CS200166B2 - Method of producing n-substituted prostaglandincarboxamides - Google Patents

Abstract

1439512 Phosphonium salts PFIZER Inc 29 May 1973 [7 June 1972] 42096/75 Divided out of 1439511 Headings C2P and C2C Novel phosphonium salts of the formula wherein R is C 2-8 alkanoyl, C 3-8 cycloalkanoyl, aroyl optionally substituted by methyl, methoxy or halogen, C 1-7 alkylsulphonyl, heteroarylsulphonyl, or arylsulphonyl optionally substituted by methyl, methoxy or halogen, are prepared by reacting triphenylphosphine with compounds of the formula which are prepared by acylating 5-bromovaleramide or by reacting compounds of the formula with 5-bromovaleric acid chloride.

Description

The invention relates to a process for the production of novel analogs of naturally occurring prostaglandins. In particular, it relates to a process for the preparation of novel N-substituted prostaglandin carboxamides. Substituents in these new compounds include alkanoyl, cycloalkanoyl, aroyl and substituted aroyl, alkylsulfonyl or arylsulfonyl and substituted arylsulfonyl.

Prostaglandins are C-20 unsaturated fatty acids that have various physiological effects. For example, prostaglandins of the E and A series are potent vasodilators (Bergstrom et al., Acta Physiol. Scand. 64: 332-333 (1965) and Bergstrom et al .: Life Sci. 6, 449-455, (1967)) and cause lower systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King: Federation Proc. 23, 327 (1964); Bergstrom et al., 1965, locco cit; Carlosen et al., Acta. Med. Scand. 183, 423 and Carlson et al., Acta Physiol. Scand., 75, 161-169 (1969)] Another well known physiological effect of PGE 1 and PGE 2 is in the bronchodilator effect [Cuthbert: Brit. 723-726, (1969)].

Yet another important physiological role of natural prostaglandins is related to the reproductive cycle. PGE 2 is known to have the ability to induce labor [Karim et al .: J.

Obstet Gynaec. Briton. Cwlth. 77, 200-210, (1970)], induce therapeutic abortion [Bvgdeman et al .: Contraception, 4, 293 (1971)] and are useful for controlling fertility [Karim. Contraception, 3, 173 (1971)]. Some prostaglandins of the E and F series have already been obtained as patents for inducing birth in mammals (Belgian patent 754 158 and German patent 2,034,641), and on PGFi, Fz and F3 for controlling the reproductive cycle (South African patent 69/6089) .

Yet other known physiological effects for PGE 1 include inhibition of gastric acid secretion (Shaw and Ramwell, Worcester Symp, on Prostaglandis, New York, Wiley, 1968, pp. 55-64), as well as platelet aggregation [Emmous et al. Brit. Copper. J. 2, 468-472, (1967)].

Such physiological effects are known to be exerted in vivo only for a short time after administration of prostaglandins. A substantial part of the evidence suggests that the cause of rapid relapse is that natural prostaglandins are rapidly and effectively inactivated by β-oxidation of the side chain carboxylic acid and oxidation of the 15α-hydroxyl group [Anggard et al., Acta. Physiol. Scand., 81, 396 (1971) and references therein].

It was desirable to contemplate the preparation of prostaglandin analogues which would be equivalent to natural compounds in physiologic activity, but in which the selectivity of a. duration of action increased. Increasing the selectivity of the effect would be expected to alleviate the severe side effects, especially the stomach and intestine side effects, often observed after the continuous administration of natural prostaglandins (cf. Lancet, 536, 1971).

The present invention relates to a process for the preparation of N-substituted prostaglandine carboxamides of the formula I

where

R is C 2 -C 8 alkanoyl or C 4 -C 8 cyclockanoyl, aroyl or substituted C 7 -C 11 aroyl wherein the substituent is methyl, halogen or methoxy, C 1 -C 7 alkylsulfonyl, thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl,

R1 is hydrogen or (C1-C3) -alkyl,

R 2 is C 5 -C 11 alkyl,

W denotes a single bond or a cis-double bond,

Z represents a single bond or a trans-double bond,

M denotes an oxo group, and its Ca, Cn and Cis esters, in which the ester group is formyl, C2 -C5 alkanoyl or benzoyl, characterized in that on the 11, 15-bii (tetrahydropyranyloxy) ether of the formula II

TtfPO

where

R, R 1, R 2, M, W and Z are as defined above and

ΊΉΡ is 2-tetrahydropyranyl, treated with aqueous acetic acid and optionally esterified with any of the C 9, C 11 and C 15 hydroxyl groups by treating the resulting compound of Formula I with an appropriate acylating agent.

The process for the preparation of 11,15-hydroxy compounds of the formula I consists in hydrolyzing the 11,15-bis (tetrahydropyranyloxy) ether of the formula II with acetic acid in an aqueous medium. This type of hydrolysis is generally known to those skilled in the art. Particular embodiments of the hydrolysis are illustrated in more detail by the log portion of the present invention.

