JPS5967287A - Novel bruceolide derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is H, t-butyl-dimethylsilyl, methoxyethoxymethyl, or methoymethyl; R2 is H, 5-18c straight-chain alpha,beta-unsaturated carboxylic acid residue, with the proviso that a compound of R1=R2=H is omitted). EXAMPLE:15-0-2'-Pentenoylbruceolide. USE:Having antitumor activity, useful as a carcinostatic agent. PROCESS:For example, the hydroxyl group of 15-position of bruceolide derivative shown by the formula II (R1 is t-butyldimethylsilyl, methoxyethoxymethyl, or methoxymethyl) is esterified with the residue of 5-18C straight-chain alpha,beta- unsaturated carboxylic acid to give a 15beta-carboxylic acid ester shown by the formula III(R2 is 5-18C straight-chain alpha,beta-unsaturated carboxylic acid residue), which is hydrolyzed, to give a trihydroxyl compound shown by the formula IV.

Description

[Detailed description of the invention]

(A) Background and Summary of the Invention The present invention relates to a novel pruseolide derivative represented by the following formula I and a method for producing the same. HCI) (in the formula, R represents hydrogen, a 1-butyldimethylsilyl group, a methoxyethoxymethyl group or a methoxymethyl group,
R2 represents hydrogen or a C1 to C11 straight α,β-unsaturated carboxylic acid residue. However, compounds represented by u<l-R2-H are excluded. ) The antitumor effects of various natural products and compounds derived from natural products have long been attracting attention, and a small number of these have already been put into practical use. However, in the end, there is nothing that can be said to be satisfactory. Quassinoids, which include the pruseolite compound that is the object of the present invention, are also T.
3rucea ant idysentericaMi
The active ingredient of 13ruceanLi
n(V) Discovery (f(u p c I) a n et al., J, Org
, CI+ern, 38, 178 (1973); British Patent No. 1440094), Bruceantaline (Bruceantaline) was extracted from the same plant and coexisting plants.
rin), Brucein B
cihytropurceanthin, furcein D, brucein E
, Bruceoside A
) have been clarified as natural or artificial homophyte compounds derived from them.
; J, Pharm, Sci. Average, 883 (197
9)). However, the present inventor found that 1
Brusatol, which has two fewer carbon atoms in the carbonic acid residue bonded to the 5-position carbon. The following formula ITI, J. Org, Ct+em, 33,429
(1963)). 9th (TIT) Olide derivatives to create more effective anticancer agents (by re-esterifying the following formula (I) with residues of α,β-unsaturated carbonic acids, Obtaining a new pruseolide derivative represented by the following formula (m) and looking at the scales,
I did one. However, the actual reaction is carried out, for example, according to the following steps. H In other words, the analogy is Bruceajavan.
Brusatol (I
ID wo, for example

[-phthylnomethylsilyl chloride,
Chloromethyl methoxyethyl ether (MEM)
Alternatively, when etherified using an etherifying agent such as chloromethyl methyl ether (MOMC7) in a conventional manner, the compound ■
is obtained. Here, the hydroxyl group at the 3-position of the compound αm is converted to an ether group to form a compound ①, which is a direct reaction α of 06 to CI8 selectively to the hydroxyl group at the 15-position of the compound α). This is to introduce β-unsaturated carbonic acid. When compound OX is solvolyzed using IN potassium methoxide/methanol solution, compound (1) from which the 15-position ester residue is removed is obtained. Then this compound (
]) with a desired C6-C18 linear α,β-unsaturated carboxylic acid chloride and potassium carbonate, a compound (1) in which the 15-position hydroxyl group is re-esterified is obtained. Finally, acid hydrolysis of this compound (1) with an acetotolyl solution of hydrofluoric acid or a methanol solution of P-1-luenesulfonic acid yields the corresponding compound (IT) in which the hydroxyl group at the 3-position is liberated. Among the above compounds, substituent R1 in compounds I and 11
