JPS6092284A - Bisbibenzyl diether derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is OH, lower alkoxy or lower alkanoyloxy; R<2> is H and A is group of formula II, formula III (R<3> is lower alkoxy or lower alkanoyloxy) or -C(O)-, or R<1> and R<2> are OH and A is group of formula II] and its salt. EXAMPLE:Malchantin D. USE:Carcinostatic agent. PREPARATION:For example, the compound of formula I can be produced by extracting and separating form Marchantia polymorpha, Reboulia hemisphaerica, Riccardia multifida, etc. There is no particular restriction in the extraction method, and the extraction can be carried out e.g. by the solvent extraction process taking advantage of the solubility difference in a solvent, the column chromatography, and proper combination of these methods. The solvent used in the solvent extraction process is e.g. water, methanol, etc. The compound of formula I has low toxicity and extremely weak side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel bisbibesidyl diether derivatives and salts thereof.

The bis-jibe, 17-di-ester derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

1 [In the formula, R1 represents a hydroxyl group, a lower alkoxy group, or a lower alkanoyl group, R2 represents a hydrogen atom, and A represents a lower alkanoyl group] or -C-, respectively, or R1 and R2 both represent a hydroxyl group, and A represents -
CH- is shown respectively. [H] In the present specification, examples of lower alkoxy groups include methoxy, ethy, zu0boshi, isozuroposhi, zutoshi, tert-zutoushi, pentyloxy, For example, lower alkanoyl groups include formyl group, acetyl group, 50 di onyl group, isodil group, , vesitanoyl group, tert-butylcarbonyl group, hexylcarbonyl group, and the like.

The compound of the present invention represented by the general formula t1) has excellent anticancer activity and is useful as an anticancer agent.

Furthermore, the compound of the present invention is characterized by low toxicity and extremely weak side effects.

The compounds of the present invention can be used, for example, in Marchantia polymorpha 1
．． ; Rttboulia hemisph
aerica), Kushitsuba Jizuga (Riccard)
ia multifida), Kepira jiga (Radu
la perrotttttiana), Futabane liverwort (Marchantia palttacea)
Var, dcptera), aurine liverwort (Ma
rchantia tasana), etc.

Fi is not particularly limited as a method for extracting and isolating the compound of the present invention, and ordinary separation means that utilize the physicochemical properties of the compound of general formula (1) above can be used, such as a method that utilizes the difference in solubility with the solvent. Solvent extraction method, column chromatography method that takes advantage of the difference in adsorption affinity for the adsorbent, thin layer zero mud method, countercurrent distribution method that takes advantage of the difference in distribution ratio between two liquid phases, and appropriate combinations of these methods. It can be implemented by Examples of the extraction solvent include water, methanol, ethanol, lower alcohols such as isopanol, ethyl acetate, and mixed solvents thereof.

Examples of the adsorbent include activated carbon, silica gel, cation exchange resin, and alumina.

Among the compounds of the above general formula 1+l, the compound in which at least one of R1 and R3 shows a lower alkanoyl-oxy group is acylated to the corresponding compound in which at least one of R1 and R3 shows a hydroxyl group. Manufactured by For this acylation, a wide range of reaction conditions for ordinary acylation reactions can be employed. As the acylating agent, a wide variety of conventionally known agents can be used, such as lower alkasiic acid anhydrides such as acetic anhydride;
Examples include lower alkasiic acid halogens such as chloride, pionyl mite, and the like.

The amount of such acylating agent to be used is not particularly limited and can be appropriately selected from within a wide range, but usually at least an amount of about 1,000 liters based on the raw material is used to replace one hydroxyl group of the raw metal material. It is best to use an excess amount. When using an acid anhydride or an acid halide as an acylating agent, the acylation reaction is preferably carried out in the presence of a basic compound. Specific examples of basic compounds include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates or bicarbonates of these alkalis and metals, alkyl lithium, pyridyl, N-methylbiberi, ;triethyl Examples include tertiary amici compounds such as amici.

The acylation reaction is carried out in any suitable solvent. Examples of the solvent include ketones such as acetol and methyl ethyl ketosi, ethers such as ether, dioxic acid, tetrahydrofuran, and benzene! Examples include aromatic hydrocarbons such as methane, dimethylformamide, dimethylsulfotriamide, dimethylsulfotriamide, methylsulfotriamide% 112-+; The reaction proceeds either under cooling, at room temperature, or under heating, but it is usually preferable to carry out the reaction at -10 to 80°C. The above reaction is generally completed in about 2 to 24 hours.