The esterification of the C 9, C 11 and C 18 hydroxyl groups by treating a compound of formula I obtained in the above hydrolysis with a suitable acylating agent is also a measure known per se and commonly used in the prostaglandin field. Thus, for example, the novel alkanoates, formates and benzoates of the carboxamides of prostaglandin series E, F and A can be prepared by reacting the desired prostaglandin with an acid chloride. If it responds. for example, PGE 2 -acetylcarboxamide with benzoyl chloride in the presence of an amine in a solvent inert under the reaction conditions, 11,15-dibenzoyl-PGE 2 -acetylcarbamoxide is obtained and similarly when PGE 2 _and pivaloylcarboxamide react with povaloyl chloride, 9,11,15 -? loyl-PGFor-pivaloylcarboxamide. A suitable amine is pyridine with a suitable solvent methylene chloride

In a number of in vivo and in vitro assays, it has been shown that the N-substituted prostaglandin carboxamide analogs have the same physiological effects as natural prostaglandins. These tests included, but were not limited to, an isolated smooth muscle test from guinea pig uterus, gerbilla rat colon (Gerbillinae), guinea pig ileum and rat uterus, a guinea pig histamine-induced inhibition test, a dog blood pressure test and hamster prevention .

The physiological response observed in these tests is useful for predicting the potential ability to use the test substance to treat various natural pathological conditions. The potential utility increases if the test substance has a selective effect profile comparable to that of natural prostaglandins Ez c Fk [cf. Table I).

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Test Compound * ¹ Prostaglandin Histamine. evolution, bronchospasm. in guinea pig% protection at 100 g / ml aerosol dose Limit dose for effect on blood pressure of anesthetized dog in g / kg i. V. (-) - decrease (+) - increase Relative efficacy (PGE2 = 100] for induced diarrhemia in mice (ED50 for PGE = 0.5 mg / kg i.v.) 1. 75 to 85 0.16 (-) 100 ALIGN! 2. - 1,2.4 (+) 10 (-) 10 3. 65 to 75 0.16 (-) 150 4. 30 to 35 0.08 (-) - 5. - - 80 6. - 0.1 (-) 7. 74 - 8. 59 10 (+) 9. - 10 (+) 10. 0 no response at a dose of ^ 20 11. 0 10 (-) 10 to 20 12. - no response at a dose of ^ 20 33 13. 19 Dec no response at a dose of ^ 20 14. - no response at a dose of ^ 20 15 Dec 0 no response at a dose of ^ 20 16. - no response at dose ^ 10 17. 0 - - 18. 43 - 900 19 Dec 0 - - 20 May - - - 21. 0 no response at a dose of ^ 40 no response at a dose of 1 mg 22nd 28 - 2700 23. 24 - 1100

The compounds and substituents R are those given at the beginning of Table I.

For example, carboxamide N-acetyl-13,14-dihydroprostaglandin Ei and carboxamide N-acetylprostaglandin Аз have the same great hypotensive effects in dogs with a longer duration of action than PGE ?. In addition, spasmogenic effects on various smooth muscle preparations are significantly less for carboxamide N-acetyl-13,14-dihydroprostaglandin E1 or carboxamide N-acetyl-PGA2 than for PGE2. N-acetyl-13,14-dihydroprostaglandin E1 carboxamide and N-acetyl-PGA2 carboxamide show a higher potency relative to PGE2 as a selective hypotensive agent.

N-acetylprostaglandin E2 carboxamide, N-propionoylprostaglandin E2 and N-cyclopropylcarbonylprostaglandin E2 carboxamide have similar potency to PGE2 (70 and 59 versus 80%) in guinea pig protection against histamine-induced bronchospasm. However, these carboxamide analogs exhibit substantially less spasmogenic effects in various smooth muscle preparations than PGE2. Furthermore, N-acetylprostaglandin E2 carboxamide and N-cyclopropylcarbonylprostaglandin E2 carboxamide are clearly less capable of lowering guinea pig and dog blood pressure than PGE2. The compounds are therefore more selective bronchodilators and cause fewer undesirable side effects than natural prostaglandins.

The carboxamide N-trimethylacetylprostaglandin E2, the carboxamide N-ethanesulfonylprostaglandin E2 and the carboxamide Np-toluenesulfonylprostaglandin F2 _and show spasmogenic effects on the esterogenic uterus of the rat comparable to PGE2. Carboxamide analogs are substantially less potent than PGE2 in other smooth muscle preparations, in acting on dog blood pressure and in protecting against histamine-induced bronchospasm in guinea pigs. Biological profile showing at carboxamide N trimethylacetylprostaglandinu E2 carboxamide N methansulfonylprostaglandinu F _{2 (Z} indicate that they have a greater ability than PGE2 induce labor, premature and manage fetus ^J Wear and can be expected to cause fewer cases of adverse side effects than PGE2.

