CARBACYCLINES, PROCEDE DE PRODUCTION ET UTILISATION EN PHARMACOLOGIE

CARBACYCLINS, PROCESSES FOR THEIR MANUFACTURE AND THEIR USE AS PHARMACEUTICALS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The invention relates to carbacylin derivatives with
the general formula I:
<IMG>
I,
where n is 1 or ?d R1 represents the group COOR2 where R2 is
hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl
group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is
a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is
hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a
hydroxymethylene group or
<IMG>
group where the OH group is in the .alpha. - or .beta. -position, D is a
straight-chain saturated alkylene group with 1 to 5 C-atoms, or a
branched chain saturated alkylene group with 2 to 5 C-atoms, E is
a -C?C- group ?esents an alkyl group with 1 to 4 C-atoms,
and R5 repre? a hydroxy group and, when R2 represents a
hydrogen atom and its salts with physiologically tolerable bases.
For its preparation a compound of the general formula II,
<IMG> II

where R4, R5 R9, A, W, Y, D and E have the significance as quoted
above, by reaction with a halogen alkane derivative with the
general formula III

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of carbacyclins of
the general formula I
<IMG> I,
wherein n is 1 or 3 and R1 represents the group COOR2 where R2 is
hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl
group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is
a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is
hydrogen, A is a trans -CH=CH- or -C?C- group, W is a
hydroxymethylene group or
<IMG>
group where the OH group is in the ? - or .beta. -position, D is a
straight-chain saturated alkylene group with 1 to 5 C-atoms,or a
branched chain saturated alkylene group with 2 to 5 C-atoms, E is
a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms,
and R5 represents a hydroxy group and, when R2 represents a
hydrogen atom, its salts with physiologically tolerable bases, in
which a compound of the general formula II,

<IMG>
where R4, R5, R9 A, W, Y, D and E have the significance as
quoted above, by reaction with a halogen alkane derivative with
the general formula III
<IMG>
III
wherein n is 1 or 3, Hal is a chlorine or bromine atom and R8 is
an alkyl radical with 1 to 4 C-atoms or an alkail metal is
etherified in the presence of a base, and isomers are, when
required, subsequently separated in any required order and/or
protected hydroxy groups are freed and/or free hydroxy groups are
esterified, etherified and/or a free carboxyl group is esterified
and/or an esterified carboxy group is saponified or a carboxy
group is converted into an amide or converted into a salt by
means of a physiologically tolerable base.
2. A process according to claim 1, in which any free
hydroxy groups present are protected and after the etherification
the hydroxy groups are regenerated.
3. A process according to claim 1 or 2, in which D is
selected from methylene, ethylene, 1,2-propylene, ethylethylene,
11

trimethylene, tetramethylene, pentamethylene, 1-
methyltetramethylene and 1-methyltrimethylene.
4. Carbacyclin derivatives with the general formula I:
<IMG>
I,
wherein n is 1 or 3 and R1 represents the groups COOR2 where R2
is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an
alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where
m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y
is hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a
hydroxymethylene group or
<IMG>
group where the OH group is in the .alpha.- or .beta. -position, D is a
straight-chain saturated alkylene group with 1 to 5 C-atoms, is a
branched chain saturated alkylene group with 2 to 5 C-atoms, E is
a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms,
and R5 represents a hydroxy group and, when R2 represents a
hdyrogen atom, its salts with physiologically tolerable base.
5. A compound according to claim 4, in which D is
selected from methylene, ethylene, 1,2-propylene, ethylethylene,
, trimethylene, tetramethylene, pentamethylene, 1-
methyltetramethylene, and 1-methyltrimethylene.
6. 3-Oxa-9-methyl-16-methyl-18,19-tetradehydro-
carbacyclin.
12

