 16~0, 972/c~.
~or the o~idation of the l-hy~ro~ group, 380 mg
of the 5Z-configurated fluorolefi~ ~er~ dis~olved in
10 ml of methylene chloride 7 1- 8 g of 5O11~ns reagent
~2
-- 3~ --
(chromic acid/pyridi~e comple~ were added at 0C ~nd
the ~hole ~a~ ~tirred for 15 ~inutes at O~C. ~ mi~-
ture of ether~he~ane (~+23 was then added7 filtr3tion
~a~ carried out, znd the filtrate ~a~ ~a~hed in
succession ~ith water, 10 ~ stre~gth s~lph~ric acid
and water, dried over magnesiRm ~t~pha~e ænd conce~
trated by evaporation in vac~oO ~he re~lt~ng alde-
hyde ~as then dissolved in 16 ml of acetone and, at
-20C, 1.6 ml o~ Jone~ ~eagent were added dropwi~e5
0 ~tirring WaB then carrled out for 30 mI~te~ at -2~C,
2 ml of i~opropyl alcohol were added, and the whole
~as diluted ~ith ether, ~haken three ti~e~ ~ith
water, ~ried over magnesiu~ sulphate a~d conce~-
trated by evaporation in vac~oO
To split o~f the protecting gro~ps9 the ~e~id~e
obtained by conce~tration b~ evaporation ~as stirTs3d
for 16 ko~rs 2t 25C with 30 ml of ace~ic acid/waterJ
tetrahydrof~ran ~65/~5/10). The whole was then con~
centrated by evaporation ~ith the addition of
toluene and the resid~e was chromatographed over
silica gel ~ith ethyl acetate/0.1~ tre~gth acetic
acid, a~d 245 mg of the compo~nd identified ~ n the
title ~ere obtained in the form of a colourless oil.
IR: 3600~ 3400 (broad~ 9 2920, 2870, 1719, 1602,
1430, g69/cm.
The ~arting mzterial u~ed for the proced~re
~4 ~
àescribed above was man~iact~red as follous.
la~
(~,2)-(16RS)-2-De~carbo~y-5-fl~oro-16-meth~1-2-
(dimeth~l-tert.-but~l- ilylo~meth~ 18~18,1971~-
_ . _ .
tetradehydrow6a-carbapro~t~glandi~-I2 11~15-bie-
~ . _ . . _ _
(tetrah~drop~ranyl ether)
.
1203 ml of a 1.62 molar ~ol~tion of lith~m b~tyl
- in he~ane were added at -25C in the cour~e of 15
min~te~ to a solu~io~ o~ 2.8 ml o~ diæ~oprop~lamine
in 10 ml o~ tetrah~dro~uran and the ~hole ~a8 stirred
for 1 hour a~ 25C. ~here was then added drop~ise
to th~æ mi~t~re at -7GC, ~n the co~rse of 10 minutes9
a 801utio~ 0~ 5,8 g o~ 2~fluoro-6-~dimeth~l-tertO~
b~tyl~ lo~y)-he2a~0ic acid ethyl e~ter in 5 ml of
tetrahydro~ura~. ~he ~hole was stirred fo~ 10 ~inutes
~t -70~9 ~ sol~tio~ of ~D~ ~ 0~ (IR; 5S,6R,7~3-7
(tetrahydrop~ran-2-ylo~ 6-[(~ 4-methyl-
3-(tetrahydrop~ran-2-ylo~y)-oot-1-en-6-ynyl~-bi-
cyclo~7~.0]0cta~-~-one in 15 ml 0~ diethyl ether
and 15 ml o~ ~etrahydro~uran WaB added, ~nd the whole
W2S stirred for 1 hour at -70C; 100 ml o~ a ~zturs-
ted ammoni~m chloride ~olution ~ere added and the
whole Was acidi~ied with a 10 ~ strength citric acid
solution to a p~-value of 5, ~xtractio~ was carried
out ~ith ether, and the organic phase wa~ ~shed with
- 3
~ater ~ntil neutr~, drie~ o~er magnesi~L E3~1phat~
and concentrated by evapora tio~ acuo. ~fter
chromatograp~y over ~ilica gel with he~a:ne/ether
l.B g of the a-fluor~e~ter ~a~ obtained ~hich, for
5 the purpose of h;ydrolysis ? ~as ctirred for 7 hour3
at 25C with 25 ml OI aIl eth~nolic potassi~ hydro:~ide
~olution (manu~acture: 5 g o~ potassi~ dro:~ide
were di~601ved i~ 187 ml OI ethanol and 67 ml of
wzte~. hcidiYication ~zs carried out ~ith a 10
3trength citric acid solution to a pa-value of 4~
the whole ~as e:rtracted ~ith methylene chloride, and
the organlc e2~tract was washed ~ith wat~r until
neutral and dried over ~agne~ ulphate~
~he residue obtained b~ co~centration b~ e~apor-
ation wa~ dissolved in ~5 ml of p~ridine~ 880 mg of
benzenesulpho~ic acid chloride were added at O~C and
the ~hole was stirred for 24 hours at 0C. 1.5 ml
of water were then zdded, and the whole was stirred
~or 1 hour, dil~ted with ether, shaken with a satura-
2~ ted sodium bicarbo~ate ~olutio~, wa6hed three time~with water, dried over ma~nesium sulphzte and co~-
centrated by evaporation in vacuo~ The residue ~as
stirred for 3 ho~rs at 100C In 20 .ml of pyridine
and concentrated by evaporation in vzcuo wit~ the
addition of tol~ene. ~e residue wa~ chromatographed
over silica gel wlth he~a~e¦ether (9~1~. 1.1 g of
ths compo~nd identi~ed in the title ~-ere thu~ obtained
i~ the ~orm o~ a colourle~s o~l~
IR: 2g~5, 2~68~ 1450~ 971, 8629 835/c~
lb)
~l~nufacture of 2-fluoro-6-~dimethyl-tert~-b~t~lsil~l-
o~y)-hexanoic acid ethyl eater
,
51 g o~ imidazole ~nd 45 g o~ dimeth~l-tert~
butylsilyl chloride were added at 0C to ~ ~olu~io~
o~ 27 g o~ 19 4-butanediol in 50 ml o~ dimeth~lforma
mide and the ~hole was stirred for 24 hour~ at O~C~
~he w~ole ~ the~ poured into 4~0 ~1 oi ~ater7 and
e3tracted with a miIt~re o~ ether~penta~e ~1~1), and
the or~anic phase ~as ~ashed in ~cce~si~ ~ith 5 %
~tre~th ~ulph~ric acid 7 a 5 ~ ~trength sodiu~ bi-
15 carbo~ate solution and water. ~e prod~c~ wa~ drie~over magnesi~2m sulphate and concentra~ed ~y e~apora-
tion ~i vacuo O ~ter ~iltrat~ on o~er ~ilica gel ~ith
he~ane/ether (1~1~, 18 g o~ 1 - (dimeth~l-tert.-b~tyl-
~ilylo:~y)-butan-4-ol ~ere obtained in t,he f orm o~ a
20 colourless liq~:LdO
90 g of Collins reagent were addeà at 0C to a
solution of 12 g of the monosilyl ethe~ produced PS
described abo~e in 600 ml of methylene c3~1oride a~d
the ~hole ~a~ ~tirred ~or ~0 minutes z~ OC. The
~hole uas then diluted ~ith ether and sh~en in
BucceS~ion ~ith a 5 ~ 6-trength sodium bic~rbonate
- 37 -
~ol~ion, ~ater, a 10 ~ ~trength citric ac~d sol~tio~,
a 5 ~ ~trength ~odi~m bic~rbonate ~olution and ~ate~.