means a straight chain α,β-unsaturated carbonic acid residue of C6 to C1a as described above, and specific examples thereof include trans or cis-2-pentenoic acid, l.rance or cis-2 -hexenoic acid, trans or cis-2-heptenoic acid, trans or cis-2-octenoic acid, trans or cis-2-nonenoic acid. trans or cis-2-thecenoic acid, trans or cis-2-lanticenoic acid, 1-trans or cis-2-dodecenoic acid, trans or cis-2-1-litecenoic acid,
trans or no-2-*h-latecenoic acid, trans or 3cis-2-pencutycene M, +-lance or cis-2-hexadetrinoic acid, l-lanse or cis-2-heptatecenoic acid and trans or ras-2-
It is a residue of octadecenoic acid○ (I3) Effects of the invention compoundThe invention compound (1) is an important intermediate of the compound (■)
In addition, the compound of the present invention (Kawa) has a strong antitumor activity against murine leukemia P388.Moreover, its toxicity is lower than that of the well-known Prusatol θ, so its future development as a new anti-1 Ifi tumor drug is expected.The following compounds ( Representative *z belonging to Il)
*The toxicity and survival rate (ILS%) of the three compounds are collectively shown in Table-1. Shows shisan. (0) Physical and chemical constants of the compounds of the present invention, etc. The chemical constants of the compounds of the present invention are shown in Tables 2 to 4. (The following is a blank space) 732- (D) Production example of the compound of the present invention tl! Preparation of 3-0-t-phthyrunmethylsilylbrusatol (2) 16 g of flusatol (compound fil) was dissolved in dimethylformamitro 40 d, 15.76 g of tert-butyldimethylsilyl chloride and 15.7 g of imitasol.
6 g was added and stirred at room temperature overnight. About 21 g of water was added to the reaction mixture to stop the reaction, and the mixture was extracted four times with ether. The ether layer was washed once with water, then twice with saturated brine, and then dried over anhydrous magnesium sulfate. Kieselgel 60 (manufactured by Merck, 70-230 mesh) ls
The sample was loaded onto a column with a diameter of 5 crn packed with 0 g, and eluted using a chloroform/methanol (20:1) mixture. From the eluate, about 20 g of crude 3-0-t-butyrunmethylsilylbrusatol (compound f2N) was extracted. This crude product was recrystallized from Hensen to give colorless needle crystals of 16.62
g (yield 85 mo) was obtained. 12) Production of 3-0-t-butylsimethylunrylfurtheolite (3) 4.94 g of compound (2) was mixed with 1N potassium l.
The mixture was added to 99 ml of methoxide/methanol distillate and stirred. Stirring was continued for a minute, followed by neutralization using a methanol solution of hydrochloric acid. Next, potassium chloride precipitated from the reaction solution was filtered off, and methanol was distilled off under reduced pressure. (The potassium chloride precipitated during the distillation was also filtered off each time.) The residue was loaded onto a column with a diameter of 30 c1n filled with a suspension of 100 g of -1-1 Cellgel 60 (177J rJ,'i) suspended in ethyl acetate, and when eluted with ethyl acetate, the desired 3-
0- L-butyrnomethylsilylfurtheolide (B
3.69 g was obtained. Yield 86%. f3+3-0-1-phthylnomethylsilyl 15-〇-
2'-pentenoyl bruceolide (4) OJ 550 mg of compound jJ was dissolved in 50 me of methylene monochloride, 15 g of potassium carbonate and 1.2 g of 2-pentenoyl chloride l' were added, and the mixture was heated at room temperature for 6 days. Stirred. After that, 2N hydrochloric acid is added to the reaction solution to accompany the reaction,
Extract with ether 4 times. The extract was washed once each with saturated sodium bicarbonate water, water, and saturated saline, and dried over anhydrous magnesium sulfate. This dry ether solution was subjected to column chromatography using Kieselkel 60 (chloroform/methanol solvent) and preparative thin layer chromatography (Kieselkel 60F, □0.5
Maro, solvent: chloroform/methanol type)
Then, the desired 3-0-1-butyldimethylsilyl-
