JPH0338595A - N-acryloyl-anthracyclin glycoside - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formula I (wherein R₁ is H or methoxy, R₂ is H or OH, one of R₃ and R₄ is H and the other one of them is H or OH and R₅ is H, halogen, cyano or nitro).

EXAMPLE: N-(α-bromoacryloyl)-dunorubicin.

USE: A medicine.

PROCESS: Anthracycline glycoside represented by formula II dissolved in an org. solvent such as pyridine, dimethylsulfoxide, dimethylacetamide, THF, acetone or acetonitrile is reacted with a compd. represented by formula III (wherein X is halogen, groups represented by formulae IV-VI, 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimide-N-oxy or imidazolyl) for 2-10 hr at -10-40°C in the presence of an org. base such as triethylamine.

COPYRIGHT: (C)1991,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-acryloyl anthracycle glycosides, processes for their preparation and pharmaceutical compositions containing them.

The present invention relates to formula (A) [wherein R1 represents a hydrogen atom or a methoxy group,
R2 represents a hydrogen atom or a hydroxyl group, one of R3 and R4 represents a hydrogen atom, the other of R3 and R4 represents a hydrogen atom or a hydroxyl group, and R5 represents a hydrogen atom, a halogen atom, a cyano or a nitro group]. N-acryloyl anthracycle glycosides are provided.

The anthracycle glycosides of formula (A) are N-(
α-bromoacryloyl)-daunorubicin, N-(a-bromoacryloyl)-4′-epidoxorubicin, N-(α-bromoacryloyl)-doxorubicin, N-(α-bromoacryloyl)-4′-epidoxorubicin, 4 -Demethoxy-N-(α-bromoacryloyl)-daunorubicin-(α-chloroacryloyl)-doxorubicin, including N-acrylodoxorubicin.

The present invention further provides the formula () %formula% A method for producing lycosides is provided.

This method comprises combining an anthracycle glycoside having the formula () (wherein R1R2, R and R4 are as defined above) and an anthracycle glycoside having the formula and X is a hydroxyl group or a leaving group).

The leaving group X in compound (C) is, for example, a halogen atom, preferably chlorine, or another easily substitutable group such as pivaloyloxy-0-C-CfcH3)3, ethyloxyforme1-0-C- OE t, isobrobyloxyform mate-〇-C-OCR 1 (CH3)2 2.4 5-trichlorophenoxy, 2.4-dinitrophenoxy, succinimide-N-oxy or imidazolyl group may be used.

The reaction of a compound of formula (B) with a compound of formula (C), where X is a leaving group as defined above, is usually carried out in an organic solvent in a molar ratio of 1:1 to 1:3. - Solvents useful for boat fishing include dimethylformamide, pyridine, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, acetone or acetonitrile. The reaction is
Organic bases, such as triethylamine or diisobutyl a
A compound of formula (B) and a compound (C) at about -10°C to 40°C in the presence of pyruethylamine (where X is OH)
The reaction between is preferably 1=1 to 1:3 in an organic solvent.
The molecular ratio of - Solvents useful for boat fishing include organic bases such as triethylamine or diisopropylethylamine or inorganic bases such as sodium bicarbonate and, for example, N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-(3'-dimethylamino dimethylformamide, pyridine, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, acetone or acetonitrile in the presence of a condensing agent such as propyl-carbodiimide.

Reaction temperatures vary from about -10°C to 50°C, and reaction times are about 1 to 12 hours.

Compounds of formula (A) prepared according to the procedures described above can be prepared by conventional methods such as silica gel or alumina column chromatography and/or by e.g. ethyl ether-hexane, methylene chloride-hexane, dimethylformamide-water and lower fatty alcohols - may be purified by crystallization from an organic solvent such as water.

Examples are given below to illustrate, but do not limit, the invention.

The abbreviations DMF and THF stand for dimethylformamide and tetrahydrofuran, respectively.

Syn (Formula A: (R=OCI-1, R=R==)(;I
3 2 3R4=OH; R5==B
r) α in dry DMF (30 ml) cooled to -10°C.
-To a solution of buamoacrylic acid (225 ml) was added triethylamine (0.42 ml) and pivaloyl chloride (0.14 ml).

The resulting suspension was stirred at -10°C for 30 minutes and daunorubicin hydrochloride (3011) was added.

The mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 hours.

