JPS581117B2 - 11-deoxy-ω-pentanol prostaglandins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to certain novel analogues of natural prostaglandins.

In particular, it relates to 11-deoxy-15-substituted-ω-pentanol prostaglandins.

Prostaglandins have diverse physiological effects on C2
0 unsaturated fatty acids.

For example, E and A series prostaglandins are potent vasodilators (Bergstrom et al.
siol. Scand. 64:332-33, 19
65 and Bergstrom et al. Life Sci. 6
: 449-455, 1967), which lowers systemic arterial blood pressure (vasomotor inhibition) when administered intravenously.

(Weelcs and King, Federatio
n Proc. 23:327, 1964: Bergst
rom et al., Acta Physiol. Scand. 6
4:332-33, 1965; Carlson et al. Act
a Med. Scand, 183:423-430
, 1968; and Carlson et al., ActaPhy
siol, Scand. 75:161-169, 19
69).

Another well-known physiological action of PGE1 and PGE2 is as bronchodilators (C
uthbert. Brit. Med. J. 4:723
-726, 1969+.

Yet another important physiological role for natural prostaglandins is related to the reproductive cycle.

PGE2 promotes parturition (Karim et al., J. Obs.
tet. Gynaec, Brit. Cwlth, 77
:200-210, 1970) and induced abortion (B
Ygdeman et al., Contraception, 4, 293 (1971)
, useful in suppressing fertilization (Karim, Contrace
tion, 3, 173 (1971).

Several prostaglandins of the E and F series have been patented as parturition inducers in milk supplements (Belgium patent 754158 and West German patent 20346).
41), PGE1, F2 and F3 have been patented as reproductive cycle control agents (South African Patent No. 69/6089).

It has been reported that decomposition of the corpus luteum can occur as a result of administration of PGF2 (Labhsetwar, Nature, 23
0, 528 (1971)), prostaglandins were found to be useful in controlling fertilization by a method that does not require smooth muscle stimulation.

Yet another known physiological effect for PGE1 is inhibition of gastric acid secretion (Shaw and Ramwell.
chester symp. on Prostagla
ndins, New York, Wiley, 1
968, p55-64) and inhibition of platelet aggregation (Em
mons et al., Brit. Med. J. 2:468-47
2, 1967).

It is known that such physiological activity will occur in vivo only for a short period of time after administration of prostaglandins.

The reason for this rapid cessation of activity is that natural prostaglandins are rapidly and effectively metabolically inactivated by β-oxidation of the carboxylic acid side chain and oxidation of the 15α-hydroxy group. It has been proven that (Anggard et al., Acta Physiol Sc
and. 81, 396 (1971) and other documents mentioned herein).

It was found that providing a 15-alkyl group to prostaglandins has the effect of increasing the duration of action, possibly by preventing oxidation of the C15-hydroxy group (
Yan Kee and Bundy, JACS 94;
3651 (1972), Kirton and Forb.
es, Prostaglandins, 1, 319 (
1972)).

Of course, it would be desirable to create prostaglandin-like compounds that have physiological activity equivalent to that of natural compounds, but with increased selectivity of action and increased linkage of activity.

By increasing the selectivity of action, serious side effects,
In particular, it is expected that systemic administration of natural prostaglandins will reduce gastrointestinal side effects often seen (
Lancet, 536, 1971).

These demands are met by the compounds of this invention.

The compounds of this invention are 15-substituted-11-deoxy-ω-pentanol prostaglandins of the following formula, their C15
epimers and C1 esters, and pharmaceutically suitable salts thereof: [wherein Ar is α- or β-naphthyl, phenyl, or the substituent is bromo, chromium, fluoro, trifluoromethyl, phenyl, lower alkyl or lower monosubstituted phenyl which is alkoxy: R is a hydrogen atom or methyl; Q is a single bond or a cis double bond; Z is a single bond or a trans double bond; R1 is a hydrogen atom , alkyl having 1 to 10 carbon atoms, or biphenyl.

] A particularly preferred compound is 11-deoxy-16-
Phenyl-ω-tetranor PGEO, racemic-11-deoxy-16-(β-naphthyl)-ω-tetranor PG
E2 11-deoxy-15-((-)-1-phenyl-1-ethyl)-ω-pentanol PGE2, 11-deoxy-16-(m-tolyl)-ω-tetranol PGE2
, 15-epi-11-deoxy-16-(m-tolyl)
-ω-tetranor PGE2, 11-deoxy-15-keto-16-(m-tolyl)-ω-tetranor PGE21
1-deoxy-13,14-dihydro-16-phenyl-ω-tetranor PGE2, 15-epi-11-deoxy-16-phenyl-ω-tetranor PGE2, 11-
Deoxy-15-((+)-1-phenyl-1-ethyl)-ω-pentanol PGE2,15-epi-11-deoxy-15-((+)-1-phenyl-1-ethyl)-
ω-pentanol PGE2, racemic-11-deoxy-1
6-(P-chlorophenyl)-ω-tetranor PGE2
Racemic-11-deoxy-15-keto-16-(β-naphthyl)-ω-tetranor PGE2 and 15-epi-
Deoxy-16-(p-chlorophenyl)-ω-tetranor PGE2.

