FI62067B - ANALOGIFICATION OF THERAPEUTIC ACTIVITIES OF THERAPEUTIC ACTIVATED 15-METHYL PROCEDURES - Google Patents

Description

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Patent · och registerstyrelsan 'Anaakan utlagd och utl.ikriftan pubikarad 30.07.82 (32) (33) (31) Pyydetty «uotk ^ i —BajirtJ priorttat Ql +. 05.70

Ol4.O5.7O, ll4.O5.7O, ll4.O5.7O USA (US) 3I4518, 3I45I49, 37307, 37308 (Tl) The Upjohn Company, 301 Henrietta Street, Kalamazoo, Michigan 49001, USA (72) ) Gordon Leonard Bundy, Portage, Michigan, John Edward Pike, Kalamazoo, Michigan, William Paul Schneider, Kalamazoo, Michigan, USA (US) (Tl *) Berggren Oy Ab (bl *) Analogue method for the preparation of therapeutically active 15-methylprostaglandin compounds - The present invention relates to a process for the preparation of novel therapeutically active prostaglandin compounds of therapeutically active prostaglandin compounds. for the preparation of compounds having the formula

O

O. CH 2 -Y- (CHL) o -C-OH

y ^ / 2 2 3 (A? u) / X C = C - C - (CH ~). - CH.

'/ / \ 24 3

OH H CH3 0H

wherein Y is cis-CH = CH- or and wherein the OH group at the C-15 position has the α- or 3-configuration, with the exception of 15- (t-hydroxy-15-3-methyl-PGE 4). the following structural formula and numbering

^ C00H

2 62067

Numerous prostanoic acid derivatives are known. These are called prostaglandins. See, e.g., Bergström et al., Pharmacol. Rev.

20, 1 (1968), and references therein. Prostaglandin (PGE2) has the formula

H OH HO

Prostaglandin E2 (PGE2) has the formula:

0 ^ COOH

m

H0 / H OH

Prostaglandins are also known in which the ring oxo of prostaglandins E has been replaced by secondary alpha- or beta-hydroxy. These are called prostaglandins F. Prostaglandin F_ L · G.

(PGF-), for example, has the formula za H0 '' ^ ^

HO "H OH

Prostaglandin F "s (PGF" ") has the formula:

Ä P Δ P

H 2 ^ COOH

VI1

HO ^ "H 0H

The corresponding prostaglandins F1 and F of the compounds PGE1, PGE2 are also known.

In formulas II and III, the dashed bonds leaving the cyclopentane ring denote substituents in the alpha configuration, i. substituents below the level of the cyclopentane ring] a. The bonds marked with a thick solid line 3 62067 leaving the cyclopentane ring denote the substituents in the beta configuration, i. substituents above the level of the cyclopentane ring. Thus, in formulas II and III, the side chain hydroxy at the C-15 position is in the α-configuration. See Nature, 212, 38 (1966) for the stereochemistry of prostaglandins.

Each molecule of known prostaglandins has several centers of asymmetry and can exist in racemic (optically inactive) form as well as in each of the two enantiomeric (optically active) forms, i. in right and left rotating form. As shown, formulas II and III each represent an optically active form of prostaglandin obtained from certain mammalian tissues, e.g. sheep vesicles, porcine lung or human semen, or by reducing the carbonyl and / or double bond of the prostaglandin thus obtained. See, e.g., Bergström et al., Supra, for a mirror image of a compound of formula II or III showing the second enantiomer of this prostaglandin. The racemic form of prostaglandin would contain both enantiomeric molecules in equal amounts and one compound of formula II or III, and its mirror image would be needed to properly represent the corresponding racemic prostaglandin. Hereinafter, for simplicity, the terms PGE1 or PGE2 refer to the optically active form of the prostaglandin in question having the same absolute structure as the compound PGE2 derived from mammalian tissues. When referring to the racemic form of these prostaglandins, the word "racemic" is placed in front of the name of the prostaglandins, e.g. racemic PGE2 <The novel prostanoic acid derivatives of this invention may be represented by one of the following formulas or a combination of this formula and its mirror image:

Ω, CH - Y- (OHo)., - COOH

and H VIII

C = c - C - (CHO). - OH-, "/ / \ 2 4 3

HO'H CH3 0H

4 62067

Ov -CH, -y- (CH 2), - COOH

<χΐ? / c = C - C - (CH-) - - CH-.

