Note: Descriptions are shown in the official language in which they were submitted.
This application is a division of copending
Canadian application Serial No. 270,416, filed January 25,
lg77.
BACKGROUND OF THE INVENTION
This invention relates to prostaglandin deriva-
; tives and to a process for preparing them.
The prostaglandins and analogs are well-known
organic compounds derived from prostanoic acid which has
the following structure and atom numbering:
~ 7~\6/5~/3~ COOH
~1~`~20
As drawn hereinafter the formulas represented a
particular optically active isomer having the same abso-
lute configuration as PGEl obtained from mammalian tissues.
In the formulas, broken line attachments to the
cyclopentane ring or side chain indicate substituents`in
alpha configuration, i.e. below the plane of the ring or
side chain. Heavy solid line attachments indicate sub-
stituents 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 (1971).
SUMMARY OF THE INVENTION
It is the purpose of this invention to provide
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 of-~e formula:
- 2 -
mab/~
.
2871A
~V-O-C-CH-L-R~
~ ~, "W/
~
X-C-R4
Q
: 10 wherein D is
oh OH CH2
~ , `
, or
C'H20H
wherein L is
(1) -(CH2)d-C(R2)2-
(2) -CH2-O-CH2-Y- or
. (3) ~CH2CH=CH-
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;
wherein Q is
0~ H H , Ra OH, or R8 OH
287lA
wherein R8 is hydrogen or alkyl of one to 4 carbon atoms~
i~clusive;
wherein Rl is
(1 )-COOR3
(2 )-CH20H
( S )-CH2N (Rg )2 or
(4)
NH -N
~N--N
wherei n R3 is (a) alkyl of one to 12 carbon atoms,
10 . inclusive, (b) cycloalkyl of 3 to 10 carbon atoms,
inclusiveJ (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,
inclusive;
._
O O
f ) ~9-NH -C ~NH -C -CH3,
(9) ~NH-C~9,
O
(h ) ~=~NH-C -CH3,
;) ~ N H-C-NH2
CH=N-NH-C-NH2, or
-4-
(k) ~
o
11
(1) -CH-C-Rlo
R l l
wherein R1o is pheny1, p-bromophenyl, p-biphenylyl, p-
nitrophenyl, p-benzamidophenyl, or 2-naphthyl;
wherein 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, inclusive, being the same or different;
wherein R4 is
Rs
~ F c gH29-CH3
R~
R5
(2) -C-Z ~ (T)s or
(3) -CH2_ C C ~CH2CH3
H' H
wherein CgH29 is alkylene of one to 9 carbon atoms,
inclusive, with one to 5 carbon atoms, inclusive,
in the chain between -CR5R~- and terminal methyl,
wherein R5 and R~ are hydrogen, alkyl of one to 4
.
-5-
.
., 287 lA
carbon atoms, inclusi~e, 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 fluo~ro
and the further proviso that neither R5 nor R~ is --
fluoro when Z is oxa (-0-); wherein Z represents
an oxa atom (-O-) or CjH2, wherein ClH2j is
a valence bond or alkylene of one to 9 carbon atoms,
inclusive, with one to 6 carbon atoms, inclusive
between 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 to 4 carbon atoms, inclu-
sive, and s is zero, one, 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 -(CHz)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 heretn there are represented
(a) PGFa compounds when ~ is
<~X'
OH
~0
2871A
(b) ll~-PGF,~ compounds when D is
<~
OH
(c) ll-Deoxy-ll-keto-PGF~ compounds when ~ is
<~ ,
10 (d) 11-Deoxy-11-methylene-PGFa compounds when ~i5
CH2
15(e ) 11 -Deoxy -PGFa compounds when Di s
.. ~
20~D(f ) ll-Deoxy-10,11-Didehydro-PGFa compounds when
~ ; and
(9~ 11-Deoxy~ hydroxymethyl PGFa compounds when
~ '' ¢~ '
CH20H
. ~i6~6 ~ 8 2871A
A typical example of the compounds of formula I is
: represented by the formula:
_CH-CH-(CH2)3-COOH
/~' V
~C =C
HO H \ C~-C5H
H OH
and named as a derivative of PGFla: 9-deoxy-6,9-epoxy-5-
iodo-PGF1a. The compound of formula V is a species of the
formula-l 5-iodo compounds wherein D i s
~ '
OH
L is -(CH2)3-, Q is H OH, R1 is -COOH, R4 is n-pentyl,
V is a valence bond, W is -CH2-, and X is trans-CH=CH-.
There are likewise provided compounds of the formula
: ` '
~ /V-O-C=CH~L-R
., ~
:~ 25 ~ Il
~ X-C-R4
~ , ' ' .
., .
_O_
287 lA
6~
OH
~, V-o -C -CH2 -L -R I
-) -W / I ~ I
~_- ~ X-C-R 4 and
Q
V~OHo
- ~ W-C-CH2-L-R
) lV
X-C-R 4
wherein ~ ~ L, O, R1J R4J VJ W, and X are as defined
broadly above for formula I, with the proviso that, in
the enol ether compounds of formula II, R1 jS not-COOH
when D iS ~-
~ .
bH
Q is H OH, L is -(CH2)3-, R4 jS n-pentyl,
V is a valence bond, W is -CH2-, and X is trans-CH=CH-.
In compounds of formula II, the wavy line ~ indicates
attachment in cis or trans configuration relative to the
W-C bond. In formulas l-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, ~ indicates attachment of -OH in alpha or
beta configuration.
The formula-II enol ethers are named as derivatives of
PGF2~J regardless of the variations in either of the side
., g
:, .
2B71A
chains, V and W in the heterocyclic ring, or the cyclo-
pentane ring system represented by ~ , following the
conventions known and used in the prostaglandin art. The
formula-tll 6-hydroxy compounds (hemi-ketals) and the
formula-lV 6-keto compounds are named as derivatives of
PGF~.
Typical examples of the compounds of formula ll, Ill,
and IV, when ~ , L, O, R1, R4, V, W, and X are as illustrated
above for the compound of formula V are:
O _C~-CH-(CH2)3 -COOH
¢~=C~ Vl
H~ \C-CsH
H OH
named 9-deoxy-6,9-epoxy- ~s-PGF la;
~H
_~H-(CH2)4-COOH
O ~
~ C=C ~ Vll
HO C~-C5H
H / OH
.
named 9-deoxy-6,9-epox~-6-hydroxy-PGF~a; and
.: 25
, . .
: OH O
~CH2-C-(CH2)~-COOH
, ~C-C' Vlll
' H \C-CsH
OH ~ ~
H OH
named 6-keto-pGF~aD
-10 -
6 2 8 2871A
The products of this invention, represented herein by
formulas 1, Il, Ill, and IV, are extremely potent in causing
various biological responses. For that reason, these com-
pounds are useful for pharmacological purposes. A few of
those biological responses are: inhibition o~ blood
platelet aggregation, stimulation of smooth muscle, systemic
blood pressure lowering, inhibiting gastric secretion and
reducing undesirable gastrointestinal effects from systemic
i administration of prostaglandin synthetase inhibitors.
Because of these bio10gical responses, the known
prostaglandins are useful to study, prevent, control, or
alleviate a wide variety of diseases and undesirable
physiological conditions in mammals, including humans, use-
ful domestic animals, pets, and zoological specimens, and
in laboratory animals, for example, mice, rats, rabbitsJ
and monkeys.
These compounds are useful whenever it is desired to
inhibit platelet aggregation, to reduce the adhesive
character of platelets, and to remove or prevent the forma-
tion of thrc;mbi 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
~rafts following surgery, and to treat conditions such as
atherosclerosis, arteriosclerosis, blood clotting defects
due to lipemia, and other clinical conditions in which the
underlying etiology is associated with lipid imbalance or
hyperlipidemia. Other in vivo applications include
geriatric patients to prevent cerebral ischemic attacks
~0 and long term prophylaxis following myocardial infarcts
2871A
and strokesO 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 situations3 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 animalJ and on the frequency and route of admin-
istration.
The addition of these compounds to whole blood provides
în 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 organs,
e.g. heart and kidneys, which have been removed from a donor
and prior to transplant. Also useful in 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 stimulators, for example,
oxytocic agents~ e.g., oxytocin, and the various er~ot alka-
loids including derivatives and analogs thereof. Therefore,
they are useful in place of or in combination with less than
usual amounts of these known smooth muscle stimulators, for
example, 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 placenta, and durfng
3 the puerperium. For the latter purpose, the compound is
.
-12-
6;;~
. _ . .. .
administered by intravenous infusion immediately after
abortion or delivery at a dose in the range about 0.01 to
about 50 ~y. per kg. of body weight per minute until the
desired effect is obtained. Subsequent doses are given by
intravenous, subcutaneousJ or intramuscular injection or
infusion during puerperium in the range 0.01 to 2 mg. per
kg. of body weight per day, the exact dose depending on the
age, weight, and condition of the patient or anima~
These compounds are useful as hypotensive agents to
reduce blood pressure in mammals~ including man. For this
purpose, the compounds are admi ni stered by intravenous in-
fusion at the rate about 0.01 to about 50 ~g. per ~9. of
body weight per minute or in sing1e or multiple doses of
about 25 to 500 ~9. 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
and pigs~ to reduce and control excessive gastric secretion,
thereby reduce or avoid gastrointestinal ulcer formation,
- and accelerate the healing of such u 1 cers already present
... .. . . . .
in the gastrointestinal tract. For this purpose~ these
compounds are injected or infused intravenously, sub-
cutaneously, or intramuscularly in an i nfusion dose ranyeabout 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 abou~ 10 mg. per kg. of body
weight per day, the exact dose depending on the age, we; ght,
and condition of the patient or animalJ and on the fre-
quency and route of adm;nistration.
These compound;are a1so useful i n reducing the un-
desirable gastrointestinal effects resulting from systemic
.
6~ .
admillis~:ra~lon of an~ fl,~mDIn~:ory prost~glandill Rynthe~se
inllibitor~, ~nd are used for that purpoAe by concomitant
admlnl~ration of the prostaglandin derivative and the anti~
inflammatory prostaglandin syn~hetase inhibitor. See Par~ridga
et al, U.S. Pat. No. 3,781,429 issued December 25, 1973, for
a disclosure ~hat ~heiulcerogenic effect i~lduced by certaln no~-
steroidal anti-inflammatory agents in rats is inhibited by
concomitant oral administration of certain prostaglandins of
the E and A series, including PGE,, PG~2, PGES, 13,14-dihydro-
PGEl, and the corresponding ll-deoxy-PGE and ~GA compounds.
Prostaglandins are useful, for example, in reducing the
undesirable gastrointestinal effects resulting from systemic
administration of indomethacin, phenylbutazone, and Aspirin.
These are substances specifically mentioned in Partridge et al
as non-steroidal, anti-inflammatory agents. Tnese are also
kno~7n to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, f or example,
indomethacin, Aspirin, or phenylbutazone is administered in
any of the ways known in the art to alleviate an inflamma.ory
condition, for example, in any dosage regimen and by any of
the known routes of systemic administration.
The prostaglandin derivative is administered along
wlth the anti-inflammatory prostaglandin synthetase inhibitor
either by the same route of administration or by a different
; route. For example, if the anti-inflammatory substance is
being administered orally, the prostaglandin derivative is
also administered orally, or, alternatively, is administered
rectally in the form of a suppository or9 in the case of
women, vaginally in the form of a suppository or a vaginai
device for slow release, for example às described in U.S. Pat.
. .
~' . .
Jl/ ~ -14-
* Trademark
.
No. 3,545,439 (Dec. 89 1970, The Up~ohn Company). Altern~tively,
if the an~i-inflammstory substance is being administered
rectally, the pro~taglandin derlvative is also administere~
rectally. Furtner9 the prostaglandin derivative can be con~en -
iently administered orally or, in the case of women, vaginally.
It is especially convenient when the administration route is to
be the same for both anti-inflammatory sub~tance and prostagland~n
derivative, to combine both into a single dosage form.
The dosage regimen for the prostaglandin derivative i~
accord with this treatment will depend upon a variety of factors9
- including the type9 age9 weight, sex and medical condition of
the.mammal, the nature and dosage regimen of the anti-inflammatory
synthetase inhibitor being administered to the mammal, the
sensitivity of the particular prostaglandin derivative to be
administered. For example, not every human in need of an a~ti-
inflammatory substance experiences the same adverse gastro-
intestinal effects when taking the substance. The gastro-
intestinal effects will frequently vary substantially in kind
- and degree. But it is within the skill of the attending
physician or veterinarian to determine that administration of
the anti-inflammatory substance is cau~sing undesirable gastro-
intestinal effects in 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
effec-ts.
These compounds are also useful in the treatment of
- asthma. For example9 these compounds are useful as broncho-
dilators or as inhibitors of mediators, such as SRS-A, and
histamine which are released from cells activated by an antigen-
antibody complex. Thus, these com-
.
