NL8300921A - PROCESS FOR PREPARING PROSTAGLANDIN DERIVATIVES. - Google Patents

Description

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Process for the preparation of prostaglandin derivatives.

Prostaglandins and analogues thereof are derived from prostanoic acid, which has the structure and atomic numbering as shown in formula 14 of the formula sheet.

As drawn, the formulas represent a given optically active isomer of the same configuration as PGE 1 obtained from mammalian tissue requirement.

In the formulas, broken line bonds to the cyclopentane ring or side chain indicate substituents in α configuration, ie, lying below the plane of the ring or side chain. Drawn bond lines indicate substituents in (3-phonfiguration, i.e., lying above the plane. See also, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and Pace - Asciak et al., Biochem 10, 3657 ( 1971).

The invention relates to compounds of formula 1,3 and 4 wherein formula 15, 16, 17,

18, 19, 20 or 21, wherein L

(1) - (CH2) dC (R2) 2- (2) -CH2-O-CH2-Y- or (3) -CH2CH = CH- 20, wherein dO is 1, 2, 3, 4 or 5 , R2 represents hydrogen, a methyl group or fluorine and may or may not be the same, with the proviso that one R2 represents no methyl group when the other is fluorine, y represents a valence bond or - (CH2), where k1 or 2; ... represents QO, ΗH, R0 OH or R0 OH, where R0 represents hydrogen or a 4D 600 alkyl group having 1 to 4 carbon atoms, R4 represents formulas 22, 23, 24 or 25, wherein R ^ (a) an alkyl group of 1 to 12 carbon atoms, (b) a cycloalkyl group of 3 to 10 carbon atoms, (c) an aralkyl group 8300921 * *? \. · L · with 7 to 12 'carbon atoms, (d) a phenyl group, (e) a phenyl group, substituted by 1,2 or 3 chloratoraen or alkyl groups with 1 to 15 carbon atoms, (f) the formula 26, ( g) the formula 27 »(h) the formula 28, (i) .. the formula 29» (j) the formula 30, (k) the formula 31, (l) the formula 32 where R1Q is a phenyl, p bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl group and R represents hydrogen or a benzoyl group; le-n, (m) hydrogen or (n) is a pharmacologically acceptable cation and R1 is hydrogen or a. alkyl group with 1 to U carbon atoms,; which may or may not be equal; R 1 represents the formula 33, 31 * or 35, wherein 10 C L is an alkylene group having 1 to 9 carbon atoms with 1 to 5 carbon δ atoms in the chain between and the terminal methyl group * R *. and ! Rg represents hydrogen, an alkyl group having 1 to U carbon atoms or fluorine and which may or may not be equal to each other, with the proviso that of R 1.

and Rg represents one only fluorine when the other is hydrogen or fluorine and further, with the proviso that R, _ and Rg represent none of the heather fluorine when Z is oxa (-0-), wherein Z is an oxa atom ( -0-) or CH-. represents • 0, in which C.H ?. a valence bond or an alkylene group of 1 to 9. carbon atoms with 1 to 6 carbon atoms between CR ^ Rg- and the: phenyl ring, T an alkyl group with 1 to 1 »carbon atoms, fluorine, chlorine»

20 represents a trifluoromethyl group or -R 3, where E 1 is hydrogen or an alkyl group with .1 to mb carbon atoms and s is 0,1,2 or 3, with the proviso that at most 2 groups T do not represent an alkyl group and that when s is 2 or 3, the groups T may or may not be equal, V is a valence bond or -CHg-, where W is, where h is 1 or 2 and X

2j (1) trans-CH = CH- - (2) cis-CH = CH- (3) -C = C- or (b) -CH 2 Cl 2 -;

Examples of the compounds of the invention are: (a) PGF compounds, when J represents formula 15; Ct '-is \ (b) 11S-PGF compounds, when} represents the formula ΐβ; ,

a -U 'TN

(c) 11-Deoxy-keto-PGF-compounds when j represents formula 17; (D) 11-Deoxy-11-methylene-FGF4 compounds, furthermore represents formula 18; 8300921.

t - F - - 3 - (e) 11-Deoxy-PGF compounds when X) represents the formula 19; (f) 11-Deoxy-10,11-dxdehydro-PGF compounds when the formula represents formula 20 and (g) 11-Deoxy-11-hydroxymethyl-PGF when the formula represents formula 21.

Particular examples of the compounds of formula 1, 3 and 4 are 9-deoxy-6,9-epoxy-5-iodo-PGF-a of formula 5, respectively; 9-deoxy-6,9-epoxy-6-hydroxy-PGF. of the formula 7 and 6-keto-PGF "of the formula 8. la la

The compounds of formula (I), (3) and (4) are intermediates for the preparation of compounds of the formula (II) in which ^, L, O, R,, R4, V, W and X have the above meanings, provided that R ^ does not represent -C00H when D are a group of formula 15, QH OH, L - (CH ^) an n-pentyl, V a valence bond, W-CH ^ and X trans-CH = CH.

In the compounds of the formula II, the wavy line / / indicates the bond in cis or trans configuration relative to the W-C bond. In formulas 1-4 as shown here, W is bonded to the cyclopentane ring at the C-8 site, V is at the C-9 site and X is at the C-12 site. In compounds of formula 3, the bond indicates -OH in α or β configuration.

The compounds of the formula II are the subject of Dutch patent application 77-00896. Particular examples are 9-deoxy-6,9-epoxy-A-PGF of the formula LT 6, its sodium salt of the formula 47 and the methyl ester thereof of the formula 48.

25

The compounds of formula II have pharmacological properties such as inhibition of platelet aggregation, smooth muscle stimulation, systemic reduction in blood pressure, inhibition of gastric juice secretion, reduction of undesirable gastrointestinal side effects upon systemic administration of prostaglandin systetase inhibitors , bronchi dilating effect, inhibition of mediators such as SRS-A and histamine, action against peripheral vascular disorders, and oestrus-regulating effect.

These properties are also attributed to the compounds of formula 1, 3 and 4.

These compounds are useful when it is desired to reduce platelet build-up, decrease platelet tackiness, and inhibit or prevent thrombi formation in mammals, including humans, rabbits and rats. These compounds are, for example, suitable for treating and preventing myocardial infarctions, for treating and preventing post-operative thrombosis, for promoting adhesion of vascular grafts after surgery, and for treating conditions such as atheroslerosis, arteriosclerosis Blood clotting defects from lipemia and other clinical conditions, the underlying etiology of which is associated with lipid imbalance or hyperlipidemia. Other in vivo uses include geriatric patients for the prevention of cerebral ischemic seizures and long-term prophylaxis after myocardial infarctions and strokes. For these purposes, these compounds are administered systemically, for example, intravenously, subcutaneously, intramuscularly and in the form of sterile implants for extended action. For quick response, especially in emergencies, 25 »8300921 •. t • _ * ^ · J · i, 5,.

Intravenous mode of administration is preferred. Doses in the range of about 0 * 01-10 ng / kg body weight / day are used, the correct dose depending on the age, weight and condition of the patient or animal and on frequency and method of administration. In addition, addition of these compounds to whole blood provides in vitro applications, such as whole blood storage, used in heart-lung machines. Furthermore, whole blood containing these compounds can be made to flow through organs, such as heart and kidneys, which have been removed from a donor and must be 10. " transplant !. They also apply in the preparation of platelet-rich concentrates in the treatment of thombocyto-; penia, chemotherapy and radiation therapy. In vitro applications use a dose of 0.001-1.0 pg ml of whole blood.

These compounds are exceptionally active in causing smooth muscle stimulation and also highly effective in enhancing the action of other known smooth muscle stimulants, for example, oxytocic agents and the various ergot alkaloids, including derivatives and analogs thereof . Therefore, they apply instead of or in combination with less than the. usual amounts of these known smooth muscle stimulants, for example to reduce the symptoms of paralytic ileus or to control or prevent atone bleeding from the uterus after an abortion or delivery, to promote expulsion from. the placenta and during childbirth. For the latter purpose, the compound is administered by intravenous infusion immediately after the abortion or delivery at a dose of about 0.01 to 50 µg / kg body weight / minute until the desired result is achieved. Subsequent doses are given by intravenous, subcutaneous or intramuscular injection or infusion during childbirth at a dose of 0.01-2 mg / kg body weight / day, the correct dose depending on the age, weight and condition of the the patient or animal.

These compounds are useful as hypotensive agents for lowering blood pressure in mammals and humans.

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For this purpose, the compounds are administered by intravenous infusion at a rate of about 0.01-50 µg / kg body weight / minute or in single or multiple doses of about 25 to 500 µg / kg body weight / day.

8300921 <* * ’. · 6 * m. * V ♦

These prostaglandin derivatives are useful in mammals, such as humans and certain animals, for example dogs and pigs, to reduce and control excessive gastric secretion, to reduce or avoid ulceration in the gastrointestinal tract and to heal such ulcers, which are already the gastrointestinal tract is accelerated. For this purpose, these compounds are injected or infused intravenously, subcutaneously or intramuscularly in an infusion dose range of about 0.1 - 20 µg / kg body weight / minute or in a total daily dose by injection or infusion of about 0.01-10 * 0 mg / kg bw / day, *; the correct dose will depend on the age, weight and condition of the patient or animal and on the frequency and method of administration.

These compounds are also useful in reducing the undesirable effects on the gastrointestinal tract resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors and used for that purpose by simultaneous administration of the prostaglandin derivative and the inflammation .

, anti-prostaglandin synthetase inbibitor. See U.S. Patent 3,781,1 <29 for a description that it is determined by certain 20; non-steroidal anti-inflammatory agents in rats (ulcerogenic effect is reduced by concomitant oral administration of certain prostaglandins of the E and A series, including PGE ^, PGEg, PGE ^, 13.1 ^ -dihydro-PGE ^ and the corresponding 11-deoxy-FGE, and -PGA compounds For example, prostaglandins are useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone and aspirins. are substances which are specifically mentioned in the above-mentioned United States Patent as non-steroidal anti-inflammatory agents They are also known to be prostaglandin synthase inhibitors.

The anti-inflammatory synthetase inhibitor, for example indomethacin, aspirin or phenylbutazone, is administered in one of the ways known to be an inflammatory condition; illuminated, for example, at any dose by any of the known means of systemic administration.

The prostaglandin derivative is taken at the same time as 8300921

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♦ --- »* *% 7 anti-inflammatory prostaglandin synthetase inhibitor administered, whether or not by the same route. For example, when the anti-inflammatory agent is administered orally, the prostaglandin derivative is also administered orally either rectally in the form of a suppository or, in women, vaginally in the form of a suppository or vaginal device for slow. release, for example, as described in U.S. Pat. Script 3.5 ^ 5 ^ 39 · Also, when the anti-inflammatory agent is administered rectally, the prostaglandin derivative may also be rectal. be administered. The prostaglandin derivative can further be administered orally or, in women, vaginally. It is of particular convenience when the route of administration for both the anti-inflammatory agent and the prostaglandin derivative is the same, both to be combined in a single dosage form.

. The dosage of the prostaglandin derivative in this treatment depends on a number of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage of the anti-inflammatory synthetase inhibitor, which the mammal is to be administered and the sensitivity of the particular prostaglandin derivative to be administered. Not every person who needs an anti-inflammatory substance experiences the same unfavorable effects on the gastro-intestinal tract when using the substance. The effects on the gastrointestinal tract will often differ in nature and extent. However, it is within the discretion of the treating physician or veterinarian to determine that administration of the anti-inflammatory agent causes undesirable effects on the gastrointestinal tract in humans or animals and prescribe an effective amount of the prostaglandin derivative to reduce and then practically eliminating these unwanted effects. ·.

. These compounds also apply in the treatment of asthma. For example, they are suitable as agents for dilating the bronchi or as inhibitors or mediators, such as SRS-A and histamine, which are released from cells activated by an anti-gene antibody complex, thus controlling these cramps and facilitating respiration in conditions such as bronchiole asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are presented in various dosage forms j 830 09 2 1. . 8 V ► 1 V 1 11 .administered, e.g. orally. the form of tablets, capsules or liquids; rectally in the form of suppositories, parenterally, subcutaneously or: intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers or by blowing in the form of powders. Doses of! Approx. 0.01-5 rog / kg body weight are used once a day, the correct dose depending on the age, weight, and condition of the patient and on the frequency and method of administration. For the top; said target, these prostaglandins can be advantageously combined with other anti-asthmatics, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc); anthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone).

These compounds have been successfully administered to human asthmatics by inhaling or inhaling aerosol.

15! For administration by the oral inhalation route 1: with conventional nebulizers or by aerosolization using acid! substance, it is advantageous to use the present active ingredient in dilute solution, preferably in concentrations of about 1 part of medicament to form about 100-200 parts by weight of total solution. All of the common additives can be used to stabilize these solutions or yield isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfate and the like can be used. .

For administration as a self-advancing dose! . i, 25 unit for it. administering the (active ingredient m aerosol form, ") suitable for inhalation therapy, the composition may contain the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane), • together with a co-solvent, such as ethanol, flavoring agents and stabilizers A dispersant such as oleyl alcohol may also be used in place of a cosolvent Suitable agents for using the aerosol inhalation therapy technique are fully described in, for example, U.S. Pat. No. 2,868,691.

These compounds are useful in mammals 35 and also in humans as nasal canalitisers and are used for this purpose at a dose of about 10 µg to 10 mg / ml 1 830 09 2 1 f 1. * - *. * 9 φ v of one. pharmacologically suitable liquid carrier or as an aerosol spray agent, both for topical application.

These compounds are also suitable for the treatment of human peripheral vascular disease. Peripheral vascular disease is here understood to mean disease of one of the blood vessels outside the heart and disease of the lyophilic vessels, for example, frostbite, ischemic cerebrovascular disease, artheriovenous fistulas, ischemic leg ulcers, phlebi-; tis, failure of the veins, gangrene, hepatorenal syndrome, ductus. arteriosus, non-obstructive mesentere ischemia, lynphagitis arteritis, and the like. These diseases are mentioned by way of example only and do not limit the designation of peripheral vascular disease. For these conditions, the compounds of the invention are administered orally or parenterally by injection or infusion directly into a vein or artery, with intravenous or intraarterial injections being preferred. The dosages of these compounds are between 0.01 and 1.0 pg / kg, administered by infusion at an hourly rate or by injection on a basis per day, i.e. 1-¾ times a day, the correct dose depending on the age, weight and condition of the patient and the frequency and method of administration. Treatment 20 'is continued for 1 to 5 days, although 3 days is usually sufficient to achieve a long-lasting therapeutic effect. If systemic effects or side effects are observed, the dose is reduced below the threshold at which these systemic effects or side effects occur.

These compounds are therefore suitable for the treatment of peripheral vascular diseases in the limbs of people in which the circulation in these limbs is inadequate. Such treatment produces pain relief and promotes ulcer healing.

For a full discussion of the nature and clinical manifestations of peripheral vascular disease in humans and the hitherto known method of its treatment with prostaglandins, reference is made to South African Patent 7/01 ^ 9 (Derwent. Farmdoc Ko 58 ^ 00 V). See also Elliott, et al., Lancet, January 18, 1975, page 11 * Q-1U2. .

