DE2210697A1 - NEW PROSTAGLANDIN ANALOGA AND METHOD FOR PRODUCING THE SAME - Google Patents

Description

AX

ALFREO " HOSPPENER

DR. JUR. üf? L-CM £ M. HJ. WOLFP

DR. JUR. HANS CnK. BtIL

623 FRANKFURTAM MAIM-HOCHSf

AOELOM CLASS »

[3. March 1372-

Our number 17 663

The Upjohn Company, Kalamazoo, Mich., V.St.A.

Novel prostaglandin analogs and methods of making the same

The invention relates to new analogs of some "known prostaglandins, for example prostaglandin E- (PGE-), prostaglandin. P ₁ (PGF _1α and PffF _lß ), prostaglandin A ₁ (PGA ₁ ) and prostaglandin B ₁ (PGB ₁ ) as well as a method for Manufacture of the same.

All of the above-mentioned, known prostaglandins are derivatives of prostane carboxylic acid, which have the following structure and numbering;

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According to the systematic homenklature, the designation is for Proetanecarboxylic acid 7 - [(2β-Octyl) -cyclopent-1a-yl] heptanecarboxylic acid.

PGE ₁ has the following structure:

COOH

II

PGP ₁ has the following structure:

HO

COOH

HO

H'OH

111

has the following structure:

COOH

ι ν

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g 21 O 6 9 7

! "i '* ^ has the following structure:

COOH

PGB _{1 has the} following structure:

COOH

VI

The above prostaglandin formulas all have several centers of asymmetry. Each formula represents a special one optically active form of prostaglandin, which is made up of certain Mammalian tissues, e.g. sheep semen vesicles, pig lungs or human seminal plasma, or by reduction oder.Dehydration of the prostaglandins produced in this way has been. Compare, for example, the work by Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) as well as the other works cited therein. The mirror image of the formulas each represents a molecule of the enantiomer of Prostaglandins. The racemic form of prostaglandins has the same number of the two types of molecules, One type corresponds to the formulas given above and the other type corresponds to the mirror image of these formulas. So both formulas are necessary to define a racemic prostaglandin. Compare the discussion

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on the stereochemistry of prostaglandins in the journal Nature 212: 38 (1966).

In the formulas I, II, III, IV, V and VI and in the formulas given below, broken lines denote the Attachment of the substituents to the cyclopentane ring in the alpha configuration, i.e. below the level of the cyclopentane ring. Thick, solid lines show a linkage of the substituent to the cyclopentane ring in beta configuration, i.e. above the level of the cyclopentane ring. The side chain hydroxyl group at C-15 in formulas II to VI is in the S (<x) configuration before.

All new prostane carboxylic acid analogs according to the invention will be encompassed by the following formula or by this formula and its mirror image:

, (CHa) ₈ -COOR

VII

In Formula VII, D is one of the following four carbocyclic ones Hest:

HO

HO

, or

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In these radicals, in turn, the serpentine line denotes an alpha or tdeta linkage of the hydroxyl group on the cyclopentane ring; R- represents hydrogen, an alkyl group of 1 "to 8 Represents carbon atoms or a pharmacologically acceptable cation; Rp and R ^ mean hydrogen, methyl or ethyl, where at least one of the two groups Ro or R., not hydrogen may be.

Formula VII, which was written in a general form for the sake of simplicity
if D

is written, represents the connections of the PGE ₁ type,

HO '

is; the compounds of the PGi ¹ ^ type, if D

HO '''^
is; of the PGF ₁ "type, if D

is; of the PGA ₁ type, if I »

is and of the PGB ₁ type, if

is. Λ3 / 1119

In formula VII, the hydroxyl group at C-15 is in the alpha configuration as in the known prostaglandins of formulas II to VI. Furthermore, the substituents are on the C ₁ ^ -C. .-Carbon-carbon double bond always in trans configuration.

All new prostane carboxylic acid analogs according to the invention have two alkyl substituents at C-16, ie on the carbon atom which is adjacent to the C-15 carbon atom bearing the hydroxyl group. The novel prostanecarboxylic acid analogs according to the invention can consequently be used in a simple manner as 16-methyl-prostaglandins, 16-ethyl-prostaglandins, 16,16-dimethyl-prostaglandins, 16,16-diethyl-prostaglandins or 16-methyl-16-ethyl-prostaglandins, for example 16 -Methyl-PGE.j ,, 16-A "^ yI-PGF _{1 a} , 16,16-dimethyl-PGF., _Β , 16,16-diethyl-PGA.j, 16-methyl-16-ethyl-PGB ₁ etc. are designated »

With reference to formula VII, examples of alkyl groups with 1 to 8 carbon atoms are methyl, ethyl, propyl, butyl, Pentyl, hexyl, heptyl, octyl and the isomeric forms of these Groups.

As in the case of formulas II to VI, formula VII should be optically active prostane carboxylic acid analogs with the same absolute Represent configuration such as PGE-, which has been obtained from mammalian tissues. The new invention Prostane carboxylic acid derivatives also include the corresponding racemic compounds. To describe a racemic Compound is the formula VII + whose mirror image is required «If in the following the term" racemic "the name of a is preceded by the novel prostane carboxylic acid derivative according to the invention, it is intended to express that these racemic Compound can be represented by the combination of the corresponding formula VII with its mirror image. Is the Designation "Raoemisch" not before the connection, like that they should indicate that there is an optically active connection,

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which are represented solely by the corresponding formula VI-I and which has the same absolute configuration as which has been obtained from animal tissues.

₁ ^, P £ F _1ß »I ¹ GA ₁ and PGB ₁ and their esters and pharmacologically acceptable salts are extraordinarily powerful pharmaceuticals which cause various biological reactions. The compounds are consequently used for pharmacological purposes. In this context, reference is made to the work of Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and the Mteraturstellen cited therein referred to, some of the biological effects that cause the means are the following: PGE, PGi ¹ O- and PGA compounds call a lowering of the systemic arterial blood pressure produced, which, for example, in anaesthetized (Pentobarbital sodium), pentolinium-treated rats with cannulas installed in the aorta and right ventricle; a pressure-stimulating effect in the case of the PGF _a compounds; stimulation of the smooth muscles, which has been found, for example, on test strips from guinea pig ileum, rabbit duodenum or gerbil colon; potentiation of the effects of other smooth muscle stimulants; an antilipolytic effect, which can be shown, for example, by the antagonism of the epinephrine-induced mobilization of the free fatty acids or the inhibition of the spontaneous release of glycerol on isolated rat fat lumps; an effect on the central nervous system; a decrease in blood platelet adhesion, which can be shown, for example, by tests to adhere the blood platelets to the glass, as well as a prevention of platelet aggregation and thrombus formation caused by various physical effects, e.g. arterial injuries, or various biochemical Irritants such as ADP, ATP, serotonin, thrombin and collagen are induced; in the case of the PGE and PGB compounds, a stimulation of epidermal proliferation and keratinization, which is what happens when they are used in chick embryo cultures

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and can be shown on rat skin segments.

As a result of the biological effects described above the well-known prostaglandins are used to examine, prevent, control or treat a large number of diseases and undesirable physiological conditions in birds and mammals including humans, valuable pets, lap ' animals, rare zoological species and laboratory animals such as mice, rats, rabbits and monkeys.

Said compounds, especially the PGE compounds can be, for example, at SäugetJe-en including humans as a nasal decongestant use _e For this purpose, the compounds in amounts of about 10 / Ug be up to about 10 mg per ml in a pharmacologically suitable liquid vehicle or as Aerosol spray applied topically.

The PGE, PGF and PGF "compounds are always useful when prevention of platelet aggregation, reduction in the adhesive character of platelets, and removal already formed or preventing the formation of thrombi in mammals including humans as well as rabbits and rats. «These compounds are therefore useful in the treatment and prevention of myocardial infarction, for the treatment and prevention of a post-operative thrombosis, to promote the vascular connections remaining open afterwards of surgical interventions, for the treatment of atherosclerosis, arteriosclerosis, blood coagulation defects as a result of Lipemia as well as other clinical disease states in which the underlying etiology is based on a lipid metabolism disorder or hyperlipidemia. For these purposes the compounds are administered systemically, i.e. they are administered intravenously, subcutaneously, intramuscularly, or in the form of sterile implants (to achieve a long-lasting effect) supplied. To achieve a quick effect, especially in emergency situations, intravenous administration is preferred,

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The amounts used can be between about 0.005 and about 20 mg per kg of body weight per day, the exact dose again depending on the age, weight and condition of the Patient or animal, as well as the frequency and type of administration.

The PGE, PGI ¹ and PGF _ß compounds are also excellent

(X 15

records as additives to blood, blood products, blood substitutes and other liquids that are used for artificial extracorporeal (i.e. outside the body) circulation and perfusion of isolated body parts, e.g. limbs and organs, can be used, regardless of whether the limbs and organs are still connected to the original body or from it are separate and are being preserved or prepared for transplantation or association with a new body. During this Circulations and perfusions tend to the clumped platelets, the blood vessels and parts of the circulation device to clog. This clogging or blockage is avoided by the presence of the compounds mentioned, The compounds are added gradually or all at once or in several portions to the circulating blood, the blood of the Donor animal, the body part separated from the body or still connected to the body, the recipient or two or all of these parts in a total consistent dose of about 0.001 to 10 mg per liter of circulating fluid to. It is particularly advantageous to use the compounds in laboratory animals, e.g. cats, dogs, rabbits, and monkeys and use rats for the purpose of developing new methods and techniques for organ and limb transplantation

The PGE compounds are extraordinarily potent agents in terms of smooth muscle stimulation, whereby at the same time they are also highly active in terms of potentiating the effects of other known stimulators for the smooth muscles are; for example, these other known stimulators may be oxytocic agents such as oxytocin as well

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various ergot alkaloids including derivatives and Act analogues of the same. As a result, PGEp can be used instead of or in combination with smaller amounts than usual to be used on well-known stimulants for the smooth muscles, for example, the symptoms of a paralytic To relieve hay or to control or prevent atonic uterine bleeding after an abortion or childbirth, assist in expelling the placenta or prevent bleeding during the puerperium. To the latter Purpose are the PGE compounds by intravenous infusion immediately after an abortion or childbirth in an amount from about 0.01 to about 50 / ug per kg body weight per minute until the desired effect has occurred. Additional amounts are administered intravenously, subcutaneously, or intramuscularly Injection or infusion supplied during the puerperium, the amount being 0.01 to 2 mg per kg of body weight per day lies; the exact dose also depends on the age, weight and condition of the patient or the animal «,

The PGE, PGA, and PGPβ compounds are also considered to be hypotensive Means for reducing blood pressure in mammals and humans useful. The connections are made for this purpose by intravenous infusion in an amount of 0.01 to about 50 / Ug per kg of body weight per minute, in one Single dose or in several divided doses of about 25 to 500 / Ug per kg of body weight per day.

