JPS63135391A - Novel dc-45 derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (R1 and R4 are H or methyl; R2 and R3 are H, hydroxyl group or methoxy except when R2 and R3 are H at the same time). USE:An antitumor agent. PREPARATION:For example, DC-45A2 and 2,3-dichloro-5,6-dicyano-1,4- benzoquinone are dissolved in dioxane, stirred at room temperature for 4 days, then filtered and concentrated under reduced pressure to separate residues by silica gel chromatography. A fraction corresponding to an Rf value developed using silica gel thin layer chromatography is subsequently concentrated under reduced pressure and crystallized from acetone-ether-n-hexane. The resultant crystals are then dissolved in acetone and p-toluenesulfonic acid is added. The obtained mixture is stirred at room temperature for 19hr to collect depositing crystals by filtration. The collected crystals are dissolved in chloroform and purified by silica gel chromatography to afford the aimed compound expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel derivatives of the antitumor antibiotic DC-45. The derivative has excellent antitumor activity.

Conventional Technology DC-45, represented by the following formula (n), is an antibiotic produced from a microorganism belonging to the genus Streptomyces, which has already been filed by the applicant, and has antitumor activity and antibacterial activity ( For example, JP-A-56-61398.58-
15995.58-65293 and 58-99415, etc.).

R1-HRa=)f: DC-45A
a+1)1 Furthermore, the compound represented by the following formula and its related compounds are disclosed in JP-A-60-226892 as antitumor agents and antibacterial agents.

Iu There is also an application filed by the present applicant regarding the following DC-45 type application (filed on November 2A, 1986, title of invention: DC-45 neck derivative).

Indicates a nyl group, an aralkyl group, and an aryl group.

However, Yll Y2. except when Y3 and Y4 are both hydrogen atoms].

Problems to be Solved by the Invention There is a constant need for compounds with excellent antitumor activity. As a result of various studies, we found that, unlike the above-mentioned DC-458-related substances, derivatives of the DC-45 family, in which the B ring has a quinone structure, have excellent antitumor activity and are useful as antitumor agents or intermediates for the synthesis of antitumor agents. It turns out that there is something.

Means for Solving Problem 1 The derivative of the DC-45 family having excellent antitumor activity of the present invention is represented by the following formula (1): (wherein R1 and R4 are the same or different) It represents a hydrogen atom or a methyl group, and R2 and R3 are the same or different and represent a hydrogen atom, a hydroxyl group, or a methoxy group.

However, this excludes the case where R2 and R3 are both hydrogen atoms).

Next, a method for producing the compound of the present invention will be explained.

In addition, in the description of the reaction formula below, in order to simplify the reaction formula, structures outside A and B are omitted with -], which means DC-45 derivative residues other than those listed. .

i:v' (In the formula, R means a hydrogen atom or a methyl group) (In the formula, R has the same meaning as above) (In the formula, R has the same meaning as above) Reaction formula (a) shows a method for producing the 1,4-substituted product (2) of ring A, which can be produced by maintaining compound (1) in a solvent in the presence of an acid catalyst such as p-)luenesulfonic acid or hydrochloric acid.

Reaction formula (b) shows a method for producing the 1,2,4-substituted product (4) of ring A, which can be produced by treating compound (3) with pyridinium bromide permeate in a solvent. Reaction formula (
C) shows a method for producing a 1.2-substituted product (6) of ring A, in which compound (5) is mixed with N-chloroscunnimide (NC5) 1. It is reacted with a succinimide such as N-bromosuccinimide (NBS) and a sulfide such as dimethyl sulfide, or a halogenating agent such as thionyl chloride or phosphorous pentachloride, and then a base (e.g. triethylamine, pyridine, etc.) ) can be produced by processing. Here, the compounds (1), (3), and (5) used as raw materials are new compounds, and can be produced from DC-451 represented by formula (n), as shown in the reference examples described later.