1 5-
6;28 287 lA -1
pounds control spasm and facilitate breathing in condi-
tions such as bronchial asthma, bronchitis~ bronchiectasis,
pneumonia and emphysema. For these purposes, these com-
pounds are administered in a variety of dosage ~orms, e g.,
orally in the form o~ tablets, capsules, or liquids; rec-
tally in the form of suppositories; 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 insufftation in the form of powder. Doses in the
range of about 0.01 to 5 mg. per kg. of body weight are
used 1 to 4 times a day, the exact dose depending on the
age, weight, and condition of the patient and on the fre-
quency and route of administration. For the above use
these prostaglandins can be combined advantageously with
other anti-asthmatic agents, such as sympathomimetics
(isoproteren~l J phenylephrine, ephedrine, etc.); xanthine
derivatives (theophylline and aminophylline); and cortico-
steroids (ACTH and prednisolone~.
These compounds are ef~ectively administered to
human asthma patients by oral inhalation or by aerosol
inhalation.
For administration by the oral inhalation route with
conventional nebulizers ol 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. Fntirely conventional additives
may be employed to stabilize these solutions or to pro-
vide isotonic media, for example, sodium chloride, sodium
-16-
~ 6 ~ ~
citrate, citric acid, sodium blsulf;te, and the like
can be employed
For administration as a self-propelled dosage unit for
administering the active ingredient in aerosol form suita-
ble for inhalation therapy the composition can comprisethe active ingredient suspended in an inert propellant
(such as a mixture of dich10rodifluoromethane and di-
chlorotetrafluoroethane) together with a co-solvent, such
as ethanol, flavoring materials and stabilizers. Instead
of a co-solvent there can a~lso 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.) ~or exa~ple.
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 mlO of a
pharmacologically suitable liquid vehicle or as an aerosol
spray, both for topical application.
These compounds are also useful in treating peripherai
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,
phlebitis, venous insufficiency, gangrene, hepatorenal syn-
drome, ductus arteriosus, non-obstructive mesenteric
ischemia, arteritis ly,mphangitis and the like. These
examples are included to be illustrative and should not
be construed as limiting the term peripheral vascular
3 disease. For these conditions the compounds of this
.
- -17- ,
"
~6~
invention are administered orally or parenterally vi~ in~ection
or infusion directly into a vein or artery, intra-venous or
intra-arterial in~ections 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 times a day, the exact dose depending on the age,
weight, and condition of the patient and on the frequency and
route of admlnistration. Treatment is continued for one to
five days, although three days is ordinarily sufficient 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 ~ho
have circulatory insufficiencies in said extremities, such
treatment affording relief of rest pain and induction of
healing of ulcers.
- For a complete discussion of the nature of and clinical
manifestations of human peripheral vascular disease and the
method previously known of its treatment with prostaglandins see
South African Patent No. 74/0149 (March 7, 1975, L.A. Carlson~ 9
or corresponding U.S. Patent 4,103,026 (July 25, 197~). See
Elliott, 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 term, 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-
62~ 2871A-l-F
fused intravenously at a dose of 0.01 to 50 ~g. per kg.
of body weight per minute until or near the termination
of the second stage of tabor, i.e.J expulsion of the
fetus. These compounds are especially useful when the
female is one or more weeks pos~-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 route of administration is oral.
These compounds are further useful for controlling
the reproductive cycle in menstruating female mammals,
including humans. By the term menstruating female mammals
is meant animals which are mature enough to menstruate,
but not so oJd that regular menstruation has ceased. For
that purpose the prostaglandin derivative is administered
systemically at a dose level in the range 0.01 mg. to
about 20 mg. per kg. of body weight of the female mammal,
advantageously during a span of time starting approxirnately
at the time of ovulation and ending approximately at the
time of menses or just prior to menses. Intravaginal and
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 compounds are further useful in causing cervi-
A cal dilation in pregnant and nonpregnant female = /s
for purposes of gynecology and obstetrics. In labor
induction and in clinical abortion produced by these
compoundsJ cervical dilation is also observed In cases
~0 of infertilityJ cervical dilation produced by these com-
6~ ~871A~
pounds is useful in assisting sperm movement to the
uterus. Cervical dilation by prostag1andins is also use-
ful in operative gynecology such as D and C (CerYical
Dilation and Uterine Curettage) where mechanical dilation
may cause performation of the uterus, cervical tears, or
infections. 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.
- 10 The prostaglandin derivative~ for example, is admin-
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 Alternatively the
compound is administered intramuscularly or subcutaneously
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.
These compounds are further useful in domestic anirnals
as an abortifacient (especially for feedlot heifers), as
an aid to estrus detection, and for regulation or synchroniza-
tion of estrus. Domestic animals include horses, cattle,
sheep, and swine. The regulation or synchronization 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 interva1s. This synchroniza-
tion results in a higher percentage of live births than the
percentagé achieved by natural control. The prostaglandin
is injected or applied in a feed at doses of 0.~-100 mg.
per anirnal and may be combined with other agents such as
steroids. Dosing schedules wi71 depend on the species
.
-20 -
. .
2~ 287lA-1-F
treated. For examp1e, mares are gi ven the prostaglandi n
derivative 5 to 8 days after ovulation and return to estrus.
Cattle are treated at regular i ntervals over a 3 week period
to advantageously bring all into estrus at the same time.
These compounds i ncrease the f low of blood i n the
mammalian kidney, thereby increasing volume and electro-
1 yte content of the ur i ne . For that reason, these compounds
are useful in managi ng cases of renal dysfunction, especial ly
those i nvolvi ng blockage of the renal vascular bed. I l lus-
tratively, these compounds are useful to al leviate and cor-
rect cases of edema resulting, for example, from massive
surface burns, and i n the rnanagement of shocl<. For these
purposes, these compounds are preferabl y f i rst admi ni stered
by i ntravenous i nj ecti on at a dose i n the range 10 to 1000
ug. per kg. of body weight or by intravenous infusion at
a dose i n the range 0.1 to 20 ug. per kg. of body wei ght
per minute until the desired effect is obtained. Subse-
quent doses are gi ven by i ntravenous, i ntramuscular, or
subcutaneous injection or infusion in the range 0.05 to
2 mg. per kg. of body we i ght per day.
These prostaglandin derivatives are useful for
treating proliferating skin diseases of man and domesti-
cated animala, including psoriasis, atopic dermatitis,
non-specific dermatitis, primary irritant contact dermatitis,
allergic contact dermatitis, basal and squamous cell
carcinomas of the skin, lamellar ichthyosis, epidermolytic
hyperkeratosis, premalignant sun-induced keratosis, non-
malignant keratosis, acne, and seborrheic dermatitis in
humans and a top 7 c dermat i t i s and mange i n domes t i cated
animals. These ~:ompounds al leviate the symptoms of these
- -2~ -
proliferative skin-diseases: psoriasis, for example, beiDg
alleviated when ~ scale-free psoriasis lesion is noticeably
decreased in thickness or noticenbly but incompletely cleared
or completely clea~ed.
For these purpose~, these compounds are applied topically
as compositions including a suitable pharmaceutlcal carrier,
for example as an ointment, lotion, paste, jelly, spray1 ~r
aerosol, using topical bases such as petrolatum, lanolin, poly-
ethylene glycols, and alcohols. These compounds, as the active
ingredients; constitute from about 0.1~ to about 15% by weight
of the composition, preferably from about 0.5% to about 2%.
In addition to topical administration, injection may be employed,
as intradermally, intra or peri-lesionally, or subcutaneously,
using appropriate sterile saline compositions.
These compounds are useful as antiflammatory agents for
inhibiting chronic inflammation in mammals including the
swelling and other unpleasant effects thereof using methods of
treatment and dosages generally in accord with U.S. Patent Number
3,885,041, issued to G.D. Searle and Co., May 20, 1975.
These 6-keto, iodo-ether, enol-ether, and hemi-ketal
compounds of this invention cause many of the biological
responses known for the older prostaglandin compounds. For
e~ample, 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, sublingually, intravaginally,
~1/ d,r!~ -2 2 -
~ 2871A
buccally, or rec~ally as well as by the usual methods.
Each of these novel analogs is therefore useful in p!ace
of the known prostaglandin F a -~type compounds for at least
o~e of the pharmacological purposes known for them, and is
surprisingly and unexpectedly more useful for that purpose
because it has a different and narruwer spectrum of ~iolog-
ica~ activity than the known prostag1andin, and therefore
;s more specific in its activity and causes smaller and
~ewer undesired side effects than the known prostaglandin~
Moreover, because of its pro~on~ed activity, fewer and
smaller doses of these novel compounds can frequently be
used to attain the desired result.
There are further provided the various processes for
preparing the 5-iodo compounds of formula 1, the enol ethers
of formula ll, the hemi-ketals of formula lll, and the 6-
keto compounds of formula IV.
Thus, for the formula-l, -Ill, and -IV compounds, the
: process comprises the steps of startin~ with a compound of
the formula
OH
W-CH=CH-L-Rt
-C-R4
Q
wherein L, Q, Rl, R4, and X are as ~ fined above, includ-
ing -COOH for R " and wherein ~ is
-23-
~ ~ 2871
ORl3 OR~3 CH2
~'' ~',or <~
CHzOR 13
' 10
wherein R~3 is hydrogen, tetrahydropyranyl, tetra-
hydrofuranyl, 1-ethoxyethyl, or a group of the formula
I H
R 14 -O -C C, -R 17
Rl5 R1ff
wherein Rl4 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 with one, 2, or 3 alkyl
of one to 4 carbon atoms, inclusive, wherein Rl5 and
and R1~ 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, in~lusive, or, when R 15 and Rl~ are
taken together, -(CH2)a- or -(CH2)b-O-(CH2)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 p1us c is 2, 3J or 4, and
wherein R17 is hydrogen or phenyl; and
(a) iodinatir,g and cyclizing to form a compound of the
formula
.. _. .. ..
-24-
.~6~ 2871A
:. i
~ V-O -CH-CH~L R~
I ~~W X
~ X-C-R~
Q
wherein ~ , Ll, ~, Rl, R4, Y, W, and X are as defined above,
(b) subj ecting the product of step "a" to dehalogen-
ation and hydrolyS;5 to form a keto compound of the formula
OH
V~ O
W-C-CH2-L-R
) `'Xll
. ~ X-C-R4
Q
and a hemi-ketal compound of the formula
OH
20 . ~ ~V-O;C-CH~ -L -Rt
J-w X,
_~f~x-C-R4
. ~ Q
wherein J~ L, Q, R1, R4, V, W, X, and __ are as defined
above, and
(c) separating the products.
In this disclosure of the process~for the formula-l,
-III, and -IV compounds, the symbol ~ includes all of
the ring systems of the symbol ~ defined above,together
wIth those in which there i5 a blocking group within the
-25-
~ .
?871A
scope of ~13 at C-ll. The compounds produced, as repre-
sented by formulas X, Xl, and Xll, are inclusive of the
formula~ Ill, and -IV compounds together wieh those in
which there is ~he blocking group from the formula IX
starting material. The compounds with blocking groups are
useful 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 H0
W-CH=CH-L-Rl
~ Xlll
~
X-C-R4
Q
wherein ~ , L, Q, R1, R~, V, W, and X are as defined
above, including -COOH for Rl, and
(a) iodinating and cyclizing to form an iodo compound
of the formula
y-0-CH-~H-L-R~
, ~ I
~ ,~,W
~/C -R 4
o
wherein ~,L, Q, Rl, R~, V, W, and X are as deflned above;
(b) subjecting the product of step "a" to dehydro-
-26-
..
287 lA
~ ~n~
iodination with a tertiary amine or a reagent selected from
the group consisting of sodium or potassium superoxide, sodi-
um or potass;um carbonate, sodium or potassium hydroxide,
sodium or potassium benzoate, sodium or potassium ace~ate,
sodlum or potassium trifluoroacetate, sodium or potassium
bicarbonate, silver acetate, and a tetraalkylammonium super-
oxide of the formula (R12)4N02 wherein R-~2 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-I, -III, and -IV products of this
invention.
In Chart A, the terms are defined as follows:
~ .
~ J ~s
oh OH O CH2
,
, ~ , or
~ H20H
For those instances in which the formula-X, -XI, and -XII
compounds are desired, corresponding to the formula-I, III,
and IV products, the C-ll hydroxyls o~ Xlll are suitably
protected with blocking groups within t ~e scope of Rl3 as
defined above and D then becomes ? as defined
above,
L is
(1) -(CH2~d-C(Rz)2-
-27 -
^" ' ~L~16~36~ 2871A
CHART A
H
~,W -CH=CH-L -R
~ Xlll
X - I R 4
y-~ CH-~H-L-R~
ll l ( b\
OH o
~ ,W -C -CHz L -R 1 ( d )
~ X -1i -R 4
Q ~,l`(c)
$H 1 .
~V-O-C -CHz -L -R
X-C-R4
: 30 Q
-2a-
` ~ 6~ . 287iA
(2) -CH2-O-CH2-Y- or
(3) -CH2CH=CH-
wherein d is zero to 5; R2 is hydrogen~ methy), or
fluoro~ being the same or different with ~he proviso
that one R2 is not methyl when the other is fluoro;
and Y is a valence bond or -(CH2)k-
wherein k ls one or 2;
a iS
O, H H , R8 OH, or R8 OH
wherein R8 is hydrogen or alkyl of one to 4 carbon atoms,
inclusive;
Rl is
(1) -COOR3
(2) -CH20H
(3) -CH2N(Rg )2 or
(4)
NH-N
~N -N
wherein R3 is (a) alkyl of one to 12 carbon atoms,
inclusive, (b) cycloalkyl of ~ to 10 carbon atoms,
inclusive, (c) ara1kyl 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,
inclusive;
O O
(b) ~ -NH-C ~ NH l-CH3,
-
. .
