JPS5874660A - Prostaglandin analog - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to prostaglandin derivatives and a method for preparing Sorera.

Prostaglansifs and analogs are well-known organic compounds derived from brostanic acid with the following structure and atomic numbering:

The formulas depicted herein represent specific optically active isomers with the same absolute configuration as PGE 1 obtained from mammalian tissue.

In the formula, a dashed bond to a 7-clopentane ring or side chain indicates an alpha configuration, ie, a substituent below the plane of the ring or side chain. Thick solid bonds indicate beta configuration, ie substituents above the plane.

The object of the present invention is to provide four novel products with pharmacological activity. A further object is to provide methods for making these products and intermediates.

Thus, optically active compounds of formulas including lower alkanoates or mixtures of this compound and its enantiomers are provided.

In Formula 1 and the other formulas below including the formulas in the figure, the terms I, , Ql, RI, etc. are as defined in the table. By referring to this table, it will be determined what each expression is intended to represent.

The term definition table for the formula is (1) -(Cut)ct-c(Rz)z-(2
) -CH2-O-CH2-Y- or (3) -C
H, CH==CH- (in the formula, d is O to 5, R2 is hydrogen, methi, -F is fluoro, the same or different, provided that when one R2 is fluoro, the other is not methyl, and Y is a valence bond, -CH, -1 or -(Cu
t)z-).

D+ ti top OD! : Same, but -CH2CH=CH-
Does not include.

Ll is t・1.・\ /-1 R34R3!・R34R31・straddle R34Rss and R3
Mixture with 4R35.

(Here, R and R311 are hydrogen, methyl, or fluoro. 1. They are the same or different, but R34 and R311 are hydrogen, methyl, or fluoro.
(with the proviso that only when one of ll is hydrogen or fluoro, the other is fluoro).

R2 is hydrogen, avit of 1 to 4 carbon atoms
, or -〇〇〇R,,.

(where R3t is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 8 to 10 carbon atoms, 7 to 12
Aralkyl, phenyl, or chloro or alkyl of 1 to 8 carbon atoms in fil A/1.2 is phenyl substituted with 8 atoms, same or different, with the proviso that R2.

One or more of them cannot be -COOR (R3
, is hydrogen or methi/L/).

(Ra#i hydrogen, methyl or ethyl).

(R is dihydrogen, methyl or ethyl, and R21 is tetrahydropyranyl, tetrahydrofuranyl, l-ethoxyethyl or ■ R14-〇-CC-R1? OM.

RI6 R1@ (where Rt4h alkyl of 1 to 18 carbon atoms, 3
7-chloroalkyl of ~1019 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or phenyl substituted with 1 to 8 alkyl of 1 to 4 carbon atoms,
R111 and R16 are the same or different, hydrogen,
alkyl of 1 to 4 carbon atoms, phenyl or alkyl of 1 to 4 carbon atoms substituted with 1.2 or 8, or RI3 and R111 taken together -(CHI)a-sentenceh-(cHz)b-o-(
cut) 8 in c-, here aake 8.4 or 5, b#
'i! , 2 or 3, and C are l, 2 or 8, provided that the sum of b and C is 2.3 times 4, and R1? is hydrogen or phenyl).

,・＼ Q3 is I (0Rts or HOR2゜ (R61 as defined in 91 above).

R1 is (1) -COOR.

(2) -CH20H (8) -CHzN(Ro)(Rzs)1 (4) -C-N (R book) (R2@) or) -N [Kokote R3 is (a) hydrogen, (b) 1~ alkyl of 12 carbon atoms, (C) 7-chloroalkyl of 8 to 10 carbon atoms, (d) aralkyl of 7 to 12 carbon atoms, (e) phenyl, (f) chloro, or 1 to 4 phenyl substituted with alkyl/L'1-3 of carbon atoms, 0
0 1m) -CH-C-R,.

R,1 (R+o is phenyv, p-promophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and R11 is hydrogen or phenyl/I/) or (n) drug is a physically acceptable cation, R is hydrogen, methyl or ethyl;
R2a hydrogen, alkyl of 1 to 4 carbon atoms, 7 to 1
Arrangement of 2 fl carbon atoms μ, phenyl, or 1 to 4
phenyl substituted with alkyl on the carbon atom of flff]
.

R2 is hydrogen, methyl or fluoro, the same or the same, with the proviso that when one R2 is fluoro, the other is methyl.

R4 is R6 (1) -C-C, H2g-CH.

6 (in the formula, CgH2g is an alkylene of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CR,R and the terminal methyl, and RII and R , 1~
Alkyl or fluoro of 4 carbon atoms, same or different, provided that only when one of R3 and R6 is hydrogen or fluoro, the other is fluoro, and further 2 is oxa(-
0-), the condition is that the difference between R5 and R is not 7/l/oro, and 2 is an oxa atom (-0-) or Cj
H2j, where CjH2, is a valence bond or -
〇Alkylene of 1 to 9 carbon atoms with 1 to 6 carbon atoms between R,R,- and the phenyl ring, and T
Fil ~ alkyl of 4 carbon atoms, fluoro, chloro, trifluoromethyl or alkoxy of 1 to 4 carbon atoms, S is 0.1.2 or 3 with the proviso that 2f
T not exceeding lll is other than alkyl, and S
2 or 80, with the condition that T is the same or different).

R6 and R6 are hydrogen, alkyl of 1 to 4 carbon atoms, or fluoro, the same or different, provided that Rs and R
The condition is that only when one of 6 is hydrogen or fluoro, the other is fluoro, and that neither R3 nor R6 is fluoro when 2 is oxa (-0-).

(wherein C-9 is bonded to ? or ♀-) (where C-9 is bonded to 11 or 1).

Rn Fi(1) -COOR2゜(2) -〇H20H (8) -CH2N(Ro)(Rts)■ (Except that R20 does not include "(n) pharmacologically acceptable cation," is the same as R3 above,
and R9 and R211 as defined herein).

[In the formula, R21 is as defined for -F, and C-900
- is combined with 11 or 1].

R23 is (1) -COOR2゜(2) -CH20R2゜(3) -CH2N(R,) (R211)(4)
-CN(Re)(Rza) or NH-ゞ (Re, Rz., R21 and Ro as defined herein).

R.

R26 is (1) -c-cgn2g-cus or 6R.

(R5, Ro, 0gR2g, T, z and s as defined herein) - RI is bromo or chloro.

R30 is (1) -(CHt)m-CHs, (in the formula m
is 1 to 5, and T is chloro, 7〃o, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms.

7, S is 0.1.2 or 8, and the various T's are the same or different, provided that no more than two T's are other than alkyl, and further defined for Ll above. Only when R34 and R35 are hydrogen or methyl as specified, and R30Rst is hydrogen or hydroxy, the same or different.

(where RH is as defined above and C-9 is ?
or ♀-).

R3phtil-)', bromo, or hachloro.

vr u (1) ciX CH-CH-CR2-(
CHz ) p CHz -1(2) cis-CH=
CH-CH2-(CH2), -CF, or (3)
cis-CH=CH-D- (where D is as defined above and p is 1.2
or 8).

X is (1) trans-CH=C)(- (2) cis-CH=CH- [8> -CTC- or (4) -CH2CH2-0 x is (1) trans-〇H=CH- ( 2) -C=C- or (8) -CHzCHz-0 Y is a valence bond, -CH2- or -(Cut)t-0
2 is an oxa atom (-0-) or CjH2j bonds are cyclope H at positions C-8, C-9, and C-12 according to prostaglandin nomenclature within the scope of the prostaglandin derivatives described herein. The following is expressed in

Compound.

Sea PGE' compound.

C-11-methylene-PGE compound. and H20H C11-Hydroxymethy7y-PGE compound.

Furthermore, within the scope of the prostaglandin derivatives described herein the following are represented:

(a) When R1 is -COOR, PGE type acids, esters and salts.

(b) When R1 is -CH,OH, it is a 2-decarboxy-2-hydroxymethy#-PGE type compound.

(C) 2- when Rs is -CH2N(R11)(R28).

Decarboxy-2-amino-PGE type compounds.

(') When R+ is -C-N (R9XR118), it is a PGE type amide. and -N Hoxy 2-tetrazo-/l/-1-iμ-PGE type compounds.

For formula summer compounds where the group is attached to the side chain in the alpha configuration, the C-15 configuration is similar to that of naturally occurring prostaglandins, such as PGE, which is obtained from mammalian tissues. Same as placement. The 15-epimer compound is represented by formula 1 when Q is \R,OH, and is represented by the appropriate prefix "15
-Epi' or [15βJ or [15RJ]. As is known in the art, the designations of R and S are dependent on adjacent substituents. RoS, ' Cahn, J. Chem.
Ed, Vol. 41, p. 116 (1964).

Typical examples of formula 1 compounds are 6-ke)-PGE4 represented by is a compound.

Irrespective of the number of carbon atoms in the chain between the keto group and the terminal R group, these compounds are
GE is called a "6-keF" compound from the designation of c-6 in the basic formula. Compounds with longer or shorter chains are named according to accepted conventions using "homo" or "nor". For example, the side chain -CH, C-(CH,), -COOH is named r2a-homo-6-keto...'', but
On the other hand, 10H, -C-(CH2), -COOH is "2-A/
-6-keto...''.

Ii of formula l! The products of the present invention within the scope of the present invention are highly effective in eliciting a variety of biological responses. These compounds are therefore useful for pharmacological purposes.

Some of these biological responses, inhibition of platelet aggregation,
Smooth muscle stimulation, systemic blood pressure reduction, inhibition of gastric juice secretion, and systemic administration of prostylandin synthase inhibitors reduce unwanted and unpleasant effects on the gastrointestinal tract, control attacks in asthmatic symptoms, and facilitate breathing. , nasal passage decongestion, labor inducing agent,
Its effects on mammalian reproductive organs as an abortifacient, cervical dilator, estrous phase regulator, and menstrual cycle regulator; growth of epidermal cells and keratin in animals; and alleviation of proliferative skin diseases.

Because of these biological responses, these novel compounds have been shown to be useful in humans, domesticated animals, companion animals, and mammals, including animals, and laboratory animals, such as mice, rats, and mice.
It is useful in the study, prevention, control, or mitigation of a wide range of diseases and undesirable physiological symptoms in rabbits and monkeys.

These compounds are useful whenever it is desired to inhibit platelet aggregation, reduce platelet adhesion, and eliminate or prevent thrombus formation in mammals, including humans, rabbits, and mice. For example, these compounds can be used to treat and prevent myocardial infarction, to treat and prevent postoperative thrombosis, to promote patency of vascular grafts after surgery, and to prevent blood clots caused by atherosclerosis, arteriosclerosis, and lipemia. It is useful in the treatment of symptoms such as deficiency and other clinical conditions where the underlying etiology is combined with lipid imbalance or hyperlipidemia. Other in vivo applications include prevention of chronic cerebral ischemia in geriatric patients and long-term prevention after myocardial infarction and stroke. For these purposes, these compounds are administered systemically, eg, intravenously, subcutaneously, intramuscularly, and for sustained action in the form of sterile implants. Intravenous routes of administration are preferred, especially for rapid response in emergencies. - Approximately 0.0 kg/kg of body weight per day. Ol to about Iθ
A range of dosages may be used; the exact dosage will depend on the age, weight, and condition of the patient or animal, as well as the number and route of administration.

Addition of these compounds to the surface provides in vitro applications such as the storage of surfaces used in heart-lung machinery. Additionally, surfaces containing these compounds can be circulated through organs removed from the donor prior to transplantation, such as the heart and kidneys. They are also useful in making platelet-rich concentrates for use in the treatment of thrombocytopenia, chemotherapy and radiotherapy. For in vitro applications, doses of 0.001 to 1.0 μm/d of whole blood are used.

These compounds are extremely potent in producing smooth muscle stimulation, as well as other known smooth muscle stimulants such as oxytocin and various ergot alkaloids, including its derivatives and analogs. It has high activity in synergizing drugs. They may therefore be used, for example, in place of these known smooth muscle stimulants, or in combination with smaller amounts than their usual doses, for the relief of paralytic ileus syndrome, for the prevention or control of atonic uterine bleeding after abortion or delivery. It is useful as an aid during placental expulsion and the postpartum period. For the latter purpose, the compound is administered by intravenous infusion immediately after abortion or delivery at a dosage range of about 0.01 to about 50 μm/ky body weight per minute until the desired effect is achieved. Thereafter, the dosage is 0.000 g/kg/day during the puerperal period. It may be given by intravenous, subcutaneous, or intramuscular injection or infusion in the range of 1 to 2 cm, but the exact dosage will vary depending on the age, weight, and condition of the patient or animal.

These compounds are useful as antihypertensive agents to lower blood pressure in mammals, including humans. For this purpose, the compounds are administered at a rate of from about 0.01 to about 50 μm/ky body weight per minute, or from about 25 to 500 μm/ky body weight per day. Administered by intravenous injection in single or multiple doses.

These prostaglandin derivatives are useful in humans and certain useful animals, such as mammals, including dogs and pigs, to reduce and inhibit excessive gastric secretion, thereby reducing or inhibiting gastrointestinal ulcer formation. Avoid and also promote the healing of such ulcers already present in the gastrointestinal tract. For this purpose, approximately 0.1μ/kg body weight/min? or about 20μm
These compounds may be injected or infused intravenously, subcutaneously, or intramuscularly at an injection or infusion dose ranging from about 0.01 to about 10 kg body weight per day. However, the exact dosage will depend on the age, weight, and condition of the patient or animal and the number and route of administration.

These compounds are also useful in reducing undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthase inhibitors, and prostaglandin derivatives and anti-inflammatory Used with co-administration of prostaglandin synthase inhibitors. The ulcerogenic effect induced by a non-steroidal anti-inflammatory drug in mouse odor is PGE, , PGE2, PGE, ,1(,14
-dihydro-PGE and the corresponding 11-deoxoPG
For the disclosure that all E and PGA compounds are inhibited by simultaneous oral administration of prostaglandins of the E and A series, see Partrid.
ge) et al., U.S. Patent No. 8,781.4! See No. 9. Prostaglandins are also useful in reducing undesirable gastrointestinal effects resulting from systemic administration of, for example, indomethacin, phenylbutacin, and aspirin. These are the substances specifically mentioned as non-steroidal anti-inflammatory agents by Bartridge et al. They are also known as prostaglandin synthetase inhibitors. Anti-inflammatory synthetase inhibitors, such as indomethacin, aspirin, or phenylbutacin, can be used for the reduction of inflammatory conditions in any manner known in the art, such as by ingestion in any dosage and by any known systemic route of administration. administered.

The prostaglandin derivative is administered in parallel with the anti-inflammatory prostaglandin synthase inhibitor, either by the same route of administration or by a separate route. For example, if the anti-inflammatory substance is administered orally, the prostaglandin derivative may also be administered orally or alternatively rectally in the form of a suppository or in the case of women in the form of a suppository or for slow release. may be administered intravaginally, for example in the form of an intravaginal device such as that described in U.S. Pat. Grandin derivatives are also administered rectally. Additionally, prostaglandin derivatives are conveniently administered orally or, in women, intravaginally. It is particularly advantageous to combine both in a single dosage form when they are made to be the same.

The dosage of the prostaglandin derivative for this treatment depends on the type, age, weight, sex, and medical condition of the mammal, the nature and dose of the anti-inflammatory synthase inhibitor administered to the mammal, and the specific prostaglandin administered. including the sensitivity of derivatives,
It will depend on various factors. For example, not everyone who needs an anti-inflammatory substance will experience the same adverse gastrointestinal effects when taking this substance. The effect on the gastrointestinal
Often they will vary substantially in type and extent.

However, if it has been determined that the administration of anti-inflammatory substances is causing undesirable gastrointestinal effects in human or animal subjects, prostaglandin may be used to reduce or substantially eliminate these undesirable effects. It is within the skill of the caring physician or veterinarian to prescribe an effective amount of the Gin Derivative.

These compounds are useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as release controlling agents from cells activated by antigen-antibody complexes. These compounds therefore suppress attacks and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia, and emphysema. For these purposes, these compounds may be administered orally, for example in the form of tablets, capsules or liquids, rectally in the form of suppositories, preferably intravenously in emergency situations, but parenterally, subcutaneously or intramuscularly. Inside,
By inhalation in the form of an aerosol or solution for nebulization,
or by insufflation in powder form. Approximately 0.0% per ky of body weight. Doses ranging from 1 to 5 μl are administered 1 to 4 times a day, with the exact dosage depending on the age, weight, and condition of the patient, and the frequency and route of administration.

For the above applications, these prostaglandins are combined with sympathomimetic agents (isoproterenol, phenylephrine, ephedrine, etc.), xanthine derivatives (theophylline and aminophylline), and corchigosteroids (AC
It is advantageous to combine it with other asthma treatment agents such as TH and prednisolone).

These compounds are effectively administered to human asthmatics by oral or aerosol inhalation.

For administration by the oral inhalation route with conventional nebulizers or oxygen aerosolization, the total solution is preferably 100 to 2
It is convenient to provide the active ingredient in dilute solution at a concentration of about 1 part drug to 00 parts by weight. Quite conventional additives can be used to stabilize these solutions and to provide isotonic media, such as sodium chloride, sodium citrate, citric acid, sodium bisulfite, and the like.

For administration as a self-propelled dosage unit for administering the active ingredient in an aerosol form suitable for inhalation therapy, the composition may be combined with co-solvents such as ethanol, flavoring agents and stabilizers (dichlorodifluoromethane and dichloromethane). It consists of an active ingredient suspended in an inert propellant (such as a mixture with tetrafluoroethane).

Instead of co-solvents, pharmaceutical agents such as oleyl alcohol can also be used. Suitable means of using aerosol inhalation therapy techniques are fully described, for example, in US Pat. No. 2,868,691.

These compounds are useful as nasal decongestants in mammals, including humans, at dosages ranging from about 10μ to about 1θ per pharmacologically suitable liquid vehicle, or as an aerosol spray. Both are used for topical purposes.

These compounds are also useful in the treatment of peripheral vascular disease in humans. As used herein, the term peripheral vascular disease refers to disease of any of the blood vessels external to the heart, as well as diseases of the lymphatic vessels, such as frostbite, ischemic cerebrovascular disease, arteriovenous chain holes, ischemic leg ulcers. , phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, ductus arteriosus, non-occlusive mesenteric ischemia, arteritis, phosphorus, papulitis, etc. These examples are included as illustrative and should not be construed as limiting the term "peripheral vascular disease." For these conditions, the compounds of the invention are administered orally or parenterally by injection or infusion into an artery or vein, with intravenous or intraarterial injection being preferred. Suitable amounts of these compounds range from 0.01 to 1.0 μt administered by injection per hour, or by e.g. 1 to 4 injections on a -day basis, but the exact dosage are patient's age, weight,
Depends on symptoms and number and route of administration. Treatment lasts from 1 to 5 days, but 8 days is usually sufficient to ensure long-term sustained therapeutic action. If systemic effects or side effects are observed, the dose is reduced to a level below the threshold where significant systemic effects and side effects are observed.

These compounds are therefore useful in the treatment of peripheral vascular disease in the extremities of humans with circulatory insufficiency in the extremities. Such treatment makes it possible to reduce pain at rest and induce ulcer healing. For a complete discussion of the nature and clinical manifestations of peripheral vascular disease in humans and the methods already known for treatment with prostaglandins, see South African Patent No.
No. 10149 (Dowend Farm Dock No. 58, 4)
See 0QV). Elliott
et al., Lancet, January 1, 1975
8th, pp. 140-142.

These compounds, which are useful in inducing labor in place of oxytocin, can be used in pregnant female animals, including humans, cows, sheep, and pigs, at or near birth, or in the uterus of a fetus from about 20 weeks to term. Used for pregnant animals that have died. For this purpose, the compound is injected intravenously at a dose of 0.01 to 50 microns per body weight per minute until or near the second stage of labor, ie, expulsion of the fetus. These compounds are particularly useful when a female animal is a week or more past due and labor does not begin naturally, or when the amniotic sac has ruptured and natural labor has not begun 12 to 60 hours later. It is. Another route of administration is oral.

These compounds are useful in regulating the reproductive cycle of menstruating female mammals, including humans.

A menstruating female complement is an animal that is sufficiently mature to menstruate, but not old enough to terminate normal menstruation. For this purpose, the prostaglandin derivative is advantageously administered at 0.00% per kg body weight of the female mammal during a period beginning at about the time of ovulation and ending at about or just before the time of menstruation.
It is administered systemically at dosage levels ranging from 1111p to about 20 Da. Intravaginal and intrauterine routes are alternative methods of administration. Expulsion of the embryo or fetus is achieved by similar administration of the compound during the first and second octomotor periods of otherwise normal mammalian gestation.

Additionally, these compounds are useful in producing cervical dilatation in pregnant and non-pregnant female mammals for obstetric and gynecological purposes. Cervical dilatation is also observed in cases of labor induction and clinical abortion caused by these compounds.

In cases of infertility, cervical dilation caused by these compounds is useful in aiding sperm transfer to the uterus. Cervical dilatation with prostaglandins is useful in surgical gynecology, such as D and C (cervical dilatation and curettage), when mechanical dilatation may result in uterine perforation, cervical laceration, or infection. . This is also useful in diagnostic procedures where dilation is required for tissue examination.

For these purposes, prostaglandin derivatives are administered locally or systemically.

For example, prostaglandin derivatives are administered at a dose of about 5 to 50 μg per treatment in adult women, with 1 dose per 24 hours.
Administered orally or intravaginally in ~5 treatments. Alternatively, the compound is administered intramuscularly or subcutaneously at a dosage of about 1 to 25 μm per treatment. The exact suitability for these purposes will depend on the age, weight and condition of the patient or animal.

These compounds are further useful as abortifacients in livestock (particularly for heifers in feedlots), as aids in detecting oestrus, and for regulating or synchronizing oestrus. Domestic animals include horses, cows, sheep and pigs. Regulation or synchronization of oestrus allows ranchers to more efficiently manage both pregnancy and parturition by allowing all female animals to become reproductive at short, predetermined intervals. This synchronization results in a higher rate of live birth than would be obtained with natural regulation. Glotaglandin may be injected or applied in the feed at doses ranging from 0.1 to io oTI9 per animal, and may be combined with other drugs such as steroids, and the dosing regimen may vary depending on the animal being treated. It will vary depending on the species. For example, hens are given prostaglandin derivatives for 5 to 8 days after ovulation to bring them into oestrus.

The cows are treated at regular intervals over a period of three weeks in order to advantageously bring them all into heat at the same time.

These compounds, including salts, increase renal blood flow in mammals, thereby increasing urine output and its electrolyte content.