The PGE, PGP and PGF _ß compounds are also useful in place of oxytocin to induce in pregnant female animals, including humans, cows, sheep and pigs at or near the time of birth, the uterine contractions; they are also suitable for initiating ulcer activity in pregnant animals in which the fetus has died in the body, namely from about the 20th week until birth. For this purpose the compound is administered by intravenous infusion in an amount of 0.01 to 50 / Ug per kg of body weight

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per minute until the second stage of labor, i.e. the expulsion of the fetus, is completely or almost finished. These compounds are also particularly suitable when dae female beings transmitted for one or more weeks and natural labor has not yet started or if so Labor activity 12 to 60 hours after the amniotic sac ruptured has not yet started. The agents can also be administered orally.

The PGE, PGF and PGF _n compounds are also suitable for

CC u

Regulation of the reproductive cycle in ocular females Mammals including humans and animals such as monkeys, rats, rabbits, dogs, domestic animals, etc. Under the term "ovulating female mammals "are understood to mean animals that are mature or old enough for ovulation to proceed normally but are not so old that regular ovulation has ceased. For this purpose, for example, PGE or PGF. systemically in an amount from 0.01 to about 20 mg per kg of body weight of the female mammal, preferably during a period of time around the time ovulation begins and around the time or just before Time of the Mensös ends. The funds can also be used intravaginally or intrauterine, it is also possible the expulsion of an embryo or fetus by appropriate administration of the compound during the first trimester normal gestation time of the mammal.

As stated earlier, the PGE connections are strong Antagonists of the mobilization of free fatty acids induced by epinephrine. Because of this, these connections in experimental medicine in both in vitro and in vivo studies in mammals (including Humans), rabbits and rats to help understand, prevent, and alleviate symptoms as well as healing of diseases to come, in which an abnormal fat mobilization 'and a high content of free fatty acids

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occurs, i.e. diabetes mellitus, vascular diseases and hyperthyroidism.

The PGA compounds and derivatives and salts thereof also cause an increase in the blood flow through the mammalian kidney, so that the volume and electrolyte content of the urine increase. So the PGA compounds can be used to treat Used in cases of disorders of kidney function, especially in cases of severe circulatory disorders of the kidney, as they occur, for example, in the hepatorenal syndrome and an early resection of a transplanted kidney In cases of excessive or insufficient ADH secretion (ADH = antidiuretic hormone; vasopressin), the diuretic Effect of these compounds is even greater. With anephretic The vasopressin action of these compounds is particular to these conditions useful. The PGA compounds are also suitable for the treatment of edema, for example after severe superficial burns occur, as well as for shock therapy. In the latter cases, the PGA connections first preferably injected either intravenously in an amount of 10 to 1000 / Ug per kg body weight or by intravenous Infusion administered at a dose of 0.1 to 20 / Ug per kg body weight per minute until the desired effect is achieved has been. Further doses can be intravenous, intramuscular or administered subcutaneously by injection or infusion in an amount of 0.05 to 2 mg per kg of body weight per day will.

The PGE and PGB connections encourage and accelerate that Growth of epidermal cells and keratin in humans and animals, e.g. valuable pets, pets, zoo animals and laboratory animals. The compounds are therefore suitable for promoting and accelerating the healing process of injured skin, e.g. from burns, other wounds, abrasions and surgical wounds in the skin »The connections also accelerate the ingrowth of skin autografts, especially small ones

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deep Davis grafts, the skinless areas due to subsequent should cover external growth and delay the rejection of homotransplants "

For this purpose, the compounds are preferably localized or close to the location where the cell growth and the Keratin formation should occur, administered, and preferably in the form of liquid or extremely fine powdery aerosol sprays, in the form of isotonic aqueous solutions (e.g. as wet compresses) or in the form of lotions, creams or ointments, which can be used in combination with conventional pharmaceutical diluents and Extenders can be present. In some cases, such as severe fluid loss after extensive burns or skin loss for other reasons, systemic administration may be more advantageous, for example by intravenous injection or infusion, alone or in combination with infusions of blood, plasma or blood substitutes can be done. In other cases, administration can also be subcutaneous or intramuscular in the vicinity of the affected area, orally, sublingually, buccally, rectally or vaginally. The exact dose also depends here as well in all other cases already mentioned, on the method of administration and the age, weight and condition of the Patient. Should, for example, a moist bandage for topical application in the event of a burn second and / or

third degree to be prepared for a skin area of 5 to 25 cm, so it is best to use an aqueous isotonic one solution containing 1 to 500 / ug per ml of the PGB compound or contains several times this concentration of PGE compound. In particular when used locally, the prostaglandins mentioned can be used in combination with antibiotics, for example Gentamycin, Neomycin, Polymyxin B, Bacitracin, Spectinomycin and Oxytetracyclines, other antibacterial ones Materials like Mafenide Hydrochloride, Sulfadiazine, Furazolium Chloride and nitrofurazone or oartiooid steroids such as hydrocortisone, Prednisolone, methylprednisolone, and fluprednisolone

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use, whereby the various substances mentioned are used in combination in the same concentration as in they can also be used on their own.

The novel 16-alkyl- and 16,16-dialkyl-PGE--, -PGF ^ -, -PGP ₁₃ -, -PGA ₁ - and -PGB ₁ compounds of the formula VII all produce the same biological effects as those above for the PGE, PGP _a ~, PGP _ß -, PGA and PGB compounds have been described; all new compounds can consequently be used for the same purposes and in the same way

The known PGE, PGF _a -, ^PGF ß "~ ^PGA and PGB compounds call upon all multiple biological effects even produced in very small quantities. For example, PGE ₁ causes vasodepression and stimulation of the smooth muscles with simultaneous anti-polytic activity. With many types of application, however, the known prostaglandins only have a very short duration of action. The prostaglandin analogs of the formula VII according to the invention are very much more specific than the known prostaglandins with regard to the triggering of biological effects and also have a much longer biological duration of action. All new prostaglandin analogs according to the invention can therefore be used instead of the corresponding known prostaglandins mentioned above for at least one of the pharmacological purposes which are specified for them and then surprisingly and unexpectedly prove to be more useful for this purpose because it is a has a different and narrower biological spectrum of activity than the known prostaglandin and is consequently more specific in its effect and causes fewer undesirable side effects than the known prostaglandin. In addition, because of the longer-lasting effect, lower and fewer doses of the new prostaglandin analogs can be administered in order to achieve a desired pharmacological effect.

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Another advantage of the new compounds according to the invention compared to the known prostaglandins is that it effectively orally, sublingually, intravaginally, buccally or rectally and not just intravenously, intramuscularly or can be administered subcutaneously, by injection or infusion. These properties are beneficial because they are the Allow and maintain an even level of medication in the body with fewer, shorter or smaller doses also enable self-administration by the patient »

The 16-alkyl- and 16,16-dialkyl-PGE., -, -PGi ^ -, -PGI _{1 ß} -, and -PGB ₁ compounds of Formula VII are used in the form of the free acid, in In the form of their esters or in the form of their pharmacologically acceptable salts'. If esters are used, the ester part can have any meaning within the definition given above for R ... However, the ester should preferably be an alkyl ester having 1 to 4 carbon atoms. Among the alkyl esters, the methyl and ethyl esters are best because they are optimally absorbed in the body or in the experimental animal system used.

Pharmacologically acceptable salts of the compounds of the formula VII, which are useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium and amine cations or quaternary ammonium cations.

Particularly suitable among the metal cations are those which differ from the alkali metals, e.g. lithium, sodium and potassium, and derived from the alkaline earth metals, e.g., magnesium and calcium; the metal in the cation can also consist of aluminum, Zinc or iron.

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- 1β -

221069?

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methyl, dimethyl, trimethyl, ethyl, dibutyl, triisopropyl, N-methylhexyl, decyl, dodecyl, allyl, crotyl, cyclopentyl, bicyclohexyl, benzyl, dibenzyl, α- and ß-Phenylethylamine, ethylenediamine, diethylenetriamine and similar aliphatic, cycloaliphatic and araliphatic amines, which contain up to about 18 carbon atoms, and heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, e.g. 1-methylpiperidine, 4- Ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and others; Finally, amines are also suitable which contain water-solubilizing or hydrophilic groups, for example mono-, di- and triethanolamines, ethyl diethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3- propanediol, 2-amino-2-methyl-1-propanol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (ptert.-amylphenyl) diethanolamine, galactamJLn, N-methylglucamine, N-methylglycosamine, ephedrine, phenylephrine, Epinephrine, procaine, etc.

Examples of suitable, pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, Benzyltrimethylammonium, phenyltriethylammonium and others

The compounds of the formula VII can, as already mentioned above has been suggested to be administered in any manner, for example as follows: intravenous, intramuscular, subcutaneous, oral, intravaginal, rectal, buccal, sublingual, local and in the form of sterile implants, if a longer lasting effect is to be achieved. Intravenous injections or infusions are best sterile aqueous isotonic solutions. In these cases it is favorable that R- in the compounds of the formula VII is hydrogen or means a pharmacologically acceptable cation, because the compounds then have a greater water solubility «

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For subcutaneous or intramuscular injection, sterile solutions or suspensions of the compounds in acid, Salt or ester form in aqueous or non-aqueous media, tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions that use the usual pharmaceutical excipients can be used for oral and sublingual administration. Purely rectal and vaginal administration suppositories can be produced in a manner known per se will. For tissue implants, sterile tablets or silicone rubber capsules as well as other objects that can be used with the Are impregnated or contain substance.

The 16-alkyl and 16,16-dialkyl compounds of the PGE ₁ type,

PGP _1a , PGP _1β , PGA ₁ and PGB ₁ , which correspond to the formula VII, can be produced by the reactions and processes described below.