29
~ 6 ~ ~ 2871A
`
{--3
(h) ~ NH-C-CH3,
O
(;) ~ N~-c-NH2
~ ~ CH=N-NH-C-NH2, or
(k)
0
(l) -CH-C-RIo
R
wherein Rlo is phenyl, p-bromophenyl, p-biphenylyl, p-
nitrophenyl, p-benzamidophenyl, or 2-naphthyl;
wherein R1, is hydrogen or benzoyl;
. . .
(m) hydrogen; or
(n) a pharmacologically acceptable cation; and
wherein Rg is hydrogen or alky! of one to 4 carbon
atoms, inclusiveJ being the same or different;
wherein R4 is
(1) ~~~CyH2g-CH~.
3 R~
:
. ~30
~ 287lA
Rs
(2) -C-Z ~ (T)s or
R~
(3) -CH2 ,,CH2CH3
H , C=C ~H
wherein CgH29 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 different, with the proviso that one of Rs and R~
` is fluoro only when the other is hydrogen or fluoro
and the further proviso that neither R5 nor R6 is
fluoro whe-n Z is oxa (-0-); wherein Z represents
an oxa atom (-o-) or CjH2j wherein CJH2j is.. .
a va1ence bond or alkylene of one to 9 carbon atoms,
inclusive, with one to 6 carbon atoms, inclusive
between CR5R6- and the phenyt 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 atoms, inclu-
sive, and s is zero, one, 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-
ferenti
wherein V is a valence bond or -CH2-; wherein W is -(CH2)h-
wherein h is one or 2; and
wherein X is
.
-31-
.
" ~16~628 . 2871A
.
(1) trans-CH=CH-
(2) cis-CH=CH-
(3) -C-C- or
(4) -CH2CH2-.
Examples of alkyl of one to 12 carbon atoms~ inclusive,
are methyl, ethyl/ propyl, butyl, pentyl, hexyl, hepty1,
octyl, nonylJ decyl, undecyl, dodecyl~ and isomeric forms
thereof. Examples of cycloalkyl of 3 to 10 carbon atoms,
: inclusive, which includes alkyl-substituted cycloalkyl, are
cyclopropyl,
2-methylcyclopropyl,
2,2-dimethylcyclopropyl,
2J3-diethylcyclopropyl,
2-butylcyclopropyl,
cyclobutyl,
Z-methylcyclobutyl,
3-propylcyclobuty1,
2,3J4-triethylcyclobutyl,
cyclopentyl,
2,2-dimethylcyclopentyl J
3-pentylcyclopentyl,
3-tert-butylcyclopentyl,
cyclohexyl,
4-tert-buty1cyclohexyl,
3-isopropylcyclohexyl,
2,2-dimethylcyclohexyl,
cycloheptyl,
cyclooctyl,
cyclononyl,
3 and cyclodecyl
32 -
.
-
Examples of ar~lkyl of 7 to 12 carbon atoms, lnclusive, are
benzyl 9
phenethyl,
l-phenyle~hyl,
2-phenylpropyl,
4-phenylbutyl,
3-phenylbutyl,
2-(1-naphthylethyl),
and l-(2-naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of
one to 4 carbon atoms, inclusive are
p-chlorophenyl,
m-chlorophenyl,
o-chlorophenyl,
2,4-dichlorophenyl,
2,4,6-trichlorophenyl,
p-tolyl 9
m-tolyl,
o-tolyl 9
p-ethylphenyl,
p-tert-butylphenyl,
2,5-dlmethylphenyl,
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
known in the art. For example, as to PGF2a see U.S; Pat. No.
3~706,789 (SO Bergstrom et al, December 19, 1972); as to
15-methyl- and 15-ethyl-PGFz~, see U.S. Patent No. 3,728,382
.~he Upjohn Company`, April 17, 1973); as to 16,16-dimethyl~
PGF2a, see U.SO Patent No. 3r903,131 (The Up~ohn Company,
September 2, 1975); as to 16,16-
~ -33-
.
' ~ ! '
$
.
difluoro-PGF~a co~n~oundg, 8ee The Upjohn Company's U.S. Patent
Nos. 3,962,293 (June 8 9 1976) and 3,969,380 (July 13, 1976);
as to 16-phenoxy-17,18919,20-tetranor-PGF2a, see Netherlands
Patent 7306462 (November 13, 1973, The Upjohn Company); as to
17-phenyl-18,19,20-trinor-PGF2a, see U.S. Patent No. 3,987,087
(October 19, 1976, The Upjohn Company); as to ll-deoxy-PGF2a9
see Netherlands Patent 7309856 (January 28, 1974, The Up~ohn
Company); as to PGD29 see U.S. Patent No. 3,767,813 (October 239
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 (~ugust 10, 1976,
The Upjohn Company); as to 3-oxa-PGF2a, see U.S. Patent No.
3,923,861 (December 2, 1975, The Upjohn Company); as to 3-oxa-
17-phenyl-18,19,20-trinor-PGF2a, see U.S. Patent No. 3,931,289
(January 6, 1976, The Upjohn Company); as to substituted
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
Company); as to C-l alcohols, i.e. 2-decar~oxy-2-hydroxymethyl
compounds, see U.S. Patent No. 3,636,120 (January 18, 1972,
The Upjohn Company); as to C-2 tetrazolyl derivatives, see
Pfizer9 Inc.'s U.S. Patent Nos. 3,883,513 (May 13, 1975) and
3,932,389 (January 13, 1976); as to Q2-PGF2a see Derwent Farmdoc
No. 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-PGF2a, see U.S. Patent No.
3,950,363 (April 13, 1976, The Upjohn Company); as to ll~-PGF~a
compounds, see U.S. Patent No. 3,890,371 (June 17, 1975, The
Up~ohn Company)9 as to ll-deoxy-PGFza, see Derwent Farmdoc No.
10795V; as to ll-deoxy~ hydroxy-methyl-PGF2a, see U.S. Patent
No. 3,931,282 (January 69 1976, Syntex (U.S.A.) Inc.) and the
~ -34-
5~ 6~2~
aforementloned U.S. Patent No. 3,950,363; 8S to 16-methylene-
PG~a, see Derwent Farmdoc No. 19594W and Ger. Offen. 2,440,919
(March 13, 19759 Ono Pharmaceutical Co.); as to 17,18-didehydro-
PGF2~ compounds9 see U.S. Patent No. 3,9209726 ~November 18,
19759 The Upjohn Company3; as to 3-(or 4-) oxa-17,18-didehydro-
PGF2~ compounds, see U.S. Patent 3,920,723 (November 18, 19759
The Upjohn Company); as to 15-oxo-PGF~a, see U.S. Patent NoO
3,728,382 (April 17, 1973, The Upjohn Company); as to 15-deoxy-
PGF2a, see Canadian Patent 9619489 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-PGF2a see Netherlands Patent 7208576
(American Cyanamid Company, January 16, 1973); as to ~-homo-
PGF2a compounds, see Japanese Patent 91026/47 (Ono Pharmaceutical
Co., September 27, 1974); and as to 2,2-difluoro-PGF2a compounds
see U.S. Patent 3,987,083 issued October 19, 1976 to The Upjohn
Company.
As to 2-decarboxy-2-amino-PGF2a compounds, see U.S. Patent
No. 4,085,1399 issued April 18, 1978 to the Upjohn Company.
In step "a" of Chart A, the starting material XIII is sub-
jected to iodination and cyclization to yield the formula-l iodo
compounds. For this purpose there is used either an aqueous
system containing iodine, potassium iodide, and an alkali carbonate
or bicarbonate, 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
25~C9 preferably about 0-5~C for 10-20 hr. Thereafter the
- reaction is quenched with sodium sulfite and sodium carbonate and
the formula-l compound separated from the reaction mixture.
In step "b" of Chart A the iodo compound 1 is converted to
the 6-keto compound by contact~ng with silver carbonate and
perchloric acid. The reaction is done in an inert or~anic
medium such as tetrahydrofuran and iR followed with TLC to
J -35
-
determine completlon, normally ln-1S-24 hr. at about 25C.
The reaction is preferably done in absence of light.
In step "c" of Chart A the 6-keto compound IV ~ 3
equilibrated in solution to a mixture of the formula-lll and
formula-lV compounds. This is accomplished merely by preparing
a solution of the formula-lV compound in an
: 30
j
..
~ 35a-
. .
. ' .
.
2~
organic solvent, e.g. acetone or dichloromethane, and let-
ting it stand for several days. The resulting mixture is
concentrated and separated, for example by silica gel
chromatography, to yield the formula-III hemi-ketal.
Step "d" of Chart A provides an alternate route
to the formula-III hemi-ketal. The formula-I iodo compound
is treated in alcoholic solution, e.g. methanol, with
aqueous alkali metal hydroxide, e.g. potassium hydroxide,
at a temperature in the range of 0 to 30 C. for several
hours. After acidification there is obtained a mixture of
the acid form of the formula-I compound and the formula-III
hemi-ketal together with some of the formula-IV compound,
which are separated, for example, by silica gel chroma-
tography or by fractional crystallizationO
The novel compounds of formulas I, III, and IV
wherein Rl is other than -COOH, e.g., the esters wherein
R3 of -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, inclusive, phenyl, or phenyl sub-
stituted with one to 3 chloro or alkyl of one to 4 carbon
atoms, inclusive, are prepared from the corresponding acids
of formulas I, III, and IV, i.e., wherein R1 is -COOH,
by methods known in the art. For example, the alkyl,
; cycloalkyl, and aralkyl esters are prepared by interaction
of sald acids with the appropriate diazohydrocarbon. For
example, when diazomethane is used, the methyl esters
are produced. Similar use of diazoethane, diazobutane~
l-diazo-2-ethylhexane, diazocyclohexane, and phenyldiazo-
methane, for example~ giyes the ethyl~ butyl, 2-ethylhexyl,
cyclohexyl, and benzyl esters, respectively. Of these
esters, the methyl or ether are
- 36 -
mab/l~
~i . 287 lA
.. .. .
preferred~
Esterification with diazohydrocarbons is carried out by
mixing a solution of the diazohydrocarbon in a suitable
inert solvent, preferably diethyl ether, with the acid
reactant, advantageously in the same or a different inert
diluent. after the esterification reaction is complete,
the solvent is removed by evaporation, and the ester
purified if desired by conventional methods, preferably by
chromatography. It is preferred that contact of the acid
reactants with the diazohydrocarbon be no longer than
necessary to effect the desired esterification, preferablv
about one to about ten minutës, to avoid undesired molecular
changes. Diazohydrocarbons are known in the art or can be
prepared by methods known in the art. See, for example
Organic Reactions, John Wiley & Sons, Inc., New York, N.Y.,
Vol. 8, pp. 389-394 (1954).
An alternative method for esterification of the car-
boxyl moiety Or the novel compounds of formulas I, ilI, and
IV comprises Lrans~ormations of the ~ree acid to the cor-
responding silver sal,t, followed by interaction of that saltwith an alkyl iodide. Examples of suitable iodides are methyl9
iodide, ethyl iodide~ butyl iodide, isobutyl iodide, tert-
butyl iodide, cyclopropyl iodide, cyclopentyl iodide~ benzy~
iodide, phenethyl iodide, and the like. The silver salts
are prepared by conventional methods, for example, by dis-
solving the acid in cold di!ute aqueous ammonia, evaporating
the excess ammonia at reduced pressure, and then adding
Lhe stoichiometric amount of silver nitrate.
The phenyl and substituted phenyl esters of the
3 Sormula I, III, and IV compounds are prepared by silylating
-37 -
~62~ 2871A
the acid to protect the hydroxy groups, for example, re~
placing each -OH with -O-Si-(CH3)3. Doing that may also
change -COOH to -COO-Si-(CH3)3. A brief treatment of the
silylated compound with water will change -COO-Si-(CH3)3
back to -COOH. Procedures for th;s silylation are known in
the art and are discussed hereinafter. Then, treatment of
the silylated compound with oxalyl chloride gives the acid
chloride which is reacted with phenol or the appropriate
substituted phenol to give a silylated phenyl or substituted
phenyl ester. Then the silyl groups, e.g., -O-Si-(CH3)3
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-ll products of this in-
vention.
In Chart B the terms D~ Q, R1, R4, V, W, 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 yie1d the formula-l iodo compounds.
In step "b" of Chart B the iodo compound I is con-
verted to the formula-lI enol ether compound by contacting
it with a dehydroiodination reagent. For such reagents
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 step "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-
-38-
2871A
Cha rt B
~OH
~ ~ W-C~CH-L-R
5 . _~)
-C-R7 Xl l l
Q
. (a)
.,
V-O-ICH-CH-L-R
W
~)
~ .