Dr~ing o~er magneslu~ 6ulphate and co~centration by
evapor~tion in vacuo were then carried out to ~ield
an zldehyde~
~ solution of 24 g of pho~phonofluoroPcetic acid
ethyl ester in 60 ml of dimetho~yethæne was added
drop~ise at 0C to a suspension o~ 3.9 g of sodium
h~dride (55 ~ ~tre~gth miner~l oil suspe~sion) in
200 ~1 of dimetho~ethane, ~tirring ~as carried out
for 1-5 hours, a solution o~ 16 g of the aldeh~de
prod~ced as described ab~ve in 50 ml o~ dimethox~etha~e
~as added and BtirrIng uza carried o~ for ~ ho~r~ at
0C. ~ s~turated ~mmo~i~m chloride 801~ti~n
then added; and the whole ~a~ e~tracted with ether~
washed with wa*ert dried ~ith ~ag~esium sulphate and
co~ce~trated ' n vacuoO ~hromatograph~ ~i the resid~e
over silic~ gel ~i~h he~ne/ether (4~1) yielded 17 g
~ n ~ ~nsat~r2ted esterO
~or the purpose o~ hydrogenation, the ester ~2~
shaken for 6 ho~rs at 25C i~ 750 ml of ethyl acetate
with 1.6 g of p~lladium (10 ~ on carbon) ~der a
hydrogen atmosphere. ~he whole ~as then filtered
and concen-trated i~ vacuo. The resid~e was purified
by b~lb tube di~tlllation at 0.2 torr and 140~C.
11 g oi the compound identified in the title were
~ 38 -.
th~ obtained in the fo~m o~ a colo~rless llq~idO
1~: 2950, ~91~9 2~58~ 1735, 1~6~9 1~7~, 1250, 1100,
831~m~
xample 2
(5Z)-(16RS)-2-Descarbox~-5-fluoro-2-h~drox~ethyl-
_ . . . . . . _ _
16-methyl-18,18,19,1g-tetradehydrG-6a~carbaprosta-
g~ di~l-I2
,
200 mg o~ ($~)-(16~S)-2-descarbo~y-5-~luoro-2-
h~dro~ymet~yl-16-methyl-18,18,19~19-tetradeh~dro-6a
carbapro~tagla~d-n-I2 bie-(tetrahydrop~rPnyl ether)
- (~ee ~xample 1) were stirred ~or 16 ho~r~ at 25C
~ith 20 ml o~ a mi~ture of acetic aci~/water/tetra-
hydrofuran (65~5+10). Co~centration by evaporatio~
~ith the additio~ of tol~e~e was carrled o~t and the
re6idue ~as chromatographed over silica gel~ With
methyle~e chloride/i~oprop3nol7 115 ~g ~f the co~
pound identified 1 n the title were ob~ai~ed in the
isrm of a col4~rless oil.
IR: 3600, 3410 (broad), 2925~ 2870~ 1602, 970/cm~
Exam~Ie ~
(5~)-(16RS)-5-~luoro-16-meth~l 18,18,19,19-tetrade-
hydro-6a-carbaprostaglandin-I2
In a manner analogous to t~zt described in
~ample 1, 195 mg of the compound identi-~ied in the
~9 ~
title were obtained in ~he form of a colo~le68 oil
from 340 mg of the (5~)-(16~ )-2 descarbo~y-5-flu~ro-
2-h~drox~methyl-16-methyl-18,18,19,19-te~radeh~dro~6a-
carbaprostaglandin-I? 11 9 1 5-bis- ~ t etrahyGrop~ranyl
5 ether) prod~ced in accordance ~ith E~ple 1
IR: ~600, ~410 (broad), 2922, 1720~ 16019 970/cm~
~m~le 4
(5~)-(16R~)-16,20-D1methyl-5-fl~oro-18,18,19,19-
tetradehydro-6a-carbap~ostagla:c~din-I2
In a m~nner analogo~ to th~t described i~ ~ampl~
1, there were obtained from 840 mg of (~,Z~-(16R~)
2-de~carbDx~-5-~luoro-16,2~-dimethyl-2-(dimethyl=
tert~-b~tyl-silylo~ymethyl)-18,18,19,19-tetradehydro-
6a-carbapro~taglandi~I~ 11,15-bis-(te~rahydropyr~nyl
ether) ~d tetrabutylammo~i~m fluoride, 290 ~g of
(5Z~-(16RS)-2-de6carbo~-16,2~-dimethyl-5-fluoro-2-
~ydros~met~yl 18 9 18919,19-tetrad ehydro ~ ~a - carbapro sta-
glandin-I2 11,15-bis-(tetr~hydropyranyl ether).