These compounds are therefore useful in the treatment of renal dysfunction, particularly cases involving obstruction of the renal vascular bed. By way of example, these compounds are useful, for example, in alleviating or correcting edema resulting from extensive skin burns, and in the treatment of shock. For these purposes, these compounds are initially administered by intravenous injection at doses ranging from 10 to 1000 μm/ky body weight, or at doses of 0.0 μm/ky body weight per minute.
Preferably, doses ranging from 1 to 20 μm are administered by intravenous infusion until the desired effect is achieved. Subsequent doses are -0.05 to 2 kg body weight per day.
(2) Given by intravenous, intramuscular, or subcutaneous injection or infusion.

The compounds cited above as promoters and accelerators of epidermal cell and keratin production are useful for this purpose in animals, including humans, farm animals, companion animals, zoological specimens, and laboratory animals. For this reason, these compounds can be used to treat burns, burns,
It is useful for hastening the healing of skin damaged by wounds, abrasions or after surgery. These compounds are intended to cover skinless areas by later, outward growth of skin autografts, especially small and deep (
Davis) is useful in promoting and accelerating graft union and growth and in delaying rejection of allograft tissue.

For the above purposes, it can be applied topically at or near the site where cell growth and keratinization is desired, advantageously as an aerosol solution or a fine powder dusting agent, as an isotonic aqueous solution in the case of a wet dressing, or as a conventional pharmaceutical agent. Preferably, these compounds are administered as a lotion, cream, or ointment in combination with a pharmaceutically acceptable diluent. ``In some cases, when there is a substantial loss of body fluids, for example in the case of skin loss due to extensive burns or other causes, it may be necessary to In combination, systemic administration by intravenous injection or infusion is advantageous. Alternative routes of administration include subcutaneously or intramuscularly near the site, orally,
Sublingual, oral, rectal, or vaginal. The exact dosage will depend on the route of administration and such factors as the age, weight, and condition of the patient. For example, a wet dressing applied topically to second and/or third degree burns with a skin area of 5 to 25 square centimeters may be applied using an isotonic aqueous solution containing 1 to 500 μm/g of prostaglandin derivatives. It would be advantageous to include the use of Particularly for topical use, these compounds include antibiotics such as dientamycin, neomycin, polymyxin, bacitracin, subectinomycin, and oxytetracycline, and other antibacterial agents such as mafenide hydrochloride, sulfadiazine, frazolium chloride, and nitrofurazone, and with corticoid steroids such as hydrocortiscin, prednisolone, methylprednisolone, and hyfluprednisolone, in which each of these is present at a normal concentration suitable for its individual use. used in

These prostaglandin derivatives include human prostaglandin,
Atopic dermatitis, non-specific dermatitis, first-grade irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinoma of the skin, ichthyosis, epidermoid corneal hyperplasia, sun-induced Useful in the treatment of proliferative skin diseases in humans and livestock, including precancerous external keratoses, benign keratoses, -s-healing, and seborrheic dermatitis, as well as atopic dermatitis and dermatitis in livestock. . These compounds reduce the symptoms of proliferative skin diseases. For example, psoriasis is reduced when the thickness of the unscaled psoriasis lesion is significantly reduced, one is incompletely but noticeably cleared, or one is completely cleared.

These compounds can be used in compositions with suitable pharmaceutical carriers, such as ointments, lotions, thickeners, sprays or aerosols using typical bases such as petrolatum, lanolin, polyethylene glycols and alcohols. , applied topically. As active ingredients, these compounds represent about 0.1% to about 15% by weight of the composition;
Preferably it consists of about 0.5% to about 2%. In addition to topical administration, injection using a suitable sterile saline composition intraepidermally, in or around a lesion, or subcutaneously may be used. These compounds are also incorporated herein by reference. Useful as an anti-inflammatory agent to suppress chronic inflammation in mammals, including swelling and other unpleasant effects, using treatment regimens and dosages generally in accordance with U.S. Pat. No. 8,885,041. .

Many of the biological responses known to 6-keto prostaglandin derivatives in black grass are also known to older prostaglandin compounds. However, these derivatives are surprisingly more specific in their potency to elicit prostaglandin-like biological responses. Each of these new derivatives is therefore useful for at least one of the above pharmacological purposes in place of the known prostaglandin-type compounds, and also has surprising and unexpected properties for that purpose. more useful. This is because it causes fewer and fewer unwanted side effects than known prostaglandins.

Furthermore, these new compounds are effective for oral, sublingual, intravaginal, buccal, or rectal administration, in addition to the usual intravenous, intramuscular, or subcutaneous injections or infusions used for known prostaglandins. administered to

These properties are advantageous as they facilitate maintenance of uniform levels of these compounds in the body over less frequent, shorter term or smaller doses, allowing for self-administration by the patient.

Various methods of making 6-keto compounds of Formula I are further provided. One method thus consists of the following steps starting with an H convex compound.

(a) Starting compound ,OR station It is converted to the compound of

(b) Oxidize the product of step (=) to 8° Create a compound of as well as (c) the product of step (b) 1 It is converted to the compound of

Referring to Figure A, this method step will become clear.

Figure A 1 ↓ (a) I 1 ↓ (b) 1 1 ↓ (C) λ-194 The starting materials of formula ■ are not the subject of the present invention, but will be explained in a later part of this application. Dew. The 6-keto compound of the formula is in equilibrium with the hemiketal compound of ~ 1 and therefore travels with it.

In step (a) of Figure A, the starting materials are combined with the corresponding formula ■ When the compound dropyranyl or tetrahydrofuranyl, an acid condensing agent such as p-)μenesulfonic acid or pyridine hydrochloride in an inert solvent such as dichloromethane A suitable reagent such as 2,3-dihydrobyran or 2,3-dihydrofuran is used in the presence of .

The reagent should be in slight excess, preferably 1.0 to 1.0% over the theoretical amount.
Twice as much is used and the reaction is carried out in about 20-50 tll'.

Formula R,,-0-C(R,!l)-CHR as defined herein where R21 includes 1-ethoxyethyl
, R1, suitable reagents are vinyl ethers such as ethyl vinyl ether, isopropenyl methyl ether, isobutyl vinyl ether.

Formula R,,-0-C(R,5)=CR,,R,.

(where R14, R15, R16 and R1? are as defined above) or an unsaturated cyclic or heterocyclic compound, such as l-cyclohexy-
1-yl methyl ether or 5,6-cyhydro-4-methoxy-2H-pyranteal. C-1:'--Rees
e) et al., Journal of American Chemical Society, Vol. 89, p. 3366 (1967).

The reaction conditions for such vinyl ethers or unsaturated compounds are similar to those for dihydropyran described above.

The 61-keto formula ■ compound now has a capping group at C-11 and C-15, and now also has a formula Xx with capped groups at C-11 and C-15.
It is accompanied by a hemiketal compound derived from. c-
The 6-hydroxyl is also reactive with capping agents. Whether or not the c-6 hydroxyl is blocked is irrelevant to the success of the next step (b). In the presence of the reagent used in step (b), any ether group at C-6 is easily removed. Therefore, any hemethanol is readily and rapidly equilibrated with the 6-keto compound (2) in step (b) and converted to the formula (2) compound.

In step (b) of Figure A, the hydroxyl at the C-9 position on the cyclopentane ring of the formula (II) compound is oxidized to the oxo group of the formula (II) compound.

Oxidizing reagents useful for this conversion are known in the art. A useful reagent for this purpose is Jones' reagent, acidified chromic acid. J, Chem.

See Soc, vol. 89 (1946). Formula ■C of reactant
An amount in excess of the amount required to oxidize the -9 secondary hydroxy is used. Acetone is a suitable diluent for this purpose. A low reaction temperature of at least about OC should be used. Preferred reaction temperatures are in the range of Oo to -50C. Another reagent useful for this purpose is Collins' reagent, chromium trioxide in pyridine. G.C.J.Lins (J, C+Co11ins), etc.
Tetrahedron Lett, 886B (1968
See ). Cyclo-a-methane is a suitable diluent for this purpose. A reaction temperature below 80C should be used.

Preferred reaction temperatures are in the range Oo to +80C.

Oxidation proceeds rapidly and is usually complete in about 5 to 20 minutes.

Examples of other oxidizing reagents useful in this conversion include silver carbonate (Chem, Commun, l l 02)
(1969)], a mixture of chromium trioxide and pyridine (J, A+n, Chem, Soc, Vol. 75, p. 422 (1958) and Tetrahedron Vol. 18, 1851 Ji
(1962)), t-butylchromate in pyridine (Biochem, J, 84, p. 195 (1962)), a mixture of sulfur trioxide and dimethyl sulfoxide in pyridine [J, Ar+1.Chem, SOo, 89 Volume 5505 (1967)] and Dicyclohex 7/I/
Mixture of carbodiimide and dimethyl sulfoxide [J
.

Am, Chem, Soc, vol. 87, p. 5661 (196
5 years].

In step (C) of diagram A, the capping group RZt is replaced with hydrogen by acid hydrolysis, thereby yielding the product . General procedures are known in the art. For tetrahydropyranyl groups, for example, a compound of formula V is contacted at 40-55C with methanol-HCl or with acetic acid-water-tetrahydrofuran.

Additional compounds within the formula X, such as pharmacologically acceptable salts, are optionally made from the formula II acids by methods described herein or known in the art.

As used in the formula of Figure A and elsewhere in this specification, 1-4
Examples of alkyl of 5 carbon atoms are methyl, ethyl, propyl, butyl and their isomeric forms. Examples of alkyl of 1 to 7 carbon atoms are those listed above, as well as pentyl, hexyl, heptyl and their isomeric forms. Examples of alkyl of 1 to 12 carbon atoms are those listed above and octyl, nonyl, decyl, randesyl, dodecyl and the isomeric forms thereof. Examples of alkyl of 1 to 18 carbon atoms are, in addition, tridecyl, tetradecyl, p/tadecyl, hexadecyl, heptadecyl, octadecyl and their isomeric forms.

Examples of cycloalkyl of 8 to 10 carbon atoms, including alkyl-substituted cycloalkyl, are cyclopropyl, 2-
Methylcyclopropyl, 2,2-diethylcyclopropyl, 2,8-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl,
3-propylcyclobutyμ, 2,8.4-)ethylcyclobutyl, cyclopentyl A/, 2.2-dimethylcyclopentyl, 8-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 411S 3-butylcyclohexyl, 3 -isopropylcyclohexyl,
2.2-Dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of phenylalkyl of 7 to 10 carbon atoms: C, Hen-) IV, 1-phenylethyl, ? - phenylethyl,
2-phenylpropy/L/, 4-phenylbutyl, and 8-phenylbutyl μ. Examples of aralkyls of 7 to 12 carbon atoms are, in addition, 2-(l-naphthylethy/L/) and 1-(2-naphthylmethyl).

Chloro or alkyl of 1 to 4 carbon atoms 1 to 8 flll
An example of phenyl substituted with il is p-chloropheni7
u, mJ lorophenyl 7y, o-chlorophenyl, 2,4
-dichlorophenyl, 2,4.6-)dichlorophenyl, (0-1m-straight p-)tolyl, p-ethylphenyl, p-tert-butylphenyl, 2゜5-dimethylphenyl, 4-chloro-2-methyl phenyl, and 2,4-dichloro-3-methylphenyl.

1 in the chain within the CgH2g range defined herein.
Examples of alkylene of 1 to 9 carbon atoms with ~5 carbon atoms are methylene, ethylene, trimethylene, tetramethylene, and pentamethylene, and one or more carbon atoms on one or more carbon atoms thereof. These alkylenes with the above alkyl substituents, such as -0H(CHl
)-1-C(CHl)t-1-CH(CH,CH,)-
5-CH2-CH(CH3)-1-CI((CH,)-
CH(CH,) +, -CH2-C(CHs)t-1-
CH2-CH(CH,)-CH2-1-CH,-CH2
-CH(CH2CH,CH8-CH(CH8) -CH
(CH3)-CH,'-CH2-1-CH2-CH,-
CH2-C(CH,), -CH2-, and -CH2-C
H, -CH2-CH2-CH(CH,)-.

Examples of alkylenes of 1 to 9 carbon atoms having 1 to 6 carbon atoms in the chain within the range CjH2j defined above and substituted with 0.1 or 2 7μ oro are niCg
as mentioned for H2g, and hexamethylene, hexamethylene with one or more alkyl substituents on one or more carbon atoms thereof, and one or two thereof.
Alkylene radicals with one or two fluoro substituents on carbon atoms, such as -〇HF-C)! 2-1-CH
F-CIIF-1-cH2-CH2: cF, -, -CH
2-CHF-CH2-1-CH, -Ct(, -CF(C
H3) -1-CH2-CH2-CF, -CH2-1-C
H(CH5)-CH2-CH2-CHF-, -CH,-
CH2-CH2-CH2-CF2-1-CHF-CH2
-CH2-CH2-CH2-CHF-1-CF2-CH
2-CH2-CH2-CH2-CH2-1-CH2-C
H2-CH2-CF2-CH, -CH2-1 and -C)
(2-CH, -CH2-CH2-CH2-CF2-
It is.

Phenyl (0-, m-, or p-) Tolyl, (0-
1m- or p-)ethylphenyl, (0-1m-1 or p-)propylphenyl, (0-1m-1 or p-)
Butylphenyl, (0-1m-1 or p-) isobutylphenyl, (0-1m- or p-) tert-butylphenyl, 2.3-xylyl, 2.4-xylyl, 2.5-xylyl, 2 .6-xylyl, 3.4-xylyl, 2.6-dinitylphenyl, 2-ethyl-p-)lyl, 4-ethyl-p-lyl, 5-ethyl-m-)suμ, 2- Propyl-(0-1m-1 or p-)tolyl, 4-butyl-m-)lyl, 6-tert-butyl-m-)lyl, 4-isopropyA/-2,6-xylyl, 3-propyl
v-4-ethylphenyl, (2,8,4-12,8,5
-12,8,6-1 or 2.4.5-) trimethylamine μ, (0-1m-1 or p-)fluorophenyl, 2-fluoro-(0-1m-1 or p-)tolyl, 4- Fluoro-2,5-xylyl, (2,4-12,5-12,6-13,4-1 or 3,
5-) difluorophenyl, (0-1m-1 or p-)chlorophenyl, 2-chloro-p-)suμ, (8-14-15-1 or 6-)chloro-〇-tolyl, 4-chloro- 2-chloro-7-7y, 2-isopropyl A/-4-chlorophenyl, 4-chloro-3,5-
Xylyl, (2,8-12,4-12,5-12,6-13,4-
or 8.5-) dichlorophenyl, 4-chloro-3-fluorophenyl, (84 is 4-)chloro-2-fluorophenyl, α, α, α-trifluoro = (o-1m-1 or p-)
trine, (0-1m-1 or p-)methoxyphenyl, (0-1
m-1 or p-)ethoxyphenyl, (4-1 or H5-
) chloro-2-methoxyphenyl and 2,4-dichloro(5- or ti6-)methoxyphenyl.

Compounds of formula (1) include pharmacologically acceptable salts when R8 is a cation. These pharmacologically acceptable salts useful for the above purposes are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Particularly preferred metal cations are those derived from alkali metals such as lithium, sodium and potassium and from alkaline earth metals such as magnesium and calcium, although cationic forms of other metals such as ammonium, zinc and iron are also included. Within the scope of the present invention.

Pharmacologically acceptable amine cations include primary,
It is derived from secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, Dibenzylamine, α-phenylethyl/I/7mine, β-phenylethylamine,
Aliphatic, cycloaliphatic, and araliphatic amines containing up to about 18 carbon atoms, such as ethylenediamine, diethylenetriamine, and heterocyclic amines, such as piperidine, morpholine, pyrrolidine, piperazine, and lower alkyl derivatives thereof. such as 1-methylpiperidine,
4-ethylmorpholine, 1-isopropylpyrrolidine,
2-methylpyrrolidine, 1,4-dimethylpiperazine,
2-methylpiperidi7, etc., and amines containing water-soluble or hydrophilic groups, such as mono-, di- and triethanolamine, ethyljetanolamine, N-butylethanolamine, 2-amino-1-butanol, 2
-amino-2-ethyl-1,8-propanediol, 2
-Amino-2-methyl-1-propatur, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-tertiary amyl phenyl)jetanolamine, galactamine, N-methylglycamine, N −
These include methylglucosamine, ephedrine, phenylephrine, epinephrine, and procaine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations include tetramethylammonium, tetramethylammonium,
-yv ammonium, benzyltrimethylammonium, phenyltriethylammonium, etc.

Salts containing pharmacologically acceptable cations can be prepared from the compound of the final formula in the free acid form, i.e. when R19 is 2000H, by neutralization with an appropriate amount of the corresponding inorganic or organic base. It will be done. Examples of bases correspond to the cations and amines listed here above. These conversions are carried out by a variety of procedures known in the art to be generally useful in the preparation of inorganic or metal or ammonium salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure will depend in part on the solubility characteristics of the particular salt being made. In the case of inorganic salts, it is usually suitable to dissolve the acid of formula (I) in water containing a stoichiometric amount of hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. Such use of, for example, sodium hydroxide, sodium carbonate, or sodium bicarbonate results in a sodium salt solution. Evaporation of water or addition of a water-miscible solvent of moderate polarity, such as a lower alkanol or lower alkanone, produces this type if a solid inorganic salt is desired. Amine and quaternary ammonium salts are made by similar methods using appropriate solvents.

As mentioned above, compounds of formula I can be used in a variety of ways for a variety of purposes, including intravenously, intramuscularly, subcutaneously, orally, intravaginally, intrarectally, buccally, sublingually, topically, and for sustained action. It is administered in the form of a sterile implant.

For intravenous injection or infusion, sterile isotonic aqueous solutions are preferred. For this purpose, the formula! It is advantageous for R3 in the compound to be hydrogen or a pharmacologically acceptable cation for increased aqueous solubility. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are employed. Liquid preparations such as tablets, capsules and syrups, elixirs and simple solutions with the usual pharmaceutical carriers are used for oral and sublingual administration.

For rectal or vaginal administration, herbal medicines prepared as known in the art are used. For tissue transplantation, sterile tablets or silicone rubber capsules or other objects containing or impregnated with this substance are used.

The various esters of formula 1 within R5 are optionally prepared from the corresponding acids of formula 1, where R, is -COOH, by methods known in the art. For example, alkyl, cycloalkyl or aralkyl esters are created by interaction of an acid with a suitable diazo hydrocarbon. For example, when using diazomethane, a methyl ester is created. Similarly, examples include diazoethane, diazobutane and 1-
Diazo-2-ethylhexane, diazocyclohexane,
and fene) v Diazomethane is similarly used to produce ethyl, butyl, 2-ethylhexyl.

Cyclohexyl and benzyl esters are produced.

Among these esters, methyl or ethyl is preferred.
).

Esterification with diazo hydrocarbons, carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or another inert diluent. be done. After the esterification reaction has ended, the solvent is removed by evaporation and the ester is purified, if desired, by conventional methods, preferably chromatography. To avoid unwanted molecular changes,
It is preferred that the acid reactant be contacted with the diazo hydrocarbon for no longer than necessary to effect the desired esterification, preferably from about 1 minute to about 10 minutes. Diazo hydrocarbons are known in the art or can be made by methods known in the art. For example, "Organic Reactions", John Wiley & Sons, Inc., New York, N.Y., Vol. 8, 889-894 (1954).
See 2013).

An alternative method for esterification of the carboxy moiety of the novel compounds of formula 1 is to convert the free acid to the corresponding silver salt,
Subsequently, this salt is allowed to interact with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isophyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide.
, phenethyl iodide, etc. Silver salts are prepared in conventional manner, for example, by dissolving the acid in a cold aqueous solution of ammonia, evaporating excess ammonia under reduced pressure, and then adding a stoichiometric amount of silver nitrate.

Phenyl and substituted phenyl esters of Formula I compounds can be prepared by silylating the acid to protect the hydroxy group;
For example, it is produced by substituting each -OH with -o-s;-(CHa)a. Doing this means -CO
OH may also be changed to -COO-S i -(CH8). If the converted compound is treated with water for a short time, -Coo -S i-(CH,) becomes -COOH
will return to This silylation procedure is known and available in the art. Treatment of the silylated compound with oxa chloride vyv then provides the acid chloride, which upon reaction with phenol or a suitable substituted phenol yields the silylated phenyl or substituted phenyl ester. Treatment with dilute acetic acid then removes the silyl group, e.g. -0-8i-(CH3).
3 is returned to 10H. These conversion procedures are known in the art.

A preferred method for substituted phenyl esters is that disclosed in US Pat. No. 8,890,872, in which a mixed anhydride is reacted with the appropriate phenol or naphthol. The anhydride is made from this acid with isobutyl chloroformate in the presence of a tertiary amine.

Phenacyl-type esters are made from acids using phenacyl phenacyl bromide in the presence of a tertiary amine. For example, US Pat. No. 8.984.454, German Published Patent Application No.
, 585, 693 and Downend Farm Dock No. 1
See No. 6828X.

1 R, is -CH2-N(R9) (Rts) or -〇-
Compounds in the case of N(R9XR2g) are made from the acid, i.e., the formula 1 product where R1 is -COOH. The reaction order is as follows: [2-Decarboxy-2-amino PGF
Compounds”. For example, an acid compound is converted to a mixed anhydride and then to an amide. Carboxylic reduction of amides creates amines. Instead, the mixed anhydride is converted to an azide and then to a urethane from which primary or secondary substituted amines are readily available by methods known in the art.

The compounds of the present invention also include lower alkanoates. The term "lower alkanoate" as used herein refers to a nitric acid alkanoate having 1 to 8 carbon atoms. Examples of such alkanoic acids are formic acid, acetic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid and their isomeric forms.

Compounds of formula I prepared by the above method are converted to lower alkanoates by interaction with a carboxylic acidifying agent, preferably an anhydride of a lower alkanoic acid, i.e. an alkanoic acid of 1 to 8 carbon atoms. be done. For example, use of acetic anhydride yields the corresponding diacetate t. Similarly, use of propionic anhydride, isobutyric anhydride, and hexanoic anhydride yields the corresponding carboxyacylates.

Carboxylation is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine. A substantial excess of anhydride is used, preferably from about 10 to about 1.000 moles of anhydride per mole of hydroxy compound reactant. The excess anhydride serves as a diluent and solvent for the reaction.

Inert organic diluents (eg dioxane) may also be added. It is preferred to use a sufficient amount of tertiary amine to neutralize the free carboxyl groups present in the carboxylic acid as well as hydroxy compound reactants created by the reaction.

