JPH026755B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 7-hydroxy PGI ₂ and a method for producing the same.

In recent years, prostaglandin I ₂ (PGI ₂ ) has attracted attention as an autacoid that has various physiological activities such as hypotensive action and platelet aggregation inhibiting action in vivo. However, although PGI ₂ has useful pharmacological activity, it does not have the stability required as a pharmaceutical, and its half-life in vivo is only a few minutes. On the other hand,
Regarding the pharmacological actions of PGI ₂ , it also has aspects that are considered to be inferior in action selectivity as a pharmaceutical, such as platelet aggregation inhibiting action and blood pressure lowering action being almost equivalent in dosage.

In addition, the conventional method for producing allyl alcohol by rearrangement reaction of allylsulfinyls (DA
Evans et al., Accounts of Chemical Research,
Vol. 7, p. 147, 1974, etc.) are known, but there is a possibility that the corresponding hydroxyl group can be converted to the
As far as the present inventors know, there is no known method for producing allyl alcohols in which an ether group is substituted at the position to form an enol ether.

The present inventors focused on this point, and as a result of intensive research to obtain PGI ₂ which is stable and has action selectivity, they formed an enol ether in which an ether group was substituted at the β-position of the sulfur atom. By treating the allylfinyl derivative with a sulfur compound and causing a rearrangement reaction, useful 7-hydroxyPGI ₂ , which is an allyl alcohol in which an ether group is substituted at the β-position of the hydroxyl group to form an enol ether, can be obtained. The present invention has been developed based on the discovery that it can be obtained.

Therefore, the present invention provides the following formula [], [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] 7-hydroxyPGI class ₂ represented by or when R ¹ is a hydrogen atom, a pharmaceutically acceptable salt of the acid and the following formula [] [In the formula, R ¹¹ is a C ₁ -C ₁₀ alkyl group, and R ² and R ³ each independently represent a hydrogen atom or a hydroxyl group protecting group. ] △ ⁶ -5-sulfinyl PGI class ₂ represented by
The following formula [-1], which is treated with a sulfurophilic compound and optionally subjected to a deprotection reaction and/or a salt formation reaction and/or a protection reaction. [In the formula, R ¹ represents a hydrogen atom or a C ₁ to _{C 10} alkyl group, and R ² , R ³ , and R ⁴ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] When 7-hydroxyPGI ₂ represented by the formula or R ¹ is a hydrogen atom, this is a method for producing a pharmaceutically acceptable salt of the acid.

The 7-hydroxy PGI ₂ represented by the above formula [] provided by the present invention has improved chemical instability, which is a weak point of natural PGI ₂ .
Although natural PGI ₂ is difficult to handle under normal neutral or weak acid conditions, it has the characteristic of being surprisingly stable under such conditions. Furthermore, in contrast to conventionally known stabilized PGI ₂ , in which the vinyl ether structure of natural PGI ₂ has been chemically modified, the compound of the present invention retains the natural vinyl ether structure as it is. It also has the characteristic of being 7-hydroxy provided by the present invention
In terms of pharmacological properties, PGI ₂ is expected to have properties characteristic of PGI ₂ , such as platelet aggregation inhibiting action, blood pressure lowering action, and smooth muscle relaxing action. It is useful as a therapeutic or prophylactic drug for diseases based on thrombotic diseases, an anti-asthmatic drug, an anti-ulcer drug, an antihypertensive drug, and the like. The protected 7-hydroxyPGI ₂ is also useful as an intermediate to other compounds.

In the 7-hydroxy PGI ₂ represented by the above formula [] provided by the present invention, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, t-
Examples include butyl, hexyl, octyl, 3-ethyloctyl groups, and the like. Furthermore, when R ¹ is a hydrogen atom, pharmaceutically acceptable salts of its carboxyl group and an inorganic salt or an organic base are also included. Examples of such bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium, and alkali metals such as sodium carbonate, sodium bicarbonate, and potassium carbonate. carbonates or bicarbonates, ammonia, ethanolamine, diethanolamine, and other organic bases.