Description

~ 7 ~
The invention relates to new carbacyclin derivatives,
processes for their manufacture and their use as pharmaceuticals.
In U.S. patent 4,~20,632 9-alkylated carbacyclin
derivatives are described which possess ant:ithrombosis,
antisecretion and bronchiodilatory properties. In addition they
have thrombocyte aggregation inhibiting effect. It was found
that by replacement of the methylene group in the 3-position of
these carbacyclins by oxygen or by extension of the chain in the
9-position hiologically active derivatives are produced which are
effective for a longer period of time, have greater selectlvity
and possess better efficacy. Derivatives with extended chains in
the s-pOsitiOn can be linked to polymeric carriers with only
slight loss of biological activity. The compounds in accordance
with the invention act in a bronchiodilatry manner and are
suitable for inhibiting thrombocyte aggregation, for lowering
blood pressure by a process of vasodilation and for :Lnhibiting
gastric acid secretion.
The present invention thus provides carbacyclin
derivatives with the general formula I:
~fll2~n~Rl
~.
Ii~2
C-~'
~ ~
~""s ~ 1,
R g
~ A-W-D-E-R~
wherein n is 1 or 3 and Rl repressnts the group COOR2 where R2 is
hydrogen or an alkyl with 1 to 4 C-atoms, Rg represents an alkyl
group with 1 to 10 C-atoms or the group -C_C(CH2)m-R6 where m is
a numbsr from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is
hydrogen, A is a trans- -CH=CH- or
.i ..

~ 3
-C_C-group, W is a hydroxymethylene group or ~H3
OH
group where the OH group is in the ~ - or ~ -position, D is a
straight-chain saturated alkylene group with 1 to 5 C-a-toms or a
branched chain saturated alkylene group with 2 to 5 C-atoms, E is
a -C C group, R~ represents an alkyl group with 1 to 4 C-atoms,
and R5 represents a hydroxy group and, when R2 represents a
hydrogen atom, its salts with physiologically tolerable bases.
Compounds conforming to formula I repres~nt both (5E) and (5Z)-
isomers.
Alkyl groups R2 are straight or branched chain alkyl groups with
1 to 4 C-atoms such as, e.g. methyl, ethyl, propyl, isopropyl,
butyl, isobutyl or tertiary butyl.
Alkylene groups D are straight-chain or branched chain, satura-ted
alkylene radicals, with up to 5 C-atoms such as, 1,2-methylene,
1,1-tri-methylene, 1,1-tetramethylene or 1,1-pentamethylene. For
example, mention may be made of methylene, ethylene, 1,2-
propylene~ ethylethylene, trimethylene, tetramethylene,
pentamethylene, l-methyltetramethylene, l-methyltetramethylene,
l-methyltrimethylene.
The groups already given for R4 can be taken into conslderation
as the alkyl groups R9 with 1 to 10 C-atoms.
For salt formation with the free acids ~R2=H), inorganic and
organic bases are suitable such as are familiar to the expert for
formation of physiological tolerable salts. For example, mention
may be made of the following: alkali hydroxides such as calcium
hydroxide, alkaline earth hydroxides such as calcium hydroxide,
ammonia, amines such as ethanolamine, diethanolamine,
triethanolamine, N-methylglucamine, morpholine, and tris-
~hydroxymekhyl)-methylamine.
rq~
1~

75~
The Invent/on fwrther provldes a process for the manu-
facture of carbacyc/Ins of the general formula I where X Is an
oxygen atom, In whlch a compound of the general formula T~,
~
~ 7 , I T
where R4, R5, Rg, A, W, Y, D and E have the slgnlflcance as
quoted above, posslbly after protectlon of any free hydroxy
groups present by means of a halogen alkane ac/d derlvatlve wlth
the general formula lll,
fla l - (Crl2 ) -C
OT1~3 III
where n Is 1 or 3, Hal Is a chlorlne or bromlne atom and R~ Is an
alkyl radlcal wlth 1 to 4 C-atoms or an alkall metal, Is etherl-
fled In the presence of a base, and Isomers are, as requlred,
subsequently separated In any requlred order and/or protected
hydroxy yroups are freed and/or free hydroxy groups are esterl-
- fled, e~herlfled and/or a free carboxyl group Is esterlfled
and/or an esterlfled carboxyl group Is saponlfled or a carboxyl
group Is converted Into an amlde or converted Into a salt wlth a
phys/ologlcally tolerable base.
~' ~ Reactlon of the compound of general formula ~ wlth a
halogen alkane acld derlvatlve of the general formula~ Is car-
rled out at ternperatures between 0C and 100C, preferably
between 10C and 80C In an aprotlc solvent or mlxtures of so/-
vents, for example, dlmethyl sulfoxlde, dlemthylformamlde, and
tetrahydrofuran. Posslble bases are those whlch are ~amlllar to
the expert for etherlflcatlon~ for example, sodlum hydrlde,
potasslum tert.-butylate and butyl llthlum.
Saponlflcatlon of the carbacyclln ester Is carrled out
by methods well-known to the expert such as for examp/e wlth
- 3 -

