JPS63156742A - 14-(omega,omega,omega-trifloroalkyl)-4-demethoxydaunomycinone derivative - Google Patents

Abstract

NEW MATERIAL:A 14-(omega,omega,omega-trifluoroalkyl)-4-demethoxydaunomycinone derivative expressed by formula I (R<1> is H or OH; n is 1-3). EXAMPLE:(+)-14-(2,2,2-Trifluoroethyl)-4-demethoxydaunomyucinone. USE:A medicine and raw material for producing novel 14-(omega,omega,omega-trifluoroalkyl)-4- demethoxydaunorubicins, expressed by formula II and having excellent carcinostatic activity. PREPARATION:Optically active (R)-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphth acene-6,11-di-one-2-carboxylic acid expressed by formula III is reacted with a carbonyl compound expressed by formula IV (A and A' are azole) to provide a reaction mixture, which is then reacted with a Grignard reagent expressed by formula V (X is halogen) to afford the compound expressed by formula I (R<1> is H). The 4-position of the resultant compound is then brominated and converted into hydroxide with an aqueous alkali to provided the compound expressed by formula I (R<1> is OH).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention is based on the general formula (wherein R1 represents a hydrogen atom or a hydroxyl group, and n is 1
Represents an integer from ~3. ) represented by 14-(ω, ω,
ω-Trifluoroalkyl)-4-demethoxydaunomycinone derivatives.

14-(ω) represented by the general formula (1) of the present invention.

ω, ω-Trifluoroalkyl)-4-demethoxydaunomycinone derivatives are novel 14-molecules with excellent anticancer activity due to the glycosylation reaction with daunosamine derivatives.
It is an important synthetic intermediate that can lead to -(ω,ω,ω-trifluoroalkyl)-4-demethoxydaunorubicin.

[Conventional technology]

The development of excellent anticancer agents is a strong demand from society, and anthracycline derivatives occupy an important position in medicine as a group of compounds with strong anticancer activity. In general, the pharmacological activity of a chemical substance is highly dependent on its chemical structure, so it is highly unlikely that an anthracycline analog with a structure different from existing ones will emerge that can be put to practical use as an excellent anticancer agent. expensive.

Anthracyclines are composed of anthracyclines, which are aglycones, and sugars. Therefore, a novel anthracycline can be synthesized by using a novel anthracyclinone as an intermediate.

[Problems to be Solved by the Invention] In response to the above request, the present inventors searched for a novel anthracycline derivative with excellent anticancer activity, and as a result 1
4-(ω,ω,ω-trifluoroalkyl)-4-demethoxydaunorubicin has been discovered. The purpose of the present invention is to
The present invention provides a novel daunomycinone derivative represented by anthra CI).

[Means for solving problems]

The novel 14-(ω, ω,
The ω-trifluoroalkyl)-4-demethoxydaunomycinone derivative can be produced according to the following reaction.

(In the formula, n is an integer of 1 to 3.) [First step] This step is an optically active (R)-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene- 6,
The reaction obtained by reacting 11-dione-2-carboxylic acid (II) with a carbonyl compound represented by the general formula % ([[) (wherein A and A' are azole groups) By reacting the mixture with a Grignard reagent represented by the general formula % (in which n represents an integer of 1 to 3 or is a halogen atom), the general formula % of the present invention can be obtained. Demethoxydaunomycinone derivative ((R)-2-(ω
, ω, ω-trifluoroacyl)-2,5°12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative).

The raw material of the present invention, represented by the general formula (II)
R)-2,5,12-)rihydroxy-1゜2, 3.
4-tetrahydronaphthacene-6,11-dione-2
-Carboxylic acid is a compound that can be easily synthesized from inexpensive quinizarin (Y, Kimura et al, Chem.

Lett, 1984.473 and M, 5uzuki et al,, Chem.

Lett, 1985.57).

The carbonyl compound represented by the general formula (I[I) of the present invention includes 1,1'-carbonyldiimidazole,
1.1'-carbonyl ditriazole, 1.1'-carbonyl ditriazole, etc. can be used.