These compounds use instead of oxytocin to induce labor in pregnant women and women 8300921.

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* * · - human animals, such as cows, sheep and pigs, shortly before or at the end of the maternity period or in pregnant animals if the fetus is in

* I

The uterus died in a period from about 20 weeks before the end to the end of the pregnancy period. For this purpose, the compound is infused intravenously at a dose of 0.01-50 µg / kg body weight / minute up to or close to the termination of the second stage of labor, i.e. the disturbance of the fetus, These compounds are particularly useful when the woman must have given birth one or two weeks earlier and no natural labor has begun or 12 to 60 10 hours after the membranes have ruptured and natural labor has not yet begun. Another method of administration is oral.

These compounds are further useful for controlling the reproductive cycle in menstruating women and female mammals. Among menstruating female mammals are animals that are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose, the prostaglandin derivative is administered systemically at a dose of 0.01 mg to about 20 mg / kg body weight of the female mammal advantageously for a period beginning approximately at the time of ovulation and approximately ending at the time of the menstruation or just before. menstruation. Other modes of administration are intravaginal and intrauterine. Furthermore, an embryo and fetus is ejected by similar administration of the compound during the first or second third of the normal gestational period of the mammal.

Furthermore, these compounds are suitable for dilating the cervix in pregnant or non-pregnant women and female mammals in gynecology and obstetrics. This widening of the cervix is also observed in the initiation of labor and in clinical abortions caused by these compounds. In cases of infertility, dilation of the uterus caused by these compounds is helpful in promoting the movement of the sperm to the uterus. Dilation of. the cervix by prostaglandins is also useful in operative gynecology, such as cervical dilation and uterine curettage, where mechanical dilation may cause uterine perforation, cervical tears, or infections. It is also useful for diagnostic purposes, widening 83 0 0 9 2 1. · V \ ^% 11 is essential for tissue research. For these purposes, the pros-taglandin derivative is administered topically or systemically.

For example, the prostaglandin derivative is administered orally or vaginally in doses of about 5-50 mg per treatment of a 5 adult woman with 1 -5 treatments per 2b hour period. Also, the compound can be administered intramuscularly or subcutaneously in doses of about 1-25 mg per treatment. The appropriate doses for these purposes depend on the age, weight and condition of the patient or animal. .

These compounds are further useful in pets as a miscarriage agent (especially in fattening heifers) as a means of observing oetrus and for controlling or. synchronizing estrus. Pets include horses, livestock, sheep and pigs. Controlling or synchronizing oestrus enables effective control of both conception and delivery by the. to enable farmers to breed with all their females at short predetermined intervals. This synchronization leads to; a higher percentage of live births than the percentage achieved under the natural scheme. The prostaglandin is injected or administered into 20% feed at doses of 0.1-1-0 mg / animal and can be used with others. agents, such as steroids, are combined. The dosing schedules x depend on the species treated. For example, mares receive the prostaglandin derivative 5-8 days after ovulation and return to oetrus.

* Cattle are treated at regular intervals over a period of 3 weeks. 25 * All cattle simultaneously develop oestrus.

These compounds increase blood flow through the kidneys of the mammal, increasing the volume and electrolyte content of the urine. Therefore, these compounds are useful in cases. in which the function of the kidneys is inadequate, in particular cases of blockage of the renal vascular bed. These compounds are useful, for example, in alleviating and improving edema cases resulting from, for example, major surface burns and in the treatment of shock. For these purposes, these compounds are preferably administered first by intravenous injection in a '35 dose of 70-1000 µg / kg body weight or 'by intravenous infusion in a dose of 0.1-20 µg / kg body weight / minute until the desired 8 3 0 0 9 2 1 * »« * '12 · · * * »·> result has been reached. Subsequent doses are given by intravenous, j; intramuscular or subcutaneous injection or infusion at a dose of 0.05-2 • mg / kg body weight / day.

These prostaglandin derivatives are applicable for treating expanding skin diseases in humans and pets, including psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and scaly cell carcinoma of the skin, lamellar • ichthyosis, epidermolytic hyperkeratosis, malignant sun-induced • jq keratosis, non-malignant keratosis, acne and seborrhoeic: dermatitis in humans and atopic dermatitis and mange in pets.

, These compounds relieve the symptoms of these spreading skin diseases; For example, psoriasis is relieved when a scale-free "psoriasis damage has diminished noticeably in thickness or noticeably but on-you; is completely free or completely free.

! For these purposes, these compounds are administered topically as formulations containing a suitable pharmaceutical carrier, for example, as a spread, lotion, paste, gel, spray or aerosol, using topical base such as petroleum jelly, lanolin, po-2q. luethene glycols and alcohols. As active ingredients, these compounds form about 0.1-15% by weight of the preparation, preferably about 0.5-25%.

In addition to topical administration, injection can be administered intradermally, intra- or perilesional or subcutaneously using suitable sterile salt preparations.

__ These 'compounds are applied as ignition 2? Antidrugs for preventing chronic inflammation in mammals, including their swelling and other undesirable effects, using methods of treatment and dosages generally in oven flow with U.S. Pat. No. 30 3,885. TO.

This 6-keto- ,. iodine ether, enol ether and hemicetal compounds of the invention elicit many of the biological responses known for the known prostaglandin compounds. "• For example, they are surprisingly more specific in terms of power and have a considerably longer biological duration. Furthermore, they have the advantage that they can be successfully administered orally, sublingually, intravaginally 8300921 * τ * 13 4 · • ¥ * - V · sew, buccal or rectally in addition to administration by conventional methods. Each of these new analogs is therefore useful instead of the known F ^ -type prostaglandin compounds for at least one of their known pharmacological purposes and 5. is surprisingly and unexpectedly more useful for that purpose, because it is a different and narrower has a spectrum of biological activity than the known prostaglandin and is therefore more specific and less active. and exhibits less unwanted side effects than the known prostaglandin.

> i In addition, due to its extended effect, often less or clay-10? Lower doses of these new compounds are used to achieve the desired result. . · I · "i5; The process for the preparation of the compounds of the formula (I), (3) and (i) starts from a compound of the formula (9), in which L, Q, (R) and (R) have the meanings indicated above. including -C00H for R ^ and wherein the formula is 36, 37, 17, 18, 19, 20, 20 and 38, wherein R is hydrogen ^ ”a tetrahydropyronyl group, ► tetrahydrofuranyl group, T-ethoxyethyl group or a group of the formula 39 * wherein R 1 represents an alkyl group of 1 to 18 carbon atoms, cyclo-N '' alkyl group of 3 to 10 carbon atoms, aralkyl group of 7 to 12 carbon atoms, a phenyl group substituted or unsubstituted by 1 , 2 or 3 alkyl groups. with 1 to 1f represents carbon atoms, R and R 2 may or may not be the same: hydrogen and an alkyl group with 1 to 1f carbon atoms, a phenyl group, whether or not substituted by 1,2 or 3 alkyl groups with 1 through to if represent carbon atoms, or from R, _ and together. 15 lo s taken - (CH2Ja or - (CH2} b-0- (CH2) c- proposals, where a is 3, ¾ or 5, 30 b is 1, 2 or 3 and c is 1, 2 or 3, with it is understood that b plus c is 2, 3 'or if and R represents hydrogen or a phenyl group which is (i) iodinated and cycled to form a compound of formula 10 wherein "1, Q, R ^, R ^, V, W and X have the meanings indicated above, after which 35 (b) the product from step (a) is subjected to dehalogenation and hydrolysis, 8 3 0 0 9 2 1. 1¼ · V * · w * forming a keto compound of formula 12 and a hemi-ketal compound of formula 11 wherein J, L, Q,, R 1, V, W, X and% have the meanings indicated above followed by (c ) separation of the products.

In this description of the method of preparation; of the compounds of formulas 1,3 and k includes all ring systems indicated above for the symbol, together with those containing a blocking group within the scope of C-11. The ver! compounds as represented by formulas 10, 11 and 12 included the compounds of formulas 1, 3 and U, together with those containing the blocking group from the starting material of formula 9. The compounds with blocking groups are useful as intermediates in further conversions of the products of formula 10, 11! and 12. · »15!. . For the enol ethers of the formula 12, the method uses dehydroiodination of iodine compounds of the formula 1. The process therefore comprises the following steps, starting from a compound: of the formula 13, wherein ^, R ^, V, W and X have the meanings indicated above, including -C00H of: 20 '(a) iodination and cycling, where a. iodine compound is formed of the formula I, wherein, L, Q, R, R, V, W and X have the meanings indicated above; (b) dehydroiodizing the product from step (a} with a tertiary amine or sodium or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium - or potassium trifluoroacetate, sodium or potassium bicarbonate, silver acetate or a tetraalkylammonium superoxide of the formula (R ^ 1 ^ NC ^, wherein R ^ is an alkyl group of 1 to U carbon atoms, as a reagent, forming the enol ethers, and 30 [(c) separating the products.

Scheme A shows the steps for preparing the products of formulas 1, 3 and H according to the invention. i In diagram A, the terms have the following meanings! sen: 35 j \ represents the formula 15, 16, 17, 18, 1.9., 20 or 21.

In those cases where connections are desired with 8300921 V; Formulas 10, 11 and 12, corresponding to the products of formulas 1, 3 and k, the C-11 hydroxyl groups in the starting compound 13 are protected by blocking groups R1 as defined above and then ^^^ as defined above.

^ .1 is (1) - (CH2) dC (R2) 2- (2) -CH2-0-CH2-Y- or (3) -CHgCH * CH- where d is 1,2,3, ¾ or 5i Rg hydrogen, a methyl group. or fluorine represents 10 and is the same or not, with the proviso that one Rg does not represent a methyl group, while the other represents a methyl group and Y represents a valence bond or - (CHg) - -, where k 1 or 2; Q is »A / \ / \.

0, Η H, Rg OH or Rg OH, wherein Rg represents hydrogen or an alkyl group having 1 to k carbon atoms; R ^ represents the formula 22, 23, 2¾ or 25, wherein R ^ (a) an alkyl group of 1 to 12 carbon atoms, (b) a cycloalkyl group of 3 to 10 carbon atoms, (c) an aralkyl group of 7 through 12 carbon atoms, (d) a? 0 phenyl group, (e) a phenyl group substituted by 1,2 or 3 chlorine atoms or alkyl groups with 1 through U carbon atoms, (f) a group of the formula 26, (g) a group of formula 2T, (h) a group of formula 28, (i) a group of formula 29, (j) a group of formula 30, (k) a group of formula 31, (l) ) a group of formula 32, where R is a * 5. phenyl, p-bromophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl group and R 1 is hydrogen or a benzoyl group; (m) hydrogen or (n) represents a pharmacologically acceptable cation. and R 1 represents hydrogen or an alkyl group having 1 to U carbon atoms, which may or may not be the same, R 1 represents a group with. the formula 33, 23 3¾ or 35, wherein CH is an alkylene group having 1 to 9 carbon atoms having g 1 to 5 carbon atoms in the chain between -CR ^ Rg and the terminal methyl group, wherein and Rg is hydrogen, an alkyl group having 1 to k represent carbon atoms, or fluorine * and may or may not be equal to each other, with the proviso that of and Rg the one. only represents fluorine when the other is hydrogen or fluorine and further with the proviso that R 1 or R 8 neither represent fluorine when Z is oxa (-0-); Z an oxa atom 8300921 * * i 16 * * v *. T _

(-0-) or C.H. where C / Ηχ. is a valence bond or a 0 - YY

alkylene group of 1 to 9 carbon atoms with 1 to 6 carbon atoms, between CRtjRg and the phenyl ring; T is an alkyl group with 1 to h carbon atoms, fluorine, chlorine, a trifluoromethyl group or -OR ^. wherein R 1 represents hydrogen 5. or an alkyl group having 1 to h carbon atoms and s is 0, 1,2 or 3, with the proviso that at most 2 I's do not represent an alkyl group and that 'when s is 2 or 3 the T's may or may not be' together to be equal; V is a valence bond or -CIL-; W is - (CH_) where h is 1 or 2 and X is i 2 2 h (1) trans-CH = CH-10 t (2) cis-CH = CH- (3) -C = C- or · ( U) -ch2ch2-.

Examples of alkyl groups with 1 to 12 carbon atoms are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, Ij octyl, nohyl, decyl, undecyl, dodecyl and isomeric forms.

Examples of cycloalkyl groups having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl groups, are the. cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl. 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3, - triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 30 3-tert-butylcyclopentyl, cyclohexyl, fc-tert-butylcyclohexyl 1,3-isopropylcyclohexy1,2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, 8300921. * '*. «17.

Cyclononyl and cyclodecyl groups.

Examples of aralkyl groups with 7 to 12 carbon atoms are the benzyl, 5-phenethyl, 1-phenylethyl, 2-phenylpropyl, enylbutyl, 3-phenylbutyl, 10 2- (1-naphthyl hyl} -, and 1- (2-naphthylmethyl) group »

Examples of phenyl groups substituted by 1-3 chlorine atoms or alkyl groups with 1 to h carbon atoms are the p-chlorophenyl. 15 n-chlorophenyl, o-chlorophenyl, 2,1 U-dichlorophenyl, 2,1; 6-trichlorophenyl, p-tolyl, 20 m-tolyl, 10-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 25 k-chloro-2- methylphenyl, and 2, U-dichloro-3-ethylphenyl group,

In scheme A, the starting materials of the formula 13 are known or can be easily obtained by known methods.

For example, for PGF, see U.S. Patent 3,706,789-2a for 15-methyl and 15-ethyl-FGF, U.S. Patent 3,728,382; for 16,16-dinethyl-FGF US patent 3,903,131, for 16,16-difluoro-PGF compounds US patents 3,962,293 and 3,969,380, for β-phenoxy-17,19,19, 20-tetranor- PGF Derwent Farmdoc Kr. 732790, for 17-phenyl-18, V9,20-trinor-PGF_ da da 35 Dervent Farmdoc Nr. 312791, for 1-deoxy-PGF Derwent Farmdoc Kr. 10695V, for FGDg U.S. Patent 3 * 767 * 813, for 2a, 2b-dihomo- 8300921 * * * 18 PGF Derwent Farmdoc No. 61122S and U.S. Pat. Nos. 2a · 3,852,316 and 3,991,195, for 3-oxa-PGF2a, Anerican Patent 3,923,861, for 3-oxa-17 ** phenyl-18,19, -trinor-PGF2a U.S. Patent 3,931,289, for substituted phenacyl esters Derwent Farmdoc 5 No. 16828X, for substituted phenyl esters, U.S. Patent 3,890,372, for C-1 alcohols, that is, 2-decarboxy-2-hydroxymethyl compounds, U.S. Patent 3,636,120, for C-2 tetrazolyl derivatives, U.S. Patents 3,883,513 and 3,932,389, for A2-PGF Derwent Farmdoc No. ^ 6 ^ 97 ^ and German Offenlegungsschrift 2.U60.285 I g - dtx for 5,6-trans-PGF het US Patent 3,759,978, for 2,2-

. <iCX

dimethyl-PGF. analogs Derwent Farmdoc Nr. 59033T and German Offenle-2a gungsschrift 2,209,039, for 9-deoxy-9-hydroxymethyl-PGF. U.S. Patent No. 3,950,363, for 110-PGF compounds, U.S. Patent 3,890,371, for 11-deoxy-PGF Derwent Farmdoc. 1069 $ 2a 15 for 11-deoxy-1l-hydroxymethyl-PGF-US patents

3,931,282 and 3,950,363, for 1β-methylene-PGF Derwent Farmdoc No. 1959JW

α * and German Offenlegungsschrift 2. 0.919, for 17-18-didehydro-PGF2a compounds US patent 3,920,726, for 3- (or U-) oxa-17,18-didehydro-PGF compounds US patent 3 920,723, 2a 20 for 15-oxo-FGF - U.S. Patent 3,728,382, for 15-deoxy-2a -PGF Derwent Farmdoc. 9239W, for 13.1 ^ -is compounds, U.S. 2a1se patent 3,932. ^ 79, for 11-deoxy-15-deoxy-PGF. 569 ^ 8, t 2a 8300921.