So the different connections of PGF ₁ - and PGF _1ß -

I CC 1

Corresponding to the type of formula VIi can be prepared by Carbonylredixktion the corresponding compounds of the PGE-type · example, can be carried Carbonylreäuktion of 16-methyl-PGE _1, a mixture of 16-methyl-PGF.j _a and _{16-methyl-1ß} PCRI win O

The ring carbonyl reductions are carried out with the aid of the same methods that are also used for the ring carbonyl reduction in known methods Prostaglandins are used. Compare for example Bergstrom et al., Arkiv Kemi 19 »563 (1963), Acta Chem. Scand. 16, 969 (1962) and British Patent 1 097 533p Any reducing agent can be used, which one with the carbon-carbon double bonds or ester groups not reacting. Particularly suitable Heagentien are lithium (tri-tert.-buto: r.y) aluminum hydride, the metal borohydrides, in particular sodium, potassium and tin borohydrides, as well as metal trialkoxyborohydrides, e.g. liatriumtriiaethoxyborohydriä

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The mixtures of α- and ß-hydroxy reduction products are into the individual ε- and ß-isomers using the same methods separated, which are also used for the separation of analogous pairs of known isomeric prostane carboxylic acid derivatives. In this For the context, reference is made to the work by Bergstrom already cited and also to the work of Granstrom et al., J.Biol.Chem. 240, 457 (1965) and Green et al., J. Lipid Research 5, 117 (1964). Particularly preferred separation methods Partition chromatography - with both normal and reversed phase - is preparative thin-layer chromatography and the countercurrent distribution «,

The various PGA1-type compounds represented by Formula VII are prepared by acid dehydration of the corresponding PGE-type compounds. For example, you can by acid dehydration of 16-ethyl-PGE .. 16-ethyl-PGA .. to win.

The acid dehydration is carried out with these compounds in the same way as with known prostane carboxylic acid derivatives is common. See, for example, Pike et al., Proc. Nobel Symposium II, Stockholm (1966), Interscience Publishers, New York, pp. 162-163 (1967) and British Patent 1,097,533. Alkane carboxylic acids having 2 to 6 carbon atoms, especially acetic acid, are preferably used for acidic dehydration. Dilute aqueous solutions of Mineral acids, e.g. hydrochloric acid, especially in The presence of solubilizing diluents such as tetrahydrofuran are also suitable as reagents for these Implementation, although these reagents can cause partial hydrolysis of the ester used.

The various 16-alkyl and 16,16-dialkyl compounds from PGB types, which correspond to formula VII, are replaced by basic Dehydration of the corresponding compounds of the PGE type or by reacting the corresponding compounds from

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_w ith a base won "For example, obtained both from 16,16-dimethyl-PGE .. and, of 16,16-dimethyl-PGA _1" when treated with a 16,16-Ease Dijaethyl-PGrB ...

These basic dehydrations and shifts of the double bonds are carried out in the same way as this has already been done with other known prostanecarboxylic acid derivatives. In this context, reference is made to the Work by Bergstrom et al., Jc Biol. Chem. 238, 3555 (1963) referenced. Any aqueous solution with a pH greater than 10 can be used as the base. Particularly suitable Bases are the alkali metal hydroxides. The most suitable reaction medium is a mixture of water and so much of a water-miscible alkanol that a homogeneous reaction mixture results. You leave the connection of the PGE or PGA type in this reaction medium until the formation of the compound of the PGB type is complete, what can be shown by the characteristic UV absorption of the PGB-type compound at 278m / U.

The various conversions of PGE ₁ compounds according to formula VII into the corresponding compounds of the type PGi ¹ -, PGP _1β , PGA ₁ and PGB ₁ are listed in Table A below, where E

HE ₉

C = OO- (CH ₂ ) ₅ - CH ₅ ftt

^H Λ ^E 5

H represents OH

and R ₁ , Rp, R, and '■ ** -' have the meaning already given

The new 16-alkyl and 16,16-dialkyl acids and esters of the PGE.j «type according to formula VII can be prepared according to the conversions contained in Table B; the formulas VIII, II, X, XI and XII include the optically active compounds as shown and the racemic compounds from these formulas, and their mirror image.

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In panel B, G means - (CH ₂ ), - CH ,; R ₂ and R ₅ represent hydrogen, methyl or ethyl, with either R ₂ or R 1 not being allowed to be hydrogen; R. denotes alkyl with 1 to 8 carbon atoms, R ₅ denotes alkyl with 1 to 5 carbon atoms; '"* -— ' indicates the linkage to the cyclopropane ring in the exo or endo configuration. In Table B, the _{novel esters of the PGE 1} type according to the invention are encompassed by the formula XII.

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- 21 r-

Panel A

HO

, (CHa) ₆ -COOR ₁

HO

Carbonyl reduction

Acid

. (CHa) ₆ -COORx

Base base

(CHs) ₆ -COOR ₁

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blackboard

- (CH ₂ Je-COOR ₄

R ₂

-Vx ^ CH-CH C-G

L · I

R ₅ O ₂ SO OSO ₂ R ₅ R ₃

, (CHa) ₆ -COOR ₄

C = C

HO H

. (CHz) ₆ -COOR ₄

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«23 -

The bicycloketones of formula VIII in panel B ^- exist in four isomeric forms, namely exo and endo with reference to the attachment of the ^

72

-CH = CHO-G- & group

= 5

as well as cis and trans with respect to the double bond thereof Group. All of these isomers can be used individually, alone or in "any mixtures" as starting materials in the invention. Method can be used, then essentially the same end product mixture of compounds of the PGE or PGA type is obtained «,

The process for preparing bicycloketones of formula VIII in either the exo or endo configuration is known, namely for example from Belgian patent specification 702 477 and from West German laid-open specification 1 937 912.

In said Belgian patent specification 702 4-77 one runs Reaction sequence for the formation of an esco ketone of the formula VIII for example as follows: the hydroxyl group of 3-cyclopentenol is protected, for example, with a tetrahydropyranyl group. Then a diazo acetic ester is attached to the double bond attached, so that an exo-endo mixture of a bicyclo [3.1 · θ] -hexane arises, which is substituted at 3 with the protected hydroxyl group and at 6 with an esterified carboxyl group. The exo-endo mixture is then treated with a base to cause some of the endo isomer in the mixture to further develop exo isomers isomerized. Next then is the carboxylic ester group at 6 converted into an aldehyde group «This aldehyde group is then converted into a Group of formula

-CH = CHC-G

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converted that with respect to the bicycling structure in exo configuration present »In the next step the protective group is removed so that the 3-hydroxyl group which is then oxidized, for example with Jones reagent (that is chromic acid; cf. J. Chem. Soc. 39 (1946)), so that the exo-ketone of formula VIII is formed.

The separation of the cis-exo and trans-exo isomers (VIII) is also described in Belgian patent 702,477. However, as mentioned earlier, this separation is general not necessary because the cis-trans mixture can be used as such for the next reaction stage.

The procedure described in Belgian Patent 702,477 for the preparation of exo-form of the Bicycloketons VIII used as an intermediate product, the exo-Porm a bicyclo [3.1.0] -hexans which at 3 with a protected hydroxyl group, Z ₀ as tetrahydropyranyloxy, and at 6 is substituted with an esterified carboxyl group. If the corresponding endo compound is substituted like the ex.o intermediate, then it is the process of laid-open specification 1 937 912, which leads to the endo form of the bicycloketone VIII. The endo compound to be used corresponds to the formula

XV

COOCH,

The compound XV is prepared by adding an endo-bicyclo [3.1.0] -hex-2-en-6-carboxylic acid methyl ester reacts with diborane in a mixture of tetrahydrofuran and diethyl ether;

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this implementation is known and leads to the endo-bicyclo [3.1 .Ojhexan-3 ~ ol-6-carlDonic acid methyl ester, which then with dihydropyran in the presence of a catalytic amount of POCl the desired compound is reacted o The product obtained in this way is then used in the process according to the laid-open specification 1 937 912 for the production of the endo-form of the bicyclo-ketone VIII ve rv / ends.

As with exo VIII can also be obtained in the above process, a mixture of endo-cis and trans compounds _endo-0 This Liszt in the same manner as for the separate cis and exo-exo-trans-mixture described VIII is; Here, too, the separation is generally not necessary because the cis-trans mixture can be used as such for the next process stage.

For the processes according to the aforementioned Belgian patent and the aforementioned laid-open specification, certain organic halides, for example chlorides and bromides, are required so that the Wittig reagents can be prepared which are used to form the groups -CH = CHC (R ₂ KR ₃ ) -G in the bicyelo-ketones VIII are required o These organic chlorides and bromides, GC (R ₂ ) (R ₅ ) -CH ₂ -Cl and GC (R ₂ ) (R ₃ ) -CH ₃ -Br, are known and can be used in a known manner getting produced. Such halides, which are not available, can be prepared by reacting the corresponding primary alcohol GC (R ₂ ) (R ^) - CH ₂ OH with PCl ₃ , PBr, or any other suitable halogenating agent 1-Bromo-2-methylhexane, 1-bromo-2,2-dimethylhexane, 3- (bromomethyl) heptane, 3- (bromomethyl) -3-ethylheptane and 3- (bromomethyl) -3-methylheptane or the corresponding chlorine compounds, if 16-methyl-PGE ₁ , 16,16-dimethyl-PGE.p 16-AtIIyI-PGB ₁ , 16,16-Di ^ and 16-ethyl-ie-methyl-PGE- are to be obtained as end products

309843/1119

221069?

Table B shows that the bicyclo-olefin VIII is converted into the compound of the formula IX by reacting with an alkylating agent of the formula Hal- (CH ₂ ) ₆ -COOR ,, in which R. has the meaning given above and Hal represents chlorine, bromine or iodine, alkylated. All known alkylation processes which are suitable for the alkylation of cyclic ketones with alkyl halides and haloalkanecarboxylic acid esters can be used for the conversions of VIII into IX. In this context, reference is made again to Belgian patent specification 702 477.

In the alkylations, shark should preferably mean bromine or iodine. All common alkylation bases, e.g., alkali metal alkoxides, amides and hydrides, can be used. Preferably alkali metal alkoxides, especially tertiary alkoxides, are suitable. The alkali metals should preferably be sodium or Act potassium. Potassium tert-butoxide is preferably used. Suitable diluents for this alkylation are tetrahydrofuran and 1,2-dimethoxyethane. Isolation of the desired Products of the formula IX are made in the customary and known manner.

The alkylation gives mixtures of alpha- and beta-alkylation products, i.e. there is in each case a mixture of compounds of the formula IX in which part of the - (CHp) g-COOR. radical in alpha-r configuration and another part in beta configuration is linked.