Examples of the Grignard reagent represented by the general formula (IV) include 2,2,2-)trifluoroethylmagnesium bromide, 2,2,2-trifluoroethylmagnesium iodide, and 3,3,3-trifluorochloride. Propylmagnesium, 3,3.3-trifluoropropylmagnesium bromide, 3°3.3-)lifluoropropylmagnesium iodide, 4,4.4-)lifluorobutylmagnesium chloride, 4.4.4-bromide -) Lifluorobutylmagnesium, iodide 4. 4. 4-) Lifluorobutylmagnesium etc. can be used.

Incidentally, when reacting with a Grignard reagent, the desired product can be obtained in good yield by carrying out the reaction in the presence of a Lewis acid or an alkyl halide. Examples of Lewis acids that can be used include boron trifluoride ether complex, trimethylsilyltrifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, triethylsilyltrifluoromethanesulfonate, and the like. Further, as the alkyl halide, benzyl chloride, benzyl bromide, allyl chloride, allyl bromide, hexyl bromide, phenacyl bromide, etc. can be used.

The reaction is preferably carried out in a solvent, and the solvent is preferably an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane, diglyme, etc. Hexamethylphosphoric triamide, hexamethylphosphorus triamide, etc. are added and used as a mixed solvent. You can also do that.

This reaction proceeds smoothly at 00°C to room temperature.

[Second step] In this step, the 4-position of the ω, ω, ω-trifluoroacyl compound (Ib) obtained in the first step is brominated, the obtained bromide is converted to a hydroxide with alkaline water, and the main Invention 14-(ω9 ω
, ω-trifluoroalkyl)-4-demethoxydaunomycinone derivative C1a). Bromination is carried out using bromine, N
-bromosuccinimide, N-bromoacetamide, 1
This is carried out using 3-dibromo-5,5-dimethylhydantoin or the like as a brominating agent. The reaction proceeds smoothly at 0°C to 100°C. The reaction of substituting bromide with a hydroxyl group is carried out by treating the reaction solution of the bromination reaction with a 0.1 to 1.0 M aqueous alkali solution. The reaction proceeds smoothly at 0°C to 50°C.

Examples of the alkaline aqueous solution include aqueous solutions of sodium hydroxide, potassium hydroxide, barium hydroxide, and the like.

The anthracyclinone derivative represented by the general formula (Ia) can be prepared by the following reaction process, for example, by the following general formula [Y
Anthracycline derivatives or salts thereof can be derived.

(In the formula, n has the same meaning as above, and R2 is an acyl group.) That is, the aglycone of the general formula [Iα] and the formula (V)
and α-
By obtaining an anomeric glycoside and then deprotecting the hydroxyl group and amino group, an anthracycline derivative of the general formula [■] having antitumor activity can be produced. The salt of the compound of the general formula [■] can be produced by treatment with an inorganic or organic acid. below,
The present invention will be explained in detail with reference examples, working examples, and test examples for each final product obtained using the compound of the present invention.

Reference Example I CF, /XS/-Br-- CF, /”\//M g Br Magnesium (174z, 7.16 mmo 1), iodine (catalytic amount), anhydrous tetrahydrofuran (9 ml)
3.3-)lifluoropropyl bromide (1,389 g) was added to a mixture of (1,389 g) under an argon atmosphere.

7.85 mmol) was added dropwise, and the mixture was adjusted so that reflux continued slowly. After the dripping is complete, add magnesium (11w
, 0.45 mmo 1) was added and continued heating under reflux for 1 hour.
3.3-1-Lifluoropropylmagnesium bromide was prepared.

Example 1 (R)-2,5,12-)lihydroxy-1°2.3.
4-tetrahydronaphthacene-6,11-dione-2-
Carboxylic acid (155,0■, 0.437mmol) and carbonyldiimidazole (144,5■, 0.891mmol)
mo 1) was added to anhydrous TetrahyFtl17 run (30ml
) and hexamethylphosphoric triamide (HMPA)
(0.6ml) and irradiated with ultrasonic waves for 30 minutes under an argon atmosphere. After further stirring at 35° C. for 12 hours, ultrasonic waves were irradiated for 2 hours. The reaction solution was cooled to -20°C, and a hexane solution (1M solution) of trimethylsilyl triflate (1M solution) (0.15ml 1.0.15mmol 1) was added and stirred for 10 minutes. The reaction solution was cooled to -78°C, and a tetrahydrofuran solution (7.6 mm
o 1 ) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. 3M hydrochloric acid (40 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Fuco-gel C-300, benzene-ethyl acetate (15:1)) and thin layer chromatography (silica gel, benzene-ethyl acetate (15:1)) to obtain (R)- (-”)-2-(4', 4'.

