JPS6058942A - Diastereomer of glycylretinoic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel and pharmaceutically useful diastereomers of certain glycyrrhetinic acid derivatives.

In our British Patent No. 1,387,499, we describe the general formula (1): (wherein R is a hydrogen atom or an alkyl group and R' is also a hydrogen atom or an alkyl group) Glycypredenoic acid-derived f'? and salts of these compounds in which R and/or R' are hydrogen atoms are disclosed.The specification also discloses that the compounds possessing such beneficial pharmaceutical properties, in particular good anti-inflammatory activity, is mentioned.

Subsequently, several glycyrrhetinic acid derivatives containing the general formula (1) were found to be very effective in the treatment of diseases caused by Quirnus infections and viral infections.

The compound of general formula (I) derived from cyclohexane-1,2-cica-μpoic acid can be bonded to the C-3 position of glycyμ-retic acid or attached to the ring of cyclohexane-1,2-cica-μpoic acid. It exists as a mixture of diastereomers depending on the enantiomerism of carbon atoms C1 and C2.

After further research, we have now found one diastereomer that has better antiviral activity than the others.

That is, to give an example, based on a series of experiments, mono(18β
-Glycylic acid dithi, 3β-(cis-2R-
carboxycyclohexane-18-carbonyloxy)
-11-oxo-18β-osyan-12-30
-Oic acid! /su)ium salt is converted to other diastereomers, namely 3β-(cis-2R-carboxycyclohen-1-IR-carbonyloxoV)-11-oxo-1
I(S
It was found that it has anti-I/l/nu activity against V-2 strain HG52.

Therefore, according to the present invention, the general formula (■): (in the formula,
-coonl and -GOOE2 are the same - or different, jl
#m+Punishment If Sissy) - Toss 7 Lena〒Tsu 4nノ! Diastereomers of 1-41-(R1-1-noic acid group) are provided.

When -Coonl and -C00R2 are esterified carboxylic acid groups, R1 and R7 are linear or branched, saturated or unsaturated, and substituted or unsubstituted subatomic atoms of 6t. Preferably, it is an aliphatic hydrocarbon group containing .

As a method for producing the novel compound of general formula CI) according to the present invention, 18α- or 18β-glycyrrhetinic acid or its ester μ is added to the commercially available e7hunclohexane-3-. A mixture of diastereomers is obtained by reacting with 2-dicarboxylic acid anhydride, and fractionated by a known method such as fractional crystallization, or by isocyclohexane-R2-
A method of reacting with an appropriate isomer of dicarboxylic acid anhydride can be used.

If the resulting diastereomer contains free carboxylic acid groups, it can be converted into a salt or ester by known methods. The esterification is preferably carried out by reaction with a suitable diazo compound, preferably diazomethane, or a suitable alcohol-μ and a-acid in order to obtain a methyl ester μ.

The invention also provides pharmaceutical compositions comprising at least one novel compound and a solid or liquid pharmaceutical diluent or excipient.

The following examples illustrate the invention.

Example 1 a) 101 mono-(Gly VIVVf-3-i IL/)
-cis-cyclohexane-1,2-dicarboxylic acid disodium salt (18β-glyrinuretic acid and cis-diclohexane-1,2-dicarboxylic acid anhydride are reacted in a conventional manner), and then with sodium hydroxide. [obtained by neutralizing], 6001 tl! ! of acetone/water (1/
1 V/V) with heating and the solution was filtered. Acetone was added to the hot filtrate while the haze persisted, requiring 280 units of acetone for this purpose.

The solution was cooled to room temperature, the obtained solid was separated by F,
Washed with acetone/water (85/15 v/v) and acetone and dried under vacuum at 60°C. The yield was 40 tons.

Methanol-tv/o, 25cm x 4x Spherisolp 0DSlOμ cuff using a solvent system of 1M phosphoric acid slow running liquid is a slow running isomer with a solid content of 9596.
9).