Comparison of PGE2 and PGF _{2 (β} in vivo magnitude achieved contraceptive effect with

Na show carboxamide N-methanesulfonyl prostaglandin E2 and carboxamide N-methanesulfonylprostaglandin F _2a in rats. The fact that the latter induces an insignificant uterine-stimulated effect at the dose tested (Table I) suggests that contraceptive effects are attributable to the luteolytic mechanism of action not involving smooth muscle stimulation.

The novel compounds of the invention can be used in various pharmaceutical compositions containing the compound or a salt thereof and can be administered by various routes, such as intravenously, orally and locally (including aerosol), intravaginally and intranally, among others.

Natural prostaglandins are well known abortion-inducing agents and so effective are the doses of N-substituted prostaglandin E and F carboxamides. For this treatment, an aqueous suspension of substituted PGE-carboxamide or N-substituted PGF-carboxamide is administered at a dosage level of about 0 , 2 to 5.0 mg for N-substituted PGE-carboxamide or 30 to 50 mg for N-substituted PGF-carboxamide at 1-7 oral doses per day used in that case.

When treated intravaginally to induce abortion, it is desirable to administer a suitable composition in a sterile ethanolic solution containing either both said N-substituted prostaglandin carboxamides or lactose tablets of both the same compositions. Suitable treatments are about 15 to 200 mg per dose for N-substituted PGE-carboxamides or about 35 to 500 mg per dose for N-substituted PGF-carboxamides at 1 or 2 doses.

Where abortion is necessary during pregnancy, the effective agent is an ethanolic dextrose solution containing N-substituted PGE2-carboxamide administered by intravenous infusion. A suitable dosage is about 5 to 500 µg / min. and is administered for about 1 to 48 hours. Optionally, for abortion in the middle of pregnancy, an ethanolic dextrose solution containing N-substituted PGF _2α -carboxamide is administered as an effective agent by intraamniotic injection. A suitable dose is about 1 to 50 ml per injection and 1 to 12 doses are used at an interval of 3 to 24 hours between doses. For extramniotic intranterinal administration, 0.1 to 5 mg of N-substituted PGE2-carboxamide is injected up to 12 doses over 24 hours.

Another use for N-substituted prostaglandin carboxamides is to induce labor. An ethanolic saline solution of PGE2-analog is used for this purpose by intravenous infusion in an amount of about 3 to 100 .mu.g / kg / min for about 1 to 24 hours.

Another use of N-substituted prostaglandin carboxamides is to control fertility. For this purpose, lactose tablets with a sterilized 95% solution of PGE2 or PGF _{2a are used} for intravaginal administration in an amount of 5 to 500 mg per dose at 1 to 2 doses used for the next 2 to 7 days except for menstrual days.

Another known use of natural prostaglandins is as a heart rate regulator. The doses of prostaglandin carboxamides, in particular of the E-series, have the same properties.

However, the most important application of N-substituted prostaglandin carboxamides, based on the known use of natural prostaglandins, is to induce bronchodilation or an increase in nasal passage. Suitable dosage forms for this use include aqueous ethanolic solutions of N-acetyl-PGE 2 -carboxamide used as aerosol using fluorocarbons as propellant in an amount of about 10 to 500 µg per dose.

N-substituted PGA carboxamides have utility in hypertension, for example in the treatment of hypertensive crisis. For treatment, an ethanolic solution of the compound is administered by intravenous infusion in an amount of about 1 to 30 µg / kg / min at a total dose of about 1 to 40 mg / kg / day.

The 9-, 11- and 15-alkanoates, -formates and -benzoates of PGE, A and F carboxamides have the same uses as the non-esterified compounds. Often, further reduction of adverse side effects is shown.

The 15-lower alkyl substituted carboxamides PGE and F have the same uses as unsubstituted prostaglandins, but have a longer duration of action.

PGFf1-carboxamides have the same uses as PGFf1-carboxamides and further have use as bronchodilators.

The novel prostaglandins with β-hydroxyl at position 15 are generally less potent but more selective than the corresponding α-hydroxy-epimers. Furthermore, prostaglandins having β-hydroxy on C-15 are valuable as intermediates for prostaglandins having β-hydroxy on C-15 for a recycle process involving oxidation and reduction to C-15.

Various inert diluents, excipients or carriers can be used to prepare some of the above dosage forms or some of the other possible forms. Such materials include, for example, water, ethanol, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, alcohols, gums, polyalkylene glycols, petrolatum, cholesterol, and other known drug carriers. If desired, the pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The following examples illustrate and do not limit the scope of the appended claims. All temperatures are in degrees Celsius and the melting and boiling points are uncorrected.