If about one equivalent of base is used per equivalent of ketone of the formula VIII, the alpha configuration prevails in the general before. These alpha-beta isomer mixtures can be converted into this or one of the following stages of the multi-step process described in Table B. For separation Chromatography on silica gel is best.

The conversion of the olefins IX into the glycols X is carried out with the aid of a hydroxylating agent. Suitable hydroxy

309843/1119

lierungsmittel are "known.;Tgl" to the expert, for example Gunstone, Advances in Organic Chemistry, Vol # 1 _S p 103-147, Interscience Publishers, New York, 1.1. (1960). Various isomeric glycols are obtained, depending on whether the olefin IX is in cis or trans, endo or exo form and whether a hydroxylating agent is used in cis or trans form. For example, from an endo-cis olefin IX, when reacting with an eia hydroxylating agent such as osmium tetroxide, a mixture of two isomeric erythroglycols of the formula X is obtained. a mixture of the same two erythr ο glycols «, the endo-cis- and endo-trans-olefins IX produce corresponding mixtures of two threoglycol isomers with both cis and trans-hydroxylating agents. The various glycol mixtures can be separated into the individual isomers with the aid of chromatography on silica gel. This separation is generally not necessary, however, because all isomeric erythro- and threoglytols are suitable as intermediates for the formation of the end products of the formulas XI in the process according to Table B, from which the other end products according to the invention then arise. "The various isomers Glycol mixtures encompassed by the formula X and obtained from the various isomeric olefins of the formula IX can all be used for the same purposes.

Table B also shows that the bis-alkanesulfonic acid ester XI from the glycol by reaction with an alkanesulfonyl chloride or bromide or with an alkanesulfonic anhydride - The alkyl group each having 1 to 5 carbon atoms may contain - is won. Alkanesulfonyl chlorides are preferably used in the reaction. The implementation is in Presence of a base carried out with it as a by-product acid formed is neutralized. Particularly suitable bases are tertiary amines such as dimethylaniline or pyridine. In general"

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It is sufficient to simply mix the two reactants and the base and the reaction mixture for several hours let stand at 0 to 25 ° C. The bis-sulfonic acid esters of the formula XI are then isolated in a customary and known manner.

The conversion of the bis-sulfonic acid ester XI into the compounds XII of the PGE type takes place in such a way that the bis-ester XI with water to a temperature of about 0 to about 60 C, preferably 25 ° C, heated and the reaction allowed to proceed for about 5 to 20 hours. The reaction mixture should be as homogeneous as possible. To achieve this, a sufficient amount of a water-soluble organic diluent is added, which is not involved in the reaction »A suitable solvent of this type is acetone. The desired product is isolated by the excess water and the excess solvent or diluent, if such was used, evaporated. The residue contains a mixture of formula XII isomers, which differ in terms of the configuration of the two side chain hydroxyl groups, either α. or ß, differentiate. A separation from the by-products and a separation from one another can can be achieved with the aid of silica gel chromatography. A by-product that usually occurs is the mono-sulfonic acid ester of formula XIV (panel B). This monosulfonic acid ester can be converted into the bis-sulfonic acid ester of the formula XI in the same Esterify manner described above for the conversion of the glycol X to the bis-ester XI; he will as a result returned to the process so that further end product of the formula XII can be obtained.

The conversions of XI (panel B) to PGA-type compounds XIII are carried out by treating the bis-ester XI with a mixture of water, a base that has a pH-Y / ert in aqueous solution between 8 and 12, and an amount of an inert water-soluble organic diluent sufficient to cause a basic and essentially homogeneous reaction mixture

309843/1119

forms, heated to 40 to 10O ^{0 G.} Reaction times between one and 10 hours are generally sufficient. Well-suited bases are the water-soluble salts of carboxylic acids, in particular alkali metal carbonates such as sodium carbonate. Acetone is a suitable diluent or solvent. Me products are isolated and separated from one another as described above for the conversion of the bis-ester XI into the PGE-type compound XII. The monosulfonic acid ester XIV also occurs as a by-product in the production of the PGA-type compounds XIII.

The conversions of the bis-sulfonic acid esters XI into the end products XII and XIII are preferably bis-mesyl esters, ie a compound XI in which E _{1 is} methyl.

The compounds XII of the PG-B-type and the compounds XIII of the PGA-type, which are listed in Table B, are all R, -carboxylic acid esters, where E. has the meaning given above, If these R, -esters of the PG -S-Type \ mä PGA-Type used for the production of further prostaglandin-like compounds according to Table A, then correspondingly further R, -esters are formed, especially in the case of compounds of the PGF-type. In some of the application forms described above, the new prostaglandin-like compounds of the formula VII according to the invention should be in the form of the free acid or in the form of salts (which also initially requires the free acid). The esters of the PGP type and the compounds of the PGB type can easily be hydrolyzed or saponified in a known manner in the free acids, in particular when IL _; (R.) Alkyigruppen with 1 to 4 carbon atoms, preferably methyl or ethyl aarstellen.

The esters of PGE-Tyρ and Pi-L-T-p leave iiati ciagsgsn without undesirable structural Ve räiiasrvü'i :: ■ £ ". i:". d- ·;.! / desirable acids

Ü ': ^; :: i 3/1 1 1 p

difficult to hydrolyze or saponify. Bs are however two other methods to get these compounds in the form of free To produce acids.

One of these methods is particularly suitable for production the free acids from those alkyl esters in which the alkyl group contains one to 8 carbon atoms. With this one In the process, the PG-type allyl ester becomes an acylase enzyme system from a microorganism of the genus Subphylum 2 exposed by Phylum III, whereupon the acid is then isolated can be. In this context, reference is made to West German Offenlegungsschrift 1 937 678.

Another method of making the PGE and PGA analogs According to formula VIII in the form of the free acids consists in the treatment of certain haloethyl esters of these acids with zinc metal and an alkanecarboxylic acid having 2 to 6 carbon atoms, preferably acetic acid. The halogen ethyl esters are calibrate for those in which R .. from a in ß-position through Substituted 3 chlorine, 2 or 3 bromine or 1, 2 or 3 iodine atoms. Ethyl group. It is most favorable if the halogenoethyl substituent consists of ß, ß, ß ~ trichloroethyl. That needed Zinc is best used in the form of zinc dust. The halogen ethyl ester is mixed with the zinc dust and the mixture is left stand for several hours at about 25.degree. C., the halogenoethyl group in the formula is generally completely replaced XII esters of the PGE or PGA type against hydrogen instead. the Free acid can then be isolated from the reaction mixture in a known manner. The procedure described can be also use in the preparation of the free acids of the formula VII of the PGF and PGB type.

Formula IX-olefins in which R- is a haloethyl group according to above definition, are used as intermediates on the way to the end products of the PGE, PGF, PGA and PGB type in the form of the free acids required. "These haloethyl ester intermediates

3Ü9843 / 1119

ducts can get through. Alkylation of Olsfine Uli (panel B) with a suitable alkylating agent of the formula Hal (CHp) v-GOOS .. be produced, Yfcbei R «a Hai ο genätliyl group According to the definition above, 'means, those preferably to be used Y / ege to the IOrmel IX — haloethyl ester intermediates are included in Table 0.

In panel C, G-, R _? , R * and * - * - 'have the meaning already given. Halogenoethyl is understood to mean an ethyl group which is substituted in the β-position by 3 chlorine, 2 or 3 bromine or 1, 2 or 3 iodine atoms and which preferably consists of -CHpOGl. IL- means an alkyl group with 1 to 4 carbon atoms, preferably methyl or ethyl.

Compound XY in Table G is in the range of Compound IX in Table B. The ketone XV is reduced to the corresponding hydroxy compound XVI by reaction with a carbonyl reducing agent such as sodium borohydride, as discussed earlier in the discussion of i, Table A process steps described has been explained. The hydroxy ester XVI is then, in a known manner, to the hydroxy acid _{XV (I saponified o} This hydroxy acid can be converted into the ketohaloethyl ester XX by oxidizing the hydroxyl group to a keto group and esterifying the carboxyl group to a -COO-haloethyl group. As shown in Table C. , these two reactions can be carried out in any order. However, it is preferable to first carry out the oxidation and then the esterification.

309843/1119

- 32 panel C

, (CHa) ₆ -COORe

IR ₃

HO

, (CH ₂ Je-COORe

XVI

x (CH ₂ ) e-COO-haloethyl

R ₂

XVI I I

R ₃ XVI

, (CH ₂ ) e-COOH

, (CH ₂ ) e-C00H

XX

XIX

309843/1119

The oxy acid XYII is oxidized to the keto acid XIZ and the oxyhalo ester XVIII is oxidized to the keto halo ester XX; in both cases an oxidizing agent is used which does not attack the remaining parts of the molecule, in particular the ethylene bonds in compounds XVII and XVIlI. A particularly useful reagent for this purpose is Jones reagent, ie, acidic chromic acid. A good solvent is acetone. To work with a slight excess of the oxidizing agent, and lowers the temperature to at least about ⁰ ° G, preferably about 1O ^0-G, and most preferably -2O ⁰ C. The oxidation proceeds rapidly and is completed to 30 minutes, generally in about. 5 The excess oxidizing agent is destroyed, for example by adding a lower alkanol, preferably isopropyl alcohol. The aldehyde is isolated in a customary manner, for example by adding a suitable solvent such as diethyl ether. If necessary, other oxidizing agents can also be used: Examples of such are mixtures of chromium trioxide and. pyridine or mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide. Cf. »on this J.Am.Ghem. Soc. 87, .5661 (1965).

Di »'Halogenäthylester XVIII and ZX are prepared by the acids XVII or XIX with a suitable halogenoethanol, e.g. ß, ß, ß-trichloroethanol, in counterv / kind of a carbodiimide, e.g. dicyclohexylcarbodiimide, and a base, e.g. pyridine, preferably in the presence of an inert liquid diluent, e.g. dichloromethane, several hours at about. 25 C implements.

As already explained above, the processes according to Tables A and B, even when using the intermediates from Table C, lead either to acids (R ₁ = hydrogen) or to alkyl esters (R ₁ or R ^ = alkyl group with 1 to 8 carbon atoms) . If a formula VII acid of the PGE ₁ or PGP ₁ type has been produced and the alkyl ester is to be obtained from this, so

3 09843/1119

the esterification is best carried out by reacting the acid with a suitable diazo hydrocarbon for example diazomethane, the methyl esters can be obtained. In a corresponding manner, "when using diazoethane, Diazobutane or 1-diazo-2-ethylhexane win the ethyl, butyl or 2-ethylhexyl esters.

