JPH0148266B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostaglandin-like compounds.

Prostaglandin (hereinafter referred to as PG) is a prostanoic acid derivative with the following structure (),
Various types of PG are known.

PG generally has pharmacological properties. For example, it has a blood pressure lowering effect, a diuretic effect, an effect of inhibiting platelet aggregation, an effect of suppressing gastric acid secretion and gastrointestinal ulcers, a bronchodilatory effect, an effect of inhibiting lipolysis, and an effect of inhibiting egg implantation.

Therefore, prevention and treatment of hypertension, peripheral circulation disorders, asthma and gastrointestinal ulcers, treatment and prevention of thrombosis and myocardial infarction, induction of labor and abortion of pregnant mammals,
It is effective in improving fertility, regulating estrus, contraception and normalizing menstruation in female mammals, and is also effective as a diuretic.

We find new compounds that have the pharmacological effects of "natural" PG, or have stronger activity in one or more of their properties, or have completely unknown activity. As a result of extensive research, we replaced the carboxy group of prostanoic acid with a hydroxymethyl carbonyl group, introduced a carbonyl group to the carbon atom at the 6th position, and introduced a methyl group (S configuration) to the carbon atom at the 17th position. However, they discovered that a new compound with a methyl group introduced into the 20th carbon atom has a particularly strong anti-ulcer effect on the gastrointestinal tract among the pharmacological properties of "natural" prostaglandins, and the present invention was completed. .

The present invention is based on the formula [In the formula, the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] The present invention relates to a novel prostaglandin-like compound shown in the following, and its cyclodextrin clathrate compound.

In the structural formula of this specification, the dotted line (...) is
According to generally accepted nomenclature rules, the group attached to it is on the back side of the plane, i.e. α
- configuration, and the thick line (ⓓ) indicates that the group attached to it is in front of the plane, that is, the β-configuration.

According to the invention, prostaglandin analogs of the formula [In the formula, THP represents a tetrahydropyran-2-yl group, and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] It is obtained by hydrolyzing the compound shown in the following in the presence of an acid.

Hydrolysis reactions are generally well known and include (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid or hydrochloric acid;
In an aqueous solution of an inorganic acid such as sulfuric acid or phosphoric acid, preferably a water-miscible organic solvent, such as a lower alkanol such as methyl alcohol, ethyl alcohol (preferably methyl alcohol), or 1,
(2) Methyl alcohol, in the presence of an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid, at a temperature from room temperature to 90°C in the presence of an ether (preferably tetrahydrofuran) such as 2-dimethoxyethane, thioxane, or tetrahydrofuran; In an anhydrous lower alkanol such as ethyl alcohol at a temperature of 0°C to 90°C, or (3) in the presence of p-toluenesulfonic acid-pyridine complex in an anhydrous lower alkanol such as methyl alcohol or ethyl alcohol at a temperature of 10°C to 90°C. carried out at a temperature of

Preferably, a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methyl alcohol, acetic acid,
Mixture of water and tetrahydrofuran, phosphoric acid, p-
It is carried out using a mixture of toluenesulfonic acid-pyridine complex and methyl alcohol.

A compound represented by the formula [In the formula, the absolute configuration of the carbon atoms at the 1st and 6th positions represents S, R or a mixture of RS, respectively, and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] It can be obtained by subjecting the compound represented by the above to a mild oxidation reaction in which ring opening occurs simultaneously.

Preferred mild oxidation reactions include, for example: (1) halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, or in toluene;
Dimethyl sulfide-N at temperatures from ℃ to -30℃
This is carried out by reacting with -chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethylsulfide-chlorine complex, or thioanisole-chlorine complex, followed by treatment with triethylamine [J.Am.
Chem.Soc., 94 , 7586 (1972)], or (2) chromium trioxide in a halogenated hydrocarbon such as chloroform, methylene chloride, or carbon tetrachloride at a temperature from room temperature to 0°C, preferably 0°C. pyridine complexes (e.g. Collins reagent) or (3) from room temperature to −30 °C using Johns reagent prepared with chromium trioxide and dilute sulfuric acid in acetone.
carried out at a temperature of

A compound represented by the formula [In the formula, the absolute configurations of the carbon atoms at the 1st, 5th, 6th, and 3' positions each represent S or R, or a mixture thereof, and the double bond between the carbon atoms at the 13th and 14th positions is trans represents. ] After subjecting the compound shown to a dehydrobromination reaction,
It is obtained by subjecting it to a hydrolysis reaction under acidic conditions.