- X - lC - R.. , I
Q
(b )
"'
V- O- C= CH- L-R
X~ R.g, I I
; Q
-39 ~
2871A
sium benzoate, sodium or potassium acetate, sodium or
potassium trifluoroacetate, sodium or potassium bicarbonate,
silver acetate, and a tetraalkylammonium superoxide of the
formula (R12~NOz wherein Rl2 is alkyl of one to 4 carbon
atoms,inclusivel
Of the tertiary amines, preferred amines are
1,5-diazabicyclo[4.~.0]nonene-5 ("DBN"),
1,4-diazabicyclo[2.2.2]octane ("DABCO"),
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, 1680 (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 such 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-
, 30 ition of the product is avoided by pretreating the column
-40-
with triethylamineO
Ester groups such as the p-phenylphenacyl group on the
C-1 carboxyl or 4-bromobenzoate on C-ll and C-15 hydroxyls
are unchanged by the transfor~ations of Chart B, and, if
present on the formula-Xlll stcrting material, are also
present on the formula-ll productO For the final products
of formula 11 which are esters the preferred method of
preparation is from formula-l iodo compounds which are
corresponding esters.
Especially useful 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 hydroxide
in a solvent, preferably an alcohol-water solution, thereafter
lyophilizing (freeze-drying) the mixture to obtain the powdered
product. The starting esters are preferably alkyl esters, of
which methyl or ethyl are especially preferred.
This invention also includes the 1,15-lactones obtained
from the formula-l, -11, -111, and -lV compounds wherein R
is -COOH and Q is H
. OH,
for example
9-deoxy-6,9-epoxy-5-iodo-PGFla 1,15-lactone and
9-deoxy-6, 9-epoxy- ~ -PGFlc~, 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,
41
,
.2~ -
to The Upjohn Company.
It should be understood that although the Charts hav~
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 are desired, optically
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
chromatography, liquid-liquid extraction, and the like,
before proceeding.
To obtain the optimum combination of biological
response specificity, potency, and duration of activity,
certain compounds within the scope of formulas l-lV are
preferred. For example it is preferred that R 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, ls that R3 in -COOR3 be either hydro
~ 42 ~
6 ~ ~ 2871~
gen or alkyl of one to 12 carbon atoms, inclusive~ It is
further preferred that R3 be alkyl of one to 4 carbon atoms3
inclusive, especially methyl or ethyl, for optimum absorption
on administration. For the compounds of formula-ll, it is
preferred that R3 not be hydrogen but rather an alkyl ester
or a salt of a pharmacologically acceptable cation.
For purposes of stability on long storage, it is also
preferred that R3 be amido-substituted phenyl or subs~ituted
phenacyl, as illustrated herein.
As to variations in D it is preferred that D be
~ ~ ' or ~
oh o
As to variaeions in R4, it is preferred that Rg be
n-pentyl
1,1-dimethylpentyl
1,1-difluoropentyl
-CH2-O- ~ or
-C2H4 ~
As to variations in L, it is preferred that L be
-(CH2)3-, -(CH2)g~, or -(CH2)s~, especially -(CH233-.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is further illustrated by, but not
limited to, the following examples.
All temperatures are in degrees centigrade.
Infrared absorption spectra are recorded on a Perkin-
-43-
Elmer*model 421 infrared spectrophotometer. Except whe~
specified otherwise, undiluted (neat) samples are used.
The NMR spectra are recorded on a Varian*A~60, A-60D~
or T-~O spectrophotometer in deuterochloroform solutions
with tetramethylsilane as an internal standar~
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 saturated 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 11~4-diazabicyco~2.2.2]octane.
- "D~U", herein, refers to 1,5-diazabicyclo[5.4.0~un-
decene-5.
"DIBALi', herein, refers to diisobutylaluminum hydride.
"~lorisi)*", herein, is a chromatograpllic magnesium
silicate produced by the Floridin Co. See Fieser et al.
"Reagents for Organic Synthesis" p. 393 John Wiley and Sons,
Inc., New York~ N'Y. (1967).
"TLC"~ herein, refers to 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 contain the desired
product Free of starting material and impurities.
"Concentrating", 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-PGF2a, Methyl
Ester and its 9~-epimer; and 11-OPOX
5 10,11-didehydro-PGF2~ and its 9~-epimer~
A mixture of PGA2~ methyl ester (1.74 9.) and 12 ml.
of tetrahydrofuran is treated at -78 C. with 24 ml. of
10~ DIBAL in to1uene. After one hour's stirring at -78 C,
the mixture is quenched with 100 ml. of tetrahydrofuran-
~; 10 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 brine,
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-PGF2a,
methyl ester~
: 11-deoxy-10,11-didehydro-9~-PGF2~,
methyl ester,
11-deoxy-10,11-didehydro-PGF2a, 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-, R1 is -COOCH3,
R4 is n-pentyl, V is a valence bond, W is
-CH2-, X is trans-CH=CH-, ~ is
~"
-~
. ~H
-45-
2871A
2~
and Q is ~ ).
OH
Refer to Chart A, step "a". A suspension of the formula-
Xlil PGF2~, methyl ester as its 11,15-bis(~etrahydropyranyl)
ether (2.0 9.) in 23 ml. of water is treated with sodium bi-
carbonate (0.7 9.) and cooled in an ice bath. To the re-
sulting solution is added potassium iodide (1.93 9.) and
iodine (2.82 9.) and stirring continued for 16 hr. at about
0 C. Thereafter a solution of s-odium sulfite (1.66 g.)
and sodium carbonate (0.76 g.) in 10 ml. o~ water is added.
After a few minutes the mixture is extracted with chloroform.
The organic phase is washed with brine~ dried over sodium
sulfate, and concentrated to yield mainly the bis(tetra-
hydropyranyl) ether of the title compound; 2.2 9.J an oil.
Hydrolysis of this ether in acetic acid-water-tetrahydrofuran
(20:10:3) yields mainly the title compound, which is further
purified by silica gel chromatography. Rf 0.20 (TL~ on
silica gel in acetone-dichloromethane (30:70)). The mass
spectral peaks for the formula-l compound (TMS derivative)
are at 638, 623, 607, 567, 548, 511, and 477.
Following the procedures of Example 1, but replacing
the formula-XIII starting material with the following forrnula-
Xlll compounds or their C-ll ethers, there are obtained the
corresponding formula-l iodo compounds:
15-Methyl-pGF2a
15-Ethyl-PGF2a
16,l6-Dlmethyl-pGF2a
16,l6-Difluoro-pGF2a
16-Phenoxy-17,18J19,20-tetranor-PGF2a
.
-46 -
; ' ' .
2871A
~ 6~
17-Phenyl-18,19,20^trinor-PGF2a
11-Deoxy-PGF2a
2a,2b-Dihomo-PGF
3-oxa-PGF2~
; 5 3-Oxa-17-phenyl 18,19,20-trinor-PGF2a.
,
Example 2 6-Keto-PGF1a, Methyl Ester (Figure IV:
~ , L, Q, R1, R4, V, W, and X as de-
fined in Example 1).
Refer to Chart AJ step "b". A solution of the formula-
I iodo compound, methyl ester (Example 1, 0.45 9.) in
20 ml. of tetrahydrofuran is treated with silver carbonate
(0.250 9.) and perchloric acid (90~, 0.10 ml.), and stirred
at about 25 C. for 24 hr. The mixture is diluted with 25 ml.
f ethyl acetate and the organic phase~is washed with
saturated sodium carbonate solution and brine, dried, and
concentrated to an oil, 0.41 9. Separation by silica gel
chromatography eluting with ethyl acetate-Skellysolve B
(3:1) yields the formula-IV title compound as a more polar
material than the formula- I starting 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 1740 cm 1 for carbonyl; NMR peaks at 5.5, 3~2-4.8J 3.7,
2.1-2.7 ~
xample 3 9-Deoxy-6,9-epoxy-6-hydroxy-PGFla, Methyl
Ester (Formula III: ~ , L, Q, R1, R4,
V, W, and X as defined in Example 1, and
~ indicates attachment in alpha or beta
configuration).
Refer to Chart A, step "c". A so1ution of the formula-
-47-
6~ 287l~
IV 6-keto compound (Example 2, 0.2 9.) in io ml. of ac~tbne
is left standing at abou~ 25~ C. for 2 days. It is then
concentrated and subjected to silica gel chromatography to
yield the formuia-llltitle compound having Rf 0.50 (TLC on
silica gel in acetone-dichloromethane (~
Examele 4 9-Deoxy-6,9-epoxy-5-iodo-PGFla (Formula 13
and
9-Deoxy-6,9-epoxy-6-hydroxy-PGFla (Formula
lll): ~ , L, Q~ R1, R4, V~ W, and X as
:
defined in Example 1.
Refer to Chart A, step "d". A solution of the formula-
I iodo compound (Exampl~ 1, 1.0 9.) 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
acid sulfate and 50 ml. of water to pH 1.0, saturated with
sodium chloride and extracted with ethyl acetate. The
organic phase is washed with brine, dried over sodium sul-
fate and concentrated to an oil, 1.3 9. The oil i5 subjected
to silica gel chromatography, eluting with acetone-dichloro-
methane (30:70 to 50:50) to yield,first the formula l
compound and later, the formula:lllcompound as a more polar
fraction.
The formula- l cor;?ound is an oil, 0.33 g., having Rf
0.33 (TLC on silica gel in acetone-dichloromethane tl 1)
plus 2~ acetic acid); infra red spectral peaks at 3360,
2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185,
1075, 1050, 1015, 970, and 730 ~m~l; and mass spectral peaks
(JMS derivative) at 681, 625, 606, 569, 535, 479, and 173.
The formula-lllcompound is a solid 0.113 9., melting
3 93-98 C., recrystallized from acetone-Skellysolve 8 and
-48-
~ z ~ 2871A
'
meltiny at 95-105.2 C~; containing no iodine; having R~
0.1~ (TLC on silica gel in acetone-dichloromethane ( 1~1 )
plus 2~ acetic acid) and having mass s~ectral peaks (TMS
derivative) at 587J 568~ 55~J 497, 435, 478, 407, 395, 388,
and 17~.
The formula1llcompound, above, is methylated with
- diazomethane to form the methyl estPr, having idential
properties with the product of Example 3 herein.
Following the procedures of Examples 2 and 4, but
replacing the formula- I iodo compound therein with those
formula-l iodo compounds described subsequent to Example
1, there are obtained the corresponding formula-lV and -lii
compounds. Further following the procedures of Example 3
but utilizlng ~he thus-obtained formula-lV compou nds there
are also obtained the corresponding formula~llcompounds by
that method.
Exam?!e 5 9-Deoxy-6~9-epoxy-~5-pGF~ Methyl Ester rFor~ula
ll: L is -(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
methylene).
Refer to Chart B. A mixture of the formula-l iodo
compound (Example 1, 0.25 g.) 0.25 ml. of 1,5-diazabicyclo-
[4.3.0)nonene-5 (DBN), and 15 ml. of benzene is left
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,
-49-
2871A
~6~ 6 ~ ~
,
and the layers separated. The organic phase is dried over
magnesium sulfate and concentrated to the title compound~
an Oj1J 0.20 9. The product is crystallized from cold
(-10 C.) hexane to yield 0.14 g., 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, 3.62, 3.53, and 0.9 ~;
infrared absorption at 1755 and 1720 cm ~; and mass spectral
peaks (TMS derivative) at 495, 479, 4~9, 423.2724, 349, 199,
and 173.
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-PGFla, Methyl Ester (FormlJla
ll: L is -(CH2)3-, Q is
~ "
H OH,
Rl is -COOCH3~ 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
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 h,. 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 title compound, an oil, 0.9 9. The
product is dissolved in 8 ml. of diethyl ether and crysta1-
lized from cold (-10 C.) hexane containing a trace of tri-
-50~
;~1 6~ ~ 2 8 2871A
ethylamine~to yield crystals o~46 g,, mushy at 25 C. Addi-
tional fractions of crystals, Q.33 g., are combined and sub-
jected to chromatographic puri~ication 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 g~ 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-P~Fla, methyl ester (Example 1,
0.213 9.) in 3 ml. of dimethylformamide is treated with
a fresh solution of potassium superoxide (0.45 9.) in 10
ml. of dimethylformamide containing dicyclohexyl-18-crown-`~
6 (0.75 g.) in an ice bath. A-fter 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
compound~ having the same Rf by TLC as the product of
Example 5.
The above product is subjected to column chromatography
on Florisil~ pretreated with triethylamine (5%)-dichloro-
methane. The product is eluted with ethyl acetate-hexane-
triethylamine (50:50:0.1) to give the title compound,
o.o76 9., having Rf 0.45 (TLC on silica gel in acetate-
dichlorornethane (3:7) using plates pretreated with tri-
ethylamine (5~)-dichloromethane).
Following the procedure of Example 7, but replacing
potassium superoxide with each of the following reagents,
~0 the title compound is likewise obtained:
-51-
~ 6 ~ 8 2871A
`
sodium superoxide
tetramethylammonium superoxide
sodium carbonate
potassium carbonate
sodium hydroxide
potassium hydroxide
sodium benzoate
potassium benzoate
sodium acetate
potassium acetate
sodium trifluoroacetate
potassium trifluoroacetate
sodium bicarbonate
potassium bicarbonate
and
silver acetate.