// '' \ 24 3 HO H CH3 OH

In formulas VIII and IX, Y is cis-CH = CH- or -CH2CH2-. However, formula VIII does not include a compound in which Y represents a group -CH 2 -CH 2, i.e. a compound 15-α-hydroxy-15-β-methyl-PGE 2. Formula VIII has a hydroxy group at the 015 position in the α-configuration, as in known prostaglandins of formulas II and III. In Formula IX, the hydroxy at the C-15 position is in the non-natural 0 configuration. See J.Chem.Education, 41, 116 (1964) for α- and β-structures.

A significant feature of all known prostaglandins is the secondary hydroxy group at the C-15 position, i. atomic group · In prostaglandins derived from organ tissues

H '' OH

they always have this group. In contrast, the novel prostanoic acid derivatives of this invention have a tertiary hydroxy group at the C-15 position, i. atomic group -C- or the like

CH ^^ '' OH

p.-configuration -C-. These new prostanoic acid derivatives

CH3 OH

women can thus be conveniently referred to as 15-methylprostaglandins, e.g. 15-methyl-PGE2.

As in formulas II and III, formulas VIII and IX each represent optically active prostanoic acid derivatives having the same absolute configuration as the compound PGE 2 obtained from mammalian tissues. The novel prostanoic acid derivatives of formulas VIII and IX of this invention also include the corresponding racemic compounds. One of formulas VIII and IX and a mirror image of this formula are required in combination to represent the racemic compound. When the name of one of the novel prostanoic acid derivatives of the present invention is preceded by the word "racemic", below for the sake of simplicity is meant a racemic compound represented by a combination of a suitable formula VIII and IX and a mirror image of this formula. When the word "racemic" is not above the name of compound 5 62067, it is meant an optically active compound represented only by the appropriate formula VIII or IX and having the same absolute structure as the compound PGE 2 derived from mammalian tissues.

The compounds PGE1 and PGE2 very efficiently induce different biological reactions. Therefore, these compounds are useful for pharmacological purposes. See, e.g., Bergström et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. Some of these biological reactions are the antihypertensive effect of the arterial system as measured by PGE as measured, for example, in anesthetized (pentobarvital sodium) pentolinium-treated rats with anesthetized arterial and right half junction of the artery, pressure-increasing effect, smooth muscle stimulation, such as smooth muscle stimulation. , experiments with strips from the rumen of the rabbit or the colon of a rodent species (gerbil), strengthening effect of other smooth muscle stimulants, anti-fat breakdown effect shown by epinephrine-induced anti-fatty acid motility, inhibitory effect on abdominal secretion, as seen in dogs whose secretion is stimulated by food or histamine injection, effect on the central nervous system, blood, 62007 flake infectivity depletion due to platelet adhesion to glass, inhibition of platelet aggregation and thrombosis by various physical stimuli such as arterial injury and various biochemical stimuli such as ADP, ATP, serotonin, thrombin and collagen, and when used in the cultivation of fetal and rat skin fractions.

Due to these biological reactions, these known prostaglandins are useful in the study, prevention, control or alleviation of many diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets and zoos, as well as zoos. in rats, rabbits and monkeys.

The PGE compounds are particularly useful, e.g., in mammals, including humans, as agents for reducing nasal congestion.

For this purpose, these compounds are used in dosage amounts between about 10 μg and about 10 mg per ml of a pharmacologically acceptable liquid solvent or aerosol spray, both for topical use.

The PGE compounds can be administered to mammals, including humans, as well as certain useful animals, e.g., dogs and piglets, to control excessive gastric secretion to reduce or prevent gastric ulcer formation and to accelerate the healing of wounds already present in the gastrointestinal tract. For this purpose, the compounds are injected intravenously, subcutaneously or intramuscularly in an injection dose of between about 0.1 μg 3a to about 5-0 μg per kg body weight per minute, or by injection as a total daily dose of between about 0.1 and about 20 mg per kg of body weight per day, the exact dose depending on the age, weight and condition of the patient or animal and the frequency and mode of administration.