Example 1 (Starting substance)

To a solution of 5.82 g (12.0 mmol) of [4- (acetylaminocarbonyl) butyl] tritones of 1-phosphonium bromide in (6.0 mL of dry dimethylsulfoxide) was added dropwise 9.8 mL (23.5 mmol) of 2.4 M To this red ylide solution is added dropwise a solution of 1.32 g (3.00 moles) of 2- [5-hydroxy-3- [alpha] -tetrahydropyran-2-yloxy] -2β- (3'-hydroxy) -acetamide. - (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl / cyclopent-1-yl] acetaldehyde in 3.0 mL of dry dimethyl sulfoxide for 0.5 h. After stirring at room temperature for 20 h, the reaction mixture was poured onto The aqueous solution was layered with ether and the vigorously stirred mixture was acidified to pH 3 by the addition of 10% aqueous hydrochloric acid, the acidic aqueous layer was further extracted twice with ether, the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give semi-solid, 4.0 g. This semi-solid is purified by columns Silica gel chromatography using chloroform and then ethyl acetate as eluents. Removal of high Rf impurities gave 1.15 g (67.8% yield) of N-acetyl-9α-hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadiene amide, as a viscous colorless oil.

Example 2

A solution of 108 mg (0.192 mmol) of the product of Example 1 in 2 mL of 65:35 acetic acid / water was stirred under nitrogen at 42 ° C for 3 hours. The solvent was then removed under reduced pressure and the remaining oil was purified by column chromatography using chloroform, ethyl acetate and then a 9: 1 mixture of methylene chloride and methanol as eluents. Removal of the less polar impurities gave 42 mg (89% yield) of N-acetyl-9α, 11α, 15α-hydroxy-5-cis-13-trans-prostadiene amide as a viscous colorless oil.

The NMR spectrum (CDCl 3) of the product shows a multiplet at 5.65 to 5.22 δ (4H) for olefinic protons, a multiplet at 4.31 to 3.80 δ (3 H) for CHO, a broad singlet at 3.20 to 2, 73 δ (4 H) for OH and NH, singlet at 2,41 δ (3 H) for СОСНз and multiplets at 2,60 to 0,71 δ (23 H) for remaining protons.

Example 3

A solution of 1.12 g (0.20 mmol) of N-acetyl-9-oxo-11β-bis (tetrahydropyran-2-yloxy) cis-5-trans-13-prostadienamides in 14.0 mL of acetic acid mixture and water 65:35 was stirred under nitrogen at room temperature for hours and then evaporated on a rotary evaporator. The resulting crude oil was purified by silica gel column chromatography using mixtures of chloroform and ethyl acetate as eluent. After less polar impurities, 407 mg (51.8% yield) of N-acetyl-9-oxo-11a, 15α-dihydroxy-cis-5-trans-13-prostadienamide, the N-acetylprostaglandin carboxamide, m.p. 86.5 ° C, from a mixture of ethyl acetate and hexane.

The IR spectrum (CHCl3) of the product shows strong desorption at 5.78 μ [carbonyl ketone] and 5.92 μ (carbonyl imide).

The NMR spectrum (CDCl 3) of the product shows multiplets at 5.26 to 5.72 δ for olefinic protons, multiplet at 3.85 to 4.28 δ for —CHO, singlet at 2.35 δ for СОСНз, and multiplets at 0.68 to 5.80 2.82 δ for remaining protons.

Example 4

A solution of 416 mg of [N-propionyl-O-oxo-11a, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide and 50 ml of a 65:35 acetic acid / water mixture is stirred under nitrogen at room temperature overnight. Evaporation of the mixture gave an oil which was purified by silica gel column chromatography using chloroform / ethyl acetate mixtures as eluents. Removal of the less polar impurities yields crystalline N-propionoyl-9-oxo-11a, 15α-dihydroxy-cis-5-trans-13-prostadienamide, carboxamide N-propionoylprostaglandin E2 weighing 76 mg, m.p. ° C, from ethyl acetate and hexane.

The IC spectrum (CHCl 3) of the product shows strong adsorption at 1735 and 1695 cm ^-1 for carbonyl groups and a mean adsorption at 970 cm ^-1 for trans-double bond.

The NMR spectrum (CDCl 3) of the product shows a multiplet at 5.70 to 5.43 δ for the trans double bond, a multiplet at 5.43 to 5.10 δ for the cis double bond, a multiplet at 4.30 to 3.69 δ for the CHO, wide sfnglet at 3.42 to 2.80 δ for OH and NH, quartet center at 2.60 δ for COCH2, triplet center at 1.13 δ for —СНз and multiplets at 2.72 to 0.60 δ for the remaining protons.

