JPH0272186A - 10-noranthracycline - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formulae I, II (X is H or OH) or its acid addition salt.

EXAMPLE: (7S,9R)-4-Demethoxy-7-deoxy-7-daunosaminyloxymethyl-10-nor- daunomycin.

USE: An antitumor agent.

PROCESS: 7(R,S), 9(R,S)-4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor-daunomycin represented by formula III and 2,3,6,-trideoxy-3-trifluoroacetamide-4-O- trifluoroacetamaido-α-L-lyxopyranosyl chloride represented by formula IV are reacted in the presence of silver trifluoromethanesulfonate to obtain a diastereomer mixture of N, O-protective glycosides and N- and O-trifluoroacetyl groups are removed to obtain free bases of diastereomer represented by the formulae I, II.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel class of synthetic anthracene glycosides with antitumor activity, a process for their preparation, pharmaceutical compositions containing them and their use in treating mammalian tumors of the following types: It is related to. The present invention further relates to aglycones of novel glycosides and a class of novel intermediates.

The present invention provides - Formula 1 (a, b) or II (a, b)
Anthracycline glycoside or a pharmaceutically acceptable phosphoric acid addition salt thereof is provided.

With respect to suitable structural characteristics of the species, the novel compounds of the present invention are related to the known antitumor glycosides daunorubicin and doxorubicin, both of which are well described in the literature and are effective in treating tumors of the species. Currently used clinically to However, the new anthracyclines differ from natural glycosides in the presence of an alicyclic five-membered ring in the aglycone moiety.

These novel glycosides convert aglycone (3) into N,O
obtained by coupling with the 1-chloro derivative of -trifluoroacetyl-daunosamine (4): [wherein X
represents a hydrogen atom or a hydroxy group] Therefore, the present invention also provides a method for producing an anthracycline glycoside of formula I or n or a pharmaceutically acceptable acid addition salt thereof, which method comprises ),
2 with 9(R,S)-4-demethoxy-7-deoxy-7-hydroxymethyl-IO-nor-daunomycinone
．． 3. Reacting 6-drideoxy-3-trifluoroacetamide-4-0-1-lifluoroacetamide-α-L-lyxopyranosyl chloride in the presence of silver trifluoromethanesulfonate to produce N, A diastereomeric mixture of O-protected glycosides was obtained, (II) N- and O-
Removal of the trifluoroacetyl group provides formulas 1a and IIa
(I[I) optionally converting said free base into a pharmaceutically acceptable acid addition salt thereof; (rV) a diastereomeric free base of Formulas Ia and IIa or its (V) optionally brominating the free base or the pharmaceutically acceptable acid addition salt thereof and hydrating the 14-bromo derivative thus obtained; decomposition to form the free base of formula Ib or nb, (Vl) optionally of formula r
characterized in that the free base of b or nb is converted into its pharmaceutically acceptable phosphoric acid addition salt.

The present invention also provides racemic intermediate 7 (R,S) of formula (3)
.

9(R,5)-4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor-daunomycinone is provided.

This racemic compound is 7(1?,S),9(R,S)-
Reacting the diastereomeric mixture of 4-demethoxy-6,10-dimethoxy-7,9-dideoxy-7-hydroxymethyl-10-nor-daunomycinone with potassium t-butoxide and oxygen, followed by treatment with aluminum trichloride. Manufactured by a method consisting of:

The racemic intermediate of formula (3) can be obtained by a method starting from p-benzoquinone and methylcyclopentadiene. The overall reaction formula is as follows: The actual starting material in the above reaction formula is a Diels-Alder reaction with an isomeric mixture of p-benzoquinone (5) and methylcyclopentadiene (6). 2-Methyl-1,4,4a,8a-tetrahydro-endo-1,4-methanonaphthalene-5,8-dione (7) produced by
[A, P. Marchiant et al., Journal Organic Chemistry, Vol. 49, p. 670 (19S
4)]. Compound (7) is rapidly converted to the corresponding dimethoxy-tetrahydro-naphthalene derivative (8) by treatment with sodium hydroxide and methyl iodide.

Cis-hydroxylation of the double bond in compound (8) is carried out with potassium permanganate in the presence of an organic salt such as triethylbenzylammonium chloride in an aprotic solvent such as methylene dichloride to form the compound (9), which is protected as the phenylboronate by treatment with phenylboric acid in trifluoroacetic acid. This phenylborone) (10) is acylated with phthalic acid monomethyl ester under reflux in the presence of trifluoroacetic acid and trifluoroacetic anhydride to convert it into a compound (a mixture of lla02 isomers).

Alkaline hydrolysis of the methyl ester followed by reduction of the aroylcarbonyl group gives the derivative (llb), which is rapidly converted to the anthrone mixture (12) by treatment with trifluoroacetic acid and trifluoroacetic anhydride at room temperature. let Oxidation of compound (12) to anthraquinone system (13) and removal of the phenylborate protecting group by treatment with alkaline oxygen results in a novel tetracyclic system (14
)give. Compound (14) by sodium periodate
), 10 having an acyl group and a formyl group
- Noranthracycline (15a) is produced. A mixture of alcohols (15b) is obtained by selective reduction of the formyl group, which does not affect the ketone group, carried out using tetra-n-butylammonium triacetoxyborohydride.

