JPS6147439A - Novel manufacture of steffimycinone analogue - 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 The present invention provides a synthetic analogue of stefimycinone.
A novel process for the production of ffimycinone analogues obtained thereby, new intermediates which can be used in the synthesis of these compounds and the use of these compounds as antibacterial substances and for the synthesis of anti-inflammatory agents. related to

Are there many people competing with Ant 2? Icrine antibiotics exist. That is, if the compound is steffix
For example, US Patent No. 5,50
9.275 and 3,976,667),"' OOH,.

In this case, the compound is compatible with Stefimycin B [□For example: Rhcs J Vol. 84, No. 3182 (196
See 2)].

If the compound is acinthiamycin (arancia
Equivalent to [JA (3SJ! Vol. 84, No. 3)
182 (1962)], d) When R1-H and R2=OH, the compound is aranciamycinone.
none), edited by Mr. Bahn [Antibioti
csj Vol.

These compounds are either produced directly in the fermentation medium or obtained by acid hydrolysis of the fermentation product (as is the case for example with aglycone d) obtained by acid hydrolysis of alanciamycin).

All these compounds are highly active against Gram-positive bacteria, and some of them (in particular compounds a) and b)) even pose a cytotoxic threat. Indeed, strong packaging similarities exist between each of these vertebrae aglycones and the aglycones of certain clinically used anti-tumor agents such as downmycin or adriamycin.

It is an object of the present invention to provide, in one way, novel aglycones that appear to be analogues of stenimicinone;
Another object of the present invention is to provide a simple and economical method for synthesizing these analogs, thereby making it possible to utilize aglycones useful in the synthesis of antitumor agents by binding them to sugars.

The subject of the present invention is analogues of stephimicinone, and in particular derivatives demethoxylated at the 8-position corresponding to the general formula (1).

According to the invention, this analogue consists of (to)-8-demethoxystephimycinone.

According to another aspect of the invention, the analogue is (i)-7-
It consists of shrimp-8-demethoxystephimycinone.

The present invention also relates to the following steps, namely: 1) General formula ■ R [wherein %R represents a substituted or unsubstituted alkyl or aryl group, represents an alkyl group] is combined with lithium amide and a silylating agent to form an alkyl or bly/l/2.4 compound of the general formula ■ (wherein R has the meaning given above). -Producing by dimethyl-1,3-cyclohexadienecarboxylate reaction, 2) 5,7-dihydroxy-9-methoxy-2 represented by formula V
-Methi, 11/-3,4-dihydro-6,11-naph
- A process for producing tacenedione by reacting compound (1) with 5-hydroxy-7-medoxy-1,4-naphthoquinone represented by formula (2) (wherein X represents a norogen atom or an aqueous atom).

3) (t)-5,7-dihydroxy-1,2- represented by the formula ■
Epoxy-9-methoxy-2-methyl-1,2,3,4
- A process for producing tetrahydro-6,11-naphthacenedione by reaction of an olefin represented by the formula ■ with a peracid, a process for producing racemic diol (1α, 2α and 1β,
2α) A step of preparing IJi by treating the epoxide obtained in the previous step with an acid.

5) (1)-9-methoxy-2-methyl-2, represented by the formula ■ HOOOH
5,7-)dihydroxy-3,4-dihydro-1,6,
11(2H)-naphthacentrion obtained in the previous step (tho)-9-methoxy-2-methyl = 1α, 2α, 5,
7-tetrahydroxy-1.2,3.4-tetrahydro-6,11-naphthacenedione and (f)-9-methoxy-2-methyl-1β,2i,5.7-tetrahydroxy-1.2, 3. Process of producing by oxidation of a mixture of 4-tetrahydro-6,11-naphthacenedione, 6)
The 8-demethoxy analogue of stephimisionone of general formula II is prepared by treatment of product IX with a strong non-nucleophilic base in a polar solvent followed by acid hydrolysis. The subject matter of the method is the production of stepimicinone analogues represented by

According to one aspect of the present subject matter, (to)-9-methoxy-2-methyl-.1α,2α,5,7-tetrahydroxy-1.2,3.4-tetrahydro-6,11-naphtha Sendione (compound ■) is 5.7' -Q h)"
By treating Roxy9-methoxy2-methyl-6,4-dihydro-6,11-naphthacenedione (Compound V) with osmium tetroxide (0θ04)! #,Obtainable.

According to this variant, a single isomer, i.e.'g:)1α,2
Although it is possible to obtain the α-isomer, the yield is low.