"for u-homo-PGF. compounds Derwent Farmdoc No. U728W, for 2,2-difluoro-2a.

: PGF-compounds Derwent Farmdoc Nr. 67U38R.

25. The starting product and of reaction scheme A of the formula 13, wherein the group represents -CHg / KRR / Jg, can be prepared according to reaction scheme G.

Scheme G-concerns a method by which the free acid of the PGF, - or 11-deoxy-PGF - type of the formula 101 is converted into the different compounds of the 2-decarboxy-2-aminomethyl or 2 -decarboxy-2- (substituted amino) methyl-PGF or 11-deoxy-PGF type α α of formulas 10lt, 106, 107, 108, 109 'or 110.

». ! With the. method of scheme G, the compounds of the formula 101 are converted into a mixed anhydride of the formula. 102.

These blend hydrides can be easily prepared from the corresponding alkyl, aralkyl, phenyl or substituted phenyl chloroformate at. 19.

t * presence of an organic "base" (e.g. triethylamine). Reaction thinners are. e.g. water, in combination with water-miscible organic solvents (e.g. tetrahydrofuran). This mixed anhydride is then converted to either PG type 5 amide of the formula. 103 or the azide of the PG type of the formula 105.

For the preparation of the P0F_ type amide • 2 ft. (formula 103}, the mixed anhydride of formula 102 is reacted with liquid ammonia or ammonium hydroxide.

*! Also, the compound of formula 103 from the f · 10; free acid of the formula 101 are prepared by methods which are known for converting carboxylic acids into corresponding carboxyamides. For example, the free acid is converted into a corresponding methyl ester (using known methods; for example, excess diazomethane; in ether) and a methyl ester thus prepared is added to the amide of the formula 103 converted using the methods described for converting the mixed anhydride of the formula 102 into the amide of the formula 103 - Then the compound of the 2-decarboxy-2-aminomethyl-PGFg - or 11 - deoxy-FGF 2 type of the formula 10U from the compound of the formula 103 prepared by reduction of the carbonyl group. In front of . Known methods are used in this conversion. Lithium aluminum hydride. can be used well for example.

The compound of the formula 102 is also used to prepare the azide of the formula 105. This reaction can be easily carried out using sodium azide according to known methods. See, for example, Fieser and Fieser, Reagents for Organic • Synthesis dl. 1, biz. 10 ^ 1-10 ^ 3, in which reagents and reaction conditions for forming azide are discussed.

Finally, the urethane of the formula 106 is prepared from the azide of the formula 105 by reaction with an alkanol, aralkanol, phenol or substituted phenol. For example, when methanol is used, the compound of the formula 106 is prepared in which R1 is a methyigrcep. This product of the PG type with the formula 106. is then used in the preparation of the product of either formula 107 or formula 108.

When preparing the promaire amine with the 8300921 • 20 »*».

Known methods are used for the reaction of the urethane of the formula [10], for example, treatment of the urethane of the formula 107 with a strong base at temperatures above 50 [deg.] C. Sodium, potassium or lithium hydroxide is used, for example. .

Also, the compound of the formula 1θ6 is used in the preparation of the compound of the formula 108. Thus, when Lj is an alkyl group, the compound of the formula 108 is prepared by reduction of the urethane of the formula 106, wherein an alkyl group is. For this purpose, lithium aluminum hydride is the preferred reducing agent.

ï *

Then the product of formula 108 is used

for preparing the corresponding urethane of the formula 109 r I

by reacting the secondary amine of formula 108 (where L is an alkyl group) with an alkyl chloroformate. The reaction proceeds in this way; according to methods known for the preparation of carbamates from corresponding secondary amines. Finally, the product of the formula 1, wherein L 1 and both, represent an alkyl group, is prepared - by reducing the carbamides of the formula 109 · Accordingly; methods described above are used to prepare the compound of the formula 108 from the compound of the formula: 106. Thus, scheme A gives a method by which each of the different products of the PGF-11 -deoxy-PGFg-type according to the invention is prepared. Optionally, the various reaction stages indicated herein may be preceded by the use of blocking groups R255, necessitating their subsequent hydrolysis in preparing any of the above-mentioned products. Methods described above for introduction and hydrolysis of blocking groups R ^ are used.

Finally, the methods described above lead • 30. converting the compound of formula 102 to that of formula 105 and the various subsequent compounds to shorten the 80 side chain of the compound of formula 101 by one carbon atoms. Therefore, the starting material of formula 101 must be selected to compensate for the methylene group consumed in the steps of the synthesis described above. Thus, if a 2a gay product is desired, a corresponding 2a, 2b-dihomo starting material must be used with the formula 101 * 8 8 0 0 9 2 1 21 a «m * ♦ · ·. ·. In scheme G, Y 1 represents trans-CH = CH-, -CfC- or -CHgCJIg-, where Μ,> \ 1 y \ y \ HH or R 'OH, where R 2 represents hydrogen or a methyl-5. / \ / \ group; represents R ^, R ^ R ^ or a mixture of R ^ R ^ and / \. · R ^ 1¾ for, in which R ^ and R ^ represent hydrogen, a methyl group or fluorine and may or may not be equal to each other, with the proviso that one of R ^ and R ^ represents only fluorine when the other is hydrogen or fluorine; (1) cis-CHsCH-CH _- {CH ") -CIL · -, (2) cis-CK = CH-CH2- (CH2) g-CF2-," (3) cis-CK2-CH = CH- (CII2) g-CH2-, 15 1 (¾) -CH2) 3- (CH2) g-CH2-, (5) - (CH2) 3- (CH2) g-CF2-.

(6) -Ci2-0-CH2- (CH2) g-CH2-, • (7) -C = C-CH2- (CH2) g-CH2-, (8) -CH2-C = C- (CH2) g-CH 2 -, (9) the formula h 2 or (10) the formula 1 * 3, wherein g is 1,2 or 3; R ^ suggests.

O) - (CH1) -CH1 v. c a. j: (2) the formula UU or. (3) for the formula 1 * 5, wherein m is 1,2,3, ¾ or 5, T is chlorine, fluorine, a trifluoromethyl group, an alkyl group with 1 to 3 carbon atoms or an alkoxy group with 1 t / m 3 carbon atoms and s is 0,1,2 or 3, the • different T's being equal or not to each other, with the proviso that • at most two T's do not represent an alkyl group and furthermore with that 30. it is understood that only the formula W represents where T and s have the meanings indicated above, when R 1 represents hydrogen or a methyl group and are the same or different; X represents -CH2NI2L3, wherein Dg and hydrogen represent an alkyl group having 1 to U carbon atoms or -COOR 4, which has the meaning indicated above.

The 1,15-lactones of the compounds of the formulas 8300921 .. '22 • - «

η I

1,2,3 and 1+ are "prepared as described below. The preparation of 1,9-, 1,11 or 1,15 lactones is not difficult if the 9-, 11- or 15-hydroxy1 group is the only one free hydroxyl group, thereby allowing the carboxyl function to lactonize. When more than one hydroxy group is present, "as for example in FGF 5, for example, and the hydroxyl groups necessary for lactone function are optionally made into derivatives for lactonization .

Selective methods of selectively derivatizing all but one hydroxyl group of a prostaglandin or. prostaglandin analog containing 2 or more hydroxyl groups are known.

. Suitable derivatives are the 9-11 cyclic feryl or butyl boronates of 9α, 11α or 96,11-dydroxylated prostaglandins and prostaglandin; analogs, acylates, such as acetate, silyl ethers, such as trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl ether and the like. Such functions; -tional derivatives are known in prostaglandin chemistry and are used with stereoselectivity, or when stereoselectivity cannot be achieved, with careful purification of the resulting mixtures; thereby obtaining the desired functionally protected prostaglandins and prostaglandin analogs further described in the examples.

1 Optionally, one or more hydroxyl groups are optionally protected by oxidation by a ketone before or after lactonization. After lactonization I, the ketone is reduced again, whereby a free hydroxyl group 1 is obtained with the same or the opposite configuration as the hydroxyl group originally present.

In all cases, however, it is essential to protect the hydroxyl groups that are present but not desirable to participate in the lactone formation. Lactone formation occurs at different relative rates at different hydroxyl groups, depending on the stereochemistry, the steric hindrance in the vicinity of the hydroxyl group and the size of the ring. In addition, it is possible to separate 1.9, 1.11 and 1.15 lactones, as indicated below for example for FGF. 1.9, 1.11 and 1.15 lactones. Thus * * *. Dct. 15-methyl-1-5-hydroxy- and 16,16-dimethyl-15-hydroxy-prostaglendine analogs are sterically hindered in the vicinity of C-15 and a lactone function does not compete with 15 with lactone function on a 9- or 11-hydroxyl group. As a result, it is for making a lactone with an "hindered hydroxyl-. group, such as 15-methyl-15-hydroxy- or l, 16-dinethyl-15-hydroxy-, essential, 8300921 * T * '*. - that other hydroxyl groups, if any, are protected. It is also necessary to extend the duration of the reaction until analysis of the reaction mixture shows that an undesirable product has been formed.

Prostaglandins, which are known as the lower alkyl (eg, methyl, ethyl,) ester, but not as its free acid, can be converted to free acid in a known manner for use in lactone function by chemical hydrolysis. When the relevant. prostaglandin is unstable to chemical hydroxy, such as the PGE-methyl-. ester, PGD-methyl ester and the like, it is preferred the free 1G | acid obtainable by enzymatic hydrolysis, for example by applying. method of U.S. Pat. No. 3, 1,356.

With these limitations and possibilities for simultaneous protection by hydroxyl groups present, selectively hydrolyzing the functionally protected hydroxyl groups without hydrolyzing the desired lactone, separating undesired from desired products and modifying the lactones by chemical methods known to those skilled in the art. Obviously, such as oxidizing, reducing, alkylating and the like, it is possible to prepare the 1,9-, 1,11- and 1,15-lactones of prostaglandins and prostaglanid analogues of biological interest.

The preferred method for lactone function between the carbonyl group and the 9-, 11- or 15-hydroxyl group is that: described by Corey et al., J.Am.Chem.Soc. 96, 561k (lpjk) and beyond

"V

described by Corey et al., J. Am. Chem. Soc. 97, 653 (1975) and further as described herein by way of example. Optionally, other methods can be used, such as, for example, that of Masamure et al., J.

Am. Chem. Soc. £ 7.3515 (1975) and Gerloeh et al., Helv. Chem. Acta 57, 2661 (197¾).

In step (a) of scheme A, the starting material 13 is iodinated and cyclized, whereby the iodine compounds are obtained.

of the formula 1. For this purpose, either an aqueous system containing iodine, potassium iodine and an alkali carbonate or bicarbonate is used or an organic solvent system, such as dichloromethane, which contains iodine, in the presence of an alkali carbonate. The reaction is carried out at temperatures below 25 ° C, preferably about 0-5 ° C, for 10-35 hours. Then the reaction is performed with sodium sulfite and sodium carbonate. quenched and the compound of formula 1 is removed from the reaction mixture 8300 9 2 1.

* *,. j- 2k 9 · * * ♦ separated.

In step (b) of scheme A, the iodine compound 1 is converted to the 6-keto compound by contacting with silver carbonate and perchloric acid. The reaction is run in an inert organic medium, such as tetrahydrofuran, and is followed by TLC to determine completion, normally in 15-2H hours at about 25 ° C. Preferably, the reaction is conducted in the absence of light.

In step (c) of scheme Λ, the 6-keto compound k is equilibrated in solution with a mixture of the compounds 10 of formulas 3 and U. This is accomplished by simply dissolving. to prepare a compound of the formula U in an organic solvent, for example acetone or dichloromethane and leave it for several days. The resulting mixture was concentrated and separated. , for example, by chromatography on silica gel, with the .15 hemi-ketal containing. obtains formula 3.

Stage (d) from scheme A gives another way to arrive at • the hemi-ketal with formula 3. The iodine compound of the formula 1 is treated with aqueous alkali metal hydroxide, for example potassium hydroxide, for several hours at a temperature of 0-30 ° C in an alcoholic solution, for example methanol. After acidification, a mixture of the acid form of the compound of the formula I and the kemetalic of the formula 3 is obtained together with a little of the compound of the formula U, which compounds are separated, for example, by chromatography over silica gel or fractional crystallization.

The new compounds of the formulas 1, 3 and U, in which R ^ is not -C00H, for example the esters, in which R ^ of -COOR ^ is an alkyl group with 1 to 12 carbon atoms, cycloalkyl group with 3 to 10 carbon Atoms, aralkyl group having 7 to 12 carbon atoms, an phenyl group optionally substituted by 1-3 chlorine atoms or alkyl groups, are prepared from the corresponding acids of formulas 1, 3 and 1, which. ; i.e., wherein R 1 -C00H is by methods known in the art. The alkyl, cycloalkyl and aralkyl esters are prepared, for example, • by reaction of the acids with the appropriate diazo hydrocarbon. For example, when diazomethane is used, the methyl esters are obtained. Similar use of, for example, diazoethane, diazobutane, 1-diazo-2-ethylhexane, diazocyclohexane and phenyldiazomethane provides the 8300921. 25 * ft f »·. . ethyl, butyl, 2-ethylhexyl, cyclohexyl, respectively. benzyl ester. Of these esters, the methyl and ethyl esters are preferred.

Esterification with diazo hydrocarbons is carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acidic reactant, advantageously in the same or different inert diluent. After the esterification reaction is complete, the solvent is evaporated and the ester purified, if desired, by conventional methods, preferably by chromatography. It is preferred that the contact of the acidic TO reaction components with the diazocarbon lasts no longer than is necessary to achieve the desired esterification, preferably about 1 to about 10 minutes to avoid undesired molecular changes. can be prepared in known manner.

See, e.g., Organic Reactions, John Wiley & Sons, Inc. New York, N, Y.