Introduction of tertiary hydroxyl groups is carried out by known methods using potassium t-butyl oxide and oxygen [J, N. Gardner et al., Journal Organic Chemistry, Vol. 33, p. 3294 (19Sg).
Reference. Finally, treatment with aluminum trichloride
The target anthracyclinone (3) can be obtained. Racemic anthracyclinone (3) was protected with I-chloroN in the presence of silver trifluoromethanesulfonate.
, condensed with O-ditrifluoroacetyldaunosamine (4) to form the diastereomeric α4-glycoside (17).
to obtain a mixture of This is typically done in an inert organic solvent such as methylene dichloride.

Compounds (Ia) and (IIa) are obtained by removing the N-trifluoroacetyl group with an alkali and then performing chromatographic separation. These daunorubicin derivatives are characterized by bromination of the acyl side chain and U.S. Pat.
The corresponding doxorubicin derivatives (17) and (
Il b).

In one embodiment, a methanolic solution of p-penzoquinone (5) cooled to -50°C is treated with an isomer mixture of methylcyclopentadiene, the solution is slowly warmed to room temperature, and 3
After an hour, the 2-methyl-1,4,4a thus produced
, 8a-tetrahydro-endo-1,4-methanaphthalene-5,8-dione (7): was isolated after crystallization from methanol in a methanolic solution at 0° C. under a nitrogen atmosphere at 10% 5,6-dimethoxy-2-methyl-1,4-dihydro-1(R,S),4(R,S)methanonaphthalene (8):QC) by reaction with an aqueous solution of sodium hydroxide and methyl iodide i.

which was treated with potassium permanganate and triethylbenzylammonium chloride in methylene dichloride solution at 0°C, followed by methylene dichloride-dichloride as the eluent system.
The crude reaction product was purified by chromatography on silica gel using acetone (95:5 v/v) to give pure 1.2.3.4-tetrahydro-2(R,S),
3(R,5)-eis-hydroxy-5,8-dimethoxy-2-methyl-1-(R,S),4(R,S)-methanonaphthalene was obtained, which was then treated with trifluoro at 0°C. After reacting with phenylboric acid in an acetic acid solution and stirring at room temperature for 4 hours, the desired 1, 2, 3.4 was obtained from the reaction mixture.
-tetrahydro-2(R,S), 3(R,5)-cl
s-Phenylboronate-5,8-dimethoxy-2-methyl-1-(R,S).

4(1?, S) methanonaphthalene (10): was isolated and dissolved in a mixture of trifluoroacetic acid and trifluoroacetic anhydride and treated with phthalic acid monomethyl ester: for 12 hours at reflux temperature. A mixture of isomers of compound (lla) is obtained, and the monomethyl ester is hydrolyzed with a hydroalcoholic mixture of potassium hydroxide at 0° C. for 30 minutes,
The hydrolyzed product was reduced with triethylsilane in trifluoroacetic acid solution at 50°C for 24 hours to obtain 1,2,3
．． 4-tetrahydro-2-(R,S), 3(R,5)-
cls-phenylborone) -5,8-dimethoxy-
2-methyl-8-(2'-carboxybenzyl) -1
-(R,S),4(R,S)-methanonaphthalene and 1.2.3.4-tetrahydro-2-(R,S),3(
R,5)-cis-phenylboropho15,6-dimethoxy-2-methyl-7-(2°-carboxybenzyl)
-1 (R, S), 4 (I?, S) methanonaphthalene (l
lb): 11a: T=C00CHs 11b: Anthrone mixture (12 ): Convert to
This mixture was oxidized in methanolic solution in the presence of N-benzyltrimethylammonium hydroxide with a stream of oxygen at room temperature for 4 hours and toluene-
The new pure anthraquinone derivative (13) was isolated after chromatographic purification on silica gel using acetone (10:IV/V) and crystallization from diethyl ether and dissolved in methylene dichloride solution at room temperature for 48 hours. 7(I?,S), 8(R,S), LO(
R,5)-4-demethoxy-6,11-dimethoxy-7
-dioxy-7,10-methano-8-hydroxy-9-
Desacetyl-9-methyl-daunomycinone (14)
: which was treated with an aqueous solution of sodium periodate in methylene dichloride solution at room temperature to give 4-demethoxy-6,1O-dimethoxy-7,9-dideoxy-7
-Formyl-1O-nor-daunomycinone (15a)
: late: c=cH.

This intermediate was then selectively reduced in the 7-formyl group with tetra-lobyl-ammonium-triacetoxy-borohydride in anhydrous benzene at reflux temperature for 2 hours to give 7(I?,S).

