JPS5825670B2 - Production method of prostanic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing novel brostanic acid derivatives, specifically, a method for producing novel brostannic acid derivatives, specifically, brostaglandin F2 α and prostaglandin E, which have the same spectrum of pharmacological properties and are useful for the same purpose.
The present invention relates to a method for producing a novel brostanic acid derivative similar to the naturally occurring compound known as 2.

However, the relative potency of this new compound with respect to specific pharmacological actions differs from that of the naturally occurring prostaglandins.

In particular, the new compounds have greater potency as luteol-degrading agents than the corresponding natural grosstaglandins.

That is, the grosstaglandin F2 α analog according to the present invention has superior efficacy to natural prostaglandin F2 α, and the grosstaglandin R2 analog according to the present invention has superior efficacy to natural prostaglandin E2. has.

The new compounds likewise have superior potency as stimulants of uterine smooth muscle over the corresponding natural grosstaglandins F2α and R2, and the prostaglandin E2 analogues according to the invention are particularly useful in this respect.

Furthermore, the novel compounds are advantageous when used as pregnancy regulators for contraception or for controlling the estrous cycle;
and is useful for adding to semen for artificial insemination of livestock;
This increases the success rate of insemination, especially in pigs.

Certain compounds are useful as vasodilators and bronchodilators and as inhibitors of platelet aggregation and gastrointestinal secretion.

The cyclopentane derivatives described herein may be named as brostanic acid derivatives, represented by the formula shown and numbered below: According to the invention, the formula: [wherein R1 represents a carboxy group and A represents represents a trans-vinylene group, R4 is a phenyl group or naphthyl which is unsubstituted or substituted by a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group, a nitro group or a phenyl group group, R2 represents a hydroxy group, R3 represents a hydrogen atom, and this compound contains O or 1 alkyl group having up to 4 carbon atoms as a substituent at the carbon atom at the 2-position], For compounds in which R1 is a carboxy group, pharmaceutically and veterinarily acceptable salts are obtained.

When the phenyl group or naphthyl group that is R4 is substituted, it is advantageous to have more than two of the above-mentioned substituents.

A suitable . . . rogene substituent in R4 which is a phenyl or naphthyl group is, for example, a fluorine, chlorine, bromine or iodine atom, and a suitable alkyl substituent is, for example, a methyl, ethyl or propyl group. Alkoxy groups are, for example, methoxy and ethoxy groups.

Therefore, suitable examples of R4 include phenyl group, ■-nabutyl group, 2-naphthyl group, fluorophenyl group, chlorophenyl group, bromphenyl group, iodophenyl group, nitrophenyl group, biphenylyl group, tolyl group, ethylphenyl group. group, fluorobylphenyl group, methoxyphenyl group, ethoxyphenyl group and trifluoromethylphenyl group.

Particularly good examples of R4 include phenyl group, 2-naphthyl group,
4-fluorophenyl group, 3- and 4-chlorophenyl group, 3,4-dichlorophenyl group, 4-nitrophenyl group, 4-biphenylyl group, 4-tolyl group, and 3- and 4-trifluoromethyl It is a phenyl group.

; A suitable alkyl substituent on the carbon atom in position 2 is, for example, a methyl group.

Examples of pharmacologically and veterinarily acceptable salts are ammonium, alkylammonium containing 1 to 4 alkyl groups of 1 to 6 carbon atoms, 2-hydro;
~3 alkanol ammonium and alkali metal salts, such as triethylammonium, ethanol ammonium, jetanol ammonium, sodium and potassium salts.

) Compounds of formula 1 contain at least 4 asymmetric carbon atoms, namely positions 8, 11, 12 and 15 (of which 8.1
The correlated configuration at the three positions 1 and 12 includes carbon atoms (as shown in formula 1), and the carbon atoms at positions 2.3.4 and 9 may also be asymmetrically substituted, thus It is clear that this compound can exist in racemic form and also in at least two optically active forms.