T5 volume 8, biz. 3Ö9-391 * (195 * 0)

Another method of esterifying the carbo. xyl residue of the new compounds of formulas 1, 3 and, includes conversions of the free acid to the corresponding silver salt, followed by reaction of this salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide and the like. The silver salts are prepared in conventional ways, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia under reduced pressure, followed by adding. the stoichiometric amount of silver nitrate.

The phenyl and substituted phenyl esters of the. compounds of the formula 1.3 and are prepared by silylating the acid to protect the hydroxyl groups, for example, replacing each -OH with -Q-Si-CCH2} ^ By doing this, -C00H30 can also be changed to -COO-Si- (CH ^). A brief treatment of the silylated compound with water again changes -COO-Si-CCH2} ^ to -C00H. Methods for this silylation are known and are discussed below. Thereafter, treatment of the silylated compound with oxalyl chloride yields the acid chloride, which is reacted with phenol or the suitably substituted phenol to yield a silylated phenyl or substituted phenyl ester. Then the silyl groups, for example -O-Si-iCH ^) ^ 8300 9 2 1 β ψ Λ. .26. Changed back to -OH by treatment with dilute acetic acid. Methods for these conversions are known. .. · ^; Scheme B describes the steps for preparing the products of the formula II according to the invention.

5 In scheme B, j}, L, Q »R ,, Rjj> V, W and X

the meanings indicated in scheme A.

In step (a) of scheme B, as in scheme • A, the starting materials 13 are iodinated and cyclized, whereby the iodine | compounds of the formula 1.10. In step (b) of scheme B, the iodine compound .1 is converted into the enolether compounds of the formula II by contacting them with a dehydroiodic acid reagent. For such reagents, • see, for example, Fieser and Fieser, "Reagents for Organic Synthesis",] biz, 13θ8, John Wiley and Sons, Inc. New fork, N.Y. (1967). For the reaction T5 i from step (b), preference is given to tertiary amines and to atrium | or potassium superoxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or potassium trifluoroacetate, sodium or potassium bicarbonate, silver; veracetate or a tetraalkylammonium superoxide reagent of formula 20 (Rg in which R 1 represents an alkyl group having 1 to 1 carbon atoms.

! Earn from the tertiary amines; 1,5-diazabicyclo / U.3.77noneen-5 ("DBN"), v 1, U-diazabicyclo / ** 2.2.27octane ("DABCO"), "and 26; 1 t5-diazabicyclo / "* 5 * 7 * 7decene-5 - (" DBU ").

the preference. Other preferred reagents are sodium or potassium superoxide and tetramethylammonium superoxide. For further support; details of the superoxides see Johnson and Nidy, J, Org. Chem.

. 4θ, 1680 (1975) · For larger scale preparation, the electro ...

Chemical development of superoxide is preferred. See Dietz et al., J. Chem. Soc (B), I87O, biz. 816-820.

The dehydroiodination step is performed in an inert organic medium, such as dimethylformamide, and is followed by TLC to indicate disappearance of starting material. The reaction proceeds at 25 ° C and can be accelerated at 50-50 ° C.

When working up the reaction mixture, it is advantageous to maintain basic conditions, for example with triethyl amide to avoid acid decomposition or structural changes of the product. Purification is carried out by crystallization followed by separation of impurities or starting material remaining in the master liquor or by column chromatography. For the chromatographic separation, a column of magnesium silicate ("Florisil") over silica gel is preferred. Decomposition of the product is avoided by pretreating the column with triethylamine.

. Ester groups, such as the p-phenylphenacyl group on the tO C-1 carboxyl group or U-bromobenzoate on C-11 and C-15 hydroxyl groups, remain unchanged in the reactions of scheme B and when they are on the starting material of the formula 13 present, they are also present on the product of formula 2. For the final products of formula 2, which are esters, the preferred preparation method is «.

5 '* those from iodine compounds of the formula I which are corresponding esters. *: Of particular use for administration by their form • as free-flowing powders and the ease with which they dissolve are sodium salts.

They are obtained from the esters of the formula II by saponification with equivalent amounts of sodium hydroxide in a solvent, preferably a solution of alcohol and water, followed by lyophilization. (freeze-drying) the mixture, whereby the powdery product is obtained. The starting esters are preferably alkyl esters, the methyl or ethyl esters of which are particularly preferred.

The invention also includes the 1,15-lactones obtained from the compounds of formulas 1,2,3 and ^, wherein -COOH is y \. j and Q represents H OH, for example 9-deoxy-6,9-epoxy-5-iodo-PGF, 1,15-lactone

iG

30 and 9-deoxy-6,9-epoxy-d--PGF, 1,15-lactone.

not

Methods analogous to those described in a previously filed U.S. Patent are used for their preparation. See in this regard the attached Appendix.

35 It should be noted that although in the diagrams the formulas are drawn with a specific configuration for the reactx file - 8300921 • o «· 28 • -v parts and. products, the method steps apply not only to the other optically active isomers and cis / trans geometric isomers but also to mixtures such as racemic mixtures or mixtures of enantiomeric forms.

When optically active products are desired, optically active starting materials or intermediates are used or when racemic starting materials or intermediates are used, the products are decomposed in ways known for prostaglandins.

The products, which at each step of the reaction 10! are often mixtures and, as is known to those skilled in the art, they can be used for subsequent steps or optionally by known methods such as fractionation, column chromatography, liquid-liquid extraction and the like.

In order to obtain the optimal combination of biological response, specificity, potency and duration of action, certain compounds are preferred within the scope of formulas 1-1 *. For example, it is preferable that Q is Rg OH, with it being particularly preferred that Rg represents hydrogen or a methyl-20 group.

Another preference for the compounds of the formulas; 1,3 and vessel R, is that R_ is in -C00R, either hydrogen or a. * 3 represents an alkyl group with 1 to U carbon atoms, in particular a * methyl or ethyl group. for optimal absorption when administered. In the case of the compounds of the formula II, it is recommended that R 1 does not represent hydrogen, but rather an alkyl ester or a salt of a pharmacologically acceptable cation.

In view of long-term storage stability, it is also recommended that R 1 be an amido-substituted phenyl-30 group or substituted phenacyl group as indicated herein.

What variations in'j '' ^ ') is concerned, it is preferable, dartTy ^ of the formula 15, 17 or 19 shows.

As far as variations in R ^ are concerned, it is recommended that. that Rj represents an n-pentyl group, 1,1-dimethylpentyl group, 1,1-difluoropentyl group, a group of the formula hO or a group of the formula hl.

As for variations in L, it is preferable, 8300921 t ''. 29 *> - »r which represents L - (Cir 2) u - or - (CH 2} 5, in particular - (CH 2 -).

The invention is further illustrated by the following examples.

! The infrared absorption spectra were recorded with a 5 infrared spectrophotometer from Perkin-Elmer, model U21. Unless otherwise indicated, undiluted (unmixed) samples have been used.

The KMR spectra were recorded with a Varian A-60,. A-60D or T-60 spectrophotometer in deuterochloroform solutions with tetra-! methyl silane as an internal standard.

10; -. The mass spectra were recorded with a Varian Model • MAT CII7 Mass Spectrometer, a CEC Model 11 OB Double Focusing High Resolution Mass Spectrometer or an LKB Model 900Q Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ff).

By "saline" is here meant a saturated sodium chloride solution, "Skellysolve B" is a mixture of isomeric hexanes. "DBN" is an abbreviation for 1,5-diazabicyclo / ”li.3.07. noneen-5 · "DABCO" is an abbreviation for 1, H-diazabicyclo / 2.2.27 20 octane.

"DBU" is short for 1,5-diazabicyclo / * 5 "^ * 07" undecene-5.

DIBAL is short for diisobutylaluminum hydride.

fiïV

25 "Florisil ^" is a chromatographic magnesium silicate prepared by the Floridin Co. See Fieser et al., "Reagents for Organic Synthesis" biz. 393, John Wiley and Sons, Inc., Hew York, N.Y. (19 ^ 7) · "DLC" is short for thin layer chromatography. Silica gel chromatography here includes elution, collection of fractions and combination of those fractions, which are shown by DLC to contain the desired product free of starting material and impurities.

"Concentrating" means concentrating under evaporated pressure, preferably at less than 50 mm and at temperatures below 35 ° C. 8300921 • '«. .

. 30 V>,, ·

Preparation 1'11-Deoxy-1O, 11-didehydro-PGF. , methyl ester and its 96 epimer and 11-deoxy-10,11-dxdehydro-PGF2a and its 9B epimer »

A mixture of PGAg, methyl ester 0.7 ** g) and 12 ml tetrahydrofuran is treated at -78 ° C with 2 h ml 10 $ DIBAL in 90 # 5 toluene. After stirring for 1 hour at -7 ° C, the mixture is quenched with 100 ml of tetrahydrofuran saturated aqueous ammonium chloride (1: 1 ratio) and heated to about 25 ° C. The mixture is acidified with sodium bisulfate and extracted with ethyl acetate. The organic phase is washed with sodium bisulfate, sodium carbonate and brine, over sodium sulfate. dried and concentrated to give 1.8 g.

The crude product is subjected to column chromatography, whereby the title compounds are separated in the order of: -11.1-deoxy-10,11-didehydro-PGF. 2a 15 methyl ester, 1t-deoxy-10,11-didehydro-9S, PGF-20, the methyl ester, 11-deoxy-10,11-didehydro-PGFs; 1l-deoxy- * 10,1-didehydro-98-PGF0 ... 2a.

20 (Preparation 2 v 2-Decarboxy-2-azidomethyl-PGF2a or P-nor-PGF ^, azide (formula 105: I is CH = CH- (CH2) 2 and CH ^ 1MCHgJg, Rg is a hydroxyl group, is trans -CH = CK-, B ^, and of the residue and R_ of the Mj residue represent • jm *! All hydrogen and R ^ is an n-butylgreen ~ 25 A. To a cold solution (0 ° C) of PGF "(7.1 g), 125 ml of acetone, 10 ml of water and 2.2 g of triethylamine are added with stirring 3.01 g of isobutyl chloroformate. The mixture is stirred at 0 ° C for about 30 minutes, followed by a cold solution of. 7 g of sodium azide in 35 ral water are added, the mixture is then stirred at 0 ° C for 1 hour, after which it is diluted with 300 ml of water and extracted with diethyl ether.

The organic layers are then combined, washed with water, dilute carbonate solution and saturated brine, dried and reduced; pressure concentrated, maintaining the bath temperature below 30 ° C, whereby 2-nor-PGF-azide is obtained.

2a 35 8300921.

31 B. 2-Decarboxy-2-azidomethyl-PGFg ^ is prepared in the following reaction order: i (1) A solution of t-butyldimethylsilyl chloride (10 g), imidazole (9.1¾β) and PGF (3 g). ) in 12 ml of dimethylformamide is stirred magnetically for 2 hours under a nitrogen atmosphere. The resulting mixture is then cooled in an ice bath and the reaction quenched by the addition of ice water. The resulting mixture is then heated with 150 ml of water. ; thin and extracted with diethyl ether. The combined ether extracts; are then washed with water, saturated ammonium chloride, sodium chloride solution, and then dried over sodium sulfate. The solvent 1 is removed in vacuo to give PGP1, t-butyldimethylsilyl ester, 9,11,15-tris (t-butyldimethylsilyl ether). KMR absorptions are observed at 0.20, 0.30, 0.83, 0.87, 0.89, 1.07-2.50, 3.10-U, 21 *; and 5.38 δ * Characteristic infrared absorptions are observed at 15. 970, 1000, 10β, 1250, 1355, itéo, 1720 and 2950 cm "1.

* (2) To a magnetically stirred suspension of lithium aluminum hydride (7.75 g) in 18 ml of diethyl ether is added dropwise 8.71 g of the reaction product from the above part (1) in 1 ml of diethyl ether over 12 minutes at room temperature. After stirring for 1 hour at room temperature, it becomes 20. product obtained is cooled in an ice water bath and saturated sodium. sulfate added dropwise until a milky suspension appears. The product obtained is coagulated with sodium sulfate, triturated with diethyl ether, and the solvent is removed by suction filtration. Concentrating the diethyl ether under vacuum 25 gives 7.01 g of 2-decarboxy-2-hydroxymethyl-PGF, 9,11,15-tris- (t-butyldi-2, methylsilyl ether). KMR absorbances are observed at 0.03, 0.82, 1.10-2.60, 3.30-1 *, 30 and 5.37 δ. Characteristic infrared absorptions are observed at 775 µU, 970, 1065, 1250, 1h60, 2895, 2995, and 3350-1 CH.

30 (3) p-Toluenesulfonyl chloride (3.51¾g), pyridine (¾¾ml) and the reaction product from part (2), 7.01¾g, are placed in a freezer at -20 ° C for 3 days. put. Then, 7,200 g of 2-decarboxy-2-p-toluenesulfonyloxymethyl- 9,11,15-tris- (t-butyldimethylsilyl ether) are recovered.

KMR absorptions are observed at 0.10, 0.9 ^ 0.97, 1.10, 2.50, 2.50, 35 ^ 3, 3.80 ^, 80, 5.1 * 5.7, 35 and 7.80 d. Infrared absorptions are observed at 775, 970, 110 °, 1190, 1250, 1360, 11 * 70, 2900 and 2995 cm ”1.

8300921 * '' 32 r „q» ». · »*. (1 ») The reaction product from part (3), (2.13 g) is placed in 1 * 2 ml of a. mixture of acetic acid, tetrahydrofuran and water (ratio 3: 1: 1), which; 0.25 ml of 10JS aqueous hydrochloric acid. The reaction mixture becomes homogeneous after vigorous stirring at room temperature for 16 hours. The 5 'solution obtained is then diluted with 500 ml of ethyl acetate, washed with saturated sodium chloride and ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure to obtain 1.301 g of an oil. The crude product is chromatographed on 150 g of silica gel, placed on a column with ethyl acetate. Elution with ethyl acetate gives 0.953 g of 10. 2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF0.