9(R,5)-4-demethoxy-6,10-dimethoxy-7,9-dideoxy-7-hydroquinemethyl-10-
True Doubts Main Non (15b): Kataoki: A diastereomeric mixture of G=CH20H was obtained, which was dissolved in anhydrous dimethylformamide and then first reacted with potassium t-butyl oxide in the presence of triethyl phosphite. a stream of oxygen was bubbled through for 30 minutes while stirring, and then the crude product obtained was treated with anhydrous aluminum trichloride in methylene dichloride at reflux temperature for 40 minutes, and finally with methylene dichloride; methanol as eluent system. (95
: 5 v/v) after chromatographic purification on silica gel to obtain the desired 7(1?,S), 9(I
? , 5) to obtain a racemic mixture of -4-demethoxy-7=deoxy-7-hydroxymethyl-10-true dautzmainone (3).

In a specific example for preparing glycosides I and 1 and their salts, 7(R,S), 9(I?, 5)- of formula (3) dissolved in anhydrous methylene chloride is used. 4-
Demethoxy-7-deoxy-7-hydroxymethyl-1
0-nordaunomycinone was converted to 2.3.6-drideoxy-3-trifluoroacetamide-4-0-1- of formula (4) in the presence of syam-collidine and an ethereal solution of silver trifluoromethanesulfonate. Reaction with lifluoroacetamide-α-L-lyxopyranosyl chloride for 2 hours at room temperature yielded a diastereomeric mixture of N,O-protected glycodos, which was treated with methanol for 30 minutes at room temperature to give the formula A diastereomeric N-protected trifluoroacetyl derivative of (17) was obtained, which was combined with 0. The diastereomeric free base 1 was prepared by mild alkaline hydrolysis with IN aqueous sodium hydroxide solution at 0°C for 30 min to remove the N-trifluoroacetyl protecting group.
A mixture of (a) and II (a) (X - H) is obtained which is treated with methanolic hydrogen chloride to isolate the free base as its hydrochloride; the diastereomeric mixture of this hydrochloride is methylene dichloride:methanol:water (1
The pure diastereomeric hydrochloride salts of formulas I (a) and II (a) (X - H) were obtained separately by chromatographic separation on a column of silica gel using 00:20 + 2 : v/v); If desired, each pure diastereomer was treated with a solution of bromine in chloroform and the 14-bromo derivative thus obtained was hydrolyzed with an aqueous solution of sodium formate to form the free bases I(b) and
(b) (X-oH) is isolated as its corresponding hydrochloride salt by treatment with methanolic hydrogen chloride.

As is clear from the above, the methods involve the production and use of several novel intermediates, which are also within the scope of the present invention.

Still further, the present invention provides a pharmaceutical composition comprising an anthracycline glycoside of formula (1) or (2) or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

Conventional carriers and diluents and conventional compounding techniques can be used.

Finally, the present invention also provides a method for treating tumors in mammalian species using the novel anthracycline glycosides or salts thereof according to the present invention. A therapeutically effective amount of a compound according to the invention is administered to a patient in need thereof. Conventional routes of administration can be used, especially parenteral routes such as intravenous.

The present invention will be explained below with reference to Examples.

Example 1 5,6-dimethoxy-2-methyl-1,4-dihydro-
Preparation of 1(R,S),4(R,S)methanonaphthalene (8) - 50 g (0,462 mol) of p-benzoquinone (5
), 50 ml (0.5 mmol) of a freshly distilled isomer mixture of methylcyclopentadiene (6) was added to A,
The procedure described by P. Marchant [Journal
of Organic Chemistry, Volume 49, No. 67
0 (19S4)]. The solution was gradually warmed to room temperature, and after 3 hours the reaction mixture was concentrated to a small volume and crystallized from methanol.
-Methyl-1,4,4a,8a-tetrahydro-endo-1,4-methanonaphthalene-5,8-dione (7) was isolated. Yield 45%.

33. Dissolved in 900 ml of methanol and 540 ml of 10% aqueous sodium hydroxide solution. f3g (0,18
mol) of compound (7) was cooled at 0° C. and nitrogen was bubbled through it for 1 hour. Then methanol 14
80 ml of methyl iodide diluted with 0 ml were added dropwise and the mixture was stirred overnight. The reaction mixture was then neutralized by the addition of IN aqueous hydrochloric acid and the solvent was removed under reduced pressure. The crude product was chromatographed on a silica gel column and chromatographed in petroleum ether and diethyl ether (10
0:1, volume ratio) to give the title product (8) as an oil. 29g 1 yield 75%.

TLC Kieselgel plate, Merck F (petroleum nityl:
diethyl ether, 20:1 volume ratio): Rf-0,2
8゜El-MS: ll1e 21B (M +) PM
R/ (200MHz, CDCN) δ, especially: G, 52 (s, 2) 1. H-6, H-7): 13
．． 24 (m, IH, H-3); 4.07 (nit (, H
-4)+3,65(+a,ll(,H-1);3.78
(s, 6H, 2xOCH). 2.24-2.15 (2
Personal belief, 2H, CI-9).

