DK143939B - PROCEDURE FOR THE PREPARATION OF PROSTAGLANDIN-FBETA DERIVATIVES - Google Patents

Description

os) DENMARK

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W (12) PUBLICATION DATE di) 1U3939B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

, (21) Application No. 39 ^ / 75 (51) Int.CI.3 C 07 C 177/00 (22) Filing Day 2. s ep. 1975 C 07 C 35/06 (24) Running day Sep 2 1975 C 07 D 257/04 (41) Aim. available March 7 1976 C 07 D 305/06 (44) Presented 2 Nov. 1981 C 07 D 333/24 (86) International filing no. - (86) International filing day - (85) Continuation day - (62) Regular filing no. -

(30) Priority 6. eep. 1974, 26994/74, IT

(71) Applicant FARMITALIA CARLO ERBA S.P.A., 20159 Milan, IT, (72) Inventor Carmelo Gandolfl, IT: Renato Pellegata, IT: Angelo

Fumagalli, IT.

(74) Clerk Th. Ostenfeld Patentbureau A / S.

(54) Process for the preparation of prostaglandin Fbeta derivatives.

It is well known that prostaglandin Fp compounds, especially PGF2g, (5c, 13t-9 | 3, 11a, 15S-trihydroxy-prostadioic acid) possess useful pharmacological properties; in particular, they have a relaxing effect on the bronchial muscle and are therefore suitable for the treatment of asthma.

PGFQ compounds have so far been prepared by reducing p of the corresponding PGE compounds.

However, this reaction leads in all cases - whether the reduction is carried out with mixed hydrides, e.g. alkaline boron hydrides, or, if possible, catalytic, to a mixture of the two epimeric alcohols (9β and 9a), which mixture must be separated by complex and costly chromatographic methods resulting in a yield of PGFβ derivatives not exceeding 50%.

The present invention provides a novel general method for the synthesis of PGFg compounds, starting from the corresponding PGFα compounds, thereby obtaining practically quantitative yields.

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Thus, the present invention relates to a process for the preparation of prostaglandin Fg derivatives of the general formula:

R1 O H

\ __ (N)

HO> E G

'2 V 3 R R

wherein D is a free or salt converted carboxy group, a carboxyamide, a carboxyester, a tetrazolyl or a -CH 2 OH group, R 1 is hydrogen or an organic acyl group, one of R 2 and R 3 represents hydroxy and the other hydrogen or alkyl, A represents -CH 2 -CH 2 - or cis-CH = CH-, E is -CH 2 -CH 2 -, trans-CH = CH- or -CEC-, R 4 G is -C- (CH-) -R 6, or cis-CH 2 -CH = CH-CH 2 -CHO, iin - c. ii 4 · 5 R 3 wherein n is zero or an integer from 1 to 5, 45 R and R is hydrogen or alkyl, / <CH2> ln R ° is hydrogen or the group -ch wherein X is -CH₂ or an oxygen or sulfur atom and m is an integer from 1 to 4 and the process of the invention is characterized by esterifying a corresponding prostaglandin Fa compound in which the 11 and 15 hydroxy groups are protected in a manner known per se and an optionally present 1-hydroxy group is optionally protected in a manner known per se, with a carboxylic acid and in the presence of a compound of the formula MVY3, wherein Mv is a metalloid of group V and Y is an alkyl, a dialkylamino or an aryl group, and in the presence of a hydrogen-acceptor compound to directly obtain a corresponding PGFβ-9 acyloxy derivative or PGFβ-1.9 diacyloxy derivative to either (i) be deprotected by the protecting groups from the protected 11 and 15 hydroxy groups and any optionally protected 1-hydroxy group and then, if desired, the acyloxy group splits into the 9 position and any acyloxy group then forms at the 1 position of a free hydroxy group or (ii) cleaves the acyloxy group at the 9-position and optionally acyloxy group at the 1-position to form a free hydroxy group, upon which the protecting groups from the protected 11 and 15 hydroxy groups and eu any present protected 1-hydroxy group, whereupon, if desired, a formed acid is converted to an ester, or a formed ester to an acid or salt thereof with a cation.

The above-mentioned method, which involves the complete inversion of the configuration of the hydroxy group at the 9 position, is particularly important not only because, as mentioned above, it allows to obtain practically quantitative yields, but also because a PGFα compound with the free hydroxy group in the 9 position is obtained. position and hydroxy groups protected at the 11 and 15 positions, especially in the formation of ether linkages, are the usual intermediate of the most widely used methods for total synthesis of natural prostaglandins and prostaglandin-like compounds (Fried et al., J.

Am. Chem. Soc., 94, 4342 (1972); Corey et al., J. Am. Chem. Soc., 91, 5675 (1969) and 92, 397 (1970)).

The above reaction is preferably carried out at room temperature in an inert anhydrous solvent, preferably selected from the group consisting of aromatic hydrocarbons such as benzene and toluene, linear or cyclic ethers, e.g. ethyl ether, dimethoxyethane, tetrahydrofuran and dioxane, and halogenated hydrocarbons such as dichloromethane and dichloroethane.

All the reagents used, i.e. the compound of formula MvY2 the esterifying acid and the hydrogen-acceptor compound are preferably used at a ratio of at least 1.5 µl / ml. and most preferably from 2 to 4 moles of reagent per mole are used. mole PGFα compound.

In the compound of formula MVY3, MV preferably represents P, As, Sb, in particular P. When in said compound Y is alkyl, it is preferably a C 1 -C 6 alkyl group, preferably methyl, and when Y is aryl, it is preferably phenylj when Y is dialkylamino, it is preferably dimethylamino.

The compound of formula MVY3 is preferably selected from the group consisting of triphenylphosphine, triphenylarsine, triphenylstilbin and hexamethyltriaminophosphine of formula [(CH

The hydrogen acceptor used is preferably an ester or amide of azodicarboxylic acid, but other hydrogen acceptors may also be used, for example, quinones such as chloranil (2,3,5,6-tetrachlorobenzozoquinone) and 2,3-dicyan -5,6-dichloro-benzoquinone or azobis formamide.

A preferred hydrogen acceptor is the compound of the formula: N - COOR "N - COOR" wherein R "represents an alkyl group.

For example, the esterification reaction with inversion of the configuration of the hydroxy group at the 9 position proceeds. according to the following system: MVY, 3 "v. _ HO H. "Y3M ° H ,? + | -C00R hn-coor "/ -i" (in N-COOR "^ HN-COOR" \ _1 j

Z 1 R -COOH Z

CL

wherein Z represents an acyloph group or other known protecting group bonded to the ring by an ethereal oxygen atom, and RaCO is an organic acyl group and with the following course of reaction comprising the formation of an oxonium intermediate salt from which the oxide of the compound of formula mVY3 and the ester of the inverted prostaglandin is formed: 5 N-COOR "// \ v R -C-OH + b - C-OH + HY, + b. y 2 ->.

C N-COOR "P a. ,, HN-COOR" "ft (_) \ l + l [Ra-C-Ol 'b - C-0 --- MVY3] + I HN-COOR" 0 a 4 / // / R -COC-b + MVY-, -> 0 c wherein the symbols a, b and c on the carbon atom of the alcohol denote the three mutually different substituents (i.e., the carbon atom of the alcohol is asymmetric), which together with the carbon atom and the hydroxy group constitute prostaglandin.

There is no limitation as to the nature of the carboxylic acid used as the esterifying agent as it may be either aliphatic such as acetic acid, formic acid or propionic acid, or aromatic such as benzoic acid and p-phenylbenzoic acid, or cycloalkyl aliphatic such as cyclopentyl acid. propionic acid, or aromatic such as phenylacetic acid, aliphatic substituted with a heterocyclic group, e.g. (2'-tetrahydrofuryl) -propionic acid.