Example 5

A solution of 90 ml of N-cyclopropanecarbonyl-9α-hydroxy-11t, 15α-bis (tetrahydropyran-2200166)

-yloxy) -cis-5-trans-13-prostadienamide in 2.0 ml of a 65:35 acetic acid / water mixture was stirred at 42 ° C under nitrogen for 4.5 hours. Evaporation of the reaction mixture yielded an oil which was purified by column chromatography on silica gel. silica gel. After eluting the less polar impurities with a 2: 1 mixture of ethyl acetate and benzene, eluting with a 9: 1 mixture of methylene chloride and methanol gave a colorless semisolid product, N-cyclopropanecarbonyl-9a, 11a, 55r-trihedroxy-cis-5-trans 13-Prostadienamide, 39 mg (60.7% yield), m.p. 99-102 ° C (from ether).

IR (CHCl 3) oil has a strong adsorption at 1680 and 1720 Cma attributed to carboxyl groups, and at 970 the ^{CRM-1 is} attributed to the trans double bond.

The NMR spectrum (CDCl3) of the product shows a broad singlet at 9.36 δ for NH, a muitiplet at 5.70 to 5.10 δ for rlefinic protons, multiplets at 4.27 to 3.00 δ for —CHO, and multiplets at 2.84 up to 0.56 δ for the remaining protons.

Example

A solution of 1.84 mg of N-cyclopropanecarbonyl-9-oxo-11a, 15'-bis (tetrahydropyran-2-yloxyl-cis-4-trans-4-prostadiene amide) and 4.00 ml of a 65:35 mixture of acetic acid and water. The mixture was heated at 42 DEG C. under nitrogen for 4.5 hours to give an oil which was purified by column chromatography on silica gel, eluting with ethyl acetate / benzene (2: 1) to remove less polar impurities, eluting with ethyl acetate and ethyl acetate. to give a colorless oil, N-cyclopropanecarbonyl-9-oxo-11 H, 15α-dihydric-cis-5-tranes-13-prostldienamide, N-cyclopropanecarbonhlprostaglandin E2 carboxamide, 83 mg (63.5% yield).

IR (CHCl 3) oil shows strong adsorption at 1730 cm ^-1 for the ketone carbonyl at 1680 and 1730 cm ^_1 for imide carbonyls and at 970 ^cm-1 for trans double bond.

The NMR spectrum (CDCl 3) of the oily product shows singlet at 9.17 δ for NH, multiplet at 5.70 to 5.49 δ for trans-olefins, muitiplet at 5.49 to 5.17 δ for cis-olefin, muitiplet at 4 , 30 to 3.77 δ for CH-O, singlet at 3.50 δ, and multiplets at 3.04 to 0.63 δ for the remaining protons.

Example 7

A solution of 352 mg of N-trimethylacety-9-o.xo-11a, 15α-bis (tetlahydropylnin-2-y-rxyl) - cis -5-trans-13-prostadienaimide in 4.0 ml of a mixture of acetic acid and water in a ratio of 65:35 was stirred under nitrogen at 40 + 2 ° C for 4.5 hours and then evaporated. The resulting oil was subjected to column chromatography on silica gel using benzene and ethyl acetate as eluant. After removal of the high Rf impurities, an oily product, N-trimethylacetyl-9-oxo-11a, 15α-dihydroxy-cis-5-trans-13-prostadienamide, carboxamide N-trimethylacethyl-propylglandin E2 weighing 45 mg is eluted.

The IC spectrum (CHCl 3) of the product shows strong absorption at 1680 and 1730 cm ^-1 attributed to carbonyl groups and at 965 cm ⁴ attributed to the trans-double bond.

The NMR spectrum (CDCl 3) shows. singlet at 1,22 δ for C (CH3),.

wide singlet at 3.31 δ for OH, multiplet at 3.90 to 4.23 δ for ChO, muitiplet at 5.23 to 5.52 δ for cis-olefin, multiplet at 5.52 to 5.76 δ for trans -olefin, broad singlet at 8.20 δ for N — H and multiplets at 0.70 to 3.05 δ for remaining protons.

The UV spectrum (MeOH) after treatment with base (KOH) shows characteristic PGB absorption at 278 ημ.

Example 8

A solution of 3.16 g of N-methanesulfonyl-9α-hydroxy-11,11,4-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadiene amide and _32 ml of a 65: mixture of acetic acid and water: 35 was stirred at room temperature overnight under nitrogen. The solution was then evaporated and the resulting oil was purified by silica gel column chromatography using chloroform-ethyl acetate mixtures as eluents. After removal of the less polar impurities, crystalline N-methanesulfonyl-4-calla-.alpha.-trihydroxy-cis-4-trans-4-prostadienamide, 1.14 g of N-methanesulfonylprostlglandin F2 carboxylate having a melting point of 121-121.5 DEG C. is collected. C, from ethyl acetate and ether.

The IC spectrum (CHCl 3) shows strong absorption at 1720 cm ^-1 for carbonyl groups and at 970 cm ^-1 for trans-double bond. The mass spectrum shows peaks for the loss of one, two and three molecules of water and a peak for the loss of H2O + C5H11.