4'-trifluorobutanoyl)-2,5,12-trihydroxy-1,2,3,4-tetrahydro-6,11
- Naphthacenedione (100,0■.

53%) was obtained as a red solid. Further, it was recrystallized from benzene to obtain a pure product.

mp　179.5-180.5℃.

[α]2°-53.6' (c O, 097, chloroform).

IR(KBr)=3450.1720°1620.15
90.1255,1145゜1100cl-weight.

'HNMR(CDCls): 61.9
7-2.07 (2H, m, 3 Hz), 2.48
~2.61 (2H,q,m,J-10,7Hz.

3' Hz), 2.86-3.18 (6H,
m.

4-Ht + I Hz + 2' Hz)
, 3.30 (IH, s, 2-0H), 7
．． 80-7.86 (2H, m, Aromati
cpr o t ons), 8.30-8.3
7 (2H.

m, Aromatic protones).

13.43 (LH, s, Ar0H), 13.44 (
IH,s, ArO and).

Heavy”F NMR (CDCIs): δ −
67,13 (3F, tt J=10.7Hz,
4'F3).

MS (m/z) = 434 (M”),
309゜Elemental analysis value: C2□HI? ObFs・
Calculated value as 0.25H,O: C, 60,21: H, 4,02%.

Measured value: C, 60,19; H, 4,00%.

-16= Example 2 (R)-2,5,12-)lihydroxy-1°2.3.
4-tetrahydronaphthacene-6,11-dio7-2-
Carboxylic acid (51,9■, 0.146mmol) and carbonyldiimidazole (46,7■, 0.288mmol)
Acylimidazole was prepared from 1) in the same manner as in Example 1. Benzyl bromide (29,3■,0
．． 171 mmol 1) was added and stirred at the same temperature for 10 minutes. Reaction - All at once cooled to -78°C, and added a tetrahydrofuran solution (2.2 mmol) of 3.3.3-)lifluoropropylmagnesium bromide prepared in the same manner as in Reference Example 1.
) was added dropwise and stirred at the same temperature for 2 hours. The same post-treatment and purification operations as in Example 1 were performed to obtain (R)-(-)-
2-(4',4',4'-)lifluorobutanoyl)-
2,5,12-)lihydroxy-1,2,3,4-tetrahydro-6,11-naphthacenedione (25,2■,
40%) was obtained as a red solid. NMR of this sample
, the IR spectrum was consistent with that of the sample obtained in Example 1.

Example 3 (R)-(-)-2-(4',4',4'-)lifluorobutanoyl)-2,5,12-trihydroxy-1,2,3,4-tetrahydro-6゜11-Naphthacenedione (103,1■, 0.237 mmol) was dissolved in chloroform (2 ml) and carbon tetrachloride (4 ml), and a solution of bromine in carbon tetrachloride (0, 0484M solution) was added at 5 minute intervals (1 ml
x6.0.5ml x2゜Total 7ml, 0.339mmo
1) Stirred while irradiating with 60H white light. While cooling with water, IM aqueous sodium hydroxide solution (5 ml) was added, and after stirring for 30 minutes, 3M hydrochloric acid was added to make it acidic. It was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine.

After MgSOa drying, filtration, and concentration under reduced pressure, the residue was purified by column chromatography (silica gel, benzene-ethyl acetate (10:1)) to obtain (+)-14-
(2,2,2-)lifluoroethyl)-4-demethoxydaunomycinone (30,5■.

29%) was obtained as a red-orange solid. A pure product was obtained by recrystallization from benzene.

mp　194-196.5℃.

(α) “+118” (c O, 110, dioxane).

TR (KBr): 3450.1725°1625.15
90.1270.1255°1230.1130cm-
'.

'HNMR (CDCIs): δ 2.16 (IH, dd
d, J = 14.8Hz, 4.7Hz.

and 1.6Hz, 8. , -H), 2.37 (IH
, ddd, J=14.8H2,2,OH2゜and
2.0Hz, 8eq H), 2.42~2.56 (
2H, m, 15 Hz), 2.98 (IH
, d, J-18, 7Hz, 10. , -H).

3.13 (IH, ddd, J=19.5Hz.