The useful properties of racemates can exist differently in optical isomers, and the present invention relates to racemic forms and any optically active forms of a set of compounds exhibiting the above-mentioned useful properties.

How to obtain optically active forms and to measure their biological properties is based on common knowledge.

Furthermore, the above definition encompasses both C-15 epimers and in all formulas shown later herein the stereochemistry at the C-8, 11 and 12 positions means the same as shown in Formula 1. .

An excellent group of brostanic acid derivatives according to the invention is that R4 is 3
One sentence consists of compounds in which R4 is a 4-chlorophenyl group, a 3,4-dichlorophenyl group, a 4-nitrophenyl group, or a 4-trifluoromethylphenyl group, and particularly excellent ones include compounds in which R4 is a 4-chlorophenyl group, a 4-trifluoromethylphenyl group, and a 4-chlorophenyl group. It is a compound that is a nitrophenyl group or a 4-trifluoromethylphenyl group.

For any pair of C-15 epimers, the more polar epimer is superior to the less polar epimer in silica gel thin layer chromatography.

The excellent brostanic acid derivatives according to the present invention are described in the Examples, but the particularly excellent ones are 9α, 11α, 1
5-trihydroxy-13-(4-)chloromethylphenyl)-16,17,18,19,20-pentanol-5-cis, 13-trans-prostadienoic acid, 15-(4-chlorophenyl) -9α・11α Bow 5-
Trihydroxy-16, 17, 18, 19, 20-pentanol-5-cis, 13-trans-prostadienoic acid, methyl 15-(4-chlorophenyl)-9α, 1
1α・15-trihydroxy-16・17・18・1
9,20-pentanol-5-cis, 13-trans-
Prostadienate, 9α・11α・15-trihydroxy-13-(4-nitrophenyl)-16.17.1
8,19,20-pentano'-5-cis,13-trans-prostadienoic acid, 15-(3-chlorophenyl)-9α,11α,15-)IJ hydroxy-16,1
7, 18, 19, 20-pentanol-5-cis, 13
-) lance-prostadienoic acid and 15-(3,4-cy:ylorphenyl)-9α, 11α, 15-trihydroxy-16, 17, 18, 19, 20-pentanol-
5-cis, 13-trans-prostadienoic acid theal.

The method of the present invention has the formula: [wherein R1, R3 and R4 represent the above, and R6
and R7 each represent a hydroxy group or a protected hydroxy group, and this compound has zero or one alkyl group having 1 to 4 carbon atoms at the carbon atom at the 2-position], for example, zinc borohydride, Reduction with aluminum tolyl isopropoxide or di-imbornyl oxydialuminium isopropoxide, followed by removal of the protecting groups if R6 and R7 are each protected hydroxy groups, and if a salt is required. is characterized in that the carboxylic acid thus obtained is reacted with a base to form a pharmaceutically and veterinarily acceptable salt.

Suitable protected hydroxyl groups are, for example, alkanoyloxy groups having up to 6 carbon atoms, such as the acetoxy group, or aroyloxy groups having up to 12 carbon atoms, such as the p-phenylbenzoyloxy group.

The starting material of formula (2) is a known compound 4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5
It can be obtained by treating α-hydroxy-6β-iodo-2-oxocyclopenteno(6)furan (X) with tributyltin hydride to yield a deiodinated lactone of formula M.

5α~Hydroxy group is tetrahydropyran-2- of the formula
protected as a yl ether, the lactone is reduced to a lactol of formula This is then esterified to protect the two hydroxyl groups as p-phenylbenzoic acid ester, and the acetal is hydrolyzed to give the formula (CH
30) By reacting with the phosphonate of 2PO0CH2COR4 in the presence of a strong base and decomposing the tetrahydropyranyl group with methanol, the starting material of the formula (R1-methoxycarbonyl R6=R?-hydroxy) is obtained.

As mentioned above, the compounds according to the invention have different pharmacological properties from the naturally occurring glosstaglandins F2α and R2.