For example, DC45A2 (R7 in formula (II) above)
By oxidizing [compound =R, =H] in a solvent, [reaction formula (6)] starting compound (1) can be obtained (see Reference Example 1).As an oxidizing agent, secondary alcohol is generally used to convert carbonyl An oxidizing agent capable of converting into a DC group is used, such as permanganates, manganese dioxide, chromic acids, silver carbonate, silver oxide, organic peroxides, dimethyl sulfoxides, benzoquinones, oxygen, etc. −
By methylating 45Δ2 in a solvent, [reaction formula (e
)] Compound (7) and/or starting compound (5) are obtained (see Reference Examples 2 and 3). Methylation is carried out with alkylating agents such as methyl iodide/silver(I) oxide, diazomethane or dimethyl sulfate. Compounds (7) and (5) obtained here are further oxidized in the same manner as described above [reaction formulas (f) and ((to)]), and the raw material compound (1
) and (3) can be obtained (see Reference Example 4).
, Reaction formulas (a), (b) and (C) are obtained as described above.
In compounds (2), (4) and (6) obtained in
The unsubstituted hydroxyl group can be used as a synthetic intermediate to further lead to a new derivative by methylation as described above.

The solvent used in the reaction varies depending on the reaction mode, but there are generally no particular limitations as long as it does not participate in the reaction, such as acetone, methylene chloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methanol, ethanol, It is appropriately selected from N,N-dimethylformamide, water, etc., and used alone or in the form of a mixed solvent. The reaction temperature can generally range from cooling to the boiling point of the solvent used, and the reaction time can proceed from a few minutes to a few days. The target compound (I) is isolated and purified by extraction chromatography, crystallization, etc., which are commonly practiced.

Next, Table 1 shows the anticancer effects of representative compounds of the present invention on P388 ascites-type tumors.

Test method: 106 P388 cells were intraperitoneally transplanted into a DBA/2 mouse, the cells were collected from the ascites fluid on the 7th day, and after washing once with sterile physiological saline, 7 ml of 5X10' cells were suspended in sterile physiological saline. The liquid was adjusted. This 0.2T111 weighs 24
±2 g CDFI male mice were implanted intraperitoneally. The drug was dissolved in physiological saline or physiological saline containing Tween 80, and administered intraperitoneally once a day 24 hours after transplantation, and continuously once a day 24 hours after transplantation for 9 days. “
Note that one group consisted of 4 to 5 mice. From the survival days of each individual in the group to which the drug was administered at each concentration, the average survival days (T) in that group is calculated. On the other hand, find the average survival days (C) of the drug-free group (T-C/C) x 100 (%)
was calculated and set as the life extension rate (ILS%).

Example The present invention will be described in detail below with reference to Reference Examples and Examples.

Reference example 1 Formula (■) TeY, =Y, =y, =H,X=
0117) Compound IDC-45A22.08g and 2,
4.55 g of 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was dissolved in 4 Q ml of dioxane, stirred at room temperature for 4 days, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (elution Separate with chloroform:methanol=40:1). A fraction corresponding to the Rf value developed by silica gel thin layer chromatography (described in the Rf value section of the physical and chemical properties of each compound) is concentrated under reduced pressure (the same applies to the following Reference Examples and Examples). The condensation residue was crystallized from acetone-ether-n-hexane to obtain 0.59 g of compound 1 as a yellow powder.

oRf value 0.60 (chloroform: methanol = 9:
1) 0 UV absorption spectrum (in methanol) λ,,, (
nm) (ε): 205 (26,800), 24
5 <30.200), 274 (35,50[1
), 405 (13,800), 424 (14゜2
00)0 Infrared absorption spectrum (KBr tablet) νmax(
cm-'): 1695, 1615. 1575.
1430. 13g5. 1315. 1210°1
110, 1065.985 0PMR spectrum (in CDCjfz) (ppm)
:2.6(1(3)1.s), 2.89(1)1.
d, J=5.6), 3. Old (1) 1. d.

J=5.6>, 3.3 to 3.5 (2tl, m
), 3.44 (38,s).

3.63(38,s), 3.87(3)1. s),
4.71 (1N, s), 4.72 (IH, dd, J=
8.1.11.3), 5.03 (IH, d, J=4
．． 0).

5, 24 (ill, d, J=4.0), 7.33
(IH, d, J=0.9).