As shown in Scheme A, the first step (1 → 2) involves the known aldehyde 1 (Corey and Ravindrana
than, Tetrahedron Lett. ,1
971, 4753) with the appropriate 3-ketophosphonate to produce enone 2.

The ketophosphonates are usually produced by condensation of a suitable carboxylic ester with a dialkylmethylphosphonate.

The desired methyl ester is typically condensed with dimethylmethylphosphonate.

Enone 2 is then reduced to enol 3 by zinc borohydride or an alkylborohydride similar to lithium triethylborohydride or potassium tri-sec-butylborohydride.

This reduction yields an epimer mixture that becomes the reactant for the next reaction.

Using this method, a prostaglandin-like compound having an α-hydroxy group at C15 is produced.

The epimer of 3 is used to generate a prostaglandin analog having a β-hydroxy group at C15.

Additionally, a mixture of C15 epimers is used to generate 15-keto prostaglandin analogs.

The epimers produced in the hydride reduction described above can be separated by column chromatography, preparative thin layer chromatography, or preparative high pressure liquid chromatography.

In the above reduction reaction, tetrahydrofuran or 1.2
-Ethers such as dimethoxyethane or acetonitrile are commonly used as solvents.

Enone 2 is catalytically reduced with hydrogen to give ketone 6.

This is a suitable starting compound for the preparation of the 13,14-dihydroprostaglandin analogues of this invention.

This reduction can be carried out either by homogeneous catalysts such as tris-triphenylphosphine rhodium chloride or by heterogeneous catalyst systems such as platinum, palladium or rhodium.

The stages in which the reduction is performed are not limited to the following.

Enone 2 is also reduced with boron hydride ions to alcohol 7 in a single step, or enol 3 is catalytically reduced to alcohol 7 under the conditions described above.

(3→4) indicates protection of free hydroxy groups by acid-labile groups.

Sufficiently acid-labile groups are preferred, but common ones include tetrahydropyranyl or dimethyl-
tert-butylsilyl, which can be introduced into the molecule by treatment with dihydropyran and an acid catalyst, usually p-toluenesulfonic acid, or dimethyl-tert-butylsilyl chloride and imidazole, respectively, in an anhydrous medium.

(4→5) shows the reduction of lactone 4 to hemiacetal 5 using a suitable reducing agent such as disobutyl aluminum hydride in an inert solvent.

Low reaction temperatures are preferred, with -60 to -80°C commonly used.

However, higher temperatures can be used as long as excessive reduction does not occur.

If desired, 5 is then purified by column chromatography.

As shown in Scheme A, compounds 4 and 5 are catalytically reduced to 8 and 9, respectively, by the method described above.

The conversion (6→9) is similar to the conversion (2→5) already described.

The synthetic route for two series of prossoglandin-like compounds of this invention is shown in Scheme B.

(5→10) is a Wittig condensation in which hemiacetal 5 is reacted with 4-(carboxy)butyltriphenylphosphonium (22) bromide in dimethylsulfoxide in the presence of sodium methylsulfinylmethide.

10 is then purified as described above.

E2 series prostaglandin analogue compound of this invention (
13) is prepared from intermediate 10 and can be oxidized by reagents that oxidize the hydroxy group without attacking the double bond.

This product is purified as described above to provide intermediate 12.

Intermediate 12 can be converted to the E2 series of prostaglandin-like compounds (13) of the present invention by hydrolysis with an acid catalyst (such as 65% acetic acid).

Various reduced prostaglandin analogues of this invention,
That is, 1,0 and 13,14-dihydro biseries prostaglandins are produced as shown in Scheme C.

Intermediate 6 can be converted to 19 by the steps described for the (2→10) conversion.

19 can then be converted to 20 by the steps described for the 10→15 conversion.

20 was catalytically reduced to 18 (R1
=THP or (CH3)2S:C(CH3)3).

This is a precursor of the 0 series prostaglandin analogues of this invention.

(16→17) is a selective catalytic hydrogenation of a 5-6 cis double bond at low temperature using a catalyst as described above.

A particularly suitable catalyst for this reduction is carbonated palladium, and the reaction temperature is -20°C.

17 (R1=THP or (CH3)SiC(CH3)
3 is not only a precursor of one series of prostaglandin-like compounds of this invention, but also a precursor of the 0 (zero) series.