The solvent was evaporated to dryness under reduced pressure, the residue was dissolved in methylene chloride and the 4 solvents washed with water were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The residue was diluted with methylene chloride-methane 98:2 (F/
chromatography on silica gel using f) as eluent.

The product-containing fractions were combined and evaporated under reduced pressure, and the residue was recrystallized from methylene chloride-hexane to give N-(α-bromoacryloyl)-daunorubicin (1
60■) was obtained.

U, V, 1 mtx (CH30H) (e)
:496 (116821,251(f17911t)
.

233 (3!1402).

FAR-MS: a/+ 660. M”+l
; 398 (aglycone) (acylated sugar).

PMR (2001JHx IIMSO-d6): δ
ppm14.011 (s, IH, OH6);
13, 25 (s, IH, 0811) 7.9-7.
8 (1,2HII e 1(217,72(d,
J=8.0 old, 111. Ml(CO)? , 51
fi, I)! , )13)! , 64 (d, I=2.48!, l)I
, = CH-old 1,09 (d, I; 2.4)
1! , IH,=CH-H)5,53 (L I
L 0H91 5,22(d, Ite3.5Ht, IH,H1'
)5.00 (d, J=6.OH3ill, O
H4') 4.91 (■, II (, 117) 4.20 (Q, J=6.9Ht, LH, H5
') L! III ((IH, f13') 62 3.95 (I, 3H, 0 tomo 3) 3.43 (s, IH, H4') 192
(s, 2H, CH210) 2, 25 (s, 3H, COCl+3) 2.3-2
．． 0 (m, 2H, 4dan 24-) 1.90
(ddd, J=3.5. 1+, 11. 12.
9H low, IH, +12' margin 1.51 (d
d, 1=4.9; 12.9Hs, 18.
2'■) 1.13 (d, J=6.911t,
3H9CH35').

Example-2 N-(α-bromoacryloyl)-4′-epidaunorubicin Formula A (R=OC)I, R=R=H; R3=1
3 2 4 0 H; Rs = Br) Following the procedure described in Example 1, 300 μ of 4′-epidaunorubicin hydrochloride was combined with 225 μ of α-
Treatment with bromoacrylic acid and 0.147 ml of pivaloyl chloride yielded 185 μl of pure N- after chromatographic separation and recrystallization from methylene chloride-hexane.
(α-bromoacryloyl)-4'-dipedaunorubicin was obtained.

U, V, λm5x(CH30H)(ε):...(1
418), 251 (26268).

233 (3112141゜F^B-MS: mat 660. &l"+1
; 39B (aglycone); 262 (acylated sugar)
.

PMR (200MHs CDG23);
δHm14.00 (s, IH, 0H-6)
;H,25(g, IH,0H-1111H(d,
J=7. OHt, IL old) 7.77 (
1,1=7. L8. lH! , IH, 112) 7
．． 38 (d,, J=8.lHs, IH,I
3) 6.97 (d, J=1.7H window, Il
+, =Cl1-H)6.53 (d, J=6
゜8Ht, IH, NHCO) 6, 03 (L
J=1.7Hs, IH,=CH-H)5.51
(d, J=3.2FIg, IH, H1')6 (dd.

1=2 4.28! .

18° I7) 7 3H, Yuri 3 ) 3 9-4.0 (4211, 113'85') 0 ([.

J=9 4[1t.

IH, H4') 3.22 (dd.

J=1.7° 8 8H window IH RIOeq) 2.91 (d.

1=18.8Hz.

IH LOII ) 2.43 (S IH 蜆■,) 5 (ddd +=1 7゜ 4 9H! .

■L H8eq) 2.0 2.2 (Il 2H.

811 H2' eq) 0 (ddd.

J=3.2 11.0° 13, [lHx.

IH H2’ll) G (d.

J=6 Hz 3H, CH3 5') Example-3 - (α-bromoacryloyl) monodoxorubicin formula A (R=OCH1R3=H; R2 depth R4=3 OH; Rs=Br) cooled to -10°C To a solution of α-bromoacrylic acid (225 ml) in dry THF (15 ml) was added triethylamine (0.42 ml) and pivaloyl chloride (0.147 ml).

The resulting suspension was stirred at -10°C for 30 minutes and added to a cooled solution of doquinrubicin hydrochloride (293 ml) in dry DMF (35 ml).

The mixture was stirred at 0° C. for 30 minutes and at room temperature for 2 hours.

