Note: Descriptions are shown in the official language in which they were submitted.
liB~ 9
This application is a division o~ copendiny
Canadian application Serial No 270,416, filed January
25, 197?.
BACK~;P~OUND OF THE IN_ENTION
This invention relates to prostaglandin
derivatives and to a process for prepariny them.
The prostaglandins and analoys are well-
known oryanic compounds derived from prostanoi.c acid
which has the following structure and a-tom numbering:
CCOH
Q~
~ \~20
As drawn hereinaf-ter the formulas represen-t
a particular optically active isomer having -the same
absolute configuration as PGEl obtained from mammalian
tlsques.
In the formulas, broken line attachments to .
the cyclopentane ring or side chain indicate substituents
in alpha conEiguration, i.e. below ~he plane of the ring
or side chain. Heavy solid line at-tachments indicate
substituents in beta configuration, i~e. above the plane.
For background, see for example Bergstrom et
al., Pharmacol. Rev. 20, 1 (1968) and Pace-Asciak et al.,
Biochem. 10, 3657 (19713.
SU~lARY OF THE INVENTION
It is the purpose of this invention to
provic~e novel products having pharmacological activity.
It is a further purpose to provide a process for
preparing these products and their intermediates~
Accordingly, there is provided a compound
o.E the formula:
- 2 -
mab/ \.rl
2~37 lA
i
,V -O -C -CH -L -R
_ ~ ,WI '
_~
X~C-R~
Q
wherein D is
J ¢~
O~l OH O CH2
~ , ~ , or
C'H2OH
where i n L is
~O (1) -(CH2)d-C(R2 )2 -
(2) -CH2-O-CH2-Y- or
(3) -CH2CH~CH-
wherein d is zero to 5; R~ is hy~rogen, methyl, or
fluoroJ being the s~me or different with the proviso
that one R2 is not methyl when the other is.fluoro;
and Y is a valence bond or -(CH2)k-
where i n k is one or 2;
wherei n Q is
Il /\ ~'~ ~'\
3 O, H H , R~3 OH, or R,3 OH
39~ ,~ 287lA
wherein Ra is hydrogen or alkyl of one to 4 carbon atoms~
inclus;ve,
wherein Rl 3S
~ COOR3
(2) -CH2~
(3) -CH2N(R9 )2 or
(4)
~NH-N
~N -N
wherein R3 is (a) alkyl of one to 12 carbon atoms,
inclusive, (b) cyc loalkyl of ~ to 10 carbon atoms,
inclusive, (c) aralkyl of 7 to 12 carbon atoms, in-
clusive, (d) phenyl, (e) phenyl substituted with
one, 2, or 3 chloro or alkyl of one to 4 carbon atoms,
inclusiv~;
:l5 .
- ~ -NH-C ~ NH-C-CH3,
{~ e3
O
(h) ~ ~ NH-l-CH3,
;) ~ NH-C-NH2
~ CH=N-NH-l-NH2, or
(k)
(1) -CH-C-R1 Q
R l l
wherein Rlo is phenyl, p-bromophenylJ p-biphenylyl, p-
nitrophenyl, p-benzamidophenyl, or 2-naphthyl;
whereîn R11 is hydrogen or benzoyl;
(m) hydrogen; or
(n) a pharmacologically acceptable cation; and
wherein Rg is hydrogen or alkyl of one to 4 carbon
atoms J i nclus ive, being the same or different;
wherein R~ is
1 5
(1) -IC-CyH29-CH3
R~
Rs
(2) -C-Z ~ (T)s or
R~
(3) -CH2 ,CH2CH3
H ' H
wherein CgH2~ is alkylene of one to 9 carbon atoms,
inclusiveJ with one to 5 carbon atoms~ inclusive,
in the chain between -CR5R6- and terminal methyl,
wherein R5 and R~ are hydrogen, alkyl of one to 4
. 2871A
r~
carbon atoms, inclusive~ or fluoro, being the same
or different, with the proviso that one of R5 and R~
is fluoro only when the other is hydrogen or fluoro
and the further proviso tha~ neither R5 nor R~ is
fluoro when Z is oxa ( 0-); wherein Z represents
an oxa atom ( 0-~ or CjH~j wherein C~H23 is
a valence bond or alkylene of one ~o 9 carbon atoms,
inclusiveJ with one to 6 carbon atomsJ inclusive
between CR5R~- and the phenyl ring;
wherein T is alkyl of one to 4 carbon atoms~ inclusive~
fluoro, chloro, trifluoromethyl, or -OR7- wherein R7
is hydrogen or alkyl of one to 4 carbon atomsJ inclu-
siveJ and s is zero~ oneJ 2 or 3~ with the proviso
that not more than two T's are other than alkyl and
when s is 2 or 3 the T's are either the same or dif-
ferent;
whercin V is a valence bond or -CH2-; wherein W is -(CH2)h-
wherein h is one or 2; and
wherein X is
(1) trans-CH=CH-
(2) cis-CH=CH-
(3) -C-C- or
(4) -CH2CH2--
Within the scope of the prostaglandin derivatives
described herein there are represented
(a) PGFa compounds when ~ is
<,~' ,
OH
3o
-6 -
2871
(b) 11~-PGF~l compounds when D ;s
¢~'
OH
(c ) 11 -Deoxy~ keto^PGF~ compounds when ~ is
~,
(d) l1-Deoxy-11-methylene-PGF~ compounds when ~ is
<'T'
CH~ ;
1tj (e) 11-Deoxy-PGF~ compounds when Dis
20~ (f) 11-Deoxy-10,11-Didehydro-PGFa compounds when
~ and
(9? 11-Deoxy-11-hydroxymethyl-PGFa compounds when
¢~ ' .
CH20H
287 lA
A typical example of the compounds of formula I is
represented by the formula:
5_C11-CH- (CH2 )3-COOH
~' V
~C =C
HO H' /~
H OH
and named as a derivative of PGF1a: 9-deoxy-6,9-epoxy-5-
iodo^PGF1~ The compound oF formula V is a species of the
formula-l 5-iodo compounds wherein ~ is
<~
L is -(CH2)3-, Q is H OH, R, is -COOHJ R~ is n-perltyl
~t) V Is a valence bond, W is -CH2-, and X.is trans-CH=CH-.
There are lil<ewise provided compounds of the formula
/V-O-C=CH~L-RI
~_/ .
2s L~
-_ X-C-R4
-8 -
287 lA
3~
- OH
~,V-OjC-CH2-L-R~ i 11
~ ~ X-~-R~ and
OH
V~ O
~ ~ W-C-CH2-L-R
~ lV
X-C-R 4
ll
wherein ~ ~ L, O, R1, R4, V, W, and X are as defined
broadly above for formula I, with the proviso that~ in
-L~ the enol ether compounds of formula II, R1 is not-COOH
when D is ~
~ .
bH
Q is Il OH, L is -(CH2)3 -, R4 is n-pentyl,
V is a valence bond, W is -CH2-, and X is trans-CH=CH-.
In compounds of formula II J the wavy line ~ indicates
attachment in cis or trans configuration relative to the
'~-C bond. In formulas I-IV as used herein, W is bonded to
the cyclopentane ring at the C-8 position~ V at the C-9
position, and X at the C-12 position. In compounds of
formula III 9 ~ indîcates attachment of -OH in alpha or
beta configurat;on.
The formwla-II enol ethers are named as derivatives of
PGF2~, regc~rdless of the variations irl either of the side
.
g
~ 2871~
chains, V and W în the heterocyclic ring, or the cyclo-
pentane ring syste~ represented by ~ , following the
conventions known and used in the prostaglandin art. The
formula-lll 6-hydroxy compounds (hemi-ketals) and the
fGrmula~lV 6-keto compounds are named as derivatives of
PGFl~.
Typical examples of the compounds of formula ll, Ill,
and IV, when ~ , L, O, R1J R4s VJ W~ and X are as il7ustrated
above for the compound of formula V are:
O _C-CH-(CH2)3-COOH
~ ~,H Vl
HO /C~CsH
H OH
named 9-deoxy-6,9-epoxy- ~5 -PGF la;
O~H
_~H-(CH2)~ COOH
O \
~ C=C ~ H Vll
HO /C~-C5H
H OH
named 9-deoxy-6,9-epox~-6-hydroxy-PGFla; and
~5
OH O
11
~ ~CH2-C-(CH2)~-COOH
S~C-C' Vlll
' H ~ c-C5H
O~
H OH
named 6-l<eto-PGFla,
-10-
2~71A
The products of this invention, represented herein by
formulas 1, ll~ IJI, and IV, are extremely poten~ in causing
various biological responses. For tha~ reason~ these com-
pounds are useful for pharmacolo~ical purposes. A few of
those biological responses are: inhibition of blood
pla~elet aggregation, stimulation of smooth musc1e, systemic
blood pressure lowering, inhibiting gastric secretion and
reducing undesirable gastrointestinal effects from systemic
adminis~ration of pros~aglandin synthetase inhibitors.
Because of these biological responsesJ the known
prostaglandins are useful to study~ prevent, control, or
allevia~e a wide variety of diseases and undesirable
physiological conditions in mammals, including humans, use-
ful domestic animals, pets, and zoolc,gical specimens, and
1~ in laboratory animals, for example, mice, rats, rabbits,
and monl<cys.
These compounds are useful whenever it is desired to
inhibit platelet aggregation, to reduce the adhesive
chalacter of platelets, and to remove or prevent the forma-
2~ tion of thlombi in mammals~ including man~ rabbits, and rats~For example, these compounds are useful in the treatment
and prevention of myocardial infarcts, to treat and prevent
post-operative thrombosis, to promote patency of vascular
grafts following surgery~ and to tr-eat conditions such as
atherosclerosis) arteriosclerosis, blood clotting defects
due to lipemia, and other clinical conditions in which the
underlying ctiology is associated with lipid imbaiance or
hyperlipidemia. Other in vivo applications include
~eliatric patients to prevent cerebral ischemic attacks
and )ong term prophylaxis following myocardial infarcts
-11
287lA
~ ~ 5~ ~
and strokes~ For these purposes, these compounds are ad-
ministered systemically, e.g., intravenously, subcutane-
ously, intramuscularly, and in the form of sterile implants
for prolonged action. For rapid response~ especially in
emergency situations, the intravenous route of administra-
tion is preferred. Doses in the range about 0.01 to about
10 mg. per kg. of body weight per day are used~ the exact
dose depending on the age~ weight, and condition of the
patient or animal, and on the frequency and route of admin-
istrationO
The addition of these compounds to whole blood provide~
In vitro applications such as, storage of whole blood to be
used in heart-lung machines. Additionally whole blood con-
taining these compounds can be circulated through organsJ
e.g. heart and kidneys~ which have been removed from a donor
and prior to transplant. Also useful i n preparing platlet
rich concentrates for use in treating thrombocytopenia,
chemotherapy, and radiation therapy. In vitro applications
utilize a dose of 0.001-1.0 ~g/ml of ~hole blood.
These compounds are extremely potent in causing stimula-
tion of smooth muscle, and are also highly active in poten-
tiating other known smooth muscle stimu1ators, for example,
oxytoci c agents, e.g., oxytocin, and the various ergot alka-
loids including derivatives and analogs thereof. Therefore,
they are useful in place of or in combination with less than
usual arnounts of these known smooth muscle stimulators, for
e~ample, to relieve the symptoms of paralytic ileus, or to
control or prevent atonic uterine bleeding after abortion or
delivery~ to aid in expulsion of the place~ta, and during
3 thc puerperium. For the latter purpose, the compound is
.
:1.2
adm; ni sLered by intravenous infusion immediate~y after
abortion or delîYery a~ a dose in ~he range about 0.01 to
about 50 ~9~ per kg. of body weight per minute until the
desired effect is c,btained. Subsequent doses are given by
intravenous9 s~bcutaneous~ or intramuscular injection or
infusion duri ng puerperium in the range 0.01 to 2 mg. per
kg. of body weight per day, the exact dose depending on the
- age, weigh~, and condition of the patient or animal.
These compounds are useful as hypotensive agents to
reduce blood pressure in mammals, including man. For this
purpose~ the compounds are administered by intravenous in-
fusion at the rate about 0.01 to abou~ 50 ~9. per kg. ofbody weight per minute or in single or multiple doses of
about 25 to 500 ~g. per kg. of body weight total per day.
These prostaglandin derivatives are as useful in mam-
mals, including man and certain useful animals~ e.g., dogs
~nd pigs) to reduce and control excessive gastric secretion,
thereby reduce or avoid gastrointestinal ulcer formation,
and accelerate the healing of such ulcers already present
~ in the yastrointestinal tract. For this purpose~ these
compounds are injected or infused intravenously~ sub-
cutaneously~ or intramuscularly in an infusion dose rangeabout 0.1 ~9 to about 20 ~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 fre-
quency and route o~ administration.
These compoundiare a ! S useful in reducing the un-
desirable gastrointestinal efFects resulting from systemic
-13-
~ 3
admini~trn~ion o nntl-Ain1~mm~ltory pro~ lundin uyn~lle~as~
~nhibi~ors, ~nd ~re ~Iled for tl~t p~rpo~e by concomit~nt
adminl~tration s)~ the prostn~landln deriva~lvc and ~he ~n~l
inflAmma~ory pro6~aglandin syn~hetase inhibltor. See P~r~rid~e
et al, ~.S. Pa~. No. 3~781,429 lssued December 259 1~73, for
a disclosure that ~he ulc~rogenic effect induced by cer~ain non-
steroidal anti~inflammatory agen~s in rats is lnhlblted by
concomitant oral administra~ion o~ certa:Ln prostaglandins of
the E and A series9 includin~ PGEl, l'GE2, PGE3, 13,14-dihydro-
PGEl, and the correspondin~ deoxy-PGE and PGA compound5.
Prostaglandins are useful, for example, in reducing the
undesirable ~asLrointestinal effects resulting fro~ systemic
administration of indomethacin, phenylbutazone, znd ~spirin.
These are substances specifically mentioned in Partridge et al
as non-steroidal, anti-inflammatory agen~s. These are also
known to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhib;tor, for example,
*
illdomethacin, ~pirin, or phenylbutazone is administered in
nny of the ways known in the art to alleviate an inflammatory
collcli~ion, for e~ample, in any dosage regimen and by any of.
tho known routes of systemic administration.
The prostaglandin derivative is administered along
with tlle anti-illflammatory prostaglandin synthetase inhibitor
elther by the same route of administration or by a different
route. For exampleS if the anti-inflammatory substance is
being administered orally, the prostaglandin derivative is
also administered orally, orD alternatively~ is administer~d
rectally in the form of a suppository or, in the case of
women, vaginally in the form of ~ suppository or a vaginal
dcvice for slow release, for example as described in U.S. Pat.
.
c~
* Trademark
~h
'
~ S~
No. 3,545,439 (Dec. 8, 1970, The IJp~ohn Comp~ny). Alternatively,
lf the anti-inflammatory substance i8 being admlnistered
rectally9 the prostaglandin derivative is also adminlstered
rectally~ Fur~her 3 tlle progtagl.andin derlva~ive can be conve
iently administered orally or, in the case of women~ vaginally.
It is especially convenient when the adminlstration route is to
be the same for both anti-inflammatory substance and prostaglandin
deriva~ive, to combine both into a single dosa~e orm.
The dosage regimen for the prostaglandin derivative in
accord with this treatment will depend upon a variety of factors,
including the ~ype~ age, weight, sex and medical condition of
the mammal, the nature and dosage regimen of the anti-inflammatory
synthetase inhibitor being administered to the mammal9 the
sensitivity of the particular prostaglandin derivative to be
administered. For example, not every human in need of an anti-
inflammatory substance experiences the same adverse gastro-
Lntest:lnal effects when taking the substance. The gastro-
ln~estinal effects will frequently vary subs~antially in kind
ncl degree. But it is within the skill of the attending
~0 plly~:Lclan or ve.terinarian to determine that administration of
the ~nti~inflammatory substance is causing undesirable gastro-
.lntestinal e:Efects i.n the human or animal subject and to pre-
scribe an effective amount of the prostaglandin derivative to
reduce and then substantially to eliminate those undesirable
effects.
These compounds are also useful ln the treatment of
asthma. For example, these compounds are useful as broncho-
dilators or as inhibitors of mediators, such as SRS-A, and
histamine which are released from cells activa~ed by an antigen-
antibody complex. Thus, these com-
- 1 5 -
. .