=2 Example 2 1.2,3.4-tetrahydro-2(R,S), 3(R
,5)-cis-methylene dichloridelooOml medium 2
A solution of 0 g (0,092 mol) of compound (8) was added with 21.9 g (0,138 mol) of compound (8) in 1200 ml of methylene dichloride.
moles) of potassium permanganate and 31.5 g (0
, 138 mol) of triethylbenzylammonium chloride was treated with 250 ml of 10% aqueous sodium hydroxide solution at 0° C. under nitrogen for 2 hours. Manganese dioxide generated by the alkali treatment was removed by filtration, and the organic phase was washed with a saturated aqueous sodium metabisulfite solution. After working up in a conventional manner, the crude product was purified by chromatography on a silica gel column, eluting with methylene dioxide/acetone (95:5, volume ratio) to give 13.6 g of pure 1.2,3.4-tetrahydrogen. o-2(R,S), 3(R,5)-cis-hydroxy-5,8-dimethoxy-2-methyl-1(R,S),
4(R,S)-methanonaphthalene (9) was obtained. Yield 6
o%.

TLC Kieselgel plate, Merck F (methylene dichloride: acetone, LO:, 1 volume ratio): Rr-0,2° PD-MS: ale 250 (M+)P M
RZ (200MHz, CD CD3) δ,
Especially: 8, l1i (s, 2H, H-7, H-8); 3.
7B (s, 6H, 2xOCH); 3.63 (wide signal,
IH, 0H-3); 3.38 (m, LH, H-3)
:3.35-3.28 (2 i, 2H, H-1,8
-4); 2.31-1,68 (two 1°2H, ll-
9a, H-9s); 0.99 (s, 3) 1. C)I
).

12f (48 mmol) of compound (9) in 150 ml
of trifluoroacetic acid, cooled to 0.degree. C. and added thereto 7.8 g of phenylboric acid. This mixture was heated to 0°C.
The mixture was stirred for 2 hours at room temperature and for 4 hours at room temperature.

The reaction mixture was then poured into a branch funnel and washed with aqueous sodium bicarbonate and water. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain 12.5 g of benzene boronate derivative (1o) after crystallization from methanol. Yield 78%, melting point 9
1”C0 TLC Kieselgel plate, Merck F (methylene dichloride:acetone, 2o:1 volume ratio): Rf' -0,68
, FD-) 1s:ale 33B (M+).

Example 3)-1(R,S), 4(R,S) methanonaphthalene (
12 g (35.7 mmol) of compound (1o) prepared as described in Example 2 and 9.72 g
(54 mmol) of phthalic acid monomethyl ester was dissolved in a mixture of 200 ml of trifluoroacetic anhydride and 100 ml of trifluoroacetic acid, and this was refluxed for 12 hours. The residue obtained by evaporating the solvent under reduced pressure is
Purification on a column of silica gel using methylene dichloride as solvent for elution gave 13.6 g of the isomer mixture (lla) after crystallization from diethyl ether.

Yield 78%, melting point 169-172°C.

TLC Kieselgel plate, Merck F (methylene dichloride:acetone, 20:0.1 volume ratio): Rf = 0.3
2. El-MS: m/s 470 (M+) 13g
(26 mmol) of compound (lla) in 240 ml
The solution was dissolved in ethanol, cooled to 0°C, and 150 ml of an aqueous potassium hydroxide solution was added. After 30 minutes, the mixture was acidified with 2N hydrochloric acid and extracted with methylene dichloride. The organic phase was separated and the solvent was removed under reduced pressure. The residue was then dissolved in 50 ml of trifluoroacetic acid,
To this was added dropwise 12 ml of triethylsilane.

The reaction mixture was heated at 50°C for 24 hours,
It was then cooled, diluted with water and extracted with methylene dichloride. The organic phase was separated and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column using methylene dichloride:methanol (20:0.5 by volume) as the elution system to give an isomer mixture of (llb) (8.5 g, yield 70%). Melting point: 171°C.

TLC Kieselgel plate, Merck F (methylene dichloride:methanol, 20:1 volume ratio): Rf = 0,62
．． El-MS: ale 470 (M+).

PM (200MHz, CD3) δ
, especially: 8.0-7.1 (*, 9H, aromatic substances)
; 6.40 (s, LH, H-6); 4.43-4.
37 (2 d, j=16.o Hz, 2HAr-C
H-Ar); 4.1 g (m, LH, H-3); 3.70
(s, 6H, 2xOCH); 3.6B□-3 (m, LH,)I-4): 3.47 CIl, lH,
) I-1); 2.18-1.99 (2 d, j
-10,0Hz, 2H, H-9a, H-9b).

Example 4 To a solution of 8 g (16.6 mmol) of the compound (llb) prepared as described in Example 3 in 100 ml of trifluoroacetic anhydride, 40 ml of trifluoroacetic acid was added to 0.
It was added dropwise under stirring at .degree. After 5 minutes, the reaction was complete, the solvent mixture was evaporated and the residue was dissolved in methylene dichloride and washed with a saturated aqueous solution of sodium bicarbonate and then with water.

