DE2355540C2 - 16-phenoxy-ω-tetranorprostaglandin derivatives - Google Patents

Description

ο γ \ τΪργ 4

X.

or

OH

10

15th

20th

and X denotes the p-phenylphenoxycarbonyl group or a group -CONHR, in which R is the acetyl, benzoyl or methylsulfonyl group means their cis epimers, lower alkanoic acid and benzoic acid esters and Cn and cis tetrahydropyranyl ethers.

2.16-Phenoxy-ω-tetranor-PGE2-p-biphenylesteΓ.

3.16 Phenoxy-cü-tetranor-PGF ^ -p-biphenyl ester.

4. Ib-phenoxy-tü-tetranor-PGFy-p-biphenyl ester.

5. N-methylsulfonyl-16-phenoxy- <a-tetranor-PGEramide.

35

The invention relates to the 16-phenoxy-a) -tetranorprostaglandin derivatives described in the claims, the analogs of naturally occurring prostaglandins or derivatives of ω-tetranorprostaglandins represent.

The prostaglandins are unsaturated fatty acids with 20 carbon atoms that have various physiological effects demonstrate. For example, the prostaglandins of the E and Α series are effective vasodilators [cf. Acta Physiol. Scand., Vol. 64; Pp. 332-333 (1965) and Life Sei, Vol. 6; Pp. 449-455 (1967)] and set the systemic arterial blood pressure decreased after intravenous administration (vasodepressant effect) [Federation Proc, Vol. 23; P. 327 (1964); Acta Physiol. Scand. Vol. 64, pp. 332 ff. (1965); Acta Med. Scand., Vol. 183, pp. 423-430 (1968) and Acta Physiol. Scand., Vol. 75, pp. 161-169 (1969)]. Another known physiological effect from PGEi and PGE? is the one used as a bronchodilator [Brit. Med. J., Vol. 4 pp. 723-726 (1969)].

The natural prostaglandins play another important physiological role in connection with the reproductive cycle. PGE2 is known to induce labor [cf. J. Obstet Gynaec. Brit. Cwlth., Vol. 77, pp. 200-210 (1970) and Contraception, Vol, 4, p. 293 (1971)] and is useful for fertility control [Contraception, Vol. 3, S, 173 (1971)], The use of various prostaglandins of the E * and F 'series as agents for inducing labor in mammals is described in BE-PS 7 54 158 and DE-PS 2034 641, while the use of PGFi, PGF ₂ and PGF ₃ as agents for controlling the reproduction cycle is described in ZA-PS 69/6089.

Other known physiological activities of PGEi are the inhibition of gastric acid secretion (Shaw and Ramwell, in "Worcester Symp. On Prostaglandins," New York, Wiley, 1968, pp. 55-64) and also the inhibition of platelet aggregation [Brit Med. J, Vol. 2, pp. 468-472 (1967)].

However, it is known that such physiological effects are only for a short period of time after Administration of a prostaglandin in vivo spawned The reason for this rapid decline in the Effectiveness can be seen in the fact that natural prostaglandins quickly and effectively through the metabolism, namely by /? - oxidation of the carboxylic acid side chain and by oxidation of the 15oc-HydroxyI group are deactivated [cf. Acta Physiol. Scand, Vol. 81, p. 396 (1971) and the Literatu ·] cited there.

The invention is based on the object of creating analogs of prostaglandins which are physiological Have activities that are equivalent to those of the natural compounds, their selectivity the effect and its duration of action are increased, with the increased selectivity of action Serious side effects, especially gastrointestinal side effects that often occur after the systemic administration of natural prostaglandins have been observed (cf. Lancet, 536, 1971), should be reduced.

According to the invention, this object is achieved by 16-phenoxy-cü-tetranorprostaglandin derivatives the general formula

wherein M is the oxo group or one of the groups

OH

ζ or ζ
OH H

and X represents the p-phenylphenoxycarbonyl group or a group -CONHR, in which R is the acetyl, benzoyl or methylsulfonyl group, their cis-epimers, lower alkanoic acid and benzoic acid esters and Cn- and cis-tetrahydropyranyl ethers solved.

The invention particularly includes compounds of the general formulas

OH

HO

dB)

10

wherein X has the above meaning, their Ci5-epimers, lower alkanoic acid and benzoic acid esters and Cu and Cis tetrahydropyranyl ethers.

Preferred compounds are the 16-phenoxy-a) -tetranor-PGE ₂ -p-biphenyl ester, 16-phenoxy-to-tetranor-PGFax-p-biphenyl ester, 16-phenoxy- £ ü-tetranor-PGF ₂ (! - p- biphenyl ester and the N-methylsulfonyl-16-phenoxycu-tetranor-PGE ₂ -amide.

The starting materials for the various new compounds are or can be commercially available be produced by known methods. For example, to produce dimethyl 2-oxo-3-phenoxypropylphosphonate, the starting material for the synthesis of 16-phenoxy-prostaglandins, a solution of dimethyl methyl phosphonate in tetrahydrofuran under a nitrogen atmosphere - 78 ° C, and then slowly add n-butyllithium drop by drop in hexane too. After stirring, methyl 2-phenoxyacetate is added dropwise. After 3 to 4 Hours at -78 ° C, the reaction mixture is warmed to ambient temperatures with acetic acid neutralized and concentrated in a rotary evaporator to a white gel. The gelatinous material is in Water taken up, the aqueous phase is extracted with chloroform and the combined organic Extracts are washed again, dried and concentrated, the desired product being obtained will.