Among the compounds of the above general formula (1), at least one of R1 and R3 has a lower alkoxy group; It is manufactured by converting For this alrylation, a wide range of reaction conditions for ordinary alhylation reactions can be employed. For example, in the above-mentioned acylation reaction, the reaction conditions for the above-mentioned acylation reaction can be applied as they are, except that an appropriate alkylating agent is used instead of the acylating agent, and the reaction temperature is between room temperature and 100°C. . As the alkylating agent, a wide variety of conventionally known alkylating agents can be used, such as those represented by the general formula % (2) [wherein R4 represents a lower alkyl group and X represents a halogen atom]. ] Compounds represented by the following, sialic acids such as diadimetasi, sialyl sulfuric acid such as dimethyl sulfate, and Meer'J (Meer'J) such as trimethylsonium fluoroborate.
Wein) reagents and the like.

Specifically, the compound of general formula (2) is methyl iodide,
Methyl bromide, ethyl iodide, l-bromide''50 pills, 1-
Examples include vesicyl iodide. When a sialic oak or a Meawaishi reagent is used as the alkalizing agent, it is preferable to carry out the reaction at -80 to 50°C. In addition, when using sialic acid as an arylation agent, compounds such as tetrafluoroboron hydride, p-toluethysulfosic acid, BF3.0(C2H5)2, etc. may be present in one reaction system.

Among the compounds of the above general formula (1), the compound in which A represents -C- can also be produced by reducing the corresponding compound in which A represents -C- by 1. This reduction is carried out using sodium borohydride in a lower alcohol such as methanol or ethanol. The amount of sodium borohydride to be used is not particularly limited, but it is usually about 0.5 to 2 times the amount of the raw material compound, preferably about the same amount to about 2 times the amount. The reaction is usually carried out at 0°C
The reaction is carried out at around room temperature and the reaction time is generally 1 to 6 hours.

Among the compounds of general formula (1) produced in this way, the compound having an acidic group can easily form a salt with a pharmaceutically acceptable ordinary basic compound. Examples of such basic compounds include strong basic compounds such as sodium hydroxide, calcium hydroxide, and potassium hydroxide.

The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means.

Examples of the separation means include solvent extraction, dilution, recrystallization, columnar extraction, thin layer separation, and the like.

Examples of manufacturing the compounds of the present invention are listed below.

Production example 1 75 cm of methanol extract 652 of Futabane liverwort
Silica gel (Sellgel 6) was added to a 5cm x 5cm glass column.
0.35-70 mesh, Merck & Co., Ltd.) Fill with 200f or add to n- at 0, 71t.

5% ethyl acetate/n-hex: Jlt, 10% 11゜2
0%It, 30chi 1.5t, 50chi 2t, 80chi 11,
Elution was performed using 2 tons of ethyl acetate. Maruki Shiteishi (M
archantin) Ds Mariki City: 7E1 Mariki City, Ip and Mariki City G are included in the 50-chi elution part. This elution part 1.5 F was 4crnX4
Sephadex LH-20 (
CHCl3:CH30H (1:
Elution was performed using a mixed solvent of IV/V). As a result, 1t of eluted portions containing Maruki City'JDsE%F and G were obtained. This eluted portion was analyzed again using a column chromatogram filled with silica gel (10-Selgel 60.70-230 mesh, Merck & Co., Ltd.) 100F in a 70 cm x 4 m glass column.
%CH30H/ CHCl31t% 10chi 1t%CH
Elution was performed using 30 Hlt.

As a result, from the 5-chi elution part, Maruki City/D100 Misaki,
Maruchi city JE80mf were isolated respectively.

Maruki City'-IF%G is also included in the 5th elution area,
It was too late to isolate it. This elution part 30■ contains CHCl as a developing solvent, 3: CH30H (9: IV/
y) using TLC (-t”-Selgel 60, F25
4. Perform preparative separation (Merck & Co.)
, Maruki City: 7G5■ were isolated. In addition, Maruki City' JD, E, F, and G could also be detected in the methanol extract of liverwort.

Maruki City'JD is expressed by the following formula.

The physical properties of Maruki City 7D are as follows.

MS: CC28H2406 (+456, calculated value 456)
IRCCHC13): 3560.3400.161O
11510, 1470, 1450, 1180cm-”N
MR (CDC13/TMS): 7.15 (t,
J=7.8.

lH), 7.02 (dd, /= 7.8~1.I
H), 6.92 (d, J=7.8, 2H), 6
．． 89 (/, J=7.8.IH)%6.86 (
dd, J=7.8, ~1. IH), 6.73(d,
J=1.5 6.72Cdd, J=2.4°~1. IH
), 6.55 (d, J=7.8, 2H), 6.
46 (ddd, /=7.3.2.now, ~1, IH)
, 6.15 (ddd, /=7.3, ~l, ~l
, IH), 5.00 (d, J=1.5.IH), 4.7
1 (dd, J=4.10.IH), 3.06-2
．． 99 (m, 4H), 3.04 (dd, J=4.
12. IH), 2.71 (dd.