The reagents used in the dehydrobromation reaction are well known, for example, 15-diazabicyclo[5.4.0]
Bicyclic amines such as undecane-5-ene [DBU], 1,5-diazabicyclo[4.3.0]nonan-5-ene (DBN), or 1,4-diazabicyclo[2.2.0]octane (DABCO) Alternatively, alkali metal alcoholates, such as sodium or potassium lower alcoholates, may be mentioned. The reaction is carried out at a temperature of 40°C to 80°C. When using amines, the solvent may or may not be used, but preferably in toluene or without a solvent. When using an alcoholate, the same lower alkanol is used as the solvent. Good to use.

Hydrochloric acid is preferably used for the hydrolysis reaction under acidic conditions.

A compound represented by the formula [In the formula, the absolute configuration of carbon atoms at the 5th and 6th positions is
(5S, 6S), (5S, 6R), (5R, 6S) or (5R,
6R), and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] The compound represented by (2,4-dioxa-3-
It is obtained by a known method of subjecting methyl-hexyl)-tri-n-butylstannane to an addition reaction.

This reaction can be carried out using inert organic solvents such as ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, n-hexane,
using n-butyllithium and (2,4-dioxa-3-methylhexyl)-tri-n-butylstannane in a hydrocarbon such as n-heptane or a mixed solvent thereof at a temperature of 0 to -80°C. It is done. Preferably -78 in tetrahydrofuran
(2,4-dioxa-3-methylhexyl) at °C
-A solution of n-butyllithium in n-hexane is added dropwise to tri-n-butylstannane, and a solution of an aldehyde represented by the general formula () in tetrahydrofuran is added dropwise to the resulting mixture [J.Am. Chem.Soc., 100 , 1481 (1981)].

A compound represented by the formula [In the formula, the absolute configuration of carbon atoms at the 5th and 6th positions is
(5S, 6S), (5S, 6R), (5R, 6S) or (5R,
6R), and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] It can be obtained by subjecting the compound represented by to a reduction reaction. This reduction reaction can be carried out, for example, in hexane, tetrahydrofuran or toluene from 0°C to -80°C.
It is preferably carried out using diisobutylaluminum hydride (DIBAL) at a temperature of -78°C in toluene.

A compound represented by the formula [In the formula, the double bond between the carbon atoms at the 5th and 6th positions represents cis, and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] It can be obtained by brominating the carbon atom at the 5-position of the compound shown.

The bromination reaction is carried out in an aprotic organic solvent such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether, N,N-dimethylformamide, tetrahydrofuran, or a mixed solvent of two or more thereof at a temperature of -30°C to 70°C. with N-bromosuccinimide (NBS) or N-bromoacetamide at room temperature, preferably with NBS in tetrahydrofuran at room temperature.

A compound represented by the formula [In the formula, Ac is an acetyl group (i.e. CH ₃ CO-)
, the double bond between the carbon atoms at the 5th and 6th positions represents cis, and the double bond between the carbon atoms at the 13th and 14th positions represents trans. ] It can be obtained by converting the hydroxyl group attached to the carbon atom at the 15th position of the compound represented by the formula into a tetrahydropyran-2-yloxy group, and subjecting the acetoxy group attached to the carbon atom at the 9th position to a reaction for converting the hydroxyl group.

The reaction of converting the hydroxyl group attached to the carbon atom at position 15 into a tetrahydropyran-2-yloxy group is carried out using a condensing agent such as p
- in the presence of toluenesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoroborane etherate, phosphorus oxychloride, camphorsulfonic acid, 2,
It is carried out using 3-dihydropyran at temperatures from room temperature to -30°C.

In addition, the reaction of converting the acetoxy group attached to the carbon atom at the 9-position into a hydroxyl group is carried out in the presence of an alkali, using anhydrous potassium carbonate in an anhydrous alkanol having 1 to 4 carbon atoms, preferably methyl alcohol, between room temperature and 70°C. It is carried out at a temperature of

The compound represented by the formula can be obtained by the method of Reference Example 3(2) in JP-A-50-13362.