Preferably, the carboxyacylation reaction is carried out at a temperature ranging from about 0° to about 1000°. The required reaction time will depend on factors such as reaction temperature and the nature of the anhydride. At reaction temperature of acetic anhydride, pyridine and 25C, 12-24
A reaction time of hours is used.

The carboxyacylated product is isolated from the reaction mixture by conventional methods. For example, excess anhydride is destroyed with water, the resulting mixture is made acidic, and then extracted with a solvent such as diethyl ether.

The desired carboxylate is recovered from the diethyl ether extract by evaporation. The carboxylate is then purified by conventional methods, preferably by chromatography.

Another method for 6-keto compounds of formula I consists of the following steps starting from a halogenated ether of.

(a) This starting material Q+ It is converted into a compound of

fb) The product of step (a) is subjected to dehydrohalogenation and hydrolysis to produce the compound X-(, R 1 Q+.

(C) The product of step (b) is 1 Q! oxidizes to the compound of and (d) hydrolyzing the product of step (C) to produce the compound.

Next is the ceremony! Salts within the range are made from acids of formula (■).

Figure B herein shows the steps of the method.

The starting materials of formula (II) are not the subject of this invention, but will be explained below.

Figure B 1 ↓(d) I I ↓(e) 1 Q.

↓(f) In the first step (dl) of Figure B, the starting material 4[ is the corresponding formula blocking group R21 may be the same as or different from the blocking group R2 of Figure A, but depending on the reagents and procedure. Details have already been described above for step (a) of Figure A.

In step (e) of Figure B, the halogenated compound of formula (1) is subjected to dehydrogenation treatment and hydrolysis to yield a 6-ke) PGF type compound of formula (2). In one method, a halogenated compound (1) is contacted with silver carbonate and perchloric acid in an organic medium such as tetrahydroborane. The reaction is followed by TLC (thin layer chromatography) to determine completion. Usually at about 25C for 15-24 hours. Preferably, the reaction is carried out in the absence of light.

In another method, the no-logogenated compound (1) is treated with de-no-logogenated reagents known in the art.

For example, Fieser & Fieser 1 Organic Synthesis Reagents,” p. 1808, John Wiley & Sons, Inc.
See New York, NY (1967). Useful for this purpose are tertiary amines, preferably 1,5-
Diazabicyclo(4,8,0]nonene-5 (DBN) 1,4-Diazabicyclo(2,2,2)octane (DA
BCO) and 1,5-diazabicyclo(5,4,0:l undecene-
5 (DBU).

The reaction is carried out in an inert medium such as dimethylformamide and followed by TLC to indicate the disappearance of starting material. The reaction proceeds at 25C and can be accelerated at 40-50C. An intermediate enol ether is thereby obtained, which is preferably purified amine-free by washing and then treated with a dilute aqueous acid solution, preferably a Treated with acetic acid.

The 6-keto compound of formula (1) is in equilibrium with the hemiketal of, and is therefore accompanied by, Such hemiketals rapidly equilibrate with the 61-keto compound ■ during oxidation and are converted to the formula V compound in step (f).

In steps (f) and (g), the above product is then oxidized to the formula V compound and finally hydrolyzed to yield the formula I product. Reagents and conditions for these steps are shown in Figure A (
As stated above for b) and (C).

A method for the preparation of 6-kedo18.14-didehydro-PGE type compounds of 2 is disclosed, which consists of the following steps starting from the compound of .

(a) This starting material is subjected to selective mono-logenation and selective demono-hydrogenation treatments to produce a 5,6.14-)lino-logonated compound represented by 1.

(b) reducing the product of step (a) to 2 Create a compound.

(C) Subjecting the product of step (b) to selective rogogenation to produce the compound 1,OH2.

(d) Q by performing norogenation and cyclization.

Create a compound.

(e) the product of step (d) \ H/C-R, 6 μ It is converted into a compound of

(f) The product of step (e) Q.

It is converted into a compound of

(g) oxidizing the product of step (f) to 3 Create a compound.

(h) Hydrolyzing the product of step (g) to replace the capping group R21 with hydrogen, thereby creating a 6-kedo18.14-didehydro PGE type compound of formula X.

Diagram C herein shows the method steps.

The starting material of formula x1 is a 15-oxoPGF type compound known in the art or obtainable by methods described herein or by methods known in the art. See, eg, US Pat. No. 8,728,882.

It is not important which one is used, since both the Δ5.6-cis and 5.6-1-lance compounds ultimately yield the desired Formula X compound.

Figure C ρ■ I ↓ (h) ↓ (i) 2 ↓ 0) H 2 ↓ (k) 2 ↓ (1) 3 ↓ (m) 1 3 ↓ (0) U3shi-t;-526 1 Q! In the first step (h) of diagram C, a compound of formula XI) IJ... is prepared, for example, by reaction of a compound of formula XI with viridinium hydrobromide perpromide in pyridine. Other novelizing agents are useful, such as ttfN-bromo- or N-chlorosuccinimide. Other tertiary amines are useful for selective on-membrane hydrogenation.

In step (i), the compound of formula X is obtained as a mixture of alpha and beta hydroxy isomers by reduction of XrI. Any known ketone carboni)V reducing agent may be used for this reduction that does not reduce ester or acid groups or reduce carbon-carbon double bonds when reduction is undesired.

Examples of these are metal borohydrides, in particular sodium, potassium and zinc borohydride, lithium (tri-tert-butoxy)aluminum hydride, metal trialkoxyborohydrides such as sodium trimethoxyborohydride, lithium borohydride or hydrogen. diisobutylaluminum oxide. For the preparation of prostaglandin derivatives of the preferred natural configuration, the alpha form of a compound of formula X1 is separated from the beta isomer by silica gel chromatography using methods known in the art.

In step (j) the C-5 and C-6 halogen atoms are removed by selective dehalogenation, e.g. contact with zinc in methanolic ammonium chloride, yielding a formula XIV monohalogenated gold compound. Other items within the scope of XfV
- Rodanized compounds are known in this art. See, eg, US Pat. No. 4,029,681.

In step (k), the formula XN compound is halogenated and cyclized to yield the formula xv/-halogenated ether. Various methods are available for this purpose. For iodine compounds, use an aqueous solution system containing iodine, potassium iodide, and an alkali carbonate or bicarbonate, or an organic solvent system such as dichloromethane containing iodine in the presence of an alkali metal carbonate. It's fine. The reaction is carried out below 25C, preferably at about θ~5C for 10-20 hours. The reaction was then quenched with sodium sulfite and sodium carbonate, formula XV
Separate the compound from the reaction mixture.

For bromo compounds, N-promosuccinimide or N-bromoacetamide are useful.

Fieser et al., [Organic Synthesis Reagents J (Reagents
for Organic 5 synthesis)
See Volume 1, pages 74 and 78, Volume 4, page 51, John Wiley & Sons, Inc., New York.

For chloro compounds, such as the exchange of bromo with chloro using the silver salt of chlorodifluoroacetic acid,
Various methods are available. I.T. Harris 7
(1, T, Harrison) etc., Compend
ium ofOrganic 5ynthetic M
ethos, p. 846, 1.971, Wiley Interscience, New York.

The halogenated compound of formula X■ is obtained as two isomers with different chromatographic mobilities, one in minor amounts and the other in major amounts. These c-5 and c-6 isomers can be separated by silica gel chromatography, but are usually not separated as they all yield the desired formulas X, X, and X compounds.

In step (1) compounds of formula XI are made by substitution with blocking groups Rtt known in the art.

In step ←), the compound of formula XVI is treated with a dehydrohalogenation reagent,
Preferably upon treatment with potassium tert-butoxide, formula
(2) Generates 6-ke)-PGF type compounds.

The remaining steps (n) and (0) of the method are similar to those in Figure A. In step (n), the compound of formula X■ is oxidized as in step (b) of diagram A. At stage (0), Figure A
As in step (C), the compound of formula X is hydrolyzed to remove the capping group.

Now referring to the diagram, the formula I6-kedo PGF in diagram A,
The sources of the type a starting material and the formula halogenated ether starting material of Figure B are shown.

Figure D H 11 ↓(p) 1 ↓(q) I XX Formula XIx Starting materials are available or readily available by methods known in the art. For example, PGF2. No. 8,706,78 for
See No. 9. 15-methyl- and 15-ethyl-PGF
2a, see US Pat. No. 8,728.882. See US Pat. No. 8,908,181 for 16.16-dimethyv-PGF2°.

x6. U.S. Pat. Nos. 8,962,298 and 8,969,8 for
See No. 80. 16-7e/xy-17, 18, 19,
For 20-tetranyv-PGF2a, see Downend Farm Dock No. 78279U. 17
-phenyl-18,19,20-)linol-PGF'2
For a, Downend Farm Dock No. 81279
See T. For 11-deoxy-PGF, a see Downend Farm Dock No. 10695 V. 2a, 2b-dihomo-PGF2a by Downend Farm Dock No. 61412S and U.S. Pat. Nos. 8,852,816 and 8,974,159.
See issue. See US Pat. No. 8,928,861 for 8-oxo-PGF 2a. 3-oxa-17
-Feni/l'-18,19,20-)LinoμmPGF
No. 8,931.2a for U.S. Patent No. 8,931. See '289. For substituted phenacyl esters, see Downend Farm Dock No. 16828X. U.S. Pat. No. 8,890,87 for substituted phenyl esters.
See issue 2. See US Pat. No. 8,636,120 for c-1 alcohols, 2-decarboxy-2-human 7a-oxymethyl compounds. U.S. Pat. No. 8,982,88 for c-2-tetrazolyl derivatives.
See No. 9. Downend for Δ2-PGF2a
See Farm Doc No. 46497 W and German Published Patent Application No. 2,460.285. 5.6-) Lance-
U.S. Patent No. 8,759,978 for PGF2a
See issue. For 2,2-dimethy#-PGF2a analogs see Downend Farm Dock No. 59088 T and German Published Patent Application No. 2,209,089.

11β-PGF2a compounds in U.S. Patent No. 8,
See No. 890,871. 11-deoxy-PGF2.
For K, Downend Farm Dock No. 10695
See No. V. U.S. Pat. No. 8,981,2 for 11-deoxy-11-hydroxymethyl-PGF2a.
See No. 82 and No. 8,950,868. For 16-methylene-PGF2a, see Downend Farmdoc No. 19594 W and German Published Patent Application No. 2.440.
, No. 919. 17.18-didehydro-PGF2
See US Pat. No. 8,920.726 for compound a. 8-(or 4-)oxa-17°18-didehydro-pGF2a compounds are described in U.S. Pat.
See No. 920,728. See US Pat. No. 8,728,882 for 15-oxo-PGF2a. 1
For 5-deoxy-PGF2a, see Downend Farm Dock No. 9289 W. See US Pat. No. 8,982,479 for 13.14-cis compounds. For 11-deoxy-15-deoxy-pGF za, please contact Downend Farm Dock No. 5694 U.
See. For ω-homo PGF2a compounds, see Downend Farm Dock No. 4728W. 2.2
-Schiff-Oro-See Downend Farm Dock No. 67488 R for the PGF2a compound.

For 2-decarboxy-2-amino-PGF2a compounds, see the section taken from the prior co-owned United States patent application and incorporated herein.

The starting material XIX is subjected to halogenation and cyclization in step (p) of the design to yield the halogenated compound of formula (1).

For this purpose, any of the -F halogenation methods for step (k) of Figure C may be used. Again, it is immaterial whether the 5,6-cis compound of formula XIX or the 5,6-trans compound is used, or which isomer of the halogenated compound of formula (2) is used.

In step (q), the halogenated compound is converted by dehydrohalogenation and hydrolysis into a mixture of compounds 1 and Xx. See, for example, method step (e) in Figure B above.

Figure E of this specification is A-4;-R.

++ XXV Shows the steps in the preparation of O2-delyρboxy-2-hydroxymethyl compound.

Figure E □ 1 1 ↓ (r) Bright ↓ (-) ↓ (1) When the formula XXI starting materials in Figure E are known in the art) and when R4 is n-bench μ, Corie
ey ) et al., J, Am, Chem, Soc, vol. 92, 89
See page 7 (1970). When R4 is s + CCgH2gOH3 6 where R6 and R6 are methyl or ethyl, see US Pat. No. 8,954,888. R6 and 86 National Patent No. 8,864,887 and No. 8,981,279O
R<2>tons are prepared by methods known in the art such as via 11-mesylate or 11-tosylate to obtain lactones with the corresponding 11α configuration.

It can be obtained by appropriately blocking the C-15 position and isomerizing it if desired.

See U.S. Pat. No. 8,981,279 and Downend Farm Dock Abstract No. 10695 V. When R4 is phenyl substituted, the same synthesis No. 2,487
, No. 622 and Downend Farm Dock No. 12714.
See W. For example, the compound is reduced to the corresponding one CH,OH compound at the -COOH position using diporan and then reacted with a suitable capping agent.

In step (r) of diagram E, the starting material XXI has the formula Li -C20-(CHt)rC(R1)z-CHz-0-8i(
CHs)sXx■ is condensed with an alkynyllithium compound. Sea, Ecchi, Su7 (C0H0Lin) etc., Syntheti
cCOmm, vol. 6, p. 503 (1976) and Lin, J.
, Org, Chem, vol. 41, p. 4045 (1976
See ). Lithium compounds are conveniently prepared in situ from silylated alkynes by reaction with methyl- or butyllithium in an ether such as diethyl ether or tetrahydrofuran. To work up the product, the siliμ group is easily removed to yield XXI.

In step (-) the formula XXI compound is oxidized at the C-9 position, preferably by Jones reagent. At this stage c-
1 Some of the alcohol groups are oxidized to carboxylic acid groups. These are then methylated with diazomethane to facilitate removal of by-products by chromatography. THP
Replacement of the capping group R□ with hydrogen in a conventional manner, such as mild acid hydrolysis to yield the compound IIXXIV.

At step (t3), compound XXIV is
14 or CI? ~01g XX without reducing ethylene bonds
It is reduced to V compound. Catalytic hydrogenation with palladium over barium sulfate is useful for this purpose, for example.

Figure F herein shows the steps in the preparation of the 6,15-diketo compound. Starting materials are formula XXVI 6-kedo PGF1a type and formula XXW
It is an equilibrium mixture of hemiketal compounds. For example, Johnson 7, etc., J, Am, Ch
em.

See Soc, Vol. 99, p. 4182 (1977).

Figure F R2, is added. For example, in the case of dihydrobilane, the main product is bis(TH
P ether).

In step (v), the free acid is produced by saponification and acidification of the carboxylic ester groups.

In step (-), the blocked 6-kedo PGF1a type compound of 2XXX II is converted into a compound of formula XX with e.g. Jones reagent.
XIV 6.15-s”y)-PGEt type compound.

Finally, in step (x), the capping group is removed in a conventional manner to yield the formula xxxv product.

Figure 1 shows steps in a preferred method for producing amides.

The starting materials for Formula XXXW are 5-halogenated acids within the scope of Formula ■ of Diagram B herein.

Figure G II ↓(y) Q+ ↓(z) Q.

↓(,a) II ↓ (bb) In step (y), the 2XXXVI halogenated acid is converted to the amide xXX■, for example via a mixture. To this end, compound XXXVI is treated with isobutyl chloroformate in the presence of a tertiary atom such as triethylamine, followed by an amine of formula HN(RO) (R2M). : Dehalogenation of halogenated amide XXX■ on the first floor (z)＼
When subjected to hydrogenation and hydrolysis, a compound of formula XXX■ is obtained. Silver carbonate and perchloric acid are useful for this purpose.

In step (aa), with appropriate blockade at C-11 and C-15, -PGF, a-type compound, for example about -15 L-20t:', which is heavily used in Jones reagent. It is acidified to the PGE1 compound by methods known in the art.

At step (bb) after old age, removal of the blocking group results in the compound <L
will occur.

Although these figures depict formulas drawn with specific configurations for the reactants and products, the first method step represents not only the optically active isomer of the other, but also racemic or enantiomeric mixtures. It should be understood that it is intended to apply to mixtures including the following.

If an optically active product is desired, an optically active starting material or intermediate is used, or if a racemic starting material or intermediate is used, the product is divided by methods known in the art.

The products produced from each reaction step are often mixtures and may be used as is in the next step, or optionally subjected to fractionation, column chromatography, liquid reaction, etc. before proceeding, as known to those skilled in the art. - May be separated by conventional methods such as liquid extraction.

It is converted to the case of H. Compounds in which the CI3 to CI4 group
-, or converted to another compound in the case of -CH, CH, -. For example -C=C- is obtained by selective bromination and dehydrobromination. Compounds where the C2 substituent is 100OR3, e.g.
-substituents, such as CH, OH or -C-N (RoXRt
s) is converted into another compound with s).

Formulas with blocking groups ■ (Figure A), XVI (Figure C), XXN
(Panel E), XXXIV (Panel F), and XXXIK (Panel G) are useful as intermediates in various methods of making other useful compounds described herein or known in the art. It is.

To obtain the optimal combination of specificity of biological response, potency, and duration of activity, a range within formula 1 is preferred, where R8 is particularly preferred.

is preferred.

Another option for compounds of formula I is for R,
-The R port in COOR3 is either hydrogen, alkyl of 1 to 12 carbon atoms, or a salt of a pharmacologically acceptable cation. Furthermore, when R3 is alkyl, it is even more preferred that it is an alkyl of 1 to 4 carbon atoms, especially methyl or ethyl.

For purposes of long-term storage stability, it is preferred for Formula 1 compounds that R8 in -COOR3 is an amide substituted phenyl or phenacyl as exemplified herein.

For oral administration of compound ■, R1 is ? -C-N(ReXRzs) is preferred, and it is particularly preferred that at least one of 9°R. and Rts is hydrogen.

Regarding the variation of D, it is preferred that d is 2.3 or 4, especially 2. When both R2 are fluoro, R8 in Q is methyl or R4 is CH3-C-(CH2)3-CH.

CH8 It is preferable that

R4 in the compound of formula 1 is -C-CgH2, -CH.

When R6, it is preferred that CgH2g is alkylene of 2.3 or 4 carbon atoms, and especially that it is trimethylene. Furthermore, it is preferred that R and R6 are hydrogen, methyl, ethyl or fluoro and are the same or yjl. Furthermore, when RII and R6 are not hydrogen, it is preferred that both R6 and R6 are methyl or fluoro. R, is n
-pentyl, 1,1-dimethylpentyl or 1,1-difluoropentyl are particularly preferred.

Formula ■ R4 in the compound is 6 When , S is preferably zero or l.

When s is not -'a, T is methyl, chloro, fluoro, trifluoromethyl, or methoxy in a meta or para bond to the phenyl ring; preferred. z is r
*S(-0-)o Kid, 'R, and R6 are hydrogen, methyl, or ethyl, preferably the same or different. Furthermore, when R3 and R6 are not hydrogen, it is preferred that both R and R6 are methyl. When 2 is CjH2J,
Preferably, CjH2j is a valence bond, methylene or ethylene. It is particularly preferred that R4 is -C12-0-<III> or -C2H, -.

In Figure H, PGF2a of formula C7 or 11-deoxy-P
The GF2a type free acid has the formula ('Iy, cyl, c■・0■
Provided are methods for converting Cl or CX into various 2-decarboxy-2-aminomethyl-2-decarboxy-2-(substituted amine)methyl-PGF" a- or 11-deoxy-PGFa type compounds. .

HO↓ ↓ I(Q By the procedure in Figure H, formula CI compounds are converted to formula C■ mixed acid anhydrides. These mixed anhydrides are converted into the corresponding alkyl, Conveniently prepared from aralkyl, phenyl, or ha-substituted phenyl chloroformates. Diluents for the reaction include water in combination with a water-miscible organic solvent (e.g., tetrahydrofuran). This mixed anhydride is then of the formula C,' l[P
The G-type theamide is converted to the formula CvPG-type azide.

For the preparation of PGF2a type amide (formula Mido), a mixed acid anhydride is reacted with liquid ammonia or ammonium hydroxide.

Alternatively, Formula C compounds are made from the Formula CI free acid by methods known in the art for converting carboxylic acids to the corresponding carboxamides. for example,
The free acid is converted to the corresponding methyl ester using methods known in the art, for example using an excess of ethereal diazomethane, and the methyl ester thus produced converts the formula C1 mixed acid anhydride to the formula C amide. is converted to the formula C■ amide using the method described above.

Next, 2C■ 2-decarboxy 2-aminomethyl-PG
The F2a- or 11-deoxy-PGFzaG compound is
Prepared from formula CIII compounds by carbonyl reduction. Methods known in the art are used for this conversion. For example, it is convenient to use lithium aluminum hydride.

Formula C* compounds can alternatively be used to make Formula C* thiazides. This reaction is conveniently carried out using sodium azide according to methods known in the art. For example, Feaser and Feaser - "Organic synthesis reagents"
See Vol. 1, pp. 1041-1043. In it, reagents and reaction conditions for azide formation are discussed.

Finally, formula CVI urethanes are made from formula Cv thiazides by reaction with alkanols, alkanols, phenols, or substituted phenols. For example, when methanol is used, formula CVI compounds are created where k32 is methyl. This formula CVIPG type product is then used to prepare a formula C■ or C■ product.

In the preparation of formula C■ primary amines from formula CVI urethanes,
Methods known in this field are used. Thus, for example,
Treatment of Formula C urethanes with strong bases at temperatures above 50°C is used. For example, sodium, potassium or lithium hydroxide is used.

Instead, a formula CVI compound is used to prepare a formula C■ compound. Thus, when Lo is alkyl, R32
Reduction of a formula CVI urethane where is alkyl produces a formula C⋅ compound. Lithium aluminum hydride is a conveniently used reducing agent for this purpose.

The Formula C product is then used to make the corresponding IC urethane by reaction of a IC secondary amine (L2 is alkyl) with an alkyl chloroformate. The reaction then proceeds in a manner known in the art for making carnolito from the corresponding secondary amine. Finally L2
and L3 are both alkyl, the product of formula CX is of formula C■
Produced by reduction of carbamide. Therefore, the method described above is used for the preparation of the 2C■ compound from the formula 1 compound. Optionally, the various reaction steps herein include R2□
may proceed by the use of blocking groups, thus requiring subsequent hydrolysis in making each of the above various products. The methods described above are used for the introduction and hydrolysis of blocking groups by R2□.

Finally, the methods described above for converting formula CII compounds into formula CII compounds and various subsequent compounds result in the shortening of the 8α side chain of the formula CI compound by one carbon atom. Therefore, the formula CI starting material should be selected to compensate for the methylene groups consumed in the above synthetic steps. Thus, if a 2a-homo product is desired, the corresponding formula C 2a.

A 2b-dihomo starting material must be used.

The invention is further illustrated by, but not limited to, the following examples.