~ter o~idation and spl~tt~ng off protecting groups9
20 170 ~g of the compound identified in the ~itle ~rere
obtained in the ~orm of a colourles~ oil.
IR: ~6~0, 3410 (broad)p 2921, 28689 1719, 16019
g70/cm.
The s~arting material used for the pr~cedure
described abo~e ~as prod~ced a~ ~OllO~B:
4a)
(~9Z)-(16RS)-2-De~carbo~-5-~luoro 16,2~dimethyl-
2-(dimeth~l-ter~.-b~tyl-silyloxymethyl)-18,18 9 19 ~19-
tetradehydro-6a-carbapro~tagla~din-I2 11?15-bi~
(tetrah~dropyranyl e~her)
,
In a man~er a~alogous to that described in
~ample la), 0~7 g of the compound ide~tified i~ the
title ~as obtained in the ~orm o~ a colo~rles~ o~l
~rom 0.8 g of (1~,5S76~97~)-7-(tetræhydropyran-2-
~10~ 6 ~ ~4RS)-4-~ethyl-~-(tetrah~dropyra~-2
ylo~y)-non-l-en-6-y~yl~-bicycl~.3~0~octan-3-one.
IR: 2947 9 2870, 1451, 970 9 8~5/cm~
(5Z)~(16~S)-2 Descarbo~-16,2~-di~eth~ iluoro-2;
.. ~
pro~taglandin-I2
In a m2nner analogous to that described i~
Example 29 95 mg of the compQund ide~tified in the
title were obtained in the form of a colo~rless oil
~rom 180 mg oi (5Z)-(16~S)-2-descarbo~-16,20-di-
methyl-5-fluoro-2-hydro~ymeth~1-18,18,19,19-tetra-
dehyàro-6a-c~rbaprostaglzndin-I2 11,15-bis-(tetra-
h~dropyra~l ether).
IR: 3600, 3400 (broad), 2925, 2868, 1601, 971/cm~
~ample 6
~ 5--~luoro-2~ ~ethyl~18~18,19 ? 19-tetradeh~dr~
16,16-trimethylene-6a-carbaprostagland~n-I2
I~ a m2nne~ 2n210go~s ~o that described i~
~xample 1 there were obt2i~ed from 920 mg of
(5~,Z)-2-de~carbo~y-2-(dimethyl-tert~-butyl-silyl-
o~ymethyl)-5-fluoro-20-meth~1-18,18,19,13-tetra-
dehydro-16,16-trimeth~lene-6~-carb~prostaglandin~I2
11,15-bis-(tetrah~dropyranyl ether) and tetrabutyl-
ammonium fluoride, 320 mg o~ (5Z)-2-de~carbo~y-5
fluor~-2 hydroxymethyl-20-methyl-18,18,1g919 tetra-
dehydro-16~16-trimethylene-6a-carbapr~s~aglandin-I2
il,l5-bi~-(tetrah~drop~ranyl ether)~ ~ter oxida-
tion 2~d ~plitti ng of ~ protecting g~Dllp9 ~ 220 mg of
15 the c~mpo~d identified i n the title ~ere ~btai:l:Led
in the f or~ of a colourle~s o;l 2
610y 3400 (broad), 2920, 28709 1720, 1601,
971/cm.
The starting material used ~or the procedure
20 described above was prod~:Lced as ~ollows:
~a)
( 5E,Z)~2-Descarboxy-2-(dimethyl-tert. -bu~yl-~ilyl-
o~ethyl)-5~1uorv-20-methyl 18,18,19,1~-tetra-
dehydro-16,16-trimethyle~e-6a-carb2prostaglandin-I2
25 11,15-bis-(tetr~hydropyran;yl ether)
... .. _ _ _~, _ .. . ..
~ 3
- 42 ~
In a manner analogous to t~at described in
~a~ple la), 0055 g of the compo~d identified in
the title wa~ obtained in the form of a colo~rles3
oil ~rom 1.4 g of (1~,5S,6R,7~)-7-(te~rahydropyran-
~-~lo~y)-6-[(~ (tetrahydrop~ran-2-~lo~y)-4,4-
trimethyle~e-no~ en-6-ynyl~-bicy~o~3~.O~octan-3-
one~
IR: 2950, 2868, 1451, 971, 835/cmO
3~amPle
18,18,19~19-tetradeh~dr~-16,16-trimeth~lene~6a carba-
prostaglandin I2
In a manner aa210gOUB to that described in
~xample 2~ 70 mg of the co~pound identi~ied in the
- 15 title were obtained i~ the form of a colo~rless oil
from 120 mg of (5Z) 2~de~carbo~y-5-fl~oro-2 h~dro~y
methyl-20-methyl-18,18,19,19-tetradehydro-16~16
trimethyle~e 6a-carbaprostagla~di~-I2 11,15-bis-
(tetr~hydropyranyl ether).