The cyclodextrin inclusion compound of a prostaglandin-like compound represented by the formula uses α-, β-, or γ-cyclodextrin or a mixture thereof, and is described in Japanese Patent No. 790979 and JP-A-47-39057. It can be obtained by using the method of

By converting to a cyclodextrin clathrate compound, the stability of the prosglandin-like compound represented by the formula increases, and the water solubility increases,
It is convenient for use as a medicine.

The prostaglandin-like compound represented by the formula and its cyclodextrin clathrate selectively have effective pharmacological properties specific to prostaglandins, and in particular have gastric acid secretion suppressing activity and gastric ulcer suppressing activity, and are effective against gastric ulcers. It is useful for the prevention and/or treatment of.

For example, in laboratory experiments, Takagi and
Method by Okabe [Ja.J.Pharmac., 18 , 9-18
(1968)], the compound of the present invention was administered at 20 μg/Kg of animal body weight or
When administered orally to rats immediately before water immersion at a dose of 50 μg/Kg of animal body weight, the occurrence of stress ulcers was inhibited by 56.8% and 91.8%, respectively.

The following Reference Examples and Examples show methods for producing the novel prostaglandin-like compounds of the present invention.

"TLC", "IR" in reference examples and examples,
The symbols "NMR" and "MS" stand for "thin layer chromatography,""infrared absorption spectroscopy,""nuclear magnetic resonance spectroscopy," and "mass spectrometry," respectively.

The proportions of solvents listed in the section for separation by chromatography indicate the proportions by volume.

Reference example 1 (5Z, 13E)-(9α, 11α, 15α, 17S)-9-hydroxy-11,15bis(tetrahydropyran-
2-yloxy)-17,20-dimethyl-prosta-5,13-dienoic acid methyl ester (5Z,13E)-(9α,11α,15α,17S)-9-acetoxy-11-(tetrahydropyran-2-yloxy )-15-hydroxy-17,20-dimethyl-
Prostar-5,13-dienoic acid methyl ester
A mixture of 4.8 g, dihydropyran 1.2 ml, p-toluenesulfonic acid 17 mg and methylene chloride 30 ml was stirred at room temperature for 10 minutes.

Triethylamine was added to the reaction solution to adjust the pH to 9-10, and the mixture was concentrated under reduced pressure.

Dissolve the residue in 30ml of methyl alcohol,
Add 3.8g of K ₂ CO ₃ and stir at 45℃ for 50 minutes.

The reaction solution was cooled to a temperature of -5°C, acetic acid was added to adjust the pH to 4, and the mixture was diluted with 350 ml of ethyl acetate, followed by washing with water, washing with saturated sodium bicarbonate solution, washing with water, and further washing with saturated brine. conduct.
After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the mixture was separated and purified by silica gel column chromatography using a mixture of cyclohexane and ethyl acetate as an eluent to obtain 4.7 g of the title compound having the following physical properties.

TLC (developing solvent, benzene: ethyl acetate =
3:1): Rf=0.25.

MS: m/e=462, 378, 360, 306.

Reference example 2 (13E)-(6RS, 11α, 15α, 17S)-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethyl-prost-13 -enoic acid methyl ester (5Z,13E)-(9α,11α,15α,17S)-9-hydroxy-11,15bis(tetrahydropyran-2
-yloxy)-17,20-dimethyl-prostar-
Dissolve 4.35 g of 5,13-dienoic acid in 60 ml of methylene chloride and 7.7 ml of tetrahydrofuran, add 1.65 g of N-bromosuccinimide, and stir at room temperature for 1 hour.

Add 350 ml of diethyl ether to the reaction mixture, wash with water, and then with saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain the crude title compound.
Obtained 5.8g.

TLC (developing solvent, cyclohexane: ethyl acetate = 2:1): Rf = 0.64.

MS: m/e=456, 438, 412, 377, 346.

IR (liquid film method): ν=2930, 2860, 1740,
1435, 1350, 1240, 1120, 1070, 1030,
1015, 970cm ^-1 .

NMR (CDCl ₃ solution): δ = 5.6 ~ 5.1 (2H,
m), 5.0-4.3 (3H, m), 4.3-3.0 (8H, m),
3.6 (3H, s) ppm.