Example 8 9-Deoxy-6~9-epoxy-5-iodo-PGFla, p-Phenyl-
phenacyl Ester (Formula 1) and
- 9-Deoxy-6,9-epoxy-PGF2a, p-Phenylphenacyl
Ester (Formula ll).
A. A mi,Yture of the formula-l iodo acid compound
(Example 4, Formula 1, 0.20 9.) , p-phenylphenacyl bromide
(0.50 g.)g 0.4 ml. of diisopropylethylamine, and 10 ml.
of acetonitrile is stirred at about 25 C. for 40 min. It
is mixed with dilute aqueous citric acid and brine and
extracted with ethyl 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 colorless oil, 0.20 g.
.
2871A
B. The product of Part A above (0.20 9. ) is treated
wl th 0. 4 ml O of DBN i n 15 ml of benzene at 42 C. for 22 hr.
The reaction mixture is cooled, washed with ice-water con-
taining sodium chloride, dried over magnesium sulfate and
5 concentrated to the second title compound, an oil, 0.12 9.
The oil is crystallized From benzene-hexane. All fractions
are combi n~ti and subjected to chromatographic separation on
a Florisi l column pretreated wi th hexane-ethyl acetate-
triethylamine (80:20:0.5), eluting with ethyl acetate to
10 yield the forrnula-l I compound, an oil. Crystallization
from ether-hexane yields crystals, 0.016 9., m. 71-2 C.
(si nteri ng at 65-7 C.).
Examp ~e ~ 9 - Deox ,v -6, 9 -epoxy -5 - i odo - PGF la~ Methy l Es ter
11,15 -bi s ( 4-Bromobenzoate ) and
9-Deoxy-6,9-epoxy-~S-PGFla, Methyl Ester, 11,
15 -bi s ( 4-Bromobenzoate ) .
A A mi xture of the f ormu l a - I i odo compound ( Examp l e
1, 0.494 9. ) in 5 ml . pyridi ne cooled in an ice bath,
is treated with 0.657 9. of 4-bromobenzoyl chloride
20 with stirring. The mixture is left stirring 16 hr., then
poured into cold 10% sulfuric acid and extracted with ethyl
acetate . The organi c phase i s washed wi th sodi um bi carbonate
solution and brine, driecl, and concentrated. The residue
is subjected to si lica gel chromatography to yield the5-iodo
ti tle compoundJ 0.70 9., a colorless oi l, havi ng NMR peaks
at 7.3-8.0, 5.65, 3.8-5.5, 3.65, and 0.9 ~.
B The product of Part A above (0 20 g.) is treated
wi th 0. 4 ml . of DBN i n 15 ml . of benzene at 42 C. for
22 hr . The react i on mixture i s cooled, washed wi th i ce
30 water, dried, and conc~intrated to the second ti tle compound,
-53-
2871A
6 ~ 8
an oil, 0.18 9
The preparation is repeated with 0.50 9. of the iods
compound, 1 ml. of DBN and 25 ml. of benzene.
The combined products are subjected to chromatographic
5 separation on a Florisi ~column pretreated with hexane-
ethyl acetate-triethylamine (gO:lo:l), eluting with hexane-
ethyl acetate triethylamine (90: 10 :0.25) to yield the second
title compound, 0.37 g., a colorless oil, having NMR peaks
at 7.2-7.8, 5.6, 4.9-5~4, 4.6, 4.0, 3.6, and 0.9 ~.
Example 10 9-Deoxy-6,9-epoxy-~5-PGFla~ Sodium Salt.
A mixture of 9-deoxy -6,9 -epoxy-~5 - PGFIa~ methyl ester
(Example 5, 0.030 g. ) i n 5 ml. of methanol is treated with
9 ml. of 0.01 N NaOH and stirred at about 25 C. for 72 hr.
The solution is then diluted with 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 g. of the enol ether methyl ester there is ob-
tained 0.155 g. 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
i n triethylamine-(5%)-dichloromethane).
Following the procedures of Examples 1, 2, 3, 5, and 7,
but employin~ corresponding starting materials as described
above, there are prepared the formula ~ Ill, and
-IV compounds, namely
3 9-deoxy-6,9-epoxy-5-iodo-PGFla-,
-5l~-
287lA -1-F
.6~6~ ~
9-deoxy-6,~9-epoxy-~5-PGFla-~
9-deoxy-6,9-epoxy-6-hydroxy-PGF~-, and
9-deoxy-6,9~epoxy-6-keto-PGFI type compounds,
in methyl ester form wherein R~ is -COOCH3, having the
following structural features:
16-Methyl-;
16,16-Dimethyl~;
16-Fluoro-;
16,16-Difluoro-;
17-Phenyl-18,19,20-trinor-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-;
17-(m-chlorophenyl)-18,19,20-trinor-;
17_(p-fluorophenyl)-18J19,20-trinor-;
16-Methyl-17-phenyl-18,19,20-trinor-,
16,16-Dimethyl-17-phenyl-18J19J20-trinor-;
16-Fluoro-17-phenyl-18,19J20-trinor-;
16,16-Difluoro-17-phenyl 18,19,20-trinor-;
16-phenoxy-l7Jl8ilgJ2o-tetranor-;
16-(m-trifluoromethylphenoxy)-17J18J19J20-tetranor-;
16-(m-chlorophenoxy)-17J18J19,20-tetranor-;
16-(p-fluorophenoxy)-17J18J19,20-tetranor-;
16-Phenoxy-18,19J20-trinor-;
16-Methyl-16-phenoxy-l8JlgJ2o-trinor-;
13,14~Didehydro- 16-~r-t-hy~ 4-~idehydr
16~l6-Dimethyl-l3J 14-didehydro-;
16-Fluor,o-l~i,14-didehydro-
16J16-Difluoro-13,14-didehydro-; -
17-Phenyl-18,19,20-trinor-13,14-didehydro-;
17-(m-trifluoromethyiphenyl)-18,19,20~trinor-13,1~~
dldehydro-;
2871A~
17-(m-chlorophenyl)-18,19,20~trinor-13,14~di~ehydro~;
17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;
16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-Dimethyl-17 phenyl-18,19,20-trinor-13,1~-dide-
hydro-;
16-Fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-Oifluoro-17-phenyl-18,19,20-trinor-13~14-didehy-
dro ;
16-Phenoxy-17J18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-
13,14-didehydro-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-1~,14-dide-
hydro-;
16-Phenoxy-18,19J20-trinor-13,14-didehydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-13,14-d;dehydro-;
13,14-Dihydro-; .
16-Methyl-13,14-dihydro-;
16,16-Dimethyl-13,14-dihydro-;
16-Fluoro-13,14-dihydro-;
16,16-Difluoro-13,14-dihydro-;
17-Phenyl-18,19,20-trinor-13,14-dihydro-;
17- (m~tr i ~luorcrnethyl phenyl )-18,19,20-trinor-13,14
dihydro-;
17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;
17 (p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;
16-Methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-
dThydro-;
16-~luoro-17-phenyl-18,19J20-trinor-13,14-dihydro-;
16,16-Difluoro-17-phenyl-18,19J20-trinor-1~,14
-56-
~ 2871A-1-t
dlhydro-;
16-Phenoxy~17,18,,19J20-tetranor-13,,14-dihydro-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetr~nor~
1~,14-dihydro-; .
16-(m-chlorophenoxy)-17,18,19,20-tetranor-1~,14~
dihydro-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-1~,14
dihydro-;
16-phenoxy-18,19,20-trinor-1~,14-dihydro-;
16-Methyl-16-phenoxy-18,19,20-trinor-l~J14-dihydro-;
2,2-Difluoro-;
2,2 Difluoro-16-methyl-;
2,2-Difluoro-1~,16-dimethyl-;
2,2-Difluoro-16-fluoro-,
2,2-Difluoro-16,16-difluoro-;
2,2-Difluoro-17-phenyl-18~19,20-trinor-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-
trlnor-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;
2,2-Dirluoro-17-(p fluorophenyl)-18,19,20-trinor-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16,16-dimethyl-17-phenyl-18~19,20-trinor-;
2,2-Difluoro-16-fluoro-17-phenyl--8,19,20-trinor-;
2,2-Difluoro-16,16-~ifluoro-17-phenyl-18,19,20-trinor-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-;
-2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,1~,20-
~etranor-;
2,2-Difluoro 16-(m-chlorophenoxy)-17,18,19,20-.
tetranor~;
2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-
-57-
.
'
,
- ` ' l.~L6i~il62:~3 2871A-l-F
tet ranor-;
2,2-Dt fluoro-16-phenoxy-18,19,20-trinor-; ;
2,2-D i f 1 uoro-16-methy 1 -16-phenoxy-18,19J20- tr i nor-;
2,2-D i f luoro-16-methyl -16 phenoxy-18,19,20-trinor-;
2,2-Di fluoro-16-methyl-13,14-didehydro~;
2,2-Difluoro-16,16-dimethyl-13,14-didehydro-;
2,2-Di fluoro-16-f luoro-1~,14-didehydro-;
2,2-Difluoro-16,16-difluoro-13,14-didehydro-;
2,2-Di fluoro-17-phenyl-18,19,20-trinor-13,14-dide-
hyd ro-;
2,2-Di f luoro-17- (m-tri fluorornethylphenyl )-18,19,20-
tr7nor-13,14-didehydro-;
2,2-Difluoro-17- (m-ch1orophenyl)-18,19,20-trinor-13,14-
- didehydro-;
2,2-Di fluoro-17- (p-fluorophenyl )-18,19,20-trinor-13,14-
didehydro-;
2,2-Di fluoro-16-methyl-17-phenyl-18,19,20-trinor-
1~,14-didehydro-;
2,2-Di fluoro-16,16-dimethyl-17-phenyl -18,19,20-trinos-
13,14- d i dehyd ro-;
2,2,16-Trifluoro-17-phenyl -18,19,?0-trinor-
13,14-didehydro-;
2,2,16,16-Tetraf luoro-17-phenyl -18,19,20-tri nor-
13,14-didehydro-;
- 25 2,2-Difluoro-16-phenr~ y-17,18,19,20-tetranor-1~,14-
didehydro-;
2,2-Difluoro-16-(rn-trifluor~nethylphenoxy) 17,18,1~3,20-
tet ranor-13,14-d i dehyd ro-;
2,2-D i f luoro-15- (rn-ch lorophenoxy)-17,18J19,20~etra-
nor - 13,14- d i deh yd ro-;
-58 ~
,
-
2871A Yl -F
i2~
.
2~2 -a ifluoro-16-phenoxy-18,19,20-trinor 13,14-did~-
hydro-;
2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-
13,14-didehydro~;
2,2-Difluoro-13,14-d;hydro-.;
2,2-Difluoro-16-methyl-13,14-dihydro-;
2,2-Difluoro-16,16-dimethyl-13,14-dihydro-;
2,2,16-Trifluoro-13,14-dihydro-;
2,2,16,16-Tetrafluoro-13~14-dihydro-;
2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-
dihydro-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18~19,20-
trinor-13,14-dihydro-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-
1~,14-dihydro-;
2,2-Difluoro-17-(p-fluorophenyl)-18,19~20-trinor-
13,14-dihydro-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-
13,14-dihydro-;
2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-
trlnor-13,14-dihydro-;
. 2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-
dihydro-;
2,2~16,16-Tetraflu~~o-17-phenyl-18,19,20-trinor-
13,14-dihydro-;
2,2-Difluoro-16-phenox.y-17,18,19,20-tetr~nor-13jl4-
dihydro-;
2,2-Difluoro-16-~m-trif1uoromethylphenoxyj-
17,18,19p20-tetranor-13914-dihydro-;
2~2-~ifluoro-16-(~-chlorophenoxy~-17,18,19920-
,;
.
.
2~37 lA -1 - F
.
tetranor-13J14-dihydro-;
2,2-D.ifluoro-16-tp-fluorophenoxy)-17,18,19,20-
tetranor~l~J14-dThydro-; -
2,2-Dlfluoro-16-phenoxy-18,19,20-trinor-1~,14-
dihydro~;
2,2~Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-
13,14-dihydro ;
16-Methyl cis-13; r'
16,16-Dimethyl-cis-13~;
16-Fluoro-cis-13-;
16,16-Difluoro-cis-13-;
17-Phenyl-18,19,20-trinor-cis-13-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;
: 17-(m-chlorophenyl)-18,19,20-trinor-cis 13-;
17-(p-fluorophenyl)-18~19,20-trinor-cis-13-;
16-Methyl-17-phenyl-18,19,20-trinor-cis-13-;
16,16-Dimethyl-17-phenyl-18,19,20-trinor~cis-13-;
16-Fluoro-17-phenyl-18,19,20-trinor-ci$-13-;
16~16-Difluoro-17-phenyl-18,19,20-trinor-cis-13-;
16-Phenoxy-17,18,19,20-tetranor-cis-13-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-
cis.-13-;
16-(m-chlorophenoxy)-17,18J19,20-tetranor-cis-13-;
16-(p-fluorophenoxy~-17,18,19,20-tetranor-cis-13-;
16-Phenoxy-18,19,20-trinor-cis-13-;
16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-.