Among these R ¹ , preferred are methyl group,
Lower alkyl groups such as ethyl groups and sodium,
It is an alkali metal salt such as potassium, and among them, a methyl group, an ethyl group, a sodium salt, and a potassium salt are particularly preferable.

Furthermore, R ² and R ³ in the above formula [] each independently represent a hydrogen atom or a hydroxyl group-protecting group. Examples of the protecting group for the hydroxyl group include those bonded by an ether bond or an ester bond.

Such protective groups include those known in the art, such as those bonded with an ether bond such as tetrahydropyranyl, tetrahydrofuranyl, methyl, α-ethoxyethyl, and t-butyldimethylsilyl, and ester bonds such as acetyl and benzoyl groups. Examples include those combined with . Preferred examples of R ² and R ³ include a hydrogen atom, a t-butylmethylsilyl group, and a tetrahydropyranyl group.

Also, 7-hydroxy represented by the above formula []
PGI class ₂ △ ⁵ - configuration of double bond is (Z) - configuration,
The configuration at position 7 includes all (R)-configurations, (S)-configurations and mixtures thereof, but the preferred configuration is that the △ ⁵ -double bond is (Z )-configuration, the configuration at position 7 is the (S)-configuration.

Preferred specific examples of the 7-hydroxy PGI ₂ of the present invention include the following.

(1) 7-hydroxyPGI ₂ , (2) 7-hydroxyPGI ₂ methyl ester, (3) 7-hydroxyPGI ₂ ethyl ester, (4) 7-hydroxyPGI ₂ isopropyl ester, (5) 7-hydroxyPGI ₂ t-Butyl ester, (6) 7-hydroxyPGI _2hexyl ester, (7) 7-hydroxyPGI _2decyl ester, (8) 7 _- hydroxyPGI disodium salt, (9) 7-hydroxyPGI _dipotassium salt, ( 10) 7-hydroxyPGI _2calcium salt, (11) 7-hydroxyPGI _2magnesium salt, (12) 7-hydroxyPGI _2ammonium salt, (13) Hydroxyl groups at positions 11 and 15 of compounds (1) to (12) Examples include compounds in which is protected with t-butyldimethylsilyl ether, 2-tetrahydropyranyl, or an acetyl group.

In the present invention, when 7-hydroxyPGI ₂ represented by the above formula [] or R ¹ is a hydrogen atom, the pharmaceutically acceptable salt of the acid is the following formula [] [In the formula, R ¹¹ is an alkyl group having 1 to 10 carbon atoms, R ² , R ³
represents a hydrogen atom or a protecting group for a hydroxyl group. ] △ ⁶ -5-sulfinyl PGI ₂ represented by 2 is treated with a sulfur compound, and optionally deprotected and/or
Alternatively, it can be obtained by subjecting it to a salt-forming reaction. Also, the 7-hydroxy group represented by the above formula [] in which the hydroxyl group at the 7-position obtained in this way is not protected
By subjecting PGI ₂ to a protection reaction, 7-hydroxy PGI ₂ in which the hydroxyl group at the 7-position is protected is obtained. According to the present invention, the following formula [] [In the formula, R ¹¹ , R ² , and R ³ are the same as defined above] △ ⁶ -5-sulfinyl PGI ₂ is treated with a sulfur compound, and optionally subjected to a deprotection reaction and/or a salt formation reaction. and/or the following formula [-1] characterized by being subjected to a protection reaction [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ² , R ³ , and R ⁴ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] When 7-hydroxyPGI ₂ represented by the formula or R ¹ is a hydrogen atom, a method for producing a pharmaceutically acceptable salt of the acid is provided.