14, 15 (IH, s) ocMIt x vector (CDCf, medium > (ppm)
:2(1,4(q), 47.7(t),
49.9(t), 56.6(q), 57.
1 (q), 63.4 (q), 69. Hq), 6
9J(s), 70.0(d).

73J(cl), 99.1(d), 100. Hs
), 104.1(s).

107.7(s), 116.2(s), 118
．． 0(d),'l18.2(s).

121.4(S), 135.9(S), 143.3
(S), 148.0 (S>,.

151.0(s), 161.8(s), 192.
3(s), 201.8(s) Reference Example 2 Formula (III)
So, Yl=Y2=Y3=l(SY4=CI(3 compound view and Yl・Y4=CH3Y2=Y3=H compound view D
468 ml of methyl iodide was added to a suspension of 2.0 g of C45Az and 9.0 g of silver (I) oxide in 3 Q ml of acetone, stirred at room temperature for 5.5 hours, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography (elution) in the usual manner. Liquid: Chloroform:methanol = 40:1) l: was added, and then crystallized to give 490 mg of yellow powder Compound 2 and 230 mg of Compound 3.
Get mg. Other compounds (y+・CH,
Y, = Y, .Y, .H) 50 mg is obtained.

Compound 2 oRf value 0.39 (chloroform:methanol=15
:L) 0 Melting point 160-163℃ 0 Ultraviolet absorption spectrum (in methanol) J,,,(
nm) (g) 210 (shoulder) (15,800), 23
1 (30,800), 270 (40,700).

398 (10,700) 0 infrared absorption spectrum (Br tablet) max (Cm-
) :1620, 1570.1445.1385.
1220.1110.1075゜0 PMR spectrum (CDC (in 13-DMSO-ds) (ppm)
:2, 10 (LH, dt, J=2.9.12.7),
2.5-2.7(1)l,'m).

2.60 (3H, s), 2.79 (IH, d, J=5
．． 7), 2.86(1)1. d.

J=5.7), 3.44(3)1. s), 3.62
(3)1. s), 3.75 (3) 1゜s>, 3.93
(3H, s), 4.72 (lft, s),
4.92 (1N, d, J = 4, 2), 4.96 (IH
, dd, J=5.1.12.7), 5.23(IH
,d.

J = 4.2), 5.44 (IH, t, J = 2.9),
7.45 (LH, d, J = 1.0), 14.25 (
LH,s) OfjlR spectrum (CDCff, -DMSO-d
6) (ppm): 20.3 (q), 38.1
(t), 47.9(t), 52.7(q), 56
．． 6(q), 56.8<q), 61.2(
d), 63.0(q), 67.7(d).

68.8(d), 69. Hs), 71.2(d),
99.8 ((1).

102, Hs), 104.4(s), 107.8(
s), 114.5 X2(s, s), 116.3(
d), 130.1(S), 135.7(s).

142.2(s), 144.2(s), 151.4
(s), 166.4(s).

204,3 (s) Compound 3 oRf value 0.61 (chloroform:methanol = 15
+1>0 Melting point 214-215℃ 0 Ultraviolet absorption spectrum (in methanol) λIla (
r+m) (ε): 210 (30, 300>, 23
0 (35,500), 272 (43,500).

402 (12,200) 0 infrared absorption spectrum (KO2 tablets) max (am-
) :1620, 1570. 1445. 13
90. 1220. 1110. 1075°0P! J
R spectrum (in CDCl 3) (ppm): 2
, 24 (1N, ddd, J=3.7.11.5.1
3.2), 2.58(1)1. ddd.

J=3.7, 4.9.13.2), 2.61 (3H,
d, J=0.7), 2.84(LH, d, J=5.7
), 2.88 (E, d, J = 5.7), 3.45 (
3H.

s), 3.63(:3H,s), 3.66(3H,
s), 3.76 (3N, s).

3.9H3fl,s), 4.45(IH,dd,J=
4.9.11.5), 4.74(LH,s), 4.
85 (LH, d, J=4.2), 5.22 (Ift,
d, J=4.2).