The esterification with the diazo hydrocarbons is carried out in such a way that that a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid to be reacted, which is preferably dissolved in the same - or a different - inert solvent, mixed Once the esterification is complete, the solvent is evaporated and the ester is in a conventional manner, for example by chromatography. Preferably, the acid to be reacted with the diazo hydrocarbon should no longer be in Maintain contact therewith as necessary to achieve the desired esterification, preferably for about 1 to about 10 minutes unwanted molecular changes are avoided.

Another method of esterifying the carboxyl group in the PGP and PGE type compounds is to convert the free acid into the corresponding silver salts, which are then reacted with an alkyl iodide. Examples of suitable iodides are methyl-j ethyl, butyl, isobutyl, tert-butyl iodide. the Silver salts are made in the usual way, for example by dissolving the acid in cold dilute aqueous ammonia, Evaporation of the excess ammonia under reduced pressure and subsequent addition of the stoichiometric amount of silver nitrate.

The end products of the process according to the invention, i.e. the ver_

Bonds of the formula VII, which are in the form of the free acid, are converted into the pharmacologically acceptable salts by one with sufficient amounts of a suitable inorganic or organic base (corresponding to those listed above Cations and amines). The conversion takes place in

3 09843/1119

- OD -

famous Y / eise; the choice of working method depends on the individual case on the solubility of the salt to be produced. If inorganic salts are to be prepared, the acid is usually dissolved of the formula YII in volume, which is the stoichiometric amount a hydroxide, carbonate or bicarbonate according to the desired inorganic salt. When using the appropriate The sodium salt is obtained from sodium compounds. By evaporating the water or by adding one with water Miscible solvent of moderate polarity, for example a lower alkanol or lower alkanone, the inorganic. Salt can also be obtained in solid form.

To produce an amine salt, the acid of the formula VII dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, Acetone and ethyl acetate. Examples of the latter diethyl ethers and benzene. Thereafter, at least the stoichiometric amount of an amine corresponding to the desired cation is used the solution too. If the desired salt does not precipitate, it can be obtained in solid form by using a miscible solvent low polarity or when you evaporate. If the amine is relatively volatile, the excess can easily can be removed by evaporation. Less volatile amines are preferably used in stoichiometric amounts.

Salts in which the cation consists of a quaternary ammonium ion are prepared by combining the formula VII acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide mixed in aqueous solution and then evaporated .

If the compound desired as the end product is to be present in optically active form, a resolution of the racemic end compound must be carried out or perform a separation of one of the asymmetric chemical intermediates. These separations are known in V / else done »If the end connection is VII.

309843/1119

"For example a free acid, so" can be the dl form the same can be converted into the two d- and 1-forms by reacting the free acid in a known manner with an optical active base, e.g. brucine or strychnine, so that a mixture of the two diastereoisomers is obtained, which then also in a known manner, e.g. by fractional crystallization into the two different diastereoisomeric salts is separated. The optically active acid of the formula VII is then obtained by treating the salt with an acid. It is It is also possible to separate the olefin IX or glycol X in the form of the free acid into the two d- and 1-forms, then to esterify them and to carry out the further conversions so that the end product, i.e. compound VII, is in optically active form wins.

The glycols X, in exo or endo form, can be converted by reaction with a 1,2-glycol, e.g. D- () -2,3-butanediol, in

Presence of a strong acid, e.g. p-toluenesulfonic acid, in Convert ketals. The resulting ketal is a mixture of the diastereoisomers, which are separated into the two d- and 1-forms will. The latter are then hydrolyzed separately with acid, e.g. oxalic acid, so that the original keto compound, now in optically active form, regained. The separation processes described are known; Daily in this context for example Ghem. Ind. 1664 (1961) and J.Am. Chem. Soc. 84, 2938 (1962). Instead of glycols, dithiols can also be used.

The optically active and racemic forms of 16-methyl-PGE .. and _{-PG ^ 101} , 16,16-dimethyl-PGE., And -'PGP ₁₀₁ , 16-ethyl-PGE., And -PGF ₁ , 16,16 - Diethyl PGE. and -PGF ₁ and 16-ethyl-16-

ία ι like ^{1 a}

methyl-PGE .. and -PGF ₁ can also be obtained in US Pat. No. 3,514,383 by the same applicant. In the process described there, pure cis-16-methyl-ETS (ETS = 8,11,14-eicosatrienecarboxylic acid) consisting only of the cis form is used as the starting material for the production of the T6 methyl

309843/1119

Prostaglandin analogs and pure eis-16,16-dimethyl-ETS used as starting material for the preparation of the '16,16-dimethylprostaglandin analogs. The preparation of pure cis-15-methyl-ETS is also described in the said patent. By using 2-Methylhexanon instead of 2-heptanone as a starting material in the "described process can be pure cis-16-methyl-ETS win. In a corresponding manner can be reached with 2,2-Dimethylhezanon to 16,16-dimethyl-ETS, 2-ethylhexanone to 16-1thyl-ETS, 2,2-diethylhexanone to 16,16-diethyl-ETS and 2-ethyl-2-methylliexanone to 16-ethyl-16-methyl-ETS.

From the patent mentioned it also emerges that only-cis-16-methyl-ETS and only-cis-16,16-dimethyl-ES3 in racial 16-Methy1-PGE or racemic 16-methyl-PGrF .. or racemic 16,16-dimethyl-PGE., Or racemic 16,16-dimethyl-PGl- converted if you treat the acids with singlet oxygen and the resulting product of the action of a Reducing agent - when producing PGl -type derivatives - or the action of a mild reducing agent and then a base, a metal ion catalyst or from ultraviolet light - when producing PGE-type derivatives should be - suspends.

It is also described that only-cis-16-ethyl-E! ES in racemic 16-ethyl-PGE,. or -PG-F. *, only-cis-16,16-diethyl-ETS in racemic 16,16-diethyl-PG-E .. or -PG-F- and only-cis-16-ethyl-16-methyl -ETS is converted into racemic 16-ethyl-16-methyl-PG-E ₁ or -PGF-.

The optically active prostaglandin analogs, 16-methyl-PGS and -PGF _{1 a} , 16,16-dimethyl-PGE and -P & F ^ are prepared according to the patent mentioned by separating the corresponding racemic forms. The same applies to the optically active analogues 16-AtIIyI-PGE ₁ and -PGF ₁ , 16,16-

and PGF _{1 a} , 16-ethyl-16-methyl-PGE ₁ and -P ^ _{1 α} ·

309843/1119

Furthermore, the optically active 16-methyl and 16,16-dimethyl analogs by aerobic incubation of cis-16-methyl-ETS only or cis -16,16-dimethyl-ETS only using crushed Sheep seminal vesicle tissue - or the enzyme system contained therein - obtained in an essentially aqueous medium will. The optically active 16-ethyl, 16,16-diethyl and 16-ethyl-16-methyl analogs can also be used in a corresponding manner to win. For further procedural details, see US Pat. No. 3,296,091 as well as the work of Kupiecki, life Sciences, 4, 1811 (1965), Struijk, ReCoTrav.Chim. 85, 1233 (1966) and Nugteren et al., Rec. Trav. Ghim., 85, 405 (1966).

In the biological oxidations described, mixtures of the PGE ₁ and PGF ₁ forms of the 16-methyl analogs are obtained. _{Mixtures of the PGE 1} and PGF ₁ forms of the 16,16-dimethyl, 16-ethyl, 16,16-diethyl and 16-ethyl-16-methyl analogs can also be obtained in a corresponding manner. The components of all of these mixtures can be separated from one another; each individual component can be cleaned in the manner described in U.S. Patent 3,296,091; Other methods already used for separation and purification of known prostaglandins can also be used. In the separations, the advantage of the greater polarity of the PGF ₁ compounds compared to the compounds of the PGE ₁ type is perceived in particular, generally in chromatography over acid-washed silica gel, partition chromatography with reversed phase, preparative thin-layer chromatography and / or countercurrent distribution.

In the following examples, which are intended to further illustrate the invention, certain frequently recurring examples Terms and designations of connections the following abbreviations are used:

309843/1119

2210637

DSG = thin layer chromatography;

SGC = silica gel learning chromatography5

SSB - Skellyscrve B fd.i. a mixture of isomeric

Hexanes);

THF = tetrahydrofuran;

Ether = diethyl ether, *

Brine = saturated aqueous sodium chloride solution.

example 1

Racemic 16-methyl-PGE ^ methyl ester (formula VII: D = 0.

R- and R ^ = methyl;

R ₂ = hydrogen).

See Table B. First, the formula VIII-olefin is prepared, in which R _{2 is} hydrogen, R-, methyl and G - (0H ₂ ) ^ CH.,. Endo-bicyclo (3 «1.0) hexan-3- * ol-6-carboxaldehyde-3-tetrahydropyranyl ether (100 g) is treated with (2-methylhexyl) triphenyl-phosphonium bromide, which is obtained from racemic 1-bromo-2-methylhexane by the process the West German Offenlegungsschrift 1 937 has been obtained, implemented. In the manner described Ie, the formula VIII-olefin in which Rp is hydrogen and R3 is methyl, is then prepared and isolated by SGG.

Next, the Formula IX compound is made. To a Solution of 10.0 g of the aforementioned Formula VIII olefin and 12 g of methyl 7-3odheptanoate in 250 ml of THF was added under nitrogen and a solution of potassium tert-butoxide (7.0 g) in 500 ml of THF, which is mixed with nitrogen, dropwise at 25 ° C.

309843/1119

fabric had been flushed through, given over the course of 45 minutes. The mixture is then present, acidified to once with about 120 ml of 5 $ strength HC £ and concentrated under reduced pressure at a temperature below 4O ⁰ G. 400 ml of water were added to the residue. The mixture was extracted several times with 400 ml of ether each time. The ether extracts were washed with water and brine, dried over sodium sulfate and evaporated. The remaining residue contained the formula IX compound, namely methyl 7- [endo-6- (3-methyl-1-heptenyl) -3-oxobicyclo (3.1.0) hex-2a-yljheptanoate as a mixture of 2 pairs of racemates.