All temperatures are in Serra's degrees.

Infrared M (IR) absorption spectra were recorded on a Perkin-Kulmer model 421 infrared spectrophotometer. Unless otherwise specified, undiluted (
unadulterated samples are used.

Nuclear magnetic resonance (NMR) spectra are Parian A-60
, A-60D, T-60 or XL-100 spectrophotometer in deuterochloroform solution with tetramethylsilane as internal standard (downfield).

Mass spectra were performed on a Parian model MAT CH7 mass spectrometer, a CEC model 110B dual focus high resolution mass spectrometer or an LKB model 9000.
Recorded on a gas chromatography mass spectrometer (ionization voltage 22 or 70 electron volts), samples are usually carried out as TMS (trimethylsilyl) derivatives.

As used herein, "brine" refers to a saturated aqueous solution of II chloride.

In this specification, "DBNJ" means 1,5-diazabicyclo(
4,3,0) nonene-5.

CycloC2,2,2': l octane.

In this specification, “DBUJ means 1,5-diazabicyclo[
. 5.4.01 Undecene-5.

[DIRALJ in this specification refers to diisobutylaluminum hydride.

"E" and rZJ herein are in accordance with Blackwood et al. cited above.

In the present specification, "Florisil Co., Ltd." is a magnesium silicate for chromatography manufactured by Florizoin Co., Ltd. Fieser et al., “Organic Synthesis Reagents J, p. 393,
See John Wiley & Sons, Inc., New York, NY (u967).

In this specification, "HPLCJ" refers to high pressure liquid chromatography.

As used herein, "Skerisolve B" refers to mixed isomer hexanes.

In this specification, “TIIPJ is tetrahydropyran-2-
I'm talking about Ile.

As used herein, "TLC" refers to thin layer chromatography.

As used herein, "concentration" refers to reduced pressure, preferably 50
．． This refers to concentration at temperatures below 35°C and below 35°C.

As used herein, "drying" refers to contacting a compound in solution with an anhydrous reagent, such as sodium sulfate or magnesium sulfate, to remove water and filtration to remove solids.

As used herein, silica gel chromatography is understood to include elution, collection of fractions, and combining the fractions shown by TLC to contain the starting material and the desired product free of impurities. Ru.

The solvent systems used in thin layer chromatography are M Hamberg (M, Hamberg) and B Samuel V7 (B, Samuelsson),
J, Biol Chem, vol. 241, p. 247 (196
6) from ethyl acetate-acetic acid-2,2,4-trimethylpentane-water (90:20:50:100).

Preparation Example 1 5ξ-iodo-9-deoxy-6,9-epoxy-PGFia methyl ester (formula ■: D is -(CI
K2) 3-1Q is H. H1H "19 is -C00CH3 and X is trans-CH=CH
7) See diagram. 11.15-bis(
A suspension of 2.0 y of PGF2a methyl ester as (tetrahydropyranyl) ether is treated with 0.7 y of IJ (bicarbonate) and cooled in a water bath.

1.93 F of potassium iodide and 2.82 F of iodine are added to the resulting solution and stirring is continued at about θ° C. for 16 hours.

A solution of 1.66 F of sodium sulfite and 0.76 y of sodium carbonate in 10 d of water is then added. After 2-3 minutes, the mixture is extracted with chloroform. Wash the organic phase with brine;
Drying over sodium sulfate and concentrating yields an oil primarily of bis(tetrahydropyranyl) ether of the title compound.2.
yields 2y. Hydrolysis of this solution in acetic acid-water-tetrahydrofuran (20:10:3) yields primarily the title compound. This is further purified by silica gel chromatography. RfO,20 (TLC on silica gel with acetone-dichloromethane (30 nia)).

The mass-vector peak for the formula ■ compound (TMS derivative) is 638.623.607.567.548.51
1 and 477.

Following the procedure of Preparation Example 1 as shown in the diagram, but formula
In place of X starting material, the following formula XIX compounds or C-1
1 derivatives, namely 15-methyl-PGF2a (15R)-15-methyl-PGF2a15-ethyl-
PGF2a 16.16-dimethyl-PGF2a 16.16-difluoro-PGF2a 16-phuninoxy 17.18,19.20-tetratrue PGF2a 17-phenyl-18,19,20-1 linol-PGF
11-deoxy-PG F 2 aa 2a, 2b-dihomo-PGF2a 3-oxa-PGF2a '3-oxer 17-phenyl-18,19.20-trinor-P GF 2 a Using the corresponding formula ■Iodo A compound is obtained.

See diagram. A solution of the methyl ester of the formula (I) iodo compound (Preparation Example 1.o, +sf) in 20.1 ml of tetrahydrofuran was mixed with 0.250 y of silver carbonate and perchloric acid (70%, 0.0 y).
10. Z) and stirred at about 25°C for 24 hours.

The mixture was diluted with 25 me of ethyl acetate, the organic phase was washed with saturated sodium carbonate solution and brine, dried and reduced to an oil, 4 i
Concentrate to y. Separation by silica gel chromatography and elution with ethyl acetate-Kelisolve B (3:l) yields the formula I11 title compound as a more polar material than the formula I starting material.

The product is 0.32p oil. BE□, 38 (T on silica gel with acetone-dichloromethane (1:l)
LC).・The infrared spectrum peak is 1740° for carbonyl, and the NMR peak is 5.5.3.2~4
．． 8.3.7.2.1-2.7δ.

Preparation Example 3 5ξ-iodo-1-deoxy-6ξ.

9α-epoxy-PGF, mixed isomers (formula ■) and 9-deoxy-6ξ,9a-epoxy-6ξ-hydro'F PG F1 (formula XX) and 6-ketoPG
F l (formula ■) A solution of the formula ■ iodine compound methyl ester (preparation example 1.1.0 g) in methanol 30 g/methanol was mixed with 20 d of 3N potassium hydroxide aqueous solution at about 0°C for about 5 minutes, then about 25 min. Treat at ℃ for 2 hours. 2N acidic potassium sulfate 45d and water 50m
The mixture is acidified with / to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated to an oil of 1.3F. The oil is chromatographed on silica gel and eluted with acetone-dichloromethane (30:7G to 50:50), yielding first the free acid compound of formula I and later the mixed formula II and XX compounds as more polar fractions.

, the formula (II) compound is oil 0.33r. RfO, 33 (TLC on silica gel with acetone-dichloromethane (1:l) plus 2% acetic acid). [α), = +20°c 1710.1455.1410.1380.1235.
1185.1075.1050.1015.970, and 7'30 (II.

Mass spectrum peak (TMS derivative) is 696.2
554.681.625.606.569.535.4
The mixture of 79 and 173°9-deoxy-6ξ,9α-epoxy-6ξ-hydroxy-PGF and 6-keto PGF1a is a solid 0.113F. It has a melting point of 93-98°C and does not contain any iodine. R[0,13 (TLC on silica gel with acetone-dichloromethane (1:1) plus 2% acetic acid
). Mass spectrum peak (TMS derivative) is 587
．． 568.553.497.485, 478.407.
395, 388, and 173° Following the procedures of Preparations 2 and 3, but substituting the formula ■ iodo compound described after Preparation Example 1 in place of the formula ■ iodo compound, the corresponding formulas ■ and -
Compound XX is obtained.

Compounds of the formula 9-deoxy-6,9-epoxy-5-halo PGFla type, including iodo, bromo and chloro compounds, by following the procedures of Preparation Examples 1.2 and 3 above, but using the corresponding starting materials. , a compound of the formula 1 [6-kedoPGFla type, and a compound of the formula xx g-deoxy-6,9-epoxy-6-hydroxy-PGFla type, which have the following structural characteristics.

16-Methyl-1 16,16-dimethyl-, 16-fluoro-1 16,16-difluoro-1 17-phenyl-18,19,20-)linol-1, 17
-(m-trifluoromethylphenyl)-u8,19.
20-trinor-1 17-(m-rioo7z=l)-18,19,20-trinor-1 17-(p-fluorophenyl)-18,19,20-
Trinor-1 16-methyl-17-phenyl-18,19,20-trinor-1 16,16-dimethyl-17-phenyl-18,19゜20-trinor-1 16-fluoro-17-phenyl-18,19, 20-
Trinol-1 16,16-difluoro-17-phenyl-18゜19
．． 20-trinor-16-funinoxy17.18,19.20-tetratrue, 16-(m-)lifluoromethylphenoxy)-17,
18,19,20-tetratrue, 16-(m-rioo
7z/xy) -17,18,19゜20-tetratrue, 16-(p-fluorophenoxy)-17,18゜19
．． 20-tetratrue, 16-funinoxy18.19.20-)linolue, 1
6-Methyl-16-phenoxy-18,19,20-trinor-1 16-methyl-13,14-didehydro-1.16.1
6-Simethyl-13.14-didehydro-116-fluoro-13,14-didehydro-116,16-difluoro-13,14-didehydro-117-phenyl-1
8,19,20-trinor-13゜14-didehydro-
1 17-(m-)lifluoromethylphenyl)-18,1
9,20-)Tunoru13.14-didehydro-117
-(m-rioophenyl)-18,19,20-trinor-13,14-didehydro-117-(p-fluorophenyl)-18,19°20-trinor-13,14
-didehydro-116-methyl-17-phenyl-18
,19,20-trinor-13,14-didehydro-1
16,16-dimethyl-17-phenyl-18,19゜20-trinor-13,14-didehydro-116-fluoro-17-phenyl-18,19,20-dolinol-13,14-didehydro-116,16-difluoro- 17-phenyl-18゜19.20-trinor-13
, 14-didehydro-116-funinoxy 17.18
, 19.20-f Tratrue 13.14-didehydro-1 16-(m-trifluoromethylphenoxy)-17,
18,19,20-fto5/nt-13,14-didehydro-1 16-(m-chlorophenoxy)-17,18,19°20-tetratrue-13,14-didehydro-116-
Funinoxie 18.19.20-) Rinoru 13.1
4-didehydro-1 16-1 thyl-16-7e/xy-18,19,20-
Trinor-13,14-didehydro-113,14-dihydro-1 16-methyl-13,14-dihydro-1,16,16
-Simethyl-13.14]dihydro-116-fluoro-13,14-dihydro-116,16-difluoro-
13,14-dihydro-117-7Znyl-18,19
,20-tIJ/ru 13゜l4-dihydro-1 17-(m-trifluoromethylphenyl)-18,1
9,20-trinor-13,14-dihydro-117-
(m-rioo7znyl)-18,19,20-trinor-13,14-dihydro-117-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-116-methyl-17 -phenyl-18,19
,20-trinor-13,14-dihydro-1 16,16-dimethyl-17-phenyl-18,19°20-trinor-13,14-dihydro-116-fluoro-17-phenyl-18,19,20-trinor −
13,14-dihydro-116,16-difluoro-1
7-phenyl-18゜19.20-trinor-13,1
4-dihydro-116-funinoxy 17.18,19
．． 20-tetratrue 13.14-dihydro9-9 -116-(trifluoromethylphenoxy)-17,
18,19,20-tetratrue 13.14-dihydro-1 20-tetratrue 13.14-dihydro-116-(
p-fluorophenoxy)-17,18゜19.20-
Tetratrue 13.14-dihydro-116-phninoxy 18.19.20- ) Linole 13.14-dihydro-1 16-methyl-16-phenoxy-18,19,20-
Trinor-13,14-dihydro-12,2-difluoro-1 2,2-difluoro-16-methyl-12,2-difluoro-16,16-dimethyl-, 2,2-difluoro-
16-fluoro-12,2-difluoro-16,16-
difluoro-12,2-difluoro-17-phenyl-
18,19゜20-trinor-1 2,2-difluoro-17-(m-trifluoromethylphenyl) -18,19,20-1-IJ / Ru, 2,2-difluoro-17-(m-chlorophenyl )
-18,19,20-)linol-2,2-difluoro-17-(p-fluorophenyl)-18,19,20
-trinor-1"2,2-difluoro-16-methyl-
17-phenyl-18,19,20-trinor-12,
2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-)linol-2,2-difluoro-16-fluoro-17-phenyl-18,19,2
0-trinor-12,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-)linol-2,2-difluoro-16-phuninoxy 17,
118゜19.20-tetratrue, 2,2-difluoro-16-(m-)lifluoromethylphenoxy)-17,18,19,20-tetratrue, 2.2-difluoro-16-(In-chlorophenoxy) -17,18,19,20-tetratrue, 2.2-
Difluoro-16-funinoxy 18.19゜20-trinor-1 2,2-difluoro-16-methyl-16-funinoxy 18.19.20-)linol-2,2-difluoro-16-methyl-16-funinoxy 18 .19.20
-) linol-2,2-difluoro-16-methyl-1
3,14-didehydro-1 2,2-difluoro-16,16-dimethyl-13゜1
4-didehydro-1 2,2-difluoro-16-fluoro-13,14-didehydro-1 2,2-difluoro-16,16-difluoro-13,
14-didehydro-1 2,2-difluoro-17-phenyl-18,19゜2
0-trinor-13,147 didehydro, 2,2-difluoro-17-(m-1-lifluoromethylphenyl)-18,19,20-trinor-13゜14-didehydro-1 2,2-difluoro-17 -(m-chlorophenyl)-
18,19,20-) dinor-13,14-didehydro-1 2,2-difluoro-17-(P-fluorophenyl)
-18,19,20-1-Lino-13.,14-didehydro-1 2,2-difluoro-16-methyl-17-phenyl-
18,19,20-) reflu 13.14-didehydro-1 2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-) dinor-13,14-didehydro-1 2,2, 16-) refluoro-17-phenyl-18,
19,20-trinor-13,14-didehydro-12
,2,16,16-tetrafluoro-1fuphenyl-
18,19,20-trinor-13,14-didehydro-1 2,2-difluoro-16-phetoxy17,18°19.20-tetratrue 13,14-didehydro-1
2,2-difluoro-16-(m-trifluoromethylphenoxy) -17,18,19,20-tetratrue 13.14-didehydro-1 2,2-difluoro-16-(m-chlorophenoxy'
) -17,18,19,20-Tetra True 13゜1
4-didehydro-1 2,2-difluoro-16-funinoxy 18°19.
20-) Reflu 13.14-didehydro-12,2-
Difluoro-16-methyl-16-funinoxy18.
19.20-) Reflu 13.14-didehydro-1 2,2-difluoro-13,14-dihydro-12,2
-difluoro-16-methyl-13,14-dihydro-
1 2,2-difluoro-16,16-cystyl 13゜1
4-dihydro-1 2,2,1-rotrifluoro-13,14-dihydro-
12,2,16,16-tetrafluoro-13,14-
Dihydro-1 2,2-difluoro-17-phenyl-18,19゜2
0-trinor-13,14-dihydro-12,2-difluoro-17-(m-)lifluoromethylphenyl)-
18,19,20-trinor-13゜14-dihydro-
1 2,2-difluoro-17-(m-chlorophenyl')
-18,19,20-trinor-13,14-dihydro-1 2,2-difluoro-17-(P-fluorophenyl'
)-18,19,20-) Reflu 13.14-dihydro-1 2,2-difluoro-16-methyl-17-phenyl-
18,19,20-trinor-13,14-dihydro-
1 2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-1 2,2,1 lotifluoro-17-phenyl-18゜19.20- ) Reflu 13.14-dihydro-12,
2,16,16-tetra,fluoro-17-phenyl-
1g, 19.20-trinor-13,14-dihydro-1 2,2-difluoro-16-phetoxy 17,18°19.20-tetratrue 13.14-dihydro-12
,2-difluoro-16-(m-)lifluoromethylphenoxy)-17,18,19,20-tetratrue 1
3.14-dihydro-1 2,2-difluoro-16-(m-chlorophenoxy)
-17,18,19,20-Tetra True 13°14-
Dihydro-1゛2,2-difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetratrue 13゜14
-dihydro-1 2,2-difluoro-16-phninoxy18.19゜20-trinor-13,14-dihydro-12,2-difluoro-16-methyl-16-phenoxy-18,1
9,20-trinor-13,14-dihydro-1 16-methyl-cis-13-1 16,16-dimethyl-cis-13-116-fluoro-cis-13-1 16,16-cyfluoro-cis-13-117 -Phenyl-18,19,20-trinor-cis-13-1 17-(m-)lifluoromethylphenyl)-18,1
9,20-) rhinorosis-13-117-(m-rio
o7znyl)-18,19,20-trinor-cis-1
3-1 17-(p-fluorophenyl)-18,19゜20-
trinor-cis-13-1 16-methyl-17-7-18, (9,20
-trinor-cis-13-1 16,16-dimethyl-17-phenyl-18,19゜20-trinor-cis-13-1 16-fluoro-17-7z=ru 18,19,20-
Trinor-cis-13-1 16,16-difluoro-17-phenyl-18゜19
．． 20-1 linorosis-13-116-7x/xy-
17, 18, 19, 20-f To5 Truth-13-
1 16-(m-)lifluoromethylphenoxy)-17,
18,19,20-tetratrusis-13-116-
(m-rioo phenoxy) -17,18,19゜20
-tetratrusis-13-1 16-(p-fluorophenoxy)-,17,18゜1
9.20-Tetratrucis-13-116-phenoxy-18,19,20-trinor-cis-13-1 16-methyl-16-phenoxy-18,19,20-
Trinor-cis-13-1 2,2-difluoro-cis-13-1 2,2-difluoro-16-methyl-cis-13-12
,2-difluoro-16,16-dimethyl-cis-13
-1 2,2-difluoro-16-fluoro-cis-13-1
2,2-difluoro-16,16-difluoro-cis-13-1 2,2-difluoro-17-phenyl-18,19゜2
0-trinor-cis-13-1 2,2-difluoro-17-(m-)lifluoromethylphenyl)-18,19,20-)rinorsis-13
-1 2,2-difluoro-17-(m-chlorophenyl)-
18,19,20-trinor-cis-13-12,2-
difluoro-17-(p-fluorophenyl)-18,
19,20-trinor-cis-13-12,2-difluoro-16-methyl-17-phenyl-18,19,2
0-) Linorosis-13-12,2-difluoro-1
6,16-cymethyl-17-phenyl-18,19,2
0-trinor-cis-13-13,2-difluoro-1
6-fluoro-17-phenyl-18,19,20-)
Linorosis-13-12,2-difluoro-16,1
6-difluoro-17-phenyl-18,19,20!
Trinor-cis-13-1 2,2-difluoro-16-fluoro-18-phenyl-19,20-dinor-cis-13-12,2-difluoroli, 16-difluoro-18-phenyl-19,
20-dinor-cis-13-12,2-difluoro-1
6-Fetoxy17゜18.19.20-Tetratrucis-13-12,2-difluoro-16-(m-)
(fluoromethylphenoxy)-17,18,19,2
0-fto5trucis-13-1 2,2-difluoro-16-(m-chlorophenoxy'
)-17,18,19,20-tetratrusis-13
-5 2,2-difluoro-16-(P-fluorophenoxy)-17,18,19,20-tetratrusis-13
-12,2-difluoro-16-funinoxy 18.1
9゜20-trinor-cis-13-1 2,2-difluoro-16-methyl-16-futxy 18.19.20-1-riflusis-13-13-
Oxa-1 3-oxa-16-methyl-1 3-oxa-16,16-cystyl, 3-oxa-1
6-fluoro-1 3-oxa-16,16-difluoro-13-oxa-
17-phenyl-18,19,20-)linoleux, 3-
Oxa-17-(m-)lifluoromethylphenyl”
) -18,19,20-trinor-13-oxa-1
7-(fn-chloroo7xnyl)-18°19.2
0-)Linoru, 3-oxa-17-(p-fluorophenyl)-18,
19,20-trinor-1 3-oxa-16-methyl-17-phenyl-18゜1
9.20-)linol-1, 3-oxa-16,16-dimethyl-17-7enyl-18.19.20-trinor-1 3-oxa-16-fluoro-17-phenyl-18,
19,20-1” linoleum, 3-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13-oxa-16-
Funinoxy 17.18,19゜20-tetratrue, 3-oxa-16-(m-)lifluoromethylphenoxy')-17,18,19,20-tetratrue, 3-
Oxa-16-(m-chlorophenoxy)-17,18
,19,'20-tetratrue,3-oxa-16-(
p-fluorophenoxy)-17,18,19,20-
Tetra True, 3-t-t-l-16-7x) key/-
18,19,20-trinor-1 3-oxa-16-methyl-16-funinoxy18.
19.20-)Linoru, 3-oxa-13,14-didehydro-53-oxa-
16-Methyl-13,14-didehydro-13-oxa-16,16-dimethyl-13.14-didehydro-1 3-oxa-16-fluoro-13,14-didehydro-1 3-oxa-16,16-difluoro -13,14-didehydro-1 3-oxa-17-7e: 18,19.20-trinor-13,14-didehydro-13-oxa-17-
(m-trifluoromethylphenyl)-18,19,2
0-)! J/Lou, 13.14-didehydro-1 3-oxa-17-(m-chlorophenyl)-18,1
9,20-trinor-13,14-didehydro-13-
Oxa-17-(P-fluorophenyl)-18,19
,20-trinor-13,14-didehydro-53-oxa-16-methyl-17-phenyl-18°19.2
0-) Reflu 13.14-didehydro-13-oxa-16,16-cymethyl-17-7 enyl 18.19
．． 20-tIJ/A/-13.14-ditehydro, 3-oxa-16-fluoro-17-phenyl-18,
19,20-1 linol-13,14-didehydro-13
-oxa-16,16-difluoro-17-phenyl-
18,19,20-trinor-13,14-didehydro-1 3-oxa-16-funinoxy 17 , 18 , 19
.

