JPS59186988A - Bergenin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is -CO2X (X is H, alkali or alkaline earth metal), -CH2Y (Y is azide, halogen, t-butylmethylsilyloxy, amino); R<2> is H, lower alkyl, acyl, phenylalkyl]. USE:Coronary vasodilator, antitumor agent. PREPARATION:The compound of formula II is reduced or a compound of formula III (R<1> is t-butyldimethylsilyl; R<2> is H, acyl, phenylalkyl) is oxidized.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field of the Invention The present invention relates to a novel irgenin derivative represented by general formula (1) and a method for producing the same.

[In the formula, R represents the general formula -C02x (where X represents a hydrogen atom, an alkyl group, an alkali metal, or an alkaline earth metal.)
, or the general formula -CH2Y (where Y represents an azide V group, a halogen atom, a t-butyldimethylsilyloxy group, an amino group, a dialkylamino group, or an N-acylamino group), and R2 is a hydrogen atom or a lower alkyl group , represents an acyl group or a phenylalkyl group. [Background of the invention] Bergenin (2) is an isocoumarin C-glucosil that is widely distributed in plants of the Fabaceae family, Dipterocarpaceae family, as well as Prunus japonicus, Sacrifragaceae family, Cornflower, and other plants of the Fabaceae family and Dipterocarpaceae family, and has been used as a folk medicine since ancient times. ing. In addition to its antiulcer effect, bergenin (2) also has antitussive, antiinflammatory, and antipyretic effects, albeit weakly, and is also known to inhibit prostaglandin synthase.

As a result of intensive research to further improve the known medicinal effects of bergenin, the present inventors discovered that the compound represented by general formula (1) has coronary vasodilatory and anti-ulcer effects, and has further improved its efficiency. The present invention was completed by establishing a good manufacturing method.

Manufacturing process of the compound of the present invention The compound of general formula (1) of the present invention can be manufactured as follows.

As shown in Scheme A, irgenin (2), the main component of red-eye wrinkle extract, is used as a raw material and dimethyl sulfate is added to the methyl form (
3) is obtained.

This method is the diazomethane method (P, A) described in the literature.

Ramaiah et al. J, Chem, 5oc-, 2313 (
1979) and J, E., Hay et al., J. Chem, 5
oc0.2231 (1958)), it has advantages such as being able to handle large quantities and allowing safe reactions.

Using dimethylirgenine (3) as a raw material, tosyl chloride' and mesyl chloride are converted to tosyl compound (4) and mesyl compound (5) by treating them under basic conditions, and further converted to azide compound (6) by treatment with sodium azide. ), halogen compound (7) can be converted to nitrile compound (8) by treatment with sodium or potassium halide and sodium cyanide or potassium cyanide.

The azide compound (6) is converted into an amino compound (9) by catalytic reduction using Pd-black, Pd-carbon, platinum oxide, platinum, Raney nickel, or the like as a catalyst. The amino compound (9) can be converted into an N-dialkyl compound (IP) by using, for example, the Eschweiler-Clarke reaction, and immediately after being treated with an alkyl aldehyde to form an imine. By reduction, N-alkyl body (1
It can be converted to 1. For example, if formic acid and formalin are used in the Eschweiler-Clarke reaction, the N-dimethyl form (
get ill. For example, the N-alkyl form can be converted into an N-butyl form by condensing the imine with n-butyraldehyde F and immediately using a reducing agent such as sodium borohydride. In addition, by treating the amino compound (9) with an acylating agent, pyridine, it can be converted to the acyl (7) compound (121). For example, by using acetic anhydride, acetyl chloride r, propionic anhydride, etc. as an acylating agent, Each becomes a corresponding compound a'a.

Furthermore, as an alternative method, as shown in Scheme B, the silyl compound a3 obtained by treating dimethylirgenine (3) with t-butyldimethylsilchloride in the presence of imidazole is treated with acetic anhydride, propionyl chloride, valeryl chloride, and valeryl chloride. Acylated products (I4!) can be obtained by treatment with acylating agents such as silyl chloride (I4!), or silyl compounds (JI, aa, ct!19 can be converted into carboxylic acid derivatives (10%) by oxidation with chromic acid. Compound αη can be converted into a compound (18) by catalytic reduction using a catalyst such as Pd-black or Pa-carbon. get.

Compounds α0, (17) and R21 are treated with an equivalent amount of an alkaline solution to obtain their respective salts α1, (A) and r21). At this time, the alkaline solution is preferably sodium hydroxide, potassium hydroxide, or lithium hydroxide.