The PGE compounds are useful whenever it is desired to inhibit platelet aggregation, reduce the infectious nature of platelets, and eliminate or prevent the formation of blockages in mammals, including man, rabbits, and rats. These compounds are e.g.

7 6 2 O 6 7 useful in the treatment and prevention of myocardial infarction, in the treatment and prevention of post-operative obstruction, in the promotion of surgical vascular grafting and in the treatment of conditions such as hypertension and hypertensive causation is linked to lipid imbalance or blood obesity. For this purpose, these compounds are administered systemically, e.g. intravenously, subcutaneously, intramuscularly and for long-term action as sterile grafts. For rapid effect, especially in emergencies, intravenous administration is the most popular. Doses ranging from about 0.005 to 20 mg per kg of body weight per day are used, with the exact dose depending on the age, weight and condition of the patient or animal, and the frequency or route of administration.

PGEs are particularly useful additives for blood, blood products, blood substitutes and other fluids used in the extracorporeal circulation and for the perfusion of isolated parts of the body, e.g., limbs and organs, either attached to the original body, separated and stored, or ready for transplantation or attached. to a new body. In these cycles and flushing, the aggregated platelets tend to clog the blood vessels and parts of the circulating device. The presence of these compounds prevents such blockages. For this purpose, the compound is added gradually, in one or more doses, to the circulating blood, to the blood of the donating animal, to the perfused body part, attached or detached, to the recipient or to two or all of them in a uniform total dose of about 0.001 to 10 mg per liter of circulating fluid. It is particularly preferred to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes to develop new methods and procedures for organ and limb transplants.

PGEs are particularly potent smooth muscle stimulants and also greatly potentiate other known smooth muscle stimulants, e.g., progeny agents, e.g., oxytokines, and various ergot alkaloids, including derivatives and analogs thereof. Therefore, for example, PGEI is useful as a substitute for these known smooth muscle stimulants or for use in combination with lower amounts of these agents, e.g., to alleviate the symptoms of intestinal paralysis, to control or prevent flaccid uterine bleeding after abortion or childbirth, placental abruption and during childhood. For the latter purpose, PGE is administered by intravenous injection immediately after abortion or childbirth at a dose of between about 0.01 and about 50 per kg of body weight per minute until the desired effect is obtained. Subsequent doses are administered by intravenous, subcutaneous or intramuscular injection during infancy in amounts of 0.01 to 2 mg per kg of body weight per day, the exact dosage depending on the age, weight and condition of the patient or animal.

PGEs are useful antihypertensive agents for lowering blood pressure in mammals, including humans.

To this end, these compounds are administered intravenously by injection at a rate of about 0.01 to 50 μg of body weight per minute or in one or more doses of about 25 to 500 μg per kg of body weight in total per day.

PGEs are useful oxytokine substitutes for initiating labor in or near pregnant females, including humans, cows, sheep, and piglets, or in pregnant animals in which the fetus has died in utero approximately 20 weeks before the due date. For this purpose, the compound is injected intravenously at a dose of 0.01 to 50 μg per kg of body weight per minute during the second stage of labor, i.e. at or near the end of fetal ejection. These compounds are particularly useful when the female is one week or more weeks late and natural labor has not yet begun or 12 to 60 hours after membrane rupture and when natural labor has not yet begun. The PGE compounds are useful in regulating the reproductive cycle of ovum-producing female mammals, including humans, as well as animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For this purpose, for example, PGE2 is administered systemically, e.g., intravenously, subcutaneously, and intraperitoneally in doses ranging from 0.001 mg to about 20 mg per kg of female body weight, preferably at a time beginning approximately at the time of ovulation and ending approximately 9 months. 62067 at or just before that date. In addition, fetal protrusion is achieved by similar administration of the compound to the mammal during the first trimester of normal gestation.