The following scheme A gives an overview of the synthetic route:

Scheme A

OO OCH ₃

Il t /

C ₆ Hj-O-CH ₂ COOCH ₃ > C ₄ H ₅ -O-CH ₂ -C-CH ₂ -P

1 2 OCH ₃

OXO V-C-0

Ο - C ₆ H ₅

As can be seen from scheme A, there is the 1st stage (1 - »- 2) in the condensation of the corresponding ester with a dialkyl methylphosphonate, the ketophosphonate 2 is obtained. These esters are obtained as previously described.

In the 2- »· 3 stage, the ketophosphonate is 2 with the well-known [J. At the. Chem. Soa, Vol. 93, p. 1491 (1971)] Aldehyde H reacted, the enone 3 being obtained after chromatography or crystallization.

The enone 3 can be treated with zinc borohydride or trialkyl borohydrides, such as B. Lithium triethylborohydride, be reduced to a mixture of alcohols 4 and 5, which can be separated by column chromatography. This reaction will usually be Ether, such as B. tetrahydrofuran or 1,2-dimethoxyethane, is used, although methanol is sometimes preferred in order to give a specificity of the reduction guarantee. Broad transformations of compound 4 are shown in Scheme B:

Reaction stage 4 - »- 6 is a base catalyzed one Transesterification, with the p-biphenyl-carbonyl protecting group Will get removed. This is most conveniently done with potassium carbonate in methanol or methanol-tetrahydrofuran carried out as a solvent. Stage 6- »· 7 protects the two free hydroxyl groups with an acid-labile protecting group with it. Any sufficiently acid labile group is satisfactory; however, the most common protecting group is a tetrahydropyranyl group found in the molecule introduced by treating with dihydropyran and an acidic catalyst in an anhydrous medium can be. The catalyst is usually p-toluenesulfonic acid.

Scheme B

HO

\. Ο -C ₆ H ₅ H OH

THPO

THPO

\ Ο -C ₆ H ₅ H OTHP

THPO

HO

\ O — C _e H ₅ H OTHP

THPO

OH

OH

^ 0-C ₄ H ₅ H OTHP

HO

\ 0-C ₆ H ₅ H OTHP

N 0-C ₆ H ₅ H OH

11th

The stage 7 - »■ 8 is a reduction of the lactone 7 to the malbacetal 8 using diisobutylaluminum hydride in an inert solvent. There are lower reaction temperatures, generally a temperature of preferably -60 ° to -70 ⁰ C. ₁ However, higher temperatures can also be used if over-reduction does not take place. The compound 8 is if desired by column chromium? v »; graphics cleaned

Difc reaction stage 8- «· 9 is a Wittig condensate tion, the hemiacetal 8 with (4-carbohydroxy-n-butyl ^ triphenylphosphonium bromide reacted in pimethyl sulfoxide in the presence of sodium methyl sulfinyl methide will. Compound 9 is purified as described above.

The transformation 9 - »- 12 is an acid hydrolysis of the Tetrahydropyranyl groups. Any acid can be used

10

15 , which in the course of the removal of the protective group does not cause any degradation of the molecule; however, a 65% strength aqueous acetic acid is mostly used. The product is cleaned as described above

The stage 9- + 10 is an oxidation of the secondary Alcohol 9 to the ketone Id This can be brought about by adding any oxidizing agent that has the Does not attack double bonds, used; however, Jones reagent is usually preferred Product is cleaned as outlined above.

The stage 10 - »· 11 becomes in the same way as the stage 9 - * - 12 carried out. The product will be as above shown cleaned.

For the preparation of prostaglandin derivatives 11 'and 12', the compound 4 in scheme B by the Compound 5 from Scheme A can be replaced:

Scheme C

HO

\ 0-C ₆ H ₅ HO H

12 '

HO

HO H

11 '

The substituents X are converted into the compounds according to the invention by reacting them with suitable ones Esterification and amidation reagents introduced

If necessary, these compounds are reacted with the appropriate acylating agents converted into the 9a, 11 "and 15" -lower alkanoyl and benzoyl esters.

One modification of the upper side chain that can be made on the new prostaglandins is the substitution of the carboxylate residue in the Ci position by a carboxyamide residue. The methods for making these compounds are described in US-PA 2 60 518. The new tetrahydropyranyl ethers of the compounds of formula I wherein X is a CONHR group, where R is as defined above, can be selected from the compounds 9 and 10 of the Scheme B (or the corresponding 15-epimers of 9 and 10) by reaction with corresponding ones Isocyanates and subsequent hydrolysis with dilute acid can be produced.

Particularly advantageous esters are the p-biphenyl esters. Such esters are, as shown in the examples below, by simply adding p-phenylphenol to the prostaglandin in methylene chloride in the presence of a dehydrating agent, e.g. B. of dicyclohexylcarbodiimide, and stirred overnight

In the procedures described above, when purification by chromatography is desired suitable chromatographic supports including neutral alumina and silica gel used, silica gel with a mesh size of 0.248 to 0.074 mm is generally preferred. the Chromatography is expediently in a reaction-inert solvent, such as. B. ether, ethyl acetate Benzene, chloroform, methylene chloride, cyclohexane or η-hexane carried out as follows in the Examples is explained.

The above formulas describe optically active compounds. It is obvious, however, that the corresponding racemates thanks to their content of the aforementioned biologically active optical isomers Have valuable biological activity, and it should be noted that such racemates also encompassed and claimed by the preceding formulas. The racemic mixtures are made according to the same methods as those used for the synthesis of the optically active species, easily prepared by using appropriate racemic precursors instead of optically active starting materials be used.