As indicated above, the hydroxy groups at the 11 and 15 positions of the PGFα compound used for starting material and, optionally, any 1-hydroxy group present, are protected by conventional means by protecting groups such as ester and ether groups.

Examples of conventional protective ether groups are acetal ethers, enol ethers and silyl ethers.

The preferred ether groups are: CH3 OAlk (CH2), SiO-, (CH2), - C-C-SiO-,

ch3 I

o- · · al · wherein Æ is -O- or -CH 2 - / and Alk is a C 1 -C 6 alkyl group.

6 143939

The protection of the hydroxy groups mentioned above can also be achieved by acylation with acids such as, for example. acetic acid or p-phenylbenzoic acid.

As mentioned above, the reaction is practically quantitative in that the quantity of Δ unsaturated derivatives is always lower than 10% and generally no higher than 2-3%, especially using p-phenylbenzoic acid or benzoic acid as the esterifying agent.

The 9-acyloxy-PGF ^ compound obtained by the reaction can be readily purified by column chromatography, preferably with silica gel, using as the eluent e.g. uses methylene chloride, ethyl ether, cyclohexane or ethyl acetate.

When the compound of formula MVY3 is hexamethyltriaminophosphine, the resulting oxide [(CH₂ NNlgP—> 0) can be removed directly by leaching with acids, thereby simplifying the purification process, avoiding the purification step of the column at this stage.

The deetherization of compounds wherein the hydroxy groups are protected by ether groups is preferably carried out in water-miscible solvents such as low molecular weight aliphatic alcohols, linear or cyclic ethers, tetrahydrofuran, dioxane, dimethoxyethane or ketones, e.g. acetone, in reaction with aqueous mineral acids, e.g. hydrochloric acid or 0.5-2N sulfuric acid or a polycarboxylic acid, e.g. 0.25N oxalic acid at a temperature between room temperature and the boiling point and subsequently evaporating the organic solvent in vacuo.

Depending on the reaction conditions used, hydrolysis of the compound resulting from the esterification of the 9-hydroxywPGFQ compound can lead to different results.

When the hydrolysis is carried out in an alcohol, preferably an aliphatic alcohol, in the presence of a base such as anhydrous potassium carbonate, the PGFβ compound is obtained, wherein any esterified carboxyl group remains esterified while a free carboxyl group is obtained when the hydrolysis is carried out in aqueous alcohols. In both cases, the hydrolysis provides compounds in which the 93-hydroxy group and the other hydroxy groups are free hydroxy groups, if previously protected by acetylation.

The above method can be used in the synthesis of any of the PGFβ compounds of the claims, natural or synthetic, regardless of the modifications to the α and ω side chains.

According to an embodiment of the method according to the invention, a PGFq compound of the following formula (Q) is used: 7 1Λ 3 9 3 9 HO h ^ aaAad, / (Q)

Vs wherein D 'is a carboxy ester, a carboxyamide, a tetrazolyl or a -C 2 -OH radical with the hydroxy group protected in a conventional manner, A, E and G have the meaning given above, 2 3 Z and one of R' and R 'represents an acyloxy group or an etherified hydroxy group and the other of R' and R 'represents hydrogen or (C 1 -C 6) alkyl, which compound is acylated with a carboxylic acid R-COOH wherein a

RaCO is an organic acyl group, in the presence of a compound of formula MVY3, wherein Mv and Y are as defined above, and of a hydrogen acceptor, to give a compound of the following general formula (T): \ (T). Woe

£ V

Wherein D *, R CO, R1, R1, A, E, G and Z have the a meaning above, purifying this compound at random, the protecting groups are separated from the protected 11 and 15 hydroxy groups, and an optionally protected 1-hydroxy group, converting a formed ester to an acid or a salt thereof with a pharmaceutically useful cation and, if desired, in a manner known per se, the group R C00 at the 9 position to form a hydroxy group.

The PGFq compounds of formula (Q) used as starting material can be prepared in accordance with methods disclosed in the literature; for example. the PGFα compounds in which E is trans-CH = CH- can be obtained according to Corey's general procedure mentioned above; the compounds wherein E is -CH 2 -CH 2 - can be obtained from the compounds wherein E is -011 = 011-, by catalytic hydrogenation, e.g. with palladium on charcoal, while the PGFα compounds wherein E is -C = C- can be prepared e.g. as described by C. Gandolfi et al., Il Farmaco, Ed. Sc., 22.1125 (1972). The PGFα linkages with the various substituents on the ω chain can be readily obtained using a corresponding phosphonate which can be prepared in accordance with E.J. Corey et al., J. Am. Chem. Soc., 90, 3247 (1968) and E.J. Corey and G.K. Kwiatkowsky, J. Am. Chem. Soc., 88, 5654 (1966).

Furthermore, according to one embodiment of the method according to the invention, novel drug-active PGFβ compounds of the following general formula (I) can be prepared:

R O „H

(I * 2ν (i) * 3 '* 5'

R R

wherein R represents a tetrazolyl or a -CH -OH group or one

2 IV

-COR "group wherein R" is an amino group or an -OR group wherein RIV is hydrogen, C1-C12alkyl, trihaloalkyl or a pharmaceutically useful cation, R1 'is hydrogen or -COR4 wherein R is hydrogen, C ^-C ^ alkyl or φ- (CH₂) n ^ wherein n n is zero or an integer from 1 to 5 and φ is a phenyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkoxy, trifluoromethyl, phenyl and cycloalkyl-alkyl, or R 2 is the following group: «®2> m>: '9 143339 wherein m is an integer from 1 to 4, X is -CHg' or a oxygen or a sulfur atom, and n · has the meaning given above, the 21 t of one of R and R is hydroxy and the other is hydrogen or C 1 -C 6 alkyl, R 4 and R 5 are independently hydrogen or C 1 -C 6 alkyl, n is zero or an integer from 1 to 5, R5 is hydrogen or a (CH2) m group

-CH

wherein x and m have the meaning given above, A is or cis-CH = CH-, however - when R is a COR "group" wherein R "is IV 1 *

is an -OR- group - n represents 3 or 4, A is cis-CH = CH-, R

6 4 '5 "and R is hydrogen and one of R and R is hydrogen, the other is 16S- or 16R-C1 -C6 alkyl, by a process characterized by esterizing the 9-α-hydroxy group in a prostaglandin Fa compound of formula (II): OH-) L.-a ^ rv (I *; 2? 4 'i ^ C = C-é-C- (CH-) -R6 z Up R' R 3 wherein RV is a tetrazolyl or an - (3 H) OH group with the hydroxy group protected in a conventional manner, or a COR "group, wherein R" represents an amino or an OR'IV group wherein R, IV is C 1 -C 4 alkyl or trihaloalkyl, A, R, R, R and n have the meaning given above and Z and one of R 'and R' is an acyloxy group 2 3 or an etherified hydroxy group and the other of R 1 and R 1 is hydrogen or C 1-6 C 1-4 alkyl, with a carboxylic acid of the formula R 1 -COOH wherein R 10 is as defined above, in the presence of a hydrogen acceptor compound and a compound of the formula MvY3 wherein Mv is a metalloid of group V and Y is an alkyl, dialkylamino or aryl group of to obtain a compound of formula (III) for R, C 00 * λ ..

b SL ^ a ^ r7 (III) \ _ R ^ 2 R4 * i ▼ csc-fi-c- (chj -r6 z U5 'R'3 R5 10 U3939 V A9 51 6 2 3 wherein R, A, Rfc, R, R, R, η, Z, R 'and R' have the above meaning, in which, in any order, this compound is purified, the protecting groups are separated from the protected 11 and 15 hydroxy groups, and any protected 1-hydroxy group present, converting a formed acid into an ester, or a formed ester to an acid or a salt thereof with a pharmaceutically useful cation and, if desired, in a manner known per se, the group splits the R 2 COO at the 9 position to form a hydroxy group.

