JPS62228039A - 13-methyl-13-dihydrodaunomycinone derivative - Google Patents

Abstract

NEW MATERIAL:A 13-methyl-13-dihydrodaunomycinone derivative shown by formula I (R is H trialkylsilyl). EXAMPLE:13-Methyl-13-dihydro-7-o-t-butyldimethylsilylaunomycinone. USE:A carcinostatic agent. PREPARATION:The hydroxyl group of a compound shown by formula II at the 7-position is selectively protected with a silyl group to give a compound shown by formula III (R<1>-R<3> are alkyl), which is treated wit a methylating agent shown by formula IV (M is metallic atom or metal-containing atom group) to give a compound shown by formula V (R in the compound shown by formula I is trialkylsilyl), which is desilylated to give a compound shown by formula VI (R in the compound shown by formula I is H).

Description

Detailed Description of the Invention Field of Use of P Koichi The present invention provides 13-methyl-13-dihydroglucose represented by the general formula (wherein, ■ is a hydrogen atom or a trialkylsilyl group). This invention relates to nomycinone derivatives.

13-methyl-13 represented by general formula (I) of the present invention
-Dihydrodaunomycinone iA4 can be used as an important synthetic intermediate of 13-methyl-13-dihydrodaunorubicin, which has excellent anticancer activity, through the glycosylation reaction of a daunosamine derivative to the water rp group at the 7-position.

[Conventional technology]

The development of excellent anticancer drugs is a strong demand from society and is an urgent matter. Anthrazycline derivatives, represented by adriamycin, are known for their strong anticancer activity.
It occupies an important position in medicine as an anticancer agent, and many anthracycline analogs have been developed to date. However, since these derivatives have anticancer activity, hair loss, and myocardial activity, there is a strong desire to develop novel anthracycline analogues that exhibit superior and characteristic anticancer activity.

[Problem that the invention seeks to solve]

Against the above background, the present inventors searched for novel anthracycline analogues with excellent anticancer activity and found that the novel 13-methyl-13-dihydrodaunorubicin has strong anticancer activity. They discovered this and completed the present invention.

[Means for resolving the problem]

Novel 13-1 chill-1 represented by the above general formula (■)
3-dihydrodaunomycinone derivatives can be produced according to the following reaction.

(In the formula, 11. and RlR are alkyl groups, and M represents a metal atom or an atomic group containing a metal.) [Step 1] This step selectively retains the 7-position hydroxyl group with a silyl group. hΦ. The reaction can be carried out by the method described in U1] Sho 60-94986.

[Second step] In this step, the compound (III) obtained in the first step is reacted with a methylating agent to form a compound of the general formula (■) having a tertiary hydroxyl group at the 13th position.
This is to produce a compound represented by:

Examples of the methylating agent used include methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, methylridium, dimethylzinc, and dimethylmanganese. The reaction is carried out in a mortar, and suitable solvents include ether solvents such as tetrahydrofuran, ether, dioxane and dioxane, and aromatic solvents such as Hensen, toluene and xylene. The reaction proceeds smoothly at -50°C - room temperature.

[Third Step] In this step, the compound represented by the general formula M obtained in the second step is desilylated to produce 13-methyl-13-dihydrodaunomycinone.

Reagents used in the desilylation reaction in this step include protonic acids such as acetic acid, hydrochloric acid, sulfuric acid, and hydrofluoric acid, Lewis acids such as titanium tetrachloride, tin tetrachloride, and aluminum chloride, tetrabutylammonium fluoride, Examples include fluorine compounds such as cesium fluoride and potassium fluoride.

The present invention will be explained in detail below using F1 Reference Examples, Examples, and Test Examples.

\-111 The meanings of the abbreviations in the examples are as follows.

TBDMS: t-butyldimethylsilyl group 1) MF
:N,N-dimethylformamide THF:
Tetrahydrofuran pNBZ: p-nitrobenzoyl group Reference example 1 Daunorubicin hydrochloride 85.0■ (0,151m-mo
1) was dissolved in 8.5 ml of 0.2M hydrochloric acid, and 90-10
Heated at 0°C for 1 hour. After cooling, the reaction solution was poured into saturated brine and extracted with ethyl acetate and a small amount of THF. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under slight pressure to obtain 60.1 μm (100%) of crude daunomycinone.

A portion of this was recrystallized from benzene to obtain pure daunomycinone as red needle crystals.

mp　213-215℃ (Literature value: F, Arcamone, et al.