~ 2871~-1
pounds control spasm and facilitate breathing in condi-
~ions such as bronchial asthma, bronchitis, bronchiectasis,
pneumonia and emphysema. For these purposes~ these com-
pounds are administered in a variety of dosage forms, e.g.,
orally in the form of tablets, capsules, or liquids; rec~
tally in the form of suppositorles; parenterally~ sub-
cutaneously~ or intramuscularly~ with intravenous adminis-
tration being preferred in emergency situations; by inhala-
tion 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 mgO 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 fre-
quency and route of administration. For the above use
these prostaglandins can be combined advantageously with
other anti-asthmatic agents~ such as sympathomimetics
(isoproterenol, phenylephrine, ephedrine, etc.); xanthine
derivatives (theophylline and aminophylline); and cortico-
steroids (ACTH and prednisolone),
Tl~ese 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 o~ by oxygen aerosolization it is
convenient to provide the instant active ingredient in
dilute solution~ preferably at concéntrations of about 1
part of medicament to form about 100 to 200 parts by
weight of total solution. Entirely conventional additives
may be employed to stabilize these solutions or to pro-
3o vide isotonic media, for example, sodium chloride~ sodiunn
- -16-
D~9
citrate~ citric acid, sodium bisulfiteJ and the like
can be emp10yedO
For administration as a self-propelled dosage unit for
administering the act;ve ingredient in aerosol form suita-
ble for inhalation therapy the composition can compr;sethe active ingredient suspended in an inert propellant
(such as a mixture of dichlorodifluoromethane and di-
chlorotetrafluoroethane) together with a co-solvent, such
as ethanolJ flavoring materials and stabilizers. Instead
of a co-solvent there can a.~so be used a dispersing agent
such as oleyl alcohol. Suitable means to employ the
aerosol inhalation therapy technique are described fully
in U.S. 2,868,691 (Jan. 13/59, Riker Laboratories, Inc.) ror exarr~le.
These compounds are useful in mammals, including man,
as nasal decongestants and are used for this purpose in a
dose range of about 10 ~g. to about 10 mg. per ml. of a
pharmacologically suitable liquid vehicle or as an aerosol
sprayJ bo~h -for topical application.
These compounds are also useful in treating peripheral
vascular disease in humans. The term peripheral vascular
disease as used herein means disease of any of the blood
vessels outside of the heart and to disease of -the lymph
vessels, for example, frostbite, ischemic cerebrovascular
disease, artheriovenous flstulas, ischemic leg ulcers,
~5 phlebitis, venous insufficiency, gangrene, hepatorenal syn
drome, ductus arteriosus, non-obstructive mesenteric
ischemia, arteritis lymphangitis and the like. These
examples are included to be illustrative and should no~
be construed as limiting the term peripheral vascular
3 disease. For these conditions the compounds of this
-17
I
lnve~ion are admlnis~ered orally or parenterally via $nJection
or infuslon directly lnto a veln or artery, intra venous or
intra-arterlal injec~ions being preferred. The dosages of
these compounds are in the range of 0.01-1.0 ~g/kg administered
by infusion at an hourly rate or by injection on a daily basis
i.e 1-4 tlmes a day, the exac~ dose depending on the age~
weight, and condltion of ~he patient and on the frequency and
route of administration. Treatment is continued for one to
five days, although three days is ordinarily suEficient to
assure long-lasting therapeutic action. In the event that
systemic or side effects are observed the dosage is lowered
below the threshold at which such systemic or side effects are
observed.
These compounds are accordingly useful for treating
peripheral vascular diseases in the extremities of humans who
have circulatory insufficiencies in said extremities, such
treatment affording relief of rest pain and induction of
he~llng of ulcers.
For a complete discussion of the nature of and clinical
m~lllfestations of human peripheral vascular disease and the
etllod previously known of its treatment with prostaglandins see
South African Patent No. 74/0149 (March 7, 1975, L.A. Carlson~,
or corresponding U.S. Patent 4,103,026 ~July 25, 1978). See
~lliott, et al~ Lancet, January 18, 1975, pp. 140~142.
These compounds are useful in place of oxytocin to induce -
labor in pregnant female animals, including man, cows, sheep,
and pigs, at or near term9 or in pregnant animals with intra-
uterine death of the fetus from about 20 weeks to term. For
this purpose, the compound is in-
~ 18-
1~R~ 2871A-1-F
fused intraverously at a dose of 0.01 to 50 ug. p~r kg~
of body weigh~ per minute until or near the ~ermination
of the second stage of labor, i.e., expulsion of the
fetus. These compounds are especially useful when the
5 female is one or more weeks post-mature and natural
labor has not started, or 12 to 60 hours after the mem-
branes have ruptured and natural labor has not yet started.
An alternative rou~e of administration is oral.
These compounds are further useful for controlling
the reproductive cycle in menstruating female marnmals,
including humans. By the term menstruating female mammals
is meant animals which are mature enough to menstruate~
but not so old that regular menstruation has ceased. For
that purpose the prostaglandin derivative is administered
1~ systcmically at a dose level în the range 0.01 mg. to
abou~ 20 m9 per kg. of body weigh~ of the female mammal~
acIvaIlta 9~0US 1y during a span of time starting approximately
~t tl~c time of ovulation and ending approximately at the
time of menses or just prior to menses. Intravaginal and
2~ intrauterine routes are laternate methods of administra-
tion. Additionally, expulsion of an embryo or a fetus is
accomplished by similar administration of the compound
during the first or second trimester of the normal mam-
malian gestation period.
These compo-Inds are further use-ful in causing cervi-
cal dilation in pregnant and nonpregnant female ~a~-~
for purposes of gynecology and obstetrics. In labor
inductioIl and in clinical abortion produced by these
compounds, cervical dilation is also observed. In cases
of infertility, cervical dilation produced by these com-
-19-
r 2871A~
pounds is useful in assisting sperm movement to the
uterus. Cervical dilation by prostaglandins is also use-
ful in operative ~ynecology such as D and C (Cervical
Dilation and Uterine Curettage) where mechanical dilation
may cause performation of the uterus, cervical tears, or
infectionsO It is also useful for diagnostic procedures
where dilation is necessary for tissue examination. For
these purposes, the prostaglandin derivative is administered
locally or systemically.
The prostaglandin derivative, for example, is admîn-
istered orally or vaginally at doses of about 5 to 50 mg.
per treatment of an adult female human~ with From one to
five treatments per 24 hour period. Alterna~ively the
compound is administered intramuscularly or subcutaneously
L5 at doses of about one to 25 mg. per treatment. The exact
dosages for these purposes depend on the age, weight, and
condition oF the patient or animal.
Thcse compouncls are further useful in domestic animals
as an abortifacient (especially for feedlot heifers), as
~'0 an aid to estrus detection, and for regulation or synchroniza-
tion of estrus. Domestic animals include horses3 cattle,
sheep, and swine. The regulation or syr.chronization of
estrus allows for more efficient management of both con-
ception and labor by enabling the herdsman to breed all
his femals in short pre-defined intervals. This synchroniza-
tion results in a higher percentage of live births than the
percentage achieved by natural control. The prostaglandîn
is injected or applied in a feed at doses of 0.1-100 mg.
per animal and may be combined with other agents such as
steroids. Dosing schedules will depend on the species
~0 -
2871A -l -F
treated. For example, mares are given the prostaglandin
derivative 5 to 8 days after ovulation and return to estrus.
Cat~le are treated at regular intervals over a ~ week period
to advantageously bring all into estrus at the same time.
These compounds increase ~he flow of blood in the
mammalian kidney, thereby increasing volume and electro-
lyte content of the urine For that reason, these compounds
are useful in managing cases of renal dysfunction, especially
those involving blockage of the renal vascular bed. Illus-
tratively, these compounds are useful to alleviate and cor-
rect cases of edema resulting, for example, from massive
surface burns, and in the management of shock. For these
purposes, these compounds are preferably first administered
by intravenous injection at a dose in ~he range 10 to 1000
~lg per kg. of body weigh~ or by intravenous infusion at
a dose in the range 0.1 to 20 ~g. per kg. of body weight
p~r minute until the desired effect is obtained. Subse-
ent doses are given by intravenous, intramuscular, or
subcutaneous injection or infusion in the range 0.05 to
2 mg. per k9. of body weight per day.
These prostaglandin derivatives are useful for
treating proliferating skin diseases of man and domesti-
cated animala, including psoriasis~ atopic dermatitis,
non-5pecific dermatitis, primary irri~ant contact dermatitis~
"5 allergic contact dermatitis, basal and squamous cell
carcinomas of the sl<in, lamellar ichthyosis, epidermolytic
hypel-keratosis, premalignant sun-induced keratosis, non-
malignant keratosis, acne, and seborrheic dermatitis in
humans and atopic dermatitis and mange in domesticated
animals, These compounds alleviate the symptoms of these
-21~
5~
proliferative slcin dlseases: pgorlasis, for example3 belng
alleviated when ~ scale-free p~oriasis lesion 1B notlceably
decreased in thickness or noticeably but incomple~ely cleared
or completely clearedO
For these purposes 9 these compounds are applied topically
as composltions includlng a gultable pharmaceutlcal carrier,
for e~ample as an ointment, lotlon, paste~ Jelly, spray, or
aerosol, using ~opical bases such as petrolatum, lanolin, poly-
ethylene glycols~ and alcohols~ These compounds, as the actlve
ingredients; constitute from about 0.1% to about 15~ by weight
of the composition, preferably from about 0.5% to about 2%.
In addltion to topical administration, injection may be employed,
as intradermally, intra- or peri-lesionally, or subcutaneously9
using appropriate sterile saline compositions.
These compounds are useful as antifl~mmatory agents for
inh:Lbiting chronic inflammation in mammals including the
swelllng and other unpleasant effects thereof using methods of
~ren~ment and dosages generally in accord with U.S. Patent Number
3,885,041, :issued to G.D. Searle and Co., May 20, 1~75.
~0 'rhese 6-keto, iodo-ether, enol-ether, and hemi-ketal
compounds of this invention cause many of the biological
~esponses known for the older prostaglandin compounds. For
example, they are surprisingly more specific with regard to
potency and have a substantially longer duration of biological
activity. They have the further advantage that they may be
administered effectively orally, subllngually, intravaginally,
~ c~ -22-
3~>'7~ 2871A
buccally, or rectally as well as by the usual methods.
Each of these novPl analogs is therefore useful in place
of ~he known prostaglandin F~ -~type compounds for at least
. one of ~he pharmacological purposes known for them, and is
surprisingly and unexpectedly more useful for that purpose
because it has a differen~ and narrower spectrum of biolog-
ical activity than the known prostaglandin, and therefor
is more specific in its activity and causes smaller and
~fewer undesired side effects than the known prostaglandin.
Moreover9 because of its prolonged activity, fewer and
smaller doses of these novel compounds can frequently be
used to attain the desired result.
Th~re are further provided the various processes for
preparing the 5-iodo compounds of formula i, the enol ethers
of formula II, the hemi-ketals of formula II3, and the 6-
k~to compounds of formula IV.
Thus, for the formula~ III, and -IV compounds, the
process comprises the steps of startir-g with a compound of
th~ formul a
OH
~t)
W-CH=CH-L-Rl
~ -C-R~ IX
wherein L, Q, R1, R4, and X are as ~ fined above, includ-
ing -COOH for R 1J and wherein ~ is
. .
-2~-
~ ~r~?~ ~ 2~71A
\
<~9 <~J
ORI3 ORl3 CH2
9 ~ ~ o r <~
CH20RI3
' 10
wherein Rl3 is hydrogen, tetrahydropyranyl, tetra-
hydrofuranyl 3 1-ethoxyethyl, or a group of the formula
R 14 - -C--C -R 17
R1s R,~
wherein R1~ is alkyl of one to 18 carbon atoms, in-
clusive, cycloalkyl of 3 to 10 carbon atoms, inclu-
sive, aralkyl of 7 to 12 carbon atoms, inclusive,
phenyl, or phenyl substituted wlth one, 2, or 3 alkyl
~0
of one to 4 carbon atoms, inclusive, wherein Rl5 and
and Rlt3 are the same or different, being hydrogen,
alkyl of one to 4 carbon atoms, inclusive, phenyl or
phenyl substituted with one, 2, or 3 alkyl of one to
4 carbon atoms, inclusive, or, when Rl5 and Rl~ are
taken together, -(CH2)a- or -(CH2)b-O-(C~)c- wherein
a is 3, 4, or 5, b is one, 2~ or 3, and c is one, 2~
or 3 with the proviso that b plus c is 2, 3, or 49 and
wherein R 17 i S hydrogen Ot' phenyl; and
(a) lodinating and cyclizing to form a compound of the
formula
. _ . .. ...
-24-
2~7lA
V-O -CH-CH-L-R~
, ,,~
~W X
_ ~ X-C-R~
wherein ~ , L19 O) Rl, R~, V, ~, and X are as de~ined above,
(b) subjec~ing the product of step "a" to dehalogen-
ation and hydroly5;s to form a keto compound of the formula
0~
V~ O
W-C-CH2-L-R
J X,,
`--~ -'n~X-C-R 4
- Q
and a hemi-ketal compound of the formula
OH
~ ,V-OjC-CH2-L-R
J-w X,
X-C-R~
..
wherein J, L, Q, R " R4, V, W, X~ and _ are as defined
a bove, and
(c) separating the products.
In this disclosure of the process~ or the formula-l,
-111~ and -IV compounds~ the symbol ~ includes all of
the ring systems of the symbol ~ defined above,together
~0 wlth those in which there Is a blocking group within the
-25-
2871A
~ 3~ ~ ~
scope of R13 at C~ll. The compounds produced, as repre~
sented by formulas X, Xl~ and Xll, are inclusive of the
formula-l9 -Ill, and -IV compounds together with those in
which there is the blocking group from the formula-lX
starting material. The compounds with b'locking groups are
uscful as intermediates in further transformations of the
formula-X, -Xl, and -Xll products.
For the formula-ll enol ethers, the process employs
dehydroiodination of formula-l iodo compounds. Accordingly,
the process comprises the steps of starting with a compound
of the formula HCv
_-
-CH=CH-L-Rl
1 Xlll
~ ~
X-C-R4
wherein ~ , L, Q, Rl, R4, V, W, and X are as defined
above, including -COOH for R1, and
(a) iodinating and cyclizing to form an iodo compound
of the formula
I
V-0-CH-~H-L-R
~
-~-R 4
whercin D L~ Q~ Rl9 R~9 V, Wp and X are as deflned above;
(b) sub,jectin~ the product of step "a" to dehydro-
-26 -
287lA
~ 3~3~'~
iodinatlon with a tertiary amine or a reagent selected from
the group consisting of sodium or potassium superoxide3 sodi-
um or potassium carbonate, sodium or potassium hydroxide,
sodium or po~assi um benzoate, sodium or potassium acetate,
sodium or potassium ~rifluoroacetate, sodium or potassium
bicarbonate, silver acetate, and a tetraalkylammonium super-
oxide of the formula (R12)4NO2 wherein Rl2 is alkyl of one
to 4 carbon atoms) inclusive to form the enol ethers; and
(c) separating the products.
Reference to Chart A, herein, will make clear the steps
for preparing the formula-l, -111, and -IV products of this
invention,
In Chart A, the terms are de-fined as follows:
~ is
'l~
\
OH OH O CH2
\
, or .
C'H20H
For those instances in which the formula-X, -Xl, and -Xll
compounds are desired, corresponding to the formula-l, 111,
and IV products, the C-ll hydroxyls of Xlll are suitably
p1-otected with blocking groups within t )e scope of Rl3 as
de~ined above and D then becomes ? as defined
above,
L is
(1) -(CH2)d-C(R2)2
287 lA
CHAP~T A
V/ H
~ W -CH=CH-L -R
,~J , Xlll
X - C - R 4
l (a )
y-o -CH-CH-L -R
~'1
~ R ~ 1 ~
,W -C -CH2 -L -R 1 ( d )
X - C - R ~ I V
Q
~5 (~
,V -O -C -Cl 12 -L -R
I ~ t-~W 111
~ X-C-R~
. Q
-28 -
2871A
~ 3
(2) -CH2-O-CH2-Y- or
C l~2 C~I =C ~ ~
wherein d is zero to 5; R2 is hydrogen, methyl, or
fluoro, being the same or different with the proviso
that one R2 is not methyl when the other is fluoro;
and Y is a valence bond or -(CH2)k-
wherein k is one or 2;
Q iS
, H H J R8 OH, or R8 OH
wherein R~ is hydrogen or alkyl of one to 4 carbon atoms~
inclusive;
Rl is
(1) COOR3
(2) -CH20H
(3) -CH2N(R9 )2 or
(4)
~NH-N
~N _ll
whereirl R3 is (a) alkyl of one to 12 carbon atoms,
inclusive, (b) cycloalkyl of 3 to 10 carbon atoms,
inclusive, (c~ aralkyl of 7 to 12 carbon atoms, in-
clusive, (d) phenyl, (e) pl-enyl substituted with
oneg 2, or 3 chloro or alkyl of one to 4 carbon atoms,
inclusive,
O O
(b) ~ -NH-C- ~ NH-C-CH3, -
~SO
-~?9
287 lA
-
(g) ~ NH-C ~ 3 .