Numerous tests in vivo and in vitro have shown that the new prostaglandin analogues Have physiological activities which are comparable to those of natural prostaglandins. These tests included a test for an isolated smooth muscle effect Guinea Pig Uterus, Guinea Pig Ieums

and rat uterus, a test for inhibition of histamine-induced brochospasm in guinea pigs, as well as tests regarding the effect on the blood pressure of dogs, the inhibition of a stress-induced Ulceration in the Rat, Inhibition of Gastric Acid and Pepsin Secretion in the Rat and in dogs, the inhibition of collagen- or ADP-induced platelet aggregation and the abortionist efficacy in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

The physiological effects observed in these tests were valuable in determining the Utility of the test substance for the treatment of various natural and pathological conditions. Such specific uses include: antihypertensive efficacy as a bronchodilator, antithrombogenic activity, antiulcerogenic activity, smooth muscle activity [useful as an anti-fertility drug, for inducing labor, and as an abortion agent Medium] as well as an anti-fertility effect based on a mechanism that the smooth muscles do not influenced, e.g. B. according to a luteolytic mechanism, and also the timing of the oestrus cycle in breeding animals.

The new compounds have more selective action profiles than the corresponding naturally occurring ones Prostaglandins and they show a longer duration of action in many cases.

The changes to the upper side chain of the new prostaglandins usually change the The basic biological effectiveness of the prostaglandin does not, however, increase the selectivity and duration of action and reduce toxicity.

_{The 16-phenoxy-o) -tetranorprostaglandins of the E 2} , F ₂₁₁ and F20 series are particularly useful for controlling fertility, for abortion and for inducing labor, due to their excellent smooth muscle stimulation effect and, at the same time, reduced effects on blood pressure.

The new prostaglandins with a jS-OH group in 15 divisions tend to be less effective, though they are often more selective than the corresponding -hydroxyl epimers are. Furthermore, the prostaglandins, which have a / ^ - hydroxyl group in the cis position, valuable intermediates for prostaglandins with a -hydroxyl group in the cis position by subjects them to a cycle process that involves oxidation and reduction at the carbon atom in 15 position includes.

In order to show the deliberation of the selective effectiveness of the compounds according to the invention, subjected them to the following test methods:

(A) Determination of the späsmogenic effect in vitro on the guinea pig uterus - a test on the Anti-fertility and abortion effects;

(B) Determination of the effect on blood pressure of anesthetized dogs - a test on a Side effect that can sometimes be seen with prostaglandin;

(C) Assessment of the in vivo effect of diarrhea in mice - a test for a side effect that usually beubachiei in Frostagiandiiien will;

(D) Determination of the in vivo abortion-causing effect in rats - a test for the anti-fertility and abortion effect in vivc due to a non-smooth muscle mechanism (i.e., luteolytic activity).

In test (D), PGF ₂ years proves to be more effective than PGE ₂ ; Because of the luteolytic mechanism, compounds which have been shown to be effective in this test are suitable as abortion-inducing agents and anti-fertility agents and as agents for timing the rut in domestic animals such as horses and cattle.

As can be seen from Table 1 below, the compounds tested are 10 to 1000 times more effective in this regard than PGF ₂ * (serial no. 1, comparison). In addition, compound no. 5 according to the invention shows a 10-fold lower (undesirable) antihypertensive side effect than PGF _2a , while compounds no. 2 and 3 according to the invention have a significant effect

more favorable therapeutic index
exhibit.

- ± - as
MD

PGF ₂₁₁

Tabefle 1

Serial link

test

A ⁰ ) B *)

Structural formula

1 PGF ₂ , (comparison)

2 16-phenoxy - <»- tetranor-PGF ₂ " -p-biphenyl ester

3 16-Phenoxy-6) -tetranor-PGE ₂ -p-biphenyl ester

4 N-methylsulfonyl-16-phenoxy-w-tetranor-PGF _2o -carboxamide

oil

100 1.0 6.5 100 15

oil

QH

CO ₂ H

OH

101-103 ° 150 1.0 1 400 100 000 71 QH

OH

100-101 ° 100 0.4 55 100 000 1 818

CO ₂ - <O> XO

HO "= O ^ C O

OH

100 1.0 200 1000 5

CONHSO ₂ CH ₃
O

OH

15th

O cn

Cl Cl

O Cl

I. r ~

s _ά 's

ΐ iff «ι

sä «! i s δ i §

c 5 ^Ν ° S =

si 5?]

read

Sl

-S

«G

O <

. U ο 4> C3

• g> yes a · ° s

. -ο · α

yes XJ

^: Xl

j <"ä i2 ^ ^?

■ 8 «111 ^ S 5 ^ 3

IO

20th

25th

30th

The above test methods (A) to (C) and the following test methods were added to the tests carried out further Method (D) used:

(D) Determination of the abortion-inducing effect in vivo with guinea pigs - a test on the Anti-fertility and abortion effects due to a smooth muscle mechanism (i.e., uterine stimulation).

The results contained in the following Table 2 clearly show that the tested according to the invention Compound (No. 2) as an abortifacient and anti-fertility agent more effective and selective than is the comparative compounds (Nos. 1 and 3)

It is also noteworthy that the tested compound according to the invention has a blood pressure lowering side effect 200 times or 20 times lower than PGE ₂ or the comparison compound known from DE-OS 22 23 365.

