JPH0830025B2 - 2-fluoro-3-hydroxy fatty acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Purpose] (Field of Industrial Application) The present invention relates to novel 2-fluoro-3-hydroxy fatty acids and salts thereof as therapeutic agents for diabetic complications (eg, cataract).

(Problems to be Solved by the Invention) The inventors of the present invention have conducted extensive studies for many years on the synthesis of a derivative having an aldose reductase inhibitory action and its pharmacological activity, and as a result, the known compound has no structure. It has been found that different novel 2-fluoro-3-hydroxy fatty acids and salts thereof have an aldose reductase inhibitory effect and are useful as a therapeutic drug for diabetic complications (for example, cataract), and the present invention completed.

[Structure] The novel 2-fluoro-3-hydroxy fatty acids of the present invention have the general formula [In the formula, R ¹ represents a linear or branched alkyl group having 4 to 20 carbon atoms, R ² represents a hydrogen atom or a hydroxyl-protecting group, and R ³ represents a hydrogen atom or a carboxy group. Indicates a protecting group. ].

In the above general formula (I), the “linear or branched alkyl group having 4 to 20 carbon atoms” defined by R ¹ is, for example, n-butyl, isobutyl,
s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3
-Dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 4-methylhexyl, 3-methylhexyl, 2-methylhexyl, 3,3-dimethylpentyl, 2,2-dimethylpentyl, 1,1-dimethylpentyl , 1,2-dimethylpentyl, 1,3-dimethylpentyl, 2,3-dimethylpentyl, n-octyl, 4-methylheptyl, 3-methylheptyl, 2-methylheptyl, 3,3-dimethylhexyl, 2, 2-dimethylhexyl, 1,1-dimethylhexyl,
1,2-dimethylhexyl, 1,3-dimethylhexyl, 2,3
-Dimethylhexyl, n-nonyl, 4-methyloctyl, 3-methyloctyl, 2-methyloctyl, 3,3-
Dimethylheptyl, 2,2-dimethylheptyl, 1,1-dimethylheptyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, 2,3-dimethylheptyl, decyl, 3-methylnonyl, 8-methylnonyl, 3- Ethyl octyl, 3,
7-dimethyloctyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, 1
-Methylpentadecyl, 14-Methylpentadecyl, 13,1
Examples thereof include 3-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, aicosyl, heniicosyl and docosyl, but preferably a straight chain or branched chain having 5 to 18 carbon atoms. It is a chain alkyl group.

The "hydroxyl-protecting group" defined in R ^{2 represents} a protecting group in a reaction and a protecting group for prodrug formation when administered to a living body, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, lower alkyl groups such as s-butyl, t-butyl, pentyl, hexyl; such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl, stearoyl. Alkylcarbonyl group, halogenated alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl group such as methoxyacetyl, (E)
Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as 2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, etc. Halogenated arylcarbonyl group, 2,4,6-trimethylbenzoyl, lower alkylated arylcarbonyl group such as 4-toluoyl, lower alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl, 2-nitro Aromatic acyl groups such as nitrated arylcarbonyl groups such as benzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, arylated arylarbonyl groups such as 4-phenylbenzoyl; trimethylsilyl, Triethylsilyl Isopropyl dimethylsilyl,
Tri-lower alkylsilyl groups such as t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl, 1 to 2 such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl. A silyl group such as a tri-lower alkylsilyl group substituted with an aryl group; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl,
a lower alkoxymethyl group such as t-butoxymethyl,
Lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, alkoxymethyl group such as halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1- Lower alkoxylated ethyl groups such as ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, halogenated ethyl groups such as 2,2,2-trichloroethyl, 2- (phenylzelenyl) ethyl A substituted ethyl group such as an arylzelenylated ethyl group such as;
Substituted with 1 to 3 aryl groups such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, Lower alkyl such as 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl, lower alkoxy, nitro,
1 to 3 in which the aryl ring is substituted with a halogen or cyano group
Aralkyl groups such as lower alkyl groups substituted with 4 aryl groups; methoxycarbonyl, ethoxycarbonyl, t
Lower alkoxycarbonyl groups such as butoxycarbonyl, isobutoxycarbonyl, lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc. Alkoxycarbonyl group; Alkenyloxycarbonyl group such as vinyloxycarbonyl and allyloxycarbonyl;
Aryl ring with 1 to 2 lower alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl A protecting group in a reaction such as optionally substituted aralkyloxycarbonyl group and a protecting group such as pivaloyloxymethyloxycarbonyl which is easily hydrolyzed in vivo for prodrug formation upon administration to a living body. Examples thereof include a lower alkyl group, an aliphatic acyl group, an aromatic acyl group, an aralkyl group, an alkenyloxycarbonyl group and an aralkyloxycarbonyl group.