The next step is to make the Formula X Glycol. A solution of 10 g of the recovered as above Pormel IX-racemates in 160 ml of THF was stirred under nitrogen at 5O ⁰ C and then added as well as 1.0 g of osmium tetroxide with a solution of 6.5 g of potassium chlorate in 75 ml of water. Stirring was continued for 3 hours at 5O ⁰ C. Thereafter, the THF was evaporated under reduced pressure and the remaining residue was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate and evaporated; in this way a mixture of the formula X-glycols was obtained. This glycol mixture was chromatographed over 2 kg of silica gel which had been wet packed with 15% ethyl acetate in SSB; to elute successively mixtures were used 15 #, 25 #, 35 #, i »ethyl acetate in SSB contained 60% and 80th The fractions of the eluate which, as indicated by DSC, contained the desired glycols were combined and evaporated. In this way, the formula X product, in which R «is hydrogen and R, is methyl, was obtained as a mixture of the isomers.

7.1 g of the glycol mixture described above were dissolved in 90 ml of pyridine and ^{stirred at 0} ° C. under nitrogen, while 8.5 ml of methanesulfonyl chloride were added over the course of 15 minutes. The mixture was kept at ⁰ ° C. for a further 2.5 hours

309843/1 1 19

stirred, then cooled to -15 ° C. and slowly mixed with 10 ml of ice and water. Compartment 5 minutes more. Stirring at -5 to OC, the mixture was poured into 500 ml of ice and water. Then first 200 ml of cold 1: 3 dichloromethane-ether mixture and then another 360 ml of cold 3m HCl were added; the mixture was quickly extracted with methylene chloride ether. The organic extracts were washed with 2 ^c / o ± ger sulfuric acid, water, aqueous bicarbonate and brine, and dried over sodium sulfate evaporated. The formula XI bismethanesulfonate was obtained in this way.

10.5 g of the above-described bismesylate of the mixed Glycols were dissolved in 400 ml of a 2: 1 acetone-water mixture and stored at 25 ° C. for about 18 hours. Subsequently was diluted with 400 ml of water. The acetone was removed by evaporation under reduced pressure. The aqueous residue was extracted with ethyl acetate. The extracts were washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. A mixture of the isomeric formula XII products was obtained in this way. The residue contained 4 racemates, i.e. 4 pairs of the isomeric formula XII products with different centers of asymmetry at 0-8, G-15 and Ö-16. The following Methods relate to the separation of the racemates. Two of these racemates are similar in that they are more polar than the other two racemates and can therefore be separated from these two others using the SGO.

The residue was over 1.6 kg of silica gel containing $ 30 Ethyl acetate was wet packed in SSB, chromatographed and then eluted with the following solutions: 8 1 30 $,

4 1 40 $, 13 1 60 $ and 16 1 80 $ ethyl acetate in SSB and 10 1 Ethyl acetate; this was followed by a gradient elution

5 1 ethyl acetate and 5 1 5 $ strength methanol in ethyl acetate. 500 ml fractions were collected. The factions that loud Detection by DSC the two more polar (more slowly eluted) Racemates were combined and concentrated.

309043/1119

The mixed racemates have the natural Prostqg.andin configuration at C-8 and C-15, namely R and S, respectively, and differ in their stereochemistry at C-16. For separation, the formula XII product is converted into the bis (trimethylsilyl) ether. A solution of 5.0 grams of the Formula XII product, 25 ml of hexamethyldisilazane and 10 ml of trimethylchlorosilane in 20 ml of THF was placed at about 25 ° C. for 20 hours. The mixture was filtered through a bed of diatomaceous earth; the filtrate was evaporated under reduced pressure. The residue was purified over 1.6 kg of silica gel which had been packed wet with 30 $ ethyl acetate in SSB chromatographed and eluted with the following solutions: 1 8 30% 4 1 40 # 13 1 60 16 1 $ and 80 fo ethyl acetate in SSB and 10 1 pure ethyl acetate; this was followed by a gradient elution with 5 l of ethyl acetate and 5 l of 5% methanol in ethyl acetate. 500 ml fractions were collected.

The fractions which, according to DSC evidence, contained the separated silylated racemates, free of intermediate products and by-products, were combined and concentrated. The trimethylsilyl groups were replaced with hydrogen by leaving both residues treated in each case with a solution of 50 ml of methanol and 20 ml of water at 25 C for 16 hours and then the solvents removed under reduced pressure. In this way the racemic formula XII title compounds were obtained. the Racemates, which have been shown to have a stronger biological effect on test strips from smooth muscles, are for the the purposes described above are more suitable. In this context, see J.R. Weeks et al, Journal of Applied Physiology 25, (No. 6), 783 (1968).

If you work as indicated in Example 1 above, however, replace the formula VIII compound mentioned there by a formula VIII compound in which Rp is hydrogen and R, Mean ethyl, the corresponding racemic 16-ethyl-PGE ^ products are obtained. If you put a formula VIII compound, in which both Rp and R, represent methyl, a, so

3 0 9 8 4 3/1119

«43 -

the corresponding racial 16,16-dimethyl-PG-E products are obtained. With these 16-disubstituted compounds, the last of the steps described above, cLh. chromatography of the silylated product, optionally v / eggelassen because the asymmetry center "at G-16 lacks" If one goes by formula VIII Yerbindungen from in which R ₂ ^wcl ^ ^ x is either ethyl or Rp ethyl and R ,, "mean, one obtains the corresponding 16,16-diethyl" methyl Substituting Έοτπιβΐ or "16-ethyl-16-methyl-PGE ₁ compounds. IX compounds in which R is not methyl, but an alkyl group with 2 Ms denotes 8 carbon atoms, the corresponding compounds of the PGE .. type, in which H denotes a corresponding alkyl group, are obtained.

Example 2

7- [Endo-6- (3-methyl-1-heptenyl) -3-oxobicyclo [3.1.0] hex-2a-yl] -heptanoate trichloroethyl ester

(Formula XX, panel C:

G = - (GF O ₅ CH ₅ ;

Haloethyl = -CH ₂ CCl ₅ ;

R ₂ = hydrogen;

R ₅ = methyl; r-x_x = endo)

Reference is made to panel C. The formula XV compound, ie the methyl ester of the formula IX compound from Example 1, is reduced to the formula XVI compound with sodium borohydride as follows. To a solution of 4.0 g of the formula XY compound in 110 ml of absolute ethanol, a solution of 1.5 g of sodium borohydride in 10 ml of water was added ^{at 0 ° C. with stirring.} To. For 2.5 hours of stirring at ⁰ ° C. to 5 ° C., about 40 ml of acetone were added, whereupon the mixture was evaporated under reduced pressure after a further 5 minutes. The residue was extracted with diehlomethane; the extract was successively diluted with

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Washed HCl and brine, dried and evaporated. The formula XVI compound was obtained in this way.

This ester was in a mixture of 100 ml of methanol and 30 ml of a 45% aqueous potassium hydroxide solution dissolved; the solution was stirred under nitrogen at 25 ° C. for 15 hours. Two volumes of water were then added and the AYurde mixture was acidified with cold HCl and finally with a Mixture of dichlorine than and ether (1: 3) extracted. Of the The extract was washed with brine, dried and evaporated. The formula XVII-oxy acid was obtained in this way.

Jones reagent (7 ml of a solution of 21 g of chromic anhydride, 60 ml of water and 17 g of concentrated sulfuric acid), which ^{had been precooled to 0} ° C., was added dropwise to a solution of this oxy acid in 120 ml of acetone at ⁰ ° C. The mixture was ^{stirred at 0} ° C. for 5 minutes. Then 5 parts by volume of water were added and the mixture was extracted with a mixture of dichloromethane and diethyl ether (1: 3). The extract was washed successively with dilute HCl and brine, dried and evaporated. The formula XIX-3-oxo compound was obtained in this way.

To a solution of 2.0 g of the above-described free acid of the formula XIX in 100 ml of dichloromethane were added successively 25 ml ß, ß, ß_Trichloräthanol, 15 ml pyridine and 4.0 g dicyclohexylcarbodiimide given. The mixture was stirred at 25 ° C. under nitrogen for 3 hours. Then 50 ml of water were added and the mixture was stirred for an additional 10 minutes. The dichloromethane was evaporated under reduced pressure and the The residue was extracted several times with ethyl acetate. The combined extracts were washed with ice-cold 3N hydrochloric acid extracted. The extracts in turn were washed successively with aqueous sodium bicarbonate solution and brine and dried and evaporated under reduced pressure. The residue was

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Chromatographed over 600 g of silica gel. 10 1 of a mixture of ethyl acetate and SSB were used for elution. The amounts of ethyl acetate in the mixture gradually increased from 20 to 100 ? * . 250 ml fractions were collected. The fractions which, according to DSG evidence, contained the desired product free of starting materials and by-products were combined and evaporated under reduced pressure. This gave the formula XX title compound, ie the trichlo räthylester.

If you work as indicated in Example 2 above, but instead of the formula XV-3-oxobicyclo [3.1. Ojhexanesters all endo- and exo-intermediates of the formula IX of Example 1, the corresponding β, β, β-trichloroethyl ester is obtained in each case that 3-oxobicyclo [3.1.ojhexanoic acids. Instead of of the 3-methyl-formula-XX-heptanoate you get the 3,3-dimethyl-, 3-ethyl-, 3,3-diethyl- and 3-ethyl-3-methyl-formula XX-heptanoate as trichloroethyl ester.

Example 3

Racemic 16-methyl-PGE.j (Formula VII: D =

HO

R ₁ and Rp = hydrogen;

R ₅ = methyl)

Reference is made to panel B. If you work as indicated in Example 1, but replacing the formula IX-methyl ester derivative used there by the formula XX-trichloroethyl ester derivative of Example 2, the corresponding racemic 16-methyl-PGjD ₁ -trichloroethyl ester is obtained.

420 mg of zinc dust were converted into a solution of 100 mg of the ß, ß, ß-trichloroethyl ester in 5 ml of a mixture of acetic acid and

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Water (9: W / V) given. The mongrel was under nitrogen two hours "at 25 ° C. Thereafter, 4 parts by volume of ethyl acetate and then another part by volume of 1N hydrochloric acid were added added. The ethyl acetate layer was separated, washed with water and then with brine, dried and evaporated. The residue was acid washed over 15 g of silica gel (Silicar CC4) and then eluted with 100 ml 50 $, 100 ml 80 $ and 200 ml 100 $ ethyl acetate in SSB, where 20 ml fractions were collected »The fractions, the 16-methyl-PGE., and no starting material or dehydration products (detected by DSC) were combined and evaporated = the formula VII title compound was obtained in this way.