JP-A No. 59-18G988 (5) Effects of the Compound of the Invention The following tests were conducted on the potency of the bergenin derivative of the invention.

1) Experimental method (coronary vasodilatory effect) Hartley (Hart, 1ey) weighing 500-8009
) method (J, Phe) method (J, Phe
, rmacol Methods 2; 143 (1979
)), a Krebsu-Henseleit (Kr
ebs-Henseleit) solution at a constant flow rate (6 ml/
m1n) perfused. Perfusion pressure was measured with a pressure transducer.

All test compounds were dissolved in 0.9% physiological saline and administered directly into the coronary artery through the Vim tube connected to the aortic cannula, and data on ED5o (μg/heart) were obtained.

<Acute Toxicity> Male ddY mice weighing 18 to 22 g were used after fasting for 18 to 24 hours. The test compound was orally administered using a gastric tube, and the mortality rate within two weeks was determined to be up-end.
The 950% mortality rate (LD5o) was calculated by the up and down method.

<Anti-ulcer effect> - 16-1 ddY male mice weighing 25-60
After fasting for 8 hours, the animals were divided into groups of 5. The mouse was placed in a stress cage, placed in a water bath at 23°C, and submerged up to the xiphoid region of the thorax. After 5 hours of immersion, the animals were sacrificed by cervical dislocation, and their stomachs were removed through laparotomy. Fill the stomach with 0.9% saline for 2 d.
% formalin solution for 30 minutes. Thereafter, an incision was made along the large bone to remove the ulcer that appeared in the glandular stomach area using the Adami method [Adami was orally administered 30 minutes beforehand].

2) Results Although the maximum dose was measured at 100 μg/heart, there is a possibility that the activity will be increased by increasing the dose further.

The compounds (cL) to (#I) used in the test are expressed by the following formula. However, it seems that the suppression rate will improve if the dose is further increased.

Note that although (6) is 0% (inhibition rate), there is a possibility that activity may occur due to the above-mentioned reason.

Also, dimethylirgenin has a suppression rate of 0 at 100mp/ky.
%Met.

Specific Examples of the Invention The present invention will be explained in more detail by the following examples. The compound numbers in the Examples are the numbers of the compounds of Schemes A and B above.

Example 1 (1) is a method for isolating lugenin. 500 g of red megawattle extract is dissolved in methanol, silica gel is added thereto, and the solvent is distilled off to form a powder. This was loaded onto a silica gel column, developed with ethyl acetate containing 5% methanol, and Bergenin 38.8. ! I got i'.

Instrumental data for this compound are provided in J.

E, Hay et alo, J-Chpm-8oc-
2231 (1958) and P-A, Ramaiah e.
t all, J-Chem-8oC2313 (1979
), - (2) Synthesis of dimethylbergenin (3) Irgenin 15
Dissolve g in 750 ml of methanol, add 60 g of anhydrous potassium carbonate, add 86 ml of dimethyl sulfate, and add 50 g of anhydrous potassium carbonate.
After stirring at ℃ for 18 hours, remove the carbonic acid rum from F and concentrate the mother liquor. The residue is made into a suspension with a mixed solvent of methanol and ethyl acetate, and purified by silica gel column chromatography.

The reaction mixture was developed with ethyl acetate and then with ethyl acetate containing 10% methanol. The obtained crude crystals were recrystallized from methanol/ether, and dimethyl was added to 12.1 g (74%) of Lugenin (3).
Obtained. Data for this compound are provided by J, JHay et a.
l, J. Chem-8Oc, 2231 (1958
) and P, A, R/3maiah et al., J.
Chpm-8ac, ) 313 (1979).

(3) Synthesis of azide compound (6) Dimethylirgenine (3) 109 is converted into anhydrous pyridine 13
Dissolved at 5 dK and cooled with water.
Add 6.4 g and stir at room temperature for 16 hours.

The reaction mixture was made acidic with 10% aqueous hydrochloric acid and extracted with ethyl acetate. After drying with magnesium sulfate, the supersolvent was distilled off to leave a residue fiiO,4,! I got i'. This was dissolved in anhydrous dimethylformamide (50d), 2.37.!i+ of sulfur azide was added, and after stirring at 100°C for 3 hours,
Dilute with water and extract with ethyl acetate. Purification was performed in the same manner as in (2) above to obtain 7.09 g of the azide compound (6).

mp 166-167℃ IR (OHC/3) ν111aX(m-') 3350
．． 2100.1715NMR (CDOA'3) δ3.8
7.3.90.3.93 (3H each,,?.