As mentioned above, the compounds PGE are active agents against epinephrine-induced free fatty acid mobility. Therefore, this compound is useful in experimental medicine for both in vitro and living experiments in mammals, including humans, rabbits and rats, to increase understanding, prevent, alleviate symptoms and ameliorate diseases including abnormal lipid motility and high levels of free fatty acids. .diabetes, vascular diseases and hyperthyroidism.

The novel 15-methylprostaglandin analogs of formulas VIII and IX each elicit the same biological reactions as described above for the corresponding known prostaglandins. Thus, each of these known 15-methyl compounds is useful for the above-mentioned pharmacological purposes and is used for these purposes as described above. However, each of these 15-methyl and 15-ethyl prostaglandin analogs is surprisingly and unexpectedly much more useful than the corresponding known prostaglandin for at least one of the pharmacological purposes described above, as the analog is more potent for this purpose and has a substantially longer duration of activity. Therefore, fewer and lower doses of these prostaglandin analogs are needed to achieve the desired pharmacological results.

Pharmacological tests

The effect of the compounds prepared by the method of the invention as mammalian birth control agents and gastric acid secretion reducing agents was compared with the effects obtained with known similar compounds PGE 2 and 8-iso PGF 2α.

Test to determine the birth control effect Pregnant female golden hamsters were given a solution containing the test analog by subcutaneous injection. A solution of the analog 10 62067 was prepared by dissolving the compound in ethanol (0.05 ml of ethanol per mg of compound) and diluting this solution with physiological saline until 0.5 ml of the resulting solution contained the desired amount of compound. The solution was administered subcutaneously as a single injection of 0.5 ml to all eight pregnant female golden hamsters on the fourth day of gestation. On the eighth day, all eight animals were killed and their uteri removed and exposed. Possible attachment sites were considered in both uterine horns. In this method, 12-14 attachment sites are present in the control animals (excipient only) (James R. Weeks et al., Journal of Pharmacology and Experimental Therapeutics, Vol. 186, pages 67.74 (1973)).

Table

Compound Dose% (yug / animal) inhibition of PGE. 500 100 250 57 62 17

8-iso PGF1a 1000 O

15-methyl-PGE. 20 100

10 66 15-methyl-PGE2 6 100 11. Assay for Inhibitory Effect on Gastric Acid Secretion Used in Robert et al., American Journal of Digestive Diseases, New Series Vol. 12, no. 10, October 1967.

The test compounds were administered intravenously in a predetermined dose. The volume of gastric acid secreted per unit time was noted. The results are expressed as the percentage change in the volume of gastric acid secreted per unit time obtained after treatment with the compound compared to the secretion observed before administration of the compound.

The previously known compound PGE2 was required to achieve a 50% change of 20 ml / kg, whereas 15-methyl-PGE2 already gave 0.25 micrograms / kg at 90% change and 15-methyl-PGE2 at 1.0 micrograms / kg % change.

H 62067 It is clear from these results that the compounds prepared by the process of the invention are much more effective in inhibiting fertility and reducing gastric acid secretion than similar known compounds.

As described above, prostaglandin analogs are administered in various ways for various purposes, e.g., intravenously, intramuscularly, subcutaneously, orally, intrauterinely, rectally, buccally, sublingually, topically, and as sterile grafts for sustained action.

For intravenous injection, sterile aqueous solutions of the same voltage are preferred. Therefore, due to the increased water solubility, the use of the free acid form or a pharmacologically acceptable salt form is preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt or ester form in aqueous or non-aqueous media are used in the form of tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions with conventional pharmaceutical carriers. For rectal or uterine administration, suppositories, tampons, ring devices, and preparations intended to provide sprays or foams, or for rinsing, all prepared in a manner known per se, are used. For tissue grafts, a sterile tablet, silicone capsule or the like containing or impregnated with a substance is used.