The organic phase was dried over anhydrous sodium sulfate to obtain an isomer mixture of compound (12) after evaporation of the solvent.

TLC Kieselgel plate, Merck F () Luene: Acetone, 95: 5 f (D capacity kk:): Rf
-0,53° FD-MS: m/e 548 (M+).

7.6 g (7.5 mmol) of compound (12) was added to 8
0.00 ml of methanol, 14 ml of a 40% methanolic solution of Triton B (N-pendyltrimethylammonium hydroxide) were added and a stream of oxygen was bubbled through at room temperature. After 4 hours, the reaction mixture was dissolved in 0.00 ml of methanol. The pH was adjusted to 5 by the addition of aqueous hydrochloric acid and extracted with methylene dichloride. After working up in the usual manner, the crude product was purified on silica gel using a mixture of toluene:acetone (10:1 by volume) as the elution system. Column chromatography gave 5 g of the new anthraquinone derivative (13) after crystallization from diethyl ether. Yield 68%. Melting point 20.
4℃.

TLC Kieselgel plate, Merck F (toluene:acetone, 95:5) capacity ratio): Rf -0, 31° PD-MD: m/e 467 (M+).

Compound (13) was dissolved in 300 ml of methylene dichloride and treated with 80 ml of 2-methyl-pentane-2,4-diol diluted with 15 ml of acetic acid to remove the phenylborate protecting group. The reaction mixture was stirred at room temperature for 48 hours.
Stir for hours. The mixture was then reduced to 0. The pH was adjusted to 7 with an aqueous IN sodium hydroxide solution and the product was extracted with methylene dichloride. The solvent was removed under reduced pressure and the title compound (14) was obtained after crystallization from diethyl ether (3.6 g, yield 87%). Melting point 205°C (with decomposition).

TLC Kieselgel plate, Merck F (methylene dichloride:acetone, 90:1O17) volume ratio): Rf-
0.2゜FD-MS: Il/e 380 (M +) PM
R/(200MH2, CD0g3)δ, especially: 8.2-
8.1 (m, 2)1. H-1, H-4); 7,6
-7.7 (■, 2H, H-2°"; 3-99-3.9
S(s, 8H, OCHa-84fl, -11);
(s, IH, 0H-9); 2.47-1.99 (
2 ta, 2H, CH).

Example 5 3.5 g (9 mmol) of compound (14) prepared as described in Example 3 dissolved in 400 ml of methylene dichloride are mixed with 2-8 g (9 mmol) of the compound (14) prepared as described in Example 3 in 120 ml of water. , 3 mmol), stirred for 2 hours at room temperature and worked up in a conventional manner to give 4-demethoxy-6,1O-dimethoxy-7,9-dideoxy-7-formyl-10-nordauno. Mycinon (15a
) was obtained. This was used in the next step without purification.

TLC Kieselgel plate, Merck F (methylene dichloride:acetone, 10:1 volume ratio): Rr-0,43° FD-MS: i/e 378 (M+) P M R/(200 MHz, CD Cfl 3
) δ, especially: 8.9Hz, LH, h-9); 4.2
5 (ddd, j=1.9.4.9, 6.7Hz, LH.

H-7) ; 3.94-3,67 (2 s, 8H,
QC)! -6゜□3 OCH-11); 2.7-2.3 (Il, 2H, C)
I-8); 2.33 (s, 3) 1°□3-2 COCH).

Compound (L5a) was dissolved in 50ml of anhydrous benzene, 8
4,3 in 30 ml of anhydrous benzene heated to 0°C.
g (10 mmol) of tetralobyl-ammonium-triacetoxyborohydride CC,W, Gripuru et al., Tetrahedron Letters, Vol. 24, No. 42
[Prepared by the method described on page 87 (19S3)] at once. The reaction mixture was refluxed for 2 hours, then worked up by pouring into water, then extracted with diethyl ether, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was dissolved in a methylene dichloride/acetone mixture (
The title compound (15b) was obtained as a diastereomeric mixture (2
．． 4g.

yield 71%).

TLC Kieselgel plate, Merck F (methylene dichloride:acetone 8:2 volume ratio): Rr-0,49°F
D-MS: m/e 380 (M+).

pMR7 (2a MHz, CDCΩ3) δ, especially: 3
,67 (2 s, 6H, OCR-8, OCR-11
); 3.92□yo □3 ('', 2H1CH20H) ; 3,6-3.7(r
B, LH, H-7); 2. [15(ddd.

j-13,9,lO,2,9,6Hz,lH,H-8a
); 2.35 (s, 3H.

C0CH) ; 2.17 (ddd, j-13,9,
4,8,4,7 Hz, lH, H-8b) Preparation of Example 6 2-2 g (5,7 mmol) of compound (15b) prepared according to Example 5 are dissolved in 50 ml of anhydrous dimethylformamide. , and this was added to a solution of 100 ml of anhydrous dimethylformamide containing 1 g of potassium tert-butoxide and 1 ml of triethyl phosphite cooled to -15°C. A stream of oxygen was bubbled through the mixture. The color of the reaction mixture became brown.