While the compound according to the invention has a diarrhea effect of the order of magnitude comparable to that of the comparison compounds (which is the most common side effect occurring when prostaglandins are administered to humans), it has a 30-fold increase (compared to PGE2) or (compared to the compound according to DE-OS 22 23 365) 10 times greater abortion-inducing effect a therapeutic index - 36 times greater than that for PGE2 or 18 times greater than that for
22 23 365 is.

the connection according to the DE-OS

230 246/140

Table 2

LXd. link

F. ( ⁰ C)

test

A ") B * ¹ )

Ό ¹ ) structural formula

1 PGE ₂ (comparison)

65-66 °

100 0.1 100

CO ₂ H

OH

2 N-MethylsiaIfonyl-16-phenoxy-ö> -tctranor-PGEj-amidl

81-82 °

110 20 83 3 000

CONHSO ₂ CH ₃

3 16-Phenoxy-ia-tetranor-PGE ₂ (comparison) *)

89-91 °

75

1.0

150

300

") i Relative effectiveness (PGE ₂ ZPGF ₂₁ , = 100) with regard to the spasmogenic effect on the isolated guinea pig uterus.

*) Threshold value (jig / kg; iv.) With regard to the antihypertensive effect in dogs.

*) Relative effectiveness (PGE ₂ = 100) with regard to the induction of diarrhea in mice.

*) Relative effectiveness (PGE ₂ = 100) with regard to the effect causing the abortion in guinea pigs.

*) Ratio in vivo of the effect causing the abortion to the effect of diarrhea.

*) see DE-OS 22 23 365.

iwg ^ iWlWjSB ^

The new compounds can be used in a wide variety of pharmaceutical formulations and they can be in a wide variety of ways in the same way as natural prostaglandins Because of, e.g. B. be administered by intravenous, oral, intravaginal, intra- and extra-amniotic routes.

To initiate an abortion, the inventive Compounds in the form of tablets or aqueous suspensions or alcoholic solutions, expediently at oral doses of 0.1 to 20 mg, to be administered, with 1 to 7 doses per day can be applied. Lactose tablets are a suitable form of application for intravaginal administration or a tampon impregnated with this agent suitable for these treatments Doses are 0.1 to 20 mg / dose, with 1 to 7 doses being used. A suitable formulation for intra-amniotic administration is an aqueous solution which contains 0.05 to 10 mg / dose, using 1 to 7 doses. A suitable formulation for extraamniotic administration is an aqueous solution containing 0.005 to 1 mg / dose, using 1 to 5 doses. the new 16-phenoxy-cü-tetranorprostaglandins can but also to initiate an abortion at doses of 0.05 to 50 μg / min. during a period of about To be given as an intravenous infusion for 1 to 24 hours. For the timing of the The oestrus cycle of pigs, sheep, cows or horses is a solution or suspension that is 0.03 to 30 mg / day of a 16-phenoxy-cö-tetranorprostaglai.dins according to the invention contains, administered subcutaneously for 1 to 4 days

For the preparation of the aforementioned dosage forms or the numerous other possible ones Various inert diluents, excipients, or carriers can be used will. Such substances are z. E.g .: water, ethanol, gelatins, lactose, starches, magnesium stearate, Talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycols, petrolatum, cholestrin and others known carriers for drugs. These pharmaceutical compositions can optionally Auxiliaries, such as. B. preservatives, humectants, stabilizers or other therapeutic agents Means such as B. antibiotics contain.

The following examples serve to further illustrate the invention. In these examples, all temperatures are given in ⁰ C, all melting and boiling points uncorrected.

example 1

p-Biphenyl-9-oxo-11 <%, 15 <% - dihydroxy-16-phenoxycis-5-trans-13-co-tetranor-prostadienoate

55

A. 5.4 g of dimethyl 2-oxo-3-phenoxypropylphosphonate (21 mmol) in 200 ml of anhydrous ether were with 7.9 ml (19 mmol) of a 2.5 molar solution of n-butyllithium in η-hexane (Alfa Inorganics, Inc.) under a dryer. Nitrogen atmosphere at room temperature treated. After stirring for 5 minutes, a further 400 ml anhydrous ether and then 6.0 g (17 mmol) J-pa ^ p-Phenylbenzoyloxy-SiX-hydröxy ^^ -formylcyclopentan-la-yr ^ acetic acid-y-lactone at once and 50 ml of anhydrous ether was added, after 35 minutes the reaction mixture is mixed with 5 ml of glacial acetic acid and 4 times with 100 ml of saturated sodium carbonate solution each time, 2 times with 100 ml water, once with 10 ml more saturated Washed brine, dried over magnesium sulfate and evaporated, giving 5.2 g of 2-pÄ-p-PhenyIbenzoyloxy-5oc-hydroxy-2 /? - (3-oxo-4-phenoxy-transl-buten-1-ylj-cyclopent-la -yij-acetic acid-y-lactone as a solid after column chromatography (Baker silica gel with a clear mesh size of 0.248 to 0.074 mm) were obtained, which after crystallization from a Mixture of methylene chloride and hexane had a melting point of 112-114 ° C.