J=I0,12.1#) Maruki City JR is expressed by the following formula.

The physical properties of Maruti Shiteishi E are as follows.

MS(DI): (II”29H2606(7Lf
470, calculated value 47o)”H-NMRCCDC13/T
MS'): 7.17 (/, J=7.8.l
H), 7.02 (dd, J=7.8, 1.5, I
H), 6.94 (et, J=8.3,.2H),
6.88 (t, J=7.8.IH), 6.87
(dd, J=7.8, 1.5.

IH), 6.78 (dd, J=2.9, ~1.
IH), 6.69 (d, J=1.5, IH), 6.5
7 (d, J=8.3, 2H), 6.42 (d
dd, J=7.8, 2.9.

~1. IH), 6.12 (ddd, /=7.8,
~l, ~1°IH), 4.95 (d, /= 1.
5, IH), 4.10 (dd.

/=4.10. iH), 3.0B (dd, J=12.1
0゜IH), 3.08 (m, IH), 3.06-2.8
6 Cnt.

4H), 3.25 (z, 3H) The power city 'JF is expressed by the following formula.

H'H-NMR (CD30D/TMS): 6.91 (
d, /=8.3.

2H), 6.88 (t, J=7.6, IH
), 6.83 (d.

J=8.3, IH), 6.74 (d, J=8.
．． 3. IH), 6.65 (d, J= 1.7,
IH), 6.63 (dd, J=~1.~1.I
H), 6.50 (d, J=8.3, 2H), 6
．． 50 (ddd, J=~I, ~1, 7.5, IH
), 6.10 (ddd, J-~l, ~1, 7.5,
IH), 5.50 (d, /= 1.7, I
H), 4.58 (dd, J=10.4.IH),
3.06 (dd, J=12,4.

IH), 3.03 (m, IH), 2.90 (m, 3H)
, 2.60 (dd, J = 10.12, 111 > Maruti city, 7+ is expressed by the following formula.

The physical properties of Maruki City, 7G are as follows.

JR (CHCL3>: 3550.3350.167
5.1605.1510.1470.1445.132
0.1230.1180.1028.960 cm-”
'H-NMR (CD30D/TMS): 7.22
(d, J=1.5.IH), 7.10 (/, / 7.8.IH), 7, o8 (t, J=7.8,
IH), 7.07 (ddd, J=~l, 2
．． 5, 7.8, IH), 6.95 (d, J
=8.4.

2H), 6.87 (dd, /=7.8, 1.5
, I H), 6.75 (tttttt, /=
~1, 1.5, 7.8, IH), 6.59 (
d, /=8.4, 2H), 6.52 (d,
/=1.5. IH), 6.48 (dd, J=, 7
．． 8, 1.5.

lH), 6.14 (dd, /=2.5, 1.5
, 1 //), 3.76 (br, s, 2H)
, 3.03-3.13 (m, 4H) Preparation Example 2 Maruki City'JD50''f-methyl iodide 1 m/, potassium carbonate 12 and aceto':J3d are refluxed for 3 hours.

Thereafter, it is filtered and the solvent of the Oki liquid is distilled off. Then, at step 15, water was added to the residue and extracted with ether. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 40 ml of the trimethyl form of Marishitoshi D in the form of white crystals.

The triacetate form of Marcateis D is represented by the following formula.

The physical properties of the triacetate of Maruki Tei'JD are as follows.

rp(cyct3): 3450.1593.15o5
．． 1475.1465.1450.1423.1310
゜1268.1232.1135, +095, 16-! 078.1005crr1-1'H-NMR (CDC13/TMS): 7.19 (
/ , J=7.8.

lH), 7.05 (dd, J=7.8.1.5.IH)
, 6.88 (d, J=8.3, 2H), 6.8
3 (t, J=7.8.IH), 6.80 (dd
, /=7.8, 1.5.

IH), 6.76 (d, / 1.9.IH), 6
．． 66 (dd, J=1.9.~1.IH), 6.51 (
d, /=8.3, 2H), 6.36 (ddd,
J=~1, 1.9.

7.8. Il, 6.06 (ddd, J=~l,~
1.7.8゜lH), 5.06 (d, J=1.
9, III), 4.07 (dd.

J=4. IO, lH), 3.88 (s, 6#),
3.62 (s, 3H), 3.11 (dd, J=I2
．． 4, IH), 3.10-2.97 (m, 4
H), 2.65 (dd, J=I2゜10, lH) Production Example 3 Trimethyl compound of Maruki Shishi D obtained in Production Example 2 40■
, 1 ynl of acetic anhydride, and 77 ml of cypress were stirred at o'c for 1 day and night. The reaction mixture is then poured into water and extracted with ethyl ether. After drying the ethyl ether layer over sodium sulfate, the solvent was distilled off to obtain 30 ml of 1-dimethylacetate ID as a colorless oil.