IR: 3600, 3410 (broad~g 2925, 2870, 1601, 970/cm~
Example 8
(5Z)-16,16-Dimethyl~6-fluoro~18,18,19,19-tetrade-
hydro-6a-carbapro~tzglandin-I2
In a manner an~logous to that described i~
~ 3
- 43 -
~xample 17 there were obtained -~rom 0~9 g of (~Z)~
2-descarbo~y-16~16-di~ethyl-2 (dimeth~1-tert~ butyl-
silylo~ymeth~ fluoro-18,18,19~1g-betradehydrQ 6a-
carbaprostaglandin-I2 11~15-biB~ (tetr&hydropyranyl
ether) and tetrabutylammonium fluoride, ~10 mg of
(5Z)~2-descarbo~y-16~16-dimethyl-5 fl~Dro-~-hydro~y-
methyl-18,13,19,19-tetradeh~dro-6a-cz~bapro~taglan-
din-I2 11,15-b iB-( tetrahydropvran~l e ~her~. h~t er
oxidatio~ and ~plitting olf protectinS gro~p9, 195 ~g
of the compo~nd identi~ied in the title we~e obta~ned
in the fo~m of a colo~rles~ oil~
I~: 3600, ~420 (broad), 29229 286~ 1718~ 1600,
972/cmO
lhe starting material used for the p~oced~re
de~cribed above ~a~ produced as foll ~R .
aa)
(5E~Z)-2-De~carbo~y-16,15-d~meth~1-2-(dimetnyl-tertO-
butyl-~ilylo~ymethyl)-5-~luoro-18,18 9 19 ~ 19- tetra-
dehydro--6a-carbaprostagl2ndin-I2 ll,lS-bl~-(tetra~
_
?0 hydrop~ran~l ether)
_.
In a manner analogous to that described i~
:E~x~mple la), 0.7 g o~ the compound identified ~n the
title wa~ obtained in the ~orm of a colo~rless oil
fro~ 1.6 g of (IR,5S,6R,7~-7-(tetrah~drop~ran-2~
ylo~y)-6~ 4,4-d~me~t~yl-~-(te~ra~dropyran-
2-ylo~)-oct-1-en--6~yn~1~ bicyclo[3~3.0~octan-3-one.
- 44 -
IR: 2950, 2870~ 1450, 972, 8~5/cm~
~ am~le
(5~)-2-De~carbo~-16,16~di ethyl-5--fluoro-2-hydroxy~
methyl-18,18,19~19-tetradehydro 6a-carbapro~taglan-
.
di -I2
In a manner analogou~ to that described in
~ample 2, 95 mg of the comp3und identified in the
title were obtained in the form of a colourle3s oil
~rom 160 mg o~ (5Z)-2-descarbo~y-16,16-dImethyl-5
fl~oro-2-hydro~ymethyl-18,18,19,19-tetradehydro-6a-
carbapro~taglandi~-I2 11 9 l~-bis-(tetrahydrop~ranyl
- ether).
I~: 3610t ~400 (broad), 2926, 2868~ 16~0, 972/cm.
Dle 10
(5Z)-5~ ro-18J18,19,19-tetradehydr~-16,16,20-
trimethyl-6a-carbaprostagl-dndin-I2
In a manner a~alogou~ to that described in
~ample 1, there were obtained from 1.1 g o~ (5E,~)-
2-descarbo~-2-(d~methyl~tert.-butyl-silylo~methyl)-
5-il~oro-18,18,19,19-tetradehydro-16,16,20-trimethyl-
6~-carb2prcstagl~ndin-I2 11,15-bis-(tetrzhydropyrPn_
yl ethe~) ænd tetrabutylammonium fluoride t ~80 mg of
(5~)-2-desc2rbo~y-5-fluoro-2-hydro~ymethyl-18,18,19-
l9-tetradeh~dro-16,16,20-trimethyl 6a-carbaprostag-
- 45
landln-I~ llS15 bi~-(tetrahydrop~ranyl ether), ~iter
oxidPtion and ~plitting OL~ protect~n~ group~9 240 mg
of the compo~nd identiiied in the title were obtai~ed
in the ~orm o~ a colo~rles~ oil.
5 IR: 3610, 3400 (broad) 9 2925, 2870, 1718, 1602,
g72/cmO
~ he starting material used ~or the proced~re
de~cribed above was prod~ced as follo~æ:
lOa~
10 (5E,Z)-2 De6carbo~y-2 (d~methyl-tert~-butyl-silyl-
-- o~ymethyl)-5-fluoro-18,18,19,19-tetradehydro-
16,16~20-trimethyl-6a~carbapro~taglandin I2 11,15-
bic-(tetrahydrop~ran~l ether)
I~ a manner a~alogo~ to that described in
15 ~ample la~, 0~95 g of the compound ide~ti*ied in the
title ~as obtained in the fo~m o~ a colo~rless oil
~rom 1.8 g of (I~95S,6~97R)-7-(tetrah~dropyran-2-
ylo~y)-6-[(~)-(3R)-4,4-dimethyl-3-(te~rahydropyran-2-
yloxy~-non-l-en-6-ynyl~-bic~clo[3.3.0~octan-3-one~
20 IR: 2g52, 2868, 14507 972, 835/cm.
E am~le 11
(5~)-2-Descarbo3y-5-fluoro-2-hydro~methyl-
18,18,19,19-tetradehydro-16,16,20-tri~ethyl-6a-
carb2prostaglandi:~-I2
In a manner anal~gous to that de~cri~ed .~n
~ 3 ~
46
~xample 2 9 63 mg o~ the compo~nd identi~ied in the
title were ~btained i~ the form of a col~urles~ o~l
from 95 mg of (5~)-2-de~carbo~-5-~luoro-2-hydrox~-
methyl-18,18,19,19 tetradehydro-16,16,20-trimethyl~
6a-carbaprostaglandin-I2 11,15-bis-(tetrahydropyranyl
ether).
I~: 3600, 3410 (broad), 2925, 28707 1602, 970/cmO
~am~le 12
(5~ 16~S)-16919-Dimethyl 18,19-dide~yaro-5 fluoro-
10 6a-carbaprostagland ~ -I2
In a manner analogou~ to th~t descri~ed i~
~xample ls there was obta~ned from 2~1 g o~ ~SE7Z3-
(16~)-2-de8carbo2 ~ Lg-didehydro-16 91~-d:L~et~ 2-
(dimethyl-tert~-b~t~ lo~y~ethyl)-5-fluor~-6a
carbaprostaglandiR~I2 11, 15-~iB- (tetrahydropyran~l
ether) and tetrabutylammonium fluori~e, 0.81 g of
(5Z)-(16RS)-2-de~czrbo~y-18,19-didehydro-16,19~
dimethyl-5-fl~oro-2-h~dro~meth~1~6a-carbaprostag
landin-I2 11,15-bis-(tetrahydropyranyl ether). ~ter
o~id~tio~ and splitting o~ protecting ~roups, 420 mg
of the compo~d identilied in the title were obtai~ed
in the form o~ 2 colourless oilO
IR: 3600, 3420 (broad~, 29~59 2870, 1720, 1601,
974/cm.