15-0-2'-pentenoylbruceolide compound +
4+ 166 mq was obtained in 34% yield, besides]2
5 mg of raw material smoke was recovered. U+ 3-0- t-butyrunmethylsilyl-15-
Production of 〇-2'-hexenoyl bruceolide (5) 550 mg of compound (a) was dissolved in 50 me of methylene chloride, 15 g of potassium carbonate and 12 g of 2-hexenoyl chloride were added, and the mixture was reacted at room temperature for 3 days. I let it happen. When the reactant is treated, extracted, and purified in the same manner as in Example (3), the objective 3
-0-t-phytyldimethylsilyl-15-O-2''-
Hexenoylbruceolite (Iillolmg is 16
% yield was not obtained. (5) 3-0-1-butyldimethylsilyl 15-0-2
'-Heptenoyl bruceolite j-((il) Preparation Compound (5550 m! The resulting reaction product is treated, treated and purified in the same manner as in Example (3), resulting in the desired 3-0-1-butylsomethylsilyl 1)k-15-0-2'
-Heptenoyl bruceolae V136yry (yield 35
%) was obtained, and 125 mg of raw S1 material was also recovered. (6) 3 0-1-butyrunmethylsilyl-15-
Production of 〇-2'-octenoylbrucellite (7) The compound (3550+++g) was reacted with 1.30 g of 2-oftenoyl chloride for 4 days in the same manner as in the previous example (3),
When the reaction product was treated in the same manner as on the same side, the desired 3-o-[-butyltmethylsilyl-15-0-21-octenoylbruceolide (7) was obtained with a yield of 51% (yield: 198 mg)
(7) 3-0-t-butyltmethylsilyl-15-〇-
Production compound of 2'-decenoylbruceolide (8) (
3) Dissolve 500 ~ in 30 me of methylene chloride, and add 249 g of potassium carbonate and 1 2-tesenoyl chloride to this.
24 g was added, and one liquid was stirred at room temperature. Let the reactants be the antecedent (
The product was treated and purified in the same manner as in 3) to obtain 101 mfl of the desired 3-0-1-butyldimethylsilyl-15-〇-2'-decenoylbruceolite (8). Yield 16% (a) 3-C! -L-butyltmethylsilyl-]]5-
Production of 0-2'-tridecenoyl bruceolide The compound (31,555 mg) was dissolved in 50 me of methylene chloride, 16 g of potassium carbonate and 16 g of 2-1-lidecenoyl chloride were added, and the reaction was stirred at room temperature for 4 days. Reaction product was treated and purified in the same manner as in Example (3), and the treated 3-0-1-butyldimethylsilyl-15-0-2
128 mg of '-tritecenoylbruceolite (9) was obtained. Yield 17%. (9) Production of 15-0-2'-pentenoylbruceolide (10) 260 mg of compound (4) was dissolved in 7 ml/(bar) of a 47% hydrofluoric acid mixture (10:). and stirred at room temperature for 5 hours. Next, water was added to the reaction solution and extracted with ether, and the ether layer was washed with saturated brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent from this dry ether solution was loaded into a chromatography column in which 20 g of Kieselgel 60 (70-230 mesh manufactured by Merck) was suspended in chloroform and packed in a column with a diameter of 15 crn. methanol jl liquid t
When eluted with 100:]), the target ]h-0-2'
-Pentenoyl fluoride! IOi 122 m
g was obtained in a yield of 57%. (10) Compounds (lJ, lJ, IJ and rl'L5
) Production of the following compounds (]], 12.13 and 1 from compounds (5, 6, 7 and 9) in the same manner as in Example (9)
5) or synthesized (2]). The results are shown in Table 5 below. Table 5 Production of flll 15-0-2'-decenoylbruceolide θ4) Compound f81101 rq was dissolved in 5 ml of methanol, 0.5 me of water and 270 μ of o:p-toluenesulfonic acid were added, and the solution was dissolved at room temperature. Stirred overnight. After completion of the reaction, methanol was removed under reduced pressure, water was added to the residue, and the mixture was extracted five times with chloroform. The chloroform portion was first washed twice with water and then once with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was sealed in silica gel chromatography using Kieselgel 60 reinst (Art 7754, manufactured by Merck) and eluted with Hensen-ethyl acetate solvent to obtain the desired 15-0-2.
