JPH0238593B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel prostaglandin ₁ derivative and a method for producing the same. Prostaglandins are local hormones with high biological and pharmacological activity;
Therefore, many studies on these derivatives have been conducted. The present inventors focused on the anti-ulcer and anti-asthmatic effects of prostaglandin ₁ , and as a result of intensive research to obtain a new prostaglandin ₁ derivative, they discovered a novel prostaglandin ₁ derivative and its production method. This is the heading that led to the present invention. Prostaglandin obtained by the present invention
₁ derivative is the following formula [] [In the formula, R ¹ is a hydrogen atom or a lower alkyl group, R ²
represents a cycloalkyl group having 3 to 10 carbon atoms, R ³ represents a hydrogen atom or a methyl group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a trialkylsilyl group. ] It is a prostaglandin ₁ derivative represented by In formula [], R ¹ represents a hydrogen atom or a lower alkyl group, and such lower alkyl groups include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and in particular, a hydrogen atom or a lower alkyl group. Methyl group is preferred. or
R ² represents a cycloalkyl group having 3 to 10 carbon atoms,
Among them, a particularly preferable example is a cyclohexyl group. Further, R ³ represents a hydrogen atom or a methyl group. R ⁴ and R ⁵ represent a hydrogen atom or a trialkylsilyl group (hereinafter also referred to as a protecting group), and as a protecting group, it exists stably without being eliminated during the reaction and post-treatment steps carried out in the present invention. Any protective group may be used as long as it is a protective group. Specific examples of such protecting groups include t-butyldimethylsilyl group, silyl ethers of diphenylmethylsilyl group, and particularly preferred examples include t-butyldimethylsilyl group. can be mentioned.
Furthermore, the protecting groups used in R ⁴ and R ⁵ may be the same or different. The prostaglandin ₁ derivative according to the present invention has six asymmetric carbon atoms, that is, the asymmetric carbon atoms are present at the prostaglandin number positions 6, 7, 8, 9, 11, and 15. The present invention includes R configurations of these asymmetric carbon atoms, or mixtures thereof in arbitrary proportions. Among these, in the prostaglandin ₁ derivative of the present invention, the substituents on the cyclopentane ring are as follows:
Prostaglandin 1 derivatives have a cis relationship with each other, and these three substituents and the 12th-position substituent have a trans relationship, that is, _the following formula [
Compounds represented by a], [b], [c] and [d] and their enantiomers, or mixtures thereof in arbitrary proportions are preferred. Furthermore, when R ¹ of the prostaglandin ₁ derivative obtained in the present invention is a hydrogen atom, it can also be made into a salt with a base by taking advantage of the fact that it has a carboxylic acid moiety in the molecule. In this case, any base may be used as long as it is a pharmacologically acceptable non-toxic salt. Examples of the base include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, Inorganic bases such as sodium carbonate, potassium bicarbonate, and ammonia, and organic bases such as ethanolamine, diethanolamine, and morpholine are preferably used. The prostaglandin ₁ derivative represented by the above formula [] of the present invention or the non-toxic salt of the acid when R ¹ represents a hydrogen atom is produced as follows. In other words, the following formula [] [In the formula, R ² and R ³ are the same as defined above, and R ^4-1 ,
R ^5-1 is the same or different and represents a protecting group. ] The cyclopentanol derivative represented by the following formula [] [In the formula, R ^1-1 is a lower alkyl group, X is a chlorine atom

【formula】

[Formula] represents a group. ] It is produced by reacting with a sulfenyl derivative represented by the following, followed by deprotection and/or hydrolysis as necessary. The sulfenyl derivative represented by the above formula [], which is one of the raw materials in the production method of the present invention, is produced by a method known per se, that is, from 3-mercaptopropionic acid lower alkyl ester and, for example, N-chlorosuccinimide, sulfenyl chloride is produced. A derivative is easily obtained, and a sulfenyl imide derivative can be obtained by reacting a sulfinyl chloride derivative with a sodium salt of succinimide or phthalimide. The reaction between the cyclopentanol derivative represented