B. A solution of 5.1 g (10.5 mmol) 2- [3 "-p-phenylbenzoyloxy-5" -hydroxy-2j9- (3-oxo-4-phenoxy-trans-1- butene-l-yO-cyclopent-la-yl-acetic acid-y-lactone in 30 ml dry 1,2-dimethoxyethane was under a dry nitrogen atmosphere at ambient temperature dropwise with 11 ml (5.5 mmol) of a 0.5 molar Tin borohydride solution was added. After stirring at room temperature for 2 hours, the mixture was added dropwise a saturated sodium bitartrate solution was added until the evolution of hydrogen ceased. That The reaction mixture was stirred for 5 minutes, after which 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (Water aspirator) the semi-solid obtained was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0J248 to 0.074 mm) using ether Purified as eluent after Elut'on of less polar impurities, a fraction containing 896 mg of 2- [3 «-p-phenylbenzoyloxy-5« -hydroxy-2j? - (3ochydroxy-4-phenoxy-trans-1 -butene-1-yl-cyclopent-1 ayl] -acetic acid-y-lac * on contained, a fraction of 600 mg of the mixed compounds 4 and 5 and finally a fraction of 1.5 g of 2- [3 «-p-phenyl-

benzoyloxy-5'-hydroxy-2j3- (3j3-hydroxy-4-phenoxytrans-1 -buten-ylj-cyclopent-1 «-yl] -acetic acid-γ-lactone obtain.

C. A heterogeneous mixture of 846 mg (1.7 mmol) 2- [3 "-p-phenylbenzoyloxy-5" -hydroxy-2 / J- (3 "-hydroxy-4-phenoxy-trans-1-butene-1 -yl) -cyclopent-1 «-yl] -acetic acid-y-lactone, 10 ml of absolute methanol and 120 mg of finely powdered, anhydrous potassium carbonate were stirred at room temperature for 20 hours and then cooled to 0 ° C. The cooled solution was mixed with 1, 75 ml of a 1.0N aqueous hydrochloric acid are added. After stirring at 0 ⁰ C for a further 10 minutes, 10 ml of water were added, at the same time, methyl p-phenylbenzoate formed was filtered off. The filtrate was saturated with solid sodium chloride, extracted 4 times with 10 ml of ethyl acetate each time, and the combined organic extracts were washed with 10 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated, whereby A \ 5 mg of the viscous, oily 2- [3a, 5Ä -Dihydroxy-2 /? - (3 «-

hydroxy-4-phenoxy-trans-1-butene-1 -yl) -cyclopent-1 <x-yl] -acetic acid-y-lactones were obtained.

D. A solution of 445 mg (1.46 mmol) 2- [3 &, 5a-dihydroxy-2 | 9- (3 "-hydroxy-4-phenoxy-trans.1-buten-yl) -cyclopent-1a-yl ] -acetic acid-γ-lactone in 5 ml of anhydrous methylene chloride and 0.4 ml of?, 3-dihydropyran was mixed with 5 mg of p-toluosulionic acid monohydrate at 0 ° C. under an atmosphere of dry nitrogen 100 ml of ether combined, the ethereal solution would Imal washed with 15 ml of saturated sodium bicarbonate solution and then Imal with 15 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, with 752 mg (over 100%) of crude 2- [5a-tefrahydröpyrän-2-yIoxy -4-phenoxy-trans ⁱ

l-buten-l-ylj-cyclopent-la-yri-acetic acid-j'-lactone, were holding.

E A solution of 690 mg (1.46 mmol) 2- [5 "-hydroxy-3oc- (tetrahydropyran-2-yloxy) -2 /? - (3" -tetrahydropyran-2-yloxy-4-phenoxy-trans- 1-buten-1-ylj-cyclopent-ctylj-acetic acid-y-lactone in 8 ml of dry toluene was cooled to -78 ° C. under a dry nitrogen atmosphere. This cooled solution was mixed with 2.0 ml of a 20% strength solution of diisobutylaluminum hydride offset in η-hexane (Alfa Inorganics, Inc.) was added dropwise with a ίο such a rate that the internal temperature never rose above -65 ° C (15 minutes). After further stirring for 45 minutes at -78 ⁰ C, anhydrous methanol was added until the Gas evolution ceased, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then treated with 100 ml of ether, washed 4 times with 20 ml of a 50% sodium-potassium tartrate solution each time, dried over Na2SO4 and concentrated, whereby 613 mg of 2- [5 " -Hydroxy-3a- (tetrahydropyran-2-

yIoxy) -2j9- (3'-tetrahydropyran-2-yloxy-4-phenoxytrans-1 -buten-1 · yl) -cyclopent-1-yl] -acetaldehyde-y-hemiacetal were obtained.

F. A solution of 1.6 g (3.6 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in 6.0 ml of dry dimethyl sulfoxide was under a dry Nitrogen atmosphere with 3.24 ml (6.5 mmol) of a 2.0 molar solution of sodium methylsulfinyl methide in Dimethyl sulfoxide was added. A solution of 613 mg was added dropwise to this red ylide solution (1.29 mmol) 2- [5Ä-Hydroxy-3Ä- (tetrahydropyran-2-yl-

oxy) -2jS- (3a-tetrahydropyran-2-yloxy-4-phenoxytrans-1 -buten-1 -yl) -cyclopent-1 a-yl] -acetaldehyde-haJbacetal in 5.0 ml of dry dimethyl sulfoxide added over 20 minutes. After stirring for a further 2 hours at room temperature the reaction mixture was poured into ice water. The basic aqueous solution was 2 times with each Washed 20 ml of ethyl acetate and acidified to pH 3 with 10% strength aqueous hydrochloric acid. Pie acidic solution was extracted 3 times with 20 ml of ethyl acetate each time, and the combined organic Extracts were washed once with 10 ml of water, dried over magnesium sulfate and evaporated to a solid residue. This solid residue was triturated with ethyl acetate, and the filtrate was cingedatipft, whereby 754 mg of 9 <x-Hy-

droxy-11 oc, l 5a-bis (tetrahydropyran-2-yIoxy) -16-phenoxy-cis-5-trans-13- <B-tetranorprostadienoic acid were obtained. The IR spectrum (CHCl3) showed a strong one Band at 1720 cm - 'Mr the carboxyl group.