The solid was dissolved in 3001 acetone/water (1/l v/■
) was dissolved with heating, and acetone was added to the hot filtrate while a fuzzy cloud continued, requiring 90 tons of acetone for this purpose. The solution was cooled to room temperature, the solid 'fcP separated and acetone/water (sa/x5 v,/
v) and washed with acetone and dried under reduced pressure at 60° C. to constant weight. The yield was 22.62.

High performance liquid chromatography in the same manner as above revealed that it contained a fast flowing isomer of 196 or less.

n-getano/l/10.88 ammoniay (5/1
The thin layer chromatogram of the sample (v/v) used showed no impurities.

Infrared absorption spectrum/1/(Nujol method)
:lfu10 (zste/L/), 1650 (jl-non), 156Q (Broad, Co,, Na) ty
It was shown that there is an Oite principal bond in m. The melting point of the substance is) 360 t: 9, optical rotation [α seat = +l18
°±2° (196 methano-A//0.296 sodium subacid).

The melting point of the corresponding free acid was 295-291°C (decomposed). Infrared absorption Svec)/l/(Nugeot p method) is v
max=1740~Woo(re!!, 10 beauty salons/L/
), had a main bond at 1660 (enone) am.

b) Mix with 32 N diastereomeric diacids - t3ome methanol, add enough dichloromethane to obtain a clear solution and add supercharge needle-like diazomethane. After 2.3 minutes, a small amount of acetic acid was added to eliminate the supercharge diazomethane to obtain a clear bath liquid. The resulting solution was condensed f4 on a hot grate until crystallization began.
It was then removed to cool to room temperature. The crystalline solid was separated by F, washed with methanol (SL), and dried in a fisho oven with a width of 80 tm until it was saturated. The yield of dimethyl ester of diastereomeric diacid was 3.16 f.

The melting point of the product is 19°C to 198°C, and according to the infrared absorption spectrum (Nujol method), v = 1740aX (C-3 and side chain z, cte/L/), l'/10 (C
-30:r-ste/I/) and 1655 (enon]C
was found to have a principal bond. NMR Nubec)
IV (CDCIs) verified its structure.

Petroleum ether (boiling point 60-80℃) / dichloromethane /
The product was tested by thin layer chromatography using acetone (6/3/l v/v/v) to show purity >99.
It was found that %.

The free diastereomeric diacid of Q,)if was suspended in dry toluene in part 2d and oxalyl chloride was added. The resulting mixture was magnetically stirred for 1 hour at room temperature under anhydrous conditions. After this time the reaction mixture remained a suspension. An additional 0.6 d of oxalichloride μ was added and the reaction mixture was left stirring overnight. The clear solution was rotary evaporated and the residue was dried in a vacuum oven to constant weight. 1.071 of diacid chloride was obtained.

1°072 diacid chloride, 2111 anhydrous pyridine and 0
．． Added to a mixture of 8xt hexan-1-ol. ?
The heated mixture was rapidly flowed in hot water for 2 hours in an oil bath at 140°C. Thin layer chromadoguf, (petroleum ether/L'
60~SO/dichloromethane/acetone; 6:3:l
V/V/V) showed that the reaction was complete at 959 (i). The reaction mixture was refluxed for an additional hour and then cooled. The reaction mixture was poured into wood/astringent hydrochloric acid and
Extracted twice with ethyl acetate. The ethyl acetate phase was washed with distilled water until the washings were neutral, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness. 1.
A di-n-hexyl etch of the diastereomeric diacid p of 35f was obtained.

The product was found to have a purity of 9596 by thin layer chromatography as described above.

25F Silicage/L/(Merck 734) was sealed in the column. The column is petroleum ether/L/60~8
0/dichloromethane/acetone (6:3:1V/V/V
m*L in a solvent mixture of ) and then the dimethyl ester of 1,35 F dissolved in the same solvent mixture was made up with the same solvent mixture as above. First, 251111? fractions were collected and discarded. A 10 m fraction was then collected and spotted onto a thin layer chromatography plate. The pure fractions were combined and rotary evaporated to dryness. A dimethyl ester of 0.88 tlDla was obtained.