2,2-Difluoro-cis-13-;
2,2-Dtfluoro-16-methyl-cis-13-;
2,2-Difluoro-~6,16-dimethyl-cis-13-;
2,2-Difluoro-16-fluoro-cis-13-;
. -60-
'' . '
.
~ 2871A-1-F
.
. _.. .
2,2-Difluoro-16916-difluoro-cis-13~;
2,2-Difluoro-1.7-phenyl-18,19,20-trinor~cis~1.3-;
2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-
trinor-cis-13-;
2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-
cis-13-;
2j2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-cis 13-;
2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-cis-
13-;
10 2,2-Difluoro-16,16-dimethyl-1~-~hc-,y'-18,19,20-
trinor-cis-13-;
2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-
cis-13-;
2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trlnor-
cis-13-;
2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-;
2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-
tetranor-cis-13-;
2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-
tetranor-cis-13-;
2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-
tetranor-cis-13-;
2~2-Difluoro-16-phenoxy-18~19,20-trinor-cis-13-;
2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-
cTs-13-;
- 2~2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-
c1s-13-;
3-Oxa-;
3-Oxa-16-methyl-;
3 3-Oxa-16,16-dimethyl~;
-6i -
6;~ 2871A -l -F
3-Oxa-16-fluoro~
3-Oxa-16,16-dif1uoro-;
~-oxa-l7-phenyl-l8~lg~2o-trlnor-;
3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trino~-;
3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-;
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor~;
3-Oxa-16-methyl-17-phenyl-18J19,20-trinor-;
3-oxa-l6~l6-di~ethyl-l7-phenyl-l8~l9~2o-trinor-;
3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-;
3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-;
- 3-Oxa-16-phenoxy-17,18,19,20-tetranor-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetra-
nor-;
` 3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-te~ranor-;
3-Oxa-16-(p-fluorophenoxy)-17,18,19J20-tetranor-;
3-Oxa-16- phenoxy-18,19,20-trinor~;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-;
~Oxa-13l14-didehydro-;
3-Oxa-16-methyl-1~,14-dtdehydro-;
3-Oxa-16,16-dimethyl-13,14-didehydro-;
3-Oxa-16-fluoro-13,14-didehydro-;
3-Oxa-16~i6-di f1uoro-1~14-didehydro-;
3-oxa-l7-phenyl-l8~l9~2o-trinor-l3~l4-didehydro-;
3-Oxa-17-(m-trifluoromethylphenyl)^18,19,20-trinor-
13,14-didehydro-;
3-Oxa-17-(m-chloropheny1)-18,19,20-trinor-13,14-
didehydro-;
3-Oxa-17~(p-f1uorophenyl)-18,19,20-trinor-13,14
dldehydro~;
:: 30 ~-Oxa-16-methyl-17^phenyl-18,19,20-trinor-13,14-
,' .. .
-62 -
287 lA -1 -F
dTdehydro~;
3-Oxa-16~16-dimethyl-17-phenyl-18,19,20-trinor~
13,14-d;dehydro~;
3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-
didehydro-;
3-Oxa-16,16-difluoro-17 phenyl-18,1g,20-trinor-
13,14-didehydro~;
3-Oxa-16-phenoxy-17,18,19,20-tetranor-13~14-
didehydro-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-
tëtranor-13,14-didehydro-;
3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-
13,14-didehydro-;
3-oxa-l6-pheno~y-l~3~l9~2o-trinor-l3~l4-didehydro-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-
didehydro-;
3-Oxa-13,14-dihydro-;
3-Oxa-16-methyl-13,14-dihydro-;
3-Oxa-16,16-dimethyl-13,14-dihydro-;
} Oxa-16-fluoro-13,14-dihydro-;
~Oxa-16,16-difluoro-13,14-dihydro-;
".' 3-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-;
3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-
13,14-dihydro-;
3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-
dihydro~
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-
~ dlhydro-;
~-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-
dlhydro-;
-6
1'16~62~3 2~71i4-1-F
.
3~0xa-16,16-Dimethyl-17-phenyl-lB~19,23-trinor-
13,14-dThydro-;
3-Oxa-16-fluoro-17-phenyl-18,~,2~-~r;nor~ 14-
dihydro-;
3-Oxa-16,16-difluoro-17-phe~yl~18,19, ~-trîno~-
13,14-dihydro-;
3-Oxa-16-phenoxy-17,18,19,20-te~ranor-1~,14-
dThydro-;
3-Oxa-16-(m-trifluoromethyl~h~noxy3-17,18,19920
tetranor-13,14-dihydro-;
3-oxa-l6-(m-chlorophen~xy~ Jlg~2~-tetranor- ~~~~~
13 J 14-dihydro-;
3-Oxa-16-(p-fluorophen~xy)-17,1B,19,20-te~ranor-
13,14-dihydro-;
3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihyd~o-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-tr;nor-
13,14-dihydro-;
3-Oxa-cis-13-;
3-Oxa-16-methyl-cis~
3-Oxa-16,16-dimethyl-cis-13-;
3~0xa-16-fluoro-cis-13-; .
3-Oxa-16,16-difluoro-cis-13-;
3-Oxa-17-phenyl-18,19,~0-trinor-cis-13-;
3-Oxa-17-(m-trifluor~methylphenyl)-18,19,20-trinor-
: 25 cis-13-;
~-Oxa-17-(m-chlorophenyl)-1~ 0-tr;nor-cis-13-;
3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-cis-13--;
3-Oxa-16-methyl-17-phenyl-~ g,2o-trinor-cis-l3-;
3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-
1~-;
I
287 lA -1 -F
. . _ . ..
3-Oxa-16~fluoro-17-ph~nyl-18,19,20-trinor-cis-13-;
3-Oxa-16,16-difluoro-17-phenyl-18,19~20-trinor-cis-1
3~0xa-16-phenoxy-17,18,19,20-tetranor-cis-13-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19320-
tetranor~c i s~l~o 9
3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-
13-;
3-Oxa-(p-fluorophenoxy)-17,~8,19,20-tetranor~cis-1~ ;
3-Oxa-16-phenoxy-18,19,20-trinor-cis-13-;
3~0xa-16-methyl~16-phenoxy-18,19,20-trinor-cis-13-;
3-oxa-l3sl4-dihydro-trans-l4Jl5-didehydro-;
3~0xa-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-;
3-Oxa-16,16~difluoro-13,14-dihydro-trans-14,15-
didehydro~
3-Oxa-I7-phenyl-18,19,20-trinor-13,14-dihydro~trans-
14,15-didehydro-;
3-Oxa-17-(m-trifluorumethylphenyl)-18,19,20-trinor-
13,14-dihydro-trans-14,15-didehydro-;
3-Oxa-17-(m-chlorophenyl)-18~19,20-trinor-13,14-
dihydro-trans-14,15-didehydro-;
3-Oxa-17-(p-fluorop!.enyl)-18,19,20-trinor-13,14-
dihydro-trans-14,15-didehydro-;
3 -Oxa-16-methyl -17-phenyl -18,19J20-trinor-1~,14-
dihydro-trans-14,15-didehydro-;
:~ 3-Oxa-16,16-Dimethyl-17-phenyl-18,19,20-trinor-
13,14-dlhydro-trans-14,15-didehydro-;
: 30 3-Oxa-16-fluoro-17-phenyl-18,19,29-trinor-13,14-
,
-65
287 lA
dihydro-trans-14,15-didehydro-;
,
~-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor~
13,14-dihydro-trans-14,~5-didehydro-;
3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14
dihydro-trans-14~15-didehydro-;
3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19~20-
tetranor-13,14-dihydro-trans-14,15-dihydro-;
3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-
13,14 dihydro-trans~14,15-didehydro-;
3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor~
_ . . . _ _ . . .
13~14-dihydro-trans-14,15-didehydro-;
3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-
~rans-14,15-d~idehydro-;
3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-
13,14-dihydro-trans-14,15-didehydro-.
Likewise following the procedures of Examples 1, 2, 3,
5, and 7, but employing correspond;ng starting materials as
described above, there are obtained the formula -I/ -II,
-III, and -IV compounds, namely
9-deoxy-6,9-epoxy-5-iodo- PG Fl a~
: 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 R1 is -COOCH3, havin~ the
following structural features:
: 2,3-Didehydro-;
2,2-Dimethyl-;
. 2a,2b-Dihomo-;
4-Oxa-4a-homo~;
7a-Homo~;
- -66 -
. 1~6~ 6Z~.~ 2871A-1-F
_ . _ . . ....... . _ . .. _ ... _
ll-Deoxy-10,11-didehydro-;
11-Keto-;
ll-Deoxy-;
ll-Deoxy-ll-methylene-;
11-Deoxy-ll-hydroxymethyl-;
15~-;
15-Keto-;
15-Deoxy-;
15-Methyl-15(S)-;
15-Methyl-15(R)-; and
17,18-Didehydro-
. _ .
,-67-
A~pendix
1. 2-Decarboxy-2-amino PGF Compounds
Chart G, below, shows the steps for preparing start
ing materials of formula Xlll for Chart A wherein Rl is
-CH2N(R3)2o Accordingly in Chart G, the formula Cl PGF2~-
or ll-deoxy PGF2~-type free acid is transformed to the
various 2-decarboxy-2-aminomethyl or 2-decarboxy-2-(sub-
stituted amino)methyl-PGFa- or ll-deoxy-PGFa-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 anhydrides 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~
Chart G
HO
, C ~2 - Z ~ Qtl
~ Cl
RB Y 1 -11--Il~R7
M 1 L
.. . ~
n o
HO
~, ,CH2 -Z 1 -C -0 -C -R I
~ Cll
Y I -C--C -R7
R8
Ml L1
/ O
H0~ ll
~"C H2 - Z ~ - C -IYH2
\~ C l l l
F~B I I h
I M, L
.
.,
HO ~
. ~ ~,CH2-Zl~CH2NH2
.. . ~ ' CIV
, Y 1 -C--C~R7
R~3 11 ,1
Ml L
\~ H CH2 -Z I -C -N=N=~i ~V
` Y 1 -C--C -R7
11 11
R~3 Ml L
-69 -
.
Cha r t G ( cont i nued
HO CH2 - Z ~ -NH -COOR 1
~ ' CVI'
\~ ~ -R7
R,~ Ma Ll .
.' ' ~
HO -
- 10 ` CH?-Z~-NH2 . . ..
S l~ .cvll
R Y 1 ICl 1l -R7
.. ~
'" .
~ ,CH2-Zl-NHL2
<~ , CVIII
Y ~ -C--C -R7
R8 1 1 ll .
Ll M~
~0
~C~12 -Z 1 -NL2COOR
<~ CIX '
Y I fi--C -R7
R8 MS L
,, ' 1 ' ,
HO
, CH2-Zl-NL2L9
~ CX
~ y~ 7
R~ Ml Ll
~70 -
:, --
trTethylam7ne) Reaction diluents include water in com^
bination ~ith water miscible organic solvents (e~g., tetra-
. .
hydrofuran). This mixed anhydride is then transformed to
either the formula Clll PG-type, amide or formula CV PG-type~
azide.
tor prepara~ion of the PGF2a-type, amide ~formula Clll~
the formula Cll mixed acid anhydride is reacted with liquid
ammonia or ammonium hydroxide.
Alternatively, the formula Clll compound is prepared
from the formula Cl free acid by methods known in the art
for tr3nsformation of carboxy acids to corresponding car-
boxyamides. For example, the free acid is transformed to
a corresponding methyl ester (employing methods known in
the art; e.g., excess etheral diazo~ethane)~ and a methyl
ester thus prepared is transformed to the formula Clll amidé
employing the methods described for the transformation of
the formula Cll mixed acld anhydride to the formu1a Clll
amTde.
Thereafter the formula C1V 2-decarboxy-2-aminomethyl-
PGF2a- or 11-deoxy-PGF2a-type compound is prepared from
the formula Clll compound by carbonyl reduction. Methods
known in the art art are employed in this transformation
For example, lithium aluminum hydride is conveniently
employed.
The ~ormula Cll compound is alternatively used to pre-
pare the formula CV azide. This reaction is conveniently
cat-ried out employing sodium azide by methods known in the
art, See for example, Fieser and Fieser, Reagcnts for
Organlc Synthesis vol, 1, pgs. 1041-1043, wherein reagents
3~ and reactlon conditlons for the azide ~ormation are dis-
.
-71 -
cussed.
Flnally, the formula CVI urethane is prepared from the
formula CV a2ide reaction with an alkanol, aralkanol, pheno1,
or substituted phenol. For example, when methanol is em-
ployed the formula CVI compound is prepared wherein Rl ismethyl. This formula CVI PG-type product is then employed
in the preparation of either the formula CVII or CVIII pro-
duct.
In the preparation of the formula CVII primary amine
from the formula CVI urethane, methods known in the art
are employed. Thus, for example, treatment of the formula
CVII urethane with strong base at temperatures above 50~ C.
are employed. For example, sodium potassium or lithium
hydroxide is employed.
Alternatively, the formula CVI compound is employed
in the preparation of the formula CVIII compound. Thus,
when Ll is alkyl the formula CVIII compound is prepared
by reduction of the formula CVI urethane wherein R1 is
alkyl. For this purpose, lithium aluminum hydride is
the conveniently employed reducing agent.