5.44 (IH, t, J = 3.7), 7.43 (1)
1. d, J=0.7), 14.47 (LH, 5) QC! JR spectrum (in CDCj23) (ppm
) :20.4(q), 35.6(t), 48.1
(t), 52.9(q), 56.7(q), 57
．． 0(q), 59. Hq), 62.3(d), 6
2.6(q).

68.9(d), 69.2(s), 71.5(d)
, 76.6(d), 99.9(d), 102.2
(S), 104.6(s), 108.1-(s),
114.7(s), 114.8(s), 116.
0(d), 129.5(s), 135.3(s),
142.5(s), 143.9(s), 151.
6 (s), 16304 (s), 202.3 (s
) Reference example 3 In formula (III), Y,=Y3=Y,・CH,
, Y2=H Compound 4 10.0 g of DC-45A2 is dissolved in 15 Qml of acetone, 30.0 g of freshly prepared silver (I) oxide and 10 Qml of methyl iodide are added, and the mixture is stirred at room temperature for 3 hours. Thereafter, 42.1 g of a pale yellow powdery compound was obtained by the same operation as in Reference Example 2.

oRf value 0.50 (chloroform:methanol=20
:1) 0 melting point 124-128℃ 0 ultraviolet absorption spectrum (in methanol) λ,,, (
nm) (ε): 206 (shoulder) (23,600), 2
30 (35,000), 265 (42,000)
.

369 (7,800) 0 Infrared absorption spectrum (KO2 tablets) νmax (cm-
) :1695, 1620.1550.1450.
1415.1370.1330°1110, 1070.
10150 PMR spectrum (in COCl) (ppm)
:2,38 (18,dt, J=4.0.12°8)
, 2.57 (IH, ddd, J=4.0°4.9,1
2.8), 2.62 (3H, S), 2.80 (LH
, d, J=5.5).

2.86 (1) l, d, J = 5.5), 3.45 (3
H,S), 3.59 (3H,s).

3.64 (3H, s), 3.76 (3H, s), 3
．． 96 (3H, S), 3.98 (3H, S), 4.
38 (IH, 6d, J = 4°9, 12.8), 4.7
4 (IH.

s), 4.92 (lft, d, J=4.3), 5.
26 (IH, d, J=4J).

5, 47 (1)1. t, J=4.0), 7.5
2 (LH, s) OCMR spectrum (in CDCj!3) (ppm): 20.4 (Q), 36.3 (t
), 47.9(t), 52.9(q), 56.7
(q), 57.1 (ci), 58.6 (q), 6
2.5(q), 63.0(d).

64.0(q), 68.7(s), 69.0(d)
, 70.7(d), 79.0(d), 99.8
(d), 102.6(s), 104.6(s)
, 115.1(s), 116.0(d), 11
9.7(s), 121.2(s), 132.7
(s), 133.8(s), 140.3(s)
, 148.9(s), 150.0(s),
156. ．． 2(s), 196.2(s) Reference Example 4
Formula (I [I) Te, Y, = Y, = Y, = CH,, X = O Compound 5 Compound 4 obtained in Reference Example 3 (Y, .Y, =Y4.CH
3Y,=H) 1. A solution of Og and 1.0 g of pyridinium chlorochromate (pcc) in 5 Qml of methylene chloride is stirred at room temperature for 2.5 hours, then filtered and washed with water. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue is subjected to silica gel chromatography in a conventional manner and then crystallized to obtain 5280 ml of a pale yellow powdery compound.

oRf value 0.63 (chloroform:methanol=40
:1) 0 Melting point 213-216℃ 0 Ultraviolet absorption spectrum (in methanol) λ,,X(n
m) (ε): 203 (20,300), 243 (3
1,600>, 273 (42,300).

378 (8,000), 393 (8,700) ○ Infrared absorption spectrum (K8r tablet) νmax (am-')
:1700, 1615. 1565. 1450.
1410. 1370. 1335°1190, 11
15.10?0.1010.985 OPMR spectrum (CDC1, medium) (ppm): 2.65 (3H,
s), 2.82 (IH, d, J=5.5), 2
．． 90 (LH, tj, J=5.5), 3.11 (IH
, dd, J=8.3.16.9), 3.27 (IH,
dd.