The novel PGE-type acids of formula VIII and IX are prepared by oxidizing the corresponding PGF-type or PGF-type acids. For this purpose, an oxidizing agent is used which selectively oxidizes secondary hydroxy groups to carbonyl groups in the presence of a carbon-carbon double bond. These reactions are shown in Table A, where formulas X and XI comprise optically active compounds as shown, and racemic compounds of these formulas, as well as mirror images thereof, as well as the 15-epimers of both, i. wherein the configuration at the C-15 position is β rather than a, as shown. Similarly, in Table A, Y is cis-CH = CH or -Cl 2 Cl · ^ - and ~ represents the bond of the hydroxy group to the ring in the alpha or beta configuration.

In the reactions of Table A, the beta isomers of the reactant of formula X are the preferred starting materials, although the corresponding alpha isomers are also useful for this purpose.

Oxidizing agents useful for the reactions shown in Table A are known in the art. A particularly preferred reactant for this purpose is Jones reagent, i. oxidized chromic acid. See J.Chem.Soc. 39 (1946). Acetone is a suitable diluent for this purpose and the oxidizing agent is used in such an amount that it slightly exceeds the amount required to oxidize one of the secondary hydroxy groups in the reactant of formula X. Reaction temperatures of up to about 0 ° C must be used. Reaction temperatures are preferably between -10 and -50 ° C. Oxidation occurs rapidly and the conversion is usually complete in about 5-80 minutes. The excess oxidizing agent is destroyed, e.g., by the addition of a lower alkanol, preferably isopropyl alcohol, and the PGE-type product of formula XI is separated by conventional methods.

Table A

O

HO · *

CH, Y- (CH 2) -, - C-OH

ti »'c = C - C - (CH-) .CH-, I S \ 2 4 3

HO H CH3 OH

(Oxidation) Ψ

O

O 2, CH-Y- (CH 2), - C-OH

v-i f / C = C - c - (CH,), CH, / j ^ v 2. 4 «3

HO H CH3 OH

Examples of other oxidizing amines useful in the reaction of Table A include silver carbonate on Celite (Chem. Conn. 1102 13 62 0 6 7 (1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters 3363 (1968), J.Am.Chem.Soc. 75, 422 (1953)), mixtures of sulfur trioxide and dimethyl isoxide in pyridine (J. Am. Chem. Soc. 89, 5505 (1967)) and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87, 5661 (1965)).

PGFβ-type and PGFβ-type acids are prepared by the series of reactions shown in Table B, wherein formulas XII-XIV comprise the optically active compounds shown, as well as racemic compounds thereof and mirror images thereof. Similarly, in Table B, Y is cis-CH = CH- or -CH2CH2- and ~ represents the bond of the hydroxy group to the ring in the alpha or beta configuration.

Table B

(CH3) 3 "S1" O-, CH2-Y- (CH2) 3-C-OH

\ X 7 / C = C-C- (CH _) .CH ~ / I li 2 4 3

(CH3) 3-Si-O H O

CH ^ MgX '

V

(hydrolysis)

V

HO °

V xCH2-Y- (CH2) 3-C-OH

/! H XIII

? = c -yc- (ch2) 4ch3 ho 'H CH3 oh + HO °

-CH- -Y- (CH ") -, - C-OH

a t / Nf = c (CH2) 4CH3

HO H C [i3 ° H

The silyl compounds of the formula XII are prepared by the method according to Finnish patent application 1227/71.

14 62067

With further reference to Table B, a silyl compound of formula XII is reacted to give final products of formulas XIII + XIV by first reacting a silyl compound with a Grignard reagent of formula CH 2 MgX 'wherein X' is chlorine, bromine or iodine. For this purpose, X 'is preferably bromine. The reaction is carried out in a Grignard reaction by conventional methods using diethyl ether as the reaction solvent and a saturated aqueous solution of ammonium chloride to hydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove silyl groups. In this case, a mixture of water with a sufficient amount of a water-soluble solvent, e.g. ethanol, is preferably used to obtain a homogeneous reaction mixture. The hydrolysis is usually complete within 2-6 hours at 25 ° C and is preferably carried out in an inert gas atmosphere, e.g. nitrogen or argon.