That is, for example, 1-(4-chlorophenyl)-9α・1
1α・15-)IJ hydroxy-16・17・18・1
9,20-pentanol-5-cis, 13-) lance-
The highly polar C-15 epimer of prostadienoic acid is a luteol-degrading agent that has less activity than prostaglandin F2α (both have 50 times the activity, but grosstaglandin F2α
It has almost the same smooth muscle stimulating effect.

If the compounds according to the invention are to be used, for example for inducing labor, they are used analogously to the methods known for using the naturally occurring prostaglandins E2 and F1a; A virtually sterile aqueous solution containing up to 1/lal is administered by intravenous, extra-amniotic cervical or intra-amniotic injection until the onset of labor.

Furthermore, when the brostanic acid derivatives produced by the method of the present invention are used for the above-mentioned purposes, they can be used in a pharmaceutical or veterinary manner, consisting of such brostanic acid derivatives and a pharmaceutically or veterinarily acceptable diluent or carrier. formed into a composition.

These compositions may be in a form suitable for oral administration, such as tablets or capsules, in a form suitable for inhalation, such as an aerosol or solution suitable for spraying, in a form suitable for intrauterine injection or parenteral administration, such as a virtually sterile aqueous solution; It can be used in the form of suppositories suitable for anal or vaginal use.

As mentioned above, when the present compounds are to be used for induction of labor during parturition, the preferred composition is in fact a sterile aqueous solution.

The composition can be manufactured by conventional methods and can include conventional excipients.

Next, the present invention will be explained in detail with reference to examples, but the present invention is not limited thereto.

RF values are based on thin layer chromatography on Merck silica gel unless otherwise stated.

Example 1 Methyl 15-(4-methoxymethylphenyl)-15-
Oxo-9α・11α-di(4-phenylbenzyloxy)-5-cis, 13-)7nesuprostadienoate) (110) was heated in anhydrous toluene (5,0yd) at room temperature under an argon atmosphere. Stir with toluene (2.0m
1) with a 0.323 molar solution of di-isobornyl oxydialuminum isopropoxide dissolved in the solution.

After 1% of the time, the hardware was dissolved in water (0.5 ml) and ethyl acetate (1 ml).
, 0rILl), and while washing the filter pad with ethyl acetate (2 x 4ml)
o).

The organic phase was isolated, washed with brine (4 ml), dried over magnesium sulfate and filtered, and the solvent was evaporated to give a crude oily product which was mixed with Florisil (2 g).
Chromatography was performed.

Elution with 5-10% ethyl acetate in toluene yields the enol i.e. methyl 15-hydroxy-15-(4-meth)oxymethylphenyl)-9α·11α-di(4-phenylbenzoyloxy)-5-cis, 13 -) Lance-prostagenoate was produced as a thick oil.

RF=0.4 (20% methyl acetate in methylene dichloride)
.

Crude enol (69~), methanol (4aβ), water (
0.7 ml) and N-potassium hydroxide (0.9aβ) under an argon atmosphere for 18 hours.

The mixture was acidified to pH 5 with oxalic acid, extracted with ethyl acetate, the extract was washed with a 1:1 mixture of saturated prine/water,
Dry.

Evaporation of the solvent yielded a residue that separated two C-15 epimers (RF = 0.3 and 0.4) on thin layer chromatography using 3% acetic acid in ethyl acetate.

n0m, r of each epimer in shooterolated acetone.

The spectrum showed the following characteristic peaks (δ values) near, 2
~7.4.4H1 aromatic 5.1~5.6.5H, 4 olefinic protons and -C
H(OH), CH=CH- 4,4,2H, CH2.OMe 3.32.3H1-CH.OMe.

The mass spectrum is (M-CH3)+= It showed 677.3493.

Calculated value for C35H6406S i 4 = 677.
3547 (regarding tetra-trimethylsilyl derivatives)
.