Example 9

A solution of 2.45 g of N-methanesulfonyl-9-oxo-11a, 15 &apos; -bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadiene amide in 24 mL of 65:35 acetic acid / water was added. The mixture was then evaporated and the resulting oily product was purified by silica gel column chromatography using chloroform / ethyl acetate mixtures as eluents to remove 865 mg (49.2 mg) of less polar impurities. % yield] of N-methanesulfonylprostaglandin E2 carboxamide, which is a solid, m.p. 118.5-119 ° C, from acetone and hexane.

IR (CHCl 3] of the crystalline product showed absorptions at 1720 cm ^"1 the imide carbonyl at 1730 cm ^{- 1} for the carbonyl ketone and at 970 cm for the trans double bond.

The NMR spectrum (CDCl 3) of the crystalline product shows a multiplet at 5.70 to 5.44 δ for trans-olefin, multiplet at 5.44 to 5.18 δ for cis-olefin, multiplet at 4.33 to 3.80 δ for CH —OH, singlet at 3.23 δ for SO2CH3 and multiplets at 2.78 to 1.65 δ for remaining protons.

Analysis:

calculated:

% H, 8.21;% N, 7.46;% S, 7.46. Found:

% C, 59.1;% H, 8.12;% N, 3.19;

He did

A solution of 523 mg (0.855 mmol) of N-methanesulfonyl-9-oxo-11a, 15tibis (tetrahydropyran-2-yloxy) -15 ₍ N, 4-methylcis-5-trans-13-pradadiene amide and N-methanesulfonyl-9-oxo). -II ^ iZ 15wbis (tetrahydropyran-2-yloxy) -15. _ί and methyl cis-5-trans-13-prostadienamidu in 5.0 ml of acetic acid and water in a ratio of 65:35 is stirred under nitrogen at room temperature The crude oil was purified by column chromatography on silica gel using chloroform / ethyl acetate mixtures as eluents to give a colorless oil of N-methanesulfonyl-9-oxo-11laf, 15'-dihydroxy. -1S6-methyl-S-cis-13-trans-prostadenamide and N-methanesulfonyl-4-oxo-llo, N-dihydroxy-1α-methyl-4-cis-13-trans-prostadienamide weighing 159 mg (42% yield) .

The NMR spectrum (CDCl3) of the product shows a multiplet at 5.72 to 5.49 δ for the trans double bond, a multiplet at 5.49 · to 5.12 δ for the cis double bond, a multiplet at 4.37 to 3.48 δ for CHO, singlet at 3.26 δ for SO2CH3 and multiplets at 0.74. up to 0.63 δ for the remaining protons.

The mass spectrum shows m / e at 443 for the parent molecule, at 425 for M-H 2 O and at 407 for m-2H 2 O ·.

Example 11

A solution of 220 mg (0.36 mmol) of N-methanesulfonyl-9-oxo-11,15-bis (tetrahydro-pyran-2-yloxyl) -16,1-dimethyl-5-trans-13-prostadenamide in 5 ml of acetic acid / water (65:35) was stirred under nitrogen at room temperature overnight and then evaporated on a rotary evaporator.The resulting crude oil was purified by silica gel column chromatography using chloroform / ethyl acetate mixtures as eluents. impurities gave N-methanesulfonyl-9-oxo-11a, 15α-dihydroxy-16,16-dimethyl-cis-5-trans-13-prostadienamide as a viscous colorless oil weighing 73 mg (44.5% yield).

The IC spectrum (CHCl 3) of the chromatographed product shows strong absorption at 1735 and 1720 cm ^-1 for carbonyl groups and at 970 cm for trans-double bond.

The NMR spectrum (CDCl 3) of the product shows a multiplet at 5.78-5.50 δ for the trans double bond, a multiplet at 5.50-5.20 δ for the cis double bond, multiplets at 4.29-3. , 70 δ for CHO, singlet at 3,27 δ for SO2CH3, singlet at 0,86 δ for attached dimethyl groups and multiplets at 2,80 to 0,56 δ for the remaining.

Example 12

A solution of 226 mg of N-acetyl-9-oxo-1α, 15α-bis (tetrahyropan-2-yloxy) -16,16-dimethylethyl-cis-5-oxanes-1-carboxylic acid. of t -adienamide in 5.0 ml of a 65:35 mixture of acetic acid and water was stirred under nitrogen at room temperature overnight and then concentrated by rotary evaporation, and the resulting crude oil was purified by column chromatography on silica gel using mixtures. chloroform and ethyl acetate as eluents After elution of the less polar impurities, the desired N-acetyl-9-oxo-11a, 15-diethydooxy-16,16-dimethyl-cis-5-trans-13-prostadiene amide was collected as a viscous colorless oil weighing 57 milligrams. .