Thereafter, the formula C~lll product is used to
prepare the corresponding CIX urethane by reaction of the
formula CVIII secondary amine (wherein L2 is alkyl3 with an
alkyl chloroformate. The reaction thus proceeds by methods
known in the ar!~ for the preparation of carbamates from
corresponding secondard amines. Finally, the formula CX
product wherein L2 and L3 are both alkyl is prepared by
reduction of the formula CIX carbamide. Accordingly,
methods hereinabove descrlbed for the preparation of the
formula CYIII compound from the formula CVI compound are
-72-
6~
.
used. Thus~ Chart A provides a method whereby each of the
various PGF2a- or 11-deoxy-PGF2~-type products vf this
invention is prepared. Optional ly, the varlous reaction
steps herein may be proceeded by the employment of block-
S ing,groups according to R~oJ thus necessitating their sub-
sequent hydrolys7s in preparing each of the various products
above. Methods described hereinabove for the introducti~n
and hydrolysis of blocking groups according to Rlo are em-
ployed.
Finally, the processes described above for convertiny
the formula Cll compound to the formula CV compound and
the various compounds thereafter, result in shortening
the 8a-side chain of the formula Cl compound by one carbon
atom. Accordingly, the formula Cl starting material should
be selected so as to compensate for the methylene group
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.
In Chart G,
Yl is trans-CH=CH-j -C-C-, or -CH2CH2-;
wherein Ml is
Rs OH
or
R5 OH
wherein R5 is hydrogen or methyl;
. wherein L1 is
R9 R4,
- R9 R4,
or a mixture of
. R3 R4
and
R3 R4~
25 wherein R3 and R4 are hydrogen, methyl, or fluoro, ~eing
the same or different, with the proviso that one of R3
and R~ is fluoro only when the other is hydrogen or fluoro;
wherein ll Is
(1) cis-CH=CH-CHz-(CH2)9-CH2-.
3 (2) cis-CH=CH-CH2-(CH2)9-CFz-,
-74-
(3) cis-cH2-cH=cHv(c~2)9-cH2~,
(4) -(CH2)3-(CH2)g CH2-,
(5) -(CH~ )3- (CHz)9-CF2^,
(6) -CH2-O~CH2-(CH2)9 CH2-~
~7) -C-C-CH~(cH2)9-cH2-9
(8) -CH2-C~C-(CH2)g CHz-,
~9) ~ CH2 (CH2) , or
(lo) ~ o-(CH2)9-,
w~erein g is one, 2, or 3;
where i n R7 i s
~1) -(CH2)m-CH9~
(2) -o ~ ( )5
~3) -CH2 ~ (T~s ~ - -- _
?5
~herein m is one to 5, inclus ive, T is chloro, fluoro,
tri fluoromethyl, alkyl of one to 3 carbon atoms, inclu-
slve, or a1ko~y of one to 3 carbon atoms, inclusive, and
s is zero, one, 29 or 3, the various ~'s betng the same
30 or dl fferentg with the provlso that not more than th~o
75 -
T's are other than alkyl, with the further proviso that
R7 is
_~( T ) S
wherein T and s are as defeind above, only when R3 and R~
are hydrogen or methyl, being the same or different; and
wherein Xl is
-CH2NL2L3, wherein L2 and L3 are hydrogen, alkyl
of one to 4 carbon- atoms, inclusive, or -COORl, wherein R
is as defi ned above -
3n
76
6;~:~
Preparation 2: 2-Decarboxy-2-azidomethyl-PGF , or 2-nor-
2~
PGF2a, azide (Formula CV: Zl is CH=CH-(CH2)3 or C~=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)O
A. To a cold solution 10C.) of PGF2a ~7.1 g.),
125 ml. of acetone, 10 ml. of water, and 2.2 g. of triethyl-
amine is added with stirring 3.01 g. of isobutylch~o~o~-
formate. The mixture is stirred at 0C. 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 with 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 30C.,
to yield 2-nor-PGF2a, azide.
B. 2-Decarboxy-2-azidomethyl-PGF2a, is prepared by
the ~ollowing reaction sequence:
cb/ - 77 -
~ 0 6 ~
- (1) A solution of t-butyldimethylsilyl chloride ~10 9.~,
imidazole ~9.14 9.), and PGF2a (3 9.) in 12 ml. ~f d;methyI-
formamide are ~agnetically stirred under nitrogen atmo5phere
for 24 hr~ The resulting ~ixture is then co~led in an ice
bath and the reaction quenched by addition of ice water.
The resulting mixture is then diluted with 150 ml. of
water and extracted with diethyl ether. The co~bined
ethereal extracts are then washed with water, saturated-
ammonium chloride, a sodium chloride solution~ and ther~-
after dried over sodium sulfa~e. Solvent is removed under
vacuum yielding PGF2,s, t-butyldimethylsilyl ester,
9,11,15-tris-(t-butyldimethylsilyl ether). NMR absorptions
are observed at0.20, 0.~0, o.8~, o.87, o.8g, 1.07-2.50,
3 10-4.21, and 5.38 ~. Characteristic infrared absorptions
are observed at 970, 1000, 1060, 1250, 1355, 1460, 1720,
and 2950 cm. 1.
(2) To a magnetically stirred suspension of lithium
aluminum hydride (7.75 9.) in 18 ml. of diethyl ether is
added dropwise at room temperature over a period of 12 min.
8.71 9. of the reaction product of part (1~ above in 40 ml.
-of diethyl ether. After stirring at ambient ternper~ture for
one hr., the resulting product ;s cooled in an lce water
bath and saturated sodium sulfate is added drop~Jise until
the appearance of a milky suspension. The resulting pro-
duct is coagulated with sodium sulfate, triturated with
diethyl ether~ and the solvent is removed by suction fil-
tration. Concentration of the diethyl ether under vacuum
yfelds 7 014 g. of 2-decarboxy-2-hydroxymethy~-pGF2a~
9,11,15-tris-(t-butyldimethylsilyl ether) N~R absorp-
tfons are observed at 0.03, 0.82, o.87, 1.10-2 .60, 3.30^
-78-
.
62~3
.
4.30, and 5,37 ~, Characteristic infrared absorptions are
observed at 775, B40J 970., 1065, 1250, 1460, 2895, 299~7
and 3350 ~mO 1,
(3) p-Toluenesulfonyl chloride [3.514 9.), pyridine
~44 ml.)9 and the reaction product of subpart (2), 7.014 9.,
are placed in a freezer at -20 C. for 3 days. Thereafter,
7~200 9. of 2-dec~rboxy-2-p-toluenesulfonyloxymethyl-pGF
9,11,15-tris-(t-butyldimethylsilyl ether), is recovered.
NMR absorptions are observed at 0.10, 0.94, 0.97, 1.10,
2.50, 2.50J 4.03, 3.80-4.80, 5.45, 7.35, and 7.80 6. Infra-
red absorptions are observed at 775, 970, 1180, 1190, 1250J
1~60~ 1470, 29001 and 299~ cm.~~.
(4) The reac:tion product oF subpart (~) (2.13 g.) is
placed in 42 ml. of acetic acid, tetrahydrofuran, and
water (3:1:1) containing 0.25 ml. of 10 percent aqueous hy-
- drochloric acid. The reac~ion mixture becomes homogeneous
after vigorous stlrring for 16 hr at room temperature. The
resulting solution is then diluted with 500 ml. of ethyl
acetate; washed with saturated sodium chloride and ethyl
acetate; dried over sodium sulfate; and evaporated under
reduced pressure, yielding 1.301 9. of an oil. Crude pro-
duct is chro~atographed on 150 9. of silica gel packed
with ethyl acetate. Eluting with ethyl acetate yields
0.953 g, of 2-decarboxy-2-p-toluenesulfonyloxym ethyl-PGF2~.
(5) The reaction product of subpart (4)J ~0.500 9.)
;n 5.0 mlO of dimethylformamide was added to a stirred sus-
pension of sodium azide (1.5 9.) in 20 ml. of dimethylfor~
mamide. Stirring is contfnued at ambient temperature for
3 hr. The reaction mixture is then diluted with water
~0 (75 ml.), extracted with dlethyl ether (500 ml.), and the
-79 -
,'
the etheralextracts washedsuccessively w;thwater, sa~u-
rated sodiu~,chloride, and dried cversodiu~ sulfate. Re~oval
ofthe diethyl etherunder reduced pressure y;elds o.~64 9. of
2-decarboxy-2-azid~nethyl-PGF2Q. A characteristic azido
infrared absorption is observed at 2~10 cm.~l.
,. .
` ! . " ~
-80-
Preparation 3: 2-Decarboxy-2-aminomethyl-PGF2~ ~Formula
CXXV: Zl i5 CiS-C~=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-butyl).
Crude 2-decarboxy-2-azidomethyl-PGF2~ ~Example 2,
0.364 g.) in 12 ml. of diethyl ether is added to a magnetically
stirred suspension of lithium aluminum hydride (0.380 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 ambient 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 filtration. The filtrate is then dried with sodium sul-
c-/ - 81 -
6~
fate, and evaporated under reduced pressure to yield 0,30~ 9.
of a slightly yellow oil. This oil (100 mg .) is then pur~
ified by preparative thin layer chromato3raphyJ yieldlng
42 9. of title product. NMR absorptions are observed at
0.90, 1.10-2.80, 3.28, ~.65-4.25, and 5.45 ~O Charaeter;s-
klc tn~rared absorptions are observed at 970, 1060, 1460,
2995, and ~400 cm.~a, The m3ss spectru~ shows parent peak
at 699.4786 and other peaks at 628, 684, 595, 217, and
27~.
i0
~0
-82-
.
z~
11~ 1,15-Lactones
As discussed above, the 1,15-lactones of the formula-l,
-11, -111, and -lV compounds are prepared by analogous
methods to those 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 hydroxy group with which the
carboxy function can lactonize. Thus, when more than one
hydroxy group is present, as for example in PGF2~, those
hydroxyl groups not required for lactone function are
optionally derivatized prior to lactonization to require
formation of the desired lactone. Selective methods for
selective deri~atization of all but one hydroxy of a
prostaglandin or prostaglandin analog which contains two or
more hydroxys are known in the art. Suitable derivatives
are the ~ cyclic phenyl- or butyl-boronates of 9a,11a-
cb/ ~ 83 -
`; ``
or 9~ dihydroxylated prostaglandins and prostaglandin
I analogs, acylates such as acetate, silyl ethers such as
¦ trimethylsilyl-, t-butyldimethylsilyl-, and triphenylsilyl
and the like. Such functional derivatives are known in the
prostaglandin art and are used with stereoselectivity or
where stereoselectivity is not achievable, with careful
purification of the mixtures produced, -to obtain the
desired functionally protected prostaglandins,and prostag-
landin analogs as exemplified further in the examples~
Optionally if desired, one or more hydroxy groups are pro-
tected by oxidation to a ketone before or after lactoni-
zation. After lactonization, the ketone is reduced again
to produce a free hydroxy group of the same configuration
or of opposite configuration to that originally present.
However, it is not essential in all cases to
protect hydroxy groups which may be present but are not
desired to participate in the lactone formation. Lactone
formation occurs at different relative rates with differ-
ent. hydroxy groups depending on the stereochemlstry,
steric bulk in the Yicinity 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 PGF
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. As a corollary,
in order to make a lactone with a hindered hydroxy group
such as 15-methyl-15-hydroxy- or 16,16-dimethyl-15-
hydroxy-~ it is essential that other hydroxy groups
which may be present be protected. It is also necessary
,~ ~
- 84 -
mab/
,.
to extend the duration of the reaction until analysis of
the reaction mixture indicates that some desired product
is formed.
Prostaglandins known in the art as their lower
alkyl (e.g. 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 prostaglandin 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, for example by using the process
of U.S. patent No. 3,761,356, issued September 25, 1973
to The Upjohn Company.
With these limitation~, and options for pro-
tecting concommitant by present hydroxy groups, select-
ively hydrolyzing the functionally protected hydroxy
groups without hydrolyzing the desired lactone, separating
undesired products from those desired, and modi~ying the
lactones by subsequent chemistry obvious to those skilled
in the art, such as oxidatlon, reduction, alkylation and
the like, it is possible to prepare the l,9-, l,ll-, and
1,15-lactones of prostaglandins and of prostaglandin
analogs 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 et 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 further
herein. Optionally other methods 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, ~661(1974).
.
~ - 85 -
; mab/~
. . ..