'-decenoylbruceolide L5ony (22) was obtained. Yield 93%. (12) Production of 3-0-methoxy 11-xymethylbrusatol bleaching Thorium hydride (50% oil) 106
mii' was dispersed in 50 ml of terahydrofuran,
To this was added 300 mg of Boursa l-le full at room temperature. Cool the solvent with water and add chloroform dissolved in a small amount of tetrahydrofuran!・Xyethyl ether 27
6 mg was added dropwise and then stirred in chambers A and I overnight. After completion, water was added to the reaction mixture to make it acidic with tetrahydrofuran under reduced pressure, followed by extraction with methylene chloride five times, and the extract was washed twice each with water and saturated brine, and dried over magnesium sulfate. . The residue obtained by removing the solvent from the methylene chloride solution was subjected to silica gel chromatography (Kiesel Gel 60 (70-230 mesh manufactured by Merck), two hands of penzene acetic acid + L
, system), 223 ml of the desired 3-0-methoxyethquinemethylbursal 1--ol Q6) was obtained with a yield of 83%, and an additional 68 mg of raw material [1,1 was recovered. (+3) 3-0-Me-1-xymethylbursa 1~
-)L<Q)9B. +9 LiA 23 mg of sulfur hydride (50% oil) was dispersed in 20 d of tetrahydrofuran, and while cooling with water, a solution of 55 m'j of brusatol tl+ in tetrahydrofuran was added, stirred for 1 hour, and dissolved in chloromethyl methyl ether. 42 ml of tetrahydrofuran solution was added dropwise and stirred for 2 hours at room temperature.Next, saturated brine was added to the reaction solution to stop the reaction, and tetrahydrofuran was distilled off under reduced pressure, followed by extraction four times with ether. After washing the ether solution twice with saturated saline, it was dried with machinic acid sulfate, and then treated in the same manner as above (12) to obtain the desired 3-0
-Methoxymethylbursal 1--(+7) 60yt+
I got a 7. Yield quantitative. Q4) Production of 3-0-methoxyel 1-oxymethyl fluoresolide (+8) 50ml of compound (lfl) was dissolved in 1N potassium methoxide/methanol solution 0.8.1, and stirred at room temperature for 25 minutes. . After neutralizing the reaction mixture by adding a methanol solution of hydrochloric acid, precipitated potassium chloride was filtered off. The residue obtained by concentrating the solution under reduced pressure is directly applied to preparative R layer chromatography and purified (24).
i) Left - Hatake7. (15j Production of 3-0-methoxymethylbruceolite wings Dissolve 52.3 mg of compound (+7) in 0.90 me of 1N potassium methoxide methanol solution, stir at room temperature for 25 minutes, and then dissolve the upper side (14). The same purification treatment as above was performed to obtain 24.6'mg of the desired 3-0-methoxymethylbruceolide (lq). Yield 55%. (+6) 3-0-methoxye! xymethyl-15
Production of -0-2'-decenoyl bruceolide (20) 30 mg of compound (+8) was reacted with 60 mg of older brother-decenoyl chloride for 3 days in the same manner as in the case of Example (3),
The reaction product was treated in the same manner as in the same example to obtain the desired 3-0-methoxyethoxymethyl-15-0-2'-decenoylbruceolide (20). (17) 3-0-methoxymethyl-15-0-2'
- Preparation of compound (19) 24.6 mFI as in the case of the previous example (3), 2-decenoyl chloride lj 60m'i and 3
(25) The reaction product was treated in the same manner as in the same example to obtain the desired 3-0-methoxymethyl-15-0-2-decenoylbruceolide (
2I) was obtained. (18) ] ]5-o-2′-tesenoylbruce 1
Production of olide Compound (11omy) was dissolved in 0.5 ml of dry methylene chloride, 21~ zinc bromide was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative thin layer chromatography to obtain the desired 15- ()-2'-decenoylbruceolide (1
b) Obtained 3~. (10) ] Production of 5-o-2'-decenoylbruceolide 14) Compound (B) s rq was dissolved in a hydrogen chloride-methanol solution and stirred at room temperature for 1 hour. The reaction mixture was purified by preparative thin layer chromatography to obtain 5 mg of the desired 15-0-2-decenoylbruceolide (14). ``-system)''r'+Neyama 11'nee shi (l-1 shot) 1