In the manner described in Examples 3 and 1, all haloethyl ester intermediates of the formula XX of Example 2 can be converted into the corresponding racemic haloethyl ester derivatives of the PGE ..- type and from these into the corresponding racemic free acids. Racemic acids are obtained in this way 16,16-dimethyl-PGE .., 16-ethyl-PGE. ,, 16,16-diethyl-PGE ₁ and 16-ethyl-16-methyl-PGE.,.

Example 4

16-methyl racemic PGF. and 16-methyl-PGF (Formula VII: D =

R. and R ₂ = hydrogen R,. = Methyl;

r - ^ _ s = alpha or beta)

Reference is made to panel A. A solution of 400 mg des

l-PGE ^ methyl ester

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racemic 16-methyl-PGE ^ methyl ester of Example 1 in

20 ml of isopropyl alcohol is ^{cooled to 0} G under nitrogen and a solution of 0.2 g of sodium borohydride in 4 ml of cold water is added. The mixture was stirred at 0 C for 2.5 hours and then 1 ml of acetone and 10 minutes later 1.2 ml of glacial acetic acid were added. The organic solvents were evaporated under reduced pressure and the residue was mixed with water and ethyl acetate. The organic extracts were washed with water and brine, dried over sodium sulfate and concentrated; thus obtaining a mixture of racemic methyl-16-PGI ¹ methyl ester .. racemisehem and 16-methyl-PGP .. _ß methyl ester. The mixture was chromatographed over 150 g of silica gel, which had been packed wet with 30% ethyl acetate in cyclohexane, and then eluted, in succession with 500 ml 30%, 500 ml 50%, 500 ml 60%, 500 ml 70%, 1 , 5 1 80 $ and 1.0 1 90 $ ethyl acetate in cyclohexane, 5 1 ethyl acetate, 11 5 $ and 1 1 20 $ methanol in ethyl acetate, 50 ml of eluate fractions being removed. The fractions which, according to DSC-Naohweis, contained the desired products free of starting material and by-products were combined and concentrated. This gave the SOrmel YlX-PG-IP .. - bsw.

-PGi ¹ derivatives in the form of their methyl esters. 1ß

A solution of 0.15 g of racemic 16-methyl-PG! .. -methyls in a mixture of 4.5 ml of methanol and 1.5 ml of water was cooled to 5 ° and with 0.6 ml mixed with aqueous sodium hydroxide. The mixture was left to stand at 25 G for 3.5 hours and then diluted with 75 ml of water. The mixture was extracted once with ethyl acetate to remove any neutral material present. The aqueous layer was separated, acidified with dilute hydrochloric acid and extracted 4 times with ethyl acetate. Me extracts were combined and three times with "summarization and washed once with brine, over sodium sulfate dried and evaporated. There was thus raeemisches 16-methyl-PG ·]? ... In a corresponding manner, the raeemisohe 16-methyl-PGL can _ß ~ saponify methyl ester with aqueous potassium hydroxide?

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Acidification gives racemic 16-methyl-P GF .. _ß as a free acid.

In the manner described in Example 4, all a derivatives of the PGE type described in connection with Example 1 can be converted into the corresponding PGP ₁ and PGF _1β esters and free acids; 16,16- dimethyl-PGF ..- and -PGP- “ethyl ester as well as the free acids are obtained from 1 6,16-dimethyl-PGE ..- ethyl ester.

Example 5

Chemical 16-methyl-PGF ₁ -ethyl ester and free acid (Formula VII: J

D =

R ₁ = ethyl or hydrogen; R ₂ * hydrogen;

R ₅ = methyl)

Reference is made to panel A.

1. Use of hydrochloric acid. A solution of 400 mg of racemic 16-methyl-PGE ..- ethyl ester in a mixture of 5 ml of THF and 5 ml of 0.5N HCl is placed under nitrogen at 25 ° C. for 5 days. The resulting mixture is diluted with one volume of brine and extracted with a mixture of diethyl ether and dichloromethane (3: t). The extract is washed with brine, dried and evaporated. The residue (380 mg) is dissolved in ether; the solution is extracted with cold 5 # aqueous sodium bicarbonate, an aqueous layer A and an ether layer B being obtained. The aqueous layer A is acidified with dilute HCl and extracted with dichloromethane. This extract is washed with brine, dried and evaporated and gives the title compound as the free acid. The ether layer B is also evaporated and yields the title compound as an ethyl ester.

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2. Use of acetic acid. A solution of racemic 16-methyl-PGE ..- ethyl ester in a mixture of 9 ml of glacial acetic acid and 1 ml of water is heated to 6O ⁰ C under nitrogen for 18 hours. Thereafter, acetic acid and water are evaporated off under reduced pressure and the residue is chromatographed over 500 g of acid-washed silica gel. A mixture of ethyl acetate in SSB is used for elution, the amounts of ethyl acetate gradually increasing from 25 to 100 fo . The fractions which contain the desired product free of starting material and by-products (verified by DSG) are combined and evaporated; the title compound was thus obtained as an ethyl ester.

In the manner described in Example 5, all racemic derivatives of the PGE ₁ type, which are described in the paragraphs following Example 1, can be converted into the corresponding esters and free acids of the PGA ₁ type; 16,16-dimethyl-PGE.j-methyl ester is thus obtained from 16,16-dimethyl-PGE.j-methyl ester.

In the manner described in Example 5, all halogen ethyl ester derivatives of the PGE ₁ type can be converted into the corresponding halogen ethyl esters of the PGA ₁ type. With the procedure described in Example 3, all halogen ethyl ester derivatives of the PGA ₁ -type can be converted with zinc, acetic acid and water into the corresponding racemic free acids of the PGA ₁ -type. In this way, racemic 16,16-dimethyl-PGA. ., 16-ÄUiYl-PGA ₁ , 16,16-diethyl-PGA.j and 16-ethyl-16-methyl-PGA.j.

Example 6

Racemic 16-methyl-PGA ₁ -methyl ester

Reference is made to panel B. A solution of about 1.0 g of the Formula XI-Bismesylates of Example 1 in 75 ml of acetone with 10 ml of water and 20 ml of saturated aqueous sodium bicarbonate

309843/1119

natural solution mixed. The mongrel is under nitrogen for 4 hours heated to reflux. The mixture is then cooled, acidified with 5 # HCl and extracted with ethyl acetate. Of the The extract was washed with brine, dried and evaporated. The title compound was obtained in this way.

In the manner described in Example 6, all of the bismeaylates mentioned in connection with Examples 1 and 3 can be converted into the corresponding esters of the PG-A type including the ß, ß, ß ~ Convert trichloroethyl ester. The latter are used to manufacture of the free acids of the PGA type, using the procedure given in Example 3.

Example 7

Racemic 16-methyl (formula VII:

R-. and R ₂ = hydrogen; R, = methyl.

The workflow is the same as that given in Table A. A solution of 200 mg of racemic 16-methyl-PGE ₁ from Example 1 in 100 ml of 50% aqueous ethanol which contained 10 g of potassium hydroxide was heated ^{to 25 ° C. under nitrogen for 10 hours.} The solution was then ^{cooled to 10 °} C. and neutralized ^{at 10 °} C. by adding 3N HCl. The resulting solution was extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried and evaporated. The title compound was thus obtained.

309843/1119

In the manner described in Example 7, all 16,16-dimethyl-PGE ₁ and -PGA ₁ derivatives can be converted into 16,16-dimethyl-PGB.j.

The JBOrmel YII derivatives of the PGE .. and PGA ₁ type described above can also be converted into the corresponding PGB ₁ derivatives in this way.

Example 8

16-methyl-PGB.j-methyl ester

A solution of about 0.5 g of diazomethane in 25 ml of ether became a solution of 50 mg of 16-methyl-PGB ₁ in 25 ml of a mixture

given from methanol and ether (1: 1), the mixture was allowed to stand ^{at 25 ° C. for 5 minutes.} The mixture was then evaporated to give the title compound.

In the manner described in Example 8, all other free acids of the PGB ₁ , PGA ₁ , PGE ₁ and PGI ¹ type can also be converted into the corresponding methyl esters. If diazoethane, diazobutane, 1-diazo-2-ethylhexane or liazocyclohexane are used instead of diazomethane, the corresponding ethyl, butyl, 2-ethylhexyl or cyclohexyl esters of 16-methyl-PGB _{1 are obtained} . In the same way, all other above-mentioned free acids of the PGB ₁ -, PGA ₁ -, PGE .. and PGP ^^ type can be converted into the mentioned esters.

Example 9

Sodium salt of 16-methyl- ₁

A solution of 100 mg of 16-methyl-PGE .. 50 in a water-ethanol mixture ml (1: 1) was cooled to 5 ⁰ C and neutralized with one equivalent of 0.1N aqueous sodium hydroxide solution, the neutral solution yielded in Evaporate the title compound.

309843/1119

If, in the procedure described above, potassium, calcium, tetramethylammonium or benzene trimethylammonium hydroxide is used instead of sodium hydroxide, the corresponding salts of 16-methyl-PGE are obtained ... These salts can also be obtained from the other acids from PGE ₁ -, PGF ₁ -, PGA ₁ - and PGIL-type can be produced.

The examples given so far describe the preparation of racemic intermediates and end products. All of these intermediates and end products can also be obtained in the enantiomeric forms, ie as d- and 1-isomers, by separating the end product or one of the intermediates. For example, optically active 16-methyl-PGA .. in the form of the free acid can be prepared by separating the racemic 16-ltethyl-PGA ₁ acid from Example 5 or by using the optically active 16-methyl-PGE .. acid the same absolute configuration as in Example 5 is dehydrated. The separation takes place in a known manner and allows prostaglandin-like products to be obtained which, apart from 0-16, have the same stereochemical configuration as natural prostaglandins, which is explained in the following example.

Example 10

16-methyl-PGE .. methyl ester derivatives which, with the exception of C-16, have the natural configuration of PGE ₁ .

Reference is made to panel B. First, in the manner described in Example 1, the bicyclic olefin VIII produced, but (2-methylhexyl) triphenylphosphonium bromide is produced used, which has been prepared from d-1-bromo-2-methylhexane »This d-isomer can be obtained in a known manner, e.g. by dissolving d-2-methylhexanecarboxylic acid (see P.A. Levene and L.W. Bass, Journal of Biological Chemistry 70, 211 (1926)), reduction of this acid to the corresponding one primary alcohol with lithium aluminum hydride and

309843/1119

Conversion of the alcohol into the halide by reaction with PBr ,, HBr or any other halogenating agent known to be suitable for this purpose.