The PGF ^ derivatives of formula (II) used as starting materials are obtained in accordance with the process mentioned above in the preparation of the PGF PG derivatives of formula (Q) wherein E is -C = C -.

In the formulas of this specification, the broken dashes (iimiii) indicate that the substituents are in α-configuration, i.e. below the plane of the ring or chain, while the thick black bars () indicate that the substituents are in β-configuration, i.e. above the plane of the ring or chain.

As can be seen from the above formulas, the hydroxy group attached to the carbon atom at the 15 position may be either in α configuration (-C-: 15S oils) or in β configuration, lp .c_. .

% (-.C-: 15R oils).

R · 3 OH V

R 2 OH

Where in the above formula (I) R represents a -COR "1 group, wherein R" 1 is an -OR 2 group, n is 3 or 4, A is cis-CH = CH- and R 2 represents hydrogen, and only one alkyl group is present on the carbon atom at the 16-position, this substituent can only be in the α-position 4 '(R 2) or in the β-position (H) ~ b -bi 15, HR "*

In other words, when at the same time R is a COR "group, IV 1 1

wherein R "is an -OR -: group, n is 3 or 4, A is cis-CH = CH-, R

and R 6 represents hydrogen, and only in the alkyl group is present on the carbon atom at the 16 position, said alkyl group can never be a 16 (S, R) alkyl group, but only a 16 S or a 16 R alkyl group while R is different from -COR "wherein R" is a -0RIV- group and / or n is different from 3 or 4 and / or A is -CH - CH - and / or R3 "and or R is different from hydrogen - the above formulas also include 16 (S, R) - (Cj-Cg)]] yl compounds, i.e., a mixture of the two 16R and 16S diastereoisomers.

6 ^ (CH) When in formula (I) R represents the 2'm group, it is

-CH

Preferably selected from the group consisting of cyclohexyl, cyclopentyl, 21-tetrahydrofuryl, n is preferably 2 or 4, while n 1 is preferably zero, 1 or 2.

If Φ is substituted by a cycloalkyl-alkyl group, this group is preferably cyclopentyl-methyl or cyclopentyl-ethyl or cyclohexyl-methyl or cyclohexyl-ethyl.

When Rt is alkyl, it is preferably methyl, ethyl or propyl; when it is a 4> - (CH 2) nj group, it is preferably phenyl, benzyl or p-phenyl-phenyl; when Rb then represents '' (ca 2) m - (CH 9) -CH I is preferably cyclopentyl-ethyl or ά nl -'X 7 cyclohexyl-ethyl or (2'-tetrahydrofuryl) -ethyl. When R represents trihaloalkyl, it is preferably -Cl 2 -CCl 2.

The alkyl groups may be branched or straight-chain.

Examples of cations of pharmaceutically useful bases are either metal cations such as sodium, potassium, calcium and aluminum, or organic amine cations such as trialkylamines.

The ω-homo compounds are those compounds wherein R ° is hydrogen and n is 5.

The Nor compounds are those compounds in which n is zero or 1 or 2.

Particularly preferred compounds of the invention are the following: 16S-methyl-13,14-dehydro-PGF2gf 16S-methyl-20u-homo-13,14-dehydro-PGF2p; 16R-methyl-13,14-dehydro-PGF2p; 16R-methyl-20oj-homo-13,14-dehydro-PGF2g, which has the physical data set forth in the examples below.

The novel compounds of formula (I) can be used on the same therapeutic indications as natural prostaglandins, however, which are characterized by a lower rate of inactivation, as they are not substrates for the enzyme 15-hydroxy-prostaglandin dehydrogenase which as known to quickly inactivate natural prostaglandins, as well as by a more selective effect.

They, in particular, like PGF2β, may be used as gastric anti-secretion and anti-ulcer agents, but in comparison with PGF2β, they exhibit higher activity, as will be seen in the following table, in which PGF2's anti-ulcer * and anti-secretion activity is conventionally assigned the value 1.

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TABLE

Anti-ulcer Anti-secretion (°) activity in rats

Relative Strength ED ^ W Relative Strength ED ^ q (· * ·)? GF2p 1 1,579 1 1.45 L6S-methyl-L3,14-dehydro-? GF2j3 3.5 0.472 2.5 0.558 (o) ulcer is induced by the Takagi-Okabe method described (K. Takagi et al., Jap. J. Pharm., 18 ^, 9 (1968); (oo) according to Shay (H. Shay et al., Gastroenter., 26, 906 (1954 Expressed in mg / kg

In the same tests, the compound 16R-methyl-13,14-dehydro-PGF₂ has been found to be four times more active as an anti-ulcer and anti-secreting agent than PGF „.

In the above tests, the compounds were administered subcutaneously. Furthermore, the compounds of formula (I) possess bronchial dilating activity and are therefore useful in the treatment of asthma.

For example, 16S-methyl-13,14-dehydro-PGF2β has a 5-6 times greater effect on guinea pig bronchospasm than the natural PGF2β. The anti-bronchospastic (anti-asthmatic) activity was determined on guinea pigs divided into groups and treated with a histamine spray (0.2% aqueous solution of histamine hydrochloride); the time when the animal showed signs of bronchospasm was recorded. Four hours later, the same animals were treated with a spray of the test compounds at various concentrations in saline or with a spray of standard PGF 2 They were again treated with a histamine spray (0.2%) and again the time elapsed before bronchospasm occurred.

The compounds of general formula (I) may be administered orally, parenterally or intravenously, by rectal suppositories or by inhalation. For example, they can is administered by intravenous infusion of a sterile isotonic saline at a rate of 0.01 to 10, preferably 0 ', 05 to 1 µg / kg body weight per day. minute.

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Pharmaceutical compositions may be prepared by conventional methods, and they may e.g. be in the form of tablets, capsules, pills, suppositories or bougies, or in liquid form, e.g. solutions, suspensions or emulsions.

Examples of substances that can serve as carriers or diluents are water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oil, benzyl alcohol and cholesterol.

The invention is illustrated in the following by examples in which the abbreviations MTHP "," DIOX "and" THF "stand for tetrahydropyranyl, dioxanyl and tetrahydrofuran respectively.

Examples 1-3

A solution of azodicarboxylic acid diethyl ester (0.26 g, 1.44x10 mol) in dry THF (2 ml) is added dropwise over 5 minutes to a -3 stirred solution of triphenylphosphine (0.38 g, 1.44x10 mol). -phenyl-benzoic acid (0.285 g, 1.44x10 mol) and 5c, 13t-9a, 11a-15S-trihydroxy-prostadioic acid methyl ester-11, 15-bis-THP-ether (0.2g,

- in Island

3.73x10 mol) under cooling at 20-22 C. After further stirring for 15 minutes, the reaction mixture is evaporated in vacuo to dryness to give a crude product which is dissolved in ethyl ether. The organic layer is washed with saturated NaHCO, and water to neutrality, J s dried (Na 2 SO 4), and the solution is evaporated in vacuo to dryness.

The obtained mixture of triphenylphosphine oxide and 5c, 13t-93,11a, 15S-trihydroxy-prostadienic acid methyl ester-11, 15-bis-THP-ether-9-p-phenylbenzoate is treated with acetone (8ml) and aqueous 0.2N oxalic acid * ( 6 ml) at reflux temperature for 30 minutes.