This is because 17 can be reduced to 18 by the method described for (4-8).

Similarly, 16 can be reduced to 18 by the same method.

Removal of the protecting groups was carried out as previously described for 17, 18, 19 and 20 (R1=THP or (CH3)2SiC(C
H3) The protective group of 3) is removed by this method to obtain the “
1", "zero" and 13,14-dihydro 2 series prostaglandins can be produced.

Prostaglandin is “zero”, “1”, or 13.
Prostaglandins of the E series, the 14-dihydro 2 series, are prepared from 16, 17, 18, 19 and 20 by the methods described for the conversion of 10→11, 12, 13, 14, and 15.

R1=H, THP or (CH3)2SiC(C
H3)3 Furthermore, E1 series 15-substituted-ω-pentanol prostaglandin analogue compounds protect the hydroxyl group by introducing a dimethylisopropylsilyl group, selectively reduce the cis-double bond, and protect the protecting group. can be obtained directly from the corresponding "2 series" prostaglandin compounds by elimination of .

This reduction is carried out as described for 16→17, and removal of the protecting group is performed by converting the reduced protected compound into acetic acid and water (
3:1) for 10 minutes, or until the reaction is fully completed.

A series of 11-deoxy-15-substituted-ω- of this invention
Pentanor prostaglandin compounds can also be prepared by alternative synthetic routes summarized in Scheme D.

As a first step in the production of the above-mentioned prostaglandin compounds, hemiacetal 2-[5α-hydroxy-2β-benzyloxymethylcyclopent-1α-yl]acetaldehyde, r-hemiacetal, was prepared with reference to 5 → 10. - React with the disodium salt of (carboxy)butyltriphenylphosphonium bromide (22).

This intermediate can be converted by the methods detailed in the examples below.

As shown in Scheme D, hemiacetal 21 is added to reagent 2.
React with 2 to obtain 23.

23→24 esterifies the carbonyl group with diazomethane to produce a methyl ester intermediate.

Other blocking groups can be used provided they are stable to hydrogenation and mild acidic hydrolysis and can be removed by mild basic hydrolysis.

Such groups include alkyl having 1 to 8 carbon atoms, phenalthyl having up to 9 carbon atoms, phenyl, tolyl, p-biphenyl,
or α- or β-naphthyl.

Acylation of the methyl ester intermediate with acetic anhydride and pyridine produces the acetate intermediate.

Other blocking groups can be used if they are stable to hydrogenation and mild acid hydrolysis.

Such groups include alkanoyl having 2 to 9 carbon atoms, 1 carbon alkanoyl,
Fuenalcanoyl, benzoyl, troyl, p up to 0
-phenylbenzoyl or α- or β-naphthoyl.

Reduction of the protected benzyl ether with hydrogen and palladium on carbon in a suitable solvent containing a suitable acid catalyst, preferably ethanol and acetic acid or ethyl acetate and hydrochloric acid, provides the hydroxy compound, which upon oxidation with Collins reagent gives the aldehyde. 24 is obtained.

24→17 is an appropriate 3- under the conditions described for 1→2.
Treatment of 24 with the sodium salt of a ketophosphonate produces the enone, which is treated with lithium triethylborohydride or potassium tri-sec-butylborohydride and similar alkylborohydrides or zinc borohydride. Reduction produces enol.

The hydroxy group is then protected by treatment with dihydropyran to form the tetrahydropyranyl ether.

Other protecting groups may be used provided they are stable to mild basic hydrolysis and can be easily removed by mild acid hydrolysis.

Such groups are tetrahydrofuryl or dimethyl-t
-butylsilyl.

This protected compound is then contacted with aqueous sodium hydroxide to yield 17.

17 “1” series 11-deoxy-15- of this invention
Conversion to substituted -ω-pentanol prostaglandins is carried out by the method described above.

11-deoxy-15-mono-keto-15-substituted-
Omega-pentanol prostaglandin E is prepared as summarized in Scheme E.

25-26 is the oxidation of the C15 alcohol moiety of 25.

Although any reagent capable of oxidizing hydroxy groups without attacking double bonds can be used, Jones reagent is usually preferred.

The 13,14-dihydro 2-, 1-, and 0-series 15-keto prostaglandin E compounds of this invention are 25
→ Can be prepared from compounds 27, 29 and 31 as described above for 26.

In the above method requiring purification by column chromatography, suitable chromatography supports include neutral alumina and silica gel, with 60 to 200 mesh silica gel being particularly preferred.

Chromatography is performed using ether, as in the example below.
Ethyl acetate, benzene, chloroform, methylene chloride,
Suitably, the reaction is carried out in inert solvents such as cyclohexane and n-hexane.