Methyl 15-(4-
methoxymethylphenyl)-15-oxo-9α・11
α-di(4-phenylbenzyloxy)-5-cis,13-)7nesuprostadienoate can be obtained as follows: 4β-dimethoxymethyl-2 in anhydrous toluene (40 TLl)・3.3aβ・6aβ-tetrahydro-5α-hydroxy-6β-iodo-2-oxocyclopenteno (
6) Hydrogenation of furan (4,Of) at 80 °C under argon atmosphere) IJ -1 with n-butyltin (6,6f)
Stirred for 8 hours.

The solvent was evaporated under reduced pressure and the residue was dissolved in petroleum ether (boiling point 4
0-60℃.

100 rul) for 30 minutes. The solvent was decanted and the residual oil was chromatographed on Florisil (5 of).

Elution with a mixture containing 25% ethyl acetate in toluene and finally with ethyl acetate gave 4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α as an oil.
-Hydroxy-2-oxocyclopenteno(6)furan was obtained.

RF=0.3 (20% acetone in chloroform).

The n0 m, r, spectrum in deuteriochloroform showed the following characteristic peaks (δ values): 3.40 and 3.42.6 H1 singlets, 2, methoxy 4.04-4.36, IH1 multiplet term, 5β proton IH
, doublet, CH(OMe)2 1H1 multiplet, 6aβ proton 4β-dimethoxymethyl-2,3,3aβ,6aβ-tetrahydro-5α-hydroxy-2-oxocyclopenteno(5)furan (4,011) was stirred in anhydrous toluene (3QTLl) under an argon atmosphere and the remaining solution was dissolved in an excess of freshly distilled dihydropyran (17TLl).
and then with 2.0 ml of a 0.1% W/V solution of toluene-p-sulfonic acid in anhydrous tetrahydrofuran.

After % time the mixture was treated with pyridine (0.50 ml) and
Then ethyl acetate (15 oml) and saturated bicarbonate (I)
Jum (75 ml).

The organic phase was isolated, washed with saturated brine (50 TLl), dried over magnesium sulfate, filtered and the solvent was evaporated to give the crude lactone, 4β-dimethoxy-methyl-2
・3.3aβ・6aβ-tetrahydro-2-oxo-5
[alpha]-(tetrahydropyran-2-yloxy)-cyclopenteno]furan was obtained.

RF-0,70 (20% acetone in chloroform).

The crude lactone (6,2P) was dissolved in anhydrous dimethoxyethane (
1207nl? ) under an argon atmosphere at about -60 DEG C. (chloroform-Drikold cooling bath) and 1.7 mol (11.2 ml) of di-isobutylaluminum hydride were added.

After 30 minutes methanol (3d) was added and the mixture was heated to room temperature and partitioned between ethyl acetate (600TLl) and saturated prine/water (1:1) (30QTLl).

The entire mixture was passed through a "hyphen" and the two phases were separated.

The aqueous phase was re-extracted with ethyl acetate (3007711) and the combined organic phases were washed with water (100 ml), dried over magnesium sulfate, filtered and the solvent was evaporated to give the crude lactol (Vl), i.e. 4β -dimethoxymethyl-2.
3,3aβ,6aβ-tetrahydro-2-hydroxy-
5α-(tetrahydropyran-2-yloxy)-cyclopenteno(6)furan resulted as an oil.

RF=0.4 (20% acetone in chloroform).

A stirred solution of (4-carboxybutyl)triphenylphosphonium bromide (24,8P) dissolved in anhydrous dimethyl sulfoxide (150 ml of DMSO) was gradually cooled under an argon atmosphere and in an ice-water bath, and then dissolved in DMSO (50 ml).
A solution of the corresponding ylide was formed by treatment with 2 mol of sodium methanesulfinylmethyl in 4.5 ml, 2.5 eq).

Crude lactol in anhydrous DMSO (150ml) was then added to the ylide solution at room temperature.

The mixture was stirred for 1% time and then water was added.

The DMSO was then evaporated under high vacuum at a temperature not exceeding 50°C.

Dissolve the remaining gum in ether (4 x 225ml) and water (15oTL).
l).

The aqueous phase was isolated and acidified to approximately pH 4 with 2N oxalic acid, then a 1:1 mixture of ether and pentane (3x300TI
Extracted with Ll).