~7~ 3
baslc catalysts.
The ester group COOR2 ~or R1, where R2 represents an
alkyl group wlth 1 to 4 C-atoms, Is Introduced by methods we/l-
known to the expert. The carboxy compounds are converted forexample wlth dlazo hydrocarbons In a conventlonal manner. Ester-
Iflcatlon wlth dlazo hydrocarbons takes place for exampl0 by mlx-
lng a solutlon of the dlazo hydrocarbon In an Inert solvent,
prefarably In dlethyl ether, wlth the carboxy compound In the
same or In a dlfferent Inert solvent such as, for example, methy-
lene chlorlde After completlon of the reactlon after 1 to 30
. mlnutes the solvent Is removed and the ester /s purlfled by nor-
mal methods. Dlazo alkanes are already known In the art or can
be manufactured by well-known methods ~Org, Reactlons Vo/. 8,
Pages 389-394 (1954)7-
Carbacyclln derlvatlves of the general formula I wlth
R1 belng a carboxyl group can be converted Into salts uslng sult-
able quantltles of the correspondlng Inorganlc bases wlth accom-
panylng neura/Isatlon, For example, on dlssolutlon of the corre-
spondlng PG aclds In water contalnlng the stolchlometrlc quantlty
of the base the solld Inorganlc salt Is obtalned after evapora-
tlon of the water or after addltlon of a solvent mlsclble wlth
water, for example, alcoho/ or acetone.
The amlne salts are prepared In a conventlonal manner.
For thls purpose the PG acld Is, for examPle, dlssolved In a
sultable solvent such as ethanol, acetone, dlethyl ether or ben-
zene and at least the stolchlometrlc quantlty of the am/ne Is
added to thls solvent. I~n thls connectlon the salt Is normally
produced In a solld form or Is Isolated In a conventlonal way
after evaporatlon of the solvent.
Functlonal modlflcatlon of the free 0~ groups takes
p/ace by conventlonal methods. For Introductlot7 of tl~e ether

protectlon groups the react/on /s carr/ed out e.g. wlth dlhy-
dropyran In methylene chlorlde or chloroform wlth use of a n acld
condensatlon agent swch as, e.g. p-toluene-sulfon/c acld. The
dlhydropyran Is used In excess preferably wlth 4 to 10 t/mes the
theoretlcally requlred amount. At 0C to 30C the reactlon Is
normally completed after 15 to 30 mlnutes.
The acy/ protectlon group are Introduced by causlng a
compound of the general formula I to react In a conventlonal man-
ner wlth carboxyllc acld derlvatlve such as, for example, theacId chlorIde or the acId anhydrIde.
Freelng of a functlonally modlfled OH group In the com-
pounds of general formula I takes p/ace by conventlonal methods.
For example, the spllttlng off of ether protectlon groups Is car-
rled out In an aqueous solutlon of an organ/c acld such as acet/c
acld or proplonlc ac/d, or In an aqueous solutlon of an Inorganlc
acld such as, e.g. hydrochlorlc ac/d. To /mprove the solublllty,
It Is conventlone to add an Inert organ/c so/vent mlsclble wlth
O water. Sultable organlc solvents Include for example alcohols,
such as methanol and ethanol, and ethers such as dlmethoxy-
ethane, dloxane and terahydrofuran. Tetrahydrofuran Is used by
preference. Spllt-off Is preferably carr/ed out at temperatures
between 2QC and 80C.
The sllyl ether protectlve groups are spllt off for
examp/e wlth tetrabutylammonlum fluorlde. The followln~ are for
example sultable for use as so/vents: tetrahydrofuran, dlethyl
ether, d/oxane, methylene chlorlde etc. The spllt-off react/on
Is carr/ed out preferably at temperatures between 0C and 80C.
Saponlflcatlon of the acy/ groups Is carrled out for
example wlth alkall or alkallne earth carbonates or hydroxldes In
an alcohol or an aqueous solutlon of an alcohol. Posslble alco-
hols are allphatlc alcohols suc/7 as, e.g. methanol, ethanol orbutanol etc., preferably methanol. As aIkall carbonates and
- 5 -