8.0Hz and 7.2Hz, 14-H), 3
．． 22 (IH, ddd, J=19.5Hz, 8.5Hz
2O- and 7. IH2,14H), 3.25(I
H, dd, J=18.7Hz and2.0H
z, 10. q-H), 3.45 (IH.

dd, J=3.4Hz and 1.6H
z.

7-0H), 4.61 (IH, s, 9-0H).

5.38 (IH, m, 7-H), 7.83
~7.90 (2H, m, Aroma tic
protones), 8.33-8.40 (2H.

m, Aromatic protones).

13.30 (IH, s, Ar0H), 13.60 (
I H, s + A r O and).

”F NMR (CDCI: δ-67,07(
3F, t, J=11Hz, 15CF
,).

MS (m/z): 450 (M"),
307゜Elemental analysis value: Cz z HIq Oq F
Calculated value as s: C, 58,67, H, 3,80%
.

Measured values: C, 58,89, H, 4,11%.

\ −/′ Reference Example 2 (+)-14-(2,2,2-trifluoroethyl)-
4-demethoxydaunomycinone (36.3g, 0.0
806mmo 1) and 3-N-)lifluoroacetyl-
1,4-bis-(0-p-nitrobenzoyl)-L-daunosamine (53.8w, 0.0994mmo 1) was mixed with anhydrous methylene chloride (10ml) and anhydrous ether (2ml).
) and dried molecular sieves 4A (44
6■) was added. The reaction solution was heated at -20°C under an argon atmosphere.
Cooled to
1,0.207 mmol 1) was added and stirred for 2 hours. Furthermore, trimethylsilyl triflate (0.02 mmo
1,0.103 mmol 1) was added, and the reaction was continued for 30 minutes under the same conditions. A saturated Na HCOs aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, washed with Mg5O, dried, filtered, and concentrated under reduced pressure. The obtained crude glycoside was dissolved in methylene chloride (0.5 ml).
and methanol (50 ml) and 0.1 M NaOH
An aqueous solution (1 ml) was added and stirred for 30 minutes under water cooling to remove the benzoyl group. After adding enough acetic acid to make the reaction solution turn orange, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried with Mg5O, filtered, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (silica gel, chloroform-acetone (20:1)) to give (+)-3'-N-)lifluoroacetyl-14
-(2,2,2-)lifluoroethyl)-4-demethoxydaunorubicin (31.5μ, 58%) was obtained as a red-orange solid. A pure product was obtained as an amorphous powder by recrystallization from methylene chloride, ether, and n-hexane.

[α)”+1436 (CO, 112, dioxane).

IR (KBr): 3475,1730°1630.15
95,1260.1235°1170.1120.10
15.990cm-'.

'HNMR (CD C1s): δ 1,32 (3H
, d, J=6.6H2,5'-Me).

1. 85 (LH, ddd, J-13, 5H2゜13
．． 5Hz, and 4.2Hz, 2', -H).

1.97 (IH, d, J=8.2Hz, 4'-0H
), 2.03 (IH, dd, J=13.5Hz a
nd 5.3Hz, 2 +119-H) +2.15
(IH, dd, J=14.8Hz and4.0Hz
, 8. , -H), 2.34 (LH.

ddd, J=14.8Hz, 2.0Hz
andl, 9H2,8, -H), 2.38-2.
62 (2H, m, 15-Hz), 3.04
(IH.

d, J-18,9H2,10,, -H), 3.
10 (IH, ddd, J=19.5Hz, 8.
9Hz.

and 6.1Hz, 14-H), 3.2
1 (IH.

ddd, J=19.5Hz, 9.0Hz
and6.2Hz, 14-H), 3.31
(IH, dd.

J-18,9Hz and 1.9Hz,
10-q-H), 3.70 (IH, dd,
J=8.2Hz and 2.4Hz, 4'-
H), 4.19-4.28 (I H,m,
3'-H), 4.26 (IH, q, J=6.
6Hz, 5'-H).

4.42 (IH, s, 9-0H), 5.2
9 (IH, dd, J=4.0Hz and
2.0Hz, 7-H), 5.52 (IH
, d, J-4,2H2,1'-H), 6.6
7 (IH, d.

J-8,6Hz, NH), 7.83~7.89
(2H, m, Aroma ti cproton
es), 8.34-8.40 (2H.

m, Aromatic protones).

13.35 (IH, s, ArOdan), 13.62 (
IH,s, Ar0H).