OMe), 7.38 (IH,,?, aromatic ring proton) M-80m/z 381 (4) Synthesis of ioP form (7) Tosyl form of dimethyl vargenin (3) (4184 rv anhydrous dimethoxymeth 71 m7 !Dissolve, add 72 μm of sodium iodide, and heat under reflux for 2 hours. Dilute the reaction solution with water and extract with ethyl acetate. After drying the solvent, evaporate,
Iodine form (force (X=I) 68TII9 was obtained.

NMR (δ') 3.90 (3H,,?)
(CDCl2: CD30D 3.95 (6H,
S)=1:1) 7.40(IH,y)M
S 111/Z 466 (5) Synthesis of amine compound (9) Compound (6) 1.4.9 was dissolved in hot methanol 3Qme) (
After melting and cooling, 10% pa-c (Alfa) 414
mg and subjected to catalytic reduction under hydrogen. After 18 hours, the catalyst was removed and the mother liquor was concentrated to give the amine (9) 1.28
& got.

mp, 129-132℃ IR (CHC73) 3350.172ONMR (CDC
/3) 3.78.3.83.3.88 (3H, S each.

OMe) MS m/z 355 (6) Synthetic amine compound of compound 01) (9) 62CIIf? 72 ml of 99% formic acid
Add 72d of 35% formalin aqueous solution,
Time heating-flow. The reaction solution was made slightly alkaline with a saturated aqueous solution of soybean and extracted with ethyl acetate to obtain the compound (Ill (
R/-OH5) crystal 520Tn9 was obtained.

mp 95-98℃ IR (Nujol') 3350.172ONM E
((CDCl3: CD30D = 1: 2)
2.39 (6H-g.

Warehouse e2) 3.82-3.90-3.94 (3H each,
，? .

OMe), 745 (I H,s, aromatic ring proton) MS maz 38!1 (Synthetic amine compound of compound Q21 +9) 129# was dissolved in 11 acetic anhydride and 1 ml of pyridine anhydride, and left at room temperature for 14 hours. .

The solvent was distilled off under reduced pressure, and the residue was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The residue was purified by thin-layer silica gel chromatography (developing solvent chloroform:acetone 5:1, eluent solvent acetone) Compound Q, 21 (R
“=CH3) was obtained 81Tn9.mp.

222-225.5°C IR (C) (C/3) 1740. 1720 (shoulder), 675 NMR (CDG13)2. rl O(3H9S), 2.
09 (6)I.

S), 3.83. :'5.8B, 3°93 (3H each
, 5°-OMP), 738 (I H,s, aromatic ring proton) MSm/2481 Example 2 (1) Synthesis of compound (131) Dimethylirgenine (311.65 g was dissolved in 10'fLl of anhydrous dimethylformamide, Imidazole 409
■, 4-dimethylaminopyridine 764■ is added, t
, -butyldimethylcyl]ruchlorite 4907■ was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was made acidic with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate.

The residue was purified by thin layer chromatography (developing solvent: ethyl acetate:hexane 4:1, elution solvent: ethyl acetate:
methanol 4:1), compound c311.39 was obtained.

IR (CHCA3) 3600, 3400, 173ONM
R(CD(J3) 0.10 (6H,,?, SiM
e2)e O,90(9H* s t S 1t-Bl
l ) * 5.85 (3Ht' v ”e) 3.8
8 (6H, JP, pMe), 7.38 (IH
,s.

(aromatic ring proton) MS maz 47[1 (2) Compound [0 synthesis compound (1311,18g
Dissolve lK and acetic anhydride3. Add OWLl and stir at room temperature for 18 hours. The acetic anhydride was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: ethyl acetate:hexane 1:1, elution solvent: ethyl acetate).
1.20 g of R=CH3Go) was obtained.

IR (CHC13) 174O NMR (CDCI!s) 0.05 (6H2s,
SiMez)y O,90(9Ht', S it
-Bu)y 2-03 s 2.10 (3Hz each,
-0Ac), ro, 85. 5.89. 3.93
(3 hours each.

OMe), 7.40 (IH, r, aromatic ring proton) compound *4J (R-OH3Co) 8057
Dissolve V in 4.83 ml of acetone and add
Add reagent 1.071R1 and stir for 10 minutes at room temperature. The reaction mixture was diluted with methanol and then water, extracted with ethyl acetate, and extracted with carboxylic acid α61 (R, , CH3Co
) 660 ■ was obtained.