If purification by high pressure liquid chromatography is desired, suitable supports include “Corasil”, “Poras”
il" and "Lichrosorb" using inert solvents such as ether, chloroform, methylene chloride, cyclohexane and n-hexane.

It will be appreciated that each of the above formulas represents an optically active compound.

Both optical enantiomers, e.g. 8.12-nat or 8
-12-ent is included in each of the above formulas in this specification.

The two optical antipodes can be easily prepared by the same method by using the appropriate optically active precursor aldehydes.

However, it will be clear that the corresponding racemate exhibits valuable biological activity since it contains the biologically active isomer mentioned above.

Such racemates are also included in the above formulas.

Racemic mixtures are readily prepared by the same method used herein, substituting the corresponding racemic precursor for the optically active starting compound.

Furthermore, whenever R is methyl, each of the above formulas
It has an optically active center at 16.

Both C16 optical antipodes (eg, R and S) are intended to be included in each of the above formulas.

The two C16 optical antipodes are easily prepared by the same method by using the appropriate optically active precursor phosphonates.

In multiple in vivo and in vitro tests, the novel prostaglandin compounds of this invention have comparable physiological activity compared to natural grosstaglandin, and are much more tissue selective and longer active. It has been shown.

These tests were: effects on smooth muscle isolated from the guinea pig uterus and guinea pig ileum and rat uterus, inhibition of histamine-induced bronchospasm in guinea pigs, effect on blood pressure in dogs, inhibition of stress-induced ulcers in rats, and effect on diarrhea in mice. and a test on suppressing excessive gastric acid secretion in rats and dogs.

The physiological responses observed in these tests are useful in determining the usefulness of test substances for the treatment of various natural pathological conditions.

Such usefulness includes vasodilation, antihyperoppression,
It has bronchodilatory, antiarrhythmic, cardiac stimulatory, antifertility, and antiulcer effects.

Generally, the advantage of E series 11-deoxy prostaglandins is that they are more stable than PGE2.

Furthermore, the novel 11-deoxy-15-substituted-
Omega-pentanol prostaglandins have highly selective active properties compared to the corresponding natural prostaglandins and often have a long duration of action.

The novel prostaglandin compounds of this invention have useful vasodilatory effects.

A first example of the therapeutic importance of these prostaglandin compounds is 11-deoxy-16-phenyl-ω-tetranorprostaglandin E.

and 15-epi-11-deoxy-16-(m-tolyl)-ω-tetranorprostaglandin E2 is PGE
It shows greatly increased potency and long-lasting antihypertensive effect compared to 2 itself.

At the same time, the smooth muscle stimulating effect is significantly suppressed compared to PGE2.

Similarly, other E compounds of this invention also exhibit desirable hypotensive effects.

Furthermore, 11-deoxy-16-(m-tolyl)-ω-
Tetranorprostaglandin E2 and 11-deoxy-16-(5-phenyl-α-thenyl)-ω-tetranorprostaglandin E2 exhibit high bronchodilatory effects, but their effects on non-vascular smooth muscle are reduced. are doing.

Similarly, other 11-deoxy-15-substituted-
Omega-pentanol prostaglandin E1 and E2 compounds also exhibit desirable bronchodilatory effects.

Another notable example of the therapeutic importance of these prostaglandin compounds is 11-deoxy-16-(β-naphthyl)-ω-tetranor PGE2 and 11-deoxy-15-keto-16-(β- (naphthyl)-ω-tetranor PGE2 exhibits potent selective anti-ulcer and anti-secretory effects.

Similarly, other PGE and 15-keto compounds of this invention also have these desirable gastrointestinal effects.

The C1 phenyl esters of the prostaglandin compounds of this invention are prepared from the corresponding acid by contacting with the desired phenyl in the presence of dicyclohexylcarbodiimide in an inert solvent.

The C1 alkyl or phenalkyl esters of the prostaglandin compounds of this invention are prepared by contacting the corresponding acid with the appropriate diazo compound in an inert solvent.

Such esters have the effect of the parent acid.

Esters of the prostaglandin compounds of this invention that are acylated at C15 are readily prepared from the corresponding parent compounds by acylation, usually using carboxylic anhydrides or carboxylic acid chlorides as acylating agents.

Such acyl groups are lower alkanoyl, benzoyl and substituted benzoyl in which the substituent is halo, trifluoromethyl, lower alkoxy or phenyl or formyl.

Such esters possess the effects of the original prostaglandin compounds.

Prostaglandin compounds having a β-hydroxy group at C15 and a C15 lower alkyl group have actions similar to their epimers.

However, in some cases, the selectivity that these compounds exhibit,
For example, the antihypertensive effect of the 15-epi-16-m-tolyl PGE2 compound exceeds that of its epimer.