by the above formula [] and the sulfenyl chloride derivative represented by the above formula [] is usually carried out in an organic solvent. Any organic solvent may be used as long as it is inert to the reaction, but examples include ethers such as ethyl ether, tetrahydrofuran dioxane, and dimethoxyethane, aliphatic hydrocarbons such as hexane, pentane, and petroleum ether, benzene, and toluene. Aromatic hydrocarbons such as, halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide are used. The sulfenyl chloride derivative is used in an amount of 0.9 to 2.0 times the mole of the cyclopentanol derivative, particularly preferably 1.0 to 1.5 times the mole. The reaction temperature can be carried out at -100°C to 50°C, but since there are two double bonds in the cyclopentanol derivative that react with the sulfenyl derivative, in order to selectively obtain the desired compound, It is preferable to carry out the reaction in the range of -80°C to 20°C. The reaction time is 3 minutes to 20 hours, preferably 5 minutes to 5 hours. When a sulfenyl chloride derivative is used, hydrogen chloride is generated as the reaction progresses. Since the generated hydrogen chloride may prevent the reaction from proceeding smoothly and cause undesirable reactions such as side reactions, a base is usually added to capture the hydrogen chloride and allow the reaction to proceed smoothly. It is preferable to carry out the process in the presence of The base used is appropriately selected from the following organic bases and inorganic bases. That is, organic bases include primary amines such as butylamine, isopropylamine, and benzylamine, secondary amines such as diethylamine, diisopropylamine, pyrrolidone, and morpholine;
Tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, 1,5-diasabicyclo[4,3,0]non-5-ene, 1,5-diasabicyclo[5,4,0]undec-5-ene, pyridine , 4-dimethylaminopyridine, 2,6-lutidine, imidasol, and other aromatic amines, and as the inorganic base, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, etc. are used. The base is used in an equivalent amount of 1 to 10 times the amount of the cyclopentanol derivative represented by the above formula []. When using a thioimide derivative as the sulfenyl derivative, there is no particular need to use a base. The reaction product thus obtained is usually treated by distilling off the organic solvent or washing with water, drying the solution, concentrating the organic solvent, and subjecting it to silica gel column chromatography or prisyl column chromatography. It is isolated by methods such as tography, thin layer illustration, and liquid clostography. In the above manufacturing process, the following formula [-1] [In the formula, R ^1-1 , R ² , R ³ , R ^4-1 , and R ^5-1 are the same as defined above. ] A prostaglandin ₁ derivative represented by the following is obtained. Furthermore, if necessary, the prostaglandin ₁ derivative represented by the above formula [] or a non-toxic salt of its acid can be obtained by removing the protective group or by hydrolysis. The protective group may be removed by any commonly used method, such as hydrochloric acid, acetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt,
Cation exchange resins are preferably used, but
In the case of a silyl ether type protecting group, in addition to the above acids, fluorine anionic reagents such as tetrabutylammonium fluoride and cesium fluoride can also be preferably used. As the reaction solvent, water, tetrahydrofuran, dioxane, methanol, ethanol, etc. are preferably used when an acid is used, and tetrahydrofuran, ethyl ether, dimethylformacide, etc. are preferably used when a fluorine anionic reagent is used. The reaction temperature was from -10℃ to 60℃, and the reaction time was
It is sufficient to do this for 10 minutes to 3 days. In this way, the prostaglandin ₁ derivative obtained is
It is a lower alkyl ester. as needed,
By alkaline hydrolysis, a carboxylic acid or a pharmacologically acceptable non-toxic cation salt can be obtained. That is, caustic soda,
Using a base such as caustic barium hydroxide,
Alkaline hydrolysis is accomplished by reaction in water and an organic solvent. Any organic solvent may be used as long as it is inert to the reaction, but in order for the reaction to proceed smoothly, solvents that are miscible with water, such as methyl alcohol, ethyl alcohol, dioxane, and tetrahydrofefuran, are recommended. is preferably used. The base may be used in an amount of 1 to 5 times the amount of the ester. The reaction temperature is preferably carried out in the range of -10°C to 50°C, and the reaction time varies depending on the reaction temperature, etc.