After removal of the acetone in vacuo, the aqueous phase is extracted with ethyl acetate, the combined organic extracts are washed with saturated (NH 2 SO 2, dried (Na 2 SO 4) and evaporated to dryness).

The resulting crude material is absorbed on a short silica gel column (10 g) and after elution with cyclohexane-ethyl ether (60:40) (to remove the impurities) and then with ethyl ether pure 5c, 13t-9 £, 11a, 15S trihydroxy-prostadioic acid methyl ester 9-p-phenylbenzoate, 180 mg, oil, [α] D = -44.1 °, [α] 355 ° iggiggO (CHCl1)

A solution of this compound in dry methanol is heated to reflux temperature for 1 hour and 30 minutes in the presence of K 2 CO 3 (55 mg). The solvent is evaporated in vacuo and the oily residue is taken up in methylene chloride and water. The organic layer is washed to neutrality, dried (Na 2 SO 4), concentrated to a small volume and then the residue is absorbed on a small silica gel column (3 g).

14 143939

Subsequent elution with ethyl ether to remove methyl p-phenylbenzoate and then with ethyl ether ethyl acetate gives 5c, 13t-93, 11a, 15S-trihydroxy-prostadioic acid methyl ester, 117 mg, 93% yield, m.p. -isopropyl ether), [α] D = -4.9 °; [α] 365 ° = -2 ° (EtOH).

After thin-layer chromatographic analysis on silica gel plates, using ethyl acetate as the eluent, and with two 17 cm passages at 20 ° C, this compound, R f 0.076, is found to be completely free of PGF2a methyl ester (R f 0.116).

A solution of PGF 2 + methyl ester (100 mg) in 6% in 80% aqueous methanol (6 ml) is refluxed for 1 hour.

After evaporation of excess solvent and acidification to pH 4.5 and by extraction with ethyl acetate pure 5c, 13t-9p, 11a, -15S-trihydroxy-prostadioic acid (PGF2), 39 mg, [a] Q = -1.8 °, [et] 365 ° = -2.6 ° (EtOH).

Example 2

A solution of azodicarboxylic acid diethyl ester (0.26 g) in dry THF (2 ml) is added dropwise over 5 minutes to a stirred -3 solution of triphenylphosphine (0.38 g, 1.44.10 mol), propionic acid -3 ( 0.107 g, 1.44.10 mole) and 5c, 13t-9a, 11a, 15S-trihydroxy-prostadienic acid methyl ester-11,15-bis-THP ether (0.2 g, 3.73.10 mole) .

After further stirring for 15 minutes, the reaction mixture is evaporated to dryness in vacuo and the crude material, a mixture of triphenylphosphine oxide and PGF2 + methyl ester-11, 15-bis-THP-ether-9-propionate is treated with 6% 1 80% aqueous methanol at reflux temperature for 2.5 hours.

After removing most of the alcohol in vacuo, the aqueous phase is diluted with 0.25N KOH (8 mL) and extracted with benzene-ethyl ether (30:70) to remove the triphenylphosphine oxide.

The aqueous phase is acidified to pH 4.5-4.8, extracted with pentane-ethyl ether (1: 1) and then, after washing with saturated (NH to give PGF2g-11, 15-bis-THP ether (168 mg, 86% yield) A solution of this compound in acetone (10 ml) and 0.2N aqueous oxalic acid (6 ml) is heated at 40 ° C for 6 hours. after removal of acetone in vacuo is obtained by extraction with ethyl ether PGF 2

Example 3 143939

To a stirred solution of triphenylphosphine (0.79 g), acetic acid (0.18 g) and 5c-9a, 11a, 15S-trihydroxy-prost-5-ene-13-amino acid ethyl ester-11a, 15S-bis-THP ether (535 mg) in dry benzene (30 ml) is added dropwise over a period of 5-7 minutes azodicarboxylic acid diethyl ester (523 mg) in dry benzene (10 ml).

After 10 minutes, the reaction mixture is washed with 5%

NaHCO-and water, dried (Na₂SO ^) and evaporated to dryness. The residue dissolved in acetone (20 ml) and 0.2N aqueous oxalic acid (15 ml) is refluxed for 1 hour? the acetone is evaporated and the aqueous phase is extracted with ethyl ether. The combined extracts are evaporated to give the crude 5c-9fJ, 11a, 15S-trihydroxy-prost-5-ene-13-ynoic acid ethyl ester-9-acetate.

The pure compound [α] β = -19.2 ° (EtOH), 530 mg, 90% yield was obtained by purification on a short silica gel column (20 g) under application; view of cyclohexane ether (75:25) as eluent; A solution of the pure inverted ester in 6% 1 CO 2 in MeOH-O (80:20), 25 ml, is refluxed for 2 hours. After concentration in vacuo to remove the methanol, the solution is acidified and extracted with ethyl ether. The combined extracts are washed with saturated (NH 2 SO 2), dried and evaporated to dryness to give 5 ~ cis-93, 11a, 15S-trihydroxy-prost-5-ene-13-ynoic acid (13,14-dehydro-PGF2g ) [α] D + 3 ° (EtOH).

Example 4

A solution of 1.05 g of diethyl azodicarboxylate in dry THF (10 ml) is added dropwise over 5 minutes to a stirred solution of 1.095 g of 5c-9a, 11a, 15S-trihydroxy-16s-methyl-prost-5-en-13 Acetic acid methyl ester 11a, 15-bis-THP ether, 1.5 g of triphenylphosphine and 0.735 g of benzoic acid in dry THF (25 ml), cooled at 20-22 ° C.

After 15 minutes, the reaction mixture is evaporated to dryness and the residue is treated with ethyl ether and pentane (2: 1) to remove most of the triphenylphosphine oxide.

The organic phase is concentrated to a small volume and absorbed on a silica gel column (40 g). Eluting with cyclohexane-ethyl ether (80:20) gives 1.15 g of 5c-9P, 11a, 15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester-9-benzoate-11, 15-bis -THP ether [α] D = -28 ° (CHClC).

143938 16

Under essentially the same procedure, but substituting the benzoic acid with equimolar amounts of formic, propionic, vinegar, butter, p-phenylbenzoic, capron, cyclopentylpropionic, cyclohexylpropionic-2-tetrahydrofurylpropionic, phenylacetic acid propionic acids, the following 9-esters are prepared from 5c-9P, 11a, 15S-tri-hydroxy-16S-methyl-prost-5-ene-13-amino acid methyl ester-11,15-bis-THP-ether: - formate, [ α] β = -42 ° (CHCl3); - acetate, [α] D = -38 ° (CHCl13); - propionate, [α] D = -37 ° (CKCl 3); - butyrate, [α] D = -36 ° (CHCl 3); - p-phenylbenzoate, [α] D = -30 ° (CHCl 3); [a] 3g, -o = -103 ° (CHCl3); - capronate, [α] β = -40 ° (CHCl3); - cyclopentyl propionate, [α] D = 37 ° (CHCl13)? t cyclohexyl propionate, [α] D = -37 ° (CHCl13); - 2'-tetrahydrofuryl propionate, [α] = 1818 ° (CHCl13); phenylacetate, M-168 = m / e 498, phenyl propionate, M-168 = m / e 512.