Next, the bicyclic intermediate of formula IX is prepared, in which R _{2 is} hydrogen, R_ and R, methyl, G - (CHo) ₁₅ -CH ^ and / ^ - 'endo, and zv / ar in that given in Example 1 Way. The 16-methyl formula IX derivative is obtained as a mixture of the diastereomers, which is separated as follows: the mixture is chromatographed over a silica gel column (500 g) which has been wet packed with 5% ethyl acetate SSB (1 liter) and then eluieri * with ethyl acetate in SSB, the amounts of ethyl acetate increasing from $ 5 to $ 25. The fractions which, according to DSC evidence, contain the relevant formula IX derivatives were combined and evaporated; there was thus obtained the separate 8R and 8S formula IX derivatives in which the stereochemistry at C-16 is the same as in the preceding d-Isbmer intermediate.

Subsequently, in the manner described in Example 1, all of the above formula IX derivatives are converted into the mixed formula X-glycols, from these into the formula XI-bismesylates and finally into a mixture of the formula XII-1.6-methyl-PGE- derivatives and the corresponding formula XII-IS-epi-io-methyl-PGE .. derivatives converted. All mixtures of derivatives of PGE type ₇ and 15-epi-PGE ^ -type be purified by chromatography on Silikagelkolonnen (500 g) with 50 fo Äthylaeetat in SSB (1 liter) have been packed wet, separately; to elute was respectively 50 fo ethyl acetate in SSB, then ethyl acetate and finally 10 used fo ethanol in ethyl acetate. The more polar or less polar fractions (detected by DSC) which contain the derivatives of the PGE ^ type or 15-epi-PGE.-type are combined separately and evaporated so that the compounds in question are obtained.

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In a corresponding manner, (2-methylhexyl) triphenylphosphonium bromide, which has been prepared from l-1-bromo-2-methylhexane, is used in the process sequence described above. This 1-isomer can be obtained in the manner described by PA levene and IA Mikeska, Journal of Biological Chemistry 84, 571 (1929) from separated 1-2-methylhexanecarboxylic acid. Finally, the corresponding optically active PGE ₁ - and 15- epi-PGE ..- »derivatives which have a different configuration at C-16 than the d-isomer intermediate mentioned above.

Of the separate PGE ₁ derivatives listed above, those which, in corresponding tests, show a stronger biological effect on strips of smooth muscle, are more suitable for the purposes mentioned.

If you work as in Examples 10 and 3 or as in Example 3 stated, the optically active 16-methyl-PGE .. derivatives are obtained as free acids.

If you work as indicated in Example 5, you can convert the optically active 16-methyl-PGE .. derivatives into the optically active 16-methyl-PGA ₁ derivatives.

If you work as indicated in Example 4, you can _{convert the optically active 16-methyl-PGE 1} derivatives into the optically active 16-methyl-PGF ₁ - and -PGF., _Q derivatives.

1 ct 1 yoy

If you work as indicated in Example 7, you can _{convert the optically active 16-methyl-PGE 1} derivatives into the optically active 16-methyl-PGB ₁ derivatives. .

If you work as in Example 10 or in the paragraphs given after Example 10, however, the 16-ethyl-formula IX derivatives are used instead of the 16-methyl derivatives of the formula IX, see above one obtains the corresponding optically active 16-ethyl-PGE .. · -,

30 9 843/1119

₀₁ -, -PCHF _{1 ß} -, -PGA ₁ _ and PGB ₁ derivatives. · Example 1T
16_, 16-Dimethyl-PGE .. methyl ester with natural configuration

Reference is made to panel B. The bicyclic intermediate of the formula IX, in which R ₂ , E, and R ^, methyl, G - (GHg) ₅ CH ₅ and '■ ^ -' endo "are, is prepared according to the procedure given in Example 1.

The formula IX derivative is then prepared according to the method of Gorey et al., J.Am.Chem. Soe. 84, 2938 (1962) separated into the optical isomers by reacting the keto compound with optically active L (+) -2,3-butanedithiol of p-toluenesulfonic acid. The diastereomeric ketals are separated on a preparative chromatography column and hydrolyzed individually to the bicyclic ketone of the formula IX in a known manner _9, for example using 1: 1 HCl-water in THF at 25 ° G in 6 hours. All isomeric derivatives of the formula IX are then converted into the corresponding derivatives of the formula XII in the manner described in Example 1. The PSS ₁ -Tit elTirMndungen and 15-epi-PGE.j «compounds are separated in the manner described in Example 1, namely by silica gel othromatography. Due to the lack of a center of asymmetry at 0-16, the silylation step and the subsequent chromatography of the 16,16-dimethyl derivatives have been omitted.

The optically active 16,16-dimethyl-PGE ₁ acids are prepared in the manner described in Example 3 using the halogenated ethyl ester from the separate formula IX derivatives (Example 2).

In the manner described in Example XI and in the preceding paragraph, when using the corresponding 16,16-dialkyl derivatives of the formula IX the corresponding optically active

* in present

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16,16-Dialkyl-PGE ..- derivatives including the esters and free ones Prepare acids, where R. has the meaning given above Has.

If one works according to the guidelines of Table A and in the manner indicated in Examples 4, 5-6 and 7, the optically active 16,16-MaIkYl-PGE ₁ derivatives mentioned can be converted into the corresponding optically active 16,16-dialkyl -PGF-, -PGF ₁ R-, -PGA ₁ - or -PGB ₁ derivatives. In this way, optically active 16,16-dimethyl- or 16,16-diethyl- or 16-ethyl-16-methyl-PGE., -, -PGF ^ -, -PGA ₁ - and -PGB _{1 are obtained} .

3 0 ΰ: '/ ·. 3/1 1 1 9

Claims (1)

Claims as well as the racemates, which from the formula I and the This formula is a mirror image of this formula, where D is one of the three carbocyclic radicals V. - B ■ C and R .. denotes hydrogen, an alkyl group having 1 to 8 carbon atoms or a pharmaceutically acceptable cation and Rp and R ~ represent hydrogen, methyl or ethyl, provided that at least one of the two radicals R ₂ and R- is not hydrogen. 2. The optically active compounds according to claim 1. 3. The racemic compounds according to claim 1. 4. Optically active or racemic compounds according to claim 1, in which D is the carbocyclic radical A and R ^ is hydrogen or an alkyl group with Represents 1 to 4 carbon atoms. 309843/1119 5 »Optically active or racemic compounds according to claim 1, in which D is the carbocyclic radical B- and R _{1 is} hydrogen or an alkyl group having 1 to 4 carbon atoms 6. Optically active or racemic compounds according to claim 1, in which D is the carbocyclic radical C and R _{1 is} hydrogen or an alkyl group having 1 to 4 carbon atoms » 7. Optically active 16-Methy1-PGF ₁ "derivatives according to claim 4, characterized in that R ₁ and R" are hydrogen and R, methyl and ^r ^ ~ ^ indicates a linkage in ß-configuration. 8. Racemic 16-methyl-PGF .. "derivatives according to claim 4, characterized in that R ₁ and R _{2 are} hydrogen and R ~ methyl and ^ - indicates a linkage in ß-configuration. 9. Optically active 16,16-dimethyl-PGF _1ß derivatives according to claim 4> characterized in that R _{1 is} hydrogen and R ₂ and R, are methyl and ^ - ^ indicates a link in .ß-configuration. 10. Racemic 16,16-dimethyl-PGF .. "derivatives according to claim 4, characterized in that R _{1 is} hydrogen and R" and R are methyl and ^ - ^ indicates a linkage in ß-configuration. 11. Optically active 16-methyl-PGA .. derivatives according to claim 5, characterized in that R ₁ and R _{2 are} hydrogen and R-, methyl. 12. Racemic 16-methyl-PGA ..- derivatives according to claim 5 »characterized in that R ₁ and R _{2 are} hydrogen and R, methyl, 309843/1119 13. Optically active 16,16-dimethyl-PGA ₁ derivatives according to claim. '5, characterized in that R _{1 is} hydrogen and Rp and R are methyl, 14. Racemic 16,16-dimethyl-PGA ..- derivatives according to claim 5 » characterized in that JL hydrogen and Rp and R-, Mean methyl. 15. Optically active 16-methyl-PGB ..- derivatives according to claim 6, characterized in that R ₁ and Rp are hydrogen and R ~ is methyl. 16. Racemic 16-methyl-PGB ₁ derivatives according to claim 6, characterized in that R ₁ and Rp are Y / hydrogen and R- are methyl. 17. Optically active 16,16-dimethyl-PGB - derivatives according to claim. 6, characterized in that R _{1 is} hydrogen and R ₂ and R are methyl. 18. Racemic 16,16-dimethyl-PG-B ₁ derivatives according to claim 6, characterized in that R _{1 is} Y / hydrogen and Rg and methyl. 19. Process for the preparation of compounds of the formula "(CH ₂ ) ₆ -COOR., R ₀ IA in optically active form or as a racemate, where R ₁ and R are as defined in claim 1, characterized in that the optically active form or the racemate of a compound of the I formula 303843/1119 fro μη ' W in which R ₁ , R2 and R, likewise have the meaning given, with a carbonyl reducing agent which does not change the ester, acid or ethylene groups, and the resulting 9-ß-hydroxy isomer is isolated. 20th Process for the preparation of compounds of the formula ° _v \, (CH ₂ ) C-COOR ₁ R ₂ C- (CHa) ₃ -CH ₃ ^IB R ₃ in optically active form or in the form of the racemates, where R ₁ , Hp and R have the meaning given in claim 1, daduroh characterized in that one is a compound of the formula claim II according to 19 in optically active or racemic form with a neutral or acidic dehydrating agent. 21. Process for the preparation of compounds of the formula '(CH ₂ Je-COOR ₁ C- (CHs) ₃ -CH ₃ R ₃ in optically active or racemic form, where R ₁ , H «and R have the meaning given in Claim 1, 309843/1 1 19 characterized in that one is a compound of the formula II according to claim 19 in optically active or ra.oemisch.er form or a compound IB according to claim 20 in optically active or racemic form with a "basic dehydrating agent implements. For The Upjohn Company, Kalamazoo, Mich., V.St.A. Dr. H. J. Wolff Lawyer 309843/1119