, See the patent application No. 178210-2 of 1982, the title of the invention, 7 loaves, "Luseolide derivatives and their production 1 person 3,"
Relationship with the Toma case to be amended Patent applicant address: 2 Dojimahama, Kita-ku, Sasaka-shi 1-40 a3- Name: Suntory Ltd. 1 (Name) Representative: Kei Saji -2; 4, Dainobu Address Higashi, Yodoyo-ku, Osaka City] f country 1-32-12 None [1] Akira: Yftl 2'l, 5th white, 3 lines from the bottom]] ” is replaced by [(formula below (
ENG “)” is changed to “J”. 121 Specification 11:, No. 61, Chemical formula (I'), (I
The next line of I): Change the phrase ``in the ceremony'' to ``koboshin.'' j, 31 Details 11? , times, chemical formula (■”), (II
) to 4 lines January: r t((,) 1(を・ト.i[1
11.Excludes compounds represented by Ryo=R2=H. ”
Changed the text to ``Yu, indicating a residue.'' 1 city details i'! 'F - No. 9n 4th line: [The compound (I) of the present invention is]
ni) is changed to ``. l', +l Change the heading column and first column of Ql Details-1, Times 9 Table-1 to indicate C. 1 Table-1; f'+1 Specification, page 1I, line 1 [ ], insert the following sentence. 171 Specification, same, line 3 []: "The chemical constant of a compound is 1. is changed to ``chemical constants of compounds''. I;) 1 Details j11i, 12th to 15th-Good [Table-
2, 3, 4, and 1 are revised as shown in the attached sheet. 1"91 Specification, Near 1.16 page, 4 lines 11. [(
Compound [11188 is replaced by J] (Compound l11)
Change +eg to ". (XO) Details Ipj, 17th 17th A, 311th row 11
・ "Potassium 7-toxide in methanol 1#"
The text has been changed to [Karik ni methanol molten tra J]. (11) Details, line 180-.5 V1. Change "Each once" to "Each once." (12) Details, !i Same, lines 12, lines 11 to 13 11.
``Compound Sho 1fi 6 mg?''
41. l-IBeimz ga". (13) Specification, page 19, line 8, 11: ``To this, 1.I+, 5 g of chlorinating power'' is replaced with ``to this'' potassium 1.
Changed to ``5 grams.'' (14) 1314 detailed book, same, line 9 to line 10 line 11: [
``The reactant that was reacted'' was changed to ``[anti+4'f, the 5 reactant that was made to react''. (15) Specifications, page ff 120, line 9, line 11: "Stir one liquid at room temperature" is changed to "stir overnight at room temperature." N8) Ming I ancient, page 21, line 6 11: rase I
・1,1 ru (/<-, '+ 472' has been changed to ``Ace 13'' Riruni 47z1. (17) Specification, page 22, line 7 from C to 1] 21 Kerorofol J 1 part ``First, with water,'' is changed to ``Part of Chloropol L is first mixed with water, then J.'' (+8) Specification, page 23, line 5, 11. (19) In the specification, the second line from the bottom, IJ: rt + 7 raw material (11 is) is changed to "raw material!il is". (20) In the specification, same, 1st line from the bottom: ``Production of r (+7)'' has been changed to ``Production of r (+7).'' (21) Specification, page 24, line 2 [1.
Changed the text to [Water cooling -1.] to J. 9 Inventory of attached documents A and I (1) Attachment 1 copy

Claims (1)

[Scope of Claims] 1) General formula ((In the formula, R1 is hydrogen, [-butyldimethylsilyl group. A new pruseolide derivative containing a methoxyethoxymethyl group or a methoxymethyl group. (2) General formula (In the formula, R11, tt-butyldimethylsilyl group. (Indicates methylsilyl group, methoxyethoxymethyl group or methoxymethyl group.)
The 15-position hydroxyl group of the pruseolide derivative represented by C
It is esterified with a residue of a 5-C56 linear α,β-unsaturated carboxylic acid to form a compound of the general formula (wherein R1 represents a [-butyltmethylsilyl group, a metquinethoquinomethyl group, or a methoxymethyl group, and R1 is a Indicates C1 to C11 linear α,β-unsaturated carboxyl acid residues)? ll-represented 15β-
converting it into a carboxylic acid ester, and then hydrolyzing it (in the formula, R is a C6 to C18 linear α,β-unsaturated unsaturated norboic acid residue) to convert it into an I-lihydroxy compound. Characteristic method for producing novel puruseolide derivatives.