20-Tetratrue 13.14-didehydro-53-oxa-16-(m-trifluoromethylphenoxy)-
17,18,19,20-tetratrue 13.14-didehydro-1 3-oxa-16-(m-chlorophenoxy)-17,
18,19,20-tetratrue-13.14-didehydro-1 3-ox4J--16-7e/xy-18,19,2°-trinor-13,14-didehydro-13-oxa-
16-methyl-1,6-phetoxy 18.19.20
-trinor-13,14-didehydro-13-oxa-
13,14-dihydro-13-oxa-16-methyl-
13,14-dihydro-13-oxa-16,16-dimethyl-13,14-dihydro-1 3-oxa-16-fluoro-13,14-dihydro-
13-oxa-16,16-difluoro-13,14-
dihydro-1 3-oxa-17-7z=ru-18,19.20-trinor-13,14-dihydro-1゜3-oxa-17-(m-1lifluoromethylphe-'
-k) -18,19,20-tIJ/Rue 13.14
-dihydro-1 3-oxa-17-(m-chlorophenyl)-18,1
9,20-trinor-13,14-dihydro-13-oxa-17-(p-fluorophenyl)-18,19,
20-) Reflu 13.14-dihydro-13-oxa-16-methyl-17-phenyl-18,19,20-
) Reflu 13.14-dihydro-13-oxa-16
,16-dimethyl-17-phenyl-18,19,20
-trinor-13,14-dihydro-13-oxa-1
6-Fluoro-17-phenyl-18., 19.20-
Trinor-13,14-dihydro-13-oxa-16
,16-difluoro-17-phenyl-18,19.2
0-trinor-13,14-dihydro-13-oxa-
16-Funinoxy 17.18,19゜20-tetratrue 13.14-dihydro-13-oxa-16-(m
-)Lifluoromethylphenoxy)-17,18,19
, 20-tetratrue 13.14-dihydro-1 3-oxa-16-(m-chlorophenoxy)-17,
18,19,20-tetratrue 13.14-dihydro-1 3-oxa-16-(p-fluorophenoxy)-17
,18,19,20-tetratrue-13.14-dihydro-1 3-oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-13-oxa-16-
Methyl-16-Funinoxy 18.19.20-)Reflu 13.14-Dihydro-13-Okifushu-Sisu 13
-1 3-oxa-16-methyl-cis-13-13-oxa-16,16-dimethyl-cis-13-13-oxa-
16-fluoro-cis-13-13-oxa-16,1
6-difluoro-cis-13-13-oxa-17-phenyl-18,19,20-trinor-cis-13-1 3-oxa-17-(m-trifluoromethylphenyl)-18,19,20-) Reflusis-13-13-
Oxa-17-Cm-chlorophenyl)-18,19,
20-trinor-cis-13-13-oxa-17-(
p-fluorophenyl)-18,19,20-trinor-cis-13-13-oxa-16-methyl-17-phenyl-18,19,20-trinor-cis-13-1
3-oxa-16,16-dimethyl-17-phenyl-
1B, 19.20-trinor-cis-13-53-oxa-16-fluoro-17-phenyl-1g, 19.
20-) Reflusis-13-13-oxa-16,1
6-difluoro-17-phenyl-18,19,20-
Trinor-cis-13-13-oxa-16-phetoxy 17.18,19°20-tetratrucis-13
-1 3-oxa-16-(m-)lifluoromethylphenoxy)-1"7.18,19.20-tetratrusis-
13-1 3-oxa-16-(m-chlorophenoxy)-17,
18,19,20-Tetraturusi Sue 13-13-
Oxa-16-(p-fluorophenoxy) 717.1
8,19.20-tetratrucis-13-13-oxa-16-phenoxy-18,19,20-trinor-
Cis-13-1 3-oxa-16-methyl-16-phoxy 18.
19.20-) Reflusis-13-13-oxa-1
3,14-dihydro-trans-14,15-didehydro-3-oxa-16-methyl-13,14-dihydro-trans-14,15-didehydro-13-oxa-16
,16-dimethyl-13.14-dihydro-trans-
14,15-didehydro-13-oxa-16-fluoro-13,14-dihydro-trans-14,15-didehydro-13-oxa-16,16-difluoro-1
3,14-dihydro-trans-14,15-didehydro-13-oxa-17-phenyl-18,19,20
-trinor-13,14-dihydro-trans-14,
15-didehydro-1 3-oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-13-oxa-17-(m -chlorophenyl)-us.

19.20-trinor-13,14-dihydro-trans-14.15-didehydro-1 3-oxa-17-(P-fluorophenyl)-18,
19,20-trinor-13,14-dihydro-trans-14,15-didehydro-13-oxa-16-methyl-17-phenyl-18,19,20-) reflu 13.14-dihydro-trans-14, 15-didehydro-3-oxa-16,16-cymethyl-17-phenyl-
18,19,20-trinor-13,14-dihydro-
trans-14,15-didehydro-13-oxa-1
6-fluoro-17-phenyl-18,19,20-)
Linol-13.14-dihydro-trans-14,15
-didehydro-13-oxa-16,16-difluoro-17-phenyl-18,19,20-) reflu 13
．． 14-dihydrotrans-14,15-didehydro-13-oxa-16-funinoxy 17.18,19
゜20-tetratrue 13.14-dihydro-trans-14,15-didehydro-1 3-oxa-16-(m-)lifluoromethylphenoxy)-17,18,19,20-tetratrue 13゜1
4-dihydro-trans-14,15-didehydro-1
3-oxa-16-(m-chlorophenoxy)-17,
18,19,20-tetratrue-13.14-dihydro-trans-14,15-didehydro-13-oxa-
16-(p-fluorophenoxy)-17,18,19
, 20-tetratrue 13.14-dihydro-trans-14,15-didehydro-13-oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-14°15-didehydro- and 3 -Oxa-16-methyl-16-funinoxy18.
19.20-) Reflu 13.14-dihydrotrans-14,15-didehydro-0 Following the procedures of Preparations 1 to 3 as above, but using the corresponding starting materials, formula 9- Deoxy-6,9-epoxy-5-iodo-PGFla type compounds, formula 6-kedo PGF1a type compounds, and formula xx g-deoxy-6,9-epoxy-6-hydroxy-PGF1a type compounds were prepared; has the following structural properties.

2.3-didehydro-1 2,2-dimethyl-1 2a,2-b-dihomo-1 4-oxa-43-homo-5 7a-homo-1 11β-1 11-deoxy-1 11-deoxy-11 -methylene-1 11-deoxy-11-hydroxymethyl-115β-
1 15-keto-1 15-deoxy-1 15-methyl-15(S) -1 15-methyl-15(R)-1 and 17.18-didehydro-0 Preparation example 4 5ξ-iodo-9-deoxy- 6,9-epoxy-PGFlap-phenyl phenacyl ester (Formula ■) Formula ■Iodo acid compound (Preparation Example 3, Formula ■, 0.20)),
P-phenylphenacyl bromide 0.50F, diisopropylethylamine 0.4- and acetonitrile 10-
Stir the w1 mixture at about 25°C for 40 minutes. This is mixed with dilute aqueous citric acid solution and brine, and extracted with ethyl acetate. Dry and concentrate the organic phase.

The residue was chromatographed on silica gel, eluting with ethyl acetate (25-100%)-Skerisolve B.
The title 5-iodo compound is produced as a colorless oil, 0.20y.

Preparation example 5 2-decarboxylic acid 2-azidomethyl-PG
F2a or 2-true PGF2a azide (formula cv:
z, respectively -CH=CH-<CH2) 3- or -CH=CH-(
CH2)2-1R31 is hydroxy, Yl is trans-
CII=CH-1 R34 and '35 of the L0 part and R33 of the M0 part are all hydrogen, and R2O is n-butyl) A, PGF2a7.1 f, acetone 125 sd
, 10-1 y of water and 2.2 y of hydrethylamine (0
3.01y of inbutyl chloroforme) is added to the solution while stirring. The mixture was stirred at 0 °C for about 30 minutes, at which point sodium azide in 35 me of water
Add the cold solution of . Next, stir the mixture at 0℃ for 1 hour, at which point the water is 300W! and extract with diethyl ether. Combine the organic layers and add water, dilute carbonate solution,
After washing with saturated saline, drying, and concentrating under reduced pressure while keeping the bath temperature below 30°C, 2-True P G F 2
a Produces azide.

B, 2-decarboxy-2-azidomethyl-PGF2a
is produced by the following reaction sequence.

(1) A solution of t-butyldimethylsilyl chloride 10y, imidazole 9.14y and PGF2a3y in 1.2 me dimethylformamide is stirred magnetically for 24 hours under nitrogen atmosphere. The resulting mixture is cooled in a water bath and the reaction is stopped by adding ice water. The resulting mixture is diluted with 150 y of water and extracted with diethyl ether. - Wash the combined ethereal extracts with water, saturated ammonium chloride, sodium chloride solution and then dry over sodium sulfate. When the solvent is removed under vacuum, PGF
2a [-butyldimethylsilyl ester 9,11.15
-Tris([-butyldimethylsilyl ether)] is produced. NMR absorption is 0.20.0.30.0.83.0,
87.0.89.1.07-2.50.3.10-4.
21. and 5.38δ. The characteristic infrared absorption is 970.1000.1060.1250.1355.
Found in 1460, 1720 and 2950.

(2) To a magnetically stirred suspension of lithium aluminum hydride 7,'15f in diethyl ether 18m/- was added the above (
8.71 g of the reaction product of part 1) are added dropwise over 12 minutes at room temperature. After stirring for 1 hour at ambient temperature, the resulting product is cooled in an ice-water bath and saturated sulfuric acid (II) is added dropwise until a milky suspension appears. The resulting product is condensed with sulfuric acid, triturated with diethyl ether and the solvent is removed by suction filtration. Concentration of diethyl ether under vacuum yields 2-decarboxy-2
-Hydroxymethyl-PGF2a9,11.15-1-
Lis-((butyldimethylsilyl ether) 7.(11
4F and is observed at 3.30-4.30 and 5.37δ. The characteristic infrared absorption is 775.840.970.
1065.1250.1460.2895.2995,
and seen at 3550 cm.

131 P-toluenesulfonyl chloride 3.51
4F, reaction product of pyridine 44-1 and (2) part 7,
Place 014p in a freezer at -20°C for 3F1.

Next, 2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF2a9. ．． 11.15-tris-(t
-butyldimethylsilyl ether)? , collect 200p. NMR absorption is 0.10.0.94.0.97.1
．． 1O12,50,4,03,3,80~4.80.5
．． 45.7.35 and 7.80δ. Infrared absorption is 775.970.1180.1190.1250
．． 1360.1470.2900, and 2995m-'
seen in

+4110% hydrochloric acid water koji solution 0.25. acetic acid containing z,
Tetrahydrofuran, and 7kl'('3:1'
: 1) Pour 2.13F of the reaction product of part (3) into 42d. The reaction mixture becomes homogeneous after 16 hours of vigorous stirring at room temperature. The resulting solution was diluted with 500 Wf of ethyl acetate.
diluted with saturated sodium chloride and washed with ethyl acetate,
Drying over sodium sulfate and evaporation under reduced pressure yields an oil of 1.30 Rf. The crude product is chromatographed on silica gel 150P packed with ethyl acetate. Elution with ethyl acetate yields 2-decarboxy-2-
p-Toluenesulfonyloxymethyl-P, GF2aO,
It produces 953y.

(5) Dimethylformamide5. The reaction product o, 5oor of part (4) in Od was dissolved in dimethylform
Added to a stirred suspension of 1.5y of sodium azide in 0me. Stirring was continued for 3 hours at ambient temperature.

The reaction mixture is then diluted with 75 d of water and extracted with 500 d of diethyl ether, and the ethereal extract is washed successively with water, saturated sodium chloride and dried over sodium sulfate. Removal of diethyl ether under reduced pressure yields 2-decarboxy-2-azidomethyl-PGF2aO,364r. A characteristic azide infrared absorption is seen at 2110 m-'.

Preparation Example 6 2-nidecarboxy-2-aminomethyl-PG
F2a (formula cxxv: zl is cis-CH=CH-(
CH2)3-1R31 is hydroxy, Yl is trans-
CH=C) R34 and 35 of the l-1L□ part and R33 of the M0 part are all hydrogen, and R30 is n-butyl) Crude 2-decarboxy- in diethyl ether 12m/
2-Azidomethyl-PGF2a (Preparation Example 5.0.364
r) is added to a magnetically stirred suspension of 0.38 (l) of lithium aluminum hydride in diethyl ether 2' Ome.The reaction temperature is maintained at approximately 0 °C and the lithium aluminum hydride is Once addition is complete, stir the resulting mixture at ambient temperature for 1.5 hours;
It is then placed in a water bath (0-5°C). Excess reducing agent is then destroyed by addition of saturated sodium sulfate. After the gas production has ceased, the resulting product is coagulated with sodium sulfate, triturated with diethyl ether, and the solid salts are removed by filtration. The filtrate is dried over sodium sulfate and evaporated under reduced pressure to yield a slightly yellow oil 0.3042. Purification of 100 sv of this oil by preparative thin layer chromatography yields the title product 42. NMR
Absorption: 0.90.1.10-2.80.

3.28, 3.65-4.25, and 5.45δ.

The characteristic infrared absorption is 970.1060.1460.
Found at 2995 and 3400 cm+-'. Mass spectrum shows parent peak at 699.4786, 628.684
．． Other peaks are shown at 595.217 and 274. Preparation Example 7 5ξ-iodo, -9-deoxy-6ξ.

More polar and less polar isomers of 9α-epoxy-PGF1 amide (formula ■: D is -(CH2)3-1q is iodo, and
is trans-CH,,,CH-)acetone 50- mixed isomers of formula ■iodoether acid (Preparation Example 3.5.0
Cool the solution of g) to about -10°C and add triethylamine 3
．． 0me and inbutyl chloroformate 3.0-. After 5 minutes, 100 d of ammonia-saturated acetonitrile are added and the reaction mixture is allowed to warm to about 25°C. Filter the mixture and concentrate the filtrate. Take up the residue in ethyl acetate and water. Wash the organic phase with water;
Dry over magnesium sulfate and concentrate.

The residue is chromatographed on silica gel, eluting with acetone (25-100%)-methylene chloride. Formula ■Less polar isomer of iodoether amide 0.02
y is obtained. RfO,40 (TLC on silica gel in acetone). 2.2 fractions of a mixture of more and less polar isomers and 1.5 y of the more polar isomer, Rf O,37 (TLC on silica gel in acetone) are obtained.

Infrared absorption is 3250.3150.1660.1610
, Preparation Example 8 5ξ-iodo-9-deoxy-6ξ.

9α-Epoxy-PGF 1 Mixed isomers of methyl ryomido (Formula ■: R09 is -C-NHCH3) Example of preparation of mixed heterogeneous isomers of Formula ■5ξ-iodo9-deoxy-6ξI9α-epoxy-PGFl in 50d of acetone 3.4.66F) solution with triethylamine 1,
42- and cooled to -5°C. Then add 1.3w41 of inbutyl chloroforme and stir for 5 minutes at 0°C, followed by the addition of 25d of 3M methylamine in acetonitrile. Leave the solution for 20 minutes or more about 25 minutes.
Stir until warmed to °C. Filter and concentrate the mixture. The oily residue is triturated with methylene chloride and filtered to remove the precipitate. The filtrate was chromatographed on silica gel and eluted with acetone (50-90%)-methylene chloride to give 5ξ-iodo-9-deoxy-6ξ19
α-Epoxy-11GF1 Methylamide mixed isomers 3
．． yields 45y. NMR peaks are 6.3.5.4-5
．． 7.3.2-4.7.2.78 and 0.7-2.65
δ0 Preparation Example 9 5ξ-iodo-9-deoxy-6ξ.

9α-Epoxy-PGF n-butyramide mixed isomers (formula ■: R09 is -C-(NH04H9)) Formula ■iodony77L in acetone 50++ Ie
A solution of mixed isomers of /acid (Preparation Example 3.5, Q y ) was cooled to about −10° C. and treated with 2.0 me of triethylamine.
and isobutyl chloroformate 1.9-. After 6 minutes, acetone 20. Add a solution of n-butylamine 15- in ff. After about 15 minutes, the reaction mixture was reduced to about 2
Allow to warm to 5℃ and stir for 3 hours. The mixture is concentrated and the residue is taken up in ethyl acetate. The solution is washed with water and brine, dried over magnesium sulfate and concentrated.

The residue is chromatographed on silica gel, eluting with acetone (5-100%)-methylene chloride to yield 5.3 of the title compound. The product was rechromatographed on silica gel for decolorization and acetone-
Elute with methylene chloride (1:3). 0.489 gives the title compound as a bluish-yellow oil 0.359. RfQ, 63 (TL on silica gel in acetone
C). The infrared peak is 3300.3100.1735.
1715.1645.1555.1070.1055.
1020 and 965cs+.

Preparation Example 10 6-Kedo PGFI, an-butyramide ■, First, (5Z)-9-deoxy-6,9α-epoxy Δ5P GFI n-butyramide is prepared. In benzene 100st, 5ξ - iodine 6ξ
, 9a-Epoxy-P G F l n-butyramide (Preparation Example 9.3.5y) was diluted with DBNgWl for 4 hours.
Process at 0-45°C for about 16 hours. The mixture is cooled, diluted with ice water and extracted with chloroform, while the organic phase is
Retain 3 drops of triethylamine. - The combined organic phases are washed with ice water, dried and concentrated to an oil of 3.64%. 3.12 of this is taken up in warm diethyl ether, and this ether solution yields 1.52 of a predominantly solid product when cooled. The product is recrystallized from ether.

0.85y, melting point 102-104°C.

■, above (5) in tetrahydrofuran 25 me
Z)-9-deoxy-6,9α-epokine-PGF
n-butylamide 3. 10% aqueous potassium hydrogen sulfate in an amount sufficient to bring the solution of Oy to pH 5.0;
Treat with liquid. The mixture is concentrated to remove tetrahydrofuran and the residue is taken up in water and ethyl acetate. Add sodium chloride to saturation and separate the organic phase.

The aqueous phase is extracted with acetone-ethyl acetate (1:4) and the organic phases are combined. The organic phase is washed with brine, dried and concentrated.

Chromatography of the residue 2.10p on silica gel, eluting with acetone (33-100%)-methylene chloride, together with the corresponding 9-deoxy-6,9α-epoxy-6-hydroxy compound yielded the title compound 1: 1 mixture. RfO, 57 (TLC on silica gel in acetone). The mixture was dissolved in tetrahydrochloride and hydrogen sulfate. 1'' acidified with an aqueous solution of rum, thereby converting substantially all of the 6-kedo-PGFlan-
Converted to butyramide. Rfo, 58 (TLC on silica gel in acetone). The solution was concentrated, partitioned between ethyl acetate and water, the organic phase was washed with brine and the oil 1.90%
The product is made by concentrating to f. The peak of the high resolution mass spectrum (TMS derivative) is 641.
4258° Preparation Example 11 5ξ-iodo-9-deoxy-6, ξ.

9α-epoxy-PGF 1 benzylamide mixed isomers (Formula ■: R0, is -C-Nl(CH2C6H5) Following the procedure of Preparation Example 8, formula ■5ξ-Iodo9-deoxy-6ξ, 9α-epoxy-PGF, Mixed isomers 4
．． 669 and benzylamine 1 instead of methylamine
．． Use 08y. The crude product was chromatographed on silica gel eluting with acetone (50-70%)-methylene chloride to give 5ξ-iodo-9-deoxy-6
ξ,9α-epoxy-PGF yielding benzylamide mixed isomers 4.12. NMR peak is 7.3.6
．． 6.5.3-5.7 and 3.5-4.6δ.

Preparation Example 12 5ξ-iodo-9-deoxy-6ξ.

9α-epoxy-PGF', anilide mixed isomers are (
Formula ■: R,9 is -C-NIIC6H5) According to the procedure of Preparation Example 8, formula ■5ξ-iodo9-deoxy-6ξ, 9α-epoxy PGF□ mixed isomers 4.
66y and aniline 0.94F are used. The crude product was chromatographed on silica gel and acetone (1
Elution with methylene chloride (0-50%) yields 4.0 g of 5ξ-iodo-9-deoxy-6ξ, 9α-epoxy-PCF, anilide mixed isomers. NMR peaks are 8.4.6.9~7.7.5.3~5.7 and 3.4~
4.7δ.

6H kl g! :! C00CHa and x are trans-
cH=ctt-).

See Figure A0. Formula ■6 in methylene chloride 25d
- Add a solution of PGF1a methyl ester (0.50y) to dihydropyran 3wI! , and a saturated solution of pyridine hydrochloride in methylene chloride 3W! and left at about 25° C. for about 5 hours, or the starting material disappears and the bis(tetrahydropyranyl) ether (formed T)
Leave until LC indicates. REO, 22 (TLC on silica gel in acetone-methylene chloride (1:9)) or RfO, 47 (TLC on silica gel in acetone-methylene chloride (1:3)). The reaction mixture is concentrated, washed with aqueous bicarbonate solution and brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with acetone (10-25%)-methylene chloride-C.
Produces the formula ■bis(tetrahydropyranyl)ether methyl ester. The infrared peak is 3500.1745.1
730.1200.1160.1130.111O11
075,1035,1020,980,915,870
, 815, and 735 -1° mass spectral line ('I
”M S ) is 552.522.366.348.33
1.330.304, and 85° NMR spectrum peaks are 5.5.4.67.3.65.3.2-3.7 and 0.9δ.

A containing 6-kedoPGFla bis(tetrahydropyranyl) ether methyl ester corresponding to B0 formula ■
The reaction product from part 2 is oxidized to compound (2). Acetone 2
A collection of several groups in 0IR1 0.939
is treated with Jones reagent 2.0- at -10°C.

After stirring for 1.5 hours, the reaction mixture is quenched with an inpropat tool and extracted with diethyl ether. Wash the extract with brine, dry and concentrate. The residue was chromatographed on silica gel with ethyl acetate (20-50%).
- When eluted with Scherisolve B, the formula ■6-Kedo PGE
This yields 0.529 g of 1 bis(tetrahydropyranyl) ether methyl ester. Rfo, 52 (TLC on silica gel in ethyl acetate-Kelisolve B (1:1))
. The infrared peaks are 1745 and 1725 side-1 (300
(no OH between 0 and 3500).

C, the product of part B was heated at 40°C in 3-acetic acid and 1.5 d of water.
Hydrolyze for 3 hours. It is then mixed with brine and extracted with chloroform. The organic phase is washed with brine, dried and concentrated.

The residue was chromatographed on silica gel, eluting with ethyl acetate (25-100%)-Skerisolve B.
This yields 0.15F of the title compound. The infrared peak is 338
0.1750.1710.1250.1200.118
0.1105.1070, and 975 cm-'. The mass spectral line (TMS) is 526.3123.511.
508.495.455.436.382.313.2
Analytical samples recrystallized as needles from 004 and 199° diethyl ether-hexane had melting points of 39-40°C.

RfO, 33 (TLC on silica gel in ethyl acetate).

Reference example 2 6-kedo P, GE, (formula ■: D is (c+
12)3,,Q is)l"'OH" R4 is H"19 is -COOH1 and
Bis(tetrahydropyranyl) ether of epoxy-5-iodo-PGl='1a methyl ester is prepared. 4 me of dihydropyran and 1 me of a saturated solution of pyridine hydrochloride in methylene chloride, 2 Od of methylene chloride.
The formula 1 product 2.0y of Preparation Example 1 in the solution was left at about 25° C. for 16 hours. The mixture is washed with aqueous sodium bicarbonate solution and brine, dried and concentrated to a colorless oil. The residue was subjected to silica gel chromatography and acetone (
Elution with methylene dichloride yields approximately 3.0%).