IR (Nujol) 3400, 1740, 1730° 1705 (shoulder) NMR (CDG13: CD30D= 1: 1)
2.05.2.10 (each !, H,, ?, -0Ae)
, 3.84.3.89.3.94 (each 3H,s, OM
FI), 7.38 (IH, j', aromatic ring proton) MS maz 454 (3) Compound αη and α-equal synthesis compound (J3496■ anhydrous tetrahydrofuran (T
HF) solution 3d with 50% sodium hydride 61~TH
Add solution F (3 m/liter, then add 0.4 ml of anhydrous hexamethylphosphorotriamide (HMPA), 1% dirubromide [], 228 m7), and stir at room temperature for 18 hours. Reaction mixture was diluted with pH 7 phosphate buffer and extracted with methylene chloride. The residue was purified by thin layer silica gel chromatography (developing solvent: ethyl acetate:hexane 1:4, elution solvent: ethyl acetate) to obtain the compound ( 15
432 ■ of 1(R'=◇)-cH2-) were obtained. IR(C
HC, g3) 1735°NMR (GDC13) 0.05
．． [), 08' (each 3 H, J', SiMe2')
.

0.89 (9H,z, Sit, -Bυ), 3
．． 85. 3.87°3.92 (each 3H,,?, OM
e) This compound (+5) (R' = 忰0H2-)424IR
Dissolve Q in acetone 10-:) Jones
s') reagent [1.52 mJ was added and stirred at room temperature for 1 hour. Methanol and then water were added to the reaction mixture, extracted with ethyl acetate, and the residue was purified by thin layer chromatography (developing solvent: ethyl acetate: methanol 6:2; elution solvent: ethyl acetate: methanol 1:5). , −(compound surface (
R'=ζnCH2-) 160 .mu. was obtained.

IR (Nujol) 310.172ONMR (CD3
0D') 5-89 (9HlS, OMe), 7
-00~7.50 (11H, m, aromatic ring phloton) compound (An (R/ x QCH2-) 153■ was dissolved in methanol 3.6d, 10% Pd-CB511
1! ;1 and subjected to catalytic reduction. After the reaction, the catalyst was removed, the mother liquor was concentrated, and the resulting residue was purified by thin layer chromatography (developing solvent: ethyl acetate: methanol 5:6; eluent solvent: ethyl acetate: methanol 1:1). Acid (la15) was obtained.

IR (CHC/'3') 3350, 1720, 17
．． 00 (Shoulder) MS rr/v 370 Patent applicant San) I) - Co., Ltd. (4 others) Procedural amendments Commissioner of the Patent Office Kazuo Wakasugi 1, Indication of case Patent application No. 59110 of 1982 2, Name of the invention Bergenin derivative and its manufacturing method 3. Relationship with the case of the person making the amendment Patent applicant address name (190) Suntory Ltd. 4. [Detailed description of the invention] column of the agent's specification - 6. Amendment Contents (1) The statement on the last line of page 9 of the specification is corrected.

(2) Correct the statement on page 10, line 8 of the specification letter 6-9. (3) Correct ``Geldorf'' on page 11, line 8 of the specification letter to ``Gendorf''.

(3) (4) Statement on page 14, line 1 of the specification I am corrected.

(5) The description shall be amended as follows.

Claims (1)

[Claims] (11 General formula [wherein R1 is the general formula -C02X (in the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal]) or the general formula -0H2Y (in the formula, Y is a: ))' group, a nitrogen atom, a t-butyldimethylsilyloxy group, an amino group, a dialkylamino group, or an N-acylamino group. )
and R represents hydrogen, a lower alkyl group, an acyl group or a phenylalkyl group. ] A novel irgenin derivative having . (2J R" represents the general formula -C02X (in the formula, X represents a hydrogen atom, an alkali metal, or an alkaline earth metal), and R is a hydrogen atom, a lower acyl group, or an indyl group. Claim 1 Novel irgenin derivatives as described in (3) R'' has the general formula -CH2-NY/Z (wherein Y/ and Z represent a hydrogen atom or an alkyl group), and R2 is a hydrogen atom. Fan product 1st
Novel 2 lugenin derivatives described in Section 2. . (41B" is -CH2Y, Y represents a di- or t-butyldimethylsilyloxy group, and R2 is a hydrogen atom or a lower alkyl group. Derivative. <5) The novel irgenin derivative according to claim 1, wherein R'' is -CH2Y, Y represents an acylamino group, and R2 is an acyl group. A method for producing a novel irgenin derivative having a formula characterized by reducing a compound having the following formula: (7) General formula (wherein R1 represents a t-butyldimethylsilyl group and R2 represents a hydrogen atom, an acyl group, or a phenylalkyl group) A method for producing a novel bergenin derivative having the same meaning as above, in which R represents a hydrogen atom, an alkali or alkaline earth metal.