Pharmaceutically suitable salts useful for the above-mentioned purposes are salts with pharmaceutically suitable metal cations, ammonium, amine cations or quaternary ammonium cations.

Particularly suitable metal cations are those derived from alkali metals such as lithium, sodium and potassium, alkaline earth metals such as magnesium and calcium, but also cations of other metals such as aluminum, zinc and iron. used in this invention.

Pharmaceutically suitable amine cations are those derived from primary, secondary or tertiary amines.

Examples of suitable amines are methylamine, dimethylamine,
Triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, β-phenyl Ethylamine, ethylenediamine, diethylenetriamine and similar 18 carbon atoms
Aliphatic, cycloaliphatic and aromatic aliphatic amines and heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine and their lower alkino derivatives such as 1-methylpyrrolidine, 1,4-dimethylpiperazine, 2 -methylpiperidine, etc., as well as amines with water-soluble or hydrophilic groups, such as mono-,
di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1
-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane, N-
Phenylethanolamine, N'-(p-tert-amylphenyl)diethanolamine, galactamine, N
- Methylglucamine, N-methylglucosamine, epinephrine, phenylepinephrine, efuedrine, procaine, etc.

Examples of pharmaceutically suitable quaternary ammonium cations are tetramethylammonium, tetraethylammonium,
These include benzyltrimethylammonium and phenyltriethylammonium.

The novel compounds of this invention can be used in various pharmaceutical preparations containing the compounds as such or in the form of their pharmaceutically suitable salts, and can be used intravenously, orally and externally, similar to natural prostaglandins. It can be administered by a variety of routes such as aerosol, intravaginal and intranasal.

In order to produce bronchodilation and increase intranasal efficacy, a suitable dosage form is a 11-deoxy-16-Ar-substituted compound using a fluorinated hydrocarbon as the propellant at about 3-500 μg/dose. Aqueous ethanol solution of ω-tetranor PGE1 or PGE2.

E2, E0 and 13,14-dihydro E2 of this invention
The compound is a useful antihypertensive agent.

For the treatment of hypertension, these drugs are approximately 0.5-10
Injected intravenously at a dose of μg/kg or 0.0
It is suitably administered in capsule or tablet form at a dosage of 0.5 to 0.5 mg/kg/day.

The 15-keto-16-Ar-substituted-ω-tetranorprostaglandin compounds or 16-4r-substituted-ω-tetranorprostaglandin E compounds of this invention are useful anti-ulcer agents.

For the treatment of peptic ulcers these drugs range from 0.005 to
It can be administered in capsule or tablet form at a dosage of 0.5 mg/kg/day.

Various inert diluents, adjuvants, or carriers can be used to prepare each of the above dosage forms or various other forms.

Such substances include, for example, water, ethanol, gelatin,
Lactose, starch, magnesium stearate, talc,
Vegetable oils, benzyl alcohol, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for pharmaceuticals.

If desired, these pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers, or other therapeutic agents such as antibiotics.

The following examples are merely illustrative of the invention and are not intended to limit it.

In these examples, all temperatures are indicated in Mr.
All melting and boiling points are uncorrected.

Reference Example 1 2-Oquine-3-phenylpropylphosphonate Dimethylmethylphosphonate (Aldrich) (6.2g)
; 50 mmol) of dry tetrahydrofuran (125 mmol)
l) The solution was cooled to -78° in a dry nitrogen atmosphere.

While stirring this solution, 21 ml of a 2.37 molar hexane solution of n-butyllithium (α-Inorg-anics, Inc.) was added at a rate that did not raise the reaction temperature above -65°. It was added dropwise over 18 minutes.

After stirring for an additional 15 minutes at -78°, 7.5 g (50.0 mmol) of methyl phenylacetate was added dropwise at a rate that kept the reaction temperature below -700 (20 minutes).

After 3.5 hours at -78°, leave it to reach ambient temperature.
Neutralized with 6 ml acetic acid and rotary evaporated to a white gel.

Add this gel to 75 ml of water and add 100 ml of the aqueous phase.
Extracted with three portions of chloroform, the combined organic phases were backwashed (50 cc H2O) and dried (MgSO4).
, concentrate (water aspirator) and distill the crude residue 3.
5 g (29%) of dimethyl 2-oxo-3-phenylpropylphosphonate (2) was obtained.

b. p. 134-5° (<0.1 mm). The doublet line representing CH3-O-CH2-CH2- is centered at 3.7δ (J=11.5cps, 6H), and the triplet line representing CH3-O-CH2-CH2- is centered at 3.3δ (J=11.5cps, 6H).
Centering on 7δ (2H), the singlet indicating CH3-O-CH2- is 328δ (3H), and the singlet for it is 3.9
In δ(2H), a broad singlet for C6H5- was shown at 7.2δ(6H).