The “carboxy group-protecting group” defined in R ³ represents a protecting group in the reaction, and includes, for example, the above lower alkyl group;
2,2,2-trichloroethyl, 2-bromoethyl, 2
-Halogeno lower alkyl groups such as -chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl; phenyl,
An aryl group such as naphthyl; an allyl group such as vinyl and allyl; a protecting group in the reaction of the above aralkyl group and the like, and a lower alkyl group, an allyl group and a lower alkyl group substituted with an aryl group are preferable. And particularly preferably a branched lower alkyl group, an aryl group,
An allyl group and a lower alkyl group substituted with an aryl group.

The compound (I) of the present invention can be made into a salt,
As such a salt, preferably, an alkali metal or alkaline earth metal salt such as sodium salt, potassium salt or calcium salt and an amino acid salt such as glutamate or aspartate can be mentioned.

The compound (I) of the present invention has an asymmetric carbon in the molecule,
There are stereoisomers of S-coordinate and R-coordinate, respectively.
Each of them, or any mixture thereof, is encompassed by the present invention.

In the compound (I), preferable groups include (1) a compound in which R ¹ is a linear or branched alkyl group having 5 to 18 carbon atoms (2) R ² is a lower alkyl group or an aliphatic acyl group Group, an aromatic acyl group, an aralkyl group, an alkenyloxycarbonyl group and an aralkyloxycarbonyl group (3) R ³ is a lower alkyl group, an aryl group, an allyl group or a lower alkyl group substituted with an aryl group Compound (4) Compound in which R ³ is a branched lower alkyl group, aryl group, allyl group and lower alkyl group substituted with an aryl group (5) R ¹ is a straight chain having 5 to 18 carbon atoms Or a branched chain alkyl group, R ² is a lower alkyl group, an aliphatic acyl group,
A compound which is an aromatic acyl group, an aralkyl group or an aralkyloxycarbonyl group, and R ³ is a lower alkyl group, an aryl group, an allyl group or a lower alkyl group substituted with an aryl group (6) R ¹ is a carbon number A linear or branched alkyl group of 5 to 18, R ² is a lower alkyl group, an aliphatic acyl group,
An aromatic acyl group, an aralkyl group and an aralkyloxycarbonyl group, R ³ is a branched lower alkyl group,
Examples thereof include an aryl group, an allyl group and a compound which is a lower alkyl group substituted with an aryl group.

Representative compounds of the present invention include, for example, the compounds shown in Table 1, but the present invention is not limited to these compounds.

Of the above-exemplified compounds, preferred compounds include 5,
6, 7, 8, 9, 19, 20, 21, 22, 23, 33, 34, 35, 3
6, 37, 47, 48, 49, 50, 51, 61, 62, 63, 64, 65, 7
The compounds 1, 72, 73, 74 and 75 may be mentioned.

Further, preferable compounds include 5, 7, 9, 19, 21,
23, 33, 35, 37, 47, 49, 51, 61, 63, 65, 71, 73 and
There can be mentioned 75 compounds.

The 2-fluoro-3-hydroxy fatty acids of the present invention are
By the method described below, the known compound (II) can be used as a starting material.

In the above formula, R ¹ , R ² and R ³ have the same meanings as described above.