The extracts were washed with saturated brine (150 ml), dried over magnesium sulfate, filtered and the solvent was evaporated to yield the crude acid, 2β-dimethoxymethyl-5α-hydroxy-3α-(tetrahydropyran-2-yloxy). Cyclopent-1α-ylhept-5-cis-enoic acid results as an oil, which is suitable for use in the next synthetic step.

The product was purified by chromatography on sample silica (70:1) as a dark oil, eluting with 2% methanol in toluene.

RF=0.4 (5% methanol in methylene chloride), n6m, r in deuterochloroform, the spectrum showed the following characteristic peaks (δ values): 3.35.6 H1 singlet, methoxy 3. 3-3.65, IH.

3.68-4.0, IH.

4.00-4.19.2H1 multiplet 1. CH-0-4,
19-4.38, LH.

4.6-4.8, IH.

5.09-5.78.2H, multiplet, olefinic protons Crude acid (4,48P) in methanol (45 ml) was dissolved in toluene-p-sulfonic acid (24
0~) for 2% of the time.

The solution was then partitioned between ethyl acetate (300TLl) and saturated sodium bicarbonate (60r/Ll) followed by saturated brine (60TrLl).

The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated to yield the crude ester diol, namely methyl 2β-dimethoxymethyl-3β·5β-dihydroxycyclobent-1α-ylhea”)-5-cis-enoate. was formed as an oil.

R,F =, 0.65 (10% methanol in methylene chloride).

The n, m, r spectrum in deuteriochloroform showed the following main peaks (δ values): 3゛39·6H·singlet, f7. 3 bases 3.64.3
H1 singlet 4.03-4.3.3H multiple ring, Cdan-〇- doublet,
Cdan-(OMe)2 5.1-5.7.2H1 multiplet, olefinic proton.

The crude ester-diol (3,3f) was dissolved in anhydrous pyridine (50 TLl) under an argon atmosphere, treated with p-phenylbenzoyl chloride (9,2P) and the mixture was stirred for 17 hours.

Water (0.8 ml) was then introduced and stirring continued for 3-4 hours.

The mixture was evaporated under reduced pressure and toluene was added to aid azeotropic removal of pyridine.

The residue was partitioned between toluene (300ml) and saturated sodium bicarbonate solution (1501 rLl).

The entire mixture was filtered through a "hifu" and the organic phase was isolated.

The aqueous phase was extracted with toluene (150 ml), the organic extracts were combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and the solvent was evaporated to give a solid crystalline residue. .

This was thoroughly triturated with methanol (70 ml), the mixture was filtered, and the product was washed with methanol (3xlOml) to give the dimethyl acetal i.e. methyl 2β-dimethoxymethyl-3α·5α-di(4-phenylbenzoyloxy)cyclobento -1α-ylhept-5-cis-enoate resulted as a white solid.

Melting point 104.5-106.5°c, RF=0.5 (
) 5% acetone in toluene).

The n, m, r, spectrum in deuteriochloroform showed the following characteristic signals (δ-values): 3.41.3H1 singlet 3.47.3H1 singlet Methyl 3.52.3H, singlet 4.59-4.61, IH1 double double-℃H (OMe
) 25.17-5.70.4H, multiple rings, 2xnCH
-0- and 2 olefinic protons 〇- The analytical sample recrystallized three times from ethanol has a melting point of 105~
The temperature was 107°C.

Methyl 2β-dimethoxymethyl-3α・5α-di(4
-phenylbenzoyloxy)-cyclobento-1α-
Irhea'')-5-cis-enoate (500 m?) was stirred vigorously for 10 minutes under an argon atmosphere in a two-phase system containing 2% Impropatol in chloroform (20 ml) and concentrated hydrochloric acid (10 ml).

The chloroform phase was isolated and the aqueous phase was dissolved in chloroform (20 r
rLl).

The organic phases were combined and then added to a saturated aqueous solution of sodium bicarbonate (
20 ml) and saturated brine (10 ml), dried over magnesium sulphate, filtered and the solvent was evaporated.