The starting m~terial used for the procedure
described above was produced as f ollows:
~ 3
- 47 -
l~a)
~5~,Z)-(16RS)-2-Descarbo~y-18,19-dideh~dro-16,19-
dimeth~l-2-(dimeth~l-tertO-butyl-æilylo~methyl~-
5-fluoro-6a-carbaprostaglandin-I2 11,15-bi~-(tetra;
hydrop~ranyl ether)
In a m nner analogous to that de~cribed in
E~ample la)~ 0.84 g of the compo~nd identified in the
title was obtained in the form o~ a colourless oil
~rom 1~7 g o~ ,5S t~ )-7-(tetrahydropyran 2-
~10~ 6-[(~ )-(3R,4~ 4~7-dimethyl-3_(tetrahydro_
pyran-2-yloxy)-octa~196-die~yl]-bicyclo~03~0]~ct~n-
~--o~
I~: 2955, 28709 1~50, 74, 8~5fcm.
~x~m~le l~
(52)-(16RS)-2-Descarboæ~-18~19-didehydro-16,19_di
methyl-5-fluoro 2-hydro~ymethyl-6a-carbaprostaglan-
din-T2
_ _
In a m~nner analogous to that described in
~ample 2, 90 mg of the compound identified i n the
title were obtai~ed in the form of a colourless oil
from 140 ~g ~f (5~)-(16RS)-2-de~carboxy-18,19-dide
hydro-16,19-dimethyl-5~ oro-2-h~dro~ymethyl-6a-
carbzprostaglandin-I2 11,15-bis-(tetr2h~dropyranyl
ether).
48
I~. 3600, ~400 (broad) t 2925, 2870~ 16027 974/cm~
~x~m~le 14
.
(5Z)-(16RS)-1~,14-Dideh~dro-5~fl~oro 16-methyl-
18,18,19~1g-tetradehydro-6a-carba~rostaglandin-I2
In a m~nner analogous to that described in
~xample 1, there ~-a6 obtained f~om 2 g of (~,Z)
(16~S)-2-descarbo~y-1~,14-d~dehydro-2-(dimethyl-
tertO-b~tyl-sil~lo~meth~ 5-fluoro-16-methyl
18,18,19,19-tetradehydro-6a-c~rb2prostagl2ndin-I2
1~ ~19l5-bis-(tetra~ydrop~ranyl ether) and tetrabut~l-
ammonium fl~oride~ O~j9 g o~ (5Z~-(16RS)~2~descar-
bo~y-13,14-didehydro-5-fluoro-2-h~dro~y~ethyl-16-
methyl-18,18,19,19-tetradehydro-6a-carbapr~ta-
gland~n-I2 11~15-bia-(tetrahydropyr2nyl ether)O
h~ter o~idation ~nd 6plitting o~ pro~ect~ ng groups,
400 mg of the compound identi.fied in the title w-ere
obtained in the form of a colourless oilO
IR: ~6~0, 3405 (broad), 2928, 2872, 2221, 1720,
1600/cm~
~he starting maberial used for the procedure
described above was produced as follo~s:
14a)
~5~,Z)-(16RS)-2-De~carbo~y-13,1~-didehydro-2-(di~
meth~l-tert.-butyl-silylo~ymethyl)-5~fluor~-16-~ethyl-
___ _ _ _
18,18,19,19-tetradehydro-6a-carbaprostaglandin~I2
~2~ 3-~
_ ~9 _
11,15 --bis- ( tetrah ydropyr~yl et~er~
In a m~nner analogo~s tc that de~cribed in
~xample la), 1. 05 g of the compou~d iàe::Ltified
the title were obt~ ed in the for~n of 2 colourles~
5 oil from 2.O ,~ OI (lR,5S,6S,7R)-7-(te"rah;ydropyran-
2-ylo~)-6-[ (E)-(3S,4RS)-4-methyl-3-(tetr~hydropyrz~-
2-ylo~ octa-l,6-diynyl~-bicyclo13.3.O]~ctan-3-o~e.
IR: 29~6, 2875, 22219 1458~cm.
~xample 1~
(5~)-(16RS)-2-De~carbo~y-13 ,14-dideh~dr~ - 5-fluor~-
2-hydro~meth~1-16-methyl-18 ,18 5,19, l9-t etradehydr~ -
6a-carbaprDstaglandi n-I~
In a man~er an~l~gous to that de~cribed in
:Example 2, 55 mg of the compoand identified in the
title ~ere obtained in the form of ~ colourless oil
~rom 100 mg o~ (5Z)-(16~S)-2-descarbo~y~13714-dide~
hydro-5-fluoro-2-h~droxymethyl-16-~ethyl-18,18,19,19-
tetradehydro-6a-carbaprostaglandin-I2 11715-bis~
(tetrahydropyranyl ether)
IR: 3600, ~402 (broad), 2930, 2873, 2223~ 1105,
1020/cm.
(5Z)-(16RS)~13,14-Didehydro-16,20-dimethyl-5~fluoro-
18,18,19~19-tetradehydro-6a-carbaprost~gland~n-I2
- 5o
1~ a manner analogo~ to thzt described i~
~ample 19 there waa obtained from 1.90 g of (5~,Z)-
(l~R~)-2-descarbo~y-1~,14 didehydro~ 20-dimeth~1~2-
(dimeth~l-tert.~butyl-silylo~ymeth~ 5~fluoro-
18,18,19 919-tetradeh~dro-6a-carbaprostagland~n-I2
11,15-bi 8- (tetrahydr~pyranyL ether) and tetrabutyl-
ammonium fluoride, 0.71 g of (5Z~-(16~S)-2-descarbo~y~
13,14~didehydrc-16,20-di~ethgl-5 fluoro-2-hydroxy~
methyl-18,18,19,19-tetradeh~dro-5a-carbaprostaglan-
din-I2 11,15-bis-(tetrahydropyranyl ether~ After
oxidation and splitting o~i protecting grCRpS ~ ~20 mg
of the compo~d identi~ied in the title were obtai~ed
i~ the form o~ a colo~rless oilb
IR: 3600, 3405 (broad)~ 2926~ 2870, 2221~ 1715
15 1110 r 1025/cm.