Fluoromethylketone compound (II) and aldehyde compound (III) were added to Welch and Seper et al. (JTWelch, K.
W. Seper, Tetrahedron Lett., 25 , 5247 (1984)) and subjected to aldol condensation reaction to produce syn-2-fluoro-
A racemate of 3-hydroxyketone derivative (IV) was obtained.
Using the compound (IV) produced, according to a conventional method with an alkaline earth metal monoperphthalate such as magnesium monoperphthalate or calcium monoperphthalate in a lower alcohol such as methanol, ethanol or propanol, An ester compound (V) was produced by carrying out a Bayer-Villiger reaction. The protecting group for the carboxy group of the ester compound (V) is converted into
The compound (VI) of the present invention was obtained by desorbing as follows.

That is, when a lower alkyl group or an allyl group is used as the protecting group for the carboxy group, it can be removed by treating with an acid or a base. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, trifluoroacetic acid is used, and the base is not particularly limited as long as it does not affect other parts of the compound, but is preferably It is carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or concentrated ammonia-methanol. Note that hydrolysis with a base may cause isomerization. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water or water and alcohols such as methanol, ethanol and n-propanol or ethers such as tetrahydrofuran and dioxane can be used. A mixed solvent with such an organic solvent is preferable. The reaction temperature and reaction time differ depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C. to 150 ° C. and 1 to 10 hours.

When the carboxy-protecting group is a diaryl-substituted methyl group such as diphenylmethyl, it is usually removed under acidic conditions. The reaction solvent used is preferably an aromatic hydrocarbon such as anisole, and the acid is a fluorine-substituted organic acid such as trifluoroacetic acid. The reaction temperature and the reaction time will differ depending on the starting materials and the like, but are usually 30 minutes to 10 hours at room temperature.

When the protecting group for the carboxy group is an aralkyl group or a halogeno lower alkyl group, it can be usually removed by bringing it into contact with a reducing agent. As the reducing agent, zinc-acetic acid is suitable when the protecting group of the carboxy group is a halogeno lower alkyl group, and when it is an aralkyl group, a catalyst such as palladium carbon or platinum is used.
It is carried out by catalytic reduction or using an alkali metal sulfide such as potassium sulfide or sodium sulfide. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; acetic acid A fatty acid such as or a mixed solvent of these organic solvents and water is suitable. The reaction temperature and reaction time will differ depending on the starting materials and the reducing agent used, etc., but will usually be between 0 ° C. and room temperature, and between 5 minutes and 12 hours.

If desired, according to a conventional method, the carboxylic acid compound produced above is dissolved in a mixed solvent of water and an organic solvent immiscible with water, such as ethyl acetate, and an alkali metal carbonate such as an aqueous solution of sodium hydrogen carbonate or an aqueous solution of potassium carbonate is dissolved. Add salt or bicarbonate solution at 0 ° C to room temperature to bring the pH to 7
A salt can be formed by filtering out the vicinity and the deposited precipitate.

On the other hand, the 3-position hydroxyl group of the compound (V) was protected with a protecting group according to a conventional method to produce the compound (VII) of the present invention, and if desired, the protecting group of the carboxy group was removed according to a conventional method to protect the hydroxyl group. The compound (VIII) of the present invention was produced.