Thin layer chromatogram (petroleum ether/L/60~SO/dichloromethane/acetone; 6:3:IV/
The product was found to be 9996 pure.

0.88F dimethyl ester to 81 l]ate/l
/60-80 and deep frozen for one week@The resulting crystalline product was filtered through a chilled glass funnel, washed with a small amount of methanol and dried in a vacuum desiccator to constant weight. Yield was 0.561.

t-rII-rzrmm force rt-y k & 41-
The w F h 3-/7'% product was found to have a purity as high as 9996. The melting point of the substance is 118-1
The temperature is 21℃ and the infrared absorption spectrum is ν = l f1o~l
'730 (ester), aX 1660 (enone) ■ had main bonds.

Example 2 a) 18α-glycyrrhetinic acid at 23.5 F, 1
'7.6 f V7--1,2-cyclohexane-cica μ boxy anhydride and 28.21!11 anhydrous pyridine were heated under reflux at an oil bath temperature of 140-160°C for 4 hours. After this time, thin layer chromatography showed that the reaction line was complete at approximately 9o96. 352.5 m of acetone was added to the cooled reaction mixture, the solution was stirred magnetically for a while, and the solution was dissolved in 112 N distilled water at room temperature.
A solution of 2.3×t concentrated hydrochloric acid was added.

The resulting precipitate was filtered, washed with 7o96 aqueous acetone, and then evaporated until the washings were neutral.
-rslh1%lfalse #Q:! 1+/rl-+11-1^
ff14#Jffilta. Yield was 28.28 f.

28.281 of the above diacid was slurried with e+-8 tnl of acetone and dissolved in 84.8- of distilled water.
The solution of sodium hydroxide in f was stirred until pH 9 and then slowly added υ. The reaction mixture was still a suspension and was warmed in a water bath. There was no change, so 2 more
4 the distilled water was added and the mixture was warmed up again.

The slightly cloudy solution was hot filtered while heating, and acetone was added until the solution became cloudy.

It was then cooled to 4°C.

The precipitated solid was separated by F and acetone/water (85:15v)
7v), then acetone and dried to constant weight in a vacuum open. The yield of the disodium salt of the diacid was 17.60 t.

The above disodium salt was mixed with 106 stations/h of hydrothermal acetone (1
: l V/V) (6 times Xfi), filtered without heating, acetone was added until the mixture was cloudy, then cooled to 4°C. The obtained crystalline solid was separated by P,
Washed with approximately 5 om acetone/water (86:lsv,'v) followed by acetone. The product was dried to constant weight during vacuum opening, and the yield was 12.05F.
High performance liquid chromatography showed that the diastereomer had a purity of 97.59(i).

The disodium salt was further recrystallized twice using the above conditions to obtain 6.95f white M crystals.

'15: 25 V/V Methano-A'10. High performance liquid chromatography using a solvent mixture of IM phosphate buffer (I)H'') showed a material containing >9996 of the desired diastereomer.

The melting point of the substance is 360 u, and according to the infrared absorption spectrum, vmax = 171 o (Este/L/), 1
660 (enon), 1570 (Co2Na) side
It was found that there is a principal bond. That China) I
The pH of the 1096 aqueous solution of J Kum salt was 8.6.

0.5 f of the disodium bulk was converted to the corresponding diacid by treating its aqueous solution with dilute hydrochloric acid. The obtained precipitate was separated by F, washed with water until the washed product became neutral, and dried at 100 U to a constant weight while opening the vacuum. The yield was 140.29F.

The melting point of the diacid was 303-305°C, and the infrared absorption spectrum showed that it had a main bond at ν = 05-1725 (ax CO2H + ester), 1665 (enone); NMR spectrum/
'((]-s hyridine) It was proved that this was the expected structure.

1))401! t of dry methanol and 1 m of concentrated sulfuric acid were added to 2f of disodium salt and the resulting mixture was refluxed in a water bath for 7 hours. After this, a thin layer chromatogram (petroleum ether/I'60~8o/dichloromethane/acetone;
6:S:lv/v/v) indicated that the reaction was incomplete.