The mixture of 15-α and 15-3 isomers obtained by the Grignard reaction and hydrolysis is separated by methods known per se to separate prostanoic acid derivatives from the mixtures, e.g. by chromatography on neutral silica gel.

The invention is described in more detail below by means of examples.

The infrared absorption spectrum is measured with a Perkin-Elmer Model 421 infrared spectrophotometer. Undiluted samples of liquids and oils are used. Solid mineral-oil (nujoi) grinds are used.

NMR spectra were measured on a Varian A-60 spectrophotometer with tetramethylsilane as the internal constant (downfield) and using the solvents described below.

Mass spectra were measured on an Atlas CH-4 mass spectrometer with a TO-4 source (ionization voltage 70 Ev.).

The phrase ".15-oxo-" in front of the name of the compound, e.g. 15-oxo-PGF, (

^ S

Means a prostaglandin analog in which the group -C- is

H '' OH

At the 15-position reacted to the group -C-.

Il

O

is 62067

Preparation 1 15-methyl-PGFβ and 15-α-methyl-15β-β-PGF.

A 3-molar solution of methylmagnesium bromide in diethyl ether (0.67 ml) is added dropwise to a stirred solution of the 15-oxo-PGF. C. The mixture is stirred for 30 min at 25 [deg.] C., after which a further 0.3 ml of methylmagnesium bromide solution are added and stirring is continued for a further 15 min. The resulting reaction mixture is poured into a mixture of ice and 75 ml of saturated aqueous ammonium chloride solution. After stirring for several minutes, the mixture is extracted several times with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Evaporation of diethyl ether under reduced pressure gives a colorless viscous oil which is dissolved in 30 ml of ethanol. This solution is diluted with 20 ml of water and the mixture is stirred for 3 hours at 25 ° C. The ethanol in the resulting solution is evaporated under reduced pressure and the aqueous residue is diluted with an equal volume of saturated aqueous sodium chloride solution and extracted several times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 700 mg of a crystalline mixture of 15-methyl-PGFβ and 15-α-methyl-15-8-OH-PGF 4. Recrystallization of this mixture 3 times from ethyl acetate containing very small amounts of methanol gives 15-methyl-PGF-β, m.p. 164-164.5 ° C, infrared absorption 3250, 3160, 2700, 1710, 1330, 1315, 1305, 1085, 1035 and 970 cm -1; NMR peaks (dimethylformamide) at 5.53 (double line), 5.10-3.6 (multiple line) and 1.20 (single line) δ, mass spectrum molecular ion peaks at 370, 352 and 334.

15-α-methyl-15-8-OH-PGF.0 is obtained from the mother liquors of the recrystallization described above.

Preparation 2 15-methyl-PGF-. and 15-α-methyl-15 - & - OH-PGF_ ____ £ _P ____ ^ p

A 3-molar solution of methylmagnesium bromide in diethyl ether (8 ml) is added dropwise to a stirred solution of 15-oxo-PGFO-p 16 62 06 7 1.9,11-tris- (trimethylsilyl) derivative (5.1 g) in 25 ml. diethyl ether at 25 ° C. The mixture is stirred for 60 minutes at 25 ° C, after which the product is hydrolysed with water for 4 hours at 25 ° C to give 15-methyl-PGF-β and 15-μ-methyl-15-i -: - OH-PGF 2 ( (4.37 g) in the form of a dark oil Crystallization of this oil from a mixture of methanol and ethyl acetate and recrystallization of the obtained crystals from a mixture of the same solvents gives 15-methyl-PGF2g, mp 134-134.5 ° C, infrared absorption 3250 , 3180, 2720, 1710, 1345, 1305, 1235, 1085, 1050, 970 and 920 cm NMR peaks (dimethyl sulfoxide) at 5.46 (double dashed line), 5.0-4.0 and 3.8 (multiple dashed line) -va) 6, molecular ion peaks at 368, 350, 332, 314, 297, 278 and 205 in the mass spectrum.

.1 5-α-methyl-15-3-OH-PGF. 15-methyl-PGF is obtained.

Zli Zp from mother liquors of crystallization and recrystallization.