Reference example 2 (nat.)-2-(5α-hydroxy-2β-(3-
oxo-4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (
2b) Dimethyl 2-oxo-3-phenylpropylphosphonate (6.93 g; 28.6 mmol) in 420 ml of anhydrous THF was dissolved in 1.21 g (28.6 mmol) in dry nitrogen at room temperature.
mmol) of 57% NaH.

2-[5α-
Hydroxy-2β-formylcyclopent-1α-yl]acetic acid and γ-lactone (1) were added.

After 95 minutes, the reaction was quenched by adding 4.2 ml of glacial acetic acid, filtered, the filtrate was evaporated, combined with 250 ml of ethyl acetate, 100 ml of saturated sodium bicarbonate solution (2 times), 150 ml of water (1 time). ), 150 ml of saturated brine (
1×), dried (Na2SO4), evaporated and after column chromatography (silica gel, Baker 60-200 mesh) 2.51 g of (nat.)-2-[5α-hydroxy-2β were obtained as a solid. −
(3-oxo-4-phenyl-trans-1-butene-
1-yl)cyclopent-1α-yl]acetic acid, γ-lactone +35.0° (c=0.8, CHCl3).

The NMR spectrum (CDCl3) consists of a pair of doublets for olefinic protons [6.80δ (1H, J=7,
16cps) and a singlet (7.26δ
(5H)) and the singlet (3.82δ(2H)), and the multiplet for the remaining protons (4.78-5.18δ(1H) and 1.2-2.8δ
(8H)).

Reference example 3 (nat.)2-(5α-hydroxy-2β-(3α-
Hydroxy-4-phenyl-trans-1-butene-1
(nat.)2-[5α-yl]cyclopent-1α-yl]acetic acid, γ-lactone (3b) in a dry nitrogen atmosphere at −78°
-Hydroxy-2β-(3-oxo-4-phenyl-trans-1-buten-1-yl)cyclopent-1α-
yl]acetic acid, γ-lactone (2b) (2.5g; 9.2
9.25 mmol) in dry THF (30 ml)
ml of 1.0 molar lithium triethylborohydride solution was added dropwise.

After stirring for 30 minutes at -78°, 20 ml of acetic acid/water (40:
60) was added.

After reaching room temperature, 40 ml of water was added and extracted with methylene chloride (3 x 50 ml), washed with brine (2 x 5 ml), dried (Na2SO4) and concentrated (water aspirator).

The residual oil was purified from silica gel (Baker's Analytical Reagent 60-20) using cyclohexane and ether as eluents.
Purified by column chromatography (0 mesh).

After eluting weakly polar impurities, 365 mg (nat.)
2-(5α-hydroxy-2β-(3α-hydroxy-
4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (3b)
5 containing mixed 3b and epi-3b
78 mg fraction, and finally (nat.) 2
-[5α-hydroxy-2β-(3β-hydroxy-4
-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone epi(3b)
A fraction of 489 mg was obtained.

1.0, CHCl3) and (nat.) epi-3b
CHCl3).

Reference example 4 (nat.) 2-[5α-hydroxy-2β-(
3α-tetrahydropyran-2-yloxy)=4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (4b) 805 to (2.96 mmol) in dry nitrogen (nat
．． ) 2-(5α-hydroxy-2β-(3α-
Hydroxy-4-phenyl-trans-1-butene-1
-yl)cyclobent-1α-yl]acetic acid, γ-lactone (3b) with 20 ml of anhydrous methylene chloride and 0.7
It was dissolved in a mixed solution (0°) with 35 ml of 2,3-dihydropyran, and 35.3~ of p-toluenesulfonic acid monoaqueous phase was added.

After stirring for 35 minutes, combine with 150 ml of ether, wash with saturated sodium bicarbonate solution (2 x 100 ml) then saturated brine (1 x 100 ml) and dry (Na2SO4).
, concentrated to 1.2 g (>100%) crude (nat.)
2-[5α-hydroxy-2β-(3α-tetrahydropyran-2-yloxy)-4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, producing γ-lactone (4b) did.

The IR (CHCl3) spectrum showed a moderate absorption for the trans double bond at 975 cm-1 and a strong absorption for the lactone carbonyl at 1770 cm-1.

Reference example 5 (nat.) 2-(5α-hydroxy-2β-
(3α-tetrahydropyran-2-yloxy-4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (5b) 2-[5α-hydroxy-2β-(3α -tetrahydropyran-2-yloxy)-4-phenyl-trans-
1-Buten-1-yl)cyclopent-1α-yl]acetic acid, a solution of γ-lactone (4b) (1.1 g; 2.96 mmol) in dry toluene (15 ml) under dry nitrogen.
Cooled to 78°.