Reference example 3 (13E)-(6RS, 11α, 15α, 17S)-5-decarboxyl-2-formyl-5-bromo-6,9
-Epoxy-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethyl-prost-13-enoic acid (13E)-(6RS,11α,15α,17S)-5-bromo-6,9 -Epoxy-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethyl-prost-13-enoic acid methyl ester (5.0 g) was dissolved in toluene (77 ml), cooled to -78°C, and then 25%
Add 13.6 ml of diisobutylaluminum hydride toluene solution dropwise and stir for 20 minutes.

Then, at a temperature of −78 °C, methyl alcohol
Add 1.97g and stir for 10 minutes.

Warm the reaction solution to -10℃, add 2.3 ml of water, and add 40 ml of water.
Stir for a minute. After filtering over Celite and separating the aqueous layer, it was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using a mixture of methylene chloride and ethyl acetate as an eluent. After separation and purification, 3.96g of the title compound
I got it.

TLC (developing solvent, cyclohexane: ethyl acetate = 2:1): Rf = 0.46.

MS: m/e=426, 408, 382, 347.

IR (liquid film method): ν=2920, 2860, 2700,
1725, 1440, 1370, 1340, 1120, 1070,
1010, 970cm ^-1 .

NMR (CDCl ₃ solution): δ = 9.7 ~ 9.6 (1H,
m), 5.7-5.1 (2H, m), 4.8-3.1 (11H, m)
ppm.

Reference example 4 (13E) - (1RS, 5RS, 6RS, 9α, 11α, 15α,
17S)-1-hydroxy-1-(2,4-dioxa-3-methyl-hexyl)-5-bromo-6,
9-Epoxy-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethylprostane (2,4-dioxa-3-methyl-hexyl)
-Dissolve 5.46 g of tri-n-butylstannane in 70 ml of tetrahydrofuran, cool it to -78°C, and prepare a solution of 1.6 mol/n-butyllithium in n-hexane.
Drop 7.91ml.

(13E)-(6RS, 11α, 15α, 17S)-5-decarboxy-2-formyl-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2
-yloxy)-17,20-dimethyl-prost-
A solution of 3.88 g of 13-enoic acid dissolved in 31 ml of tetrahydrofuran is added dropwise to the above solution at a temperature of -78°C, and stirred for 30 minutes.

The reaction solution was poured into 100 ml of saturated ammonium chloride aqueous solution, 350 ml of diethyl ether was added, and the ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and mixed with a mixture of methylene chloride and ethyl acetate. The product was separated and purified by silica gel column chromatography using as an eluent to obtain 3.62 g of the title compound.

TLC (developing solvent, cyclohexane: ethyl acetate = 1:1): Rf = 0.43.

MS: m/e=484, 440, 405.

IR (liquid film method): ν=3480, 2920, 2860,
1440, 1380, 1130, 1020 ^{, 975cm -1} .

NMR (CDCl ₃ solution): δ = 5.7 ~ 5.2 (2H,
m), 5.1-3.1 (17H, m) ppm.

Reference example 5 (13E) - (1RS, 6RS, 9α, 11α, 15α, 17S) -
1-(2,4-dioxa-3-methylhexyl)
-1,6-dihydroxy-6,9-epoxy-
11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethylprostane (13E)-(1RS, 5RS, 6RS, 9α, 11α, 15α,
17S)-1-hydroxy-1-((2,4-dioxa-3-methylhexyl)-5-bromo-6,9
-To 3.62 g of epoxy-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethylprostane, 5 ml of anhydrous toluene and 7.45 ml of diazabicyclo[5.4.0]undecane-5-ene (DBU) were added, Stir for 1 hour and 30 minutes at a temperature of 75°C.

Add 300ml of diethyl ether to the reaction solution,
After washing with 30 ml of normal hydrochloric acid, add triethylamine to adjust the pH to 9-10, wash with water, wash with saturated saline, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and elute a mixture of methylene chloride and ethyl acetate. Separation and purification was performed using silica gel column chromatography as a solvent to obtain 1.94 g of the title compound.

TLC (developing solvent, cyclohexane: ethyl acetate = 2:1): Rf = 0.08.