(h) ~ NH-C-CH3,
o
NH-C-NH2
CH=N-NH-C-NH2, or
(k) ~ `
o
(1) -CH-C-Rlo
Rll
wherein R1o is phenyl~ p-bromophenyl, p-biphenylyl~ p-
nitropllenyl, p-benzamidophenyl, or 2-naphthyl;
'~0 whereirl R1l is hydrogen or benzoyl;
(m) hydrogen; or
(n) a pharmacologically acceptable cation; and
wherein Rg is hydrogen or alkyl oF one to 4 carbon
atoms, inclusive, being the same or different;
wherein R4 is
R5
-CgH29~CH3
~0 Ro
~30-
287 lA
~ 3~
Rs
(2) -C-Z ~ (T)s or
R~
5(3~ -CHz~ ,,CH2CH3
H '
wherein C9H29 is alkylene of one to 9 carbon atoms,
inclusive, with one to 5 carbon atoms, inclusive~
in the chain between -CR5R6- and terminal methyl,
wherein R5 and R6 are hydrogen, alkyl of one to 4
carbon atoms, inclusive, or fluoro, being the same
or diff~rent, with the proviso that one of Rs and RB
is fluoro only when the other i 5 hydrogen or ~luoro
and the further proviso that neither R5 nor R6 is
fluoro when Z is oxa (-O-); wherein Z represents
an oxa atom (-O-) or Cj~2j wherein C3H2j is-.
a valence bond or alkylene of one to 9 carbon atoms,
inctusive, with one to 6 carbon atoms, inclusive
betweell CR5R6- and the phenyl ring;
wherein T is alkyl oF one to 4 carbon atoms, inclusive,
fluoro, chloro, trifluoromethyl, or -OR7- wherein R7
is hydrogen or alkyl of one ~o 4 carbon atoms, inclu-
sive, and s is zero, one~ 2 or 3, with the proviso
tha~ not rnore than two T's are other than alkyl and
when s is 2 or 3 the T's are either the same or dif-
ferent;
wherein V is a valence bond or -CH2-; wherein W is -(CH2)h-
wherein h is onc or 2; and
30- wherein X is
. .
28171
(1) trans-CH=CH-
(2) cis-CH=CH-
(3) -C-C- or
(4) -CH2CH2-o
Examples of alkyl of one ~o 12 carbon atomsJ inclusive,
are me~hyl~ ethyl, propyl, butyl~ pentyl, hexylJ heptyl,
octyl, nonyl~ decyl~ undecyl, dodecyl, and isomeric forms
thereof. Examples o~ cycloalkyl of 3 to 10 carbon atoms,
inclusive, which includes alkyl-substituted cycloalkyl, are
cyclopropyl~
2-methylcyclopropyl,
2,2-dimethylcyclopropylJ
2,3-diethylcyclopropyl,
2-butylcyclopropyl,
cyclobutyl,
2-methylcyclobutyl,
3-propylcyclobutyl,
2,3,4-triethylcyclobutyl,
cyclopentyl,
2,2-dimethylcyclopentyl,
3-?entylcyclopentyl,
3-tert-butylcyclopentyl,
cyclohexyl,
~-tert-butylcyclohexyl,
3-isopropylcyclohexyl,
2,2-dimethylcyclohexyl,
cycloheptyl~
cyclooctyl~
cyclononyl,
~ and cyctodecyl,
-32-
j8~
Examples of aralkyl of 7 to 12 carbon atoms, lnclusive, are
benzyl,
phPnethyl 9
l-phenylethyl9
2-phenylpropyl 9
4-pilenylbu~cyl 9
3-phenylbutyl 9
2-(1-naph~hylethyl),
and l-(2~naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of
one to 4 carbon atoms, inclusive are
p-chlorophenyl9
m-chlorophenyl 9
o-chlorophenyl,
2,4-dichlorophenyl9
2,4,6-trichlorophenyl,
p-tolyl,
m-tolyl,
o-tolyl,
p-ethylpllenyl,
p-tert-butylphenyl,
2,5-dimethylphenyl,
4-chloro-2-methylphenyl,
and 2,4-dichloro-3-methylphenyl.
Referring to Chart A the starting materials of formula XIII
are known in the art or are readily available by processes
kno~n in the art. For example, as to PGF2~ see U.S. Pat. No.
3,706,789 (S. B~rgstrom et al, December 199 1972); as to
15-methyl- and 15-ethyl-PGF2~, see U.S. Patent No. 3,728,382
~The Upjohn Company` April 17 9 1973); a~ to 16,16-dimethyl-
PGF2~, see U.S. Patent No. 3,9039131 (The Up~ohn Company,
September 29 1975); as to 16916-
~ 9 - 33-
.
~ t3~
difluoro-PGF~ compounds, see The Up~olln Company's U.S. Pntent
NosO 3,962,293 (June 89 1976) and 3,969,380 (July 13, 1976);
as to l&-phenoxy-17918919~20~tetranor-PGF2~, see Netherlands
Patent 7306462 (November 13, 1973, The Upjohn Company); as to
17-phenyl-18919920-trinor-PGF~a, see U.S. P~tent No. 3,987,087
(October 19, 1976, The Upjohn Company); as to ll-deoxy-PGF2a~
see Netherlands Pa~ent 73Q9856 (January 28, 1974, The Up~ohn
Company); as to PGDz~ see U.S. Patent No. 3,767,813 (October 23,
1973, B. Samuelsson); as to 2a,2b-dihomo-PGF2a, see Derwent
Farmdoc No. 61412S and U.S~ Patent No. 3,852,316 (December 3,
1974, The Upjohn Company) and 3,974,195 (August 10, 1976,
The Upjohn Company); as to 3-oxa-PGFza, see U.S. Patent No.
3,923,861 (December 29 1975, The Upjohn Company); as to 3-oxa-
17-phenyl-18,19,20-trinor-PGF2~, see U.S. Patent No. 3,931,289
(January 6, ]976, The Upjohn Company); as to substitu~ed
phenacyl esters, see The Upjohn Company's Belgian Patent No.
832,459, February 16, 1976; as to substituted phenyl esters,
see U.S. Patent No. 3,890,372 (June 17, 1975, The Upjohn
Comprlny); as to C-l alcohols, i.e. 2-decarboxy-2-hydroxymethyl
compotlnds~ see U.S. Patent No. 3,636,120 ~January 18, 1972,
'rhe Up~ohn Company); as to C-2 tetrazolyl derivatives~ see
Pfl~er, Inc~'s U.S. Patent Nos. 3,883,513 (May 13, 1975) and
3,932,389 (January 13, 1976); as to ~2-PGF2a see Derwent Farmdoc
NoO 46497W and German Offen. 2,460,285 (July 3, 1975, Ono
Pharmaceutical Co.); as to 2,2-dimethyl-PGF2a analogs, see
Belgian Patent 779898 (August 25, 1972, Imperial Chemicals, Inc.);
as to 9-deoxy-9-hydroxymethyl-PGF2~, 3ee U.S. Patent No.
3,950,363 (April 13~ 1976, The Upjohn Company); as to ll~-PGF2a
compounds, see U.S. Patent No. 3~890,371 (June 17, 1975, The
Upjohn Company); as to 11 deoxy-PGF2~, see Derwent Farmdoc NO n
10795V; as to ll-deoxy-ll-hydroxy-methyl-PGF2~, see U.S. Patent
No. 3,931,282 (January 6, 1976, Syntex (U.S.A.) Inc.) and the
~ cj 3~
~ 3~ ~
aforementloned ~.S. Pa~ent No. 3,950~363; as to 16-methylene-
PGF2~, see Derwant Farmdoc No. 19594W and ~er. Offen. 2,440,919
(March 13, 1975l Ono Pharmaceu~ical Co.); as to 17,18-didehydro-
PGF2a compoundsj see U.S. Patent No. 3,920,726 (November 18,
1975, The Upjohn Company); as ~o 3-(or 4-) oxa-17,18-didehydro-
PGF2~ compounds, see ~.S. Patent 3,920,723 (November 18, 1975
The Upjohn Company), as to 15-oxo--PGF2~, see U.S. Patent No.
3,72B,382 (April 17, 1973, The Upjohn Company); as ~o 15-deoxy-
PGF2a, see Canadian Pa~ent 961,489 issued to American Cyanamid
Co., January 21, 1975, as to 13,14-cis compounds, see U.S.
Patent No. 3,932,479 (American Cyanamid Co., January 13, 1976);
as.to ll-deoxy-15-deoxy-PGFz~ see Netherlands Patent 7208575
(American Cyanamid Company, January 16, 1973); as to ~-homo-
PGF2~ compounds, see Japanese Patent 91026/47 (Ono Pharmaceutical
Co., September 27, 1974); and a~ to 2,2-difluoro-PGF2~ compounds
see U.S. Patent 3,987,083 issued October 19, 1976 to The Upjohn
Company.
As to 2-decarboxy-2-amino-PGF2~ compounds, see U.S. Patent
No. 4,085,139, issued April 18, 1978 to the Vpjohn Company.
In step "a" of Chart A, the starting material XIII is sub-
Jected to iodination and cyclization to yield the formula-l iodo
cornpounds. For this purpose there is used either an aqueous
system containing iodine, potassium iodide, and an alkali carbonate
or bicarbonate9 or an organic solvent system such as dichloro-
methane containing iodine in the presence of an alkali metal
carbonate. The reaction is carried out at temperatures below
25C, preferably about 0-5C for 10-20 hr. Thereafter the
reaction is quenched wlth sodium sulfite and sodium carbonate and
the formula 1 compound separated from the reaction mixture.
In step "b" of Chart A the iodo cornpound 1 is converted to
the 6-keto compound by contacting with silver carbonate and
perchloric acid. The reaction is done in an inert organic
mecl:Lum such as tetrahydrofuran and is followed with TLC to
3 - 35
de~termlne completion, normally ln 15-24 hr. at abo~,t 25C.
The reaction is preferably done in absence of light.
In step "c" of Chart A ~he 6-keto compound IV 1B
equilibrated in solution to a mlxture of the formula-lll and
formula~lV compounds. This is accomplished merely by preparlng
a solution of the formula lV compound in an
Jl/~ 35a-
287lA
.
organic solven~, e 9. ace~one or cli~hloromethane, and let-
~ing it st~nd ~or several days. Tl-e resulting mixture is
concentrated and separated, for example by silica gel chroma-
tography, to yield ~he formula-lll herni-ke~al.
Step "d" of Chart A provides an alternate route to the
formula~llhemi-ketalO The formula-l iodo compound is
treated in alcoholic solution, e.g. me~hanol, with aqueous
- alkali metal hydroxide, e.g. potassium hydroxide, at a
t~mperature in the range of 0 to ~0 C. for several hoursO
After acidification there is ob~ained a mixture of the acid
form of the formula-l compound and the formula-lll hemi-
ketal together with some of the formula-lV compound3
which are separated, for example, by silica gel chroma-
tography or by frac.ional crystallization.
1~ The novel compounds of Formulas 1, Ill, and IV wherein
R1 is other than -COOH, e.g., the esters wherein R3 o~ -COOR3
is alkyl of one to 12 carbon atoms, inclusive~ cycloalkyl of
3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon
atoms, inclusiveJ phenyl, or phenyl subs~ituted with one t~
3 chloro or alkyl of one to 4 carbon atoms, inclusive, are
prepared from the corresponding acids o~ formulas 1, Ill,
and IV, i.e~, wherein R1 is -CQOH, by me-thods known in the
art. For cxample, the alkyl, cycloalkyl, and aralkyl esters
are prepal-cd by interaction of said acids with the appro-
priate diazohydrocarbon. For example, when diazomethane i5,
used, the methyll esters are produced Similar use of
diazoethane, di'azobutaneg l-diazo-2-ethylhexaneJ diazocyc!o-
hexane, and phenyldiazornethane, for example, gives the
ethyl, butyl, 2-ethylhexyl~ cyclohexyl~ and benzyl estersJ
respectivelyO Of these esters, the methyl or ether are
-36-
287 lA
preferred.
Esterification with dia~ohydrocarbons is carried out by
n)ixing a solution of the diazohydrocarbon in a suitable
inert so1vent~ preferably diethyl ether, with the acid
reactant~ advan~ageously in the same or a different inert
diluent. After ~he es~erification reaction is c~mplete,
the solvent is removed by evaporation, and the ester
purified if desired by conventional methods, preferably by
chromatography. It is preferred that contact of ~he acid
reactants with the diazohydrocarbon be no longer than
necessary to effect the desired esterification, preferablv
about one to about ten 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 ReactionsJ John Wiley & Sons, Inc., New York, N.Y.,
Vol. ~, pp. 3~9-394 (1954).
An alternative method for esterification of_the car-
boxyl nloiety of the novel compounds of formulas 1, III, and
IV comp~ises transformations of the free acid to the cor-
rcsponding silver sal,t, followed by interaction of that saltwith 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. The silver salts
are prepared by conventional methods~ for example~ by dis-
solving the acid in cold dilute aqueous ammonia, evaporating
the excess ammon;a at reduced pressure, and then adding
~he stoichiometric amount o~ silver ni trate.
The phenyl and substituted phenyl esters oF the
3 f~rmula I, II~, and iV compounds are prepared by silylating
37 -
~l~S~;9 2871A
the acid ~o pro~ect the hydroxy groups, ~or example~ re-
placing each -OH with -O-Si-(CH3) 3 . Doing that may also
change -COOH to -COO-Si-(CH3)3. A brief treatmen~ of ~he
silylated compound with water will change -COO-Si-(CH3~3
back to -COOH. Procedures for this silylation are known in
the art and are discussed hereinafter. ThenJ treatment of
the silylated compound with oxalyl ch10ride gives the acid
chloride which is reacted with phenoi or the appropriate
substituted phenol to give a sily1ated phenyl or substituted
phenyl ester. Then ~he silyl groups, e.g., -O-Si -(CH3)~
are changed back to -OH by treatment with dilute acetic
acid. Procedures for these transformations are known in
the art.
Reference to Chart B, herein will make clear the
steps for preparing the formula-lI products of this in-
vention.
In Chart B the terms D~ L, Q, R1, R~ V, Wg and
X are as defined above for Chart A.
In step "a" of Chart B, as in Chart A, the starting
materials XIII are subjected to iodination and cyclization
to yield the formula-I iodo compounds.
In step ~'b" of Chart B the iodo compound I is con-
verted to the formula-II enol ether compound by contacting
it with a dehydroiodination reagent. For such reayents
see, for example, Fieser and Fieser, "Reagents for Organic
Synthesis" p. 1308, John Wiley and Sons, Inc.,New York,
N.Y. (1967). Preferred for the reaction of s~ep "b" are
tertiary amines and reagents selected from the group con-
sisting of sodium or potassium superoxide, sodium or potas-
3 sium carbonate, sodium or potassium hydroxide, sodium or potas-
-3~
3~ 2871A
- Cha rt B
~OH
V
,~W-C~CH-L R
~$
5 R7 Xl 3 i
1 ~
(a )
.
V - O- CH - CH - L- R
~W
1~
~ '.
X-C-R4
~ .
~ (b )
\!-O-C=CH-L-R
~ .
~ ~ ' .
X-h-~ "
Q
3o
-39 -
287 lA
sium benzoate~ sodium or potassium acetateS sodium or
potassium trifluoroacetateg sodium or potassium bicarbonate,
sil~er acetate~ and a tetraalkylammonium superoxide of the
formula (R12~NO2 wherein R12 is alkyl of one to 4 carbon
atoms,inclusive~
Of' the tertiary amines, preferred amines are
1~5-diazabicyclo[4.3.0]nonene-5 ("DB~
1,4~diazabicyclo[2.2.2]octane (''DABCO'I),
and
1,5-diazabicyclo[5.4.0lundecene-5 ("DBU").
Other preferred reagents are sodium or potassium superoxide
and tetramethylammonium superoxide. For further informa-
tion on the superoxides see Johnson and Nidy, J. Org. Chem.
40, 16c,0 (1975). For larger scale preparation the electro-
chemical generation of superoxide is recommended. See
Dietz et al.~ J. Chem. Soc. (B), 1970, pp. 816-820~
The dehydroiodination step is carried out in an inert
organic medium suc'h as dimethylformamide and is followed
by TLC to show the disappearance of starting material.
The reaction proceeds at 25 C. and can be accelerated
at 40-50 C.