4.05 at a speed where the internal temperature does not exceed -65°
20% diisobutylaluminum hydride [α-Inorganics (α-Inorgan)] in ml n-hexane
ics)] was added (15 minutes).

After stirring for an additional 30 minutes at −78°, anhydrous methanol was added until gas evolution ceased and the mixture was allowed to warm to room temperature.

Combine with 150 ml of ether, 50% sodium potassium tartrate solution (2 x 50 ml), brine (1 x 75 ml)
1), dried (Na2SO4), concentrated and after column chromatography 883 mg (nat.)
2-[5α-hydroxy-2β-(3α-tetrahydropyran-2-yloxy-4-phenyl-trans-
1-Buten-1-yl)cyclopent-1-yl]acetaldehyde, γ-hemiacetal (5b) was obtained.

Reference example 6 9α-hydroxy-15α-(tetrahydropyran-2
-yloxy)-16-phenyl-cis-5-trans-13-tetranorprostadienoic acid (10b) (4-carbohydroxy-n-butyl)triphenylphosphonium bromide (23) (3.83 g
) In a solution of dry dimethyl sulfoxide (10 ml), add 11
．． 9 ml of a 2.1 molar solution of sodium methylsulfinylmethide in dimethylsulfoxide was added.

2-[5α-hydroxy-2
β-(3α-tetrahydropyran-2-1-4
-Phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (5b) (1.2 g; 3.3 mmol) was dissolved in dry dimethyl sulfoxide (15.0 ml) for 20 minutes. It was dripped over several minutes.

After stirring at room temperature for 20 hours, it was poured into ice water and diluted with 10% HCl (
60 ml) and ethyl acetate (100 ml) were added.

Extracted with ethyl acetate (2 x 100 ml) and the combined extracts were washed with water (1 x 100 ml), brine (100 ml), dried (MgSO4) and evaporated to give a residue.

The residue was purified by silica gel column chromatography (Baker's analytical reagent 60-200 mesh) using chloroform and ethyl acetate as eluents.

After removing impurities with high Rf values, 2.0 g of 9α-hydroxy-15α-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-
ω-tetranorprostadienoic acid (10b) was obtained.

Reference example 7 9-oxo-15α-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13
-ω-tetranorprostadienoic acid (12b) 9α-hydroxy-11- cooled to −10° under nitrogen
Deoxy-15α-(tetrahydropyran-2-yloxy)-16-phenyl-5-trans-13-ω-tetranorprostadienoic acid (10b) (1.33g:
1 in a solution of 29 mmol) in reagent grade acetone (30 ml).
．． 26 ml of Jones reagent was added dropwise.

After 5 minutes at -10°, 1.0 ml of 2-propanol was added, stirred for 5 minutes, combined with 100 ml of ethyl acetate, washed with water (3 x 50 ml), brine (1 x 50 ml), and dried (MgSO4 ), concentrated to give 1.3 g of 9-oxo-15α-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-ω-
Tetranorprostadienoic acid (12b) was obtained.

Example 1 9-oxo-15α-hydroxy-16-phenyl-cis-5-trans-13-ω-tetranorprostadienoic acid (13b) 9-oxo-15α-(tetrahydropyran-2-yloxy)-16- phenyl-cis-5-trans-13
-Glacial acetic acid of prostadienoic acid (12b) (1.3g):
Water (65:35) mixture (20 ml) solution was heated at 25°C under nitrogen.
Stirred for 18 hours, then concentrated by rotary evaporation.

The residual crude oil was purified on silica gel [Mallinckrodt] using chloroform/ethyl acetate as eluent.
(Rodt) CC-7] column chromatography.

After eluting weakly polar impurities, 450 mg of the desired 9-okyne-15α-hydroxy-16-phenyl-cis-5
-trans-13-ω-tetranorprostadienoic acid (
13b) was obtained.

IR spectrum (CDCl3) is 3200-3650
Broad hydroxyl absorption at cm-1, 1740 cm-1
(ketone) and 1710 cm (acid), and a moderate absorption at 970 cm (trans double bond).

Reference example 8 9-oxo-15β-(tetrahydropyrabi-2-yloxy)-16-(m-tolyl)-13-trans-ω
-Tetranorprostenic acid (17c) 9-oxo-15β- containing 30 mg of 10% Pd/C
(tetrahydropyran-2-yloxy-16-(m-
Tolyl)-5-cis,13-transprostadienoic acid (16c) (200 mg; 0.445 mmol) in ethyl acetate (20 ml) was dissolved in 1 atm of hydrogen at 0-5
The mixture was stirred for 1 hour at °C.

Hydrogen absorption was stopped, filtered and evaporated to give 200 mg of 9-
Oxo-15β-(tetrahydropyran-2-yloxy)-16-(m-tolyl)-13-trans-ω-tetranorprostenic acid (17c) was obtained as a yellow oil.