~7513~3
hydroxldes mentlon should be made of potasslum and sodlum salts,
potasslum salts, however, belng preferred. The followlng are for
example sultable as alkallne earth carbonates and hydroxldes:
calclum carbonate, calclum hydroxlde and barlum carbonate. The
reactlon takes place at -10C to ~70C, preferably at 25C.
If the startlng product contaJns OH groups In the
prostan radlcal these OH groups are also made to react. If In
concluslon end products are requ/red whlch contaln hydroxyl
groups In the prostan radlcal It ~s best to begln wlth startlng
products In whlch these are preferably protected Intermedlarlly
wlth easlly spllt-off ether or acy/ radlcals.
All the other compounds of formula I can be produced by
processes as descrlbed In Patent Appllcatlons DE-OS Nos.
28 45 770, 32 37 200, 33 22 893 and 34 05 181. If the radlcal ~9
represents an alklnyl group, sald radlcal Rg can be Introduced by
the method publIshed by R.T. Hansen et al. JACS, 100, 2244
~ 1g78) .
The compounds In accordance wlth the Inventlon are
sultable In partlcular for the treatment of dlsorders of the car-
dlovascular system, the stomach, the pancreas, the l/ver and the
kldneys. They have blood-pressure lowerlng and bronchlodl/atory
effects. Furthermore they are sultable for Inhlbltlng thrombo-
cyte aggregat/on. Thus these new carbacyclln derlvatlves of for-
mula I represent valuable pharmaceutlcal agents. In addltlon,
whlle exert/ng a slmllar prostaglandlns and prostacycllns they
show hlgher speflclty and above all exhlblts /onger effectlve-
ness. In compar/son to PGI2 they are marked by greater stabll-
lty. The hlgh t/ssue speclf/clty of the new carbacycllns /s evl-
dent In Investlgatlons on nonstrlated musc/e organs such as, e.g.
gu/nea plg l/eum or on Isolated rabblt trachea where far /ess
stlmulatlon /s to be observed than on appllcatlon of natural
prostaglandlns of the E, A or F type.
~1
,~..~

The new carbacyclln analogues possess propertles typl-
cal for prostacycllns, e.g. Iowerlng of the reslstance of the
perlpheral arterles and coronary vessels, Inhlbltlon of thrombo-
cyte aggregatlon and dlssolutlon of platelet clots, myocardlalcytoprotectlon, lowerlng of systemlc blood pressure wlthout
slmultaneous lowerlng of the card/ac output and coronary clrcula-
tlon; treatment of apoplexy , prophylaxls and therapy In the
event of coronary heart dlseases, coronary thrombosls, myocardlal
Infarctlon, perlphero-vascular dlseases, arteosclerosls and
thrombosls; prophylaxls and therapy In the event of Ischaemlc
attacks of the central nervous system, therapy In the vent of
shock, Inhlbltlon of bronchlo-constrlctlon, Inhlbltlon of gastrlc
acld secretlon and cytoprotectlon of the gastrlc and Intestlnal
mucous membrane; cytoprotectlon In the llver, pancreas and kld-
neys, antlallerglc propertles, lowerlng of the pulmonary vascular
reslstance and of the pulmonary blood pressure, promotlon of kld-
ney clrculatlon, use Instead of herapln or as an adJunct In dlal-
ysls or hemoflltratlon, preservatlon of blood plasma, In partlcu-
lar of blood platele~ preserves, Inhlbltlon of labour palns,treatment of pregnancy toxlcosls, Increase of cerebral clrcula-
tlon, treatment of asthma etc. In addltlon the new carbacyclln
analogues possess antlprollferatlve propertles. The new carbacy-
cllns can In addltlon be used In comblnatlon for example wlth ~ -
bloc~ers or dluretlcs.
The new carbacycllns are In addltlon marked by suppres-
slon of reJectlon reactlons and by thelr antlmetastatlc effects.
As a result of thelr use, the ductus botalll Is l<ept open (prlor
to operatlons). ~urthermore, they are sultable for treatment of
dlarrhoea and for Improvement of bowel movements.
Carbacycllns of formu/a I, In whlch Rg slgnlfles the
radlca/ -C-C~ (CH2)m~R6, wlth R6 represent/ng OH or NH2 groups
can readlly be llnked to polymerlc carrlers wlthout great loss of
blologlcal actlvlty. The new carbacycllns prohlblt thrombocyte
-- 7