According to an advantageous embodiment of the process that is the subject of the invention, the production of the ketene acetal (first step) is carried out.

It is carried out by sequentially adding compound 911W and then the silylating agent to a lithium amide solution at a temperature of -110 DEG C. to 0 DEG C. in an inert gas atmosphere.

According to another advantageous aspect of the method that is the subject of present invention 8A:
The peracid used in the third step is metachlorobenzoic acid.

According to the invention, the acid used in the fourth step is triflu
Kuraguchi acetic acid' (01F3000H).

Similarly, according to the present invention, the oxidation in the fifth step is 0r05, K
20r207s Jones' Test WJ (Jones'
This is carried out using an oxidizing agent selected from the group consisting of:

According to another advantageous embodiment of the process that is the subject of the invention, the polar solvent used in the sixth step consists of pyridine and the non-nucleophilic strong base consists of benzyltrimethylammonium hydroxide (Triton B).

The present invention also relates to an antitumor agent obtained by glycosidating an aglycone comprising a stephiamycinone analogue according to the present invention.

According to a particularly advantageous embodiment of the main arm of the invention, the sugar used in the glycosidation is an amino sugar.

The present invention also provides a method for preparing an itol in which the free OH functionality is replaced by a valanitrobenzoyl (PNB) group and the amine functionality is replaced by a trifluoroacetyl group (-QXF5) in a catalytic amount of paratoluenesulfone in a suitable solvent. react in the presence of an acid, separate the reaction product,
% according to the invention, which consists of deacidifying PNB and 1000 F5 groups by hydrolysis and purifying the reaction product thus obtained and optionally converting it into a salt of a pharmacologically compatible acid. The subject matter is a method for the glycosidation of aglycones consisting of analogues of stefiamycinone.

In addition to the above-mentioned features, the present invention is further evident from the following publications regarding production examples of intermediate products, examples of stephimycinone analogues, glycosidation examples of the obtained target aglycones, and pharmacological experiment reports. It also includes various characteristics.

However, these examples and this report are intended to be illustrative of the subject matter of the present invention.

84 It is not in any way restrictive in nature.
should be understood.

[Manufacturing example]

1) Preparation of compound of formula m CR=0'2H5) Diisopropylamine (2,5mQ%L 1.0178 mol) and n-BuLi (10.75 mol of hexane 791.55M solution)
mQ ) or anhydrous tetoxyhydro7rane (THF) (8,3m
K THIP (1) under nitrogen X at -78°C to a solution in
Ethyl 2,4-dimethyl-1,3- dissolved in
cyclohexadienecarboxylene) (IV) (5
jl, 0D166 mA/), then chlorotrimethylsilane (4,2 mA/), 0.045 mA/) are sequentially added.

The temperature of the reaction mixture is then gradually increased to 20° C. while continuing to stir. After solvent removal.

The obtained residue was taken up again in hexane (approximately 20 mQ),
Then centrifuge. After evaporating the hexane, the ketene acetal Qll) (3,2s 9.77%) is obtained as a pale yellow oil.

NMR (CCl2) (expressed in ppm (δ) relative to tetramethylsilane with chemical shift as standard): 0.1
7 ppm (-double line, 9H), 1.25 ppm (Mie [% J=7Hz, 6H) h 1.7 ppmC
MIV51s 3 H) h 6.77 ppm (Quadruple line, J=7Hz, 2H8 4.73 ppm
(Single line with M.

IH), 5.03 ppm (Double IVil, J”2
Hz, 1) (),, 5.671) IMn (- double line, I
H).

2) Production of 5,7-dihydroxy-9-methoxy-2-methyl-6,4-dihydro-6,11-nanthacenedione 6-chloro-5-hydroxy-7-medoxy-1,4-
A solution of naphthoquinone < 2.569.
Ketensilyl acetyl (III) in HF (40 mQ)
)<6.259.0.0129 mol) is rapidly added. After 5 hours at room temperature, the reaction mixture is quickly poured into a 0.1 N HOλ solution and then extracted with methylene chloride until the aqueous phase is decolorized. The residue was dried over Na2SO4 and evaporated in vacuo using aa2cn2 as eluent-26.
= F on silica gel (151). The compound VC29°60%) thus obtained is an orange powder. m-I)・229-230°C.

NMR (ODOn5) ” 2.0 ppm (- double line,
3H), 2.43ppm (triple line, , r-7Hr,
, 2H), 2.86T) pm (triple line.