MS: m/e=591, 563, 533, 489, 461,
449, 405.

IR (liquid film method): ν=3450, 2920, 2860,
1700 (weak peak), 1440, 1370, 1340,
1120, 1015, 970cm ^-1 .

NMR (CDCl ₃ solution): δ = 5.7 ~ 5.1 (2H,
m), 4.8-4.3 (4H, m), 4.3-3.0 (11H, m)
ppm.

Reference example 6 (13E)-(11α, 15α, 17S)-1-(2,4-dioxa-3-methylhexyl)-1,6,9-
Trioxo-11,15-bis(tetrahydropyran-2-yloxy)-17,20-dimethylprostane 5.92 g of chromic anhydride and 30 g of Celite are added to 9.56 ml of pyridine and 147 ml of methylene chloride at room temperature, and then cooled.

(13E)-(1RS, 6RS, 9α, 11α,
15α,17S)-1-(2,4-dioxa-3-methylhexyl)-1,6-dihydroxy-6,9-
Epoxy-11,15-bis(tetrahydropyran-
Add 1.94 g of 2-yloxy)-17,20-dimethylprostane and 15 ml of methylene chloride, and stir at 5°C for 10 minutes.

100 ml of diethyl ether was added to the reaction solution, filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography using a mixture of methylene chloride and ethyl acetate as an eluent to obtain 1.2 g of the title compound. Obtained.

TLC (developing solvent, cyclohexane: ethyl acetate = 1:2): Rf = 0.72.

MS: m/e=591, 533, 418.

IR (liquid film method): ν=2920, 2860, 1745,
1720, 1440, 1370, 1120, 1070, 1030,
1015, 970cm ^-1 .

NMR (CDCl ₃ solution): δ = 5.7 ~ 5.1 (2H,
m), 4.9-4.4 (3H, m), 4.4-3.1 (8H, m),
4.0 (2H, s) ppm.

Example 1 2-decarboxy-2-glycoloyl-17S,
20-Dimethyl-6-keto-PGE ₁ (13E)-(11α,15α,17S)-1-(2,4-dioxa-3-methylhexyl)1,6,9-trioxo-11,15-bis( Tetrahydropyran-2
-yloxy)-17,20-dimethylprostane
Dissolve 1.19g in 1.8ml of tetrahydrofuran, 65%
Add 18 ml of acetic acid aqueous solution and stir at 80°C for 8 minutes.

Add 350 ml of ethyl acetate to the reaction solution, wash with water, wash with saturated brine, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, add toluene and azeotropically remove acetic acid completely.

The crude product was separated and purified by column chromatography to obtain 267 mg of the pure title compound.

TLC (developing solvent, ethyl acetate: formic acid =
400:5): Rf=0.20.

MS: m/e = 410 (M ⁺ ), 392 (M ⁺ -18),
374 (M ⁺ −18−18), 361, 356, 143.

IR (liquid film method): ν=3400, 2920, 2860,
1740, 1715, 1400, 1370, ^{1070, 970cm -1} .

NMR (CDCl ₃ solution): δ = 5.75 ~ 5.35 (2H,
m), 4.4-3.9 (2H, m), 4.22 (2H, s),
2.77 (1H, dd) ppm.

When the compound of the present invention is used to treat gastric ulcers in mammals including humans, especially humans, the dosage is determined depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc. The usual dose per adult is 0.5 μg to 1 mg by oral, rectal, intravenous, intramuscular, or subcutaneous administration.

Examples of pharmaceutical compositions used for administration include tablets, pills, powders, granules, capsules, suppositories, injections, etc., and these compositions can be prepared by known methods well known to those skilled in the art. can be manufactured.

The following reference examples illustrate pharmaceutical compositions containing compounds of the invention.

Reference example 7 2-decarboxy-2-glycoloyl-17S,
Dissolve 1 mg of 20-dimethyl-6-keto-PGE ₁ in 9.999 g of tricaprylin, fill it into soft capsules according to the usual method, and add 10μ of the active ingredient per capsule.
100 soft capsules of 100 mg containing g.

Claims (1)

[Claims] 1 formula [In the formula, the double bond between the carbon atoms at the 13th and 14th positions is
Represents a transformer. ] A prostaglandin-like compound or its cyclodextrin clathrate compound.