~7~
aggregates be/ng formed on the upper surface of these potymerlc
carr/ers such as artlflclal blood vessels or artlflclal cardlac
valves.
The dosage of such compounds Is 1-1500 ug/~g/day when
admlnlstered to human patlents. The unlt dosage for the pharma-
ceutlcally acceptable carrler amounts to 0.01-100 mg.
On Intravenous InJectlon In awake, hypertonlc rats In
doses of 5, 20 and 100 ug/kg body welght, the compounds In accor-
dance w/th the Inventlon exhlblt a marked blood-pressure lowerlng
and longer lastlng effect than PGE2 and PGA2 wlthout as Is the
case wlth PGE2 produclng dlarrhoea or wlth PGA2 cardlal
arrhythmla.
On Intravenous InJectlon In narcotlzed rabblts the com-
pounds In accordance wlth the Inventlon In comparlson wlth PGE2
and PGA2 exhlblt more pronounced and longer-lastlng blood-pres-
sure lowerlng wlthout other nonstrlated musc/e organs or organ
functlons belng affected.
For parenteral admlnlstratlon sterlle InJectable, aque-
ous or oll solutlons are used. For oral appllcatlon tablets,
coated tablets or capsules are sultable.
The Inventlon thus also relates to pharmaceut/ca/s
based on compounds of the general formula I and normal auxlllary
and carr/er substances.
The substances In accordance wlth the Inventlon are
Intended to serve In comblnatlon wlth the auxlllary substances
famlllar and normally encountered In galenlcs, e.g. for the manu-
facture of blood-pressure lowerlng agents.
3~ The standard dosage range for ampou/es Is 0.1 to 0.
mg, for the tablets 0.1 - 1 mg.

~7~ 3
The present Inventlon wlll be further Illustrated by
way of the followlng Examples.
,
EXAMPLE 1
~ methyl-7 CX-(tetrahydropyran-2-yl-oxy-6 ~-[3 ~ -
(tetrahydropyr-an-2-yl-oxy)-4-methyl-~,7-tetradehydro-trans-1-
octenyl~-blcyclo-[3.3.0~octane-3-one.
10To a suspenslon of 4.28 g (22.5 mmo/~ cUII In 25 ml of
absolute ether, 27 ml of a 1,6 N methylllthlum solutlon In ether
Is added carefully In drops at -5C whlle stlrrlng wlthln 15 mln-
utes and to thls solutlon 2.21 g ~5-mmo/) of 7 ~ -(tetrahydro-
yran-2-yl-oxy)-6 ~-~3 ~ -(tetrahydropyran-2-yl-oxy)-4-methyl-
156,7-tetradehydro-trans-1-octenyl]-bl-cyclo[3.3.-Joct-1-ene-3-one
¢cf. ~Æ OS 31 42 733) In 20 ml-of ether Is slowly added In drops
at -25C to -30C, 100 ml of N~14Cl solutlon Is added carefu/ly
and the m/xture /s extracted wlth ether. After washlng wlth sat-
urated common salt solutlon, 2.37 g of the crude product Is
obtalned after drylng and evaporatlon and thls Is chromatographed
on a column of 120 g slllca ge/. Elutlon wlth hexane ether (7:3)
ylelded 1.54 g ~67%) of the above-named product.
EXAMPLE 2
2~3-oxa-9 ~-methyl-16-methyl-18,19-tetradehydro-carbacy-
clln.
The 5-rlng ketone descrlbed In Example 1 Is caused to
react In accordance wlth EP 55208 wlth dlmethoxyphophono-methyl-
acetate In the presence of potasslum tert.-butylate, then reduced
wlth llthlum alumlnum hydrlde and the E-conflgurated alkyl a/co-
hol Is flnally converted wlth ~ or esters of the 2-chloro or
2-bromo-acet/c acld In the presence of bases wlth subsequent
spllt-off of the tetrahydropyranyl protect/ve groUp to form 3-
oxa-9 ~-methyl-16-methyl-18,19-tetrahydro-carbacyclln.
~ 9 ~