; {5) The reaction product from part (1 *), (0.500 g) in 5.0 ml dimethylformamide is added to a stirred suspension of sodium azide (1.5 g) in 20 ml dimethylformomide. Stirring at room temperature is continued for 3 hours. The reaction mixture is then diluted with water (75 ml), extracted with diethyl ether (50 ml) and the ether extracts are washed successively with water and saturated sodium chloride and dried over sodium sulfate. Removal of the diethyl ether under reduced pressure yields 0.361 g of 2-decarboxy-2-azido-methyl-PGF. A character. . . . . -i α txeke azido infrared absorption is observed at 2110 cm 20 j Preparation 3 2-Decarboxy-2-aminomethyl-FGF2a (formula 125: Z ^ is cis-CH = CH- (CH2) ^ ~,

Rg represents a hydroxyl group, Y ^ trans-CH = CH-, and of the residue and R ^ of the remainder all represent hydrogen and R ^. is an n-tutylproen) _. Crude 2-decarboxy-2-azidoraethyl-PGF (Preparation 3, 2a, 0.361 * g) in 12 ml diethyl ether is added to a magnetically stirred suspension aluminum lithium hydride (0.380 g) in 20 ml diethyl ether. The reaction mixture is kept at about 0 ° C and the addition of lithium aluminum hydride is dropwise in 1 minute. After the addition is complete, the resulting mixture is stirred at room temperature for 1.5 hours and then placed in an ice bath (0-5 ° C). The excess reducing agent is destroyed by adding saturated sodium. sulfate. After cessation of gas evolution, the resulting product is coagulated with sodium sulfate, triturated with diethyl ether, and solid salts are filtered off. The filtrate is dried with sodium sulfate 35 and evaporated under reduced pressure to obtain 0.30L * g of a slightly yellow oil. This oil (2Q0 mg) is then purified by 8300921 ♦. 33 preparative thin layer chromatography to obtain 2 g of the product mentioned in the title. KMR absorptions are observed at 0.90, 1.10-2.80, 3.28, 3.65-2.25, and. 5 * ^ 5 δ · Characteristic infrared 'absorptions are observed at 970, 1θ6θ, 11; 6o, .2995 and 3l * 00 cn "^. The 5-mass spectrum shows a major peak at 699, ^ 786 and other peaks at' 628 , 68Π, 595, 217 and 27¾.

"I

Preparation U PGF ^. 1.15-1acton j A solution of 5.5 g PGFg ^ and 1.79 g 1-butane ™! boric acid in 150 ml of methylene chloride was refluxed for 15 minutes. cooler heated. - Then about half of the methylene chloride! distilled at normal pressure. Methylene chloride was added again to bring the volume back to the original 150 ml. This cycle distillation of methylene chloride followed by replacement with fresh 5'-methylene chloride was repeated three times, then the solvent was removed in vacuo to give the 9.11-cyclic boronate of PGF-as a residue. 2a! obtained.

. The residue was dissolved in 180 ml anhydrous, oxygen-free xylene and treated with 5.128 g 2,2'-dipyridyl disulfide, followed by 20% by 6.27 g triphenylphosphine. After 18 hours at 25 ° C under a nitrogen atmosphere, thin layer chromatography analysis of a portion (solvent: a mixture of 10 acetic acid, 10 methanol and 80 chloroform) showed complete; reaction to the ypridinethiol ester. The xylene solution was diluted with 300 ml oxygen-free xylene and was added dropwise over 10 hours to 3.2 liters stirred vigorously under a nitrogen atmosphere to reflux heated xylene. After the addition was complete, 100 ml of xylene were distilled off and the solution was heated to reflux for 2 hours. Then the reaction mixture was cooled and the xylene was removed in vacuo (bath temperature 35 ° C) to obtain a residue. 500 ml of tetrahydrofuran and treated with 10 ml of 30 # hydrogen peroxide and 100 ml of saturated aqueous sodium bicarbonate The three phase mixture was stirred vigorously at 25 ° C for 30 minutes and then concentrated in vacuo to give a residue. was taken up in a mixture of brine and ethyl acetate and extracted thoroughly with ethyl acetate. The combined organic layer was washed with 3 portions of 8300921 ν. 31 ψ t · ...

% 1Ν aqueous potassium bim sulfate and once with water, aqueous sodium bicarbonate and saline. After drying over sodium sulfate, the solvent was removed to obtain a viscous yellow oil which was chromatographed on 500 g of CC-U silicon dioxide washed with Mallinckrodt acid. The column was charged with a mixture of 25% ethyl acetate and 75% hexane and eluted (100ml; fractions) with a mixture of 50% ethyl acetate and 50% hexane. Fractions 26-Uo, which the product and geeeeh to prostaglandin! containing impurities were combined. The desired product. It was crystallized from 0 ml of a mixture of ether and hexane (ratio 10: ratio 1: 1), whereby pure lactone was obtained, m.p. 110-111 ° C, j. The lactone showed infrared absorption at 3500, 3370, 3290, 3010, 1700, 1320, 1310, 1290, 1260, 1105, 1080, 1055. 970 and 730 cm @ and KMR peaks at 6.00-5.75 (vinyl; multiplet; 2µl), 15; 5.75 - ^, 95 (vinyl and C-15H; multiplet; 3H), U, 30- 3.85 (CHOH; multiplet; 2H) 'and 2.65 parts per minute (OH; broad singlet; shifted downward on cooling;

1 I

i2H), The mass spectrum of the bistrimethylsilyl derivative showed fragments at U80 (M +), k65 (M-CH), 1 »36 (M-COg), U09 (MC H ^), 390, 380, 361», "238 , 217.

• 20 Anal. Ber. for C ^ O ^: C, 71.39 $; H, 9.59 $.

Found: C, 70.73 $; H, 9.31 $.

In the same manner, but using a mixture of ethyl acetate and hexane instead of a mixture of ether and hexane for recrystallization, PGF 1, 1,15-lactone: melting point 110.0-11.7 ° was obtained. C, / a7nEt ° H -71 °. - '!

iPreparation 5 'I

1 '' 1 17-Fenvl-18.19.20-t-rhinor-POF, 1,15-lactone. |

| A solution of 17-phenyl-18,19,20-trinor-PGF

2a (776 mg) and 1-butanoboric acid (225 mg), in 25 ml of methylene chloride, was refluxed for 30 minutes. After 15 minutes, the methylene chloride was slowly distilled off. Fresh methylene chloride was added when the total volume was reduced to about half the original volume. After 90 minutes, all methylene chloride was evaporated in vacuo . ,. ... was removed, thereby obtaining cyclic boronate of the starting prostaglandism 35 '.

i t; The cyclic boronate was dissolved in 5 ml of water- 8300921.

»V. , 35 '•> free, oxygen-free xylene and treated with 2,2'-dipyridyl disulfide (660 mg) and triphenylphosphine (786 mg). After 25 hours at 25 ° C, the reaction mixture was diluted with 500 ml of anhydrous, oxygen-free xylene and refluxed for 18 hours. The xylene was removed in vacuo to give a residue. This was taken up in 50 ml of tetrahydrofuran, that. 1 ml of 30 # aqueous hydrogen peroxide (11.6 nmol) and treated at 25 ° C with a solution of sodium bicarbonate (1.68 g) in 10 ml of water.

This mixture was stirred vigorously for 30 minutes and then concentrated under reduced pressure to obtain a residue. This was taken up in a mixture of brine and ethyl acetate and extracted thoroughly with ethyl acetate. The combined extracts were washed with aqueous sodium bisulfate, water, aqueous sodium bicarbonate and brine then dried over sodium sulfate and concentrated to give a residue of crude 17-phenyl-18,19,20-tinor-PGF. ,. 1,15-lactone.

t 2a I

The crude lactone was purified by chromatography on 400 g of neutral silica gel, placed in the column and eluted (22 ml fractions) with ethyl acetate. The fractions containing the product based on TLC were combined to give purified 17-phenyl-18,19,20-1 trinor-PGFg, 1,15-lactone. The lactone crystallized at tritu-2q; and after two recrystallizations from a mixture of ethyl acetate and: hexane, it showed a melting point of 116-117 ° C.

The infrared spectrum showed peaks at 3 ^ 60, 3 ^ 00 sch, 3020, 1705, 1650 »1605, 1 ^ 95, 1325, 1300, 1265, 1150, 1100, 10U0, 11020, 1000, 970 and 700 cm 1 and the mass spectrum showed fragments at 1 370 370 352, 33, 308, 298, 2β, 2fc, 225. (No peak was observed).

Anal. Ber. for ^ 3 ^ 30¾1 C * 7l |> 5 ^ 5 H, 8.16JS.

Found: C 12 H 2 T% K, 7.97: Preparation 6q 17-Phenyl-18,19,20-trinor-PGE, 1,15-lactone; A solution of 17-phenyl-18,19,20-trinor-PGE2: (735 mg), 2,2'-dipyridyldisuifide (628 mg) and triphenylphosphine (7h8 mg) in 10 ml of anhydrous, oxygen-free xylene was stirred for 2 hours a nitrogen atmosphere stirred at 25 ° C. The mixture was then diluted with 1,00 ml of water- 25-free, oxygen-free xylene, heated at reflux for 2.5 hours and evaporated under vacuum at 30 ° C to give a residue. This became 8300921 '· »’ *;. Chromatographed on 100 g of neutral silica gel, placed on a column and eluted (8 ml fractions) with a mixture of 80 # ether and 20 # hexane.

The fractions containing homogeneous product by TLC were then combined to give purified 17-phenyl-18,19,20-trinor-PGE-1,15-lactone. . Two recrystallizations from a mixture of ether and hexane yielded pure product, mp 81-83 ° C. The infrared spectrum showed peaks at 3 *, * 0, 3000, 1725 »1605, 1500, .1330, 12 *, Q,. 1160,; 11 * »5, 1085, 10 * + 5, 975» 7 * + 5 »725 and 700cm ^ and the mass spectrum showed fragments at m / e 368 (M-18), 350, 332, 297» 296, 277, 26 * », 259, 2 *» 1 15 '(no M + clear).

t *. Preparation 716-phenoxy-17,18,19,20-tetranor-PGF ^, 1,15-lactone

With the method of Preparation b, but under application! Singing of 16-phenoxy-17,18,19,20-tetranor PGF instead of PGF-2a 2a-15 gave a crude product of 16-phenoxy-17,18,19,20-tetranor-PGF-1,15-lactone 2a! like a viscous yellow oil.

"1

The crude product was purified by chromatography on neutral silica gel, charged to the column in a mixture of 50 # ethyl acetate and 50 # hexane and eluted with a mixture of 50 # ethyl acetate-20: tate and 50 # hexane followed by 70 # ethyl acetate and 30 # hexane. The fractions, which were found to contain homogeneous product by TLC, were then combined to give crystalline 16-phenoxy-17,19,19,20-tetranor, PGF-1,15 lactone. The lactone thus obtained was recrystallized 2a; ; lized from a mixture of ethyl acetate and hexane to give pure 25 'product, mp 185-186 ° C. The mass spectrum of; [the trimethylsilyl derivative peaked at M + 516.2738 (theory = for C ^ H ^ Si, ^: 516.2727) and fragments at m / e 501, * 26, * t23, * »09, j *» 00, 333 , 307, 217 and 181.

: Preparation 8, PGF 1, 1,15-lactone and 15-eni-PGF. , 1,15-lactone: ——————— 1, 2—1-.

The crude product containing PGF 1,15-lactone as a viscous yellow oil was obtained by the method of Preparation b but using PGF2 instead of PGF2.

The crude product was purified by chromatography 35 "on 700g neutral silica gel, placed on the column and eluted with a mixture of 50% ethyl acetate and 50% hexane. The first 2 liters of eluate were 8300921: 3τ.

* · »% * Discarded and fractions of 1-10 ml were collected.

A minor product which eluted first from the column (fractions 1 ^ -19), which was found to be homogeneous by DLC, was combined to give 15-epi-PGF., 1,15-lactone / 15R) -PGF2a, 5 obtained 1,15-lactone7. The infrared spectrum showed peaks at 3 ^ 50, '1730, 1585, 1250, 1100, 970 and 735 cm -1 and the KMR spectrum showed peaks) at 5.85-5 * 05 (vinyl and C-15; multiplet; 3H 25-iVlb '3.85 (CHOH; multiplet; 2H) and 3.30 µm (singlet, shifts downward on sample cooling; OK; 2H).

I - 10 'The main product, later removed from the column; eluted (fractions 21-28) was combined to give purified PGF1, 1.15-lactone. The purified PGF1,15-lactone crystallized on trituration with ether and recrystallization from a mixture of ethyl acetate and hexane yielding a pure sample, m.p. 105-106 ° C. The infrared spectrum showed peaks at vmax 3520, 3 ^ 80, 3380, j1710, 1300, 1290, 1265, 1250, 1235, 1160, 1075, 1055, 1000 and 965 cm "1.

** CDC1 • The KMR spectrum showed peaks (^ jg 3) at 6.0-5.75 (vinyl; multiplet;; 2H; 5.60-5.00 (C-15H; multiplet; 1H), Ij, 25 -3.80 (CHOH; multiplet; 2Ή) and; 3.08 din pm (OH; singlet).

20 l Preparation 9

13.1 k-Didehydro-Sg> 93,113,12a-FGF0 1,15-lactone and 13,1-didehydro-PGF

, 1.15-1 acton______________________________________________________ I With the method of Preparation U but using 13,1 ^ -didehydro-δβ, 96,11B, 12a PGF ^ (also known as ent-13-dehydro- 25:15) epi-prostaglandin F (compound 2 of J. Fried and CH Lin, 7). Med.

2a • Chem. 16, 1 »29 (1973) and 13.1 U-didehydro-FGF-instead of PGF, 13.1-didehydro-8B, 9B, Π β, 12cc-PGF yields 1,15-lactone 13, 1 2a: didehy dra-PGF, 1,15-lactone. . Preparation 10 -13,11-Didehydro-8S, 11B, 12a-PGE2 1,15-lactone and 13,1-didehydro-FGE2 1,15-.

• lactone _________________________ | . . By the method of Preparation 2 but using 13,1'-didehydro-80,11B, '12a-PGE2 (also known as ent-13-dehydro- '15 -epi-PGE2 (from 2a of Fried and CH Lin J. Med Chem Chem. (29-29 (1973)) 35 and 13,11 -didehydro-PGEg in place of PGEg, 13.1 -didehydro- is obtained.

^ 6 »11β, 12a-FGE2 1,15-lactone and 13,1 ^ -didehydro PGE2 1,15-lactone, respectively.

8300921 * 38 <I ''

Λ Q

»" Preparation 11 • 13. llj-Diriehydro-PGF .. IJ 5-lactone 5 dtX "^". " With the method of Preparation U, but using 13; 1 U-didehydro-PGF ^ instead of PGF ^ 13 * 1 ^ »- 5" didehydro PGF 1,15-lactone is obtained

Preparation 12 '(15S) -15-Methyl POF. 1J5-lactone! Using the method of Preparation U, but using (15S) 15-methyl-PGF, instead of PGF, and extending the 10! reaction time when heating xylene from 2k 1 to 1 8h on the reflux condenser, crude (15S) 15-methyl PGF, 1,15-lactone is obtained. The 2a crude lactone is purified by repeated chromatography and optionally further purified by TLC, in low yield (15S). 15-taethyl-PGFg 1.15 in practically pure form.

15 Preparation 13. '· ... *; 16,16-Pimethyl PGF 1,15-lactone i- By the method of Preparation 12 but using- | The addition of 16,15-dimethyl PGF instead of 15-methyl PGF gives 2a 2a, 16,16-dimethyl PGF, 1,15-laetone.

20! Preparation 1U ...

; By the method of Preparation 7, but using <- ': 16-m-1-trifluoromethyl-enoxy-17,18,19,20-tetranor-PGF0, 16-m-chloro-2-phenoxy-17,18 19,20-tetranor PGF ^ and 16-pf fluorophenoxy-17,18,19,20-tetranor JPGFg ^ instead of 16-phenoxy-17,18,19,20-tetranor PGF ^, the corresponding 1 is obtained. , 15-lactones. "".