Usually 30 minutes to 20 hours is sufficient. After the reaction is completed, the solvent is directly distilled off to obtain a pharmacologically acceptable salt of the carboxylic acid. In addition, after the reaction is completed, oxalic acid, hydrochloric acid, sulfuric acid,
After neutralizing or making the reaction solution acidic using an acid such as acetic acid, extraction is performed using an appropriate organic solvent such as ethyl acetate, chloroform, methylene chloride, or ethyl ether, and the resulting solution is dried and concentrated. If necessary, a carboxylic acid form, that is, a prostaglandin ₁ derivative in which R ¹ is a hydrogen atom in the above formula [], can be isolated using a separation method such as column clostography, liquid clostography, or thin layer clostography. can be obtained. The prostaglandin ₁ derivative represented by the above formula [] produced by the above steps has anti-ulcer and anti-asthmatic effects, and is expected to be used as a drug due to these physiological effects, such as a drug for treating gastric ulcers, It is useful as a drug for treating duodenal ulcers and asthma. Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Reference example 1 2-allyl-3-[3'(s)-t-butylsimethylsilyloxy-1'-octenyl)-4-t-butyldimethylsilyloxy-1-cyclopentanol
Dissolve 100mg in 0.1ml of methylene chloride and cool on ice for 3 minutes.
-Methyl chloride sulfenylpropionate solution in methylene chloride (methyl 3-mercaptopropylate
When 50 μm of N-chlorosuccinimide (prepared from 360 mg of methylene chloride and 1 ml of methylene chloride) was added dropwise, the raw material disappeared by thin layer clostography. 10 ml of ether was added, and the mixture was washed with saturated sodium bicarbonate solution, then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was purified by thin layer clostography (cyclohexane/ethyl acetate = 85/15) to obtain 45 mg of 4-thiaprostaglandin ₁ methyl ester.
A mixture of 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi isomer was obtained. The nmr (CDCl ₃ ) of this is δ; 0.88 (21H, m), 1.0−1.9 (10H, m), 2.0−
2.5 (4H, m), 2.5-3.0 (6H, m), 3.72 (3H,
s), 3.7-4.35 (3H, m), 4.35-4.6 (1H, m),
5.54 (2H, m), and the mass spectrum (20eV) is 614 (M ⁺ ), 599 (M ⁺ -15), 557 (M ⁺ -57), 482
(M ⁺ −132), 425 (482・57). Reference example 2 5ml of 100mg of 2-allyl-3-(3'(s)-t-butylsilyloxy-1'-octenyl)4-t-butyldimethylsilyloxy-1-cyclopentanol
Lolium carbonate 55 in a solution dissolved in methylene chloride
mg was added. Cool to -60℃ and add 0.8ml of 0.2m methyl chloride sulfenylpropionate solution in benzene.
It was added gradually and reacted for 0.5 hours. Treated in the same manner as in Reference Example 1, and subjected to column crosstography (cyclohexane/ethyl acetate = 97/3).
88 mg of 4-thiaprostaglandin
₁ Methyl ester-11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-
A mixture with epiform was obtained. Example 1 2-allyl-3-(3'-t-butyldimethylsilyloxy-3-cyclohexyl-1'-propenyl)-4-t-butyldimethylsilyloxy-1-
Methyl 3-chlorinated sulfenylpropionate was added to a solution of 100 mg of cyclopentanol dissolved in 5 ml of methylene chloride at room temperature, and the mixture was stirred for 2 hours. The solvent was distilled off and purified by column chromatography (cyclohexane/ethyl acetate = 99/1) to give 60 mg.