R ¹¹ in △ ⁶ -5-sulfinyl PGI ₂ represented by the above formula [] represents an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, isopropyl, t-butyl, hexyl, octyl, 3-ethyl Examples include octyl groups, but lower alkyl groups such as methyl and ethyl groups are preferred. Further, preferable examples of R ² and R ³ are the same as R ² and R ³ of the 7-hydroxy PGI ₂ represented by the above formula []. Furthermore, the configuration at position 5 is (R)-configuration, (S)-configuration,
- configuration and mixtures thereof, preferably (R)-configuration.

Preferred specific examples of such Δ ⁶ -5-sulfinyl PGI ₂ include the following.

(1) 5-phenylsulfinyl-△ ⁶ -PGI ₂ methyl ester, (2) 5-phenylsulfinyl-△ ⁶ -PGI ₂ methyl ester 11,15-bis t-butyldimethylsilyl ether, (3) 5-Phenylsulfinyl-△ ⁶ -PGI ₂ methyl ester 11, 15-bis-tetrahydropyranyl ether, (4) 5-phenylsulfinyl-△ ⁶ -PGI ₂ methyl ester 11, 15-diacetate, (5 ) The ester at position 1 of (1) to (4) is not a methyl group but ethyl, isopropyl, t-butyl, hexyl,
Compounds such as decyl groups are not limited to these.

Also, △ ⁶ − expressed by these formulas []
5-sulfinyl PGI type ₂ was obtained by the method separately applied by the present inventors, that is, the following formula [] [Formula, definitions of R ¹¹ , R ² , and R ³ are the same as in the above formula []. ] The following formula obtained by reacting PGI ₂ represented by 2 with phenylsulfenyl chloride in the presence of triethylamine [] [In the formula, the definitions of R ¹¹ , R ² , and R ³ are the same as in [] above. ] △ ⁶ -5-phenylsulfinyl represented by
It can be easily prepared by oxidizing PGI ₁ with m-chloroperbenzoic acid or the like in the presence of sodium bicarbonate. In addition, PGI ₂ represented by the above formula [] can be prepared, for example, by a method known per se [RA
Johnson et al., J. Amer. Chem. Soc., Volume 100, Page 7690, 1978].

The method of the present invention provides △ ⁶ represented by the above formula []
_The formula [-1 ] 7
-Produces hydroxy PGI type ₂ . The sulfur compound used in the present invention may be any compound that causes a rearrangement reaction without changing other positions of the molecule, but examples include amines such as diethylamine, piperidine, and pyrrolidine, hexamethylphosphorus amide, and trimethylphosphorus. Phosphite, triethyl phosphite and other phosphorus compounds, pyridine, imidazole and other aromatic heterocyclic compounds, thiophenol anion, lithium cyanoborohydride and the like are used, but are not limited thereto. Among these, particularly preferred are amines such as diethylamine, and phosphorus compounds such as hexamethylphosphorustriamide and trimethylphosphite.

The amount of the sulfur-loving compound used for the raw material [] may be any amount as long as it is equimolar or more, but preferably 1.2 to 20 times the molar amount.

As for the solvent to be used, the above-mentioned sulfur compounds may be used as they are, but in addition, alcohols such as methanol, ethanol, and isopropanol, ethers, ethers such as tetrahydrofuran, dioxane, and dimethoxyethane, benzene, toluene, Hydrocarbons such as xylene and chlorobenzene, chlorine solvents such as methylene chloride, chloroform, and carbon tetrachloride, dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamide are used, but alcohols such as methanol are used. Ethers such as , tetrahydrofuran and the like are preferably used.

The reaction temperature is -40°C to 160°C, preferably 0°C to 60°C. The reaction time varies depending on the reaction temperature, the sulfur compound used, the solvent used, etc., but is preferably about 0.5 to 48 hours, and preferably,
It takes about 3 to 24 hours.

The reaction product thus obtained is extracted by a conventional method, and subjected to silica gel column chromatography, silica gel thin layer chromatography,
It can be isolated by Florisil column chromatography or the like, but in some cases, 0.01 to 1% of a base such as triethylamine may be added to the developing solvent.