G. To a cooled to -10 ⁰ C solution of 754 mg (13 mf / ol) 9A-hydroxy-lla, 15 '-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13- <y-tetranor-prostadienoic acid in 13 ml of acetone of reagent purity grade 5 ;, 0.56 ml (1.41 mmol) of Jones reagent was added dropwise. After 20 minutes at -10 ⁰ C 0.260 ml of 2-propanol was added, and the reaction mixture was stirred for a further 5 minutes, after which it combines with 75 ml of ethyl acetate, washed 3 times with 10 ml of water ea, dried over magnesium sulfate and was concentrated to give 752 mg of 9-oxo-11E, 15E-bis (tetrahydropyran-2-yloxy) -16-phenQxy-cis-5-trans-13-ω-tetranorprostadienoic acid were obtained which were chromatographed on silica gel using ethyl acetate as the eluent, with 505 mg of the pure compound 10 were obtained.
H. A solution of 505 mg (0.9 mmol) of 9-oxo-1 loc, l 5 «-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-cu-tetranor- Prostadic acid in 6.3 ml of a mixture of glacial acetic acid and water in a ratio of 65:35 was stirred under nitrogen at 25 ° C. for 8 hours and concentrated by rotary evaporation Mesh size from 0.147 to 0.074 mm) chromatographies using ethyl acetate as the eluent. After elution of the less polar impurities, the oily 9-oxo-11, 15 "-dihy-

droxy-16-phenoxy-cis-5-trans-13- <a-tetranor-prostadienoic acid obtained in an amount of 210 mg.

The IR spectrum (CHCl ₃ ) showed a broad band at 1725 cm- 'for the carbonyl absorptions and a band at 970 cm-' for the 13,14-trans double bond. A solution of 50 mg (0.13 mmol) 9-oxo-lla, 15 "- dihydroxy-16-phenoxy-cis-5-trans-13-ω-tetranor-prostadienoic acid and 63 mg (0.4 mmol) p- Phenylphenol in 10 ml of dry methylene chloride was admixed with 825 mg (0.4 mmol) of dicyclohexylcarbodiimide, and the solution was stirred at room temperature overnight a melting point of 100-102 ⁰ C was obtained.

Analysis for C ₃ SHmO ₆ :
Calculated: C 75.53; H 6.71; Found: C, 75.65; H 6.83.

Example 2

py

cis-5-trans-13-cd-tetranor-prostadienoate

A. A mixture of 375 mg (0.65 mmol) of 9 «-hydroxy-11 ", 15" -bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-w-tetranor-prostadienoic acid (Example IF), 6.5 ml acetic acid and 3.5 ml water was added under nitrogen at room temperature for 20 hours The clear solution obtained was concentrated under reduced pressure and the residue (380 mg) was dissolved in ethyl acetate. The ethyl acetate solution was mixed with 20 ml of saturated saline solution washed, dried over sodium sulfate and concentrated to a clear oil. Chromatography on silica gel (Mallinckrodt CC-7) using chloroform and then: ethyl acetate as the eluent to the desired ^ a.lla.lSa-trihydroxy-ie-pkenoxy-cis-5-trans-13-co-tetranor-prostadic acid as colorless jul with a weight of 98 mg.

B. A solution of 106 mg of 9 ", 11", 15 "-trihydroxy-1 e-phenoxy-cis-ä-trans-13-w-tetranor-prustadienoic acid

and 189 mg of p-phenylphenol in 30 ml of dry methylene chloride was added 600 mg of dicyclohexylcarbodiimide and the solution was stirred overnight at room temperature After concentrating, the crude product was purified by silica gel chromatography to give 80 mg of pure p-biphenyl ester front Schmelzipunkt 101-103 ⁰ C.

Analysis for C ₃ ^
calculated:
found:

C 75.25; H 7.06; C 75.38; H 7.30.

Example 3-

N-methanesulfonyl'Ooc-hydfoxy-lla.lSa'bis-

(tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-

trans-13-ü) -tetranorprostadienamid

A. A mixture of 0.950 g (0.01 mole) methanesulfonamide and 180 g (0.01 mole) of 5-bromovalefic acid chloride was heated on a steam bath until the evolution of gas ceased (approx. 5 minutes). The brown one The reaction mixture was allowed to cool and taken up in methylene chloride. The methylene chloride solution was treated with Darco, filtered and diluted with hexane with cooling to give the white, crystalline Weighing N-methanesulfonyl-5-bromovaleramide of 2.22 g (86.0% yield) and a melting point of 88 to 89 ° C was obtained.

A solution of 2.20 g (8.57 mmol) of the previously prepared N-methanesulfonyl-5-bromovaleramide, 2.24 g (8.57 mivioi) of triphenylphosphine and 20 ffii of acetonitrile was refluxed overnight under nitrogen. The solution was then concentrated by rotary evaporation and the resulting solid triturated 4 times with hot benzene. The triturated solid was recrystallized from a mixture of absolute ethanol and ether, the white, crystalline [4- (methanesulfonyl-aminocarbonyl) -buty]] - triphenylphosphonium bromide weighing 2.80 g (63.7% yield) and a Melting point of 190 to 191 ⁰ C was obtained.