Rfo, 73 (TLC on silica gel in ethyl acetate).

The infrared peak is 1765.1215.1140.108
5.1045.1036.985.875.820, and 740bei-1 (no OH at aooo~3500).

A 6-keto PGF type compound of formula B1 is prepared in several steps as follows. The product of part A above (approximately 3.Or) was mixed with benzene 1
00wIl and 1,5-diazabicyclo[4,3,03
None 7-5 (DBN) 4-Ie and held at 40°C for 4 hours and then at about 25°C for 64 hours.

The mixture was washed with ice water, dried over magnesium sulfate, and the enol ether 9-deoxy-6,9-epoxy-△6
-PGF1a bis(tetrahydropyranyl) ether methyl ester Concentrate to 2.5F.

NMR peaks are 5.55, 4.5-5.1, 3.2-4
．． 5 and 0.9δ. Infrared peak is 1740.169
5.1200.1165.1130.1075.103
5.1020.975, and 870QI 0 enol ether (2,25p) with diethyl ether 2
5d, mixed with 10ml of dilute aqueous potassium hydrogen sulfate solution and stirred at about 25°C. The reaction was evaluated by TLC (acetone (1
0%) - silica gel plate with methylene chloride). After a few hours, add 50 d of tetrahydrofuran and continue stirring. The mixture is concentrated and the residue is extracted with ethyl acetate. The extract is washed with brine, dried and concentrated to an oil. The residue was chromatographed on silica gel, eluting with acetone (10-25%)-methylene chloride.
Formula 1 yields 1.912 6-kedo PGF1a bis(tetrahydropyranyl)ether methyl ester. Rfo
, 22 (TLC on silica gel in acetone (10%)-methylene chloride). It has the same infrared spectrum as the corresponding Formula 1 intermediate of Example 1.

The acid form of the CoB part product is created by saponifying this product. Methanol25. Methyl ester of part B in f and 3N sodium hydroxide 7-0.
Stir 7SP at about 25°C for 3 hours. The mixture is cooled, saturated with sodium chloride, acidified with potassium hydrogen sulfate and extracted with ethyl acetate. Wash the extract with salt water,
Dry and concentrate to 0.681 oil. Rfo, 61(A
TLC on silica gel in -IX solvent).

D0 formula (1) 6-keto PGE type compound is obtained as follows. 0 parts of the product, 0.689 in 50 ml of acetone, are cooled to -15° C. and treated with 2d of Jones reagent, which is added slowly with stirring. Stirring is continued for 1 hour at approximately the same temperature and then for 0.5 hour at -5°C. The reaction is stopped with Improper Tools and the mixture is concentrated to about half its volume.

Brine is added and the mixture is extracted with diethyl ether. The extract is washed with brine, dried and concentrated to a yellow oil 0.61F.

Rf Q, 64 (A-]) (TL on silica gel in
C). After silica gel chromatography, fraction 0
．． 311 is obtained.

E. Finally, the title compound of formula 1 is obtained by hydrolysis of the capping group. The product o, axp of part D is treated with 7 wse of acetic acid and 3 Wl of water at 40° C. for 1 hour and then at 25° C. for 16 hours. Brine is added and the mixture is extracted with chloroform. The extract is washed with water, dried and concentrated to an oil o, 2 sp. The product was subjected to silica gel chromatography.1. Elution with ethyl acetate (25-100%)-hexane yields the title compound 01065y. NMR peaks are 5.72.5, 57.3.8-4.3.2.1-2.
8, and 0.9δ. Infrared absorption peak is 3420.30
00.2800.1755.1740.1710.13
15.1255.1190.1160,1110゜10
65, and 970°□ analytical samples are obtained as needle heights by recrystallization from diethyl ether-hexane. Melting point 67-69°C.

Following the procedure of Reference Example 2, but using a preparation using silver carbonate and perchloric acid in place of Preparation i of the formula 6-keto PGF type compound in Part B, the same final product is obtained. Thus, instead of part B, 2.51 of the product of part A is mixed with 80II+e of tetrahydrofuran, 1y of silver carbonate and 7 drops of 70% perchloric acid. The mixture is stirred vigorously for 22 hours at about 25°C. Add 3 additional drops of perchloric acid and continue stirring for 4 hours. The mixture is filtered, the filtrate is treated with brine and sodium carbonate, and extracted with ethyl acetate. Wash the extract with salt water,
Dry and concentrate to 2.6F oil. Acetone (N.

~40%) - Silica gel chromatography eluting with methylene chloride yields an oil of formula 6-kedo PG'F bias (tetrahydropyranyl) ether methyl ester 0.52y. RfO635 (TLC on silica gel in ethyl acetate-cyclohexane (1:l))
. Then 6-kedo PGE, product 5, is obtained according to parts C1D and E above.

By following the procedure of Reference Examples 1 and 2 and Figure B, but using the appropriate formula (I) compound obtained by Preparation Examples 1 to 3 in place of the formula (I) starting material, the following formula (I) compound is obtained.

2.2-difluoro-6-keto-PGE1 methyl ester, 2.2-difluoro-16,16-dimethyl-6-keto-PGE1 methyl ester, 2.2-difluoro-(155)-15-methyl-6-
Keto-PGEl methyl ester, 16-phuninoxy 17.18,19.20-tetratrue 6-keto-PGEl, 16-phenyl-17,18,19,20-tetratrue 6-keto-PGEl.

17-phenyl-18,19,20-trinor-6-kedo PGE, 2,2-difluoro-16-phetoxy 17.18°19.20-tetratrue 6-keto-1) GEl methyl ester 13.14-dihydro -6-, Keto-1) GEl.

2.2-difluoro-13,14-dihydro-6-keto-PGE1 methyl ester, 2.2-difluoro-13,14-didehydro-6-keto pcil methyl ester.

Example 1 6-kedo13.14-didehydro-PGF
lall, 15-bis(tetrahydropyranyl)ether [Formula
(THP is tetrahydropyranyl), '23 is -C00
H, R26 are n-pentyl, and 5ξ-bromo-9-deoxy-6ξ,9-epoxy-14-bromo 15-keto PGF1a methyl ester A0 See diagram C. 5ξ, 6ξ, 14-tribromo-15-keto P
First, prepare GF1a methyl ester ■. A solution of 15-oxo-PGF2a methyl ester (U.S. No. 3,728.382, 3.38y) in about 25% of pyridine was added to 35% of pyridine. The mixture is treated dropwise with a solution of 7.08 f of pyridinium hydrobromide perbromide in /2.25 hours. The mixture is then stirred for 27 hours, diluted with ether and filtered. The filtrate was mixed with water, cold hydrobromic acid (5%), bicarbonate) and IJum aqueous solution (5%).
), dry and concentrate to yield the product 3.72y. Create an additional 1.06' y in the same way and combine them. The product was chromatographed on silica gel eluting with hexane-ethyl acetate (65:35) to give XI
[Produces 2,8311. NMR peak is 0.90.1
゜1~2.58.2.58~3.4.3.4~3.88
．． 3.67.3.88 to 4.61.6.96 and 7.0
3δ. The infrared peak is 3400.1730.1685.
161O11245, 1200, 1170, 1085,
and 1050 m 0 mass spectral peak (TMS)
is 746.0562.636.634.632.630
．． 555, 553, and 5510 and 5ξ-bromo-9-deoxy-6ξ, 9-epoxy-14-bromo- as a separate fraction from the chromatography of the reaction product.
0.93y of 15-keto PGFla methyl ester is obtained.

The NMR peak is 0.90.1. lO~3.03.3.0
3-3.46.3.65.3.78-5.0.6.41
1 and 7.00δ.

Infrared peak is 3480,2880.2810.173
5.1690.1615.1245.1200.117
5.1150, and 1080 am-'. Mass spectral peak (TMS) is 594.099.515, and 4
78゜B, 5ξ, 6ξ, 14-tribromo-PGF
Me1α thyl ester (Xnr). ■2 in methanol 2o*.
A solution of 38F is added to a solution of 1.28y of sodium borohydride in 40m of methanol at -35°C.

The temperature is maintained at -25°C for 1 hour. The mixture is diluted with diethyl ether and quenched with acetic acid. The solution is washed with 5% brine and 5% aqueous bicarbonate, dried and concentrated to a mixture of C-15 engineering pimers (X11). Separation is carried out by silica gel chromatography, eluting with hexane-ethyl acetate (3:2 then 1:1), initially yielding the 15R epimer (Xl[-15β) 1.57y. NMR peak is 0.9.1,1-3.35.3.35
~4.65.3.66 and 5.75~6.21δ0 infrared peaks are 3380.1735.1725.1250.
1200, 1175.1075, and 105105O'
oHigh resolution mass spectrum peak (TMS derivative) is 74
9.0362° [α')D-11° (in ethanol).

Next is 158 episodes? -(XIIL-15a)0.605
No is obtained. The NMR peak is 0.9.1. lO~3,
35.3.35-4.6.3.66, and 5.65-6
．． 15δ. The infrared peak is 3380.1740.165
0.1435.1250.1200.1175.112
0.1080, and 1045c*-'.

High resolution mass spectrum peak (TMS derivative) is 749
．． 0384°[α]D-4 (in ethanol).

C014--jomo PGF2aJ chill xxfnt (X
IV).

A solution of ■=15α0.6Of in 20 me of methanol is treated with 0.11f of ammonium chloride and 0.289 of zinc dust. The mixture is stirred for 1.5 hours, diluted with benzene and filtered. The filtrate is washed with 0.2 Mft 1k potassium sulfate, dried and concentrated to yield 0.37y.

Rf O,26 (-rtc on silica gel treated with silver nitrate in ethyl acetate). The NMR peak is 0.88.
1.1-2.71, 2.71-3.55.3.66.3
．． 80~4.35, 5.23~5.56 and 5.84δ
. The infrared peak is 3320.290"0.2820.1
940.1650.1430.1310.1240.1
215.1170%1115, and 10103O'.

D, 5ξ-iodo-9-deoxy-6ξ,9-epoxy-14-bromo-PGF1a methyl ester (XV)O
Methyl chloride L/7.30 1/) XIV 1
．． A solution of 9 f was mixed with 2.85 y of iodine and 1.8 y of potassium iodide.
885', added to a suspension of 0.92 F sodium acetate and 6 me of water. The mixture was stirred for 2 hours, treated with 2N sodium thiosulfate, washed with 5% saline solution,
Dry and concentrate to yield 2.95p of XV. Analytical samples obtained by applying chromatography on a part of silica gel are 0.89.1.1 to 3.18.3.66.3.6.
It has NMR peaks at ~4.8 and 5.88δ. Mass spectrum peak (TMS) is 701.1183.645
, 637.589.547.529.510, and q17
The peak of the 3° infrared spectrum is 3380.1740.
1655.1230.117G, 1080. and 105
0QIl.

E, 5ξ-iodo-9-deoxy-6ξ,9-nipoxy 14-bromo-PGF 11.15-bis(tetrahydropyranyl)ether methyl ester (XVI
). The methylene chloride solution is treated with dihydropyran 3d and a saturated solution of pyridine hydrochloride in methylene chloride 3d. After 20 hours, the mixture is diluted with diethyl ether, washed with 5% aqueous sodium bicarbonate and 5% saline, dried and concentrated. Residue is 1.12 yo NMR peak is 0.9.1.05-2
．． 20.2,2-3.2.3.2-4.35.3.66
．． 4.35-4.15, and 5.7-6.1δ. The infrared peak is 2900.2820.1760.1440.1
350.1210.1125.1090.103.5.
1025.970 and 910 country-1°F, 6-kedo13.14-didehydro-PGFl
A solution of all, 15-bis(tetrahydropyranyl) ether (another 0°) of XVll, 1p in dimethyl sulfoxide 15++/and methanol 1.5d is treated with potassium tert-butoxide 0.501 for 20 hours. The mixture is diluted with water 6
Dilute with 01R1, cool, acidify with 5% phosphoric acid and extract with diethyl ether. The organic phase is washed with brine, dried to an oil and concentrated. This was subjected to silica gel chromatography, and hexane-ethyl acetate (7,5:2
．． Elution with 5) yields the title compound 0.31:l+. NMR peak is 0.9.1, 1-3.0.3.0
5-5.1. And 6.5~? , 5δ0 infrared peak is 3300.3900.281O52500~2700
．． 2225.1740.1710.14. Ramie 0-146
0.1190.1130, 1120.1075.103
5.1015.975 and 905(to)-1° Example 2 6-kedo13.14-didehydro-PGF
la (formula ■: D is -(CH2)3-1Q is Ir-'OH
, R4 is n-pentyl, H and
A solution of the methyl ester (Example ID, 1.67y) was dissolved in potassium tert-butoxide t,say in methanol 3Wd.
for 23 hours at about 25° C., then diluted with 6 d of water and reacted for an additional 3 hours. The mixture is diluted with ether and partitioned between cold 3.5% phosphoric acid. The organic phase is washed with 5% sodium chloride solution, dried and concentrated. Residue 0.87
y was chromatographed on silica gel and eluted with hexane-ethyl acetate (1:l) to give the title compound of formula 0.
599. NMR peak is 0.90.1.1-3
．． 5.3.7-5,2, and 5.28-6.51δ. Mass spectrum peak (TMS derivative) is 670.383
6° infrared absorption peak is 3360.2670.2230
．． 1710.1320.1245.1205.1145
．． 1115.1090.1055, and 995cm+
.

Example 3 6-kedo13.14-didehydro-PGF
i, and 6-kedo13.14-didehydro-(55R
)-PGF, a.

A, initially 5ξ-bromo-9-deoxy-6ξ.

9-Epoxy-14-bromo-(15 and 155)-P
Create a GF 1a methyl ester compound. 5ξ-bromo-9-deoxy-6ξ, 9-epoxy-14-bromo-15-keto PGF1. in methanol 15d. A solution of methyl ester (Example IA, 0.93 g) was heated to -50°C.
Sodium borohydride in 50 me methanol at 0.
Add to the solution of 469. The reaction continues for 1.5 hours at about -30°C. The mixture was diluted with 250% diethyl ether. Carefully acidify with 5d of acetic acid in Z. The solution is diluted with 0.2M potassium hydrogen sulfate, 5% chloride. The product was 0.39 from another experiment.
chromatography on silica gel, eluting with hexane-ethyl acetate (7:3). Each fraction containing 15R and 155 products is 15R0
, 342 and 155 yielding intermediate 0.349. 15R
The compound has an NMR peak of 0.90.1.1-2.75.2
．． 75~3.30°3.66.3.78~4.8.5.
80 and also 90δ. The infrared peak is 3350.174
0.1650.1430.1365.1240.119
0.1070, and 1050-. 155 compounds are NM
R peak 0.89.1.1N, 3.2.3.2-4.8
．． 3.66, 5.78, and 5.83δ. The infrared peak is 3350.1740.1650.1430.1365
．． 1240.1190.1070, and 1050 country-1
°B, dimethyl sulfoxide 5d and methanol 0.5
A solution of 0.292 of the 155 product from Part A above in - is treated with 0.32 of potassium tert-butoxide for 20 hours. The methyl ester was hydrolyzed by treatment with 2N NaOH for 3 hours, followed by dilution with 5% sodium chloride and 10
Acidify with % phosphoric acid and extract with diethyl ether. 5%
Wash with sodium chloride, dry and concentrate to leave a residue o
, 2ops are obtained.

The residue was chromatographed on silica gel and eluted with hexane-ethyl acetate (1:1 to 3:2) to give 1
Yields 0.065 g of the 55 title compound.

It has the same properties as the product of Example 2.

Similarly, using the 15R intermediate of part A, Rfo, 20
The corresponding 15R5 title compound is obtained with (TLC on silica gel plates in A-IX solvent).

Following the procedure of Example 3, Part B, but using sodium methoxy instead of potassium tert-butoxide! The title compound is obtained using

Reference example 32-decarboxy-2-hydroxy 1% Ru6
-) r to PGE1 (Formula xxv: Q G;! ,,”
"bH%R2!i hydrogen, R4haH is trans-CH=CH-5 and f is 1) ■0 See Figure E. First, the formula XXIII n, 5-acetylene PG
Create a Fla type compound. Formula XX[+bis(THP ether) lactone (Colley et al., J. A+n, Chem, Soc, Vol. 92, p. 397 (1970)) 6.5y in tetrahydrofuran 30- is replaced with 4-trimethylsilyloxy-1-pentynyl -Lithium (C.H.S.7) (
C9H0Lin), J, Org, Chem, 4
Volume 1, 4o45 pages (1976)) 3.6g! and react at -70 to -60'C for about 0.5 hour. Isolate the adduct and use isopropyl alcohol-water (4:1) 30-
Approximately 0.5 m of 10% sodium hydrogen sulfate aqueous solution
Process with /. The mixture is stirred at about 25° C. for 0.5 hour, treated with about 10 μl of an aqueous solution of bicarbonate, and concentrated to remove the isopropyl alcohol.

The residue is extracted with diethyl ether and the organic phase is washed with water, aqueous sodium bisulfate, aqueous sodium bicarbonate and brine, dried and concentrated. The residue was chromatographed on silica gel with ethyl acetate-hexane (
1:5), the formula % formula % 4.4,5.5-tetradehydro-6-keto-PG
F 1a11.15-bis(tetrahydropyran-2-
(Ile ether) yields 5.6F. The NMR peak is 5.
68-5.36.4.8-4.5, and 4.5-3.1
8δ. The infrared absorption peak is 3440. :2210,16
75, and 975aIR-'. Mass spectral lines (TM
S derivative) is 649.3986.563.557.50
9.479.478.463, and 85.degree. 2.6y of the product from (2) above was dissolved in 50d of acetone at -30°C for 5 minutes.
Add dropwise Jones reagent (5,6ml 12.67M) in ME. The reaction is quenched with aqueous sodium bisulfite and the mixture is concentrated to remove the acetone.

The residue is extracted with ethyl acetate, the organic phase is washed with brine, dried and concentrated. The resulting mixture is then methylated with diazomethane to yield the methyl ester of any carboxylic acid present.

2-Decarboxy-2-hydroxymethyl-4゜5-tetradehydro-6-keto PGF, 11.15-bis(tetrahydropyran-2-yl-ether) and the above mixture containing methyl ester by-product. Acetic acid-tetrahydrofuran-water (3:1:1) in 20 me
Hydrolyze for 3 hours at 45°C.

The mixture is concentrated and the residue is extracted with ethyl acetate.

The organic phase is washed with aqueous bicarbonate solution and brine, dried and concentrated. Chromatography of the residue on silica gel (HPLC) eluting with acetone (25-50%)-hexanes affords the more polar compound of formula XXIV 0.27,811. NMR peak is 5.7
0-5.42, 4.32-3.80, and 3.23δ.

conductor) is 566.3299°■.Finally, the title compound is obtained by catalytic hydrogenation of the above compound. The formula XXIV compound o, asp of (1) above is stirred with palladium 35~ on barium sulfate and pyridine 5d at 1 atm hydrogenation at about 25°C for 0.5 hour. The solids are removed by filtration and the filtrate is concentrated. The residue is chromatographed (HPLC) on 30-50μ silica gel, eluting with acetone-hexane (1:1) to yield the title compound of formula xxv 0.178F. NMR peaks are 5.72-5.42.4.34-3.
78, and 3.60δ.

The infrared absorption band is 3360.1745.1710.159
0°1160.1070.1015, and 970 countries.

Mass spectrum line (TMS derivative) is 570.3563
．． 555.552.499.480.465.426.
409.383.375.355, and 313° Following the procedure of Reference Example 3 and Figure E, but substituting a suitable lactone known in the art for the formula XX■ starting material, the following formula Xx■ compound can be obtained.

2-Decarboxy-2-hydroxymethyl-6-kedo16-phenyl-17,18,19,20-tetratrue PGE1. 2-Decarboxy-2-hydroxymethyl-6-kedo 13.14-dihydro-PGE10 Example 4 6-kedo PGEt p-phenylphenacyl ester (formula ■
) See Figure B. Formula of Preparation Example 4 ■Product 5ξ-iodo-9
-Deoxy-6,9-epoxy-PGFlaP-phenylphenacyl ester is converted first to its bis(THP ether) and then to a compound of the formula 6-kedoPGFla type. This is oxidized at the C-9 position to the formula (II) compound, which is finally hydrolyzed to the formula (II) title compound.

゛The procedure of Example 4 and Figure n is followed, but the corresponding P-
Using phenyl phenacyl ester in place of that starting material, the following compound of formula 1 is obtained.

(15S)-15-Methyl-6-keto-PGE1p-phenylphenacyl ester, 16.16-dimethyl-6-keto PGE1p-phenylphenacyl ester.

Example 5 6-kedo PGE1p-1 (P-acetamidobenzamide) phenyl ester (formula ■) See Figure B. Formula ■5ξ-Iodo9-deoxy-6,9
A solution of -epoxy-PGFl,tl free acid (Preparation Example 3) is converted to the mixed anhydride with inbutyl chloroformate in the presence of triethylamine in acetone solution at about -10<0>C. The substituted phenyl ester is then approximately 25
Obtained using P-(P-acetamidobenzamido)phenol in pyridine at <RTIgt;C.

Bis(TIIP ether) is then created and has the formula IV 6
-Kedo PGF1 (converted to l-type compound, which is converted into c
Oxidation at the -g position and final deblocking by mild acid hydrolysis yields the title compound of formula 1.

Following the procedure of Example 5 and Figure B, but substituting a suitable 5-halogenated compound for the starting material of formula 1 and a suitable substituted phenol for the phenol,
The following substituted phenyl esters within formula (1) can be made.

6-keto-PGE1p-benzaldehyde semicarbazone ester, (155)-15-methyl-6-kedo PG E t
p-(P-acetamidobenzamide) phenyl ester, 16.16-dimethyl-6-keto PGEIP-CP-
acetamidobenzamide) phenyl ester, (15
5) -15-Methyl-6-keto-PGE1p-benzaldehyde semicarbazone ester, 16.16-dimethyl-6-keto PGE1p-benzaldehyde semicarbazone ester, Example 6 6-kedoPGA1, methyl ester dry methylene chloride (15d ) of 6-kedo PGE1, methyl ester (0.45F, 1.18 mmol) was dissolved in dry pyridine (1, l me
) and then treated with trifluoroacetic anhydride (0,85,/) and reacted for 45 minutes at 0°C. The pale yellow solution is treated dropwise with triethylamine (2d).

The resulting brown solution is reacted for 1.5 h at 0 °C and treated with methanol (5me). 1 of the dark solution at room temperature.
．． Stir for 5 hours, dilute with ether, wash with 0.2M acid potassium sulfite, 5% sodium chloride, dry, filter and concentrate to a brown oil (0.52y).