The solvent was evaporated to dryness under reduced pressure and the residue was dissolved in chloroform and washed with water. The solvent was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The residue was chromatographed on silica gel using methylene chloride-methanol 98:2 as eluent.

After evaporation of the solvent, the solid was stirred with a small amount of ethyl ether and, after washing with hexane, N-(α-bromoacryloyl)-doxorubicin (125μ) was obtained.

U, V, 2mtx (CH30H) (e): 49
6 (11500) ; 25N26247) ; 233
(39776).

FAR-MS: m/+676, IJ"+l
; 414 (aglycone); (acylated sugar).

P! JR (200MH! CDQ!3); δp
pm13.91t i HI 0)1-6);
H, 25 (s, 18.0H-11) 8, 04 (d
, I; 7.6H+, IH, Hl) 7.79 (
dd, 14.6. 14Ht, Ill, )
12) 7.39 (d, 1=8.4Hs, IH
, H3) 6.96 (d ] = 8.4 old, 111
．． IIHcO) 6.92 (d Jl, 5 H
t, IH,=CH-old 5,99 (d, J=
1.5 H+, IH, = CH- old 5.52 fd
, h3.4R1,IH,H1')5.30 (d
d, I=2.4. 4.2H! , Hl, Ht
)4.76 (d, J=4.5 ribs, 2, 20f
(]4.51 (s, IH, OH9)4.2-4
．． 1 (a+, 2L H3' e H
5')4.08 (s, 3H,0CH3)3.
68 (dd, J=1.7.8゜Ht,
LH, 84') 3.29 (dd, I=1.
5. 19. IHs IH, Hloeq) 3.03
(d, J=19.lH!, LH, HlOit
)2.99 (1, J=4.6Hs, llI, CH
20)! 12.34 (ddd, J=1.5.
2.4. 15.2Hs, IH,H8eq)2,H
(dd, Jl, 2. 15.2H!, IH,H
81x) ■, 97 (d, J=8.IHt,
lH,H4')1, El-8(a,2H1
CH2-2')l, 3G [d, J=6.6Hg
, 38. 3-5'l.

Example-4 N-(α-bromoacryloyl)-4′-epidoquinrubicin 2A (R=OCH3; R2=R3=OH; R4=H; R5=Br) According to the procedure described in Example 3, 300 μ of 4′-epidoxorubicin hydrochloride was treated with 225 μ of α-bromoacrylic acid and 0.147 sol of pinochloyl chloride, followed by chromatographic separation and ethyl ether-
After treatment with hexane, pure N-(α-bromoacryloyl)-4'-epidoquinrubicin of H8I was obtained.

U, V, 111! (C130H) (ε):496(
11500) ; 251 (27464) ; 233
(405H) FAB-MS: l/! 676, M”+L
; 414 (7gly:l:/); 2G2 (acylated sugar) PMR (200MW! DMSO): δppm13.
99 (+, IH, 0H-6); H, 25 (+
, 1L 0H-II) 7.9-7.8 f mouth,
3H, Hl, H2, NlIC0)7.7-
7.6 (1,IF+, 113)6,58 (d,
J=2.4HI, IH.

6,06 (d, J=2.48!, It(5
, 40 (s, IH, 0119) 5.22 (d, no 3. OH2, IH, old'
) 4.99 (-Ill, +171 = CI+-11) = C11-H) 4,811 (d, J=6.3Hg, 111
．． OH4')4-68 (j, Jl, 61(t,
IL C1 (20H) 4-55 (d, I”4.6Ht
, 2H1CI+201+)! , 98 (l, 01.
0↓3) 19-3.8 (s, 211.H
3' e 115' ) 3.00 (-
, 211, Cl121G) 2.21 (e, 2H,
2L) l, 8-1.3 (s, 2H, 22L) 1, 20
(d, I=6.2)! ! , 3H, S35L) Example-5 Formula A (R=R2=R3 ioH; R4=OH;
-demethoxy-daunorubicin hydrochloride
Treatment with 225 μ of α-bromoacrylic acid and 0.147 ml of pivaloyl chloride yielded 158 μ of pure 4-demethoxy-N-(α-bromoacryloyl )
- Daunorubicin was obtained.

U, V, λmtx (CHs OH) (ε): 496
(11582) ; 251 (27888) ; 233
(39394).

FAR-MS: l/! 630. M++1.
368 (aglycone); 262 (acylated sugar).