J,Am,Chem,Soc,,86.5334(19
64), 213-214°C).

[α],,,! ,'+197° (c=0.12.
Dioxane (Literature (direct; same as above, [α] 1) Lo-3
+193″ (C=0.1.dioxane)).

NMR (CDCI, ): δ=2.15 (IH.

dd, J=14 and 4Hz), 2.38(IH, dt
, J=14 and 2Hz).

2.43 (3H, s), 2.92 (IH, d.

J=1811z), 3.24 (IH,d, J=18
Hz), 3.69 (111,d, J-4Hz), 4.
11 (3H, s), 4.54 (1) (, s), 5.
28-5.46 (IH.

m), 7.42 (IH, dd, J=8 and IHz)
, 7.81 (IH, t, J=8Hz).

8.06 (1/H, dd, J=8 and IHz).

13.25 (L H,s), 13.96 (I
H.

s).

IR(KBr)+3500.1725°1620.15
85ca-calc.

Reference example 2 Crude daunomycinone 60.1 (0,151 mmo
l), silyl enol ether 332■ (1,55mm
o 1), a catalytic amount of p-++ in a mixture of 6 ml of DMF
Luenesulfonic acid hydrate was added and stirred at room temperature for 4.5 hours. The reaction solution was poured into water and extracted with ethyl acetate.

Add the extract to water and saturated saline. and dried over anhydrous sodium sulfate.

The solvent was distilled off under wave pressure, and the excess silylating agent was removed under vacuum and heating with a dryer. The residue was purified by column chromatography (silica gel, benzene-ethyl acetate 2
0:1) to obtain 75.3 mm (98%) of 7-0-1-butyldimethylsilyldaunomycinone as an amorphous powder.

[α),”+316” (C=0.164.
Dioxane 111]n).

NMR (CDCl2): δ-0,10 (3H.

s), 0.20 (3H, s), 0.82 (91
1°s), 1.93 (IH, dd, J-14 and 4Hz>, 2.22 (IH, d t, , J=1
4 and 2Hz), 2.36 (3H,s).

2.87 (IH, d, J=19Hz>.

3.23 (IH, d, J-19Hz).

4.04 (3H, s), 5.41 (LH, s)
.

5.30-5.48 (IH, m), 7.34 (LH
, d, J-8Hz), 7.73 (IH, t, J=8Hz), 8.00 (IH, d, J=8Hz), 13.21 (IH, s
), 13.94 (I H,s).

IR(KBr) =3480. 1725°1620
, 1585am-'.

MS m/e: 497 (CM-CHs)
”).

455.437,363,337,321゜ii- Elemental analysis value: CttH*□O++S i・0.75t
Calculated values as rzo: C, 61,64, H, 6,42%.

Analysis values: C, 61,54, H, 6,55%.

Example 1 7-0-t-butyldimethylsilyldaunomycinone 7
5.3 mg (0,1,47 mmol) of THF
0.25 ml of methylmagnesium bromide-ether 3M solution (0.75 m-m
ol) was added dropwise. After reacting for 45 minutes at -20°C, an additional 0.05 rn 1 (0
, 15 mmol I) was added and reacted at the same temperature for 30 minutes.

The reaction solution was poured into a 1M hydrochloric acid-ethyl acetate mixed solution, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate, and all the organic layers were combined and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting red residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 20:l) to obtain 13-methyl-13- Dihydro-7-0-t-butyldimethylsilyldaunomycinone 53.5■ (69%)
I got it.

A part of this product was recrystallized from a hexane-ether mixed solvent to obtain an analytical sample.

mp　217.5-219℃.

[α] 8”+277′ (c=0.120. dioxane).

NMR(Cr)C1,)jδ-0,17(3H.

s), 0.30 (3H,s), 0.88
(9H.

s), 1.26 (3H, s), 1.37
(3H.

s), 1.81 (IH, dd, J=14.t; and 4Hz), 2.53 (I H, d, J=14H
z), 2.71 (IH, d, J
=19Hz).

2.83 (IH,s), 3.27 (IH,
d.

J-19Hz), 4.12 (3H, s).

5.52 (I H,s), 5.45-5.63
(IH, m), 7.42 (IH, dd, J
=8 and IHz), 7.81 (IH,t.

J=8Hz), 8.10 (IH, dd, J
-8 and IHz), 13.40 (IH,s).

1 4.02 (LH, S).

TR (KBr): 3450. 1615°1 5
80 cii-'.