The crude title compound was dissolved in 45% ethyl acetate/hexane (3
Silica gel (50F
) on chromatography. Fraction 1-1
9 is discarded and fractions 20-44 give pure product.

Spectral analysis gives the following values: nuclear magnetic resonance (NM
R) (CDC13, δ): 0.89 (t, 3.C
H3), 1.05-1.8 (m, 12-13.C112
'), 1.9-2.6 (m.

5-6. CH2, C11), 2.6-2.95 (m, 2
-3. CH2°CH), 3.0-3.55 (m, 3.
C1l), 3.64 (8, 31C02C■13), 4
．． 05 (m, 1.C11-0), 5.40-5.75 (
m, 2, Cl1-), 6.08-6.37 (m,
1, CH= ), 7.40-7.56 (m, l
, CH=').

Mass spectrum: mee 436.2648 (M+
.

Calculated value for C24H4oS105: 436.26
45), 421.365, 346, 333, 321, 3
15,293°287.277.269,243,22
1,203,199° 143.111° Infrared absorption (film): 965,1012.11
35 (shoulder), 1185, 1255, 1278,
1450°1600.1650,1708.1740
(shoulder).

2900 (shoulder), 2980.3550cm
0 UV absorption: 216 nm (ε10,850), 27
6 nm (C1,100).

Example 7. 6-Kedo PGA 1 0.25y of 6-Kedo PGE1 is taken up in methanol and diluted with 3N sodium hydroxide. The mixture is kept under nitrogen at room temperature overnight. The mixture is concentrated and acidified with potassium hydrogen sulfate and ethyl acetate. The mixture is washed and dried and the solvent is evaporated to yield the crude product. The mixture is chromatographed on silica gel using 40% ethyl acetate/5SB (ie, a commercially available hexane mixture). The mixture is collected in 5 Q me fractions. Fractions 16-20 yield a pale yellow oil. This product was purified using ethyl acetate/SSB6.
Chromatography on 52 me acid washed silica gel and collection in 50 me fractions. Fraction 46-60 yields 1.1y of amber oil.

Spectral analysis gives the following values: NMR (CDC1
3, δ): 7.56 < 1l-1), 7.08
(S, 2H), 6.22 (IH), 4.2 (m),
3.25° infrared absorption analysis gives the following observed peaks: 3400, 2660, 2250, 1735,
1710°1585.1240,1200,1185,
1075, 1035゜1025, and 970゜-1゜Example 8 11-deoxy-6 monomer PGE1 Figure B
reference. A 250° flask is charged with 60IIIe of methanol and cooled in an acetone dry ice bath, during which time 5.5y of sodium borohydride is added at a temperature of -30°C. Add 5.0y of PGA2 methyl ester in 60me of methanol through the addition funnel over 5 minutes without stirring. Stirring is continued for 10 minutes at -25-30°C, then the mixture is removed from the water bath and stirred at 5°C for 30 minutes. The mixture is poured into 200 me cold ammonium chloride and extracted with chloroform. - Wash the combined chloroform extracts with 100 d of sodium sulfate, saturated sodium carbonate and saturated sodium chloride. sulfuric acid mixture)
Dry on IJum. Removal of the solvent under vacuum yielded a yellow part 5.1y which was chromatographed on silica gel 200v using methylene chloride at 25-50.
Elute with % ethyl acetate/Skerisolve B. Collect 50m fractions. It can be seen that fractions 54-59 contain the desired 11-deoxy-PGF2aΔ methyl ester.

Saturated sodium carbonate 25-salt, 11-desoxy-PGF methyl ester in methylene chloride 15d 1.90
Add to the solution containing F. Stir the mixture and cool in a water bath. 1.0y of iodine in 50m of methylene chloride is 5
Add drop by drop over ~10 minutes. The reaction is stirred for about 1 hour after the addition is complete at 0°C. Thin layer chromatography shows the reaction is complete. The mixture is diluted with 100 ml of methylene chloride and washed with 5% sodium sulfate and 50 ml of saturated sodium chloride. The mixture is back-extracted with methylene chloride and the combined methylene chloride fractions are dried over sodium sulfate and sodium carbonate and evaporated in vacuo to yield a brown oil. The brown oil is dissolved in 15 m of methylene chloride and chromatographed on silica gel 1002 using 5-15% acetone-methylene chloride. 50 yards
Collect fractions of Fractions 6-14 yield the desired product (brown oil 1.14F).

Add the iodoether o, soy prepared in the previous section to 10 d of methylene chloride, 0.5 d of dihydrochloride, 0.5 d of dropyran, and 10 d of p-toluenesulfonic acid. The reaction mixture was heated at room temperature for 1
Stir for an hour, dilute with 50ml of methylene chloride, and wash with 25ml of saturated sodium carbonate and 25ml of saturated sodium chloride. Dry the mixture over sodium sulfate. Evaporation of the solvent gave 7.76 g of a brown oil, which was dissolved in methylene chloride and eluted with 20% ethyl acetate.
Chromatograph on silica gel 50p using cyclohexane. Collect fractions of 50 Wl.

Fractions 2-4 are found to yield the desired product.

Add 0.55y of 5-iodo-tetrahydropyranyl ether prepared in the previous section to 30 wle of notluene in 1.5 me DBN. Heat the mixture in a water bath at 40-45°C.
Stir for 46 hours, then allow to cool and dilute with 15 me of toluene. The reaction mixture is washed with ice water containing a small amount of triethylamine and extracted with 30 ml of ether. The ether solution is washed with 15-ounces of ice water containing 8 drops of triethylamine. - The combined ether and toluene solution is dried over sodium sulfate and evaporated in vacuo to give 0.45y of a pale yellow oil, which is dissolved in tetrahydrofuran: 5% hydrochloric acid IQ me. This solution is left at room temperature for 2 hours and 15 minutes. The reaction solution was diluted with 25 s/d of saturated sodium chloride and extracted with ethyl acetate.

- Combined ethyl acetate extracts with saturated sodium chloride 25%
．． and dry over sodium sulfate.

Evaporate the solvent in vacuo to yield 0.429 as a pale yellow oil. This is dissolved in 5w1 of methylene chloride and chromatographed on 50y of silica gel. Using 5-20% acetone-methylene chloride as eluent, 5Q
Collect the me fraction. Fraction 14-2
0.0 was found to contain the desired product, a pale yellow oil 0.2
Generate 19.

Dissolve 0.19 p of the oil made in the previous section in acetone. Cool the solution to -10 to -20°C in a water bath. Add 0.35 mL of Dishin's reagent dropwise under nitrogen with stirring over a period of 1 hour at -10 to -20°C. 0.5W of isopropyl alcohol! Add while stirring constantly for 10 minutes.

Add the blue-green mixture to 25. / and extract four times with 25d portions of chloroform. The first three extracts are combined and washed with saturated ammonium chloride and backwashed with the fourth chloroform extract. - The combined chloroform fractions were dried over sodium sulfate (Ce1).
filtered through vacuum and evaporated to an oil of 0.15
produces F. Oil to 20% acetic acid - 10% water - 3% THF
Dissolve in 4 ml. This solution was heated to 21/2 at 40-45℃.
Warm for 1 hour, dilute with 6 d of water and lyophilize overnight. The residue was dissolved in 4 ml of methylene chloride, subjected to 25f silica gel chromatography, and chromatographed with 5-15% acetone.
Elute with methylene chloride and collect as a 20-25 fraction.

Fractions 19-28 were found to produce the desired product 11-deoxy-6-kedo PG E 1 methyl ester. Mass spectrum analysis (-rMS derivative) is as follows. Actual value 438.2820 o C24H42
A peak of the calculated value 438.2801° for 05 was further observed. m/e 423,420,407,405,3
67.348°317.209,199,143 and 1
11° ultraviolet analysis produced peaks seen at 86.3, 281 and 147 side-1.

Dissolve 65cm of the methyl ester prepared in the previous section in 3d of methanol and 1.5W! Dilute with 100 g of water and add 0.15 g of solid carbonate. The mixture is stirred at room temperature for 18 hours. The mixture was filtered through Celite and 10-
Wash with fresh methanol. Evaporate the filtrate in vacuo.
Acidify with 1 ml of KHSO3, dilute with 201ml of saturated sodium chloride, and extract with 25ml of ethyl acetate. - The combined ethyl acetate extracts were washed with saturated sodium chloride and sulfuric acid) and dried over IJum and evaporated under reduced pressure to yield 55 Ilv of oil, which was dissolved in methylene chloride and 10 g of silica gel. chromatography, diluted with 5-20% acetone-methylene chloride, and collected as a 10-fraction. Fraction 15-19
was found to produce the desired 11-deoxy-6-keto PGEr. Mass spectrometry analysis was as follows. Actual value 496.3055° Calculated value for C26H4305 496.3040° Other peaks are m/6481°478
．． 463,425,406,391,373,209
.

Observed at 201.199 and 111.

Example 9 6-kedo16-funinoxy 17°18.
19.20 → Tora True PGE See Figure 1 B.

Following the procedure of the previous example, 5ξ-iodo-9-deoxy-6ξ, 9α-epoxy-16-funinoxy 17.1
8,19.20-tetratrue PGF lbis-11,
15-tetrahydropyranyl ether methyl ester is 16-funinoxy 17.18,19゜2O-PGF
made from. 1.8y of that iodoether is 11
0. Dissolve / in toluene and add 6Wl of DBN. 2
Remove the reaction solution of 5-, dilute with 15 ml of toluene, and wash twice with 15d portions of ice water. -3Q of combined washing liquid
Extract with 'me ether. Ether solution is 15. /
Wash with ice water and add sulfuric acid with toluene solution) IJ
Dry with um. The solvent was evaporated in vacuo and this residue was
me THF: Dissolve in 5% HC. The solution was stirred at room temperature for 1.5 hours, diluted with 15 d of saturated sodium chloride, and finally extracted with 315 w11 portions of ethyl acetate.

- Wash the combined extracts with 25w1 of saturated sodium chloride and dry over sodium sulfate. Evaporate the solvent to 0.35F
An oil of
Chromatograph using fractional elution. 2
The 6-30 fraction is 0.02f of 16-phenoxy-6-
Contains the methyl ester of keto-PGF1.

The remainder of the reaction mixture is diluted with 50 s/d of toluene and washed with 215 d of ice water containing 20 drops of triethylamine. Combine the washing liquid with 7r100. Extract with ether f. The ether solution is washed with 50% ice water containing 20 drops of triethylamine, combined with toluene and dried over sodium sulfate. Evaporate the solution in vacuo to produce a 1.25F oil. This oil is dissolved in 45d THF-5% HC/ and stirred at room temperature for 1.5 hours. Work up this as in the previous section, dissolve the resulting oil in 7d of methylene chloride, and add 12% as before.
Chromatograph on 5 g of silica gel using 5-30% acetone-methylene chloride. Fractions 42-62 were found to produce the desired product.

16-phenoxy-6-keto PGF1 produced in the previous section
a Dissolve 0.50y of methyl ester in 10Wl of methanol. 4 d of 3N sodium hydroxide are added and the reaction is stirred at room temperature under nitrogen for 3 hours. Cool the solution in an ice water bath15. KII of 12y diluted with f saturated sodium chloride
Acidify with SO4 and extract with a 330 g portion of ethyl acetate. - The combined ethyl acetate extracts are washed with 220□e portions of saturated sodium chloride and dried over sodium sulfate. Evaporate the solvent in vacuo to produce a 0.48F colorless oil. This product is dissolved in 5 d of acetone and cooled to -40°C. Add 1 mole of Jones reagent with stirring. The reddish-brown solution is stirred at -40 to -25°C for about 1 hour.

Add 1 d of isopropyl alcohol to the mixture for 10-15 minutes while stirring. 100 are green mixture
of saturated sodium chloride and extracted with 350 me portions of ether. - The combined ether extracts are washed with 230 ml of saturated salt and dried over sodium sulfate. The mixture was filtered and evaporated in vacuo to yield 0.45 f of a yellow-green oil. Add this oil to 15Wl of acetone,
Dissolve, cool to -20°C in a water bath and add 1d of Jones reagent. The reaction is stirred at -15°C to 20°C for 1 hour. Add 1d of isopropyl alcohol and stir for 15 minutes.
Continue at -20°C for ~30 min. Mixture at 75W! of saturated sodium chloride and extracted with 475 d portions of chloroform. The extract is worked up as before and the resulting pale yellow part is dissolved in 8*e of 20% acetic acid, 10% water and 3% THF. The solution is left in a 40-45° water bath for 3.5 hours, diluted with 10 ml of water and lyophilized overnight. The residue is dissolved in 5-methylene chloride and chromatographed on 25-m of silica gel. The column is eluted with 25d portions of 20-50% acetone-methylene chloride. Fractions 11-20 yield the desired product. Mass spectrum analysis (actual value for TMS derivative: 605.2748
, Calculated value of C30H4907 is 605.2780, other peaks are mle 602+530, 526.513.4
Observed at 23.369.333.201 and 111. IR analysis shows the observed peak as 3400.2660.1?4
0,1710,1600,1590°1500.129
5,1245,1175,1080,1040°975
．． 760. and 6955-'.

Example 106-kedo-16-phenyl-17, 18゜1
9.20-TetraTrue PGE 1 See Figure B.

5ξ-iodo-9-deoxy-6ξ, 9α-epoxy-
16-Funinoxy 17.18,19.20-Tetratrue PGF1a, 11,15-Histetrahydropyranyl ether was prepared according to the procedure of Example 9 and 9.7
mmol to 109 me toluene and 10d 1.5
-Diazabicyclo[5,4,0]undec-5-ene and warmed to 43° C. with occasional stirring for 24 hours, then left overnight at room temperature. The mixture was then washed with ice water and MgSO4
It was dried and evaporated. The oily residue was taken up in 75+f ether and 25 me tetrahydrofuran at 40
Me in 10% aqueous K1-1504 solution and stirred for 4 hours. Enol ether is slowly more polar 26-
Converted to kedo-PGFla form. The organic layer is separated. Wash the aqueous layer with ethyl acetate. -The combined organic extracts are washed with salt water, dried and evaporated to an oil. The oil was taken up in 100 d of methanol and the solution was purged with nitrogen for 33 d.
of 3N NaOH solution. After 3 hours at room temperature the mixture is concentrated to 1/2 volume, covered with ethyl acetate and slowly neutralized with KH5O4 solution with stirring and cooling in a water bath. The ethyl acetate layer is separated and the mixture is extracted again. - Wash the combined extracts with salt water, dry and evaporate to an oil. This material is chromatographed on 200f acid-washed silica gel. The product is eluted with 20% acetone in methylene chloride to give 4.22 colorless oil.

T in 40% ethyl acetate-60% hexane-2% acetic acid
LO indicates Rfo, 17.

4. A solution of the 6-kedo PGF1a derivative of 22 in 200 d of acetone is cooled with dry ice and 8 d of Jones reagent is added in 1 part. The reaction temperature is slowly raised to -20°C to -25°C while stirring. This temperature is 2
Hold for 0 min, then stop the reaction by adding inpropatool. The mixture is concentrated to 0.5 volume and diluted with ether and half brine.

Separate the ether layer and extract the mixture two more times with ether. -The combined extracts are washed with salt water, dried and evaporated to an oil.

Dissolve all crude material in 25 me acetic acid; 12. Add Z water and heat to 43° C. for 2 hours, then leave at room temperature overnight. Brine is added and the mixture is extracted three times with chloroform. - The combined extracts are washed with fresh brine, dried, filtered, concentrated to a working volume and subjected to 2002 acid-washed silica gel chromatography.

Columns in methylene chloride at 20, 30, 40 and 5
Elute with 0% acetone. 2 from 40 and 50% eluent
．． The product 29p (59% overall yield from iodoether) is obtained as a pale yellow color.

NMR (CDC/39 acetone δ) has an observed peak of 7
．． 21, 6.18; 5.5, 4.18-4.6
, 3.7-4.18°2.8. and 1.6. The optical rotation is [α11)-16° (C=0.813095 E
in tOH).

Mass spectrometry showed no M+, and M+CH3 was observed at 589.2862. Calculated value of C3oH49Si306 589.283
7゜Other ions are 513,499,423,333,2
01 and 111° refrigeration parts crystallize. Ethyl acetate
Crystallization from hexane (twice) produces colorless crystals, melting point 8.
Give 9-90°C.

Calculated value of C22H2806 C68,02H7,26 Actual value C67,71H7,54 ■The spectrum has the observed peak at 3400.2650°1
740.1710,1610,1585,1495,1
410°1365.1290,1225,1160.1
09G, 1030°975.750,700 (II+
' Shown in '.

Example 116-kedo-17-phenyl-18,19゜2
0-trinor-PGE1 See Figure B.

Following the procedure of the previous example, 5ξ-iodo-9-deoxy-6,9α-epoxy-17-phenyl-18,19
,20-)linol-PGF, methylether 1α ster, 11.15-bis-tetrahydropyranyl ether is 17-phenyl-18,19,20-trinor-
Made from PGF2a, toluene (5.
49 (7.37 mmol) at ambient temperature.
(1(1+ff)) and heat the reaction at 45° C. for 20 h. The reaction is diluted with a few drops of triethylamine in toluene and partitioned with cold water. The aqueous portion is extracted with triethylamine in toluene and the organic layer is separated. Wash with water, dry, filter and concentrate to a brown color (4,93F).Original 0.67 in 50% ethyl acetate/cyclohexane with a few drops of triethylamine.

The observed NMR (CDC43δ) peak is 1.07
~2.95, 3.17~4.37, 3.64, 4
．． 37-4.97°, 5.32-5.87 and 7.20.

IR analysis shows the following peaks. 870,915,975
゜1020.1035, 1075, 1130.1145
-1180°1200.1230,1285,1310
, 1350.1435°1455.1495 (Sh),
1600.1645 (Sh).

1695 (Sh), 1735.2860 (Sh), 29
30. and 3025c*0 ether (50-re) and tetrahydrofuran (
A solution of the 4,93y ether prepared in the previous section in 100 m) of 5% potassium hydrogen sulfate (25 m/
). The suspension is stirred and distributed for 20 hours. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 5% sodium chloride, dried, filtered and concentrated to a pale yellow oil (4.63g
)give.

The crude product in methanol (100 m
of sodium hydroxide (25, f). 4 of the solution
Stir for an hour, concentrate in vacuo, cool and acidify with saturated potassium hydrogen sulfate. The aqueous layer was extracted twice with ethyl acetate, the organic extract was washed with 5% sodium chloride, 'dried,
Filter and concentrate to a light yellow oil (4,03y).

Observed peaks of NMR (CDCl3δ) range from 1.07 to 3.
08°3.10~4.38, 4.42~4.93,
5.22-5.80°7.20.

IR analysis shows the observed peak at 870,975,1020°1
075.1115,1180,1200,1240,1
435°1455j1495,1600,1710.1
735 (Sh).

2400 (Sh), 2860 (Sh), 2490 (Sh
) and 3600CI+-1.

6-kedo-17-phenyl-18,19,20-)linol-PC, F1a, 11 in acetone (6011e)
.

15-bis-tetrahydropyranyl ether (2,8p
, 4.89 mmol) was cooled to -23° C. and treated with Jones reagent (asme) by sieving.

The reaction was stirred for an additional 30 minutes at -20°C and quenched with inpropatrotool. The resulting green suspension is concentrated in vacuo, diluted with cold saturated chloride solution and diluted with 50% ether/chloride solution.
Extract with ethyl acetate. The organic portion is washed with 5% sodium chloride, dried, filtered and concentrated to a yellow oil (2,70y).

The crude product is treated with acetic acid (25 m) and water <10, t) and reacted for 4 hours at 45°C. Cool the reaction, dilute with cold 5% sodium chloride, and extract three times with ethyl acetate to give a brown fraction of 1.42.

The crude product is chromatographed on two silica gel columns to give 0.52y of impure product. The impure product was washed with acid-washed silica gel in 20% acetone/methylene chloride (
23 me fractions were collected. The column is eluted with 1 part each of 20%, 25%, 30% and 35% acetone/methylene chloride.

Fractions 80-143 were eluted with 25-35% acetone/methylene chloride to give a 0.45f oil, which was crystallized from Namotone-hexane and then recrystallized from ethyl acetate-hexane to give a 0.18F oil. It gives 1 g of 6-kedo-17-phenyl-19.20-trinor-PGE1 as white crystals, melting point 112-113°C.

The peak of NMR (CDCl3δ) is 1.07-3. Go
.

3.73-4.30, 5.43-5.65 and 7.2
It can be seen on 5.

The mass spectrum was as follows. C32H54Si
306 calculated value 618.3228, actual value 618.32
06゜Other ions are m/e 603, 528, 52
3, 495, 438.

423.405,347,201,111,91° Example 1211-Shrimp-6-Kedo PG E 1 See Figure B.

Following the procedure of the previous example, the bis-tetrahydropyranyl iodoether corresponding to the title product was converted to 11-epi-
It was prepared from PGF2a methyl ester. This ether 4. Dissolve Of in 20 me toluene and add 5f
Add DBU of ne. 42 while stirring the mixture occasionally.
Warm to ℃ for 22 hours. The solution is washed twice with water, dried over magnesium sulphate and evaporated. The residue was dissolved in 40 me of ether and 30 me of tetrahydrofuran.
Dilute with 10% KIISO4 aqueous solution. The mixture is stirred at room temperature overnight. The aqueous layer is washed with ether and the combined organic layers are washed with brine and dried over magnesium sulfate. The solvent was then evaporated and the residue was evaporated onto 50 nm of silica gel for 10-3 hours.
Chromatograph using 0% acetone-chloroform and elute in 50 portions. The fractionation produces a bright yellow part of 2.7y.

The 2,7y ester prepared in the previous section was mixed with 30. Dissolve f in methanol and add 3N sodium hydroxide 6-. The mixture is stirred at room temperature under nitrogen for 4 hours. The mixture is concentrated on a rotary evaporator, acidified with aqueous potassium sulfate and extracted three times with ethyl acetate.

- Wash the combined extracts with brine, dry over magnesium sulfate and evaporate the solvent to yield a yellow oil. This product was dissolved in 100-mL acetone and heated to 15-mL in a dry ice bath.
Cool to 0℃. 10 2.67M Jones reagent 5d
Add a little at a time over a period of minutes. Reduce the temperature to -25℃. Increase the temperature and maintain this temperature for 30 minutes. Improper tool (3W) is added and after 5 minutes the mixture is concentrated to 1/4 of its volume on a rotary evaporator, diluted with brine and extracted twice with ethyl acetate.