In working up the reaction mixture it is advantageous
to maintain basic conditions, e.g. with triethylamine, to
avoid acidic decomposition or structural changes of the
product. Purification is achieved by crystallization
and consequent separation from impurities or starting mater-
ial left in the mother liquor~ or by column chromatography.
For chromatographic separation a column of magnesium sili
cate ("Florisil~") is preferred over silica gel, Decompos-
~0 Ition of the product is avoided by pretreating the column
-40-
with triethylamineO
~ ster groups such as the p-phenylphenacyl group on the
C-l carboxyl or 4-bromobenzoate on C-ll and C-15 hydroxyls
are unchanged by the transformations of Chart B, and, if
present on the formula-Xlll stcrting material, are also
present on the formula-ll product. For the final prod~cts
of formula 11 which are estexs the preferred method of
preparation is from formula-l iodo compounds which are
corresponding esters.
Especially useEul for administration because of their
form as free-flowing powders and their ease of dissolving
are sodium salts. They are obtained from the formula-ll esters
by saponification with equivalent amounts of sodium hydroxiae
in a solvent, 2referably an alcohol-water solution, thereafter
lyophilizing (freeze-drying) the mixture to obtain the powdered
product. The s-tarting esters are preferably alkyl esters, of
which methyl or ethyl are especially preferred.
This invention also includes the 1,15-lactones obtained
~rom the formula-l, -11, -111, and -lV compounds wherein R
~0 is -COO~I and Q is
~ OH,
eor example
9-deoxy-~,9-epoxy-5-iodo-PGFl~ l,lS-lactone and
9-deoxy-6,9-epoxy- ~ -PGF
1~, 1,15-lactone.
For their preparation, analogous methods are used to those
disclosed in U.S. Patent No. 4,067,991 issued January 10, 1978,
to The Up j ohn CompanyO
It should be understood that although the Charts have
formulas drown with a specific configuration for the reactants
and products, the procedural steps are intended to apply not
only to the other optically active isomers and cis/trans
geometric isomers, but also to mixtures, including racemic
mixtures or mixtures of enantiomeric forms.
If optically active products axe desired, opticall~
active starting materials or intermediates are employed or,
if racemic starting materials or intermediates are used,
the products are resolved by methods known in the art for
prostaglandins.
The products formed from each step of the reaction
are often mixtures and, as known to one skilled in the art,
may be used as such for a succeeding step or, optionally,
separated by conventional methods of fractionation, column
ch.romatography, liquid-liquid extraction, and the like,
~fore proceedi.ng.
To obtain the optimum combination of biological
~0 .r~sponse specificity, potency, and duration of activity,
certain compounds within the scope of formulas l-lV are
preferred. For example it is preferred ~hat Q be
. R8 OH
wherein it is especially preferred that R8 be hydrogen or
methyl.
Another preference, for the compounds of formulas 1,
111, and lV as to Rl~ is that R3 in -COOR3 be either hydro-
- ~2 ~
~ 2~71~
gen or alkyl of one to 12 carbon atoms, inclusive. It is
further preferred that R3 be alkyl of one to 4 carbon atoms,
inclusive, especially methyl or ethyl J for optimum absorp~ion
on adminis~rationO For the compounds of formula-II, it is
preferred ~hat R3 not be hydrogen but rather an alkyl es~er
or a salt o~ a pharmaologically acceptable cation.
For purposes of stabili~y on long s~orage, it is also
preferred that R3 be amido-substituted phenyl or substituted
phenacyl, as illustrated herein.
As to variations in ~ g it is preferred that ~ be
~ ~ ' or
0~1 O
As to variations in R~, it is preferred that R~ be
n-pentyl
di~ethylpentyl
1,1-difluoropentyl
~O -CH2-O- ~ or
-C2~14~)
As to variations in L, it is preferred that L be
-(CH2)3-, - (CH2)~-, or -(CH2~5 -, especially -(CH2 )3~-
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is further illustrated byJ but not
limited to, the following examples,
All temperatures are in degrees centigrade.
~O Infrared absorption spectra are recorded on a Perkin-
,
'-43-
~ 3
Elmer*model 421 i nfrared spectrophotome~er. Except when
specified otherwise, undiluted (neat) samples are used.
The NMR spectra are recorded on a Varian~A-60, A-60D,
or T~60 spec~rophotometer in deuterochloroform solutions
with tetramethylsilane as an internal standard.
Mass spectra are recorded on a Varian*Model MAT CH7
Mass Spectrometer, a CEC Model 110B Double Focusing High
Resolution Mass Spectrometer~ or an LKB Model 9000 Gas
Chromatograph-Mass Spectrometer (ionization voltage 22 or
70 ev.).
"Brine", herein, refers to an aqueous sa~urated sodium
chloride solution.
"Skellysolve*B", herein, refers to mixed isomeric
hexanes.
"DBN"~ herein, refers to 1,5-diazabicyclo[4.~.0]nonene-
5.
"DABCO", herein, refers to 1,4-diazabicyco[2.2.2]octane.
"DBU", herein, refers to 1,5-diazabicyclo[5.4.0~un-
decene-5.
"DIBALi', herein, refers to diisobutylaluminum hydride.
''Florisil*''g herein, is a chromatographic magneslum
silicate produced by the Floridin Co. See Fieser et al.
"Reagents for Organic Synthesis" p. ~93 John Wiley and Sons~
Inc., New York, N.'Y. (1967).
"TLC", herein, refers ~o thin layer chromatography.
Silica gel chromatography, as used herein, is under-
stood to include elution, collection of fractions, and combin-
ations of those fractions shown by TLC to con~ain the desired
product free of starting material and impurities.
"Concen~rating", as used herein, refers to concentration
:
* - Trademarks
-44 -
2871A
under reduced pressure, preferably at less than 50 mm~ and
at temperatures below 35 C.
Preparation 1 11-Deoxy-10,11-didehydro-PGF2~, Methyl
Ester and its 9~-epimer; and 11-Deoxy-
10,11-didehydro-PGF2a and its 9~-epimer.
A mixture oF PGA2, methyl ester (1.74 9.~ and 12 ml.
of tetrahydrofuran is ~reated at -78 C. with 24 ml. of
10% DIBAL in toluene. After one hour's stirring at -78 C,
the mixture is quenched with 100 ml. of tetrahydrofuran-
saturated aqueous ammonium chloride (1:1) and warmed to
about 25 C. The mixture is acidified with sodium bi-
sulfate and extracted with ethyl acetate. The organic phase
is washed with sodium bisulfate, sodium carbonate, and brineJ
dried over sodium sulfate, and concentrated to yield 1.8 9.
The crude product is subjected to column chromatography to
separate the title compounds, in the order:
11-deoxy-10,11-didehydro-PGF2aJ
methyl ester)
11-deoxy-10,11-didehydro-9~-PGF2~5
methyl ester,
11-deoxy~10,11~didehydro-PGFz~, and
11-deoxy-10,11-didehydro-9~-PGF2a.
Example 1 9-Deoxy-6/9-epoxy-5~iodo-PGF1a, Methyl Ester
(Formula I: L is -(CH2)3-, R~ is -COOCH
R~ is n-pentyl, V is a valence bond, W is
-CH2-, X is trans-CH=CH-, ~ is
~'
~H
-45-
287 lA
and Q is ~ )0
H OH
Refer to Chart A3 step 1~3~. A suspension of the formula-
Xlll PGF2~, methyl ester as its 11,15-bis(~etrahydropyranyl)
ether (2.0 g,) in 23 ml. of water is treated with sodium bi-
carbonate (0,7 g.) and cooled in an ice bath. To the re
sulting solution is added potassium iodide (1.9~ 9.) and
iodine (2.82 g.) and stirring continued for 16 hr. at about
0 C. Thereafter a solution of sodium sulfite (1.66 g.)
and sodium carbonate (0~76 9.) in 10 ml. of water is added.
After a few minutes the mixture is ex~racted with chloroform.
The organic phase is washed with brineJ dried over sodium
sulfate, and concentrated to yield mainly the bis(tetra-
hydropyranyl) ether of the title compound; 2.~ 9., an oil.
Hydrolysis of this ether in acetic acid-water-tetrahydrofuran
(20:10:~) yields mainly the title compound~ which is further
puriFied by silica gel chromatography. Rf 0.20 (TLC on
~ilica gel in acetone-dichloromethane (30:70)). The mass
spectral pealcs for the formula-l compound (TMS derivative)
are at 6~8, 623, 607, 567, 548, 511, and 477.
Following the procedures of Example 1, but replacing
the Formula-XIII starting material with the following formula-
Xlll compounds or their C-ll ethersg there are obtained the
corresponding formula-l iodo compounds:
15-Methyl-pGF
15-Ethyt-PGF2~
16~l6-D;methyl-p~F2a
l6~l6-DiFluoro-pGF~a
16-Phenoxy-17318,19,20-tetrallor-PGF2a
-46-
2871~
S~
17-Phenyl-18,19/20-trinor-PGF2a
11 Deoxy-PGF2~
2aJ2b-Di homo-PGF2a
3-Oxa-PGF2~
3-Oxa-17-phenyl-18,19,20-trinor-PGF~.
Example 2 6-Ke~o-PGF1c~, Methyl Ester (Figure IV:
~ , E, Q, Rl~ R1, V, W, and X as de-
fined in Example 1).
Refer to Chart A, step "b'l. A solution of the formula-
I iodo compound, methyl ester (Example 13 0.45 9.) in
20 ml. of tetrahydrofuran Ts treated with silver carbonate
(0.250 9. ) and perchloric acid (90~, 0.10 ~l.), and stirred
at about 25 C. for 24 hr. The mixture is diluted with ~5 ml.
f ethyl aceta~e and the organic phase!is washed with
saturated sodium carbonate sol ution and brine, dried, and
concer)trated to an oil~ 0.41 9. Separation by silica ~el
chromatography eluting with ethyl acetate-Skellysolve B
(3.1) yields the formula-l,V title compound as a more polar
2~ material than the formula- I start~ng material. The pro
duct is an oil, 0.32 9~, having R~ o.38 (TLC on silica gel
in acetone-dichloromethane (1:1)); infrared spectral peak
at 171~0 cm 1 for carbonyl; NMR peaks at 5.5, ~.2-40~, 3.7,
2.1-2.7 ~.
Example 3 9-Deoxy-6,9-epoxy-6-hydroxy-PGF1a, Methyl
Ester (Formula lll: D~ ~ Q~ R1, R~,
V, W, and X as defined in Example 1, and
.~ indicates attachment in alpha or beta
' configuration).
Refer to Chart A~ step "c". A solution of the formula-
. 47-
2871A
~5~
IV 6-keto compound (Example 2, 0.2 9.) in io ml. of ac~tnne
i5 left s~anding a~ about 25 C. for 2 days. It is then
concen~rated and subjected to siiica gel chromatography to
yield the formula~ le compound having Rf 0.50 (TLC on
silica gel in ace~one-dich10romethane (1 D~
Example 4 9-Deoxy-6,9-epoxy-5-iodo-PGFla (Formula I3
and
g-Deoxy-6~g-epoxy-6-hydroxy-pGFla (Formula
IIi): ~ , L, Qg R1~ R~, V, W, and X as
defined in Example 1.
Refer ~o Chart A, step "d". A solution of the formula-
I iodo compound (Example 1, 1.0 g.) in 30 ml. of methanol
is treated with 20 ml. of 3N aqueous potassium hydroxide
at about 0 C. for about 5 min., then at about 25 C. for
2 hr. The mixture is acidified with 45 ml. of 2N potassium
acîd sulfate and 50 ml. of water to pH loOJ saturated with
sodium chlor;de and extracted with e~hyl acetate. The
or~anic phase is washed with brine, dried over sodium sul-
fate and concentrated to an oil, 1.3 9. The oil is subjected
~o silica gel chromatography, eluting with acetone-dichloro-
rnethane (30:70 to 50:50) to yield~first the formula-I
compo~nd and later, the formula~iIIcompound as a more polar
~raction.
The forrnula- I cor~ound is an oil, 0.~3 9., having Rf
0.33 (TLC on silica gel in acetone-dichloromethane (1:1
plus 2% acetic acid); infra red spectral peaks at 3360,
2920, 2860, 2640~ 1730, 171~ 1455, 1410, 1380, 1235, 1185,
1075, 1050, 1015, 970, and 730 ~m~l; and mass spectral peaks
(TMS derlvative) at 681J 625, 606, 569~ 535, 479, and 173.
The formula-Il1compound is a solid 0.113 g., mclting
3 93-98 C., recrystallized from ace~one-Skellysolve B and
-4~
2871A
melting at 95-105~2 CO; con~aining no iodin~; having R~
0.13 (TLC on silica gel in acetone-dichloromethane ~
plus 2~ acetTc acid~ and having mass speceral peaks (TMS
derivative) at 587~ 568, 553~ 497, 435, 478J 407, 395, 388
and 17~
The Formula1llcompound, above, is methylated wlth
diazomethane to form the methyl ester~ having ldential
properties with the product of Example 3 hereinO
Following the procedures of Examples 2 and 4g but
replacing the formula- I iodo compound thereln w;th those
formula-l iodo compounds described subsequent to Example
1, there are obtained the corresponding formula-3V and -lii
compounds. Further following the procedures of Example 3
but uti l i zi ng the thus -obtai ned formula-lV compounds there
15 are also obtai ned the corresponding formula~ilcompounds by
tha t me t hod .
_ample ~ 9-Deoxy-6,9-epoXy -~5 - P~FIa, Methyl Ester (For~ula
ll: L îs -(CH2)3-, Q is
~"
H OH
R1 is -COOCH3, R4 is n-pentyl, X is trans
-CH=CH-, V is a valence bond, and W is
methylen~)
Refer to Chart B. A mixture of the formula-l iodo
compound (Example 1, 0.25 9.) 0.25 ml. of 1,5-diazabicyclo-
[4 3.0)nonene-5 (DBN)> and 15 ml~ of benzene is lef~
standing at about 25 C. for 72 hr. and then warmed to
45 C. for 4 hr. The resulting mixture is then cooled>
mixed with ice water and a small amount of diethyl ether,
_1~9_ .
287 lA
and the layers separa~ed. The organic phase is dried over
magnesium su1fate and concentrated to the title compound~
an oil, 0.20 9. The product i5 crystallized from cold
(-10 C~) hexane to yield 0.14 9., softening at about
25 C., having Rf 0.51 (TLC on silica gel in ethyl acetate);
NMR peaks at 5.5, 4.57, 3.8-4.~, 3.62, ~.53, and 0.9 6;
infrared absorption at 1755 and 1720 cm~~; and mass spectral
peaks (TMS derivative) at 495, 479, 4~9, 423.2724, 349, 199,
and 1730
Following the procedure of the above Example but re~
placing DBN with DBU, using 0.75 ml. DBU with 0.5 9. iodo
compound, there is obtained 0.44 9. product.
Example 6 9-Deoxy-6,9-epoxy-~5 pGF~a, Methyl Ester (Formllla
ll: L is -(CH2)3-, Q is
~"
H OH,
Rl is -COOCH~, R4 is n-pentyl, X is trans-CH=CH-~
V is a valence bond, and W is methylene~.
Refer to Chart B. A mixture of the formula-l iodo
~0
compound (Example 1, 1.0 9.), 1.0 ml. of DBN,
and 60 ml. of benzene is heated at about 42 C. for 20 hr.
Thereupon 0.5 ml. of DBN is added and the heating continued
for 6 hr. more. The mixture is left stirring at about 25 C.
for 60 hr., then heated again for 8 hr. at 40-50 C. The
reaction mixture is cooled, washed with ice water mixed with
a few drops of triethylamine, and dried over magnesium sul-
fate, to yield the t;tle compound, an oil, 0~9 9. The
product is dissolved in 8 ml. of diethyl ether and crystal-
lt~ed from cold (-10 C.) hexane containing a trace o$ tri-
-50~
~ 287lA
,
ethylamine~o yield crystals o.46 9,, mushy at 25 C. Addi-
tional fractions of crystals, 0.33 g., are combined and sub-
jected to chromatographic purification on a Florisil column
pretreated with triethylamine, using hexane-ethyl acetate-
triethylamine (75:25:0.5), eluting with ethyl acetate (50-
75~)-hexane containing 0.25~ triethylamine to yield 0.21 9. of
the title compound which crystallizes on chilling.
Example 7 9-Deoxy-6~9-epoxy-~5-PGFla, Methyl Ester
(Formula ll).