PMR (200MHr DMSO); δH113,9
2 (s, IH, 086); N, 20 (1, I
H,0HII) 8.2-7.8 (1,4H,Hl,H2,H3e
H4) 7, 72 (d, J=8. O1l!,
11. NHCOI6 64 (L J=2.
4H! , 18. YoC■-■)6.09 (d
, J=2.4 old, III, =Cll-11
)S, 53 (s, LH,0H9)5.22
(d, I:3.5Ht, lll, ) If
' ) 5.0o (d, J-6, OH!,
IH, OH4') 4.91 edition, IH, [1? ) 4.20 (Q, I=6.98!, IH,H
5' ) 3.98 (s, IH, FI3'
) 3.95 (s, 3H, 0Cf13) 3.43 (s, IH, 84') 2.92
(s, 2H, CI21G) 2.25 (s, 3H1
COCH3) 2.3-2.0 (m, 28. CH28)1.
90 (dd+I, J=3.5. 11.0.
12.9H! , IH, H21, 51 (dd, J
l, 9; 12.9Hx, IH,H2'eQ)1
, H(d, 1=6.9Ht, 3H1CH35'
).

Shin Formula A (R=OCH, RsR=OHiR.

1 3 2 4 =) (; R5 = CI!') α-chloroacrylic acid (lotiml) in dry DMF (
N,N-dicyclohexylcarbodiimide (165 .mu.) was added to the 20+++ l) solution and the resulting suspension was stirred at room temperature for 20 minutes.

The mixture was treated with triethylamine (0,2+al) and doxorubicin hydrochloride (200μ),
The whole was stirred at room temperature for 6 hours.

The solvent was evaporated to dryness under reduced pressure and the residue was dissolved in chloroform and washed with water. The solvent was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The residue was dissolved in methylene chloride-methanol 98:2 (methylene chloride-methanol 98:2).
0 as eluent.

After evaporation of the solvent, the solid was stirred with a small amount of ethyl ether, filtered and washed with hexane to give N-(α-chloroacryloyl)-doxorubicin (102).

U, Y, A 11! (CH30il) (g)
:...(115B2); 251(264031.

03 (40024) FAR-MS: s/s 632. M++, l
; 414 (7guri:ff:z); 2N (acylated sugar)
.

PMR (200MHt CDa!3):
δ ppmH, 98 (s, II, 0■-6)
;13.25 (g, IH, 0H-11) ;1,
04 (d, I=7.6H!, 11(, Hl)
7.79 (dd, J:?, 6. 8.411t,
IH, H2) 7.39 (d, l=8.4 old,
IH, -H3) L 86 (d, I=8.4
8! , IH,=NHCO)1i,70 (d,
l=1. sH! , LH, chick C1l-1115,
891, 31, 5 ribs, HL fable CH-Iri 5.52
(d, 1=3.4Ht, 1L li1'
)510 (dd, J=2.4. 4.2 old,
l■, H7) 4.76 fd, I=4.6 old, 2
H1 measurement 20H) 4.51 i, IH, OH9) 4.2-4.1 (a, 2H,)13' e
[5') 4.08 (s, 3H0OCI(3) 16B (dd, J=1.?, 8.lHl,
ill, H4')129 (dd,
J=1.5. 19. lHl, IH, HIQeq
)3, (13(d, 1!19.1B!, IH,
Hlosx) 19G (1, I=4.6 old, IL
CH2廿) 2.34 (ddd, J=1.5.
2.4. L5.21h, IH, HBeq2.1
11 [dd, Jl, 2. ls, 2H! ,
IH, H811)t, ty (d, J:8.
18! , 111. OH4')1.9-1.8
(m, 2■, H2''-)1.3fl (d, I
-6,6Hj, 3H,CH3-5').

Formula A (R=OC)I; R2=R4=O)I;
R33 = R5-H) Following the procedure described in Example 6, 20 fl ■ of doxorubicin hydrochloride was treated with 72 ■ acrylic acid and 165 ■ N,N'-dicyclohexylcarbodiimide and after chromatographic separation. , 96 μm of pure N-acryloylutquin rubicin was obtained.

U,? , λm*tfcH30H) (s): 496
(11382) ; 251 (2G223) ; 233
(39642).