A solution of 0.83 g of 5c-9β, 11α, 15S-trihydroxy-16S-methyl-prost-5-en-13-amino acid methyl ester-9-benzoate-11, 15-bis-THP-ether in 25 ml of acetone treated with 0.4N citric acid (15 ml) for 2 hours at reflux temperature. The acetone is evaporated in vacuo and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed to neutrality, dried (Na 2 SO 4) and evaporated to give 5c-9 (3, 11 <x, -15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester-9-benzoate (16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-benzoate) 0.59 g, [α] D = -29 ° (CHCl13),

Using substantially the same procedure, starting from corresponding acylates, the following is obtained: 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-formate, [α] D = -32 ° (CHClC); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-acetate, ta] D = -34 ° (CHCl13)} 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-propionate, [ a] + = -18 ° (CHCl3); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-butyrate, [α] D = -32 ° (CHCl13); 16S-methyl-13,14-dehydro-PGF 2 + -methyl ester-9-p-phenylbenzoate, [α] D = -25.7 ° (CHCl 3); [α] 365 ° = -123 ° (CHCl 3); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9 capronate, [α] Q = -34 ° (CHCl 3); 16S-methyl-13,14-dehydro-PGF2- methyl ester-9-cyclopentylpropionate, [α] D = -31 ° (CHCl CH); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-cyclohexylproplonate, [α] D = -29 ° (CHCl3); 16S-methyl-13,14-dehydro-PGF2β-methyl ester 9- (2'-tetrahydrofuryl) propionate, [α] + = -27 ° (CHCl 3); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-phenylacetate] D = -31 ° (CHCl 3); 16S-methyl-13,14-dehydro-PGF2β-methyl ester-9-phenylpropionate, M + = m / e 512. Example 5

A solution of

0.47 g of 5c-9P, 11a, 15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid methyl ester-9-benzoate in 10 ml of 6% Κ2002 in MeOH-H2O (80:20) is refluxed 1 hour, concentrate to a small volume, acidify to pH

5.2 and extracted with ethyl ether. The combined organic phases are evaporated to dryness. The residue is absorbed on 2 g of acidic silica gel and eluted with ethyl ether and ethyl acetate (8: 2) to give 345 mg of 16S-methyl-13,14-dehydro-PGF2g (or 5c-9 | 3, 11a, 15S-trihydroxy-16S -methyl-prost-5-and-13-acid), [α] D = + 2.8 °; [+ 3550 + 20.5 ° (EtOH).

Example 6

A solution of 430 mg of 5c-9 (3.11a, 15S-trihydroxy-16S-methyl-prost-5-ene-13-ynoic acid methyl ester-acetate, 1x10 mol in dry methanol (10ml) is stirred. for 2 hours at room temperature with 154 mg of anhydrous potassium carbonate and after neutralization with 15% aqueous acetic acid is evaporated to near dryness, diluted with water and extracted with ethyl acetate.

The combined organic phases are washed to neutrality, dried and evaporated to dryness to give 0.36 g of 5σ-9β, 11α, 15S-tri-hydroxy-16S-methyl-prost-5-ene-13-amino acid methyl ester (13 , 14-dehydro-16S-methyl-PGF2β-methyl ester [α] D = + 4.7 °; [+ 355 ° = + 261 ° (EtOH).

Example 7

Working under dry conditions, a solution of diethyl azodicarboxylate (700 mg) in 10 ml of THF is added dropwise and at a temperature of approx. 20-22 ° C to a stirred solution of 0.67 g of 18c-9a, 11α, 15S-trihydroxy-16S-methyl-prost-5-ene-13-ynoic acid trichloroethyl ester-11,15-bis THP ether, 1.05 g of triphenylphosphine and 600 mg of phenyl-propionic acid in dry THF (25 ml.)

Stirring is continued for a further 15 minutes, the reaction mixture is evaporated to dryness and the residue is absorbed on 25 g of silica gel, whereupon, eluting with cyclohexane-ethyl ether (95: 5), 0.7 g of 5ο-9β, 11α, 15S is obtained. trihydroxy-16S-methyl-prost-5-en-13-ynoic acid trichloroethyl ester 11,15-bis-THP-ether-9-phenylpropionate (yield 87%). [α] = -15 ° (CHCl3).

Under similar experimental conditions, starting from the isomeric 16R-methyl derivative, 5c-93,11a, 15S-trihydroxy-16R-methyl-prost-5-ene-13-ynoic acid trichloroethyl ester-11, 15-bis-THP -ether- 9-phenylpropionate, [α] D = -12 ° (CHCl13).

A solution of 5c-93,11a, 15S-trihydroxy-16S-methyl-prost-5-ene-13-ynoic acid-trichloro-ethyl ter-11,15-bis-THP-ether-9-p-phenylpropionate ( 7 g) in methanol (6 ml) and aqueous 2N citric acid (1 ml) are heated at 40 ° C for three hours.

Excess methanol is evaporated and extracted with ethyl ether. The solvent is evaporated from the organic phases, which are percolated on 5 g of silica gel using cyclohexane-ethyl ether (1: 1). 0.52 g of 5c-93,11a, 15S-trihydroxy-16S-methyl-prost-5-ene-13-ynic acid trichloroethyl ester 9-phenylpropionate are obtained, [α] β = -8 ° (CHCl3) .

Using an analogous procedure, starting from the 16R isomer, 5c-93, 11a, 15S-trihydroxy-16R-methyl-prost-5-ene-13-ynoic acid trichloroethyl ester-9-phenylpropionate is obtained. a] D = -11 ° (chCl 3).

Example 8

A solution of 315 mg of 5c-90,11a, 15S-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid trichloroethyl ester-9-phenylpropionate in 15 ml of 90% aqueous acetic acid is stirred while maintaining the temperature at ca. 30-35 ° and 1.5 g of zinc dust is added. After 12 hours, the mixture is filtered, washed with ethyl acetate and the eluate evaporated in vacuo to a small volume. The residue is treated with ethyl acetate, the organic phase is washed with dilute sulfuric acid, water and saturated ammonium sulfate, dried and evaporated to dryness. The residue is purified on acidic silica gel using as eluent cyclohexane and ethyl acetate (70:30) to give 202 mg of pure 5c-9 $, 11a, 15s-trihydroxy-16S-methyl-prost-5-en-13-acid acid -9-phenylpropionate, [α] D = -9 ° (CECl ^).

Example 9

To a solution of 260 mg of 5c-93,11a, 15S-trihydroxy-16R-methyl-prost-5-ene-13-ynoic acid trichloroethyl ester-9-phenylpropionate in anhydrous methanol is added 1.2 g of zinc dust, which is refluxed for 4 hours. .

It is filtered, washed with methanol, evaporated to dryness, treated with ethyl acetate and the organic phases are washed with 2N 2 SO 2, water and saturated ammonium sulfate. Evaporation of the solvent gives pure 5c-9f3, 11a, 15S-trihydroxy-16R-methyl-prost-5-ene-13-ynoic acid-9-phenyl-propionate, [α] D = -12 ° (CHClg).

Example 10

Working as described in Examples 7 to 9, and substituting one of the corresponding acids for the phenyl propionic acid of Example 7, the following 9-esters are prepared: -f 13.14-dehydro-16S-methyl-PGF2jj-9 ~ formate M m / e 394.

13.14- dehydro-16S-methyl-PGF2β-9-acetate M + m / e 408.

13.14-dehydro-16S-methyl-PGF2β-9-propionate; M + m / e 422.

13.14-dehydro-16S-methyl-PGF 2 g “9-butyrate; M + m / e 436.

13.14-dehydro-16S-methyl-PGF2g-9 capronate; M + m / e 464.

13.14-dehydro-16S-methyl-PGF2β-9-benzoate; M + m / e 470.

13.14- dehydro-16S-methyl-PGF9f, -9-cyclohexyl propionate; M + m / e 504 ·.

13.14- dehydro-16S-methyl-PGF2? -9-cyclopentyl propionate; M m / e 490.