The IC spectrum (CHCl3) of the product shows strong absorption at 1745 and 1710 cm ^-1 for carbonyl groups and a mean absorption at 975 cm -1 for trans double bonds.

The NMR spectrum (CDCl 3) shows a multiplet at 5.75 to 5.48 δ for the trans double bond, a multiplet at 5.48 to 5.20 δ for the cis double bond,.

multiplet at 4.16 to 3.68 for CHO, singlet at 2.26 <5 for COCH3, singlet at 0.88 <5 for the attached dlmethyl groups, and multiplet at 2.62 to 0.60 δ for the remaining protons.

Example 13

A solution of 65 mg (0.11 mmol) of N-acetyl-9-oxo-11a ', 15α-bis (tetrahydropyran-2-yloxy) -15 H -methyl-cis-5-trans-11-prostadiene amide and N-acetyl -9-oo-11a (15 ') - Pisttetrahydropyran-4-yloxy) -15a-methyl-cis-5-trans-13-prstenedienamide in 2.00 ml of 65:35 acetic acid / water was stirred under nitrogen at at room temperature overnight and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography, thin layer chromatography, or liquid-liquid chromatography to give N-acetyl-9-oxs-1α, 10o-dihydooxy-1 H -methyl-cis-5-1rast-13-prostadienamide, and N-acetyl-9-oxo-η 5 -S-dihydroxy-15-ethyl-cis-5-aza-13-? Ostadienamide.

Example 1 4

A solution of 104 mg of N-benzenesulfonyl-9α-hydrsxy-11β, 15β-β (tetoahydro-2-yloxy) -cis-t-trns-13-prostinedieamide and 5.0 ml of a mixture of acetic acid and water in a ratio of 65 The temperature of 35 was heated at 40 + 2 ° C for 2.5 hours under nitrogen. The solution was then evaporated, and the resulting oil was purified by column chromatography on silica gel. After removal of the higher Rf impurities with chloroform, elution with 10% methanol in methylene chloride gave the desired N-benzenesulfonyl-9α, 11α-tri-dooxy-β-β-β-13-rgottadiesmidide as a white foam weighing 30 mg ( 38.0% yield).

The NMR spectrum (CD-13) of the chromatographic product shows multiplets at 8.10 to 7.88 <5 a

7.60 to 7.36 δ for aromatic protons, multiplets at 5.60 to 5.37 ά and 5.37 to 5.08 δ for visyl protons, multiplets at 4.24 to 3.73 δ for CHO and multiplets at 2.52 to 0.69 δ for the remaining protons.

IR (CHClsj product showed strong absorption at 1720 cm <-1 for a carbonyl group and at 965 cm ^_1 for the trans double bond.

Example 15

A solution of 175 mg (0.266 mmol) of N-besenesulfonyl-9-oxo-1,1-tert-bis (tetrahydropyrimn-2-yloxy) -4,5-dimethyl-13-stannitinamide in 3 ml of an acetic acid / water mixture in a ratio of 65: 35 was heated at 40 + 2 ° C under nitrogen for 6 hours. The mixture was then evaporated and the resulting oily product purified by silica gel column chromatography. After removal of higher Rf impurities with chloroform, elution with 1: 1 chloroform / ethyl acetate gave the desired N-besesessulfonyl-4-oxo-1, 15α-dihydroxy-cis-trin-13-prottadiesamide as a foam. weighing 35 mg (26.8% yield),

IR (CHCl3) chromntsgrafovnného product showed strong absorption at 1735 and 1720 cm "1 for the carbonyl groups and medium absorption at 970 ^cm-1 for trans double bond.

The NMR spectrum (CDCl 3) of the product shows multiplets at 8.10 α, 7.88 α and 7.67 to 7.40 δ for aromatic protons, multiplet at 5.72 to 5.50 δ for trans-double bond, and

5.39 a, 5.10 δ for cis-double bond, multiplet at 4.27 to 3.88 δ for CHO, and multiplets at 2.68 to 0.68 δ for remaining protons.

Example 1 6

A solution of 222 mg (0.329 mmol) of N? -Toluenesulfonyl-9? -Hydroxy-1?, 1? -Bis (tetrahydropyran-2-yloxy) -cis-1-trans-13-prostadiene -amide in 3 ml of 65:35 acetic acid / water was heated at 40 + 2 ° C under nitrogen for 5 hours and then evaporated. The oily product was purified by silica gel column chromatography (SilicAR CC-4). After removing the less polar impurities with chloroform, eluting with a 9: 1 mixture of methylene chloride and methanol yields the desired N, N, N, N, N, N, N, N, N and N. 15a-Trifluorophen-cis-5-trans-13-propylstadienamide as a colorless viscous oil weighing 50 mg (30% yield).