FATOMS: ts/l 5911. M”+1
; 4f4 (7guri:7:/)7 184 (acylated sugar) PMR (200MH!, CD G!3): δp
-H, H(t, ill, 0R-6);13
．． 25 (s, l)l, 0R-11);
8.04 (d; Ill7,6Ht, HL
1ll) 7.79 (dd, I-7,6,8,
414! , IH, 82) 7.39 1d, J-
8,4Hs, 11. 83) 5, 110 (d,
J=8.4H1,III,NHCO)6.46
(dd, Ill, -ritomiCl2)6.19
(dd, IH, -ri=see 2) 5.66 fdd,
111, -CO Tomitsuji 2); 5.52 (d, J=
3.4Hs, 1)1. old ゛) 5.30 (dd
, I=2.4. 4.2Ht, IH, H7) 4
, 76 (d, I=4.6Hs, 2B,
Play 20 Old 4.51 Is, II, 0III
9) 4.2-4. t (i+, 21 83'
e 115') 4.08 (s, 38.
3) 3.611 (dd, l village, 7.
L 1flt, IL H4') 3.29
(dd, J=1.5. 19. Ill, IH,
Hloeq ) 3.03 (d, JllllIB!,
IH, old 00) 2.99 ((.

11.6B! IH, CH2 0R) 4 (ddd J=t, 5 2.4° 5 11r lHl HBeq) 2.18 (dd.

1=4 2゜ 15.2H! .

Ill.

8811) 7 (d.

1=8 1H irises.

18° OH4’) 9-1.8 (waterfall.

2H・CH2 12') 1.30 (d 1=6 flt 3H Ri.

15').

Claims (10)

[Claims] (1) Anthracycle glycoside with the following structure. ▲There are mathematical formulas, chemical formulas, tables, etc.▼A [However, R_1 represents a hydrogen atom or a methoxy group, and R
_2 represents a hydrogen atom or a hydroxyl group, one of R_3 and R_4 represents a hydrogen atom, the other of R_3 and R_4 represents a hydrogen atom or a hydroxyl group, and R_5 represents a hydrogen atom, a halogen atom, a cyano group, or a nitro group. ] (2) The compound according to claim 1, which is N-(α-bromoacryloyl)-daunorubicin. (3) N-(α-bromoacryloyl)-4′-epi-
2. A compound according to claim 1, which is daunorubicin. (4) The compound according to claim 1, which is 4-demethoxy-N-(α-bromoacryloyl)-daunorubicin. (5) The compound according to claim 1, which is N-(α-bromoacryloyl)-doxorubicin. (6) N-(α-bromoacryloyl)-4′-epi-
2. A compound according to claim 1, which is doxorubicin. (7) The compound according to claim 1, which is N-(α-chloroacryloyl)-doxorubicin. (8) The compound according to claim 1, which is N-acryloyl-doxorubicin. (9) A method for producing a glycoside compound of the general formula (A) as defined in claim 1, comprising the steps of: B) ▲There are mathematical formulas, chemical formulas, tables, etc.▼B (However, R_1, R_2, R_3 and R_4 are included in claim 1.
(with the meaning defined in )) for about 2 hours to 10 hours.
time, temperature from -10℃ to 40℃, formula (C) ▲ formula,
There are chemical formulas, tables, etc. ▼C [However, R_5 is as defined above, X is a halogen atom (preferably a chlorine atom), ▲ There are numerical formulas, chemical formulas, tables, etc. There are ▼ groups, ▲mathematical formulas, chemical formulas, tables, etc.▼ groups, 2,4,5 tri-chlorophenoxy groups, 2,4-dinitrophenoxy groups, succinimide-N-oxy groups, or imidazolyl groups] in the presence of an organic base such as triethylamine to obtain a compound of formula (A) as defined above, optionally purified by methods known in the prior art. . (10) Anthracycle glycoside of formula (B) as defined in claim 9 is combined with dimethylformamide, dimethyl sulfoxide, hexamethylphosphotriamide,
Dissolved in organic solvents such as acetone and tetrahydrofuran,
At a temperature of -10°C to 50°C for 1 to 2 hours, formula (C)
Compounds ▲There are mathematical formulas, chemical formulas, tables, etc.▼C (where R_5 is as defined above and X is a hydroxyl group), an organic base such as triethylamine, and N, N'
-dicyclohexylcarbodiimide or N-ethyl-N
reaction in the presence of a condensing agent such as '-(3-dimethylaminopropyl)carbodiimide to obtain the desired compound of formula (A), optionally purified by methods known in the prior art. The general formula defined in claim 1 (
A) Method for producing the glycoside compound.