B. A solution of 1.7 g of [4- (methanesulfonyiaminocarbonylj-butylj-triphenylphosphonium bromide in 6.0 ml of dry dimethyl sulfoxide under a dry nitrogen atmosphere, 3.2 ml (6.5 mmol) of a 2.0 molar solution of sodium methylsulfinyl methide in dimethyl sulfoxide was added. About this red ylid solution a solution of 610 mg (1.29 mmol) 2- [5 «-hydroxy-3 & - (tetrahydropyran-2-yloxy) -2 /? - (3a- (tetrahydropyran-2-yloxy) -4-phenoxy-

trans-1-butene-1-yl) cyclopent-1 a-yl] acetaldehyde-y half acetal (Example 1 E) added in 5 ml of dry dimethyl sulfoxide for 20 minutes. After further Stirring for 2 hours at room temperature, the reaction mixture was poured into ice water. the basic aqueous solution was washed twice with ethyl acetate (3 × 20 ml), and the combined organic Extracts were washed once with 10 ml of water, dried over sodium sulfate and given an oil evaporated. Chromatography on silica gel gave 684 mg of pure, oily N-methanesulfonyl-9'-hydroxy-1 la, 15 "-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-1 S-ca-tetranor-prostadienamide.

Example 4

N-methanesulfonyI-9a, l 1α, 15α-

trihydroxy-ie-phenoxy-cis-S-trans-lS-ia-

tetranor-prostadienamide

55

A solution of 250 mg of the product from Example 3 in 5 ml of a mixture of glacial acetic acid and water in The ratio of 65:35 was stirred at 25 ° C. for 18 hours under nitrogen and then added concentrated to a crude oil, which by column chromatography on silica gel (Mallinckrodt CC-7; clear mesh size: 0.147-0.074 mm) using mixtures of chloroform and ethyl acetate as Eluent has been purified. After elution of less polar impurities, the colorless, oily N-methanesulfonyl ridh

oxy ^ cis'S-trans'lS'td-tetranor-prostadienamid with a Weight of 180 mg obtained. On the basis of the liquid-liquid chromatography, it turned out the product as homogeneous.

Example 5

(tetrahydropy ran-2-yloxy) -1 ö-phenoxy-cis-5 * trans-13 - «- tetränöf-pföstädienamid

A chilled to -1O ⁰ C solution of 400 mg of the product of Example 3 in 8 ml acetone from Reagensreinheitsgrad was added dropwise under nitrogen with 0.4 ml of Jones reagent were added. After 30 minutes at - 10 ⁰ C was added 0.4 ml of 2-propanol was added and the reaction mixture was stirred for an additional 5 minutes after which it combines with 60 ml of ethyl acetate, three times each with 10 ml water with

65

was concentrated, whereby 380 mg of the colorless oily N-methanesulfonyl-9-oxo-IIIa, 15Ä-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-cu-tetranorprostadienamide were obtained.

Example 6

N-methanesulfonyl-9-oxo-l Iä.15 «-

bi "-dihydroxy-1 ö -phenoxy-cis-S-trans-13-ω-

tetranor-prostadienamide

A solution of 260 mg of the product from Example 5 in 6 ml of a mixture of glacial acetic acid and water in Ratio of 65:35 was used at 25 ° C for 20 hours stirred under nitrogen and then concentrated to a crude oil, which by column chromatography Silica gel (Mallinckrodt CC-7, mesh size: 0.147-0.074 mm) using mixtures was purified from chloroform and ethyl acetate as the eluent. After elution of less polar The colorless N-methanesulfo-

nyl-9-oxo-11 ", 15" -bis-dihydroxy-16-phenoxy-cis-5-trans-13- (u-tetranor-prostadienamide obtained with a weight of 130 mg. The product crystallized from ether as colorless crystals with a melting point of 76 ° C.

Example 7

N-Benzoyl-9-oxo-11 α, Ι Soc-dihydroxy-S-cis-13-trans-16-

phenoxy-ω-tetranor-prostadienamide

1.0 mmol of 9-oxo-11, 15 "-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-S-trans-13-co-tetranor-prostd.dienoic acid (Example IG) in 40 ml of tetrahydrofuran was mixed with 2 ml of triethylamine. After stirring for 15 minutes at room temperature 10.0 ml of a 0.1 molar solution of benzoyl isocyanate in tetrahydrofuran admitted. After stirring for a further 4 hours, the reaction mixture was neutralized with acetic acid, and the solvent was evaporated in vacuo. The residue obtained was dissolved in Added methylene chloride and washed successively with water and sodium bicarbonate, whereby, after Drying and evaporation of the solvent, N-benzoyl-9-oxo-II ", 15" -bis (tetrahydropyran-2-yl-oxy) -16-phenoxy-cis-5-trans-13-u-tetranor-prostadienamide was obtained. This intermediate product was then overnight with acetic acid / water (as in Example 9) hydrolyzed and purified by column chromatography, where the desired N-benzoyl-9-oxo-lloc, 15 <x-

dihydroxy-S-cis'lS-trans-'ie-phenoxy'io-telranor-pro ' stadienamide was obtained.