J-7Hz*2H)h 3-91 ppm (-double line, 3H), 6.23ppm (-double line, I
H), 6.61PI)In(-double line s1”)s7.
16ppm (broad-heavy line b i H), z 4'pp
m (broad-heavy line, IE), 12.27ppm
(-double line, 1H), 12.33ppm (-double line, 1H
).

Engineering R (KBr disk) (characteristic absorption band is represented by saw ``'' 1) + 5275.3050, 1,680
．． 1640.1620.1600.1480.1450
．． 1420.1! +90.1! +00,1215,11
80°it spectrum (relative amounts of each peak are expressed as percentages)
(shown in parentheses): m/z = 556 < 57% 8 5 to 4 (91%), 274C 68%), 238 (100
%), 175 (57%), 133 (82%).

6) (1) -5,7-dihydroxy-1,2-epoxy-9-methoxy-2-methyl-1,2,3,4-tetrahydro-6,11-su7tacenedione (to) obtained in the previous step product V C0,3051,0,89 mmol)
is dissolved in a minimum volume of methylene chloride (approximately 25M). The solution was cooled to 0°C and
(0.46j'% 2.70 mmol) is then slowly added. After 12 hours at room temperature the reaction mixture is quickly poured into a saturated solution of sodium sulfite and then extracted with methylene chloride. Drying and evaporation of the solvent. After that, the residue was CH
Silica gel (30j1) using 2ci2 as eluent
I'll give you p treatment. Epoxide ■ (0,22j1.7Q'A)
is recovered as a yellow powder. m, p-233-234
℃.

NMR CODOR5: 1.55 ppm (-heavy line, IH), 3.66 (-heavy line, IH), 3.9
ppm (-double line, 6H), 6.64ppm (single storage with decoupling * 1H) *7.35ppm
(double line, Jm2Hys, IH), 7.79 ppm
(-heavy line 51H)s 12.2ppm (-heavy equipment, I
HJ, 12.43pprn (-heavy ah'i H)
.

Engineering R (KBr disk): 3500.3280.29
20,2960.1680%1620.1605.14
80,1445.1405.1395°1290,12
70.1235.1210.1165.1110° Mass spectrum: 552 (47%), 337 (23 H).

354C26%), 324(100%), 309(2
5%), 284 (10% included, 69 (38%), 55
(61%.

, '・4) Preparation of intermediates ■ and IX Trifluoroacetic acid (0,097 p, 0.85 mmol) was mixed with epoxide ■ (0,1 jl, 0.28 mmol) in methylene chloride (60 ml) at room temperature under nitrogen. Add to the solution inside. The mixture is then kept stirring for 12 hours.

After evaporating the solvent, the crude reaction product was dissolved in THF (6Q
2) and hydrolyzed with a saturated solution of sodium bicarbonate until complete disappearance of the starting material (monitored by thin-layer Chromadog2F (TLO) on Merck silica plates).・1α, 2α and 1β, 2α・
The mixture of isomers @ (0,068'LO 118 milli7) is extracted with methylene chloride and dried over sodium sulfate. After evaporating the solvent, the residue was dissolved in acetone (70 mf
fi) and Jones reagent (0,3 female, 0
．． 57 mmol/I/) is added at room temperature under nitrogen. The mixture was stirred for 10 hours, then hydrolyzed and a'm
Extract with 2 ci2. After drying over sodium sulfate, compound (1) is FA'd on silicage #(if) using a mixture of methylene chloride and MeOH (1%) as eluent.

In this way the product K (0,05251,0,14
Milli-7N) is obtained as a yellow powder. m, p, 245
~250℃.

Engineering R (xBy disk: 3360, 3000, 296
0, 1700.1680, 1640.1620.145
0% 1430°1400,1320.1250.11
60.1110,1035゜970.790゜Mass spectrum Cm/z): 368 (58% included 340
(52% included 325 (100%), 310 (17%), 2
97 (52%), 282 (20%).

[]V (ethanol): λmax = 240 nm ('lo
gε-4,46), 285 nm (log ε-4A5
), 440 nm (log ε-4,23).

5) Production of 8-demethoxy compounds (J! product (It) Hydroxyketone (0,0779,0,21 mmol) is dissolved in pyridine (10+111) K. Triton B
A 10% strength solution in pyridine is added at 0°C. TLC until complete disappearance of starting material (approximately 4 hours)
tracked by After hydrolysis with iN I(On solution, the crude reaction product was extracted with CfH2an2 and Na28
Dry on 04.