-Wash the combined extracts with salt water, dry and evaporate 2
．． Produces 52 oils. The product thus formed is hydrolyzed by dissolving it in 10-acetic acid, diluting with 5-d water and warming at 42° C. for 4 hours. The mixture is diluted with brine and extracted three times with methylene chloride. - The combined extracts are washed with brine, dried and evaporated to yield an oil of 2.52. 15o oil
Chromatographed on silica gel using 20-60% acetone-chloroform at 50. A collection of fractions of f. Fractions 34-44 yield 0.92p of the desired product 11-shrimp-6-kedoPGEl.

NMR (CDC/3W) peaks are 6.1, 5.7, 4
．． Observed at 45°4.15, 2°1-2.9 and 0.9. The crystals have a melting point of 79-80°C.

Example 136-kedo16-phenyl-17,18゜1
9.20-Tetratrue PGE1 p-phenylphenacyl ester 6-keto-16-phenyl-17,18,19,20-tetratrue PGE10. obtained according to the previous example.
A mixture of 35y, acetonitrile 12me, diisopropylethylamine Q, 5 ml, and P-phenylphenacyl bromide 0.35F is stirred at room temperature for 3.5 hours. Brine and K1-lSO4 solution are added and the mixture is extracted twice with ether. The extracts are combined, washed with brine, dried and evaporated to give an oil, which is chromatographed on silica gel 35y.

Elution with 40% acetone in methylene chloride gave product 9.
Get 41y. Crystallization from ether-ethyl acetate-hexane gives 0.251 of the title product.

Melting point 96-98°C. RfQ, 25 (by acetone-hexane (1:1) TLC).

C36■(38o7) Calculated value c74.2o■6・57 Actual value C73,92116,77 IR spectrum 3380.330'(1,1745,1
7151690, 1605, 1585, 1565, 14
90,12401165,1155,1075,103
0,975,960°765, 750 and 700
.

Patent Applicant: The Upjohn Company Representative Patent Attorney: Aoyama Aoyama and 2 others Continued from page 1 CY DA Priority Claim December 30, 1976 ■ United States (US)
.

■755675 ■September 2, 1977■United States (US) 0829678 @September 2, 1977 ■United States (US) ■829679 ■Inventor Berman Wolden Smith Michigan, U.S.A.

Claims (1)

[Claims] 2 [In the formula, (1) -(CHt)d-C(Rz)-
or (2) -CH, -0-CH, -Y -, where d is 0 and R2 is hydrogen, methyl or fluoro, the same or different, but one 82
When is fluoro, the other condition is not methyl,
Moreover, Y is a valence bond, -CH,- or -(Cut)t-
And □Hun r 1) 905° Cμ20H R111 is (1)=COOR2°(2)-CH,0H (8) -CHzN(Re) (R211)(4)-C
-N(RoXRzs) or where R20 is (a) hydrogen, (b) alkyl of 1-12 carbon atoms, (C) 7-chloroalkyl of 8 to 10 carbon atoms, (d) 7 Aralkyl of ~12 carbon atoms, (e) phenyl, (f) chloro or alkyl of 1 to 4 carbon atoms/I/phenyl substituted with 1 to 8, 0 (m) -CH-C- Rlo. 11 (where R3° is phenyl, p-bromophenyl, nzamidophenyl, or 2-naphthyl, and R11
is hydrogen or benzoyl), R9 is hydrogen, methyl or ethyl, R2a is hydrogen, alkyl of 1 to 4 carbon atoms, aralkyl of 7 to 12 fii carbon atoms, phenyl or It is phenyl substituted with alkyl on the carbon atom, and R6 1'E2a is (1) -C-CgH, g-CH, or
6 6 In the formula, CgH2g is an alkylene of 1 to 9 fi carbon atoms having 1 to 5 carbon atoms in the chain between -〇R, R6- and the terminal methyl, R3 and R6 are hydrogen, 1 ~
alkyl to or fluoro of 4 carbon atoms, the same or different, provided that only when one of R3 and R6 is hydrogen or fluoro, the other is fluoro;
0-), RI11! Provided that none of -R6 is fluoro, Cj H2j is represented by two oxa atoms (-'o-), where CjH2j is a valence bond or -CR, R6- and pheni)v ring. alkylene of 1 to 9 carbon atoms, with 1 to 6 carbon atoms between, T is alkyl of 1 to 4 carbon atoms,
fluoro, chloro, trifluoromethyl or alkoxy7 of 1 to 4 carbon atoms, S is 0.1.2 or 3, provided that not more than 2 T are other than alkyl, and S is Td! when it is double 8! and R29 is bromo or chloro, and L'r is iodo, bromo or chloro, and indicates a bond in alpha or beta configuration] 5ξ-Iodo-9-deoxy-6ξ, 9α-epoxy-14-bromo(15R)-PGFI methyμ ester of the compound according to claim 1. 3. 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-14-bromo-(15S)-PGF, methyl ester of the compound according to claim 1. 4. 5ξ-bromo9-deoxy-6ξ,9α-epoxy-14-promo(15R)-PGF, methyl ester of the compound according to claim 1. 5. 5ξ-bromo9-deoxy7-6ξ, 9α-epoxy7-14-bromo(15S)-PGF, methyl ester of the compound according to claim 1. 6.5ξ-bromo-9-deoxy/-6ξ,9α-epoxy-14-bromo 15-keto PGF1a methyl ester. 7゜ [In the formula, is (t) -(CH2)d-C(R2)2-
or (2) -CH2-0-CH, -Y- where d is 0 to 5 and R2 is hydrogen, methyl or fluoro, the same or different, provided that when one of R2 is fluoro, the other is not methyl, and Y is a valence bond, -CH2-, and RIG is (1) -COOR2゜(2) -CH20H (8) -CH2N(Re)(Rzs)(4) -
CN(R9)(R28) or where R20
is (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms, (C) cycloalkyl of 8 to 10 carbon atoms, (d) aralkyl of 7 to 12 carbon atoms, (e)
phenyl, (f) phenyl substituted with 1 to 3 chloro or alkyl of 1 to 4 carbon atoms, 0
0 1 (,,) -CH-C-R,o. 11 (where RIG is phenyl/l/, p-bromophenyl, p-biphenyltz, p-nitrophenyl, p-benzami, doophenyl, or 2-naphthyl;
11 is hydrogen or benzoyl), R is hydrogen, methyl or ethyl, Roll is hydrogen, alkyl of 1 to 4 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or 1 Feni/L' substituted with alkyl of ~4 carbon atoms, and alkylene of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain to the terminal methyl; R, and R6 are hydrogen, 1 to 5 carbon atoms;
Alkyl or fluoro of 4 carbon atoms, the same or different, provided that only when one of RII and R6 is hydrogen or fluoro the other is fluoro, and furthermore 2 is oxa(
-0-), the condition is that neither R5 nor R6 is fluoro, and 2 is an oxa atom (-0-) or Cj
H2j, where CjH2j is a valence bond or -
an alkylene of 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR,R,- and the phenyl ring, and T
is alkyl of 1 to 4 carbon atoms, fluoro, chloro,
trifluoromethyl or alkoxy of 1 to 4 carbon atoms, S is 0, 1, 2 or 3, provided that not more than 2 T are other than alkyl 1 or S is 2 or 8 Sometimes, provided that T is the same or different, and R2 (l is bromo or chloro, R3? is iodo, bromo or chloro, and ~ is in the alpha or beta stereo□ apparatus 8. 5ξ of the compound according to claim 7. 6ξ, 14-tribromo-(15R)-PGF1α methyl ester. 9. 5ξ of the compound according to claim 7. 6ξ, 14-tribromo-PGF1a methyl ester. A compound of IOl, its lower alkanoate or a mixture consisting of this compound and its enantiomer [in the formula Dμ(1) -
(CH2)a-C(R2)! −. (2) -cH, -o-cH, -y- or (8) -Cl
, CH=CH-, where d is 0 to 5 and R2 is hydrogen, methyl, or fluoro, the same or different, provided that one R
When 2 is fluoro, the other is not methyl, and Y is a valence bond, -CH,-, where R8
is hydrogen, methyl or ethyl, R, is (1)-COOR3 (2)-CH20H (8)-CHzN(RoXR2g) (4) -C-N(Ro)(R2g) or H-N/(51CII \ -N where R3 is (al hydrogen, (b) alkyl of 1 to 12 carbon atoms, (c) /chloroalkyl of 3 to 10 carbon atoms, (d) aralkyl of 7 to 12 ffil carbon atoms , (e) phenyl, (f) phenyl substituted with chloro or alkyl A/l of 1 to 4 carbon atoms, 2 or 8,
11. (where Rto is pheniA/, P-promopheniμ, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and Rto is water ice or benzoyl) (n) Pharmacology R, is hydrogen, methyl or ethymu; R21 is hydrogen, 1-4
Asμ of 5 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or alkyl of 1 to 4 carbon atoms
R4 is phenyl substituted with (1) -c -c g R2g cus6 where CgH2g has 1 to 5 carbon atoms in the chain between -CR,R,- and the terminal methyl. and alkylene of 1 to 9 carbon atoms, R5 and R6 are hydrogen, alkyl of 1 to 4 carbon atoms, or fluoro, the same or different, provided that one of R6 and R6 is hydrogen or fluoro. Only sometimes the other is 71V oro, and furthermore 2 is oxa r-0
-), the condition is that the φ deviation between R3 and R6 is not fluoro, and 2 is an oxa atom (-0-) or C, R2,
, where CjH2j is a valence bond or -CR,
an alkylene of 1 to 9 carbon atoms with 1 to 6 carbon atoms between R,- and the phenyl ring;
alkyl, fluoro, chloro, trifluoromethyl of 1 to 4 carbon atoms, or alkyl of 1 to 4 carbon atoms, S is 0.1.2 to 3, provided that not more than 2 T is other than alkyl, and when S is 2 or 8, T is the same or different, and X is (1) trans -CH=CH- (2) cis -C
H=CH- (3) -C=C- or 6 X is trans-CH=CH-, cis-CH=CH- or Δ
, ,・N is −050−・Q is=0・ROH or R2O(, R3 is hydrogen or methyl, R1 is −COOR3, −CH, OH
Matake-CON (all) (R2g), R8 is hydrogen, 1-
Alkyl of 12 carbon atoms or a pharmacologically acceptable cation, R28 is hydrogen, alkyl of 1 to 4 carbon atoms, 7 to . A group other than 6 to an aralkyl group of 12 carbon atoms. '] Compound according to term 10 between O. 12, D is -(CHz)(1-C(Rz)t -(
d is θ~5, and R2 are hydrogen, methyl, or fluoro, and are the same or different, provided that when one of R2 is fluoro, the other is not methyl). Compound according to item 11. 13. Claim 1 in which D is -(Cax)s-
Compound according to item 2. 14. Compounds according to claim 13, wherein X is trans-CH=CH-. 15.Q. A compound according to claim 14 which is. 15. A compound according to claim 14 which is H/I/). 17. Compounds according to claim 16, wherein R is hydrogen. 18. A compound according to claim 17, wherein R is -COOR, (R3 as defined in claim 1O)'. 19. 6-kedo-PGE, p-phenylphena, syl ester of the compound according to claim 18. 2. 6-ke) of the compound according to claim 18
-PGE, p-acetamidobenzamido) phenyl ester. 21. The compound according to claim 18,
16-keto PGE, p-benzaldehyde semicarbazone ester. 2. 16.1 of the compound according to claim 18
6-dimethyl-6-keto PGE, p-phelphenacyl main ster. 2. 16.1 of the compound according to claim 18
6-dimethyl-6-kedoPGE+ p-(p-acetamidobenzamido)phenylester)v. 16.1 of the compound according to claim 18
6-dimethy/I/-6-kedo PGE, p-benzaldehyde semicarbazone ester. 2. 16-Fetoxy17.18,19.20-tetranoA/-6 of the compound according to claim 18
-Kedo PGE, 02, 16-FuenyA/-17', 18,19.20-Tetonno/L/ of the compound according to claim 18
-6-kedo PGE, -0 nail, 17-phenyl-18,19,20-) reflu 5-keto-PG of the compound according to claim 18
E. 2g, the compound according to claim 17, in which R1 is =C) (20H). −
16- Phenyl- 17.18, 19.20=tetrano-PGE, 0 1 80- R+ 'riE -C-N (RoXRu)
17. A compound according to claim 17, wherein the compound is C. 81, Claim 16, wherein R8 is methyl
The term is a compound. 82. A compound according to claim 81, wherein R, is -COOR, (as defined in claim 10). 83, 15 of the compound according to claim 32
(S)-15-methyl-6-kedo PGE, p-
Phenyl phenacyl ester. Separately, 15 (
S) -15-methy/l/-6-kedoPGE1p -
(p-acetamidobenzamide) phenyl ester/l
/. 35, of the compound according to claim 32, 15
(S) -15-methy/l/-6-kedo PGE, benzaldehyde semicarbazone ester. 86, R, is -CH20H, Claim 3
Compound according to item 1. 1 87, R1 is -CN(R11)(R211)
A compound according to claim 10, wherein (R9 and R2, as defined in claim 10). 39, Claim 10, wherein X is -C-=C-
Compound by term. 39. A compound according to claim 39 which is (ethyl). 41. A compound according to claim 40, wherein R1 is 1'C00R3 (Rs as defined in claim 1θ). 42. A compound according to claim 40, wherein R, is -CH20H. //＼ 43, Q is R, □H (R, is hydrogen, methyl or ethyl 1v
). 44. Compounds according to claim 10, wherein X is -CH,CH,-. 45. A compound according to claim 44, wherein R, is -COOR8 (R, as defined in claim 10). 46, 6-kedo18.14'-dihydro-PGE 1°47 of the compound according to claim 45,
45. A compound according to claim 44, wherein R1 is -CH,OH. 48, 2-decarboxy-2-hydroxymethyl-6-ketone of the compound according to claim 47 18.
14-dihydro-PGE. 49. Compounds according to claim 1O, wherein D is -(CH2)2-CFs-. 50. A compound according to claim 49, wherein X is trans-CH=CH-. 1 51, Q is H. 51. A compound according to claim 50, which is H. 52, of the compound according to claim 51, 2.
2-difluoro-6-keto-PGE1 methyl ester. 58, 2.2 of the compound according to claim 51
-difluoro-16,16-dimethyl-6-keto-PG
E1 methyl ester. 2.2- of the compound according to claim 51 between
Difluoro-16-funinoxy 17.18°19.2
0-tetra/l-6-ke) -PGE, compound according to mef term. 56, 2.2 of the compound according to claim 55
-difluoro=(158)-15-methyl-6-kedo PGE, methyl ester. 57, Claim 49, wherein X is -C-''C-
Compound by term. 58, of the compound according to claim 57. 2.2-Difluoro-18,14-didehydro-6-keto PGE, methyl ester. 59. A compound according to claim 49, wherein X is -CH2CH2-. 60, of the compound according to claim 59. 2.2-Difluoro-18,14-dihydro-6-kedo PGE, methyl ester. [In the formula, +1) -(CH2)d-C(R2)t-(
2) -CH, -0-CB, -Y- or -(3)-CH,
CH=CH-, where d is θ~5 and R2 is hydrogen, methyl or fluoro, the same or different, provided that when one R2 is fluoro, the other is not methyl and Y is a valence bond, -CH2-makake-(CH
2) 2-, and Q is 11 △ t\ /
\0'HH' R, OH' or ROH (" is hydrogen, methyl or ethyl), 5 Rf is (11-C-CgH2gCH3 6 C, where CgH2g is between -CR,R,- and the terminal methyl alkylene of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain, R5 and R6 being hydrogen, alkyl of 1 to 4 carbon atoms or fluoro, the same or different; , provided that only when one of R5 and R6 is hydrogen or fluoro, the other is fluoro, and furthermore, Z is oxa ("-o
-), both R3 and R6 must be fluoro, and 2 is an oxa atom (-0-) spanning CJ H
2J, where CJH2j valence bond or -C
R,R,-,! : alkylene of 1 to 91 carbon atoms, with 1 to 6 carbon atoms between the phenibicyclic rings;
T is alkyl of 1 to 4 carbon atoms, fluoro,
chloro, tri2/L/olomethyl or alkoxy7 of 1 to 4 carbon atoms, and S is 0.1.2 or 8, provided that not more than 2 T are other than alkyl, and When S is 2 or 3, T is the same or different, where C=9 is 0 or ? "", 1 X is (1) trans-CH=CH- (2) cis-CH=CH- (3) -C3C- or (41-CH2CH2-, and (1) -COOR20 (2) -CM20H (8) -CHzN(Rg) (R2g)11
・ (41-C-N(RsXR2s) or H-N / where R20 is (a) hydrogen, (b) alkyl of 1 to 12 j-deficient atoms, (C) 3 to 0 carbon atoms 7-chloroalkyl, (d) aralkyl of 7 to 12 carbon atoms,
(e) phenyl, (f) phenyl substituted with 1 to 3 chloro or alkyl of 1 to 4 carbon atoms, 0 (rr+) -CH-C-R,. 11 (here RIG is phenyl, p-bromophenyl, p-
biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and R11 is hydrogen or be/diyl), R9 is hydrogen, methyl or ethyl, and R211 is hydrogen, 1- 41i Starting from a compound of alkyl of 1 carbon atoms, aralkyl of -7 to 12 carbon atoms, phe = also phenyl substituted with til -4 carbon atoms, (al this starting compound Q+ [wherein R4 and Formula % Formula % f) Group (coco"'Q R,, fl alkyl of 1 to 18 carbon atoms, 7-chloroalkyl of 3 to 101119 carbon atoms, aralkyl of 7 to 12 carbon atoms) phenyl phenyl substituted with 1.2 or 3 alkyls of 1 to 4 carbon atoms; RIS and R111 are the same or different; phenyl or alkyl of 1 to 4 carbon atoms; 〜1.2 or 8fl substituted phenyl, but when R111 and R11l are taken together, (C
u2) a- or -(CH2)bO-(CHz)c-'
where a is 8.4 or 5 and b is l, 2 or 8
, and C11l, 2 or 8, provided that the sum of b and C is 2.3 or #-i4, and R1? is hydrogen or phenyl A/), and 0R2t O
R. CH2CH,OR2°· where R21 is as defined above and C-9 is 0 11 or ? - and Rts is (1) -COOR2゜(21-CM20R,1 (8) -CH2N(RoXRzs) (4) -C-
(b) converting the product of step (a) (C) The product of step (a) is oxidized to form a compound (as defined), and (C) the product of step (a) is CH20H f8) -CH2N(R,)(R2g) (4) -C-
N(Ro)(R2g) or (ko\deRo,!:Rt
s is as defined above, "and R8 is as defined above as R20
(a) to (rr+) as defined in (a) to (rr+) including (n) a pharmacologically acceptable cation) to the desired compound of , or a method for producing a mixture consisting of this compound and its enantiomers. 62・OH! 1 [In the formula, (1) -(CH2)d-C(R2)t-
and (2) -CH -0-CI(2-Y- (where d is 0 to 5, and R2 is hydrogen, methyl or fluoro, the same or different, provided that L-JO
When R2 is fluoro, the other is not methyl, and Y is a valence bond, -CH2- or tf-(CH
z) t-) Teari, 0 0- , where C-9 is bonded to 11 or: and 5 R26 is (1) -C-CgH2g-CH, or 6 6 (where CgH2g is Alkylene of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CR,R6- and the terminal methyl, Ri and Ratf hydrogen, 1 to
Alkyl or fluoro of 4 carbon atoms, the same or different, provided that only when one of R, and 86 is hydrogen or fluoro, the other is fluoro;
-0-) is R. Both of alkylene of 1 to 9 carbon atoms, T is alkyl of 1 to 4 carbon atoms, fluoro, chloro, trifluoromethyl or alkylene of 1 to 4 carbon atoms; Alkoxy, S is 0.1
．． 2 or 3, provided that not more than two Ts are other than alkyl, and when S is 2 or 3, Ts are the same or different;
Also, Rn is (1) -COOR2゜(2) -CH20H (8) -CH2N(RoXRzs) 1 (4) -C-N(R@) (R211) or (where Ro is hydrogen, methyl or ethyl , RZS is hydrogen, phenyl substituted with alkyl of 1 to 4 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or alkyl of 1 to 4 carbon atoms;
0 is (a) hydrogen, (b) alkyl of 1-1211 carbon atoms, (c) 8-10fli! cycloalkyl of it carbon atoms, (d) aralkyl of 7 to 12 carbon atoms,
(e) phenyl, (f) phenyl substituted with chloro or alkyl A/1 to 8 of 1 to 4 carbon atoms, 1 1In) -0H-C-Rh. n C in the formula Rlo d phenyl, p-bromophenyl, p-
biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and R11 is hydrogen or benzoyl); 5.6.14-Trihalogenated compounds are prepared by subjecting them to demonohydrohalogenation, R2° is bromo or chloro, and ~ indicates a bond in the alpha or beta configuration. , (b) subjecting the product of step (a) to reduction to .'\ or H. H), and (C) step (b
) is subjected to selective de-logenation to produce the compound AH (as defined above), and (d)
By halogenation and cyclization, R3 is as defined above, and R3? is iodo, bromo, or chloro]; (e) the product of step (d), where R21 is a blocking group, tetrahydropyranyl, tetrahydrofuranyl, l-ethoxyethyl; or 1 R16Rta (where Ro is alkyl p of 1 to 18 carbon atoms, cycloalkyl of 8 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or 1 to 4 carbon atoms phenyl substituted with 1.2 or 8 alkyl groups, Rts and ata are the same or different,
hydrogen, alkyl of 1 to 4 carbon atoms, feniμ or 1
-(CH2)a- or -(CHII)b-
o-(CH2)c-, where a is 8.4 or 5
, b is IJ2 or 8 and C is 1.2 or Fi8, but
However, the condition is that the sum of b and C is 2.8 or 4,
R1 again? is hydrogen or phenylene/I/), R23 is (1)-COOR2゜(2) CHzOR2+ (a)-CHzN(Ro)(R2g) 1 (4) ''-N(RoXRza) or, where R11, R20w R21 and R21+ are as defined above, where C-9 is bonded to 0-9-, 11 and R2I is as defined above.
7. (Q) Treating the product of step (e) with dehydrogenation. (g) Oxidizing the product of step (f), (h)
The product of step (g) was converted to C-C-R. As it is, Roke(1)-COOR. (2) -CH,0H (81-CH2N(R・XRzs) (4) -C-N(Re)(Rz@) or seven \
, R11 and Rte are as defined earlier, and R5 is (a) ~ 6η) and (
n) include pharmacologically acceptable cations)
6-kedo-11.14-didehydro-PGE, type compound, or this compound and its A method for producing a mixture of enantiomers.