Refer to Chart B. A mixture of the formula-l 9-
deoxy-6,9-epoxy-5-iodo~PGF1a, methyl ester (Example 1,
0.21~ g.) in 3 ml. of dimethylformamide is treated with
a fresh solution of potassium superoxide (0 45 g ) in 10
ml. of dimethylformamide contatning dicyclohexyl-18~crown-`;
6 (0.75 g~) in an ice bath. After about 30 min. the
reaction mixture is quenched in ice water, thereafter
extracted with diethyl ether. The organic phase is dried
over magnesium sulfate and concentrated to yield the title
compoundJ having the same Rf by TLC as the product of
~o Example 5O
The above produc~ is subjected to column chromatography
on Florisil~ pretreated with triethylamine (5%)-dichloro-
methane. The produ~t is eluted with ethyl acetate-hexane-
triethylamine (50:50:0.1) to give the title compound,
o.o76 9,J having Rf 0.45 (TLC on siiica gel in acetate-
dichloromethane (~:7) using plates pretrea~ed wi~h tri-
ethylamine (5~)-dichloromethane3.
Follow;ng the procedure of Example 7, but replacing
potassium superoxide with each of the following reagPnts,
the title compound is likewise obtained:
-51-
~ 2~7
sodium superoxide
tetramethylammonium superoxide
sodium carbonate
potassium carbonate
sodium hydroxide
potassium hydroxlde
sodium benzoate
potassium benzoate
sodium acetate
potassium acetate
sodium trifluoroacetate
potassium trifluoroacetate
sodium bicarbonate
potassium bicarbonate
15 and
silver acetate.
Example 8 g-Deoxy-6~9-epoxy-5-iodo-pGFla~ p-Phenyl-
phenacyl Ester (Formula 1) and
9-Deoxy-6,9-epoxy-PGF2~, p-Phenylphenacyl
Ester (Formula ll).
A. A mixture of the formula-l iodo acid compound
(Example 4, Formula 1, 0,20 9.) g p-phenylphenacyl bromide
(0.50 g.), o.l~ ml. o~ diisopropylethylamine, and 10 ml.
of acetonitrile is stirred at about 25 C. for 40 min. It
is mixed with dilu~e aqueous ci~ric acid and brine and
extracted with e~hyl acetate. The organic phase is dried
and concentrated. The residue is subjected to silica gel
chromatography, eluting with ethyl acetate (25-100%)-
Skellysolve B to yield the title 5-iodo compound as a
3o coiorless oil, 0.20 9.
-52-
~3S~ 287lA
B. The product of Part A above (0.20 9.) is treated
with 0.4 ml. of DBN i~ 15 ml. of benzene 2t 42 C. for 22 hr.
The reaction mixture is cooled, washed with ice-water con-
taining sodium chloride, dried over magne~ium sulfate and
concentra~ed to the second title compound, an oil~ 0.12 9O
The oil is crystallized from benzene-hexane. All fractions
are combin ~ and subjected to chromatographic separation on
a Florisil column pretreated with hexane-ethyl acetate-
triethylamine (80:20:0.5), eluting wlth ethyl acetate to
yield the formula-ll compound, an oil. Crystallization
From ether-hexane yields crystals, 0.016 9., m. 71-2 C.
(sintering at 65-7 C.).
Examp~e 9 9-Deoxy-6,9-epoxy-5-iodo-PGF1a, Me~hyl Ester
11,15 -bis(4-Bromobenzoate) and
1~ 9-Deoxy-6~9-epoxy-~5-PGFI~, Methyl Ester, 11,
15-bis(4-Bromobenzoate).
A. A mixture of the formula-l iodo compound (Example
~, 0.49l~ ~.) in 5 ml. pyridine cooled in an ice bath,
is tre~tecl with 0.657 g. of ~-bromobenzoyl chloride
with stirrincJ. The mixture is left stirring 16 hr., then
poured into cold 10~ sulfuric acid and cxtracted with ethyl
acetate. The organic phase is washed with sodium bicarbonate
solution and brine, dried~ and concentrated. The residue
is subjected to silica gel chromatography to yield the5~;odo
title compound, 0.70 9., a colorless oil, having NMR peaks
at 7.3-8.ol 5.65~ 3.8-5.5, 3.65, and 0 9 ~.
B, The product of Part A above (0.20 9.) is ~reated
with 0.4 ml. of DBN in 15 ml. of benzene at 42 C. for
22 Ill. The reaction mixture is cooled, washed with ice
water, drled, and concentrated to the second title compound,
-5~~
2~7lA
an o;l, 0.18 9,
The prepara~ion is repeated with 0.50 9. of ~he iodo
compound, 1 mlO of DBN and 25 ml. of benzene.
The combined products are subjected to chromatographic
separation on a Florisi ~column pretreated with hexane-
ethyl ace~ate-trîethylamine (90:10:1), eluting with hexane-
ethyl acetate triethylamine (90:10:0.25) to yield the second
title compound3 0.37 9O, a colorless oil~ having NMR peaks
at 7.2-7.8, 5.6, 4.9-5.~, ~.6, 4.0, 3.6, and 0.9 ~0
Example 10 9-Deoxy-6,9-epoxy-~5-PGF~a, Sodium Sal~O
a mixture of 9-deoxy-6,9-epoxy-~S-PGF1~, methyl ester
(Example 5. 0.030 9.) in 5 ml. of methanol is treated with
y ml, of 0.01 N NaOH and stirred at about 25 C. for 72 hrO
The solution is then diluted wi~h 5 ml. of water, frozen
at about -75 C. and lyophilized overnight. The title
compound is obtained as a white free-flowing powder.
The procedure above is repeated using larger quantities.
From 0.150 9, of the enol ether methyl ester there is ob-
tained 0.155 9. of the title compound as a white free-flow-
ing powder. A sample of the material dissolved in methanol-
water shows practically no mobility by TLC on silica gel
plates in acetone-dichloromethane (3:7), compared with the
starting material which has Rf 0.45 (TLC on silica gel in
acetone-dichloromethane (3;7) using plates pretreated
in triethylamine-(5~)-dichloromethane).
Following the procedures of Examples 1, 2, 3, 5~ and 7
but employin~ corresponding star~ing materials as described
above~ there are prepared the formula -1, ~ Ill, and
-IV compounds, namely
~ 9-deoxy-6,g-epoxy~5-iodo-PGF~
-54
2871A-1-F
9-deoxy-699-epoxy ~5-PGFla~
9-deoxy-6,9-epoxy-6 hydroxy-PGFla- 7 and
9-deoxy-6,9-epoxy-6-ke~o-PGF1-type compounds,
in methyl ester form wherein R1 is -COOCH3, having the
following structural features:
16-Methyl
16gl6 Dimethyl-;
16-Fluoro- 9
16J16-Difluoro ;
17-Phenyl-18,19320-trinor-;
17- (m tri fluoromethylphenyl ~-18,19,20-~rinor-;
17-(m-çhlorophenyl)-18,19,20-tr;nor~;
17-(p-fluorophenyl)-18,19,20-trinor~;
16-Methyl-17-phenyl-18,19,~0-trinor-;
t5 16,16-Dimethyl 17-phenyl-18,19,20-trinor-;
16-Fluoro-17-phenyl-18~19,20-trinor-;
16,16-Difluoro-17-phenyl-18,19~20-trinor-;
16 Phen~xy-17,18~19,20-tetranor~;
16-(m-trifluor~nethylphenoxy)-17,18,19,20-tetranor-;
~ 16-(m-chlorophenoxy)-17,18,19,20-tetranor-;
16-(p-fluorophenoxy)-17318,19,20-tetranor-;
16-Phenoxy-18,19~20-~rinor-;
16-Methyl-16-~henoxy-18~19,20-trinor-;
i3,il~-Didehyd~o~ t~yl -13J 14-~idehydro-;
16,16 Dimethyl-13,14-didehydro~;
16-Fluor.o-13,14-didehydrQ~
16,16-Difluoro-13,14-didehydro-;
7-phenyl-l8J 19,20-trinor-1~,14-didehydro-,
17-(m-trifluoromethylpheny~ 8JlgJ2o-trinor 13,14-
dldehydro~;
2871A -1 -F
17-(m-chlorophenyl)-18,19J20-trinor-13J14~didehydro-; !
17-(p-fluorophenyl)-18,19,20-trinor-13714-didehydro-;
16-Me~hyl-17-phenyl 18~19,20-~rinor-13~14-didehydro~;
16,16 Dimethyl-17^phenyl-18~19,20 trinor-1~,14-dide-
hydro-;
16-Fluoro 17-phenyl-18319,20-trinor-13~14-didehydro-;
16,16-Difluoro-17-phenyl-18,19,20-trinor-1~,14-didehy-
dro-;
16-Phenoxy~17"18119.,20-tetranor-13,14-didehydro-;
16-(m-tri~luoromethylphenoxy)-l7Jl8~lg~2o-tetranor
13,14-didehydro-;
16-(rn-chlorophenoxy)-17,18,19,20-tetranor-13,14-dide-
hydro-;
16-Phenoxy-18,19,20-trinor-13,14-didehydro-;
16-Methyl 16-phenoxy-18,19,20-trinor-'.3,14-didehy~ro-;
1~,14-Dihydro- 9
16-Methyl-13,14-dihydro-;
16,16-Dimethyl-13,14-dihydro-;
16-Fluoro-13gl4-dihydro~;
16,16-Difluoro-13,14-dihydro-;
17-Phenyl-18,19,,20-trinor-13,14-dihydro-;
17-(m-trifluor~nethylphenyl)-18~19,20-trinor-13,14-
dihydro-;
17-(m-chlorophenyl)-18,19j20-trinor-13,14-d;hydro-;
17-(p-fluorophenyl)-18,1g,2Q-trinor-13,14-d;hydro-;
16-Methyl-17-phPnyl-18,19,20-trinor-13,14-dihydro-;
16,16-D7methyl-17-phenyl 18,19J20-~rinor-13~14-
dihydro-;
16-Fluoro-17 phenyl-18,19,20-trinor-13,14-d~hydro-;
16,16 Difluoro-l7-phenyl~l8JlgJ2o-trinor 13~14-
-56 -
~87 1
dlhydro-;
16-Phenoxy~17,18~19,20-tetranor-13,14-dihydro~;
16- ~m-~r; fluoromethylphenoxy)-17,18,19,20-tetranor-
13, ~ 4-d i hydro~,
16- (m-chlorophenoxy)-17~18919,20 tetranor-13,1~-
dihydro-;
16-~p-fluorophenoxy~-17,18,19,20-tetranor-1~,14-
dihydro-;
16-Phenoxy-18,'9,20-~rinor-1~,14-dihydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
2,2-Difluoro-;
2 , 2 -D i f l uoro-16-methyl-;
2,2-Difluoro-16,16-d;methyl-;
2~2-Di$1uoro-16-fluoro-;
2,2-DTfluoro-16,16-difluoro ;
2,2-Di~luoro-17-phenyl-18,19,20-trinor-;
2J2-Ditluoro-17-(m-trifluoro~ethylphenyl)-18,19,20-
~rinor-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;
2,2-Difluoro~17-(p~fluorophenyl)-18,19,20-trinor-;
2,2-Difluoro 16-methyl-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16J16-dimethyl-17 phenyl-1831~J20-~rinor-;
2,2 Difluoro~16-fluoro-17~phenyl~18,19J20-trinor-;
2~2~Difluoro-16,16-~ifluoro-17-phenyl-18,19,20-trinor-;
2J2-Difluoro 16-phenoxy-17, 18J 19,20-tetranor-;
-2~2-Difluoro-l6-(m-trifluoromethylphenoxy)-l7~l8~lg~2
tetranor-;
2J2-Difluoro-16-(m-chlorophenoxy~-17,18,19,20-
tetranor~;
3o 2J2 Difluoro-16-(pwfluorophenoxy)-17,18,19,20-
-57 -
287 1
tetranor-;
2,2-Difluoro~16~phenoxy-18,19920-~rinor-;
2J2-Difluoro 16-methyl-l6-pheno~y-l8~lgJ2o-trinor~;
2,2-Di fluoro-16-methyl-16-phenoxy-18,19,20~trinor-;
2,2-Di~luoro-16~methyl;13~14-didehydro-;
2,2~DTfluorool6916-dimethyl-13,14 -didehydroo;
2,2-Difluoro-16-fluoro-13,14-didehydro-;
232-Difluoro-16.,16-difluoro-13,14-didehydro-;
2,2-Difluoro~17-phenyl-18,19,20 trTnor~ 14-dide~
hydro~;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19J20-
trinor-13,14-didehydro-;
2,2-Difluoro-17-(m-chlorophenyl )-18,19~20-~rinor-1~914-
didehydro-;
2J2-Difluoro-17-(p-fluorophenyl)-18,19~20-trinor-13,14O
didehydro-;
2,2-Difluoro-16-methyl-17-phenyl-18,19~20-trinor-
13,14-didehydro~;
2J2-Di fluoro-16,16-dimethyl-17^phenyl-18,19g20-trinor-
20 1~ J 1 4 - didehydro-;
2,2,16-Trifluoro-17 phenyl-18,19,20-trinor-
1~,14-didehydro-;
2,2,16,16-Tetra~luoro-17-phenyl~18,19J20-trinor-
13,14-didehydro-;
2~ 2J2~Difluoro-16-phen~ y-17,18~19,20-tetrano~13,14
d;dehydro-;
2~2~Difluoro-16-(m-trlflLIoromethylphenoxy)-17,18,19,20-
tetranor~ .14-didehydro~;
2J2-Vifluoro-16-(m-chlorophenoxy)-17~18l19,20-tetra-
3o nor-13,1l~ ~;dehydro-;
-58 - .
287 lA -1-F
2,2-Di~luoro-16-phenoxy-18,19J20-~rinor 13,14-dide-
hydro-;
2,2-Difluoro-16-methyl 16-phenoxy~18,19920-trinor-
13,14~didehydro-;
2 9 2-Difluoro-13,14-dihydroo;
2,2-Difluoro-16-methyl-1~,14-dihydro-;
2,2-Difluoro~16,16-dimethyl-13~14-dihydro-;
2,2,16-Trifluoro-13~14-dihydro-;
2,,2,~16,16-Tetrafluoro-13,11~-dihydro-;
2,2-Difluoro-17 phenyl-18,19,20-trinor-1~,14-
dihydro-;
2~2-DiFluoro-l7-(m-trifluoromethylpheny~ 8,lg~2
trinor 13,14~dihydro ;
2,2~Difluoro-17-(m-chlorophenyl)~18,19~2Q-~rinor-
13,14-dihydro-;
2g2-Difluoro~17-(p-fluoropheny~)-18,19,20-trinor-
13,14-dihydro-;
2,2-Difluoro-16-methyl-17-phenyl-18,19320-trinor-
13,11~-dihydro-;
2,2~Difluoro-16,16-dimethyl-17-phenyl-18,19,20-
trlnor-13,14-d;hydro^;
2,2,16-Trifluoro-17~phenyl-18919~20-trinor-13314-
dihydro-;
2,2~16,16-~etrafluc~o-17~phenyl-18,19,20-trinor-
13,14-dlhydro-;
2,2-Difluoro-16-phenox.y-17,18,19~20-tetranor-13,14-
dihydro-;
2,2-Difluoro-16-(m~trifluoromethylphe~oxy)-
17,18,19,20-tetranor-13,14-dihydro-;
2,2-Difluoro-16 (m-chlorophenoxy)^17918,19,20-
-59-
2871A -l -F
.
tetranor-13,14-dihydro~;
2,2-D.ifluoro 16-(p-fluorophenoxy)-17,18~19,20-
~etranor-13J14~dlhydro-;
2,2-Difluoro-16-phenoxyol8,19,20-trinor-13J14-
dlhydro-;
2,2~Difluoro-16-me~hyl-16-phenoxy-18,19,20-trinor-
13,14-dihydro-;
16-Methyl Ci5013;
16~16-Dimethyl-cis-13~;
16-Fluoro-cls 13 ;
16,16-Difluoro-cis-13-;
17-Phenyl-18,19,20-trinor-cis~
17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;
17-(m-chlorophenyl)-18,19,20-trinor-cis~
17-(p-fluorophenyl)-18,19,20-trinor~cis-13-;
16-Me~hyl-17-phenyl-18~19,20-trinor-ClS-13-;
16,16-DImethyl-17-phenyl-18~19J20-~rinor cis-13-;
16-Fluoro-17~phenyl-18,19,20-trlnor-cis-13 ;
16,16 Difluoro-17-phenyl-18,19,20-~rinor-cis-13-;
16-Phenoxy-17,18,19,20-tetranor-cis-13-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-
cis.-13-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-ci 5 -13-;
16-(p-fluorophenoxy~-17~18,19~20-tetranor-cis-13-;
16-Phenoxy-18,19,20-trinor cis~
16-Methyl-16-phenoxy-18,19,20-trinor-cis-1
2,2-Difluoro-cis-13-;
2,2-DTfluo~o-16-methyl-cis-13-;
2,2-Dlfluoro-16,16-dTmethyl ci s 13-;
~o 2,2-Difluoro~16-fluoro~ci~13-;
-60-
287 lA -1 - F
:~L3.~
_ ...... .