13.14-dehydro-16S-methyl-PGF2β-9-phenylacetate; M + m / e 484.

13.14-dehydro-16S-methyl-PGF2β-9- [2 '] tetrahydrofuryl propionate; Mn / e492.

13.14- dehydro-16R-methyl-PGF2? -9-formate; M + -2H20 m / e 358.

13.14-dehydro-16R-methyl-PGF2β-9-acetate; ¢ ^ -21 ^ 0 m / e 372.

13.14-dehydro-16R-methyl-PGF2β-9-propionate; M + -2H20 m / e 386.

13.14- dehydro-16R-methyl-PGF2? -9-butyrate; M + -2H20 m / e 400.

13.14-dehydro-16R-methyl-PGF2β-9 capronate; 1 ^ -21 ^ 0 m / e 428.

13.14- dehydro-16R-methyl-PGF2β-benzoate; M + -2H20 m / e 434.

13.14-dehydro-16R ~ methyl PGF2β ~ 9-cyclohexyl propionate; 1 ^ -2 ^ 0 m / e 468.

13.14- dehydro-16R-methyl-PGF2β-9-cyclopentyl propionate; M + -2H20 m / e 454.

13.14-dehydro-16R-methyl-PGF2β-9-phenyl-acetate; M + -2H20 m / e 448.

13.14-dehydro-16R-methyl-PGF 2 - [9- [2 '] - tetrahydrofuryl propionate.

M + -2H20 m / e 456.

All the compounds in this example show clear IR absorption at -1718 cm and about -1150 cm which is typical of the carboxyl ester at Cg.

20

Example 11 143939

At 20-22 ° C, a solution of 2,3-dicyano-5,6-dichlorobenzoquinone (640 mg) in dry THF is added dropwise to a stirred solution of 5c, 13t-9a, 11a, 15S-trihydroxy-16, 16-dimethyl-prosta-5,13-diacetic acid methylstef-11, 15-bis-DIOX ether (0.57 g), triphenylphosphine (740 mg) and benzoic acid (345 mg) in dry THF (30 ml).

After 15 minutes, the solvent is evaporated in vacuo and the residue taken up with benzene and absorbed on a short silica gel column.

Elution with cyclohexane-ethyl ether (85:15) gives 0.63 g of 5c, 13t-90.11a, 15S-trihydroxy-16,16-dimethyl-prosta-5,13-diacetic acid methyl ester-9-benzoate-11, 15 -bis-DIOX ether, [α] D = + 0.2 ° (CHCl13).

Alkaline cleavage of ester groups is carried out by treating this compound (0.3 g) with 6% in 80% aqueous methanol (15 ml) at reflux temperature for 2 hours. The resulting alkaline solution of 16,16-dimethyl-PGF₂ø-11/15-bis-DIOX ether is cooled, acidified to pH 1.5 by the addition of 0.3M citric acid, and then heated at 35 ° for 3 hours to obtain deacetalization. After concentration in vacuo to remove most of the alcohol, the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated (NH₂SO ^) to neutrality, dried (Na₂SO ^) and evaporated to dryness. The crude product is absorbed on a silica gel column and subsequently eluted with C ^ ^ C ^ ethyl acetate (6: 4 ) gives 151 mg of 5c, 13t-90,11a, 15S-trihydroxy-16,16-dimethyl-prosta-5,13-diene acid (16,16-dimethyl-PGF2g), [α] D = +7.9 °; [a] 365 ° = +88 ° 3 ° (EtOH); methyl ester [α] β = + 7.8 ° (EtOH); methyl ester-9-benzoate, [a] D = -8.7 ° (chCl 3 ).

Example 12

A solution of diethyl azodicarboxylate (85 mg) in dry benzene (4 ml) is added dropwise (over 5 minutes) to a stirred suspension of p-phenylbenzoic acid (120 mg) in a solution of triphenylphosphine (158 mg) and PGF methyl ester-11, 15-bis-trimethylsilyl ether (154 mg). At the end of the addition, all the acid is dissolved and after 15 minutes the solution is evaporated in vacuo to dryness.

A solution of the residue in acetone (6 ml) and 0.2N aqueous oxalic acid (2 ml) is heated for 3 hours at 40 °, concentrated in vacuo to remove the acetone, diluted with water (2 ml) and extracted with ethyl acetate.

21 143939

The collected organic phases are washed to neutrality with water, dried, concentrated to a small volume and then absorbed onto a silica gel column. Subsequent elution with cyclohexane ether (40:60) and then with ether gives PGF + methyl ester-9-p-phenyl benzoate (152 mg), M + m / e 550.

By taking this compound and working as described in Example 1, the following is obtained: PGFip methyl ester, mp 106-107 ° C; PGFip, m.p. 126-128 ° C [α] β = -19.7 ° (EtOH).

Similarly, starting from the 13,14-dehydro-PGF1a methyl ester-11, 15-bis-THP ether, the following is obtained: 13.14-dehydro-PGF1β-methyl ester-9-p-phenylbenzoate; (oil). M + m / e 548.

13.14-dehydro-PGF-β-methyl ester; (oil). M + m / e 368.

13.14- dehydro-PGF ^ g. M + m / e 354; M + -2H20 m / e 318.

Examples 13 -4

A solution of 4x10 mol of 5c-9o, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl prost ~ 5-ene-13-ynoic acid 11,15-bis-THP ether (224 mg ), [a] Q = -7.8 ° (EtOH) in dry benzene (10 ml) is treated with an ethereal solution of distilled diazoethane (1.2 mol. equiv.) at room temperature for 30 minutes.

The mixture is evaporated in vacuo to dryness and the stirred solution of the resulting ethyl ester in dry THF (6 ml) is added in succession: three mol. triphenylphosphine, three mol. p-phenylbenzoic acid and then a solution of azobiscarboxylamide (218 mg) in dry THF (3 ml).

After 15 minutes, THF is removed in vacuo and the resulting crude bis-acetal-9 inverted ester hydrolyzed by treatment with acetone (10 ml) and 0.3N aqueous oxalic acid (5 ml) for 3 hours at reflux temperature.

Subsequent removal of the acetone in vacuo, extraction with ethyl acetate and chromatographic purification on a silica gel column yields 5c-93,11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid ethyl ester 9-p-phenyl benzoate.

Proceeding as described in Example 1, this compound is converted to 5c-9p, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid (18, 19,20-trinor-17-cyclohexyl-13,14-de-hydro-PGF 2 g), (a] Q = -2 ° (EtOH) and its ethyl ester, [a) D = -3 ° (CHCl 3).

Example 14 22 143939

A stirred solution of 570 mg of 5c-9a, 11a, 15R-trihydroxy-16S-methyl-20u) -homo-prost-5-ene-13-ynoic acid methyl ester-11, 15-bis-THP-ether in 25 ml of dry dimethoxyethane is treated sequentially with 790 mg of triphenylphosphine and 370 mg of benzoic acid and then, under external cooling at 20-22 ° C, with a solution of azodicarboxylamide 350 mg in dry dimethoxyethane. After 20 minutes, the reaction mixture is evaporated to dryness and partitioned between water and ethyl ether. The organic extracts are combined, dried and evaporated to dryness. After acidic hydrolysis with acetone and 0.2N oxalic acid, the crude 5c-9β, 11α, 15R-trihydroxy-16S-methyl-20u) -homo-prost-5-ene-13-ynoic acid methyl ester-9-benzoate is purified silica gel using cyclohexane and ethyl ether (80:20) as eluent to give 470 mg of pure 15-epi-16S-methyl-13,14-dehydro-20w-homo-PGF2- methyl ester-9-benzoate.