Preparation 4: PGF2~, 1,15-lactone
A solution of 5.5 g of PGF2a and 1.7g ~ of l-butane-
boronic acid in 150 ml of methylene chloride was heated at
reflux for 15 minO Then about half of the methylene chloride
was removed by distillation at atmospheric pressure. Addi-
tional methylene chloride was added to bring the volume ka~X
to the original 150 ml. This cycle-distillation of methylene
chloride followed by replacement with fresh 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 arld treated with 5.128 g of 2,2'-dipyridyl
disulfide followed by 6.27 g of triphenylphosphlne. After
18 hours at 25 under a nitrogen atmosphere, thin layer
chromatographic analysis of an aliquot ~solvent: lQ 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
atmosphere. After the addition was complete, 100 ml of
xylene was distilled off and the
cb/ - 86 -
~6~6~8
solution was heated at reflux ~or 24 hours. rl~he reaction mixture was
then cooled and the xylene was removed in vacuo (35 bath temperature)
to give a residue. The residue was taken up in 500 ml oE tetrahydro-
furan and treated with 10 ml of 30% hydrogen peroxide and 100 ml of
saturated aqueous sodium bicarbonate. The three-phase mixture was
stirred vigorously for 30 min. at 25, then concentrated in vacuo to
give a residue. The residue was taken up in brine/ethyl acetate and
extracted thoroughly with ethyl acetate. The combined organic layer
was washed with three portions of lN aqueous 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 chromatographed on 500 g of Mallinckrodt acid-
washed CC-4 silica. The column was packed with 25% et'hyl acetate/hexane
and eluted (100 ml fractions) with 50% ethyl acetate~hexane. Fractions
26-40, containing the product and no prostaglandin~related impurities,
,were ccmbined. ~he desired product was crystallized from 40'mI'of 1:1'
ether~hexane~ thereby affording pure lactone, M.P. 110-111.
The lactone exhibited infrared absorption at 3500, 3370, 3290,
3000, 1700, 1320, 1310, 1290, 1260, 1105, 1080! 1055, 970, and 730 cm 1
and NMR peaks at 6.00-5.75 (vinyl; multiplet; 2H), 5.75-4.95 (vinyl
and C-15H; multiplet; 3H), 4.30-3.85 (C OH; multiplet; 2H) and 2.65
p.p.m. (OH; broad singlet; shifted downfield on cooling; 2H). The
mass spectr~m of the bistrimethylsilyl derivative exhibited fragments
- at 480 ~M~), 465 (M-CH3)~ 436 (M~CO2), 409 (M-C5Hll), 39Q, 380, 364,
238, 217.
Anal- Calc d- for C20H324 C~ 71-39; H~ g-59-
Found: C, 70.73; H, 9.31.
In like manner, but substituting ethyl acetate hexane for ether/hexane
for recrystallization, PGF2~ 1,15-lactone was obtained: m.p. 110.0-
111.7; [~]EtOH -71
'
- 87 -
mab/; ~
Preparation 5: 17-Phenyl-18,19,20-trinor-P~F2~,1,15-lactone
A solution of l~-phenyl-18,19,20-trinor-PGF2a, t776 m~)
and 1-butaneboronic acid ~225 mg) in 25 ml of methylene chloride
was heated at reflux. After 15 min; the methylene chloride
was allowed to 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 ~rostaglandin.
The cyclic boronate was dissolved in 5 ml of anhydrous,
oxygen-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 fo~ 18
hr. The ~ylene 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
of water. This mi~ture was stirred vigorously for 30 min.
then concentrated under reduced pressure to give a residue.
The residue was taken up in brine/ethyl acetate and extracted
,
tho~oughl~ with ethyl acetate. The combined extracts were
washed with aqueous sodium bisulfate, water, aqueous sodium
bicarbonate and brine, then dried over sodium sulfate a~d
concentrated to afford a residue of crude 17-phenyl-18,19,
20-trinor PGF2~, 1,15-lactone.
The crude lactone was purified by chromatography on 400 g
of 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 acetate/hexane
exhibited m.pO 116-117.
- cl~/ - 8 R
The infrared spectrum exhibited peaks at 3460, 3400 shf
3020, 1705, 1650, 1~05, 1495, 1325, 1300, 1~65, 1150, 110~,
1040, 1020, 1000, 970 and 700 cm 1 and the mass spectrum
showed ~ragmen~s at m/e 370 tM-18), 352, 334, 308, 298, 261,
243, 225. ~No M+ peak was apparent.)
Anal. Calc'd. for C23H30O4: C, 74.56; H, 8.16.
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),
2,2'-dipyridyldisulfide (628 mg) and triphenylphosphine (748 mg)
in 10 ml of anhydrous, oxygen-free xylene was stirred at 25
in an atmosphere of 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
give a residue The residue was chromatographed on 100 g of
neutral silica, packed and eluted ~8 ml fractions) with 80%
ether/hexane. The fractions containing homogeneous product
by TLC were combined to afford purified 17-phenyl-18,19,20-
trinor-PGE2, 1,15-lactone. Two recrystallizations from
ether/hexane afforded pure product, m.p. 81-83~. The infra-
red spectrum exhibited peaks at 3440, 3000, 1725, 1605, 1500,
133~, 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, 296,277, 264, 259, 241 ~no M+ apparent).
Preparation 7: 16-Phenoxy-17,18,19,20-tetranor-PGF2a,1,15-lactone
Following the procedure of Example 1 but substituting;
16-phenoxy-17,18,19,20-tetranor PGF2a 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.
The crude product was purified by chromatography over
neutral silica packed in 50% ethyl acetate/hexane and eluted
w th 50% ethyl acetate/hexene followed by 70% ethyl acetat~
cb/ 89 -
hexane. Those fractions containing homogeneous product as
judged by TLC were combined to afford crystalline 16-pheno~y-17,
18,19,20-tetranor-PGF2a, 1,15-lactone. The lactone thus
obtained was recrystallized from ethyl acetate/hexane to
afford pure product, m.p. 185-186. The mass spectrum of the
trimethylsilyl derivative exhibited a peak at M+ 516.2738
~theory for C28~44Si2O5 516.2727) and fragments at m/e
501, 426, 423, 409, 400, 333, 307, 217 and 181.
Preparation 8: PGFla, 1,15-lactone and 15-epi-PGFla, 1,15-lactone
Following the procedure of Example 1 but substituting
PGFla for PGF2a there was obtained a crude product containing
PGFl~, 1,15-lactone as a viscous yellow oil.
The crude product was purified by chromatography on 700
g 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
14-19) which was homogeneous by TLC was combined to give 15-epi-
PGFla, 1,15-lactone ~15R)-PGF2a, 1,15-lactone]. The infrared
20 spectrum exhibited peaks at 3450, 1730, 1585, 1250, 1100, 970
and 735 cm 1 and the NMR spectrum showed peaks (~CMcl3) 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 whe~
sample is cooled; OH; 2H).
The major product, eluted later from the column ~fractions
21-28), were combined to afEord purified PGFla, 1,15-lactone.
The purified PGFla, l,lS-lactone crystallized upon trituration
with ether, and recrystallization (ethyl acetate/hexane) afforded
a pure sample, m.p. 105-106. The infrared spectrum exhibited
30 peaks at vmax 3520, 3480, 3380, 1710, 1300, 1290, 1265, 1250,
1235, 1160, 1110, 1075, 1055, 1000 and 965 cm 1 The NMR
spectrum showed peaks (~CMcl3) at 6.0-5.75 (vinyl; multiplet;
cb/ - 90
9.~ ,06~
2H; 5~60-5.00 (C-15H; multiplet; lH), 4.25-3.80 ~CHOH; multiplet;
2H) and 3.0~ ppm ~OH; singlet)
Preparation 9: 13,14-Didehydro-8~,9~ ,12a PGF2a 1,15-lactone
and 13,14-didehydro PGF2u 1,15-lactone
Following the procedure of Example 1 but substituting 13,
14-didehydro-8~, 9~ , 12a PGF2~also known as ent-13-
dehydro-15-epi-prostaglandin F2a lcompound 2 of J. Fried and C.
- H.Lin, J. Med. Chem. 16, 429 (1973)~ and 13,14-didehydro PGF2a
for PGF2a, there are produced 13,14-didehydro-8~,9~ ,12a-
PGF2a 1,15-lactone, and 13,14-didehydro-PGF2a 1,15-lactone,
respectively.
Preparation 10: 13,14-didehydro-8~ ,12a-PGE2 1,15-lactone
and 13,14-didehydro-PGE2 1,15~1actone
Following the procedure of Example 2 but substituting
13,14-didehydro-8~ ,12a-PGE2 [also known as ent-13-dehydro-
15 epi-PGE2 ~from 2a of J. Fried and C. H. Lin. J. Med. Chem.
16, 429 tl973)] and 13,14-didehydro PGE2 for PGE2 there are
produced 13,14-didehydro-8~ ,12a-PGE2 1,15-lactone and
13,14-didehydro PGE2 1,15-lactone, respectively.
- 20 Preparation 11: 13,14-dihydro PGF2a 1,15-lactone
Following the procedure of Example 1 but substituting
13,14-dihydro PGF2a for PGF2a, there is produced 13,14-dihydro
PGF2a 1,15-lactone
Preparation 12: (15S)-15-methyl PGF2a 1,15-lactone
Following the procedure of Example 1 but substituting
; ~15S) 15-methyl PGF2a for PGF2a and eY~tending the reaction
time in refluxing xylene from 24 hours to 48 hours there i5
produced crude (15S)-15-methyl PGF2a, 1,15-lactone. The crude
lactone is purified by repeated chromatography and, further,
if desired, by TLC purification to afford in low yield ~lSS)-
15-methyl-PGF2a, 1,15-lactone in essentially pure form.
Preparatlon 13 16,16-dimethyl PGF a 1,15-lactone
9 1
Following the procedure of Example 15 but substituting
16,16-dimethyl PGF2~ for ~15S) 15-methyl PGF2~ there is
produced 16,16-dimethyl PGF2a, 1,15-lactone.
Pre~aration 14:
Following the procedure of Example 8 but substituting
16~m-trifluoromethylphenoxy-17,18,19,20-tetranor PGF2, 16-m-
chlorophenoxy-17,18,19,20-tetranor PGF2~, and 16-p-fluoro-
phenoxy-17,18,19,20-tetranor PGF2a for 16-phenoxy 17,18,19,20
tetranor PGF2~ there are obtained the corresponding 1,15-lactones.
Preparation 15:
Following the procedure of Example 2 but substituting
~16S) 16-methyl-, ~16R~ 16-methyl- and 16-methylene PGE2 for
PGE2 there are produced, respectively, the corresponding (16S)
16-methyl, (16R) 16-methyl-, and 16-methylene PGE2 1,15-lactones.
Preparation 16: 16,16-dimethyl PGE2 1,15-lactone
Following the procedure of Example 3 but substituting
16,16-dimethyl PGF2~ 1,15-lactone for PGF2~ 1,15-lactone
there is produced-16,16-dimethyl PGE2 1,15-lactone.
Preparation 17: (15S) 15-methyl PGE 1,15-lactone
Following the procedure of Example 3 but substituting
~5S) 15-methyl PGF2a 1,15-lactone for PGF2~ 1,15-lactone,
there is produced ~15S) 15-methyl P OE 2 1,15-lactone.
Preparation 18: ll-deoxy PGE2 1,15-lactone
Following the procedure of Example 2 but substituting 11-
deoxy PGE2 for PGE2 there is produced ll-deoxy PGE2 1,15-lactone.
In like manner, substituting ll-deoxy PGEl for PGE2
affords PGEl~ 1,15-lactone.
Preparation 19: (15S) ll-deoxy-15-methyl PGE2 1,15-lactone
and ll-deoxy-16,16-dimethyl PGE2, 1,15-lactone
Following the procedure of Example 2 but substituting
~15S) ll-deoxy-15-methyl PGE2 and 11-deoxy-16,16-dimethyl PGE2
for PGE2 and extending the reflux period in xylene from 2
cbf - 92 -
~606;2~
hours to 48 hours there are produced the corresponding 1,15-
lactones~ The crude lactones are purified by repeated chroma-
tography and further, if desired, by TLC purification to afford
in low yield (lSS) ll-deoxy-15-methyl PGE2 1,15-lactone and
11-deoxy-16,16-dimethyl PGE2 1,15-lactone, respectivel~, in
essentially pure form.
Preparation 20: ll-deoxy PGF ~ 1,15-lactone
A solution of ll-deoxy PGE2 1,15-lactone ~0.5 g) in
methanol t50 ml) is treated at 0 with sodium borohydride
19 ~500 mg) added in 50 mg portions every Z minutes. Aqueous
sodium bisulfate (lM) is 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 11-deoxy PGF2~, 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 PGF2~ are combined to afford ll-deoxy PGF2a 1,15-lactone
; 20 in essentially 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 PGE2 1,15-lactone and PGEl 1,15-lactone for ll-deo~y
25 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 PGF2~, and PGFl~, respectively.
~b~ ~ ~3 -
SUPPLEMENTARY DISCLOSURE
. _ _
When this application was filed, it was not known
which isomer, SE form or SZ 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" and "Z" nomenclature is
discussed in the following reference: J.E. Blackwood et al.,
J. Am. Chem. Soc. 90,509 (1968).
The 5Z compounds of the present invention were made
from 5,6-cls PGF compounds, whereas the 5E isomers require
starting with 5,6-trans PGF compounds.
When cons dering Examples 5 to 7 and 10 of the
principal disclosure, it should be~noted that the prefix
"5Z-" properly belongs before each title heading, for example,
Example 5, line 17 on page 49: 5Z-9-Deoxy-6,9-epoxy-~5 -PGFla
Methyl Ester.
- 94 -