Preparation 15 1 ♦.

By the method of Preparation U, but using (16S) 16-methyl, (16R) 16-methyl, and 16-ethylene PGE 2 instead of PGEg, the corresponding (16S) 16-methyl is obtained -, (16r) -16-30 'methyl and l-methylene PGE2 1,15-lactones, respectively.

Preparation 16; 1'6.15-Dimethyl PGE »1,15-lactone 'By the method of Preparation 2, but using 16,16-dimethyl PGF-1,15-lactone instead of PGF-1,15-lactone, 35! 16.16-dimethyl PGE2 1,15-lactone is obtained.

8 3 0 0 9 2 1.: 39> a *>

"Preparation tT

15 (S) 15-Methyl POE. 1.15-1acton

^. * I

.; With the method of. Preparation 2 hours using (15S) 15-methyl PGF-1,15-lactone instead of PGF-1,15-lactone. 5 (15s) 15-methyl PGE-1,15-lactone is obtained.

Example 18 1 By the method of Preparation 2, but using 11-deoxy-PGE 2 instead of PGEg, 11-deoxy-PGE-11.15-lactone is obtained.

In the same manner, replacement of PGE 2 by 11-deoxy FGE 2 yields the PGE 1, 1,15-lactone.

: Example 19 Γ 1 '(15S) 11-Deoxy-15-methyl PGE ^ 1,15-lactone and 11-deoxy 16,16-dimethyl PGE ^, 11.15-lactone * 5' By the method of Preparation 2, but using (15S) 11-deoxy-15-methyl PGEg and 11-deoxy-16,16-dimethyl PGE ^ [instead of PGE ^ and extending the heating period of the xylene back-reflux condenser 2 to 8 hours, the corresponding 1,15-lactones are obtained. The crude lactones are purified by repeated chromatography and further optionally by purification by TLC with low yield imes (15S) 11-deoxy-15-methyl PGEg 1,15-lactone and 11-deoxy-16,16 -dimethyl PGEg 1,15 lactone in practically pure form! v | gets.

| Preparation 20,! 25'11-Deoxv POF. ^ 1,15-lactone i ΐ A solution of 11-deoxy PGE-1,15-lactone (0.5 g) in methanol (50 ml) is treated with sodium borohydride (0 ° C) at 0 ° C. 500 mg) which is added in a 50 mg serving every 2 minutes. Aqueous sodium bisulfate (1M) is added until the mixture is acidic and the product is separated by extracting with ethyl acetate. The extract is washed, dried and concentrated to leave a residue.

11: Obtains 11-deoxy PGF containing 1,15-lactone. The residue is purified by chromatography on acid-washed silica gel using mixtures consisting of .35 ethyl acetate and 99% hexane, rising to ethyl acetate and CO2% hexane. The fractions, which are found by DLC to be homogeneous, contain 8300 8 2 1 -------- 1 * 0 · and can be saponified to the known 11-deoxy PGF®, combining 11-deoxy - PGF-1.15-lactone in practically pure form. obtains. ...

Likewise, use of (15S) 11-5 deoxy-15-methyl PGF produces 1,15-lactone, 11-deoxy-16,16-dimethyl PGE-1,15-lactone PGEg, 1,15-lactone, (15S ) 15-methyl PGF ,, 1,15-lactone, 16,16-dimethyl PGEg: 1,15-lactone and PGE ^ 1,15-lactone instead of 11-deoxy PGE ^ 1,15-lactone de '1,15 lactone or (15S) 11-deoxy 15-methyl PGF-1,1-deoxy-16,16-dimethyl •; 2ct

, PGF, PGF, (15S) 15-methyl PGF. PGF, respectively. cCt 2tt 2a 1 <X

10. Example I

| ^ | 9-Deoxy-6,9-epoxy-5-iodine-PGF. , methyl ester. (formula 1: L is - (CH0) -., R, •, la c. i 1 j-COOHg »R ^ an n-pentyl group, V a valence bond, W -CHg-, X trans-! CH = CH-, ij represents the formula 15 and I (Q, H is OH). See diagram A, step (a).

; . * a suspension of the PGFg / methyl ester of the formula ^ 5 13 and its 11,15-bis (tetrahydropyranyl) ether (2.0 g) in 23 ml of water | the sodium bicarbonate (0.7 g) is treated and dissolved in cooled an ice bath.

Potassium iodide (1.93 g) and iodine (2.82 g) are added to the resulting solution and stirring is continued for 16 hours at about 0 ° C. Then a solution of sodium sulfite (1.66 g) and sodium carbonate (0.16 g) in: 20.10 ml water is added. After a few minutes, the mixture is extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate and concentrated to give essentially the bis (tetrahydropyranyl) ether of the title compound; 2.2 g of an oil. Hydrolysis of this ether in a mixture of acetic acid, water, and tetrahydrofuran (ratio 20: 10: 3), yields mainly: the title compound, which is further purified by f silica gel chromatography. (TLC over silica gel in a mixture of acetone and dichloromethane (ratio 30:70)). The mass spectral pitches for the compound of formula 1 (TMS derivative) are 638,623,

30, 607, 567, 5 ** 8, 511 and kjj

; If the methods of Example 1 are used instead of the starting material, of formula 13, the following compounds of formula 13 or their C-11 ethers are used, the corresponding iodine compounds are obtained. of the formula 1:35, 15-Methyl-PGF-1 cCt

15-Ethyl-PGF

. . 2tt 8 3 0 0 9 2 1.

* 'v i * i ‘* - *.

. 16,16-Dimethyl-FGF-s ttt 16,16-Difluor-PGF.

2a. 16-Phenoxy-17,18,19,20-t et ranor-PGF ^ _ 7-Phenyl-18,19, 20-trinor-PGF ^ 11 — Deoxy-PGF_ 1 2a 5 2a, 2b-Dihomo-PGF- 2a

- - 3-Oxa-PGF

2a, 3-Oxa-17-phenyl-18,19,20-trinor-PCF2a

Example II

6-Keto-PGF., Methyl ester (Formula 1: L, Q,, R, V, W and X have the meanings given in Example I). See scheme A, step (b) _; A solution of the iodine compound, methyl ester of the formula 1 (Example 1, 0.5 g) in 20 ml of tetrahydrofuran is treated with silver carbonate (0.250 g) and perchloric acid (90%, 0.10 ml) and 2¾ stirred for hours at about 25 ° C. The mixture is diluted with 25 ml of ethyl acetate and the organic phase is washed with saturated sodium carbonate solution and brine, dried and concentrated to an oil, 0.1; 1 g. Separation by chromatography on silica gel eluting with a mixture of ethyl acetate and Skellysolve B (ratio 3: 1) affords the title compound of formula U as a more polar material than the starting material of formula 1. The product is an oil, 0.32 g, with R ^ 0 * 33 (TLC over silica gel in a mixture of acetone, and dichloromethane (ratio 1: 1), infrared spectral peaks at 17 ^ 0: 1 cm for the carboxyl group; KMR peaks at 5 »5, 3.2-k, 8, 3.7» 2.1-2.7 5. • Example III ήγν 25 9-Beoxy-6,9-epoxy-6-hydroxy-PGF1a, methyl lester (formula 3: J »L, Q, R ^ R ^., V, ¥ and X have the meanings indicated in example I and λ, indicates the bond in g or B configuration)» See diagram A, step (c). A solution of the 6-keto compound of the formula I (Example II, 0.2 g) in 10 ml of acetone is allowed to stand for 2 days at 25 ° C.

30. Thereafter, it is concentrated and subjected to silica gel chromatography to afford the title compound of formula: 3 with R ^ 0.50 (TLC over silica gel in a mixture of acetone and dichloromethane (1: 1 ratio). )}.

• Example IV '-. 9-Deoxy-6,9-epoxy-5-iodo-FOF (formula 1) and 9-deoxy-6,9-epoxy-6-hydroxy- 8 5 0 0 9 2 1. -. .

'1 + 2 Ψ * Λ

FGF ^ (formula 3): ^ j ^, I », Q, R ^, R ^, V, W and X have the in Example I

indicated meanings). See diagram A, tran (d) _._ _ | A solution of the iodine compound of the formula 1 (Example 1, 1.0 g) in 30 ml of methanol is treated with 20 ml of 3N aqueous potassium hydroxide for about 5 minutes at about 0 ° C and then for 2 hours at about 25 ° C.

. The mixture is acidified with 1 + 5 ml of 2N potassium acid sulfate and 50 ml of water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated to an oil, 1.3 g. The oil is subjected to silica gel chromatography, eluting with a mixture of acetone and dichloromethane (ratio 30:70 to 50:50), first mixing the compound of the formula 1 and then the compound of the formula 3. obtains a more polar fraction.

The compound of formula I is an oil, 0.33 g. 15. with R 0.33 (TLC over silica gel in a mixture of acetone and dichloromethane (1: 1 ratio) plus 2% acetic acid); infrared spectral peaks at i 3360, 2920, 2860, 261 + 0, 1730, 1710, 11 * 55 »11 * 10, 1380, 1235, 1185, 1075, | 1050, 1015, 970 and 730 cm ”1 and mass spectral peaks (TMS derivative) at! 681, 625, 606, 569, 535, ^ 79 and 173. • * 1 20 j The compound of the formula 3 is a solid, I 0.113 g, mp 93-9 ° C, recrystallized from a mixture of acetone : and Skellysolve B with a melting point of 95-105.2 ° C, which does not contain iodine * N, j and-0.13 (TLC on silica gel in a mixture of acetone and dichloromethane (ratio 1: 1) plus 2 % acetic acid) and mass spectral 25 peaks (TMS derivative) at 587, 568, 553, 1 + 97, 1 + 78, 1 + 07, 395, 388, and 173.

, | The above-mentioned compound of the formula III is methylated with diazomethane to form the methyl ester, which exhibits properties corresponding to the product mentioned herein! from example III.

When the iodine compounds of the formula I mentioned in Example I and III are used instead of the iodine compound of the formula I, then the corresponding | future compounds of the formula 1+ and the formula 3. Furthermore, by using the methods of Example III, but using 35 'the compounds of the formula 1+ thus obtained, the corresponding compounds of the formula 3 are also obtained by this method. .

8300921 t * 0 - 43 -

Example V

9-Deoxy-6,9-epoxy-5-iodo-PGF 2, p-phenylphenacyl ester (Formula 1) and 9-deoxy-6,9-epoxy-PFG 2a-p-phenylphenacyl ester (Formula 2).

2 A. A mixture of the iodic acid compound of formula 1 (example IV, formula 1, 0.20 g), p-phenylphenacyl bromide (0.50 g), 0.4 ml of di-isopropylethylamine and 10 ml of acetonitrile becomes 40 stirred at about 25 ° C for minutes. It is mixed with dilute aqueous citric acid and brine and extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is subjected to silica gel chromatography eluting with mixtures of 25-100% ethyl acetate and 75-0% Skellysolve B to give the title 5-iodo compound as a colorless oil, 0.20 g.

B. The product from Part A above (0.20 g) is treated with 0.4 ml DBN in 15 ml benzene at 42 ° C for 22 hours. The reaction mixture is cooled, washed with ice water containing sodium chloride, dried over magnesium sulfate and concentrated to the second title compound, 2Q an oil, 0.12 g. This oil is crystallized from a mixture of benzene and hexane. All fractions are combined and subjected to chromatographic separation pre-prepared with a mixture of hexane, ethyl acetate and triethylamine (ratio 80: 20: 0.5).

R

Florisil column, eluting with ethyl acetate to give the compound of the formula II, an oil. Crystallization from a mixture of ether and hexane gives crystals, 0.016 g, melting point 71 - 72 ° C (sintering at 65 - 67 ° C).

Example VI

9-Deoxy-6,9-epoxy-5-iodine-PGF. methyl ester 11,15-bis (4-bromobenz-3 ° lazoate). A. A mixture of the iodine compound of the formula I (Example I, 0.494 g) in 5 ml of pyridine, cooled in an ice bath, is stirred under stirring treated with 0.657 g of 4-bromobenzoyl chloride. The mixture is stirred for 16 hours and then poured into cold 10% sulfuric acid and extracted with ethyl acetate.

83009 2 1 - 44 - * The organic phase is washed with sodium carbonate solution and brine, dried and concentrated. The residue is subjected to silica gel chromatography to give the title 5-iodine compound, 0.70 g, a colorless oil with KMR peaks 7.3-8.0, 5.65, 3.8-5. , 5, 3.65 and 0.95.

Using the methods of Examples I, II, and III but using corresponding starting materials as described above, the compound of the formula f, 3 and 4, namely, compounds of the 9-deoxy-6,9-epoxy-5- is prepared iodine PGF. -, 10 α 9-deoxy-6,9-epoxy-ö-hydroxy-PGF ^ and 9-deoxy-6,9-epoxy-6-keto-PGF ^ type, in methyl ester form, where is -COOCH ^ with the following structural features: 16-Methyl-; 5 16,16-Dimethyl-; 16- Fluorine; 16.16- Difluor-; 17-Phenyl-18,19,20-trinor-; 17- (m-trifluoromethylphenyl) -18,19,20-trinor-; 2Q 17- (m-chlorophenyl) -18,19,20-trinor-; 17- (p-fluorophenyl) -18,19,29-trinor-; 16-Methyl-17-phenyl-18,19,20-trinor-; 16.16- Dimethyl-17-phenyl-18,19,20, trinor-; 16-Fluoro-17-phenyl-18,19,20-trinor-; 16,16-Difluoro-17-phenyl-18,19,20-trinor-; 16-phenoxy-17,18,19,20-tetranor-; 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-; 16- (m-chlorophenoxy) -17,18,19,20-tetranor-; 16- (p-fluorophenoxy) -17,18,19,20-tetranor-; 2q 16-Phenoxy-18,19,2-trinor-; 16-Methoxy-16-phenoxy-18,19,20-trinor-; 13,14-Didehydro-; 16 Methyl-13,14-didehydro-; 16.16- Dimethyl-13,14-didehydro-; 16-Fluoro-13,14-didehydro- 16,16-Difluoro-13,14-didehydro-; 8300921 9 »» · * *. - 45 - t) * 17-Phenyl-10,19 · 2 O-trinor-13,1¾-di dehydro-; 17- (m-trifluoromethyl-phenyl) -18,19,20-trinor-13 f-1-didehyd.ro-; f 17- (m-chlorophenyl) -18,19,20-trinor-13,1U-didehydro-; 17- (p-fluorophenyl) -18,19 * 20-trinor-13,1¾ -didehydro-; * 5 16-Methyl-17-phenyl-18,19,20-trinor-13,1U-didehydro-; 16,16-Dimethyl-17-phenyl-18,19,20-trinor-13 * 1 k-didehydro-; 16-Fluoro-17-phenyl-18,19,20-trinor-13> 1'-didehydro-; | 16,16-Difluoro-17-phenyl-18,19,20-t-rhinor-13,1¾ -didehydr o-; 16-Phenoxy-17,18,19, 20-t etranor-13,1-lipidhydro-; 10 · 16- (m-trifluoromethylphenoxy) -17,18,19,20-t etranor-13,1 U-di dehydro-; 16- (m-chlorophenoxy) -17,18,19-20-tetranor-13,1-didehydro-; ^ 16-Phenoxy-18,19,20-t-rhinor-13,1 U-didehydro-; ! 16-Methyl-16-phenoxy-18,19,20-trinor-1311 -didehydro-; ! . 13.1 ^ -Dihydro-; 1516-Methyl-13,1k-dihydro-; | 16,16-Dimethyl-13,1'-dihydro-; (16-Fluoro-13,1'-dihydro-; 16,16-Difluoro-13'1H-dihydro-;] 17-phenyl-18,19j-20-trinor-13,1'-dihydro-20t 17 - (m-trifluoromethylphenyl) -18.1 $, 20-trinor-13,1U-dihydro-: 17 - (m-chlorophenyl) -18,19} 20-trinor-13.1 H-di hydro-; 17- (p-fluorophenyl) -18,19,20-t-rhinor-13,1 k-dihydro-: 16-methyl-17-phenyl-18,19,20-trinor -13,1¾-dihydro-; 16,16-Dimethyl-17-phenyl-18,19,20-t-rhinor-13,1¾-dihydro-; i {> 25 µl-6-Fluoro-17-phenyl-18 19,20-trinor-1,3,1-dihydro-; 1,6,16-difluoro-17-phenyl-18,19,20-trinor-13,1-di-dihydro-; 16-Phenoxy-1,18,19,20-t etranor-13,1-dihydro-; 16- (E-trifluomethylphenoxy) -1,18,19,20-tetranor-13,1-dihydro- 16- (m-chlorophenoxy} -17,18,19,20-etr anor-13,1 ^ -dihydro-; 30: 16- (p-fluorophencxy) -17,18,19 »20- tetranor-13,1'-dihydro-; 16-phenoxy-18,19,20-trinor-13,1'-dihydro-; 16-Kethyl-16-phenoxy-18,19,20-trinor-13, 1,2-dihydro-, 2,2-Difluoro-, 2,2-Difluoro-16-methyl-.