Although the method of protecting the hydroxyl group is well known, for example,
The protective group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group,
When it is an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkyloxycarbonyl group or a pivaloyloxymethyloxycarbonyl group, it has the formula R ² ′ X
(Wherein R ² ′ is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkyloxycarbonyl group or a pivaloyloxymethyloxycarbonyl group in the definition of R ² above) X has the same meaning, X is a halogen atom such as chlorine, bromine and iodine; an alkylcarbonyloxy group such as acetoxy and propionyloxy, chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy and trifluoroacetyloxy. Halogenated alkylcarbonyloxy group, lower alkoxyalkylcarbonyloxy group such as methoxyacetyloxy,
(E) Aliphatic acyloxy groups such as unsaturated alkylcarbonyloxy groups such as 2-methyl-2-butenoyloxy; arylcarbonyloxy groups such as benzoyloxy, 2-bromobenzoyloxy, 4-chlorobenzoyloxy and the like. Halogenated arylcarbonyloxy group, lower alkylated arylcarbonyloxy group such as 2,4,6-trimethylbenzoyloxy and 4-toluoyloxy, lower alkoxylated arylcarbonyloxy group such as 4-anisoyloxy, Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy, 2-nitrobenzoyloxy; trihalogenomethyloxy groups such as trichloromethyloxy; methanesulfonyloxy, ethanesulfonyloxy, etc. Lower alkanesulfonyl group; trifluoromethanesulfonyloxy, halogeno lower alkanesulfonyloxy group and benzene sulfonyloxy, such as pentafluoroethane sulfonyloxy, a leaving group such as an arylsulfonyloxy group such as p- toluenesulfonyloxy shown. ) Or the formula R ² ′ O
It is carried out in a solvent with or without heating and in the presence or absence of a base by using an acid anhydride having R ² ′ (wherein R ² ′ has the same meaning as described above). .

The protective group for the hydroxyl group is a silyl group, an alkoxymethyl group,
In the case of a substituted ethyl group, aralkyl group or lower alkyl group, for example, a compound having the formula R ² ″ X (wherein
R ² ″ has the same meaning as a silyl group, an alkoxymethyl group, a substituted ethyl group, an aralkyl group or a lower alkyl group in the definition of R ² above, and X has the same meaning as described above.) It is carried out in a solvent with or without heating, in the presence or absence of a base.

[Effect] The novel 2-fluoro-3-hydroxy fatty acids and salts thereof of the present invention have an aldose reductase inhibitory action and are useful as therapeutic agents for diabetic complications.

Examples of the administration form of the compound (I) of the present invention include:
Oral administration by tablets, capsules, granules, powders, syrups and the like or parenteral administration by injections, suppositories and the like can be mentioned. These formulations include excipients,
It is produced by a well-known method using additives such as a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent. Although the amount used varies depending on symptoms, age, etc., 0.01-100 mg / kg body weight per day can be administered to an ordinary adult once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples.

Example 1 2.7 g of (±) -t-butyl syn-2-fluoro-3-hydroxymyristate 4,5-syn-2,2-dimethyl-4-fluoro-5-hydroxy-3-oxohexadecane was added to ethanol ( 9
(9.5%) 100 ml, magnesium monoperphthalate hexahydrate 22 g was added, and the mixture was stirred at 50 ° C. overnight. It was concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed twice with water, saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residual oily substance was applied to a silica gel column, and cyclohexane: ethyl acetate =
Purification at 4: 1 gave the target compound in a yield of 1.1 g (39%).

Infrared absorption spectrum ν _max (film); 3550,1747cm
^-1 Mass spectrum m / z:. 319 (M + +1), 297,261,219,183 NMR spectrum _{(60MHz) (CDCl 3) δppm} 0.85-1,05 (3H, m), 1.1-1.8 (32H, m), 2.2 (1H , broad,
OH), 3.94 (1H, dm , J FH = 25Hz, C 3 -H), 4.67 (1H, dd, J
= 49,3Hz, C ₂ -H). Reference Example 1 (±) -syn-2-fluoro-3-hydroxymyristic acid 1.0 g of t-butyl ester obtained in Example 1 was added to 30 ml.
Was dissolved in methylene chloride, 10 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting crystals were washed with n-hexane to give 0.71 g (86
%) The target compound was obtained in a yield of Melting point: 82-83 ℃ Infrared absorption spectrum ν _max (nujol); 3280,3000-
2400 (broad), 1736 cm ^-1 Mass spectrum m / z: 263 (M ⁺ +1), 262,244,226,224,18
5.172. Reference Example (±) -t-butyl syn-2-fluoro-3-benzyloxycarbonyloxymyristate 318 mg (1 mmol) of the alcohol obtained in Example 1 was dissolved in 5 ml of methylene chloride to give benzyloxychloroformate. 255 mg (1.5 mmol) was added and 200 mg of 4 was added under ice cooling.
-Dimethylaminopyridine was added and stirred for 1 hour. The raw material remained, so add 60 mg of benzyloxychloroformate and 60 mg of triethylamine, and add 30 mg at room temperature.
After stirring for a minute, the raw material disappeared. It was diluted with ethyl acetate, washed with dilute hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residual oily substance was subjected to silica gel column chromatography, and cyclohexane: ethyl acetate = 9: 1.
The target compound was quantitatively obtained by purification with.