- The ~tarting m~terial used for the proced~re
de3cribed above Ras produced as ~ollows~
16a)
(5 ,Z)-(16RS)-2-Descarbo~y-13,14-didehydrG-16,20-
. . ~
dimethyl-2-(dimethyl-tert.-b~t~l-silylo~ymethyl~-5-
_ . ... _ _ ,,
fluoro-18,18 9 19 ,19-tetradehydrG-6a-carbapr~staglandin-
I~ 11,15-bi6-(tetrahydropyran~l ether~
In a manner an~logo~s to that descri~ed
l~ample la), 1. ~9 g o:e the compo~nd identified i~
25 the title ~ere obtained in the form of a colourless
- 51 -
o~l from 2~80 g of ( ~,5~,65~7~)-7~(tetrahydropyra~-
~-~loxy)-6~[ ~)-(3~4~ 4-methyl-3-(tetrahgdropyra~-
2 ylo~y)-nona~1,6 di~nyl~-bicycloL3~3.0~octan 3 o~e.
IR: 29519 2872, 2?20, 14hO/cm~
~xam~lQ 17
(~)-(16R~)-2-De~carboxy-1~,14-dideh~ro-16,20
~, ~
dehydro-6a--carbaprostaglandin-I2
In a mPnner analogous to that desor~bed in
~ample 2, 70 mg of the co~ps~nd identified in the
title ~ere obtai~ed in the ~orm oi a colo~rle~s oil
~rom 120 mg of (5æ)-(16~S)-2--de~carboxy-1~,14-dider
hydro-16 g 20--dimethy1-5 ~luoro-2-hydro~v~ethyl
18 ,18 9 19 9 lg-tetradehydro-6a-carbaprostaglandi~-I2
11~15-bis (tetrahydropyranyl ether~
IR 3600, 3400 ~broad), 2938, 2875, 2219, 1108,
1021/cm.
~ample 18
(5Z)-13,14 Dideh~dro-5-fluoro-20-methyl-18,18,19,19-
tetradeh~dro-16,16-trimeth~lene-6a-carbaprostaglandin-
.
In a manner ~nalogous to that described in
~xample 1, there W2S obtained from 2.0 g of (~,Z)-
2-de~carbo2y-13,14 dideh~dro-2-(dimethpl-tert~-butyl-
- ~2 -
~ilylo}~;ymethyl)-5-fluoro-20-methyl-18718plg,19-
tetradehydro-16,16-tr~methylene-6a~carbapro~tagl~
di~-I2 11,15 bi~-(tetrahydropyra~yl ether3 and tetra-
butylammonium ~luoride, 0~75 g of ~5Z)-2-desc2rboxy-
13,14-dideh~dro-5-fluoro-2-h~dro~methyl-2C-methyl-
18,18,19,19-tetradehydro-16,16-trimeth~lene-6a-carba-
prostaglandin-I2 11,15-bis-(tetrahydrop~anyl ether)~
After o~idation ~nd splitti~g o~f protecting groRps,
~28 mg of the comp~und ldentified in the title ~ere
obtained in the form of a col~rless oil~
~ 6~0~ 3420 ~broad~ t 2930? 28~19 2220t 1718
1115, 1020/cmD
The st~r~i~g material ~sed for the procedure
described above ~a~ pr~duced as follows:
18a~
~5E,Z)~2-Descarbo~y~13714-didehydro 2-(dlmethyl-tert~-
but~l-silyloxymeth~ 5-fluoro-20-methyl~18,18,19,19-
tetradehydro-16,16-trimethylene-6a carbaprostaglzn-
. . _
d~n-I2 11,15-bis- ( t e trahydropyranyl ether)
Tn a manner analogous to that described i~
~ample la)~ 1.21 g of the com~ound identi~ied in
the title ~ere obtained in the form of a colo~rless
oil ~rom 2~5 ~ o~ ,5S~6S,7R)-7-(tetrahydropyra~-
2-ylo~y) 6-~ )-3-(tetrahydropyran-2-ylo~y)-
25 4~4-trimethylene-norla-1,6 di~nyl~-bicycl~30~0~
- 53
octan-~-one~
IR: 2952, 2868, 2218, 1458/cm,
~am~le 19
(5Z~-2-Descarbo~y-13,14-didehydro-5-fluoro~2-hydro~y-
.
meth~l-20-methyl-18,18,19~1g-tetradehv~ro-16 916-
trimethylene-6a-carbaprostaglandi~-I2
In a manner analogous to that described in
E~2mple 2, 52 mg of the comp3und identified i~ the
title were ob-tained in the ~orm o~ a colourless oil
- 10 from 100 mg of (5Z~-2-descarbo~y~1~,14-didehydro-5
fl~oro-2-h~àro~methyl-20-methyl-18 918~19,l9-tetra~
dehydro-16,16~trimethylene-6~-carbaprostaglzndln-I2
11~15-bis~(~etrahydrop~ranyl ether~i
IRo ~600~ 3410 (broad) 7 2932~ 2868, 222~ o,
1020/cmO
(5Z)-13,14-Didehydro-5-~luoro-18,18,19,19-tetrade-
_
hydro-16 916 7 20-trimethyl~6a~carb2proslaglandin-I2
In a manner analogous to that described in
~ample 1~ there w~s obtained from 2 g of (5~,Z)-2-
d e s cP rbo~y-13,14-didehydr~-2-(dimethyl-tert.-butyl-
silylo~methyl)-5-fl~oro-18 t 18719,19-~etradehydro-
16,16~2~trimethyl-6a-carbaprostaglan`i n-I~ 11,15
bi~-(tetr2hydropyranyl ether) ~nd tet~butylammonium
~2~ 3
-- ~4
fluoride, 0971 g of ~ 2-descarbo~y-13,14-dide-
hydro-5-~luoro 2 h~droxymethyl-18,18,1g~19~tetra-
dehydro-16716,20-trimethyl-6a-carbaprostagla~di~-I2
11,15-bis-(tetrahydrop~ranyl ether)D ~fter o~idation
and splitting o~f protecting group~ 9 380 mg of the
compound ide~tified in the title were obtained in
the for~ of a colourless oilO
I~: 3600, 3410 (broad), 2938, 2870, 22259 1713,
11209 1018/cm.