Example 2 9-oxo-15β-hydroxy-16-( m-tolyl)-13-trans-ω-tetranorprostenic acid (
17c) 9-oxo-15β-(tetrahydropyran-2-yloxy)-16-(m-tolyl)-13-trans-ω
-Tetranorprostenic acid (17c) (200mg; 0
．． 445 mmol) of glacial acetic acid:water (65:35) mixture (
The solution was stirred for 18 hours at 25° under nitrogen and then concentrated by rotary evaporation.

The residual crude oil was purified by silica gel (Mallinckrodt CC-7) column chromatography using methylene chloride/ether as eluent.

After eluting highly polar impurities, 50 mg of the target 9-oxo-15β-hydroxy-16-(m-tolyl)-13
-trans-ω-tetranorprostenic acid (17c) was obtained.

IR spectrum (CHCl3) is 3650-3200c
m-1 with a broad hydroxyl absorption at 1740 cm-1 (
Ketone) and 1710 cm-1 (acid) showed strong carbonyl absorption and trans double bond absorption at 970 cm-1.

Example 3 9.15-dioxo-16-(m-tolyl)-5-cis,13-trans-ω-tetranorprostadienoic acid (
26c) 9-oxo-15α-hydroxy-16-(m-tolyl)-5-cis,13-trans-ω-tetranorprostadienoic acid (25c) (1
30 mg; 0.35 mmol) of reagent grade acetone (20
ml) 0.14 ml of Jones reagent was added to the solution.

After 3 minutes at 0°, add 5 drops of 2-propanol and
After stirring for several minutes, it was diluted with 50 ml of ethyl acetate, and water (2
x 20 ml), brine (1 x 20 ml), dried (Na2SO4) and concentrated by rotary evaporation.

The crude oil obtained was purified by silica gel (Brinkman) column chromatography.

After eluting weakly polar impurities, the desired 9-15-dioxo-16-(m-tolyl)-5-cis,13-trans-ω-tetranorprostadienoic acid (26c) was extracted with 1
Obtained 00mg.

The IR spectrum (CHCl3) is 1740 cm-1 (
ketone) and 1710 cm-1 (acid) and 1660 cm-1
Example 4 of strong carbonyl absorption at 1610 cm-1 (enone) (ent)-9-oxo-11-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-13
-ω-tetranorprostadienoic acid p-biphenyl (ent) -9-oxo-11-deoxy-1
5α-hydroxy-16-phenyl-cis-5-trans-1,3-ω-tetranorprostadienoic acid (365
mg: 1.02 mmol) of methylene chloride (40 m
l) To the solution were added 11.7 ml of a 0.1 molar solution of 1-(3-dimethylaminepropyl)-3-ethylcarbodiimide in methylene chloride.

Stirred under N2 for 18 hours, then concentrated. The residue was purified by silica gel chromatography using a benzene:chloroform mixture as eluent, mp 68-70°.
desired ( ent ) as a white solid (200 mg) of
- 9-oxo-11-deoxy-15α-hydroxy-16-phenyl-cis-5-trans-13-ω-
p-biphenyl tetranorprostadienoate was obtained.

Example 5 (rac)-9-oxo-11-deoxy-15α
-Hydroxy-16-phenyl-cis-5-trans-
ω-tetranorprostadienoic acid n-decyl (rac)-9-oxo-11-deoxy-15α
-Hydroxy-16-phenyl-cis-5-trans-
An ethereal solution of diazodecane was added to a solution of ω-tetranorprostadienoic acid (30 mg) in ether (25 ml) (the reaction was followed by tlc using 10% methanol in methylene chloride as eluent).

Rf of starting material = 0.33, Rf of product = 0.82)
.

It was then concentrated and the resulting crude product was purified by column chromatography to give the desired (rac)-9-oxo-11-deoxy-15 as 5 mg of a viscous oil.
n-decyl α-hydroxy-16-phenyl-cis-5-trans-ω-tetranorprostadienoate was obtained.

Example 6 Compounds in Tables ■ and ■ were obtained via the starting compounds and intermediates in Tables I to ■.

*D=trans double bond; S=single bond

Claims (1)

[Scope of Claims] 11-deoxy-ω-pentanor prostaglandin of the primary formula, its C15 epimer and C1 ester,
and their pharmaceutically suitable salts. Ar is α- or β-naphthyl, phenyl or monosubstituted phenyl (where the substituents are bromo, chloro, fluoro, trifluoromethyl, phenyl, lower alkyl or lower alkoxy); R is hydrogen or methyl; : R1 is hydrogen, alkyl having 1 to 10 carbon atoms, or biphenyl; W is a single bond or a cis double bond; Z is a single bond or a trans double bond. ]