16,17,18,19,20-pentanol-15-cyclohexyl-4-thiaprostaglandin ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form A mixture was obtained. The nmr (CDCl ₃ ) of this is δ; 0.88 (18H, S), 1.2-3.0 (23H, m), 3.68
(3H, s), 3.7-4.35 (3H, m), 4.35-4.65
(1H, m), 5.52 (2H, m) The mass spectra (20eV) were 626 (M ⁺ ), 611 (M ⁺ -15), 569 (M ⁺ -57). Reference example 3 4-thiaprostaglandin ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer mixture with 15-epi form99
mg to 4.5 ml of acetic acid, 3 ml of tetrahydrofuran, 3 ml of water.
ml and stirred at room temperature for 3 days. When the solvent was distilled off under reduced pressure, the product showed four spots on thin layer crosstography. It was purified by thin layer clostography (cyclohexane/ethyl acetate/acetic acid = 30/70/0.5, developed three times) to obtain four diastereoisotopes. In descending order of polarity, 6β-4-thiaprostaglandin ₁ methyl ester 13.5 mg, 6α-4-thiaprostaglandin ₁ methyl ester 8 mg,
15-epi-6β-4-thiaprostaglandin
10.5 mg of the enantiomer of ₁ methyl ester, and 11.5 mg of the enantiomer of 15-epi-6α-4-thiaprostaglandin ₁ methyl ester. The spectral data of these compounds were as follows. nmr (CDCl ₃ ) δ; 0.88 (3H, m), 1.1−3.0
(22H, m), 3.70 (3H, s), 3.98−4.30 (3H,
m), 4.30−4.60 (1H, m), 5.54 (2H, m),
Mass spectrum of 11,15-bis-t-butyldimethylsilyl ether (20eV); 530 (M ⁺ ),
515,499,440 11,15-bis-t-butyldimethylsilyl ether C ₂₅ H ₄₇ O ₅ SSi ₂ −15 = 515, 2685, actual value = 515, 2675 nmr (CDCl ₃ ) δ; 0.88 (3H, m), 1.1−3.0
(22H, m), 3.72 (3H, S), 3.76−4.16 (3H,
m), 4.16-4.38 (1H, m), 5.54 (2H, m) 11,15-bis-t-butyldimethylsilyl ether mass spectrum (20eV) 530 (M ⁺ ), 515, 499, 440 nmr (CDU ₃ ) δ; 0.88 (3H, m), 1.2−3.0
(22H, m), 3.70 (3H, s), 3.98−43.4 (3H,
530 (M ⁺ ), 515, 499, 440 nmr ( _CDCl3 )δ; 0.88 (3H, m), 1.1−30
(22H, m), 3.70 (3H, s), 3.79−4.20 (3H,
530 (M ⁺ ), 515, 499, 440 Implementation Example 2 50 mg of the prostaglandin ₁ methyl ester derivative obtained in Example 1 was stirred in 3 ml of acetic acid, 2 ml of tetrahydrofuran, and 2 ml of water at room temperature for one day. Treated in the same manner as Reference Example 3, 25 mg of 16, 17,
18,19,20-pentanol-15-cyclohexyl-
A mixture of 4-thiaprostaglandin ₁ methyl ester and its enantiomer 15-epi form was obtained. The nmr of this product was essentially the same as that obtained in Example 1, except that the signal due to the t-butyldimethylsilyl group of the raw material disappeared. Reference example 4 10 mg of 6β-4-thiaprostaglandin ₁ methyl ester, 0.1 ml of 2N caustic soda and methanol
Stirred in 0.2 ml at room temperature for 3 hours. Concentrate under reduced pressure, neutralize with 5% oxalic acid, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and evaporate under reduced pressure to obtain 6 mg of 6β-4-thiaprostaglandin _1.