~he starti~g material usea for the procedure
described above was produced as fo~lo~
20a~
tert.~butyl silylo~ymeth~ 5-fluors-18 ? 18,19,19-
tetradehydro-16,16 9 2C-trimethyl-6a-carbaprostaglan-
din-I2 11,15-bi~-(tetrahydrop~ranyl ether3
Tn a m~nner a~alogo~s to that described in
~xa~ple la), 2.45 g o-~ the compound identified in the
title ~ere obt2ined in the form of a colourleQs oil
~rom 4.5 g of (I~ 9 5S,6S97~)-7-(tetrah~dropyran-2~
ylo~y)-6~[(~)-(3$)-4~-dimethyl-~ (tetrahydropyran-
2-ylo~ ona 1,6-di~nyl~bic~clo[~.3 O]oct~n-3-one.
IR: 2g51, 2~73, 2220, 1451/c~
- 55 -
E~ample 21
(5Z)-2-Descarbo~y-13914-didehydro-5-~luor~2-h~dro~y-
meth~l-18,18,19~19-tetradehydro-16,16,20-trimeth~l-
6h-carbaprostaglandin-I2
In a manner analogous to that described in
~ample 2, 82 mg of the compo~nd identi~ied in the
title were obtained in the form of a colo~rle~s oil
from 150 mg o~ 2-de~carbo~-13,14~didehydr~-5-
fluoro-2-hydroxymeth~1-18,18 9 19 ~19-tetradeh~dro-16,16,-
20-trlme~h~1-6a carbaprostagland~n-I2 11,15-bi~
(tetrahydrop~rA~yl ether)~
IR: 3600, 3405 (broad), 2935, 2870~ 2220~ 1128;
1021~cmD
~ample 22
~ ~ F ~ 3 l~,l9-tetra-
deh~dro-6a-carbaprostagla~d~n-I2 meth~l ester
An ethereal solutio~ of diazomethane was added
dropwise at 0C to a sol~tio~ of 150 mg o~ (5Z)-
(16RS)-5-fluoro-16-methyl-18~18,19,19-tetradehydro-
6a-carbaprostaglandin-I2 in 10 ml of dichloromethane
until the yellow colo~r remained~ ~fter a ~urther 5
minutes, the whole was concentrated In vac~o and the
residue was purified by chromatography over silica
gel~ 130 mg of ~the comp~uad ide~tified in the title
7~
- 56 -
i~ -the form of a colonrles~ oil ~ere eluted with
toluene~2 ~ i~opropyl ~lcohol.
L~: ~600, 2937, 2866, 1450, 1435, 1025 7 976/cm~
~ample 2~
(5Z)-(16RS)-5D~luoro-16-meth~ ,18~19,19-tetrzde-
hydro-6a-carb~pro~t-g ~ -I2-2cetylamide
63 mg of trieth~lamine were added at 20C to a
solution of 260 mg of (5Z)-(16RS)-5-fl~oro-16-meth~l~
18, la 7 19 ,19-tetradeh~dro-6a~carbaprostagl~ndi~-I2
11,15-bis-~tetrPh~drop~ranyl ether) i~ 8 ~1 of
acetonitrile 7 t~e whole ~as cooled to 0~ and a
solu~ion o~ 47 mg of acetyl isocyanate m 5 ml o~
acetonitrile ~as added dropwise there-toO kfter 2
ho~rs at ~0C 7 the whole was concentrated in vacuo,
dilnted ~ith 100 ~1 o~ a citrate buf~er (pE 5), and
e~racted with ether 9 and the extract was washed in
~uccession wit~ a sodium bicarbonate solution and
brine 7 dried over ma5nesi~m sulphate and concen-
trzted by evaporation in vacuo~ To split off the
~rotecting groups, the residue was stirred with 10 ml
of glacial zcetic acid/water/tetrahydrofuran
(65/35/10) overnight at 20C and evaporated to dry-
ness in vacuo. ~he residue was chromatographed over
silica gel with dichlorometh~ne/l ~ isopropyl alcohoL
9~ mg of the compo~nd identified in the ~itle were
~2~3
- 57 -
obtained in the ~orm of a colourle~s oil~
~ 600? 3~10, 2952~ 2835g 1710; 976/c~.
3xa~ple 24
(5~)-(16R~)-5-~luoro-16-meth~1-18,18,19,19-tetra-
.~
dehydro-6a-car~apro~taglandin-I2-carbo~amide
- 65 mg of triethyla~ine and 90 m~ of chlorofor~c
acid i~obutyl ester were ad~ed at 0C to a solution
of 200 mg o~ (5Z~-(16RS)-5-fl~oro-16~etn~1-18,18,19
19-tetradehyd~o-6a-carb~prostaglandin-I2 in 6 ml o:~
dimeth~l~ormamideO ~fter ~0 min~tes, d~y ammon a
gas was introd~ced iato the sol~tion for a period
of 15 mi~ute~. ~he sol~tion ~as then le~t to sta~d
~or 2 ho~rs at 20~ dil~ted with a citrate bu~fer
(pH 5), and e~tracted 6everal time~ ~it~ ethyl ace-
1~ tzte, and the extract wa~ wa~hed with a ~odium bic~rboDæte 801~tion and brine~ dried over magnesi~
~ulphate and concentrated by evapor2tion in vacuo~
After chromatography of the resid~e o~er ~ilica gel
~ith dichloromethane~l-5 ~ isopropanol, 152 mg of
the compound identified in the title ~ere obtained
In the form o~ a colourless oil.