Example 1 .15-me is 1i-PGE2

A solution of 15-methyl-PGF.0 (95 mg) in 40 ml of acetone o - * · p is cooled to -10 ° C, Jones reagent (0.1 ml of a solution of 21 g of chromic anhydride, 60 ml water and 17 ml of concentrated sulfuric acid) pre-cooled to 0 ° C are added with vigorous stirring. After 5 minutes at -10 ° C, thin layer chromatography on silica gel (acetic acid: methanol: chloroform, 5: 5: 90) with a small portion of the reaction mixture shows that the reaction rate is about 50. An additional 0.06 mL of Jones reagent is added to the still cold reaction mixture with stirring and the mixture is stirred for a further 5 min at -10 ° C. Isopropyl alcohol (1 mL) is added to the cold reaction mixture. After 5 minutes, the mixture is filtered through a pad of dibasic silica (Celite). The filtrate is evaporated under reduced pressure and the residue is taken up in 5 ml of saturated aqueous sodium chloride solution. The mixture is repeatedly extracted with ethyl acetate, and the combined extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 20 g of neutral silica gel, eluting with 50% ethyl acetate in Sktillysolve B. Evaporation of the eluates gives 29 mg of 15-methyl-PGE 3, mass spectrum with molecular ion peaks at 350, 332, 317 and 261.

17 62067

Example 2 15-methyl-PGE2

A solution of 15-methyl-PGF_D (300 mg) in 100 ml of acetone

o ^ P

cooled to -35 ° C. Jones reagent (0.2 mL) is added with vigorous stirring and stirring is continued for 15 min. At this point, thin layer chromatography on silica gel (acetic acid: methanol: chloroform, 5: 5: 90) with a small portion of the reaction mixture shows that the reaction rate is about 75%. An additional 0.1 mL of Jones reagent is added to the reaction mixture and stirred. Stirring is continued at -35 ° C for a total reaction time of 45 min. Isopropyl alcohol (1 mL) is added to the cold reaction mixture, which is then allowed to warm to 0 ° C and filtered through Celite. The filtrate is evaporated under reduced pressure and the residue is dissolved in dichloromethane. This solution was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Each 50 mg residue is chromatographed on a thin layer plate (20 x 20 cm, 1000 μm thick layer of neutral silica gel), developing twice with solvent system A-IX. The silica gel regions containing the desired product, as seen in small scale thin layer chromatography, are removed from each plate, pooled, placed on top of a neutral silica gel column, and eluted through the column with 10% methanol in ethyl acetate. Evaporation of the eluate gives 15-methyl-PGE9, infrared absorption 3400, 2650, 1725, 1600, 1460, Δ -1 1380, 1280, 1250, 1150, 1125 and 1075 cm-1; in the mass spectrum, Mole alkyl ion peaks at 366, 348, 330, and 259.

Claims (1)

18 ¢. O Γ · / '· 7 vj Ζ. Analogous procedure for the preparation of new therapeutically active prostaglandin compounds or optical isomers and racemic mixtures thereof of the formula OO CH? -Y- (CHO) -jC-OH \ / 2 23 / "t (I), y C = C - C - (CH2) - CH0 / / / \ 2 4 3 OH H CH3 OH where Y is cis-CH = CH- or the OH group in the C-15 position at 3a has a- or The B-configuration, with the exception of 15 - (-) - hydroxy-15-3-methyl-PGE4, characterized in that the optically active compound of the general formula O (ch3) 3-si-o, ch2-y- (ch2) 3-co-si (ch3) 3 / (xii) VL.? / = C - C - (CH) - CH (0Η3) 3-51-0 f / 3 where Y is the same as above and where ~ is (CH3) ) In the α- or 3-configuration of the Si-O group attached to the ring, is reacted with a compound of the general formula CH3MgX 'wherein X' is chlorine, bromine or iodine, after which the reaction product is hydrolyzed in a manner known per se to remove silyl groups and the resulting PGF- t The PGF 8 compound is reacted with a reagent that selectively acidifies the secondary hydroxyl of said PGF compound to the carbonyl at the 9-position in the presence of carbon-carbon double deboxes.