”F NMR (CD CI: δ-67
,09(3F, t, J=10.8Hz, 1
5 CFs).

76.55 (3F, s, C0CFs).

MS (m/z) = 675 (M”),
450°307°Elemental analysis value: C3°Ht? Calculated as Olo N Fa: C, 53,34; H, 4,03.

N, 2.07%.

Measured values: C, 53,53; H, 4,23; N, 2.
15%.

Reference example 3 (+)-3'-N-)lifluoroacetyl-14-
(2,2,2-1-lifluoroethyl)-4-demethoxydaunorubicin (20,4■, 0.030 mmol)
A 0.1 M NaOH aqueous solution (3 ml) was added to the mixture, and the mixture was stirred at room temperature for 30 hours under an argon atmosphere. 3M in the reaction solution
After adjusting the pH to 8 by adding hydrochloric acid, water was added and extraction was performed with methylene chloride. The organic layer was washed with water, dried with Na, SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (0,2
m1) and chlorophor 2 fume (1.0 ml), and 0.25M hydrogen chloride methanol solution (0.2 ml, 0.05 mmol 1) was added and stirred. Ether (6 ml) was added to the reaction solution, cooled on ice, and the precipitated solid was collected by filtration to give (10)-14-
(2,2,2-)Lifluoroethyl)-4-demethoxydaunorubicin (14.9μ, 80%) was obtained as a yellow-orange solid.

mp 183.5-184°C (decomp).

(α)"+190" (CO, 100, methanol).

IR (KBr): 3450, 1725, 1625°15
90.1405.1260.1230゜1135.11
20.1005.980■-1゜'HNMR(d'-D
MSO): δ 1.15 (3H, d, J=6.6Hz,
5′-Me).

1.69 (IH, dd, J=12.6Hz and
4Hz, 2'-Q H), 1.89 (IH, d
dd.

J=12.6Hz, 12.6Hz and 3Hz
.

2',,-H), 2.08 (IH, dd,
J-14Hz and 5.5Hz, 8
ax-H).

2.22 (IH, dm, J=14Hz, 8
．． , -H), 2.50 (2H,m, 15
Hz>.

2.94-3.11 (4H, m, 14H
t+10Hz), 3.33 (I H,m,
3′-H).

3.56 (IH, m, 4'-H), 4.
23 (IH, q, J-6, 6Hz, 5'-H).

4.97 (IH, dd, J=5.5Hz
and2.7Hz, 7-H), 5.30 (
IH, d.

J=3Hz, 1'-H), 5.43 (I
H.

d, J=5.7Hz, 4'-0H), 5
．． 60 (IH, s, 9-0H), 7.97-8
．． 03<2H,m,Aroma ti cpro
tones), 8.28-8.34 (2H.

m, Aromatic protones).

"F NMR (d'-DMSO): δ-64,
64 (3F, t, J=i 1Hz, 15C
Fs).

MS (m/z): 579 (M”-HC1).

450, 414° Elemental analysis value: C*5HtqOqNCI Fs・0.7
Calculated values as 5H,O: C, 53,42, H, 4,88.

N, 2.22%.

Measured values: C, 53,38i H, 4,85; N, 2.
14%.

Test example (cancer cell growth inhibition effect) Cultured mouse lymphocytic leukemia cells (P3BB) were
The novel 14-(ω,ω,ω-trifluoroalkyl) of the present invention was added to RPMI-1640 culture medium containing % calf fat serum, and the number of cultured cells was adjusted to 5×10′/m1.
A -4-demethoxydaunorubicin derivative was added to a predetermined concentration and cultured at 37°C for 2 days. Count the number of floating cells using a Coulter counter and determine the 50% cell growth inhibition concentration IC50 from the growth inhibition rate for the control group.
Table 1 shows the results.

Table 1 14-(ω, ω, ω-trifluoroalkyl)
IC50 of -4-demethoxydaunorubicin derivative against mouse lymphocytic leukemia cultured cells (P388)

Claims (1)

[Claims] Represented by the general formula ▲There are numerical formulas, chemical formulas, tables, etc.▼-[I] (In the formula, R^1 represents a hydrogen atom or a hydroxyl group, and n represents an integer from 1 to 3.) 14-(ω, ω
, ω-trifluoroalkyl)-4-demethoxydaunomycinone derivative.