IR: ~600, ~500, ~410, 2952~ 2871, 1666, 974/cm
(5Z)-(16~S)-5-~luoro-16-methyl-18,18,19~19-tetra-
_ __ __
25 dehydr2-6a-carbaprostaglandin-I -(2,3-dih~droxypro-
__ _ ._ ? ~
~ 58 --
p~l ) amide
__.
240 mg o~ ( 5 Z ) - ( 16RS ) -5-f luoro~:L6-methyl-
18,18,19,19-tetradeh;ydro-6a carbapr~staglarldin-I2
were dissolved in 5 ~1 o~ acetone and, at 0C, 74 mg
5 of triethyla~ ne and 100 ~ng of chloroformic acid.
ls~b~t~l ester ~ere added -theretoO ~f ter 20 min~ltes,
a sol~tion o~ 300 mg of 1-amino-2, ~-dihydro~ypropane
irl 6 ml of acetone ~nd ~ ml of acetonitrile was
added, and the whole was stirred for 2 ho~rs at 20C~
10 concent~ated ~ ac o ~ diluted ~ith 100 ml o~ di-
chloromethane " sha~:e:~ ~ith 5 ml of brine " dried over
}~agne~ium sulphate and concentrated b~y evaporatio:~l
in vacuoO ~ter chromatography o~ the re~3idue over
.----
silica gel with methylene chloride/20 % i~opropyl
alco~ol~ 195 mg o~ the compound identified i~ the
title ~ere obtained in the form o~ a col~rless oil~
I~: 3600, 3410 ~broad), 29359 28657 1648~ 10~0
976/cm~
~am~le ?6
(5Z)-(16RS)-5-~luoro-16-methyl-18~18,19,19-tetrade-
__ _ _ _ _
hydro-6a-carbaproatagl~ndin-I2 phenac~l ester
240 mg o~ (5Z~-(16RS~-5-fluoro-16-methyl-
18,18,19,19-tetradehydr~-6a-carbaprostaglandin-I2
~ere disaolved in 10 ml o~ acetone, 150 mg o~ ~-
bromoacetop~enone and 2 ml o~ triethyl~mine were
- 59 -
added thereto, and the whole was ~tirred overnigh~
at room temperature~ 200 m'l of ether ~ere the~ added,
znd the whole was shaken in ~ccession ~ith water and
brine, dried over ma~nesium sulphate and concentrated
by evaporation in vac~o~ ~he resid~e Yas pu~ified by
chrom2to~-aphy over silica ~e~ with meth~lene chlor-
ide/5 ~ acetone and 235 mg of the compo~nd identifiea
i~ the title were obtainedO
IR ~600, 2935, 2862, 1740, 1702~ 1601, 97~/cm~
E~ample ?l
(5Z)-(16~S)-2-Descarho2y-5-fluoro-16-~ethyl~2-~2-
oxazolin-2-yl ) -18 ,18 ,19 ,19-tetradehydro-6a carba-
prostagland~n-I2
_
189 ~g o~ (5Z~-(16RS)-5-fluoro-16~eth~1
18,18,19 9 1~-te-tradehydro-6a-carbaprostægla~di~-I2
were suspe~ded i~ 5 ~1 o~ he~ameth~ldisilazane a~d -
heated for lo 5 hours at 140C u~der ar~on,. ~cess
reagent was then removed In vac~o~ The ~esidue wa6
dissolvea in 5 ml of absol~te ace-tonitrile, 786 mg
o~ triphenyl phosphine and 1~05 ~1 of ~riethylamine
were added thereto a~dJ ~hile cooling ~ith ice~
0.5 ml of a lM solution of etha~olamine in acetoni-
trile ~as added dropwi~e~ 1.5 ml of ~ olu-tion
of carbon tetrachloride in aceto~itrile uere then
added, and the whole was left to stand overnight at
- 60 -
20Cc ~fter concentrating in vacuo 9 the residue ~as
washed ~ive times with 75 ml o~ hexane each time.
~he crgst~ls formed ~ere removed from the oily re-
sidue, and the oily residue was dissolved i~ 15 ml
of methanol, 5 ~1 o~ a 2N sodium h~dro~ide solution
were added at 0C and the whole was stirred ~or 30
minutes at 20C. hfter concentrating in vacuo to
appro~imately 5 ml, 10 ml of water ~ere added and
the ~hole was e~tracted fo~r times with 10 ml of
ethyl acetate each time. ~fter drylng over mag~eEium
sulphate ~nd coucentrating by evaporation, ~50 mg o~
a~ oily re~idue ~ere obtained 9 a~d thi~ wa~ chroma-
tographed over silica gel with dichlorome~hanet5 %
isoprop~l alcoh~l~ 120 mg of the compound identified
in the title were obtai~ed in the form of zn oil.
~am~le 28
_
The tris-thydro~ymethyl)-aminomethane salt of (5Z)-
(16RS)-5-fl~oro-16-methyl-18,18,19,19-tetradehydro-
6a-carbapros taglandi~L~12
~ solu-tion of 60 mg of tris-(hydro~ymethyl)-
aminomethane in 0.2 ~1 o~ water was added at 70C
to a solution of 179 mg of (5Z)-(16RS)-5 fluoro-16-
methyl-18,18,19,19-tetradehydro-6a-carbaprostaglan~
din-I2 in ~5 ml of aceto~itrile. The ~hole ~as
allo~ed to cool ~hile stir~ing, and after 16 hours
~ 61 ~
decanted to remove the solvent, a~d t~e resulting
re6idue was dried in vacuQ0 154 mg of the compo~nd
identified in the title were isolzted in the fo~m of
a ~z~-like ma~