After preparative layer chromatography, compound
,0485+, 0.12 mmol). m
, p, 226-225°C.

Engineering R (KBr disk): 3360.3020.29
70.1710.1680,1620.1420,14
00,1320.1290.1260,1205,11
70.1115.1040.970.740° Mass spectrum (m/z) 184 (17%), 368 (
48 chi), 666 (42%)% 350 (90 chi), 33
8 (64%), 324 (100%), 297 (44%)
, 277 (37%), 270 (63 chi).

DV (ethanol: λrnaz-240nm (lo
gg=4.38).

233nn+ (logg is 4.21), 455nm
(logg=3.95).

[Glycosidation example]

Racemic compound (1) is dissolved in a minimum amount of benzene v in the presence of a catalytic amount of para-toluenesulfonic acid at room temperature. Then 3 equivalents of the compound of formula do. The mixture is kept stirring at room temperature for 48 hours under nitrogen.

After evaporation of the solvent, the residue is chromatographed on a layer of silica using a mixture of benzene and ethyl acetate as eluent. In this way, compound X ((2R,4B)-9-methoxy-2-methyl-04
-(2',3',6'-)lysooxy-04'-paranitrobencyyl-6'-trifluoroacetamide-α
-L-lyxo-hexapyranosyl) -2,4,5,7
-tetrahydroxy-3,4-dihydro-1,6,it
(2H)-su7tacentrion) CM=758%0
55H2975N2014) is isolated as a yellow powder.

Aqueous 0.1M caustic soda solution is added to glycoside X dissolved in excess dioxane. After 2 hours at 0°C, the pH was reduced to 0. 6 using I M HOA solution.

After extraction with methylene chloride, the aqueous phase is brought to pH 8 and extracted again with methylene chloride.

Compound store [2 [(2R,4B)-somethoxy-2-methyl-04-
(3'-amino-2',6',6'-)lysooxy-α
- Riichisukinhexapyranosyl) -2t4*5+7
-teto2hydroxy-3,4-dihydro-1,6,11
(2H)-su7tacentrion) (026H27NO1
o, M-513) is obtained as a yellow powder.

Dissolve the compound in chloroform. The resulting solution is then treated with 1 molar equivalent of hydrochloric acid in ethanol. The corresponding hydrochloride salt is precipitated by addition of ether. 026H2
8"N0IOs M=549.5C Pharmacological Experiment Report (Antibiotic Activity)] The product of the formula...
Bacillus pumilus (ONOM 7618) and Bacillus subtilis (Bacillus 5ubti: Li
e) Tested against (ATOO6535).

□ The product of formula ■ was solubilized in a mixture of DMSO (60%) and distilled water (40%) to a concentration of 100 μg/It.

After 24 hours, it was found that the growth of these two types of microorganisms was completely suppressed.

As is clear from the foregoing description, the present invention is directed to specific ttc
The present invention is not limited to the methods of use, specific examples, and applications described above.The present invention includes all modifications that can occur to those skilled in the art without departing from its scope.

Patent applicant Laboratoire Hoechst Société
anonym

Claims (1)