The trimethyl acetate form of Maruki City JD is represented by the following formula.

The physical properties of the trimethyl acetate form of Maruki City 7D are as follows.

'H-NMR (CDCl3/TMS): 7.20
(t, J = 7.8°IH), 7.08 (dd
, J=7.8, 1.5, IH), 6.90
(d, J=8.5, 2#), 6.87 (t,
J=7.8°IH), 6.82 (dd, J=7.
8, 1.5, 111), 6.68 (dd, J
=~I, 1.9, III), 6.62 (d.

J=1.9. IH), 6.52 (d, J=8.
5, 211), 6.44 (ddd, J=~I
, 1.9.7.8. IH), 6, 12 (ddd,
J = ~1, -1, 7.8, IH), 5.76 (
dd, J=4.10. IH), 5.19 (d.

J=1.9, IH), 3.92, 3.90, 3.6
6 (s.

each3H), 3.10(dd, J=I2.4.IH
), 3.08-3.02 (m, 4H), 2.77
Cdd, J=I2゜10, IH), 2.12(s, 3H
) Example 4 Maruchi City'JE507Iv, 1 ml of methyl iodide, 1f of potassium carbonate and 3 ml of aceto'J are refluxed for 3 hours. Thereafter, it is filtered and the solvent of the filtrate is distilled off. Water is then added to the residue and extracted with ether. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 40 cm of the trimethyl form of white crystals.

The trimethyl form of Marinteishi E is represented by the following formula.

The physical properties of the trimethyl compound of Marinteishi E are as follows.

1H-NMR (CDC13/TMS): 7.21C
t, J=7.8゜IH), 7.07 (dd, J=
7.8, 1.5, IH), 6.90 (d,
J=8.8, 2H), 6.82 (dd, J=7.
8, 1.5, IH), 6.81 (t, J
=7.8, IH), 6.72 (dd, J=2
．． 4, ~1. IH), 6.68 (d.

J=1.9,177), 6.53 (d, J=8.
8, 2H), 6.34 (ddd, J= 7.8
, 2.4, ~1. +77), 6.02 (ddd,
J=~1. ~1, 7.8, IH), 5.03C
d, J=1.9. IH), 4.11 (dd, J-
10,4,IH), 3-93 (s, 6717),
3.65 (s.

3H), 3.32 (s, 3H), 3.16Cdd
, J=12°4, IH), 3.110-2-95C,4
H”), 2.61 (dd, J=12.10.IH) Example 5 Maruki City: 7G5■, 0.5 ml of acetic anhydride and Piri, ;'JQ, 5 m/ were stirred at 0°C for one day and night. The reaction mixture is then poured into water and extracted with ethyl ether.

After drying the ethyl ether layer over sodium sulfate, the solvent was distilled off to obtain a colorless oily triacetate of 7G.

The triacetate of Mariki City: 7G is expressed by the following formula: % O The physical properties of the triacetate of Maruki City'JG are as follows.

MS (DI): C34H2809 (M+580 calculated value 580) JR (CIIC13): 1780.16
90.1600.1505.1465.1420.13
70.1330.1270.1180.1145.11
30.1050.1010cm-1'H-NMR (CDC13/TMS): 7.53(d
, J-1,8゜lH), 7.41 (dd, J=7
．． 8, 1.5, IH), 7.22 (t, J=
7.8, I//), 7.17 (t, J=7.8
.

lH), 7.08 (d, J=8.4, 211)
, 6.96(dd, J=7.8, 1.5,
IH), 6.95 (dd, J=2.6, 1.5
,~1. IH), 6.84 (d, J= 1.8
.

IH), 6.71 (d, /=8.4, 2H),
6.69 (ddd, J=7.8, 1.5, ~1.
IH), 5.98 (dd, /=2.6, 1.5
, IH), 3.78 (br, s.

2H), 3.22 (m, 2H), 3.19 (m, 2H)
, 2.32, 2-30, 1-58 (s, ea
ch 3H) (and above), 11

Claims (1)

[Scope of Claims] ■ 1 1 [In the formula, R1 is a hydroxyl group, a lower alkoxy group, or a lower alkanoyl group, R2 is a hydrogen atom, and A is a lower alkanoyl group] or -〇- 1 respectively, or R1 and R2 both represent a hydroxyl group,
A each represents -CH-. ] Bisbibe, 7 diyl diether derivatives represented by H 2 and salts thereof.