The thus obtained 7-hydroxy PGI type ₂ , in which the hydroxyl group at the 7-position is not protected, may be optionally added to 1
Deprotection by hydrolysis of ester groups at positions 11 and 5
The above formula [ -1] can _be obtained.

For example, a carboxylic acid compound or a salt thereof is a known method. It can be obtained by alkaline hydrolysis using caustic soda, caustic potash, calcium hydroxide aqueous solution, etc. as a base. In order to make the reaction proceed smoothly, an organic solvent such as ethanol, methanol, tetrahydrofuran, dioxane, etc. may be added. The obtained reaction product can be concentrated as it is, or the solution can be used as a salt of 7-hydroxy PGI ₂ for pharmacological purposes. In this case, therefore, the salt-forming reaction takes place simultaneously. Following the above reaction, a free carboxylic acid can be obtained by neutralizing the above solution and extracting with an organic solvent such as ether, methylene chloride, or ethyl acetate. In addition, in order to perform a salt-forming reaction, it is sufficient to react the obtained carboxylic acid with a base. For example, an amine salt can be produced by dissolving a carboxylic acid in a suitable organic solvent such as ethyl, benzene, ethanol, etc. can be obtained in a conventional manner by adding at least an equivalent amount of

Free carboxylic acid can also be obtained by enzymatic hydrolysis using known porcine pancreatic lipase.

In order to remove the protected hydroxyl group, the above-mentioned basic hydrolysis can be used for the protecting group of the acyl group, but in the case of the ether group, for example, the known method of acetic acid-water-tetrahydrofuran system can be used. In particular, in the case of a silyl ether group, in addition to the acetic acid-water-tetrahydrofuran system, a fluorine-based reagent such as a tetra-n-butylammonium fluoride-triethylamine system can also be used.

To protect unprotected hydroxyl groups,
When the protecting group is an acyl group, by reacting a carboxylic acid halide such as acetyl chloride or benzoyl chloride or an acid anhydride such as acetic anhydride or benzoic anhydride in the presence of a basic compound such as pyridine or triethylamine. When the protecting group is a silyl group, it is achieved by reacting a silyl halide such as t-butyldimethylsilyl chloride with a basic compound such as imidazole. Further, protection by esterifying a carboxylic acid can be achieved by a known method, for example, by reacting it with diazomethane.

Further, the configuration of the △ ⁵ -double bond in the 7-hydroxy PGI ₂ represented by the above formula [-1] may be the (Z)-configuration, the (E)-configuration, or a mixture thereof, and the configuration at the 7-position may be the (R)-configuration, the (S)-configuration, or a mixture ^thereof _;
If the 5th position of the class is (R)-configuration, 7-hydroxyPGI ₂ represented by the above formula [-1] is generated.
The configuration of the △ ⁵ − double bond in the class is (Z) − configuration,
The configuration at position 7 is the (S)-configuration.

7-hydroxy obtained as above
PGI ₂ is a PGI ₂ analog and is a useful compound that exhibits activities such as inhibiting platelet aggregation, smooth muscle relaxing, and lowering blood _pressure .
It can also be a useful intermediate that can lead to analogues.

The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 5-Phenylsulfinyl- ^Δ6- PGI ₁ methyl ester 96 mg (0.133 mmol) of 11,15-bis t-butyldimethylsilyl ether was dissolved in 1 ml of tetrahydrofuran, and 98 mg (0.30 mmol) of diethylamine was dissolved in 1 ml of tetrahydrofuran.
mol) was added and left at room temperature for 12 hours. The reaction solution was poured into saturated ammonium sulfate water containing a small amount of triethylamine, extracted with ethyl acetate,
A crude product was obtained. This was subjected to thin layer chromatography (silica gel: benzene/ethyl acetate = 8/
2 2% ammonia water) to obtain the desired 7-hydroxyPGI ₂ methyl ester 11,15-bis t-butyldimethylsilyl ether 32 mg (0.052 mmol,
A yield of 34% was obtained.