2,2-DTfluoro-16,16-difluoro-cis 13 ;
292-Di~lu~r~ 7-phenyl-18~19J20-trinor-cis 13~;
2/2-Difluoro-17-(m-trifluoromethylphenyl)-18~19,20
trinor-cis-13~;
2J2-Difluoro 17-(m-chlorophenyl)-18,19J20~trinor~
cis-13-;
2,2-Difluoro 17-(p-fluorophenyl)-18,19,20-trinor-cis-13-;
2,2~Difluoro-16-methyl-17-phenyl-18,19,20-trinor-çis-
13-;
2,2-Difluoro-16,16-dimethyl-~7~ .,y -18,19,20-
trinor-cis-13-; -
2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor~
~ts-13-;
2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-
~5 cis-l~-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-;
2,2-Difluoro-16-(m~trifluoromethylphenoxy)-17,18J19,20-
~etranor-cis-13~;
2,2-Ui fluoro-16- (m-chlorophenoxy)-17,18,19,20-
~() tet r anor-c i s -13-;
2,2-Difluoro-16-(p-fluorophenoxy)-17~18,19,20-
~etranor-cis-13 ;
2,2-Difluoro-16-phenoxy-18,19,20-trinor-cis-13-;
2,2-Dlfluoro-15-methyl-16-phenoxy-18,1~,20-trinor~
c~s-13-;
2~2-Difluoro-16-methyl-16-phenoxy-18,19920-trinor-
cts-13-; -
3-Oxa-; .
Oxa-16-methyl-;
~ 3 Oxa~16~16-dimethyl~;
2871A~
3-Oxa~16 fluoro-, ~~~ ~ ~~
3-Oxa-16~16-difluoro~;
3-Oxa-17~phenyl-18,19, O-trinor ;
~-Oxa-17~ (m7~ri fluorQmethylphenyl) 18,19~20-trinor-;
3-Oxa 17-~(m-chlorophenyl)-18,19,20-trinor-;
3-Oxa 17-~p-fluorophenyl)-l8~l9~2o-trinor-;
3-Oxa-16 methy1-17-phenyl-18,19,20-trinor-;
3-Oxa-16,16-di~ethyl-17~phenyl-18,19,20-trinor-;
3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-;
3-Oxa-16,16-difluoro-17-phenyl-18,19,20-~rinor-,
3-Oxa-16-phenoxy-17~18,19,?0-tetranor-;
~-Oxa-16-(m-~r;fluoromethylphenoxy)-17318,19~20^tetra-
nor-;
3-Oxa-16-`(m-chlorophenoxy)-17,18,19920-~etranor-';
3-Oxa-16-(p-fluorophenoxy)-17~18~19~20-tetranor-;
~-Oxa~16-phenoxy-18,19,20-trinor-;
~Oxa-16-methyl-16-phenoxy-18,19,20-trinor~;
~-Oxa-13,1~-didehydro-;
3-Oxa-16-me~hyl l~ didehydro-; -
3-Oxa-16,16 dimethyl-13,14-didehydro-;
3-Oxa-16-fluoro-13,14-didehydro-;
~-Oxa~16,16-difluoro 13,14-didehydro-;
7-phenyl-l8,l9~2o-trinor-l3~l4-didehydro-;
~-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-
1~,14-didehydro~;
~-Oxa-17-(m-chlorophenyl~-18~19~00~rinor-13,14
didehydrow;
3~0xa~17~(p~fluorophenyl)~18,19,20~trinor~1~14
dldehydro-;
3-Oxa~16~me~hyl 17-phenyl-l8~lg~2o~trincr-l~sl4
~G2
` 2871A-1-F
didehydro-,
3-9xa-16~16-dimethyl-17 phenyl-18,19,20-trinor~
13~14-didehydro~
~-()xa-16-fluoro-17-phenyl-18,19,20-trinor-13,14
d i dehydro~;
3-Oxa-16316-di fllJoro-17-phenylD18,î9,20-trinor~
13.,14-didehydro~9
3 - Oxa -16 ~phenoxy-17J 18, 19J20 -tet ranor-13, 14-
d I dehydro~ t
~-Oxa-16-(m trifluorornethylphenoxy~-17.tl8,19,20
tetranor 13~14-didehydro-;
3-oxa~l6-(m-chlorophenoxy)-l7~l8~l9~2o-tetranor~
13,14-didehydro-;
3-oxa-l6-phcnoxy-l8~l9~2o-trirlor-l3~l4-didehydro-;
3-Oxa-16-methyl 16-phenoxy-18,19J20-trinor-13J14-
didehydro-;
3-Oxa 13,14-dthydro-;
~-Oxa-16-rnethyl-13,14-dihydro-;
~-Oxa~16,16-dimethyl-13,1~~dihydro-,
3-Oxa-16-fluoro-13~14-dihydro~
~Oxa-16,16-difluoro-13,14-dihydro-;
3-Oxa 17-phenyl-18,19,20-trinor-13J14-dihydro-;
3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor~
1~,14-dihydro- 7
~-Oxa-17-~m-chlorophenyl)-18,19~20-trinor-1~,14^
dthydro-;
~-oxa-l7-(p-fluorophenyl~-l8~lgo2o-~rinor-l3
dlhydro-;
~-oxa-l6-methyl-l7-phenyl~l8~lg~o-~rinor-l3~l4
dlhydro-;
-63
2871A-1-F
3-Oxa-1~916-Dime~hyl-17-phenyl~18,19~20-~rinor~
13~14-dihydro-,
3-Oxaol6-fluoro-17-phenyl 18,19g20 ~rinor-13,14-
dihydro~;
3-Oxa-16,16~diF1uoro-17-phenyl-18,19,20-trinor-
13,14-dihydro
3-Oxa-16-phenoxy-17,18~19~20-tetranor-13~14
dlhydro-;
~-Oxa-16 (m-trifluoromethylphenoxy)-17,18,19,20--
tetranor-13914-dihydro-;
3-Oxa-16-(m-chlorophenoxy)-17,18~19,20-tetranor~ ~ - ~
13,14-dihydro~;
3-Oxa-16-(p-fluorophenoxy)-17,18,19,20 tetranor-
13,14-dihydro-;
3-Oxa-16 phenoxy~l8,19,20-trinor-13,14-dihydro-;
3-Oxa-16-methyl~16-phenoxy-18~19,20-tr;nor-
13,14-dihydro-;
3-Oxa-cis-13-;
3-Oxa-16-methyl-cis~13-;
~0 3-Oxa-16,16-dimethyl-cis-13-;
3-Oxa-16-fluoro-c;s-13-;
3-Oxa-16,16-difluoro-cis-13-;
3-Oxa-17-phenyl-18,19,20-trinor-cis-13-;
3-Oxa-17-~m trifluoromethylphenyl)-18,19,20-trinor-
cis-~3~;
3-Oxa-17-~m-chlorophenyl)-~8,19~2~-trinor-cis-13-;
3-Oxa-17-(p fluorophenyl) 18tl9,20-~rinor-cis-13~;
3-Oxa-16 methyl-17-phenyl-18,19,20~trinor-c;s-13-;
3-Oxa-16,16-dimethyl-17 phenyl-18,19~20-trinor-cis-
1~-;
.
-6~-
~ilB~3 2E37 lA ~1 ~ F
.
~Oxa 16-fluoro-17-phenyl l89lg~2o-trinor-cis-l3
3-Oxa-16J16 difluoro-17-phenyl-18,19,20-trinor-cis-1
3-Oxa-16-phenoxy-17,18,19,20~tetranor-cis~
3wOxa-16 (m ~rifluoromethylphenoxy)-17yl8,19~20-
tetransr-cis~13~;
3~0xa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-ciS-
13~;
3-Oxa~(p-fluorophenoxy)-17918,1g,20~tetranor~cis-13-;
3~0xa-16 phenoxy-18,19,20-tr;nor-cis-13-; -
3-Oxa-16-methyl-16-phenoxy-18,19,20 trinor-cîs-13-;
3-Oxa-13,14-dihydro-trans 14,15-didehydro-;
3-Oxa-16-methyl-13,14-dihydro-trans 14,15-didehydro-;
3-Oxa-16,16-dimethyl-13/14-dihydro-trans-14,,15-
didehydro-;
3-Oxa-16-fluoro 13,14-dihydro trans-14,15-didehydro-;
~ -Oxa-16~ difluoro-13,14-dihydro-trans-14,15-
didehydro-;
~ Oxa-1'7-phenyl-18,19,20-trinor-13,14-dihydro-trans-
14,15-didehydro ;
3-Oxa-17~(m-trifluorornethylphenyl) l8~lgJ2o-trinor
13,14~dihydro-trans-14,15-didehydro- i
3-Oxa-17-(m-chlorophenyl)-18/19,20-trinor-13,14-
dihydro trans-14,15-didehydro-;
3-Oxa-17~(p-fluoropl.enyl)-18,19,20-trinor 13,14-
dihydro-trans 14,15~didehydro~;
3-Oxa-16-rne~hyl-17-phenyl-18~19~20-trinor-13,14-
dihydro-trans-14,15-didehydro~;
3-Oxa-16J16-Dimethyl;17-phenyl-18,19,20-~rinor-
13/14-dihydro-trans-14,15-d;dehydro-;
3~0xa-1~-~luoro-17-phenyl-18~19~20-trinor-13,14
2871A -:1 -F
dihydro-trans-1l~915-diclehydro~;
3~0xa-16~16 difluoro 17-phenyl~18,19~20-trinor~
1~,14-dihydro-trans-14,15-didehydro~;
~ -Oxa-16-phenoxy-17,18,19,20-tetranor-13,1~-
dihydro~trans-14~15-didehydro-;
3-Oxa-16-(m trifluoromethylphenoxy)-17,18~1g,20
tetranor 1~,14 dlhydro-~rans-14,15-dihydro-;
3~0xa~16-~m-chlorophenoxy)-17,18,19/20-tetranor~
13~14-dlhydro-trans-14,15-didehydro-;
103-Oxa-16-(p-fl~orophenoxy)-17,18J19~200tetrahor-
_ _ .
13,14-dihydro-trans-14,15-didehydro-;
~ Oxa-16-phenoxyo18,19~20-trinor-13,14-dihydro--
trans-14,15~didehydro-;
~-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-
13,14~dihydro~trans-14915-didehydro-.
Likewise followlng the procedures oF Examples 1, 2J 3~
5~ and 7, but employIng corresp~onding starting materials as
described above, there are obtained the formula ~I
~III, and -IV compounds, namely
~9-deoxy-6,9-epoxy-5-iodo-P~F1a ,
9-deoxy-6,9-epoxy- ~5-PGF1a-,
9-deoxy-6,9-epoxy-6-hydroxy~PGF1a-, and
9-deoxy-6~9-epoxy-6~keto-PGFla-type compounds,
in methyl ester form wherein Rl is -COOCH3, having the
Following structural features.
2,3-Didehydro~;
2~2-Dimethyl-,
2a,2b-Dihcmo~;
4 - Oxa - 4a-homo ;
37a-Homo-;
-
-66 -
~r~ 2s7 lA - l -F
.. . -- ............................ .. . _ . .
ll-Deoxy~10~ didehydro-;
11~Keto~
ll-Deuxy~;
Deoxyoll-methylene~;
ll-Deoxy-ll-hydroxymethyl-;
15~-;
15-Keto i
15-Deoxy-;
15-Methyl 15(S)-;
15 Methyl-15(R)-; and
17,18-Didehydro-
!-67
A~ d_
1. 2-Decarboxy-2-amino PGF Compounds
Chart G, below, shows the steps for preparing start-
ing materials of formula Xlll for Chart A wherei~ Rl is
-CH2M(Rg)2. Accordingly in Chart G, the formula Cl PGF2a-
or ll-deoxy-PGF2~-type free acid is transformed to the
various 2-decarboxy--2-aminomethyl or 2-decarboxy-2-(sub-
stituted amino)methyl-PGF~- or ll-deoxy-P~Fa-type compounds
of formulas ClV CVl, CVll, CVlll, ClX, or CX.
By the procedure of Chart G the formula Cl compound is
transformed to a formula Cll mixed acid anhydride. These
mixed anhydxides are conveniently prepared from the corres-
ponding alkyl, aralkyl, phenyl, or substituted phenyl
chloroformate in the presence of an organic base (e.g.
. - 68
cb~
Char t t
HO
~ ~ C ~12 - Z 1 -COOH
S ~ : C~
Y I -C--C-R7
M, L a
(~ O
HO ,~H2 -Z 1 l -O -C -R
<~ Cl~
Y ~ -C--C -R7
M, Ll
/ ~ O
<~C Hz - Z ~ - C - N Hz
Ft Y I -C--C -R7
I Ml Ll
J~
~0
. ~" C H2 Z 1 - CH2 N H2
. S~ . CIV
,Yl -C ~ C-R7
R ~
M1 L~ .
:
' \ ~
~CH~ -Z 1 -C -N=N=li . CY
Y 1 -JI--fi -R~
R~Ml L~
3~ 1
-69 ~;
3S~
Lhart G (contT nued)
CH2-Z,-NH-COOR~
CYI
1 3 fi
Rq Ma Ll .
'. J, .,
HO .
CH2 ~ NH2 .
- 10 ~''
S~y .C~
L 1 M~ .
~10
~ ~CHz -Z 1 -NHL2 ~/
S~ CVIII
Y,-C--C-~7
RB I I 11
Ll M
HO~
,~112 -Z~ -NL~COOR,
~y
~X
Yl h 11 R7
R,3 M 1 L 5
~, .
HO
, CH2-Zl-NL2L3
<~ Y ~ -R7 CX
R{~ M~
-70
trlethylamine)0 Reaction diluents include wa~er in com-
blnakion wi~h water misci~le organic solven~s (e,g.~ ~e~ra-
hydrofuran). This mixed anhydride i5 then transformed to
either the formula Cill PG-~ype, amide or formula CV PG-type,
azide.
For preparation o~ the PÇF2a-type, amide (formul~ Clll)
the formula CII mixed acid anhydride is reacted with liquid
ammonia ~r ammonium hydrox;de.
- Alternatively, the formula CIII compound is prepared
from the formula Cl free aci d by methods known in the art
fo~ transformation of carboxy acids to correspondtng car-
boxyamides. For example, the free acid is transformed to
a corresponding methyl ester (employing methods known in
the art; e.g., excess etheral diaz~etha~e3y and a methyl
ester thus prepared is transformed to the formula 1II amidé
employing the methods described for the transformation of
the formula CII mixed acld anhydride to the formula CIII
amlde.
Thereafter the formula CIV 2-decarboxy-2-aminomethyl-
PGFZa- or 11 -deoxy-PGF2~ type compound is pr~pared from
the formula CIII compound by carbonyl reduction~ Methods
known in the art art are employed in this transformation.
For ~xample~ lithium aluminum hydride is conveniently
employed,
The formula Cli compound is al~erna~ively used to pre-
pare the formuia CV azide. This reaction is conveniently
carried out employing sodium azide by methods known in the
ar~. See for example, Fieser and Fieser, Reagents for
Organlc Synthesls vol. 1, pgs. 1041-104~, wherein reagents
and reactlon conditions for the azide formatio~ are dls-
,
-71~
c us sed.
Final ly, ~he formula CVI urethane is prepared from the
formula CV azlde reaction wi~h an alkanol" aralkanol3 phenol,
or subs~itu~ed phenol. tor exarnple, when methanol i5 em-
5 ployed the formula CVI compound is prepared wherei n Rl 1~methyl. This formula SVI PG-type product is then employed
in the preparation of either the formula CVII or CVlIi pro-
duct.
In the preparation of ~he formula CVII primary amTne
from the formula CYI urethane, methods known i n ~he art
are employed. Thus, for example, treatment of the formula
CVII urethane with strong base 3t temperatures above 50 C.
are employed. For example, sodium potassium ~r lithium
hydroxide is employed.
AlternatTvely, the formula CVI compound is employed
in the preparation o~ the formula CVIII compound. Thus,
wh~n Ll is alkyl ~he formula CVIII compound i5 prepared
by reduction of the formula CVi urethane wherein R1 is
alkyl. For this purpose, 1ithium aluminum hydride is
the conveniently emp1oyed reducing agen~.