The NMR spectrum (CDCl 3) of the spleen product shows two doublets at 7.85 and 7.23 δ (J = 7 cps) for aromatic protons, two overlapping multiplets at 5.68 to

4.96 δ for olefinic protons, multiplets at 4.68 to 2.90 δ for = CHO = a

OH,

O O 1 6 6

1β singlet at 2.32 δ for —СНз and multiplets at 2.50 a, 0.43 δ for remaining protons.

The NMR spectrum (GDCls) shows a multiplet

4.94 δ for olefinic protons, multiplets 183, 423 to 430 (1968) and Carlson et al., Acta multiplet at 4.27 to 3.88 δ for CHO and mulsinglet at 2.32 δ for —CH3 and

Example 17

A solution of 156 mg (0.232 mmol) of Np-toluenesilphonyl-9-oxo-11a, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-tans-13-prostadienamide in 3.0 ml of a mixture of acetic acid and water in The ratio 65:35 was heated under nitrogen at 40 + 2 ° C for 4 hours and then evaporated. The crude oil product was purified on silica gel by column chromatography. After removal of the less polar impurities with chloroform, elution with 2% methanol in chloroform gave a colorless viscous, oily Np-toluenesulfonyl-9-oxo-11a, 15α-dihydrooy-5-cis-13-ans ans-prostadienamide weighing 32 mg ( 27.4% yield).

The NMR spectrum (CDCl 3) of the product shows two doublets at 7.81 and 7.20 δ (J = 8 cps) for olefinic protons, multiplet at 5.64-5.31 δ for trans-olefin, multiplet at 5.31-3. , 98 δ for cis-olefins, multiplet at 4.23 to 3.55 δ for —CHO—, singlet at 2.23 δ for —CH3, and multiplet at 2.57 to 0.37 δ for remaining protons.

IR spectrum (CDCl3) showed a strong absorption at 1720 and 1730 ^cm-1 attributable to the carbonyl groups and at 970 cm-1 ascribed to the trans double bond.

Example 18

A solution of 121 mg (0.178 mmol) of N, N-(4-benzenesulfonyl) -9α-hyddoxo-11a, 15α ^! -bis (tetrahydropyrr, 4R, 4S, 4-yloxy) -cis-5-trans-13-prostadiene and 2.0 mL of 65:35 acetic acid / water was heated to 40 + 2 ° C. The solution was then evaporated and the resulting oil was purified by silica gel column chromatography. N-Hydroxy-cis-5-trans-13-prostadienamide as a foam of 61 mg.

The NMR spectrum (CDCl 3) of the product shows multiplets at 7.84 to 7.48 δ and 7.10 to 6.90 δ for thiophene protons, overlapping multiplets at 4.28 to 3.75 δ for CHO and multiplets at 2.57 up to 0.60 δ for the remaining protons.

Example 19

A solution of 159 mg of N- (thifensulfonyl) -9-ooo-11a, 15a-bis (tetrahydro-pyran-2-ylxoy) -cis-5- (1-carboxylic acid) -cis-5-carboxylic acid The adenamide in 3 ml of acetic acid / water (65:35) was heated at 40 + 2 ° C under nitrogen for 4.5 hours, then the mixture was evaporated and the resulting oily product was purified by silica gel column chromatography. with higher Rf by chloroform, eluting with 2% methanol in methylene chloride affords the desired N- (2-thiophenesulfonyl) -9-ooo-11,15-dihydro-5-cis-13-trans-pgxstal dienamide as a viscous oil of mass 72 milligrams.

The NMR spectrum (CDCl 3) of the product shows multiplets at 7.90 to 7.55 δ and 7.16 to 6.94 δ for thiophenone protons, multiplet at 5.72 to 5.43 δ for trans-double bond, multiplet at δ , 43 to 5.10 δ for cis-double bond, wide singlet at 5.60 to 4.75 δ for OH and NH, multiplet at 4.32 to 3.81 δ for CHO and multiplets at 2.75 up to 0.63 δ for the remaining protons.

Claims (1)

A process for the preparation of N-substituted prostaglandine carboxamides of the formula I R is C 2 -C 8 alkanoyl or C 4 -C 8 cycloalkanoyl, aroyl or substituted C 7 -C 11 aroyl wherein the substituent is methyl, halogen or methoxy, C 1 -C 7 alkylsulfonyl, thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl, R1 is hydrogen or (C1-C3) -alkyl, R 2 is C 5 -C 11 alkyl, W denotes a single bond or a cis-double bond, Z represents a single bond or a trans-double bond, M represents an oxo group, and its Ca, Cu and C 18 esters in which the ester group is formyl, C 2 -C 5 alkanoyl or benzoyl, characterized in that the 11, 15-bis (tetrahydropyranyloxy) ether of the formula II R, R 1, R 2, M, W and Z are as defined above and THP stands for 2-tetrahydropyranyl, treated with aqueous acetic acid, and optionally esterifying any of the C9, Cu, and C18 hydroxy groups by treating the resulting compound of formula I with an appropriate acylating agent.