NMR spectrum (60 MHz) (CDCl ₃ ) δppm 0.80-1,50 (3H, m), 1.1-1.9 (32H, m), 4.79 (1H, dd, J
_{= 3,47Hz.C 2 -H), 3.35 (} 5H, s). Reference Example 3 (±) -syn-2-fluoro-3-benzyloxycarbonyloxymyristic acid The compound obtained in Reference Example 2 was treated in the same manner as in Reference Example 1, and the target compound was obtained in a yield of 342 mg (86%). Got with.

Melting point: 77.5-78 ° C (recrystallized from n-hexane).

Infrared absorption spectrum ν _max (nujol); 3200,1752,
1727 cm ^-1 mass spectrum m / z: 396 (M ⁺ ). High mass spectrum Calcd: as _{C 22 H 33 O 5 F,} 396.23122 Found: 396.23192 NMR spectrum _{(60MHz) (CDCl 3) δppm} 0.80-1,0 (3H, m), 1.1-2.0 (20H, m), 4.98 (1H, dd, J ＝
_{49,3Hz.C 2 -H), 4.8-5.4 (1H} , m, C 3 -H), 5.12 (2H,
s), 7.33 (5H, s), 8.66 (1H, bs, COOH). Reference Example 4 (±) -syn-2,2-dimethyl-4-fluoro-5-hydroxy-3-oxohexadecane t-butyl fluoromethyl ketone 1.8 g (15 mmol) in tetrahydrofuran (10 ml) was added with lithium hexamethyldiethyl. Cilazide 16 mmol tetrahydrofuran (10 ml)
The solution was added at -78 ° C under a nitrogen stream. After 5 minutes, 2.8 g (15 mmol) of n-dodecanal in tetrahydrofuran (10 m
l) The solution was added. After stirring for 30 minutes, a solution of acetic acid in tetrahydrofuran was added to neutralize. Dilute with ethyl acetate,
The extract was washed with aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, it was concentrated, subjected to silica gel chromatography, and purified with cyclohexane: ethyl acetate = 9: 1 to obtain 4.0 g (87%) of the target compound.

Melting point: 34-35 ° C (recrystallized from n-hexane).

Infrared absorption spectrum ν _max (nujol); 3500,1703c
m ^-1 mass spectrum m / z: 303 (M ⁺ +1), 245,225,118,103,8
5,57. NMR spectrum (60MHz) (CDCl ₃ ) δppm 0.8-1,0 (3H, m), 1.2-2.0 (29H, m), 2.17 (1H, d, J = 7H
z, OH), 4.96 (1H, dd, J = 2.5,48Hz), 3.6-4.0 (1H, m).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 69/96 Z 9546-4H C07F 7/08 A // A61K 31/19 ABL AED

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ represents a linear or branched alkyl group having 4 to 20 carbon atoms, R ² represents a hydrogen atom or a hydroxyl-protecting group selected from the following group A, and R ³ represents , A hydrogen atom or a protective group for a carboxy group selected from Group B below). [Group A] Lower alkyl group, aliphatic acyl group, aromatic acyl group, silyl group, alkoxymethyl group, substituted ethyl group, aralkyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, aralkyloxycarbonyl group, and pivalo Iloxymethyloxycarbonyl group [Group B] Lower alkyl group, halogeno lower alkyl group, aryl group, allyl group, and aralkyl group