Thereafter, the formula CVIII product i5 used ~o
prepare the corresponding CIX urethane by reaction of the
formula C~III secondary amine (wherein L2 is alkyl3 with an
alkyl chloroformate. The reaction thus proceeds by methods
known in the a~t for the preparation of carbamates from
corresponding secondard ~mines. Final1y, thP ~ormula CX
product wherein L2 and L~ are both alkyl is prepared by
reduction of the formula CIX carbamide. Accordingly,
methods hereT nabove descrjbed for the pr~paration of th~
formula ~VIII compound from the formula ~VI compound are
-72~
a~
used. Thus, Char~ A provides a method whereby cach of the
variQus PGF2~- or 11-deoxy-PGFz~-type products of this
invention is prepared. Optionally, the v3rious reaction
steps here;n may be proceeded by the employment of block-
ing groups according to Rlog thus necessitating ~hei r sub-
sequent ~ydrolysis in prep3ring each of the various products
above. Methods described hereinabove for the introduction
and hydrolysis of blocking groups according to R~o are em~
ployed.
Finally, the processes described above for converting
the formula Cll compound to the formula CV compound and
the various compounds thereafter, result in shortening
the 8a-side chain of the form~la Cl compound by one carbon
atom, Accordingly, the formula Cl starting material shoul~
be selected so as to compensate for the methylene gr~up
which is consumed in the steps of the above synthesis.
Thus, where a 2a-homo-product is desired a corresponding
formula Cl ?a,2b-dihomo starting material must be employed.
I n Char~ ~,
Y~ i5 trans-C~CH-j -Cs~-, or -C~2CH2-;
where i n Ml i s
~5 OH
or
~5 OH
whe re i n R5 i s hyd rogen or methy l;
wherein L~ i;
R3 R4,
R9 R4,
or a mixture of
R3 R~
an~
R,
wherein R3 and f~4 are hydrogen, methyl, or fluoro,, being ~~~
the same or different, with the proviso that one of R3
and R.~ î s f luoro on l y when the other i s hydrogen c)r f 1~3oro;
wherein Z~ iS
(1) cis-CH=CH-CHz-~CH2~9-CH~, g
~ ~2) cis-C~CI~-CH~-(CH2~9-Cf2~3
-7 4 -
(3) cis-CH2-Cl~CH- (Cl~z )9-CH~-~
~4 ~ - ~CHz )3- (CH2 ~9 Ctl2~9
(5) ~ (~z~3- (~Hz)9~tF2~,
(6) -CH2-O-CH2 ~CH2)~ ~ CH2-~
(7). -C-C-CH~; (CHz~g~CH~
(~) -CHz-~-C- (~ ~2 ~9- ~lz~,
(9~ ~CH2- ~CH2 ) -, or
~0
(10) ~o- (CHz )
where i n g i s one.7 2, or 3;
whereîn R7 i5
( 1 ) - ( CHZ )m- CH9,
(r)
(2 ) - 0~ .~ or
~:)
(T ~5
( ~ ) - CHz ~ J
?5
~herein m is one to 5, inc lus ive, T is c:hloro, fluoro,
tr; fluoromethyl, alkyl of one to 3 carbon atoms, incJu-
sive, or alkoxy of one to 3 carbon a~oms, inclusive, and
~ is zero, ~ne, 2J or 3, the various T's being the salnc
or different, with the provTso tha~ not more than t~
75 -
,
5~
T's are o~her than alkyl, with the fur~her proviso thae
P~7 i~
(~ ~5
-0~
wherein T and s are as defeTnd above" oniy when R3 and R4
are hydrogen or rnethyl, be;ng the same or dlfferent; and
wherein X~ is
-CH:~NL2L~3, wherein L2 and 4 are hydrogenl alkyl
of one to 4 carbon atoms, lnclus;ve, or -COûR1, wherein R~.
i s as de f i ned above -
~0
3n . . . . ..
-76 -
~ : 2-Decarboxy-2-azidomethyl-PGF2~, or 2~nor-
PGF2~, azide (Formula CV: æl is CH=CH-(CH2)3 or CH=CH-(CH2)2,
respectively, R8 is hydroxy~ Yl is trans-CH=CH-, R3 and R4
of the Ll moiety and R5 of the Ml moiety are all hydrogen,
and R7 is n-butyl~.
Ao To a cold solution (O~C.) of PGF2~ (7~1 g.),
125 mlO of acetone~ 10 ml. of water, and 2.2 g. of triethyl-
amine is added with stirring 3.01 g. of isobutylchloxo-
forma~e. The mixtur~ is stirred at O~C. for about 30 min.
at which time a cold solution of 7 g. of sodium azide on
35 ml. of water is added. The mixture is then stirred at
0C. for one hr. at which time it is diluted with 300 ml.
of water and extracted wlth diethyl ether. The organic
layers are then combined; washed with water, dilute carbonate
solution, saturated saline; dried; and concentrated under
reduced pressure, maintaining bath temperature below 30~C.,
to yield 2-nor-PGF2~, a~ide.
B~ 2-Decarboxy-2-azidomethyl-PGF2~, is prepared by
the Eollowing reaction sequence:
cb/ - 77 -
(1) A solution of ~-butyldimethylsilyl chloride (10 g~),
imidazole (9.14 9.~ and PGF2a ~ 9.) ;n 12 ml. of dimethyl~
formamide are ~agnetically 5ti rred under nitrogen atm~sphere
for 24 hr. Tlle resulting mixture is then cooled in an ice
bath and the reaction quenched by addition of i~e water.
The resulting mixture i5 then diluted with 150 m1. of
water and extrac~ed with diethyl ether. The ccmbined
ethereal extracts are then washed with water, saturated
ammonium chloride, a sodium chloride solution, and there~
after dried over sodium sulfate. Solvent 75 removed under
vacuum yielding PGF2,l, t-butyldimethylsilyl ester~
9~11J15 tris-(t-butyldi~ethylsilyl ether). NMR absorptions
are observed at0~20, 0.~0, o.83, 0.87, 0.89, 1.07-2.50,
3.10-4.21~ and 5.38 6. Characteristic infrared absorptions
are observed at 970J 1000, 1060~ 1250, 1355, 1l~60, 1720,
and 2950 cm. 1.
(2) To a magnetically stirred suspension of li~hium
alurninum hydride (7.75 9.) in 18 ml. of diethyl ether i5
added dropwise at ro~n temperature over a period of 12 min.
~0 ~71 9. of the reaction product of part (1) above in 40 ml.
of dîethyl ether. After stirring at ambient temperature for
one hr., the resultlng product i5 cooled in an ice water
bath and saturated sodium sulfate is added dropwise until
the appe~rance o~ a milky suspension. The resulting pro-
duct is coagulated with sodium sulfate, ~riturated with
diethyl ether, and the solvent is removed by suction fil-
trationO Concentration of the d;ethyl ether under vacuum
yields 7.014 9. of 2-decarboxy-2 hydroxymethyl-PGF2a,
9,11,15-tris-(t-butyldimethylsilyl ether). NMR absorp-
tions arc observed at 0.03, 0.82, o.87, 1.~0-2 60, 3,30-
-78-
-- .
4.30, and 5037 ~. Characteris~ic infrared absorp~ions are
observed at 775~ 840, g70, 1065, 1250, 1460~ 28g5, 2995,
and 3~50 GmO~l.
(3) po~oluenesulfonyl ehlori~e (~.514 g.)~ pyr idi ne
(44 ml.)~ and the react;on product o~ subpart ~2)~ 7.014 9.,
are placed in a freezer at -20~ C. for ~ days. .Thereaf~er~
7,200 9. oF 2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF2
9,11,15-~ris-(t butyldimethylsi1yl e~her)~ is rec~vered.
NMR absorptions are observed at 0.10, 0.94, 0.97, 1.10,
10 2.50, 2.50, 4Oo~, 3.80 4.80, 5.45, 7035, and 7.80 ~. Infra-
red absorp~ions are observed at 775, g70, 1180, 1190~ 12~0,
1360, 14703 2900, and 2995 cm.~l. .
(4) The reaction product of subpart (3) (2.13 9.) is
placed in 42 ml. of acetic acid, tetrahydrofuran, and
water (3:1:1) containing 0.25 ml. of 10 percent aqueous hy-
drochloric aeid. The reaction mixture becG~es homogeneous
~ter vigorous stirring ~or 16 hr. at room te~perature. ~he
resultin~ solution is then diluted with 500 ml. of ethyl
acetate; w~shed w;th saturated sodium chloride and ethyl
acetate; dr.ied over sodium sulfate; and evaporated under
reduced pressure3 yieldin~ 01 9. of an oil. Crude pro-
duct is chromatographed on 150 9. of silica gel packed
with ethyl acetate. Eluting with ethyl acetate yields
0.953 9. of 2-decarboxy-2-p-toluenesul Fonyloxy m ~thyl-PGF2Q.
(5) The reaetion product of subpart (4), ~0.500 9.)
in 5.0 ml. of d;methylformamide was added to a s~irred s~s-
pension cf sodlum azide (1.5 9.) in 20 ml, of dimethy1for-
mamide. Stirr;ng is continued at ambient temperature for
3 hr. The re~tion mixture Ts then di1uted with water
(75 ml.), extracted with diethyl ether (500 ~l.), and the
-79~
the etheral extracts washedsuccessively withwater~ satu-
rated sodiu~chloride9 and dried cversodium sulfake~ Re~oval
ofthe diethyl e~herunder reduced pressure y;elds o.364 9. of
2-decarboxy-2-azid~nethyl-PGF2~. A characteristic azido
infrared absorption is observed at 2110 cm.~1,
, -80-
Preparation 3: 2-Decarboxy-2-aminomethyl-PGF2a ~Fo-mula
CXXV: Zl is cis~CII=CH-~CH2)3-, R8 is hydroxy, Yl is trans-
CH=CH-, R3 and R4 of the Ll moiety and R5 of the Ml moiety
are all hydrogen, and R7 is n-butyl3.
Crude 2-decarboxy-2-azidomethyl-PGF2a (Example 2,
0.364 g.) in 12 ml~ of diethyl ether is added to a magnetically
stirred suspension of lithium aluminum hydxide 10.380 g~) in
20 ml. of diethyl ether. Reaction temperature is maintained
at about 0C. and addition of lithium aluminum hydride proceeds
dropwise over a 4 min. period. After addition is complete,
the resulting mixture is stirred at ambi~nt temperature for
1.5 hr. and thereafter placed in an ice bath (0-5C.~
Excess reducing agent is then destroyed by addition of
saturated sodium sulfate. After cessation of gas evolu-
tion, the resulting product is coagulated with sodium sul-
fate, triturated with diethyl ether, and solid salts removed
by ~iltration. The filtrate is then dried with sodium sul-
~b/ - 81
fate, and evaporated under reduced pressure to yield 0.704 9.
of a s 1 i ght 1 y ye 1 1 ow oi 1 . Th i s oi 1 (100 mg, ) i 5 ~hen pur-
if ied by preparative thin layer chr~na~o~raphy, yleld~ng
42 9, o~ t;tle product. NMR absorptior~s are observed at
0.90, 1.1O-2~8OJ 3.28, 3.65~4.25, and 5.45 6. Characteris-
tic Tnfrared absorpt10ns a~e observed at 970, 1O60J 146OJ
2995, and 3400 cm.~. The m3SS spectrun~ shows parent peak
at 699.4786 and other peaks at 628, 684, 59:, 217, and
274 0
i0
~?0
~SO
-~32 -
11~ 1,15-Lactones
As discussed above, the 1,15-lactones of the formula-l,
~ 111, and -lV compounds are prepared by analogous
methods to ~hose disclosed below.
As will be particularly evident to those skilled in
the art, the preparation of a 1,9- 1,11-, or 1,15-lactone
will be relatively uncomplicated when the 9-, 11-, or 15-
hydroxy group is the only free hyd:roxy group with which the
carboxy function can lactonize. Thus, when more than one
hydroxy group is present, as for eY.ample in PGF2a, those
hydroxyl groups not required for lactone function are
optionally derivatized prior to lacton.ization to require
formation o~ the desirad lactone. Selective methods for
selective derivatization of all but one hydroxy of a
prosta~landin ox prostaglandin analog which contains two or
mor~ hydroxys are kno~n in the art. Suitable derivatives
~c the 9,11-cyclic phenyl- or butyl-boxonates of 9~,11a-
cb/
or 9~ dihydro~ylated prostaglandins and pros~aylandinanalogs, acylates such as acetate, silyl ethers such as
trimethylsilyl-, t-butyldimethylsilyl-, and triphenyl-
silyl and the like. Such functional derivatives ~re
known in -the prostaglandin art and are used with stereo-
selectivity or where s-tereoselectivity is not achievable,
with careful purification of the mix-tures produced, to
obtain the desired func-tionally protected prostaglandins
and prostaglandin analogs as exemplified fur-ther in the
examples. Optionally~ if desired, one or more hydroxy
groups are protec-ted by oxida-tion to a ketone before or
after lactoni2ation. After lactonization, the ketone is
reduced ayain to produce a free hydroxy group of the same
configuration or of opposite configuration to thac
originally presen-t.
However, it is no-t essential in all cases to
pxotect hydroxy groups which may be presen-t but are not
d~sired to participate in the lactone formation. Lactone
~ormation occurs at different relative rates with different
hydroxy groups dependlng on the stereochemistry, steric
bul}c ln the vicinity of the hydroxy group, and ring
size. Moreover it is possible to separate 1,9-, 1,11- !
and 1,15-lactones as exemplified below for PGF2~ 1,9-,
1,11-, and 1,15-lactones. Thus 15-methyl-15-hydroxy-
and 16,16-dimethyl-15-hydroxy prostaglandin analogs are
sterically hindered in -the vicinity of C-15 and lactone
function at 15 will not compete with lactone function with
a 9- or ll-hydroxy group. ~s a corollarv, in order to
make a lactone with a hindered hydroxy group such as 15-
methyl-lS-hydroxy- or 16,16-dimethyl-15-hydroxy-, it is
essential that other hydroxy groups which may be present
be protected. It is also necessary to e~tend the duration
oE the reaction until analysis of the reaction mixture
- 8~ -
mabJ 'i
indicates that some desired product is formed.
Prostaglandins known in the art as their 10~7er
alkyl (e.~ methyl, ethyl) ester but not as their free
acid may be converted -to the free acid for use in lactone
function by chemical hydrolysis by known methods. If
the involved pros-taglandin is unstable toward chemical
hydrolysis, as with PGE2-methyl ester, PGD2 methyl ester,
and the like, it is preferred to obtain the free acid
by enzymatic hydrolysis, Eor example by using the process
of UOS. patent No. 3,761~356, issued Sep-tember 25, 1973
to The Upjohn Company.
With these limita-tions, and options for
protecting concommitant by present hydroxy groups,
selec-tively hydrolyzing the functionally protected hydroxy
yroups without hydrolyzing -the desired lactone, separating
undesired products from those desired, and modifying
the lactones by subsequent chemis~ry obvious to those
s]cilled in the art, such as oxidation, reduction, alkyla-
tion and the like, it is possible to prepare the 1,9-,
~0 1,11-, and 1,15-lactones of pros-taglandins and of prosta-
cJlandin ana].ogs of biological importance.
The preferred method for lactone function
between the carboxyl group and the 9-, 11- or 15-hydroxyl
group is the method described by Corey e-t al., J. Am.
Chem. Soc. 96, 5614 (1974), as further described by Corey
et al., J. Am. Chem. Soc. 97, 653 (1975) and as exemplified
fur-ther herein. Optionally other me-thods may be used,
if desired, such as those of Masamure et al., J. Am.
Chem. Soc. 97, 3515 (1975) and Gerloch et al., Helv. Chem.
Acta 57, 2661 (1974).
- 85 -
mab/ `
.
Preparation 4~ PGF2~, l,lS-lactone
A solution of 5.5 g of PGF2~ and 1.79 g of l-butane-
boronic acid in 150 ml of methylene chloride was heated at
reflux for 15 min. Then about half of the methylene chloride
was removed by distillation at atmospheric pressure. Addi-
tional methylene chloride was added to bring the volume bac~
to the ori~inal 150 ml. This cycle-distillation of methylene
chloride followed by replacement with fr~sh methylene chloride-
was repeated three times, after which all the solvent was
removed in vacuo to produce the 9,11-cyclic boronate of
PGF2~ as a residue.
The residue was dissolved in 180 ml of anhydrous,
oxygen-free xylene and treated with 5.1~8 g of 2,2l-dipyridyl
disulfide followed by 6.27 g of triphenylphosphine. After
18 hours at 25~ tmder a nitrogen atmosphere, thin layer
chromatographic analysis of an aliquot ~solvent: 10 acetic
acid/10 methanol/80 chloroform) showed complete conversion
to the pyridinethiol ester.