2,2-Difluoro-16,16-dimethyl-; . 2,2-Difluoro-16-fluoro-; 8300921. . "- 46 - k ...

2.2- Difluor-1,6,16-difluor-; 2,2-Difluoro-17-phenyl-18,19,20-trinor-; 2.2- Difluor-17- (m-trifluoromethylphenyl) -18,19,20-t rhinor-; 2.2- Difluoro-17- (m-chlorophenyl) -1,18,19,20-trinor-; 2,2-Difluoro-17- (p-fluorophenyl) ~ 18,19 »20-trinor-; 2.2- Difluoro-16-raethyl-17-phenyl-18,19,20-trinor-; I '2.2-Difluoro-1,6,16-dimethyl-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16,16-difluoro-17-phenyl-18,19-20-trinor; 10 '; 2,2-Difluoro-16-phenoxy-17> 18,19,20-tetranor; J 2,2-Di fluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-t et ranor-; 2.2-Difluoro-16 ~ (m-chlorophenoxy) -17,18,19,20-tetranor-; ! 2,2-Difluoro-16- (p-fluorophenoxy) -17 »18,19» 20-tetranor-; 1 2,2-Difluoro-16-phenoxy-18,19,20-trinor-; (tj. 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor; 2,2-Difluoro-16-methyl-16-phenoxy-18,19-20-trinor; 2,2-Di fluoro-16-methyl-13,1'-didehydro-, 1 2,2-Difluoro-1,6,16-dimethyl-13,11 * -didehydro-; 2.2-Difluoro-16 -fluoro-13,1'-didehydro-; 2,2-Difluoro-1,6,16-difluoro-13,1k-didehydro-; 2,2-Difluoro-17-phenyl-18,19-20-trinor -13, -1-didehydro-;

1, 2,2-Difluoro-17- (m-trifluoromethylphenyl) -1,19, 20-trnor-13,14-s.

didehydro-; | 2,2-Difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,1fc-didehydro-; 2,2-Difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,1k-didehydro-; ,. 2,2-Di fluoro-16-methyl-17-phenyl-18,19,20-trinor-13,1H-didehydro-; 2,2-Difluoro-1,6,16-dimethyl-17-phenyl-18,19,29-trinor-1,3,1-dide-; hydro-; 2,2,16-Trifluoro-17-phenyl-18,19,20-trinor13,1U-didehydro-; 30! 2,2,16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-1 k, 13-di dehydro-; 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,11-didehydro-; 2,2-Difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-.

13.1 -didehydro-; . . - * · - I * | 2,2-Difluoro-16- (m -chlorophenoxy) -17,18,19,20-tetranor-13,1'-di-, 35: dehydro-; 2.2- Difluoro-16-phenoxy-18,19-20-trinor-13,1-didehydro-; 8300921.

-47- * Γ ft 2.2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor13,1U-didehydro-; 2,2-Difluoro-13,1 ^ -di hydro-; : 2,2-Difluoro-16-methyl-13,14-dihydro-; 2.2- Difluoro-16,16-dimethyl-13,1U-dihydro-; 5-2.2,16-Trifluoro-13,1'-dihydro-; 2,2, ΐβ, ΐβ-Tetrafluoro-13, -dihydro-; 2.2-Difluoro-17-phenyl-18,19,2Q-trinor-13,1U-dihydro-; ! 2,2-Difluoro-17- (ra-trifluoromethylphenyl} -18,19,20-trinor-13,1-dihydro-; f 10; 2,2-Difluoro-17- (Bi-chlorophenyl) -18 , 19,20-trinor-13,1-dihydro-; 2,2-Difluoro-17- (p-fluorophenyl) -1,19 »20-trinor-13,1-dihydro-; 1 2,2 -Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,1-dihydro-; 2,2-Difluoro-1,6,16-dimethyl-17-phenyl-18,19 »20 -trinor-13,1'-idihydro-; 15,1,2,16-Trifluoro-17-phenyl-18,19-20-trinor-13,1, i-dihydro- 2,2 16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-13,1U-dihydro-; 2,2-Difluoro-16-phenoxy-17,18,19> 20-tetranor-13, 2,2-Difluoro-1,6- (m-trifluoromethylphenoxy} -17,18,19,20-tetranor- = 13,1-dihydro-;

2,2-Di fluoro-16- (m -chlorophenoxy) -17> 18,19,20-et ranor-13,1-dihydro-; . · | 2,2-Difluor-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,1 ^ -

* I

. idihydro; . , '»- - ·! 2,2-Difluoro-16-phenoxy-18,19,20-trinor-13,11-dihydro-; 25 j, 2,2-Difluoro-16-isethyl-16-phenoxy-18,19, 20-trinor-13,1-dihydro-; . j s 16-Methyl-cis-13; "16", 16-Dinethyl-cis-13-; 16-Fluor-cis-13-; 16, 16-Difluor-cis-13-; 17-phenyl-18,19,20-trin6r-cis-13-; ! 17- (ia-trifluoroniethylphenyl) -18,19,20-trinor-cis-13-; ; j 17- (m-chlorophenyl) -1,18 »20-trinor-cis-13-; j j t7- (p-fluorophenyl) -1,18,19-20-trinor-cis-13-; 16-Methyl-17-phenyl-18,19,20-trinor-cis-13-; i 35 | 16,16-Dimethyl-17-phenyl-18,19,20-trinor-cis-13-; 16-Fluoro-17-phenyl-t8,19,20-trinor-cis-13-; 8300821 '* r * - 48 - • i ► s * • lé, 16 ~ Difluor-lT-phenyl-18,19> 20-trinor-cis-13-; ; 16-Phenoxy-17'11 V9 * 20-tetranor-cis-13-J16- (m-trifluoromethylphenoxy) -17il8,119,2-tetranor-cis-13-; | 16- (m-chlorophenoxy) -17, 18, J9,20-tetranor-cis-13-; 516- (p-fluorophenoxy) -17 µBi ^ O-tetranor-cis-IS-; 16-Phenoxy-18,19,20-trinor-cis-13- '. t | 16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-> 1 2,2-Difluor-cis-13-; 2.2- Difluoro-16-methyl-cis-13-; 2,2-Difluoro-1,6,16-dimethyl-cis-13-; 2.2- Difluoro-16-fluoro-cis-13-; 1 2,2-Difluoro-16,16-difluoro-cis-13-; | 2,2-Difluoro-17-phenyl-18,19,20-trinor-cis-13--; 2-, 2-Difluoro-17- {nt-trifluoromethylphenyl) -1,18,19,20-trinor-cis-13-; ^ 5 2,2-Difluoro-17- (m -chlorophenyl) -18,19,20-trinor-cis-13- "; 1, 2,2-Difluoro-17- (p-fluorophenyl) -18,19i20-trinor-cis-13-; ! 2,2-Difluoro-16-methyl-17-phenyl-18,19-20-trinor-cis-13-; . 2,2-Difluor-1,6,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-i-2-2-Difluor-16-fluoro-17-phenyl-18,19 »20 -trinor-cis-13-; 2,2-Difluoro-16,16-difluoro-17-phenyl-18,19-20-trinor-cis-13-; 2,2-Difluor-16-phenoxy-17, 18t19,20-tetranor-cis-13-; i j. ! | | 2> 2-Difluoro-16- (m-trifluoromethylphenoxy) -17, 18,19> 20-tetranoric-13-; _ ··; 2,2-Difluoro-16- (in-chlorophenoxy) -17,18,19 »20-tetranor-cis-13-; ^! 2,2-Difluoro-16- (p-fluorophenoxy) -17 »18,19» 20-tetranor-cis-13-; 2,2-Difluoro-16-phenoxy-18,19,20-trinor-cis-13-; ; * 2,2-Difluoro-16-raethyl-1-phenoxy-18,19,20-trinor-cis-13-; ! 2,2-Difluoro-16-methyl-1-phenoxy-18,19, 20-trinor-cis-13-; 1 I 3-0xa-; r 3-Oxa-l-nonhyl-; 3 3-0xa-16,16-dimethyl-; 3-0xa-16-fluoro-; ! 3-0xa-16,16-difluoro-; ! · ""; | . 3-0xa-17-phenyl-18,19,20-trinor-; 35; 3-Oxa-17- (trifluoromethylphenyl) -1,18> 20-trinor-; 3-0xa-17- (m-chlorophenyl) r-18,19-20-trinor-; i ^ * s 83009 2 1. > --49- \ '3-0xa-17- (p-fluorophenyl) -18,19,20-trinor-; 3-Oxa-16-raethyl-17-phenyl-18,19-29-trinor-; 3-0xa-16,16-dimethyl-17-phenyl-T8,19-20-trinor; 3-0xa-16-fluoro-17-phenyl-18,19-20-trinor-; 5'3-0xa-16,16-difluoro-17-phenyl-18,19,20-trinor-; ! 3-Oxa-16-phenoxy-17,18,19-20-tetranor; * 3-Oxa-16- (m-trifluoromethyl-phenoxy) -17 »18,19» 20-tetronor-; : 3-Oxa-16- (m-chlorophenoxy) -17, 18,19, 20-tetranor; * 3-Oxa-16- (p-fluorophenoxy) -1,18,19,20-tetranor-; 10 * "3-Oxa-16-phenoxy-18,19,20-trinor-3-Oxa-16-methyl-16-phenoxy-18,19-20-trinor-f 3-0xa- 13,1U-didehydro-; 1 3-Oxa-16-methyl-13,1U-didehydro-; 3-Oxa-16,16-dimethyl-13,1'-didehydro-; 15: 3-0xa -16-fluoro-13, -1-didehydro-; 1 3-Oxa-16,16-difluoro-13,1'-didehydro-; * 3-0xa-17-phenyl-18,19,20-trinor-13,1k-didehydro-; f 3-Oxa-17- (n-trifluoromethylphenyl} -18,19,20-trinor-13,1k-dide-! hydro-j * 9 20 y 3-Oxa-17- (m-chlorophenyl) -18,19 20-trinor-13 * 1U-didehydro-, 3-Oxa-17- (p-fluorophenyl) -18,19, 20-tinor-13,11 -didehydro-, i.

1 3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,1 U-didehydro-; 3-0xa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,1U-didehydro.

I "* ..

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13 -1-didehydro-; 25 ΐ 3-0xa-16,16-difluoro-17-phenyl-18,19-20-trinor-13 13 1U-didehydro-; i *] 3-Oxa-16-phenoxy-17,18,19-20-tetranor-13,11-di-dehydro-; 3-0xa-16- (n-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,1-dideKydrc-; k1-3-Oxa-16- (m -chlorophenoxy) -17,18,19-20-tetranor-13,1H-didehydr; 30-0xa-16-phenoxy-18,19-20-trinor-13,1-di-dehydro-; J 3-Oxa-16-ethyl-16-phenoxy-18,19-20-trinor-13,1-didehydro-; ! 3-0xa-13,14-dihydro-; 3-Oxa-16-methyl-13,1U-dihydro-; 3-0xa-16,16-dimethyl-13,1'-dihydro-; ΐ * ’" 35! 3-0xa-16-fluoro-13,1k-dihydro-; 3-0xa-16,16-difluoro-13,1'-dihydro-; 8300921 t f '- 50 - * 3-0χα-17-phenyl-18,19,20-trinor-13,1 • i-dihydro-; 3-Oxa-17 - (1-trifluoromethylphenyl) -18,19,20-trinor-13,1 ^ dihydro-; •; 3-Oxa-17 * - (m -chlorophenyl) -1 * 8,19,20-trinor-13,1-dihydro-; 3-0xa-17- (p-fluorophenyl) -18,19,20-trinor-13,1¾-dihydro-; ^ 3-Oxa-16-raethyl-17-phenyl-18,19,20% rhinor-13,1H-dihydro-; 3-Oxa-16,16-Dirae thyl-17-phenyl-18,19,20-t-rhinor-13,1 l-dihydro-; 3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,1¾-dihydro-; 3-0xa-16,16-difluoro-17-phenyl-18,19,20-trino-13,13-dihydro-; | 3-Oxa-16-phenoxy-17,110,19,20-tetranor-13,1-dihydro-; > *. 3-Oxa-16- (m-trifluononethylphenoxy) -17,18,19,20-tetranor-13; dihydro-; . 3-Oxa-16- (m -chlorophenoxy) -17,18,19,20-tetranor-13,1-dihydro-; | 3-Oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,1-dihydro-; 13-Oxa-16-phenoxy-18,19,20-trinor-13,1-dihydro-; ^ 3-Oxa-16-methyl-1d-phenoxy-18,19,20-trinor-13, -1-dihydro-; ^

i 3-0xa-cis-13-J

t r 3-0xa-16-methyl-cis-13-, I * *

3-Oxa-16,16-dimethyl-cis-13-J

* f. 3-0xa-16-fluoro-cis-13-; 2q 5 3-Oxa-16,16-difluoro-cis-13-; .

['* 3-Oxa-17-phenyl-18,19,20-trinor-cis-13-i.