Rf=0.45 (silica gel; benzene/ethyl acetate=
8/2) nmr (CCl ₄ , ppm): 3.60 (3H, s), 3.6-4.0
(2H), 4.30 (1H, t, J=7Hz), 4.07 (1H,
bs), 4.7 (1H, m), 5.45 (2H, m). mass (20eV, m/e): 610 (M ⁺ ) Analysis value: C ₃₃ H ₆₀ O ₅ Si ₂ (M-H ₂ O) Calculated value 5923982 Actual value 5923981 Example 2 5-Phenylsulfinyl-△ ⁶ -PGI ₁ methyl ester 11,15-bis t-butyldimethylsilyl ether 29 mg (0.040 mmol) by treating with 110 mg (0.680 mmol) hexamethylphosphorustriamide using a procedure similar to Example 1.
the desired 7-hydroxyPGI ₂ methyl ester 11,
15-bis t-butyldimethylsilyl ether 5mg
(0.008 mmol) with a yield of 20%.

Example 3 7-HydroxyPGI ₂ methyl ester 11,15-
Bis t-butyldimethylsilyl ether 9mg
(0.015 mmol) in 1:1 equimolar solution of n-tetrabutylammonium fluoride-triethylamine in tetrahydrofuran 800μ (0.120 mmol)
was added and reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off, and saturated ammonium sulfate water containing a small amount of triethylamine and ethyl acetate were added for extraction.
The organic layer was washed with water and treated in a conventional manner to obtain the desired 7-
Hydroxy PGI ₂ methyl ester 5mg (0.013m
mol) yield of 87% was obtained. This material was almost purer than thin layer chromatography.

Rf=0.30 (silica gel; benzene/ethyl acetate=
2/8 nmr (CCl ₄ , ppm): 3.60 (3H, s), 3.6-4.0
(2H), 4.05 (1H, bs), 4.27 (1H, t=7Hz),
4.7 (1H, m), 5.45 (2H, m), mass (20eV,
m/e): 364 (M ⁺ -18) Example 4 7-hydroxyPGI ₂ methyl ester 2 mg
(0.005 mmol) was dissolved in 500 µ of ethyl alcohol, 60 µ of 0.1N caustic soda was added thereto, and the mixture was left at room temperature for 12 hours. Thin layer chromatography
(Silica gel: benzene/ethyl acetate = 2/8)
As a result of monitoring the reaction, it was confirmed that ester hydrolysis had completely progressed, and the desired 7-hydroxy
A solution of PGI ₂ Na salt was obtained.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom or a trialkylsilyl group. ] A pharmaceutically acceptable salt of 7-hydroxyPGI ₂ represented by the following formula or an acid thereof when R ¹ is a hydrogen atom. 2. The pharmaceutically acceptable salt of 7-hydroxy PGI ₂ according to claim 1, wherein R ¹ is a sodium atom. 7-hydroxy PGI ₂ according to claim 1, wherein R ¹ is a methyl group. 4 7-Hydroxy PGI class ₂ according to any one of claims 1 to 3, wherein both R ² and R ³ are hydrogen atoms, or when R ¹ is a hydrogen atom, the pharmaceutical composition of the acid Tolerable salt. 5. Any one of claims 1 to 3, wherein both R ² and R ³ are t-butyldimethylsilyl groups.
When R ¹ is a hydrogen atom, a pharmaceutically acceptable salt of the 7-hydroxy PGI ₂ described in Section 2 or the acid thereof. 6 In the above formula [], △ ⁵ - double bond is (Z)
7-hydroxy PGI class ₂ according to any one of claims 1 to 5, wherein the steric configuration at position 7 is the (S)-configuration, or when R ¹ is a hydrogen atom, Pharmaceutically acceptable salts of acids.