I got it. In the nmr spectrum of this product, the signal at δ3.70 (3H, s) due to the methyl ester of the raw material disappeared, and a new signal appeared at δ6.8 (3H, bs). Reference example 5 2-allyl-3(3'(s)-t-butyldimethylsiloxy-1-nonenyl)-4-t-butyldimethylsiloxy-1-cyclopentanol 150mg of 6
Triethyl acine in ml tetrahydrofuran solution
Add 50 µl and 1.2 ml of 0.2 M methyl sulfinylpropionate solution in benzene at -60 °C.
The reaction was carried out in exactly the same manner as in Reference Example 2, and 110 mg of 4-
A mixture of thia-omega homoprostaglandin ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi isomer was obtained. Then, it was deprotected in the same manner as in Reference Example 3 to obtain 75 mg of ω.
A mixture of -homo-4-thiaprostaglandin ₁ methyl ester and its enantiomer 15-epi form was obtained. The nms ( _CDCl3 ) spectrum of this product is δ; 0.88 (3H, m), 1.1−3.0 (24H, m), 3.70
(3H, bs), 3.75-4.20 (3H, m), 4.20-4.50
(1H, m), 5.55 (2H, m), and the mass spectrum (20 eV) of the 11,15-bistrimethylsilyl ether substance was 544 (M ⁺ ), 529, 513. Reference example 6 2-allyl-3(3'(s)-t-butyldimethylsiloxy-5(s)-methyl-1'-nonenyl)-4-t
-Using 8.5 mg of gtylddimethylsiloxy-1-cyclopentanol, the reaction was carried out in the same manner as in Reference Example 5, and deprotection was performed to obtain 35 mg of ω-homo-17(s)-methyl-4-
A mixture of thiaprostaglandin ₁ methyl ester and its enantiomer 15-epi form was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ; 0.90 (6H, m), 1.1−3.0 (23H, m), 3.70
(3H, bs), 3.77-4.25 (3H, m), 4.25-4.55
(1H, m), 5.50 (2H, m), and the mass spectrum (20 eV) of the 11,15-bistrimethylsilyl ether was 5.58 (M ⁺ ), 543, 523, 568. Reference example 7 2-allyl-3-(3'-t-butyldimethylsiloxy-3'-methyl-1'-octenyl)-4-t
Using 180 mg of -butyldimethylsiloxy-1-cyclopentanol, the reaction was carried out in the same manner as in Example 7,
Deprotection yielded 85 mg of (dl) 15-methyl-4-thiaprostaglandin ₁ methyl ester. The nmr (CDCl ₃ ) spectrum of this product is δ; 0.88 (3H, m), 1.20 (3H, s), 1.1−3.0
(22H, m), 3.70 (3H, s), 3.70−4.30 (2H,
m), 4.30 to 4.60 (1H, m), 5.55 (2H, m), and the mass spectra (20eV) of the 11,15-bistrimethylsilyl ether were 544 (M ⁺ ), 529, 513, 454. .

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ is a hydrogen atom or a lower alkyl group, R ²
represents a cycloalkyl group having 3 to 10 carbon atoms, R ³ represents a hydrogen atom or a methyl group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a trialkylsilyl group. ] Prostaglandin ₁ derivative represented by or
Non-toxic salts of the acid when R ¹ represents a hydrogen atom. 2. The prostaglandi ¹ derivative according to claim 1, wherein R 1 is a hydrogen atom or a methyl group, or the non-toxic salt of the acid when R ¹ is _a hydrogen atom. 3. The prostaglandin ¹ derivative according to claim 1 or 2, wherein R 2 is a cyclohexyl group and R ³ is _a hydrogen atom, or a non-toxic salt of the acid when R ¹ represents a hydrogen atom. 4 The prostaglandin ₁ derivative according to any one of claims 1 to 3, wherein R ⁴ and R ⁵ are a hydrogen atom or a t-butyldimethylsilyl group, or when R ¹ represents a hydrogen atom Non-toxic salts of the acid.