* 3-Oxa-17- (m-fc: fluonethylphenyl} -18 »19» 20-trinor-cis-13-; I 3-Oxa-17- (m-chlorophenyl) -18,19,2y-trinor- cis-13-; 3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-c13-13-; 25-3-Ox-16-methyl-17-phenyl-18,19,20-trinor -cis-13-; 3-0xa-16, 16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-; 1,3-0xa-16-fluoro-17 -:? enyl- 18,19 »20-trinor-cis-13-; 3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-j '3-Oxa-16-phenoxy-17 18,19,20-tetranor-cis-13-; 2q'i. 3-0xa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-cis-13-; 1.3. Oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-cis-13-; 3-alpha-(p-fluorophenoxy) -17,18,19,20-tetranor-cis-13 - 3-xx-16-phenoxy-18,19,20-trinor-cis-13-; 3-xa-1-methyl-16-phenoxy-18,19,20-trinor-cis-13- 25 -Oxa-13, - - dihydro-trans - ^, 15-didehydro-; 3-0xa-16-methyl-13, - - dihydro-trans - ^, 15-didehydro-; \ 8300821 »• * 4 - r * *.» _ 51 _ tv ". 1" 3-0xa-16,16-dincthyl-13 µl-dihydro-trans-1,15-didehydro-; 3-oxa- 16-fluoro-13, lit-dihydro-trans-1U, 15-dide hydro-; 3-Oxa-16,16-difluoro-1 3, -1-dihydro-trans-1,15-didehydro-; 3-Oxa-17-phenyl-10,19-20-trinor-1,3,1-dihydro-trans-1,15-dide-hydrous 3-Oxa-17- (m-trifluoromethylphenyl) -18, 19> 20-trinor ~ 13.1 U-dihydro-. tra-ns-1U, 1 5-didehydro-; 3-0xa-17- (m-chlorophenyl) -18,19 »20-t-rhinor-13» 1 * »- dihydro-trans-! 1U, 15-didchydro; i * *.

TO i 3-oxa-17- (p-fluorophenyl) -18,1912 0-t rhinor-13 »T U -di hydr o -t r ans- i ·. · 1A, 15-didehydro-; 1 '3-0xa-16-methyl-17-phenyl-18,19,20-trinor-t3,1 Jt-dihydro-trans- "1 ^ 1,15-di dehydro-; 3-0xa-16,16-Dinethyl-17-phenyl-18,19-20-trinor-13,1-dihydro- * 15 * trahs-11,15-didehydro-; | 3-0xa-16-fluoro-17-phenyl-18,19,20-t rinor-13,1¼ -dihy dr o-t rans- ·! 1U, 15-didehydro-; III 3-0xa-16,16-di fluoro-17-phenyl-18,19 »20-t-rhinor-13» 1 l-di-hydro-! _. , trans-Ik, 15-didehydro-; ! · · "20 l, 3-0xa-16-phenoxy-17» 18,19 »2Q-tetranor-13> lk & ihydro-trans-lk, 15-i-didehydro-;. (m-trifluoromethylphenoxy) -17,18,19> 20-tetranor-1,3,1-: dihydro-trans-11, 15-dihydro-;. i [· · ·> j | 3-Oxa-16- ( m-chlorophenoxy) -17 »10,19» 20-tetranor-13i-dihydro-1,25-trans-1, 15-didehydro-; '';} - 3-Oxa-16- (p-fluorophenoxy ) -17 »18,19» 20-tetranor-13, 1k-dihydro-trans-lk, 15 - <&dehydro-; * 3-0xa-16-f-enoxy-18,19,20-trinor-13 » 1k-dihydro-trans-1 k, 15-dide - hydro-; 3 3-xa-16-ne thy 1-1 β-f enoxy-18,19,20-trinor-l3, 1k-dihydro-trans- 1U, 15-didehydro-.

Also the methods from the ': examples are obtained. I, II and III, but using the corresponding starting materials as described above the compounds of formula 1, 3 and k, namely compounds of the 83009 2 1 i * * ·. *. 52-9-deoxy-6,9-epoxy-5-iodine-PGF2-f; 9-deoxy-6,9-epoxy-6-liydroxy-PCFlct- and. 9-deoxy-6,9-epoxy-6-keto-PGF type 5 in methyl ester form, wherein R 1 is -COOCH 2, having the following structural features: -v 2,3-Didehydro-; 2,2-Diraethyl-; *! 2a, 2b-Dihomo ~; 10 H-Oxa-α-homo; I

Ta-Homo-; ï '- !. 11-Deoxy-10,11-didehydro-; ...

j ne-i! 11-Keto-; 15-11-Deoxy-; 11-Deoxy-11-methylene-; .

11-Deoxy-11-hydroxymethyl-; | .156-; 15-Keto; 20! 15-Deoxy-; 15-Met hyl-15 (S) - ·; 15-Methyl-15 (H) - and! . 17 »18-Didehydro-.

'n' * - i, i 25 i-; .

t ·.

! ". ·. ; i. ..... . . ; * I * * *. .

r ί.

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8300921

Claims (11)

A process for the preparation of a prostatoglandin derivative, characterized in that 1, 3 is a compound of the formula /, or 4 in which the formula is 15, 16, 17, 18, 19, 20 or 21, wherein L 5 (1) - (CH 2) dC (R 2) 2- (2) -CH 2 -O-CH 2 -Y- (3) -CH 2 CH = CH-10, wherein d is 1, 2, 3, 4 or 5; R2 represents hydrogen, a methyl group or fluorine and may or may not have the same meaning, except that one R2 represents no methyl group when the other is fluorine; Y represents a valentine bond or - (CH ^^ .-, where K is 1 or 2; »/ V * '\ 15. O, Η H, R 0 OH or R 8 OH wherein R 0 represents hydrogen or an alkyl group of 1 to 4 carbon atoms, R 1 represents formulas 22, 23 24 or 25, wherein R 1 represents hydrogen or an alkyl group having 1 to 12 carbon atoms, cycloalkyl group with 3 to 10 carbon atoms, aralkyl group with 7 to 12 carbon atoms, optionally substituted with 20 1, 2 or 3 chlorine atoms or alkyl groups with 1 to 4 carbon atoms, phenyl group group of the formula 26, 27, 28, 29, 30, 31 or 32, wherein R 1 q represents a phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl group and R 1 represents hydrogen or a benzoyl group or a pharmacologically acceptable cation thereof and R 8 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, which may or may not be the same; R ^ represents the formulas 33, 34 and 35, wherein CgH ^ g is an alkylene group having 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CRj-Rg- and the terminal methyl group, Rg and Rg hydrogen , 30 represent an alkyl group having 1 to 4 carbon atoms or flyor and which may or may not be the same, with the proviso that of Rg and R- one represents only fluorine, when the other is hydrogen or 6 and further provided that Rg and Rg do not represent either 83 0 0 9 2 t ___ - 54 - fluorine, when Z is oxa (-0-), where Z represents an oxa atom (-0-) or CjH2j, where CjH2j a valentine bond or alkylene group having 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR 1 Rg - and the phenyl ring, 1T an alkyl group having 1 to 4 carbon atoms, fluorine, chlorine, a trifluoromethyl group or -0R? wherein R 1 is hydrogen or an alkyl group having 1 to 4 carbon atoms and s is 0, 1, 2 or 3, it being understood that at most two groups T are going to be an alkyl group and that when s is 2 or 3 the groups T or not equal to each other, V a valence bond is 10 or -C ^ - / w “^ CH2 ^ h” ^ S 'k is 1 or 2, X (1) trans-CH = CH-' (2) cis -CH = CH- (3) -C = C- or 15 (4) -CH 2 CH- and the bond is denotes cis or trans configuration and prepares enantiomers thereof in a manner usual for preparing analogous compounds. 2. Process according to claim 1, characterized in that a compound of the formula 9 in which ^, L, Q, Rj, R,, V, W and X have the meanings indicated above is iodinated and cyclyzed, whereby an iodine compound is formed with the formula 1 wherein J), L, Q, R 4, R 4, V, W and X have the meanings indicated above. 3. Process according to claim 1, characterized in that a compound of the formula 9 wherein 30 is represented by the formula 36, 37, 17, 18, 19, 20 or 38, wherein R 1 is hydrogen, a tetrahydropyranyl, tetrahydrofuranyl- 1-ethoxyethyl group or a group of formula 39, wherein R 1 is an alkyl group of 1 to 18 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, aralkyl group of 7 to 12 carbon atoms, a 35 phenyl group substituted or unsubstituted with 1, 2 or 3 alkyl groups with 8300921 1 to 4 carbon atoms, R 1 and R 2 g are the same or not and hydrogen, an alkyl group, a phenyl group substituted or unsubstituted with 1, 2 or 3 alkyl groups having 1 to 4 carbon atoms or, taken together - (CH2) a- or - (CH2) ^ - 0-5 (CH_) -, wherein a is 3, 4 or 5, b 1, 2 or 3 and & C c is 1, 2 or 3 with the proviso that b plus c is 2, 3 or 4 and R y represents hydrogen or a phenyl group and the other symbols have the meanings set out in claim 1 and ^ (a) iodine and cyclize, to yield a compound of formula 1 wherein, L, Q, Rj, R4, V, W, and X have the meanings indicated above? (b) subjecting the product from step (a) 15 to dehalogenation and hydrolysis to form the keto and hemetetal compounds of formulas 4 and 3, respectively, and (c) separating the products. 4. Process according to claim 1, characterized in that 9-deoxy-6,9-epoxy-5-iodine-PGF of formula 5 is prepared. 5. Process according to claim 25, characterized in that 9-deoxy-6,9-epoxy-6-hydroxy-PGF of formula J is prepared. Process according to claim 1, characterized in that 6-kefo-PGF is used. of formula 8. - la 30 7. Process for the manufacture of a pharmaceutical preparation by bringing a prostaglandin derivative into a form suitable for therapeutic use, characterized in that as active ingredient 35 a compound of the formula 1, 3 or 4 as described in 8300921 V • sm in claims 1-6 uses mixtures or enantiomers thereof. 8. Compounds, methods as well as used, obtainable and obtained compounds, and pharmaceutical preparations as described in the specification and examples. 8300921 I / VOC —CH-LR, VO — C = CH ~ -L— Ri XCR ,, 1 X_ CR * 2 11 4 aq OH OH I. ”V o, - V— 0— C - CHa- L-R, II d-w / Ί \. W ^ -C-CH ^ -LR, 3 JAx-C-R4 4 a • • QQ 0 — CH-CH- (CH ^ ~ COOH λ) 3 0 ^ C = CH - (CH ^ S— COOH Vw "λ ·" ° ^ 5 <Xcc ^ H 0H 'Hy' 'C— CjHu HO / \ s “OH' H OH $ O ^ CH-iCH ^ -eOOH 0; \: oh \ sK 'X, -CHe-C- (CH ^ - COOH> S- <" <k, - ho 'h'> ~ csh «/ 'ƒ = <, H ^' 'OH 0H η / C \ C * h» 8 OH 7 H OH _ V! "X W-CH-CH-L- R, -I 0, CH CH L Ri 'V v / --dxx - c- R4} L in Ί II 9 fNx-c-fc lu Q OH ats Q. --- v, V-0-C-CH , -l— R,> .w ^ d '11 83 0 0 9 2 1 —x _ c - r4 -t- i | a, - ·, -0 H HO, y ο, v ~ Vj \, WC - CHl — L — R,., W-CH = CH-LR, _, Sx-c-R4,? / / V V VRRRR .13. 13 .131313 13 / t t t t 16 16 16 16 t 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 & & & CC '<X 22 CHi 18 19 20 ch ^ oh 21 - CH * 0H 23 ^ NH - N -CHjH (Rg] 2 24 ^ N_N25' -O-nh-c- ^ nh-cc ^ 26 ΝΗ "0 - ^ ~ VnH-C-CHj —ft V-NH -C-NHe W w 27 W 28 w 29 0 o <^ VcH = N-HH-C-NIHe -CH - CR, "30 3] R" 32 Rr I Rs (R) -C —CgHag-CIV / T ~ k ^ h “CH ^ ^ CH2CH3 33 R * 34 η h 35 <^ X '<^ X <fX Rrt-o-c-c-R ,? ° R «36 OR ,, 37 c * or! J 38 R, s R, t 39 _ch, -o- / 3 -c ^ -fY 8.5 0 0 9 2 f 40 _4 _. -Q ^ CH - (^) g q0pO- (CH,) g 42 43 44 / τλ oh rOl.-Q ^ rf f 45 '•' X. ^ WC-CHj-LR, ï "R« 45 QQ ^ - C-CH ^ CH ^ -COONa '!> O ^. C »CH ~ (CH ^ -COOCHi <X., OHν OH h' C ^ - (CUl) lt-CHi ^^ 0 = θ'Η '' OH OH h / V_ (chn 0¾ 47 43 h '"oh · jsi!? 8300921 nru .. rf— -«. * -> ______________________ —A— OH ./ V JV.W -CH = CH-L -R i / · \ V .__ V 13 xc-r4 -.-- 11-- Q (a) Ψ • <I. V-0-CH-ÓH-LR, • tK '. \ W' j 1 ^ XC-R4 \ II (b) \ o V \ OH 0 \ --rk II ^ WC-CHa-L-Ri (d) - ^ XC-R4 / II Q lT (c) 't V VOC-CHa-L-Ri / \ - j - w V — i ^> SX-C-R4 3 II o 8300921 - rt ~ B- / OH V W-CH = CH-LR! S (-C-R7 II 13 Q; (a) - I • I VO-CH-CH-LR! I 1 - D xc-r4 1 II Q '- (b) .V-0-C = CH-L-Ri> / • 1 \ --Y xc-r4 Q) 2 8300921 - G -, HO χCHz-Zi-COOH, <X .Ri 101. Mi Li V 0 o II | ï \, £ H2 -Z i -C -0 -C -R i <X '/ Y i - C —C -Ry /.Re II II / Mi Li · / i Hq \\ 103V, CH2-ll-c-nh2 & IY i -C —C -R7 tfa II II Ma Li V HOx V ^ CH2- Zl-CH2NH2 u / Y 1 ~ C -C -R7 Re II: i M, L, VH ° n eo \ .CH2-Zi-CN = NN Cl 105 y ^ Yi-CC-Rr II II • Re Ml Li 83 0 0 9 a 1 V 40 —G ~ ^ continued9 ^ HO V vCH2-Z, -NH-COORi CC ^ 106 r Tt-CC-r7 / II II \ Ra Ηχ Li i 'HO CHs-Zi-NHs cc Yl-SS-R7 107 Re i M * Li Mj HO \ / Ha-Zx-NHL2 / Cl ^, Y i “C — C-RT iriQ Ra II II 108 Li Ht v Ho ^ '\ ^ CHs-Z! -NLsCOOR! r ^ Yi-c-c-R7 ing II II · lu ^. , Re Hi Li HO '- \ ^ CH2-Zi-NL2L3 IIP) Cl Y, "S ^ CR7 Ra Hi Li 8300921