0.4 ml of concentrated sulfuric acid was added to the reaction mixture and the solution was refluxed for an additional 4 hours, after which the thin layer chromatograph A line showed that the reaction was 95% complete.

The cooled reaction mixture was poured into wood/water and extracted with ethyl acetate. This process was repeated 9 times, and the ethyl acetate extracts were combined, washed with water until the washed product became neutral, and dried over anhydrous sulfuric acid.

The dry ethyl acetate solution was then filtered and rotary evaporated to dryness. Revenue #! , ]: 1.6 at.

The above product was mixed with methanol/I//dichloromethane (2:l
V/V) and concentrated on a hot grate until no crystallization occurred. The crystalline solid was separated by F, washed with methanol, and dried at 80'C in open vacuum until constant weight was reached. The yield was 1.36 ml.

Thin layer chromatogram showed the product to be of purity >9996.

According to the infrared absorption spectrum, v = 1740 (ma, x ester), 171o (esthe/I/) and 1655 (
It was shown that there is a main bond in tyr+ (enone).

The melting point of the material was 235-237°C. Gas chromatography (1' 190 0V -17 column 30
5°C], the product has a purity of 9996;
It was shown that it contained 196 or less corresponding 18β compounds. NA4R Nubeku) /! / (CDC15) The expected structure was proven.

C) Diacid chloride was prepared in a similar manner to that described in C) of Example 1, except that the final step was different.

The clear solution was rotary evaporated to about half its original volume. Dry toluene was added and the same process repeated.

This was done until no oxalyl chloride remained. The final solution was concentrated to 1 oml and deep frozen for 15 minutes. The resulting crystalline solid was separated and washed with a small amount of dry toluene. The product was used in the next step without drying.

Di-n-hexyl ester μ was prepared in a similar manner to that described in Example 1, C), and the yield was 0.83F.

Thin layer chromatogram (Petroleum ether/115Q-80/dichloromethane/acetone; a:3:1 v/v/■) showed the product to be >9996 pure.

0.63f of dihexyl V/L/ester was dissolved in 7-kg petroleum ether μ and deep frozen for 3 weeks. The crystalline product obtained was separated, washed with methanol and dried at 40C in vacuum open until constant weight. The yield was 4161%l.

The melting point of the substance was 99 to 10° C., and the infrared absorption spectrum revealed that there was a main bond at simaX=1″100–1720 (Este A/), 1660 (enone) (7).

Claims (1)

[Claims] 1. General formula (■): ■ (In the formula, -COORt, !: -COO1%U and -U
2s 3β-(5/su28-carboxycyclohexane-Is-caponiμoxy)-11-oxo-18β
-Nacian-12-en-30-oy/acid, and H-t-
Compounds according to claim fl'N, which are the disodium salt, dimethyl ester and di-n-hexyl ester of. 3.3β-(cis-26-carpoquinecyclohexane-is-carbonyloxane V)-11-oxo-18σ-olean-12-ene-30-oic acid, and its disodium salt, dimethyl ester A/ and di-n The compound according to claim 1, which is a -hexyl ester. 4,18α- or 18β-glycyrrhetinic acid or its ester is reacted with cis-cyclohexane-1,2-sil)μ acid anhydride to obtain a mixture of diastereomers, which is separated by known methods, or It consists of reacting cyclohexane with a suitable isomer of 1,2-dicarboxylic anhydride, and then, if desired, converting the free μ-boxylic acid groups of the resulting product into salts or esters by known methods. A method for producing a compound of the general formula (I): H [wherein -COOR, and -COORz are the same or different and are free, salted or esterified acid groups]. 5. General formula (I): (In the formula, -COOR1 and 1000R2 are the same or different, and are free, salted or engineered acid groups) An anti-inflammatory/antiviral pharmaceutical composition comprising a compound and a liquid pharmaceutical diluent or excipient.