The reaction was complete after 30 minutes and was quenched with water and extracted with methylene dichloride. After evaporating the organic solvent, the crude product was dissolved in 200 ml of anhydrous methylene dichloride and 2
The mixture was refluxed for 40 minutes with g-g of anhydrous aluminum trichloride. The reaction mixture was quenched with 200 ml of a saturated aqueous solution of oxalic acid, extracted with methylene dichloride, and purified on a silica gel column eluted with a mixture of methylene dichloride and acetone (volume ratio of 90:10) to obtain the title compound (3 ) was obtained (0.
42g, yield 20%).

TLC Kieselgel plate, Merck F (methylene dichloride:methanol:95:5 volume ratio): Rf=0.34.
PD-MS: s/e 392 (M+).

PMR: (200MHz, DMSO) δ, especially: 13.
00-12.96(s, 2H, 0H-B, 0H-11
); 8.3-8.2 (+, 2H.

H-1, H-4); 8.0-7.9 (m, 2) 1. H
-2,8-3); 5.95 (LH.

0H-9); 5.35 (m, LH, CH-0H), 3.
60 (m, IH, H-7); -2-□ 2.57 (dd, j-8, 3, 14, OHz, LH, H
-8a): 2.34(s, 3H.

C0CH); 2. L5 (dd, j-1, 9, 14
, 0Hz, LH, H-8b).

-3□ Example 7 Saminyloxymethyl-10-nordaunomycinone 0.320 g (0.081 mmol) of racemic 7 (prepared as described in Example 6) in 200 ml of anhydrous methylene dichloride. 1?, S), 9(I?, 5)-4-demethoxy-7-deoxy-7-hydroxymethyl-lO-
A solution of nordaunomycinone (3) in 12.1 g of molecular sieves (4A).

Merck) and 0.5 g of 2.3.64 lysooxy-3-trifluoroacetamide-4-0-trifluoroacetamide-α-L-lyxopyranosyl-chloride (4) and 0
．． 200 ml of sym-collidine and 0.250 g of silver trifluoromethanesulfonate dissolved in 2 ml of anhydrous diethyl ether were added. After 2 hours at room temperature,
The reaction mixture was filtered and 0. It was washed with an IN aqueous hydrochloric acid solution, water, a saturated aqueous sodium bicarbonate solution, and again with water. The residue obtained by evaporation of the solvent is then dissolved in methanol and after 30 minutes at room temperature C-4°-0
- Hydrolysis of the trifluoroacetyl group was completed. This allows the N-trifluoroacetyl diastereomer (
A mixture of 17) was obtained. Kieselgel plates (Merck F) using methylene dichloride:methanol (volume ratio of 95:5) as the solvent system.
There were 28 te.

FD-MS: II/e 457 (M+).

The N-trifluoroacetyl derivative was dissolved in a 0.1N aqueous sodium hydroxide solution, and the N-protecting group was hydrolyzed. After standing at 0° C. for 30 minutes, the solution was adjusted to pH 8 and extracted with dichloromethane. Evaporate the solvent to a small volume and then adjust the pH to 4.5 by adding a methanol solution of 0, IN hydrogen chloride to obtain the title compound 1.
a and IIa were obtained as hydrochloride salts (0.2 g, 50% yield). Methylene dichloride:methanol as solvent system:
TLC on silica gel plates (Merck F) using acetic acid:water (30:4:1:0.5 volume ratio)
It was -0.26.

FD-MS: m/s 49S (MHz); 497 (M
One.

Solvent system methylene dichloride:methanol:water (
The pure stereomer was obtained by chromatographic separation on a silica gel column using a volume ratio of 100:20:2.

Diastereomeric mixture of compounds 1a and Ila (50:
The PMR of 50) was as follows.

Ia, IIa (200Mt(z, DMsO
) δ2 Especially: 12.94-13.01 (s, OH-6,
0H-11) ; 8.3-8.2 (i, 2H.

t(-1, H-4); 8.0-7.9(m, 2H
, H-2, H-3); 6.0B-5,99(s, L
H, 0H-9); 5.45-5.42 (d, j=
[i, 6) 1z, LH.

0ft-4') ; 4,69(m,lH,ll-
1°); 4.0-3.2(m, OH.

H-7, H-5', H-4°, H-3°, CHO)
; 2.7-2.2 (a, 2H.

CH-8); 2.30 (s, 3H, C0CH)
; 1,6-1.6 (m, 2H.

CH-2'); 1.11-1.02 (d, j-6,
6Hz, 3H, CH-C5°).

□Yo Example 8 The title compound was prepared as the hydrochloride salt by following the method described in U.S. Pat. No. 3,803,124 and using IO-true daunorubicin derivative 1a prepared in Example 7 as a starting material isolated.