[α] D = -28 ° (CHCl3).

Proceeding as described in Example 1, 5c-93, 11a, 15R-trihydroxy-16S-methyl-20a) -homo-prost-5-ene-13-ynoic acid [α] + 4 ° (CHCl ^) is obtained and its methyl ester [a] + = + 8 ° (CHCl3).

Example 15

Using the procedure described in Examples 1 and 14, using diethyl azodicarboxylate as the hydrogen acceptor and starting from an 11,15-bis-tetrahydropyranyl ether methyl ester of the following prostanoic acids: 5c-9a, 11a, 15S-trihydroxy-16S-methyl 20a) -homo-prost-5-en-13-ynoic acid; 5c-9a, lla, 15S-trihydroxy-16-R-methyl-20a) -homo-prost-5-en-13-ynoic acid; 5c-9a, 11a, 15R-trihydroxy-16R-methyl-20-homo-pros t-5-and-13-acid acid; 5c-9a, 11a, 15R-trihydroxy-pros t-5-and-13-acid; 5c-9a, 11a, 15R-trihydroxy-16S-methyl-prost-5-en-13-ynoic acid; 5c-9a, 11a, 15R-trihydroxy-16-R-methyl-prost-5-en-13-ynoic acid; 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-acid acid; 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17- (2'-tetrahydrofuryl) prost-5-en-13-ynoic acid; 5c-9a, 11a, 15S-trihydroxy-18,19,20-trinor-17- (2'-tetrahydrothiophenyl) -prost-5-en-13-acid acid; 5c-9a, 11a, 15S-trihydroxy-19,20-di-nor-18-cyclohexyl-prost-5-en-13-acid; 5c-9a, 11a, 15S-trihydroxy-17,18,19,20-tetra-nor-16-cyclohexyl-prost-5-en-13-acid acid; 5c-9a, 11a, 15S-tr ihydroxy-20 ω-homoprost-5-en-13-acid; 23 143939 5c-9 α, 11α, 15R-trihydroxy-2Οω-homo-prost-5-and-13-acid; 5c, 13t-9a, 11a, 15S-trihydroxy-15-methyl-prosta-dienoic acid; 9a, 11a, 15S-trihydroxy-prost-13-ynoic acid; 9a, 11a, 15S-trihydroxy-20a) -homo-prost-13-acid acid, and using as an acylating agent benzoic acid, after deacylation of the 9-benzoate ester, the corresponding 9β-hydroxy-prostane methyl esters were hydrolyzed to the corresponding free acids. : 5c-9β, 11α, 15S-trihydroxy-16S-methyl1-20 ω-homo-prost-5-and-13-acid acid; M + -2H20 m / e 344.

5c-93,11a, 15S-trihydroxy-16R-methyl-20ω-homo-prost-5-and-13-acid acid M + -2H20 m / e 344.

5ο-9β, 11a, 15R-trihydroxy-16R-methyl-20m-homo-prost-5-and-13-acid acid * Μ + -2ΗΗ 0 m / e 344.

5c-93, lla, 15R-trihydroxy-prost-5-en-13-ynoic acid; M + -2H90 m / e 316.

5c-93, 11a, 15R-trihydroxy-16S-methyl-prost-5-and-13-acid acid; M -2H-0xT / 330.

+ z 5c-9P, 11a, 15R-trihydroxy-16R-methyl-prost-5-en-13-acid acid; M -2H20 n / e 330. 5c-93, 11a, 15S-trihydroxy-20m-homo-prost 5-en-13-ynoic acid; M + -2H20 m / e 330. 5c-9β, 11a, 15R-trihydroxy-20α) -homo-prost-5-and-13-acid acid; M + -2H20 m / e 330. 5ο-9β, 11a, 15S-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-acid acid; M + -2H20 m / e 342.

5ο-9β, 11a, 15S-trihydroxy-18,19,20-trinor-17- (21-tetrahydrofuryl) prost-5-en-13-ynoic acid? M + -2H20 m / e 344.

5ο-9β, 11α, 15S-trihydroxy-18,19,20-trinor-17- (2'-tetrahydrothiophenyl) -prost-5-en-13-acid, M + -2H20 m / e 360.

5c-9β, llα, 15S-trihydroxy-19,20-di-nor-18-cyclohexyl-prost-5-EH-13-ynoic acid; M + -2H20 m / e 370.

5ο-9β, 11a, 15S-trihydroxy-17,18,19,20-tetra-nor-16-cyclohexyl-prost-5-en-13-acid acid; M + -2H20 m / e 342.

5c, 13t-9P, 11a, 15S-trihydroxy-15-methyl-prostacetic acid; M + -2H20 m / e 332. 93, 11a, 15S-trihydroxy-prost-13-acid acid; M + -2H20 m / e 318. 93, 11a, 15S-trihydroxy-20m-homo-prost-13-acid. M + -2H20 m / e 332.

Example 16

A solution of 358 mg of ethyl azodicarboxylate in THF (4 ml) is added dropwise to a stirred solution of 270 mg of PGF 2α methyl ester-11, 15-bis-THP ether (5c, 13t, 17c-9a, 11a, 15S-trihydroxy-prosta -5,13,17-trienoic acid methyl ester-11, 15-bis-THP-ether), 520 mg of triphenylphosphine and 395 mg of p-phenylbenzoic acid in 9 ml of dry THF.

24 143939

After 10 minutes, the reaction mixture is concentrated to dryness, diluted with 15 ml of acetone and 6 ml of 0.2N oxalic acid and then refluxed for 2 hours. The acetone is evaporated in vacuo and repeated extractions are carried out with ethyl acetate. The organic phases are combined, washed to neutrality down water, dried and evaporated to dryness. The residue is absorbed on a short silica gel column (7 g), eluting with cyclohexane and ethyl ether (60:40) and then with ethyl ether. 328 mg of PGF 3β-methyl ester-9-p-phenylbenzoate (5c, 13t, 17c-93, 11a, 15S-trihydroxy-prosta-5,13,17-trienoic acid methyl ester-9-p-phenylbenzoate) are obtained.

I.R. 1718 cm ester at Cn.

9

Example 17 5c-93,11a, 15S-trihydroxy-16S-methyl-prosta-5-ene-13-ynoic acid (100 mg) and dicyclohexylcarbodiimide (100 mg) are added successively to a stirred mixture of 5 ml of anhydrous dichloromethane, 3 g of n-octanol and 0.3 ml of anhydrous pyridine.

The mixture is stirred for three hours and then absorbed on 50 g of silica gel eluting with cyclohexane, petroleum ether and ethyl ether. There are obtained 103 mg of 5c-93,11a, 15S-trihydroxy-16S-methyl-prosta-5-en-13-ynoic acid n-octyl ester, [α] p = + 3 ° (CHCl ^).

Example 18

A solution of 5c-9a, 11a, 15S-trihydroxy-16S-methyl-prost-5-ene-13-ynoic acid methyl ester-11, 15-bis-THP-ether, Ca] D = -9.7 ° (THF) ( 1.65 g) in anhydrous ether (5 ml) is added dropwise to a suspension of LiAlH 2 (0.4 g) in anhydrous ether.

After stirring for two hours at room temperature, decomposing excess LiAlH 2, filtering from the inorganic precipitate and evaporating to dryness, 5c-1,9a, 11a, 15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene is obtained. 11, 15-bis-THP ether (1.54 g), [α] D = -2 ° (CHClCl).

A stirred solution of this compound in dry benzene (30 ml) is treated successively with triphenylphosphine (3.15 g), p-phenylbenzoic acid (1.19 g) and then with a solution of ethyl azodicarboxylate (1.05 g), cooling to approx. 5 ° C - 10 ° C.