MS' m/e: 51 3 (CM C
H3)”).

471, 453. 369. 338. 321゜Elemental analysis value: CzaHsbOsS i ・0.25Hz
Calculated values as O: C, 63.08, H, 6.90%.

Analysis values: C, 62,88; H, 7,08%.

Example 2 13-Methyl-13-dihydro-7-0-t-butyldimethylsilyldaunomycinone 10.1■ (0,019
A mixture of 1 mmol I>, 1 ml of acetonitrile-46% hydrofluoric acid (95:5 v/v) was stirred at 0° C. for 15 minutes. The reaction mixture was poured into water and extracted with THF and ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red solid residue e-10,1 obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel, benzene-ethyl acetate 2:
1→1:1) and further triturated with ether to obtain 7.8 μ (99%) of 13-methyl-13-dihydrodaunomycinone.

mp　236-239℃.

NMR (CDCI, ): δ-1,31, (3H.

s), 1.43 (3H, s), 1.90 (IH
.

dd, J = 15.0 and 5.0 Hz).

2.58 (IH, dt, J=15.0 and 2.1
Hz>, 2.60 (IH, s), 2.66 (IH,
d, J=18.7Hz), 3.23(I H, d d,
J=18.7 and 2. H(z).

3.50 (IH, brs), 4.10 (3H.

s), 4.26 (LH, s), 5.37 (IH
.

m>, 7.40 (I H, dd,, J-8,0 and 0.8 Hz), 7.79 (], H, t, J
-8,0Hz), 8.05 (IH, dd,
, J=8.0 and 0.8Hz), 13.34 (]
IHs), 13.99 (IH,s).

IR (KBr): 3450. 1615°1580
(To) 1゜MS m/e: 414 (M”), 3
96°378, 360. 338° Reference Example 3 2.3.6-) Lysooxy-1,4-di〇-p-nitrobenzoyl-3-trifluoroacetamide-α-■
, -lyxohexopyranose 24.2■ (0,0447
2. mmo I), molecular sieve 4A182■, and a mixture of 2.5 ml of methylene chloride and 2.5 ml of diethyl ether.
To the white suspension obtained by adding Qml, under an argon atmosphere, -
0.02 ml (0.104 mmol) of trimethylsilyltrifluoromethanesulfonate was added at 40° C. and stirred for 30 minutes under water cooling. 130% of the transparent reaction solution
Cool to 13-methyl-13-dihydro-7-0-
t-Butyldimethylsilyldaunomycinone 15.5■
(0,0293 mmo I) of Tl (FtS solution 8 m
1 was added dropwise to the mixture and the mixture was reacted at -10°C or lower for 5 hours. Activated daunosamine derivative 8.1■ (0,015Qm-mo
1) was added and the reaction was continued for a further 2.5 hours, and the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under slight pressure, and the resulting red residue was dissolved in 30 ml of methanol, followed by 0.6 mL of a 0.1M aqueous sodium hydroxide solution under water cooling.
ml was added and stirred for 20 minutes. After adding 3 drops of 10% acetic acid to the reaction mixture, water and ethyl acetate were added to separate the organic layer. The aqueous layer was further extracted with ethyl acetate, and all the organic layers were combined and washed successively with water and saturated brine.

After drying over anhydrous sodium sulfate, the solvent was distilled off under slight pressure to obtain a red residue. This product was purified by column chromatography (silica gel, chloroform-chloroform-acetone 30:1 → 15:1 → 8:1), and the 3'
-N-trifluoroacetyl-13-methyl-13-dihydrodaunorubicin 14.2 µ (76%) was obtained.

mp　154-157℃.

[α)”+196° (e-0,109, dioxa■) hmm).

NMR (CDCIs): δ-1,06 to 1.4
3 (9H, 4s), 1.50~2.70 (5H
.

m), 2.65 (IH, d, J=19Hz
).

3.22 (IH, d, , J = 19Hz).

3.61 (IH,brd,J=7Hz).

4.04 (3H, s), 3.85-4.40 (
2H, m), 4.21 (IH, s).

5.15-5.35 (I H, m), 5.35
~5.60 (IH, m), 6.63 (IH
.

brd, J-8Hz), 7.34 (IH.

d, J=8Hz), 7.74 (IIL
t.

J=8Hz), 7.97 (IH,d, J=
8Hz), 13.27 (I H,s), 1
3.91 (LH, s).

TR (KBr): 3500. 3450°17
20, 1615. 1580cm-'.