Example 9 By following the method described in U.S. Pat. No. 3,603.124 and using compound a prepared in Example 7 as a starting material, the title compound Tei Neyamamasa; I' ! (1) Formula) was isolated as a hydrochloride.

Claims (1)

[Claims] (1) General formula I (a, b) or II (a, b): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I a, b ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IIa , b a:X=Hb:X=OH [wherein X represents a hydrogen atom or a hydroxy group] or a pharmaceutically acceptable acid addition salt thereof. (2) The compound according to claim 1, which is (7S,9R)-4-demethoxy-7-deoxy-7-daunosaminyloxymethyl-10-nor-daunomycinone or its hydrochloride. (3) The compound according to claim 1, which is (7S,9R)-4-demethoxy-7-deoxy-7-daunosaminyloxymethyl-10-nor-adriamycinone or its hydrochloride. (4) (7R,9S)-4-demethoxy-7
-deoxy-7-daunosaminyloxymethyl-10-
2. The compound according to claim 1, which is nor-daunomycinone or its hydrochloride. (5) The compound according to claim 1, which is (7R,9S)-4-demethoxy-7-deoxy-7-daunosaminyloxymethyl-10-nor-adriamycinone or its hydrochloride. (6) (I) Formula (3): ▲There are mathematical formulas, chemical formulas, tables, etc.▼3 of 7(R,S),9(R,S)-4-demethoxy-7-
Deoxy-7-hydroxymethyl-10-nor-daunomycinone and formula (4): ▲ Numerical formula, chemical formula, table, etc. ▼ 4 of 2,3,6-trideoxy-3-trifluoroacetamide-4-O-trifluoro Reaction of loacetamide-α-L-lyxopyranosyl chloride in the presence of silver trifluoromethanesulfonate yields a diastereomeric mixture of N,O-protected glycosides, (II) N- and O-tri removing the fluoroacetyl group to obtain the diastereomeric free bases of Formulas Ia and IIa; (III) optionally converting said free bases to their pharmaceutically acceptable acid addition salts; (IV) converting said free bases to their pharmaceutically acceptable acid addition salts; (V) optionally brominating said free base or pharmaceutically acceptable acid addition salt thereof; and (VI) optionally adding a pharmaceutically acceptable acid to said free base of formula Ib or IIb; 2. A method for producing an anthracycline glycoside having formula I or II according to claim 1, or a pharmaceutically acceptable acid addition salt thereof, which comprises converting the anthracene glycoside into a salt. (7) 7 of formula (3) dissolved in anhydrous methylene dichloride
(R,S),9(R,S)-4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor-daunomycinone was prepared with the formula (4)-2,
3,6-trideoxy-3-trifluoroacetamide-
4-O-Trifluoroacetamide-α-L-lyxopyranosyl chloride was reacted with N,O-
A diastereomeric mixture of protected glycosides was obtained, which was treated with methanol at room temperature for 30 minutes to obtain a diastereomeric N-protected trifluoroacetyl derivative of formula (17): This was mildly alkaline hydrolyzed with a 0.1N aqueous sodium hydroxide solution at 0°C for 30 minutes to obtain N.
- diastereomeric free bases I (a) and II (a) (X=H
), which was treated with methanolic hydrogen chloride to isolate the free base as its hydrochloride; the diastereomeric mixture of this hydrochloride was used as the elution system in methylene dichloride:methanol:water (100:20). :2:v/v) to obtain separately the pure diastereomeric hydrochloride salts of formulas (I)(a) and II(a) (X=H): and the desired The 14-bromo derivative thus obtained was hydrolyzed with an aqueous solution of sodium formate to give the free base I.
7. A process according to claim 6, wherein (b) and II(b) (X=OH) are isolated as their corresponding hydrochloride salts by treatment with methanolic hydrogen chloride. (8) A pharmaceutical composition comprising an anthracycline glycoside having formula I or II according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, mixed with a pharmaceutically acceptable diluent or carrier. (9) Formula (3): ▲Mathematical formulas, chemical formulas, tables, etc.▼3 Racemic 7(R,S),9(R,S)-4-demethoxy-7-deoxy-7-hydroxymethyl-10- Nor-
Daunomycinone. (10) The diastereomeric mixture of 7(R,S),9(R,S)-4-demethoxy-6,10-dimethoxy-7,9-dideoxy-7-hydroxymethyl-10-nor-daunomycinone was - Formula (3) characterized by reaction with potassium butoxide and oxygen, and then treatment with aluminum trichloride: ▲Mathematical formulas, chemical formulas, tables, etc.▼3 racemic 7(R,S), 9(R, S)-4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor-
Method for producing daunomycinone. (11) p-benzoquinone (5) cooled to -50°C:
▲There are mathematical formulas, chemical formulas, tables, etc.▼A methanol solution of ￥5￥ is treated with a mixture of isomers of methylcyclopentadiene (6); After 3 hours, the 2-methyl-1,