After 15 minutes, the organic phase is washed with water, 2N H2SO4, again with water for neutrality, dried Na2SO4 and evaporated to dryness. By filtration of the residue on silica gel (eluent: CH 2 Cl 2), 5c-1.9 (3, 11a, 15S-tetrahydroxy-16S-methyl-prost-13-yn-5-en-1,93-di-p-1 phenyl benzoate-11, 15-bis-THP-ether (2.42 g).

A solution of this compound in acetone (30 ml) is hydrolyzed by treatment for 8 hours at 36 ° C with 0.6N oxalic acid (20 ml).

25 143939

After evaporation of excess acetone and extraction with ethyl acetate, the obtained crude IIa, 15S-diol in methanol (25ml) is treated with K2CO3 (0.5g) for 4 hours at room temperature, then acidified to pH 4.5 with H2SO4 2N, filtered and evaporated to dryness.

The residue is absorbed on silica gel (20 g) and eluted with cyclohexane-ethyl acetate (1: 1) to remove the methyl-p-phenylbenzoate, then with ethyl acetate and ethyl acetate-methanol to give 5c-93, 11a, 15S-tetrahydroxy-16S-methyl-prost-13-yn-5-ene-, [α] D = + 6 ° (EtOH) (0.86 g).

Similarly, the following compounds were prepared starting from the 1-tetrazolyl and the 1-carboxyamide derivatives: 5ο-9β, 11α, 15S-trihydroxy-16S-methyl-prost-5-ene-13-yn-1-carboxyamide; [<x] D = + 6 ° (CHCl3).

5ο-9β, 11a, 15S-trihydroxy-16S-methyl-prost-5-en-1-yn-1-tetrazolyl · [a] Q = + 8.1 ° (CHCl3).

Example 19

To a solution consisting of PGF2a * 11, 15-bis-THP-ether methyl ester (0.44 g), hexamethyltriamine phosphine (0.48 g) and p-phenylbenzoic acid (570 mg) in benzene (30 ml) is added. a solution of ethyl azobiscarboxylate (0.5 g) in benzene (10 ml). On continuous stirring for one hour, dilution with benzene, washing with H2SC> 4 2N, water, sodium hydrogen carbonate and water, and evaporation to dryness afforded PGF-11,15-bis-THP-ether-methyl ester-9-p phenylbenzoate (5c, 13t-90,11a, 15S-trihydroxy-prost-5-en-13-ynoic acid methyl ester-9-p-phenylbenzoate-11, 15-bis-THP-ether) (0.95 g), which was converted to PGFβ-11,15-hydroxy methyl ester-9-p-phenylbenzoate (5c, 13t-90,11a, 15S-trihydroxy-prost-5-en-13-amino acid methyl ester-9-p-phenylbenzoate) [α] β = -41 ° (CHCl 3) according to the procedure of Example 4.

Example 20

A solution of 5c-16S-methyl-93,11a, 15S-trihydroxy-prost-5-ene-13-ynoic acid (16S-methyl-13,14-dehydro-PGF2g, 0.36g) in 0.1N NaOH ( 10.2 ml) was diluted with a pH 7.4 isotonic phosphate buffer solution (200 ml).

The solid was filtered off to give the sodium salt of 5c-16S-methyl-93,11a, 15S-trihydroxy-prost-5-ene-13-ynoic acid, [α D] = + 2.5 (EtOH 90%). The buffer solution used was obtained by dissolving 1.8 g of sodium dihydrogen phosphate, monohydrate NaH2 PO4, H2 O, 9.55 g sodium monohydrogen phosphate, bihydrate Na2HPO4.2H20, and 4.40 g sodium chloride in bid distilled water to a total volume of 1 liter.

Claims (2)

A process for preparing prostaglandin F. derivatives p of the general formula R1 HO EG R2 V (N) wherein D is a free or salt-converted carboxy group, a carboxyamide, a carboxyester, a tetrazolyl or a -CH 2 "OH group, R 1 is hydrogen or an organic acyl group, one of R and R represents hydroxy and the other hydrogen or alkyl, A represents -C 1 -CH 2" or cis-CH-CH- , E is -CH 2 -CH 2 -, trans-CH = CH- or -C = C-, R 4 G is -é- (CH-) -R 6, or cis-CHO-CH = CH-CH izn - z δ j * 5 R 3 wherein n is zero or an integer from 1 to 5, 4,5 and R is hydrogen or alkyl, / (CH 2> m R is hydrogen or the group -CH wherein X is -CH9 - X or an oxygen or sulfur atom, and m is an integer from 1 to 4, characterized by esterifying a corresponding prostaglandin F 1 compound in which known manner and an optionally present 1-hydroxy group option or is protected in a manner known per se, with a carboxylic acid and in the presence of a compound of the formula MY 1, wherein M is a metalloid of group V and Y is an alkyl, a dialkylamino or an aryl group , and in the presence of a hydrogen-acceptor compound, to directly obtain a corresponding PGFg-9 acyloxy derivative or PGFg-1,9-diacyloxy derivative to either (i) be deprotected from the protected 11 and 15 hydroxy groups and any protected 1-hydroxy group present and then, if desired, cleaves the acyloxy group at the 9-position and optionally acyloxy group at the 1-position to form a free hydroxy group or (ii) cleaves the acyloxy group at the 9-position and optionally acyloxy group at the 1-position forming a free hydroxy group, whereby the protecting groups from the protected 11 and 15 hydroxy groups and any protected 1-hydroxy group present are split off, and if desired converting a formed acid to an ester, or a formed ester to an acid or salt thereof with a cation. A process according to claim 1 for the preparation of prostaglandin-F derivatives of formula (I): β R 10 H 2 (Ί A r 2 Y 'm LL R wherein R represents a tetrazolyl or a -CH -OH group or a Is a amino group or an -OR group wherein RIV is hydrogen, C 1 -C 4 alkyl, trihaloalkyl or a pharmaceutically useful cation, R 1 is hydrogen or -COR wherein R R is hydrogen, C ^-C ^ alkyl or Φ- (CH₂) n ^ wherein n n is zero or an integer from 1 to 5 and Φ is a phenyl group which is unsubstituted or substituted by a or more substituents selected from the group consisting of halogen, alkoxy, trifluoromethyl, phenyl and cycloalkylalkyl, or R 1 is the following group: 28 CH39 (CH an integer from 1 to 4, X is -CH 2 - or an oxygen or a sulfur atom / and n, has the meaning given above, the 2 '3 feet of R and R are hydroxy and the other hydrogen or C -, - C , - alkyl, 4 * 5 '0 R and R are independently hy the drug or C 1 -C 6 alkyl, n is zero or an integer from 1 to 5, R 1 is hydrogen or a "Snap -CH Nx wherein X and m have the meaning given above, A is -CH2-CH2- or cis-CH = CH-, however - when R is a COR "group" wherein R "" IV 1 * is an -OR group - n represents 3 or 4, A is cis-CH = CH-, R 6 4 '5 * and R is hydrogen and one of R and R is hydrogen, the other is 16S- or 16R-C1-C6 alkyl, characterized by esterifying the 9-α-hydroxy group in a prostaglandin Fa Compound of Formula (II): OH I 1 '' <2 4 '(II) \ _ I r: 2 ri ▼ CsC-CC- (CHO) -R6 Z ^ 3 * 5' R'3 ΈΓ wherein R ^ is a tetrazolyl or a -CH 2 OH group with the hydroxy group protected in the conventional manner, or a COR "1 group wherein r" represents an amino or an OR 'group wherein R 1 is C 1 -C 2