The crystalline oily residue was dried under high vacuum to give methyl 2β-formyl-3α·5α-di(4-phenylbenzyloxy)cyclobent-1α-ylhept-5-cis-enoate, which was purified on Merck silica gel GF 254 plates. The RF was 0.4 (5% ethyl acetate in toluene).

The n0m, r, spectrum in deuteriochloroform was consistent with the desired structure and showed the following main signals (δ values): 3.51.3H1 singlet, methyl ester 5.3-5.
6.4H, multiple rings, and olefinic protons 〇- 7,22~7,73.14H1 multiplet, remaining aromatic protons 10.01~10.14, IH1 double double -CdanO6 melting point 93~ An analytical sample at 97°C was obtained by trituring the product with ether.

Dimethyl 2-(
A solution of 4-methoxymethylphenyl)-2-oxophosphonate (104-, 1.5 eq.) was stirred under an argon atmosphere, cooled in a chloroform/tricold bath, and dissolved in hexane (148 μl). treatment with 2.2 moles of lithium and then after a few minutes with tetrahydrofuran (2.2 moles).
methyl 2β-dimethoxymethyl-3α・5 in oml)
α-di(4-phenylbenzoyloxy)cyclopent-1α-ylhept-5-cissuenoe) (157
1n9) solution.

The cooling bath was then removed and after 2 hours the pH was adjusted to approximately 6 by adding a few drops of acetic acid and then water (200 μl).

The solvent was evaporated under reduced pressure and the residue was partitioned between water (15 rrLl) and ethyl acetate (1 x 30 ml, 1 x 15 ml).

The organic phase was isolated, washed with water (10ml), then dried over magnesium sulphate, filtered and the solvent was evaporated to give a thick oil.

This oil was purified by chromatography on Florisil (2 g) eluting with 10% ethyl acetate in toluene to provide the desired enone starting material, methyl 1
5-(4-Methoxymethylphenyl)-15-oxo-9α·11α-di(4-phenylbenzyloxy)-5-cis,13-)7nesuprostadienoate resulted as an oil.

RF = 0.4 (20% ethyl acetate in methylene dichloride).

The n0m, r, spectrum in deuteriochloroform showed the following main peaks (δ values): 3.35.3H,
Singlet, methoxy3.50.3H1 singlet, -COOCH34,45,2
H-CH0CH3)-2 5,4-5.6.4H, multiplet, cis-olefinic proton and 6.12-7.1, LH, doublet, =CH,C0-7,
3-7.7.15H1 multiplet, remainder of aromatic protons + CC
--CH.

0-0 Example 2 The procedure described in Example 1 was repeated using the appropriate enone, yielding the compounds shown in the table below.

Mass spectra are measured using tetra-(trimethylsilyl)
This was done on derivatives.

Characteristic data is phosphonate reagent (CH30)2PO0C
Shown for H2COR4 and for enone starting material.

(a) Mass spectrum was (M-phenylbeizyl) Ju-568, 1973.

Claims (1)

[Claims] 1 Formula: [In the formula, R1 represents a carboxyl group, and A is trans-
represents a vinylene group, R4 is a phenyl group or a naphthyl group which is unsubstituted or substituted with a halogen atom, trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group, a nitro group or a phenyl group; Brostanic acid derivatives of the following formula, R2 represents a hydroxy group, R3 represents a hydrogen atom, and this compound contains O or 1 alkyl group having up to 4 carbon atoms as a substituent at the carbon atom at the 2-position, and pharmaceuticals. In order to obtain a scientifically and veterinarily acceptable salt, the formula:
and R7 each represent a hydroxy group or a protected hydroxy group, and this compound has 0 or 1 alkyl group having 1 to 4 carbon atoms at the carbon atom at the 2-position] is reduced, and R6 and R7 are A process for producing brostanic acid derivatives, characterized in that, in the case of a protected hydroxy group, the protecting group is subsequently removed, and if a salt is required, the carboxylic acid thus obtained is reacted with a base.