4,4a,8a-tetrahydro-endo-1,4-methanaphthalene-5,8-dione (7): ▲There are mathematical formulas, chemical formulas, tables, etc.▼￥7￥ Isolate it and crystallize it from methanol. 5, followed by reaction with a 10% aqueous solution of sodium hydroxide and methyl iodide in a methanolic solution at 0°C under a nitrogen atmosphere.
8-dimethoxy-2-methyl-1,4-dihydro-1 (
R,S),4(R,S)methanonaphthalene (8): ▲Mathematical formula, chemical formula, table, etc. are available▼￥8￥ was obtained, and this was mixed with potassium permanganate and chloride in methylene dichloride solution at 0°C. treatment with triethylbenzylammonium followed by methylene dichloride as the eluent system.
The crude reaction product was purified by chromatography on silica gel using acetone (95:5 v/v) to give pure 1,2,3,4-tetrahydro-2(R,S),3(
R,S)-cis-hydroxy-5,8-dimethoxy-
2-Methyl-1-(R,S),4(R,S)-methanonaphthalene (9): ▲Mathematical formula, chemical formula, table, etc.▼￥9￥ was obtained, and then this was trifluorinated at 0°C. After reacting with phenylboric acid in an acetic acid solution and stirring at room temperature for 4 hours, the desired 1,2,3,4-tetrahydro-2(R,S),3(R,S)-cis- Phenylboronate-5,8-dimethoxy-2-methyl-1-(R
, S), 4(R,S) methanonaphthalene (10): ▲There are mathematical formulas, chemical formulas, tables, etc.▼￥10￥ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Phthalic acid monomethyl ester dissolved in a mixture with fluoroacetic anhydride and at reflux temperature: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Compound (11a) is treated for 12 hours: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼￥11a￥: Obtain an isomer mixture of T=COOCH_3W=O, hydrolyze this monomethyl ester with a hydroalcoholic mixture of potassium hydroxide at 0°C for 30 minutes, and add the hydrolyzed product to a trifluoroacetic acid solution. 1,2,3,4-tetrahydro-2-(R,S),
3(R,S)-cis-phenylboronate-5,8-
Dimethoxy-2-methyl-6-(2'-carboxybenzyl)-1-(R,S),4(R,S)-methanonaphthalene and 1,2,3,4-tetrahydro-2-(R,
S),3(R,S)-cis-phenylboronate-5
,8-dimethoxy-2-methyl-7-(2'-carboxybenzyl)-1(R,S),4(R,S)-methanonaphthalene (11b): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 11b :T=COOHW=H_2 Anthrone mixture (12) is obtained by reacting this with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0°C for 5 minutes: [▲Mathematical formula, chemical formula, table, etc. This mixture was oxidized in methanolic solution in the presence of N-benzyltrimethylammonium hydroxide with a stream of oxygen at room temperature for 4 hours, using toluene-acetone (10: After chromatographic purification on silica gel using 1 v/v) followed by crystallization from diethyl ether, a novel pure anthraquinone derivative (13): 7(R,S),8(R,S ), 10(R,S)-4-
Demethoxy-6,11-dimethoxy-7-deoxy-7
,10-methano-8-hydroxy-9-desacetyl-
9-Methyl-daunomycinone (14): ▲Mathematical formula, chemical formula, table, etc.▼￥14￥ was obtained and treated with an aqueous solution of sodium periodate in a methylene dichloride solution at room temperature to produce 4-demethoxy-6,
10-dimethoxy-7,9-dideoxy-7-formyl-10-nor-daunomycinone (15a): ▲ Formula,
Chemical formulas, tables, etc. are available▼￥15a￥: G=CHO is obtained, and this intermediate is then converted to 7-formyl with tetra-n-butyl-ammonium-triacetoxy-borohydride in anhydrous benzene at reflux temperature for 2 hours. By selectively reducing the groups, 7(R,S), 9(R,S)
-4-Demethoxy-6,10-dimethoxy-7,9-dideoxy-7-hydroxymethyl-10-nor-daunomycinone (15b): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ¥15b¥: Dia of G=CH_2OH After obtaining the stereomer mixture and dissolving it in anhydrous dimethylformamide, a stream of oxygen was bubbled through for 30 minutes while first reacting with potassium t-butyl oxide in the presence of triethyl phosphite, and then the crude product obtained The material was treated with anhydrous aluminum trichloride in methylene dichloride at reflux temperature for 40 min, and finally methylene dichloride:methanol (95%
:5v/v) after chromatographic purification on silica gel with the desired 7(R,S),9(R,S)
11. A process according to claim 10, wherein a racemic mixture of -4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor-daunomycinone (3) is obtained. (12) Formula I according to claim 1 for use as an antitumor agent
or II or a pharmaceutically acceptable salt thereof. (13) A method for producing an anthracycline glycoside or a pharmaceutically acceptable salt thereof having the formula I or II according to claim 1 substantially as described in any one of Examples 7 to 9. (14) Racemic 7(R,S),9(R,S)-4-demethoxy-7-deoxy-7-hydroxymethyl-10-nor- substantially as described in Example 6 or Examples 1-6
Method for producing daunomycinone.