[Claims] 1) A stephimicinone analog consisting of an 8-demethoxy derivative corresponding to formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II. 2) Stephimycinone analogues according to claim 1, consisting of (±)-8-demethoxystephimycinone. 3) Stephimycinone analogue according to claim 1, consisting of (±)-7-epi-8-demethoxystephimycinone. 4) Next steps, namely (1) General formula III ▲ Numerical formulas, chemical formulas, tables, etc. ▼III [In the formula, R represents a substituted or unsubstituted alkyl or aryl group, R_1, R_2 and R_3 (these may be the same or different) represent an alkyl group] A ketene silylacetal represented by lithium amide and a silylating agent are combined with the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IV (in the formula, R is as described above) 2,4-dimethyl-1,3-cyclohexane dienecarboxylate (2) Formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V 5,7-dihydroxy-9-methoxy-2 represented
-Methyl-3,4-dihydro-6,11-naphthacenedione as compound III and formula VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼VI (in the formula, X represents a halogen atom or a hydrogen atom) 5 -Production process by reaction with hydroxy-7-methoxy-1,4-naphthoquinone, (3) Formula VII ▲ Numerical formulas, chemical formulas, tables, etc. ▼VII (±) 5,7-dihydroxy-1, A step of producing 2-epoxy-9-methoxy-2-methyl-1,2,3,4-tetrahydro-6,11-naphthacenedione by reacting an olefin represented by formula V with a peracid, (4) Formula VIII ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ VIII Racemic diol [1α, 2α and 1β,
2α] by treating the epoxide obtained in the previous step with an acid, (5) Formula IX ▲ Numerical formulas, chemical formulas, tables, etc. ▼ -methyl-2,
5,7-trihydroxy-3,4-dihydro-1,6,
11(2H)-naphthacentrion obtained in the previous step (±)-9-methoxy-2-methyl-1α,2α,5,
7-tetrahydroxy-1,2,3,4-tetrahydro-6,11-naphthacenedione and (±)-9-methoxy-2-methyl-1β,2α,5,7-tetrahydroxy-1,2, A process for producing by oxidation of a mixture of 3,4-tetrahydro-6,11-naphthacenedione, (6) 8- of stefimicinone represented by general formula II
The general formula of claim 1 comprising the combination of steps for preparing a demethoxy analog by treatment of product IX with a strong non-nucleophilic base in a polar solvent and subsequent acid hydrolysis.
A method for producing a stephimycinone analog represented by II. 5) (±)-9-methoxy-2-methyl-1α, 2α,
5,7-tetrahydroxy-1,2,3,4-tetrahydro-6,11-naphthacenedione (compound VIII)
,7-dihydroxy-9-methoxy-2-methyl-3,
4-dihydro-6,11-naphthacenedione (compound V
) with osmium tetroxide (OSO_4). 6) The production of ketene acetal (first step) is carried out by sequentially adding compound IV and then a silylating agent to a lithium amide solution at a temperature of -110°C to 0°C in an inert gas atmosphere. The method described in Section 4. 7) The method according to claim 4, wherein the peracid used in the third step is metachloroperbenzoic acid. 8) The acid used in the fourth step is trifluoroacetic acid (OF
_3COOH). 9) Oxidation in the fifth step is CrO_3, K_2Cr_2O_
5. The method of claim 4, wherein the method is carried out using an oxidizing agent selected from the group comprising: 7 and John's reagent. 10) The polar solvent used in the sixth step consists of pyridine and the non-nucleophilic strong base consists of benzyltrimethylammonium hydroxide (TritonB
) The method according to claim 4, comprising: 11) Application of a stephimicinone analog represented by the general formula II according to any one of claims 1 to 3 as an antibacterial agent. 12) Use of a stephimicinone analog represented by the general formula II according to any one of claims 1 to 3 as an aglycone for producing an antitumor agent. 13) An antitumor agent formed by glycosidation of a stephimicinone analog represented by formula II according to any one of claims 1 to 3. 14) The antitumor agent according to claim 13, which is formed by glycosidation with an amino sugar. 15) Formula XII ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ -trideoxy-α-L-lyxo-hexapyranosyl)-2,
4,5,7-tetrahydroxy-3,4-dihydro-1
, 6,11(2H)-naphthacentrion. 16) The free OH functional moiety is paranitrobenzoyl (PN
B) Reacting the itol substituted by the group and the amino functional moiety replaced by the trifluoroacetyl group (-COCF_3) in the presence of a catalytic amount of para-toluenesulfonic acid in a suitable solvent and separating the reaction products. , P.N.B.
and -COCF_3 groups are removed by hydrolysis, and the reaction product thus obtained is purified and optionally converted into a pharmacologically compatible salt of the acid. 4. A method for glycosidating an aglycone comprising a stephimicinone analog according to any one of items 1 to 3. 17) Formula III, which is a novel product that is an intermediate for the synthesis of stephimicinone analogs according to any one of claims 1 to 3. ▲There are mathematical formulas, chemical formulas, tables, etc.▼III [Formula where R represents a substituted or unsubstituted alkyl or aryl group, and R^1, R^2 and R^3 (which may be the same or different) represent an alkyl group]; Compound represented. 18) A novel product of formula V which is an intermediate for the synthesis of stephimicinone analogues according to any one of claims 1 to 3. racemic compound. 19) A novel product represented by formula VII, which is an intermediate for the synthesis of stephimicinone analogs according to any one of claims 1 to 3. racemic compound. 20) Formula VIII, which is a novel product that is an intermediate for the synthesis of stephimicinone analogs according to any one of claims 1 to 3. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ racemic compound. 21) Formula IX, which is a novel product that is an intermediate for the synthesis of stephimicinone analogs according to any one of claims 1 to 3. ▲There are mathematical formulas, chemical formulas, tables, etc.▼Represented by racemic compound.