The xylene solution was diluted with 300 ml of oxygen-
free xylene and was added dropwise over 10 hours to 3.2 litersof vigorously stirred, refluxing xylene under a nitrogen
atmosphereO After the addition was complete, 100 ml of
xylene was distilled off and the
cb~ - 86 -
solution was heate~ at re~lux for 24 hours. I'he reaction mi~ture
w~s then cooled c~nd the xyl~ne was removed in vac~to (35 bath
temperature) to yive a residue. The residue was taken u~ in 500 ml
of tetrahydrofuran and treated with 10 ml of 30% hydrogen pero~ide
and 100 ml of saturated a~teous sodium bicarbonate. The three-
phase mixture was stirred vigorously for 30 min. at 25, then con-
centra-ted in vacuo to give a residue. Ihe residue was taken up
in brine/ethyl acetate and extracted thorouyhly with ethyl acetate.
The cc~bined organic layer was washed with three por-tions of lN
aq~teous potassium bisulfate, and once with water/ aqueous sodium
bicarbonate and brine. After drying over sodium sulfate, the solvent
was removed to afford a viscous yellow oil which was chrcmatographed
on 500 g of Mallinckrodt acid-washed CC-4 silica. The column was
packed with ~5~ ethyl aceta-te/hexane and eluted (100 ml frac-~ions)
with 50% ethyl aceta-te/hexane. Fractions 26-40, containing the
product and no prostaglandin-related impurities, were combined. The
desirecl product was crystallized fro~ 40 ml of 1:1 ether/hexane,
thereby affording ~ure lactone, M.P. 110-111.
The lactone exhibited infrared absorption at 3500,
~0 3370, 3290, 3010, 1700, 1320, 1310, 12~0, 1260, 1105, 1080, 1055, 970,
~ncl 730 cm and NMR pec~ks at 6.00-5.75 (vinyl; mul-tiplet; 2H),
5.75-~.95 (vinyl and C-15H; multiplet; 3H), 4.30-3.85 (CHOH; multiplet;
211) ancl 2.65 p.prm. (OH; broad singlet; shif-ted dc~nfield on cc~ling;
21l). The mass spectrum of the bistrimethylsilyl deriva-tive exhibited
fragment~s at 480 (M+), 465 (M-CH3), 436 (l~CO2), 409 (M-C5Hll), 390,
380, 364, 238, 2~7.
Anal- Calc'd- for C20H324 C~ 71-39; H~ 9-59-
Found : C, 70.73; H, 9.31
In li~e manner, but substituting ethyl acetate h~xane for ether/hexane
for recrystallization, PGF2Nl,15-lactone was obtained: m.p. 110.0-
111.7; [~]EtO~I _ 71
- 87 -
mab/
~5~
: 17-phenyl-l8~lg~2o-trinor-pGF2a~ s lactone
A solution of 17-phenyl-1~,19,20-trinor-PGF2a, ~776 mg~
and l-butaneboronic acid (225 mg) in 25 ml of methylene chloride
was heated a~ refluxO After 15 min. the methylene chloride
was allowed ~o distill off slowly. Fresh methylene chloride
was added when the total volume was reduced to about one-half
of the original volume~ After 90 minutes, all of the
methylene chloride was removed in vacuo to afford cyclic
boronate of the starting pxostaglandin.
The cyclic boronate was dissolved in 5 ml of anhydrous,
oxy~en-free xylene and was treated with 2,2'-dipyridyl di~
sulfide (660 mg) and triphenylphosphine (786 mg). After four
hours at 25 the reaction mixture was diluted with 500 ml of
anhydrous, oxygen-free xylene and was heated at reflux for 18
hr. 'rhe xylene was removed in vacuo to give a residue. The
residue was taken up in 50 ml of tetrahydrofuran containing 1
ml of 30% aqueous hydrogen peroxide (11~6 mmoles) and treated
at 25 with a solution of sodium bicarbonate ~1.68 g) in 10 ml
o~ water. This mixture was stirred vigorously for 30 min.
-th~n concentrated under reduced pressure to give a residue.
Th~ residue was taken up in brine/ethyl acetate and extracted
thoroughl~ with ethyl acetate. The combined extracts were
washed with aqueous sodium bisulfate, water, aqueous sodium
bicarbonate and brine, then dried over sodium sulfate and
concentrated to afford a residue of crude 17-phenyl-18,19,
20-trinor PGF2a/ 1,15-lactoneO
The crude lactone was purified by chromatography on 400 g
o neutral silica packed and eluted (22 ml fractions) with ethyl
acetate. The fractions which contained the product, based on
TLC, were combined yielding purified 17-phenyl-18,19,20-trinor-
PGF2a, 1,15-lactone The lactone crystallized upon trituration
and after two recrystallizations from ethyl aretate/hexane
exhibited m.p. 116-117~
cb/ - 88 -
t~
The infrared spectrum exhibited peaks at 3460, 3400 sh,
3020, 1705, 1650, 1605, 1495, 13~5, 1300, 1265, 1150, 110~,
1040, 1020, 1000, 970 and 700 cm 1 and the mass spectrum
showed fragments at m/e 370 ~18), 352, 334, 308, 298D 261,
5 243, 225. ~No ~l~ peak was appaxent.)
~nal. Calc d. for C~3M30O4: C, 74.56; H, 8.1~.
Found : C, 74.27; H, 7.97
Preparation 6: 17 Phenyl 18,19,20-trinor-PGE2, 1,15-lactone
A solution of 17-phenyl-18,19,20-trinor-PGE2 (735 mg~,
10 2,2'-dipyridyldisulfide (628 mg) and triphenylphosphine (743 mg)
in 10 ml of anhydrous, oxygen-free xylene was stirred at 25
in an atmosphere o~ nitrogen for 2 hr. The mixture was then
diluted with 400 ml of anhydrous, oxygen-free xylene, heated
at reflux for 2.5 hrs, and evaporated under vacuum at 30 to
lS give a residue. The residue was chromatographed on 100 g of
neutral silica, pac]ced and eluted (8 ml fractions) with 80~
e~her/hexane. The fractions containing homogeneous product
by TLC were combined to afford purified 17-phenyl-18,19,20
trinor-PGE2, 1,15~1actone. ~wo recrystallizations from
~ther/hexane afforded pure product, m.p. 81-83. The infra-
red spectrum exhibited peaks at 3440, 3000, 1725, 1605, 1500,
1330, 1240, 1160, 1145, 1085, 1045, 975, 745, 725 and 700 cm 1
and the mass spectrum showed fragments at m/e 368 ~M-18), 350
332, 297, 296,~77, 264, Z59, 241 ~no M+ apparent).
Preparation 7O 16-Phenoxy-17,18,19~20-tetranor-PGF2a,1,15-lactone
Following the procedure of Example 1 but substitutingi
16-pheno~y-17,18,1~,20-tetranor PGF2~ for PGF2a there was pro-
duced a crude product of 16-phenoxy-17,18,19,20-tetranor-PGF2a,
1,15-lactone as a viscous yellow oil.
~he crude product was purified by chromatography over
neutral silica packed in 50% ethyl acetate/hexane and eluted
with 50% ethyl acetate/hexane followed by 70% ethyl acetate
cb/ - 89 ~
hexane~ Those fractions containing homogeneous product a~
judged by TLC were combined ko afford crystalline 16-phenoxy-17
18,19,20-tetranor-PGF2~, 1,15-lac~o~e. The lactone thus
obtained was recrys~allized from ethyl acetate/hexane to
afford pure product, m~p. 185-186. The mass spectrum of the
trimethylsilyl deriva~ive exhibited a peak at M~ 516.2738
(theory for C28H44Si2O5: 516.2727) and fragments a~ m/e
501, 426, 423, 409, 400, 333, 307, 217 and 181.
repara~ion 8: ~GYl~, 1,15-lac~one and 15-epi-PGFl~, 1,15-lactone
Followiny the procedure of Example 1 but substituting
PGFla for PGF2~ there was obtained a crude product containing
PGFla, 1,15-lactone as a viscous yellow oilO
The crude product was purified by chromatography on 700
y of neutral silica, packed and eluted with 50~ ethyl acetate/
hexane. The first 2 liters of eluate were discarded, after
which 100 ml fractions were collected.
A minor product eluted first from the column (fractions
14~9) which was homogeneous by TLC was combined to give 15-epi-
PGFla, 1,L5-lactone ~15R)-PGF2a, 1,15-lactone~ The infrared
20 sp~ctrum exhibited peaks at 3450, 1730~ 1585, 125Q, 1100t 970
and 735 cm 1 and the NMR spectrum showed peaks (~CMs 3) at
5.85-5.05 (vinyl and C-15; multiplet; 3H;, 4.25-3.85 (CHOH;
multiplet; 2H) and 3.30 ppm (singlet, shifts downfield when
sample is cooled; OH; 2H).
The major product, eluted later fr~m the column (fractions
21-28), were combined to afford purified P5Fla~ 1/15-lactone.
The purified PGFl~, 1,15 lactone crystallized upon trituration
with etherl and recrystallization (ethyl acetate/hexane) afforded
a pure sample~ m.pO 105-106~ The infrared spectrum exhibited
30 peaks at vmax 3520~ 3480, 3380, 1710, 1300, 1290, 1265, 1250,
1235, 1160, 1110~ 1075f 1055, 1000 and 965 cm ~. The NMR
spectrum showed peaks (~TMC 3) at 6~0-5.75 ~vinyl; multiplet~
cb/ ~ 90
2Hj 5.60-5000 (C-15~; multiplet; lH), 4.25-3.80 ~CHOH; multiplet;
2H~ and 3.08 ppm (OH; singlet~O
Preparation 90 13,14-Didehydro-8~,9~ ,12~ PGF2~ 1,15-lactone
and 13,14-didehydro PGF2~ 1,15-lactone
Following the procedure of Example 1 but substituting 13
14-didehydro-8~, 9~ , 12~ PGF2~also known as ent-13-
dehydro-15-epi-prostaglandin F2a (compound 2 of J. Fried and C.
H.Lin. J. Med. Chem. 16, 429 (1973)~ and 13,14-didehydro PGF~
for PGF2~, there are produced 13,14-didehydro-8~,9~ ,12a-
PGF2~ 1,15-lactone~ and 13,14-didehydro-PG~2a 1,15--lactone,
respectively.
Preparation 10: 13,14-didehydro-8~ ,12~-PGE 1,15-lactone
and 13,14-didehydro-PGE2 1,15-lactone
Following the procedure of Example 2 but substituting
13,14-didehydro-8~ ,12~-PGE2 [also known as ent-13-dehydro~
lS-epi-PGE2 (from 2a of J. Fried and C. H. Lin. J~ Med. Chem.
16, 429 ~1973)] and 13,14-didehydro PGE2 for PGE2 there axe
produced 13,14-didehydro-8~ ,12~-PGE2 1,15-lactone and
13,1~-clidehydro PGE2 1,15-lactone, respectively.
~0 PreE~ration 11: 13,14-dihydro PGF a 1,15-lactone
Following the procedure of Example 1 but substituting
13,14-dihydro PGF2~ for PGF2~, there is produced 13,14-dihydro
PGF2~ 1,15-lactone.
Preparation 12- tl5S)-15-methyl PGF2~ 1,15-lactone
__
Following the procedure of Example 1 but substituting
tl5S) 15-methyl PGF2~ for PGF2a and extending the reaction
time in refluxing xylene from 24 hours to 48 hours there is
produced crude tl5S)-15-methyl PGF2a, 1,15-lactone. The crude
lactone is purified by repeated chromatography and, further~
i desired, by TLC purification to afford in low yield tlSS3
15-methyl-PGF2~, 1,15-lactone in essentially pure form.
Preparation 13: 16,16-dimethyl PGF~ 1,15~1actone
d3/ ~ gl ~
Following the procedure of Example 15 but substituting
16,16-dimethyl PGF2~ for ~15S) 15-methyl PGE2a there i5
produ~ed 16,16-dimethyl PGF2~, 1,15-lactone
Preparation 14
~ollowin~ the procedure of Example 8 but substituting
16-m-trifluoromethylphenoxy-17,18,19,20-t2~ranor PGF2~l 16-m-
chlorophenoxy-17,1.8,1g~20-tetranor PGF2~, and 16~p-fluoro-
phenoxy-17,18,19,20-tetranor PGF2a for 16~phenoxy-17,18,19,20
tetranor PGF~ there are obtained ~he corresponding 1,15-lactones.
Preparation 15:
Following the procedure of Example 2 but substituting
(16S) 16-methyl-, ~16R) 16-methyl- and 16-methylene PGE2 fox
PGE2 there are produced/ respectively, the corresponding ~16S)
16-methyl, ~16R) 16-methyl-, and 16-methylene PGE2 1,15-lactones.
15 Pre~aration 16: 16,16-dimethyl PGE2 1,15-lactone
Following the procedure of Example 3 but substituting
16,16-dimethyl PGF2a 1,15-lactone for PGF2~ 1,15-lactone
there is produced 16,16-dimethyl PGE2 1,15-lactone.
_ration 17: (15S) 15-methyl PGE2 1,15-lactone
~0 Following the procedure of Exam~le 3 but substituting
~15S) 15-methyl PGF2~ 1,15-lactone for PGF2~ 1,15-lactone,
there is produced ~15S) 15-methyl PGE2 1,15-lactone.
Preparation 18~ deoxy PGE 1,15-lactone
Following the procedure of Example 2 but substituting 11-
25 deoxy PGE2 for PGE2 there is produced ll-deoxy PGE2 1,15-lactone.
In like manner, substituting ll-deoxy PGEl for PGE2
affords PGE~ 15~1actone.
Preparation 19 ~15S) ll-deoxy-15-methyl PGE2 1,15-lactone
and ll-deoxy-16,16~dimethyl PGE~, 1,15~1actone
Followiny the procedure of Example 2 but substituting
(15S) ll-deoxy-15-methyl PGE2 and 11-deoxy-16,16-dimethyl PGE2
Eor PGE2 and cxtending the reflux period in xylene from 2
cb/ ~ 92 ~
~lB~:i9t;9
hours to 48 hours there are produced the corresponding 1,15~
lactones. ~he crude lactones are purified by repeated chroma-
tography and further, if desired, by TLC purification to afford
in low yield (15S) ll-deoxy-15-methyl PGE2 1,15-lactone and
11-deoxy-16,16-dimethyl PGE2 1,15-lactone, respectively, in
essentially pure form.
Preparation 20: ll-deoxy PGF2~ 1,15-lactone
A solution of 11-deoxy PGE2 1,15-lactone (0.5 g) in
methanol ~50 ml) is treated at 0 with sodium borohydridë
~500 mg) added in 50 mg portions every 2 minutes. Aqueous
sodium bisulfate (lM) i5 added until the mixture is acidic
and the product is isolated by extraction with ethyl acetate~
The extract is washed, dried, and concentrated to yield a
residue containing ll-deoxy PGF2a, 1,15-lactone.
The residue is purified by chromatography over acid-
washed silica using 1% ethyl acetate/hexane increasing to 40%
ethyl acetate/hexane. Those fractions containing homogeneous
product as judged by TLC and by saponification to the known 11-
deoxy PGF2a are combined to afford ll-deoxy PGF2~ 1,15-lactone
in ~ssentially pure form.
In like manner, substituting ~15S~ ll-deoxy-15-methyl
PGF2~ 1,15-lactone, 11-deoxy-16,16-dimethyl PGE2 1,15-lactone
PGE2, 1,15-lactone, ~15S) 15-methyl PGF2 1,15 lactone, 16,16-
dimethyl PSE2 1,15-lactone and PGEl 1,15-lactone for ll-deoxy
PGE2 1,15-lactone there are produced the 1,15-lactones of ~15S)
ll-deoxy 15-methyl PGF2~, 11-deoxy-16,16-dimethyl PGF2~, PGF2a,
~15S) 15-methyl PGF~a, and PGEla, respectively.
~b~ - 93 -
SUEPL~ ~N~ R ~ SCLO_URE
When this application was filed, it was not known
which isomer, 5E form or 5Z form, was obtained by the
procedures set out in the examples. The structure has
now been established for the compounds of the present
invention as the 5Z form. "E" ~nd "Z" nomenclature is
discussed in the following reference: J.E. Blackwood et al~,
3. Am. Chem. Soc. 90,509 (1968).
The 5Z compounds of the present invention were made
from 5,6-cis PGF compounds, whereas the 5E isomers require
starting with 5,6-trans PGF compounds.
When considering Examples 5 to 7 and 10 of th~
principal disclosure, it should be noted that the pref1x
'l5Z_I- properly helongs before each title heading, for example,
Example 5, line 17 on page 49: 5Z-9-Deoxy-6,9-epoxy- ~5-PGF
Methyl Ester.
_ 9~ _