MS m/e: 639 (M”), 414°396, 378.338° Elemental analysis value: Czo Hs m F 3 N O+
+ Calculated value as Ht O: C, 54, 80, 1
! , 5.21; N, 2.13%.

Analysis value: C, 55,02, H, 5,48iN, 2
．． 13%.

Reference example 4 2.3.6-drideoxy-1,4-di0-p-nitrobenzoyl-3-trifluoroacetamide-α-L
-Lixohexopyranose 44.3■ (0,0818m
mo +), -E Rechiler Sieve 4A251■, and a mixture of 3.5 ml of methylene chloride and 2.0 ml of diethyl ether.
After cooling the obtained white suspension to -40°C, 0.035 ml of trimethylsilyltrifluoromethanesulfonate (0.18
1 mmol 1) was added and stirred for 30 minutes at 0°C.

Then, the reaction solution was cooled to -30°C, and 13-methyl-13
-dihydrodaunomycinone 16.9[(0,0408
After dropping 12 ml of m-mol)-THF solution-1
The reaction was carried out at 0°C or lower for 7 hours. The red residue obtained by treatment in a conventional manner was dissolved in 4Qml of methanol, and the mixture was cooled with water.
Add 3 ml of 0.1M sodium hydroxide aqueous solution Q
Stirred for 0 minutes. After adding 4 drops of 10% acetic acid to the reaction solution, it was treated in the same manner as in Reference Example 3. The obtained residue was separated and purified by column chromatography (silica gel, chloroform → chloroform acetone 30:I → 15:1 → 8:1) to give 3'-N-trifluoroacetyl-13-methyl-13-dihydro Daunorubicin 17,7■ (68%
) was obtained. The NMR spectrum of this product matched that obtained in Reference Example 3.

Reference example 5 3′-N-)lifluoroacetyl-13-methyl-
13-dihydrodaunorubicin 22.6■ (0,035
3 mmo +) to 1 ml of THF? 3. Dissolve and add 0.1M aqueous sodium hydroxide solution under argon atmosphere.
5 ml was added and stirred at room temperature for 25 minutes. p with 1M hydrochloric acid
After adjusting to H8, extraction was performed with chloroform, and the extract was washed with water and dried over anhydrous sodium sulfate. 1 solvent
Concentrate to ~2 ml and add 0.25 M hydrochloric acid-methanol solution.
．． After adding 2 ml, 10 ml of ether was added. The precipitated red powder was further triturated with ether to obtain 12.9 μm (63%) of pure 13-methyl-13-dihydrodaunorubicin hydrochloride.

mp　196.5-198.5℃.

[α] is 1±155° (c=0.102. methanol).

NMR ((CD3)iso: δ-1,15(3H.

d, J=6.5Hz), 1.22 (6H, s).

1.69 (IH, dd, J-12, 2 and 4.0
Hz), 1.89 (IT L d t,
J = 12.7 and 3.6Hz), 1.96 (I
H.

dd, J-14,9 and 4.8Hz).

2.28 (IH, d, J=1 4.9Hz).

2.78 (IH, d, J = 18.4Hz).

2.96 (IH, d, J = 1 8.4Hz)
.

3.56-3.61 (LH, m), 3.97 (
IH,s), 3.99 (3H,s).

4.18 (LH, q, J = 6.5Hz).

4.47 (IH,s), 4.95-5.01 (
IH, m), 5.25-5.31 (IH.

m), 5.45 (IH, d, J=6.1H
z).

7.62~7.68 (LH, m), 7.87~
8.02 (5H, m), 13.30 (I
H.

s), 14.03 (IH, s).

IR (KBr): 3450. 1620°1 5
80cm-'.

STMS m/z: 544 (MH”-MCI).

414, 397. 379. 321° elemental analysis value:
CzeHiaCI N O12.2 Calculated as HtO: C, 54,59; H, 6,22; N, 2.
27%.

Analysis value: C, 54,34i H, 6,19iN, 2.
17%.

Test example (cancer cell growth inhibition effect) Mouse lymphocytic leukemia cultured cells (P3+78) were
Add to RPMI-1640 culture solution containing 0% calf fat serum, adjust the number of cultured cells to 5 x 10 cells/m+, and add the novel 13-methyl-13-dihydrodaunorubicin hydrochloride of the present invention to a predetermined concentration. and cultured at 37°C for 2 days.

Claims (1)

[Claims] 13-methyl-13-dihydrodaunomycinone derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a hydrogen atom or a trialkylsilyl group.) .