Example 8

N'Methanesulfonyl'9-oxo-i 1ά, 15α-

dihydroxy-5-cis' 13-trans-16-phenoxy-co-

tetranor-prostadienamide

9-oxo-l loc, 15a-bis- (tetrahydropyran-2-yloxy ^ ie-phenoxy-cis-S'trans-IS-M-tetranor-prostadien ^ acid (see. Example IG) in 40 ml of tetrahydrofuran was mixed with 2 ml of triethylamine? offset. Next 15 minutes 10.0 ml of a 0.1 molar methanesulfonyl isocyanate solution in tetrahydrofuran were stirred at room temperature admitted. After stirring for an additional 4 hours, the reaction mixture was acidified with acetic acid neutralized and the solvent was evaporated in vacuo. The residue obtained was in Added methylene chloride and washed successively with water and sodium bicarbonate, wuuei, after Drying and evaporation of the solvent, N-methanesulfonyl-9-oxo-II (X, 15 «-bis- (tetrahydropyran-2-yloxy) -1 δ-phenoxy-cis-S-trans-13-cü-tetranor-prostadienamide was obtained. This intermediate product was then treated with acetic acid / water overnight (as in Example IH) hydrolyzed and purified by column chromatography, the desired M-methanesulfo-

nyl-9-oxo-11α, Ι5a-dihydroxy-5-cis-13-trans-16-phenoxy-M-tetranor-prostadienamide was obtained.

Example 9

N-acetyl-9a-hydroxy-11 λ, Ι 5oc-bis-

(tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13- <u-tetranor-prostadienamide

A solution of 532 g! / ♦ - (Acetamido-carbonylJ-bu tyl] triphenylphosphonium bromide in 10 ml of dry Dimethyl sulfoxide was under a dry nitrogen gas atmosphere with 17.7 ml of a 2.0 molar solution of sodium methylsulfinyl methide in dimethyl sulfoxide was added dropwise to this red ylide solution a solution of 0.524 g (1.1 mmol) 2- [5a-hydroxy-3 «- (tetrahydropyran-2-yloxy) -2 /? - (3 «- (tetrahydropyran-2-yloxy) -4-phenoxytrans-1 -buten-1 -yl) -cyclopent-1α-yl] -acetaldehyde-γ-hemiacetal (Example IE) added in 10 ml of dry dimethyl sulfoxide over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (3 × 25 ml'j, and the combined Organic extracts were mixed 1 times with 10 ml of water washed, dried over sodium sulfate and evaporated to an oil. Chromatography on silica gel resulted in 0.66 g of pure oily N-acetyl-Sla-hydroxy-1 i α, 15flc-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-co-tetranor-prostadienamide.

Example 10

y
trans-13-ü) -tetranor-prostadienamtd

A solution of 0.39 g of N-acetyl-9'-hydroxylla, 15Ä-bis- (tetahmydfopyfan'2-yloxy) -16'phenöxy-cis-5-träns-13-co-tetranöf-pröstadienamid in 5 ml of a mixture of glacial acetic acid and water in the ratio of 65:35 was taken at 25 ° C for 18 hours Stirred with nitrogen and then concentrated to a crude oil which was purified by column chromatography on silica gel (Mällinckrodt CC-7) using Mixtures of chloroform and ethyl acetate as eluent was purified. After elution of less polar impurities were 95 mg of colorless, oily N-acetyl-ga.lla.lSa-trihydroxy-iephenoxy-cis-5-trans-13-cu-tetranor-prostadienamide obtain.

BciSpicil 1

N-acetyl-9-oxo-l la, 15a-bis-

(tetrahydropyran-2-yloxy) -16-phenoxy-cis-

5-trans-13-cu-tetranor-prostadienamide

A solution, cooled to -10 ° C, of 394 mg of N-acetyl-9 (X-hydroxy-lla, 15Ä-bis- (tetrahydropyran-2-yloxyJ-Lö-phenoxy-cis-S-trans-IS-cu-tetranor- prostadienamid in 10 ml of acetone from Reagensreinheitsgrad was added dropwise under nitrogen with 0.27 ml of Jones reagent was added After 30 minutes at -10 ⁰ C was added 0.4 ml of 2-Propano added!, and the reaction mixture was stirred for a further 5 minutes, after which it combined with 60 ml of ethyl acetate, washed 3 times with 10 ml of water, dried over sodium sulfate and concentrated, with 390 mg of the colorless, oily N-acetyl-9-oxolliX.lSa-bis-ftetrahydropyran ^ -yloxyi-Lö-phenoxy-cis- 5-trans-13-co-tetranor-prostadienamids were obtained.

Example 12

N-AcetyI-9-oxo-11 ", 15" -

bis-dihydroxy-16-phenoxy-cis-5-trans-13-ω-

tetranor-prostadienamide

A solution of 390 mg y

bis- (tetrahydropyran-2-yloxy) -1 ö -phenoxy-cis-S-trans-13- <a-tetranorprostadienamid in 8 ml of a mixture of glacial acetic acid and water in the ratio of 65:35 was stirred at 25 ° C for 20 minutes under nitrogen and then concentrated to a crude oil, which by column chromatography on silica gel using mixtures of chloroform and Ethyl acetate was purified as the eluent. After elution of less polar impurities it became

the colorless, oily N-Acetyi-g-oxö-ilöciScc-bis-dihy-

droxy-ie-phenoxy-cis-S-trans-IS-w-tetranor-prostadienamide weighing 76 mg.

Claims (1)

Patent claims: 1, Lö-phenoxy-Gj-tetranorprostaglandin derivatives the general formula HO wherein M is the oxo group or one of the groups H OH