J = 4.8, 16.9), 3.46 (3H, s),
3.48 (38, s), 3.64 (3) 1. s),
3.76(:3H,s), 3.98(3H,s
>, 4.00 (3) I, s).

4, 22 (LH, dd, J=4.8.8.3),
4.74 (LH, s).

4.96 (LH, d, J = 4.0), 5.28 (1
8, d, J=4.0), 7.85 (IH, S) oCMRx vector (CDC/!, medium) (ppm)
:20.3(q), 45.7(t), 47.9
(U, 52.9(q), 56.7(q),
57.1(q), 58.2(q), 63.
2(q), 64.8(q).

68.6(s), 68.9(d), 70.4(
d), 81.7(d), 99.7(d),
102.8(s), 104.7(s), 117
．． 6(s), 118.4(d), 122.0(
s), 122.7(s), 123.2(s>,
135.1(s), 140.7(s), 1
49.6(s), 153.1(s), 155.
0(s), 192.2(s), 195.3(s
) Example 1 In formula (1), R1・R3・R1・H, R3=
0) Compound 6 of 1 Compound 1 obtained in Reference Example 1 (Yl=Y3=Y,=H
1X=0) was dissolved in 5 ml of acetone, 300 mg of p-)luenesulfonic acid was added, and the
Stir for an hour. The resulting precipitate is separated, and the p solution is concentrated under reduced pressure, dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. - Condensation under reduced pressure, and the residue is separated by silica gel chromatography (eluent: chloroform:methanol = 80:1).

This is combined with the previous precipitate and crystallized from chloroform-ether-n-hexane to obtain 1 g of an orange-yellow compound 6160L1.

oRf value 0.54 (chloroform: methanol = 40
:1) 0 Melting point 186-189℃ 0 Ultraviolet absorption spectrum (in methanol) λ,...I(
nm) (ε): 204 (21,400), 232 (
51,500), 258 (20,000).

479 (10,800), 579 (1,700) 0 infrared absorption spectrum (KO2 tablets) max (am-'
) :1625, 1585.1455.1400.13
55.1300.1210°1165, 1080.9
85 0P! ,! R spectrum (CDCA 3-D!, 1SO
-66) (ppm): 2.53 (3H, s),
2.72 (IH, d, J・5.9), 2.83 (L
H, d, J = 5.9), 3.36 (3) 1. s),
3.51(3)1. s), 4.63 (ltl, s).

4, 92 (ill, d, J・3.9), 5.1
7 (LH, d, J = 3.9), 7.28 (III, d,
J=9.6), 7.30 (III, d, J=9.6)
, 7.69 (IH.

s), 12.59 (IH, s), 13.15 (IH
,s).

QC! , tR spectrum (CDCA' 3 DMSOd
a) (ppm): 19.5 (q), 47.9 (
t), 55.8X2(Q), 68.0(s).

68.4(d), 73.6(d), 99.4(s)
, 100.0(d).

104.3(S), 112.2(s), 113.2
(s), 118.1(s).

121.1(d), 125.8(S), 127
．． 7(d), 129.7(d).

134.5 (s), 147.6 (s), 152
．． 6 (s), 156.6 X2 (s, s),
185.7 (s), 186.0 (s) Example 2 In formula (I), R3・R2・ItSR,・OCH3, R4・C
1l, compound 7 and RI=R4=CH3, R2=H,
Compound 8 with R3=OCH3 Compound 6 obtained in Example 1 (R1=R2・R4・H
R3=OH) 800 ff1g to acetone l Qml
4.0 g of silver oxide (1) and 3 Qml of methyl iodide were added, and the mixture was refluxed for 5.5 hours. Thereafter, 7140 mg of an orange compound and 8400 mg of a yellow compound were obtained by the same operation as in Reference Example 2.

Compound 7 oRf value 0.62 (chloroform:methanol = 40
:1) ○Melting point 239-241℃ O ultraviolet absorption spectrum (in methanol) λ□, (nm
) (ε)=205(19,100), 231(5
0,900), 26H19,000).

466 (8,900) 0 Infrared absorption spectrum (KO2 tablets) νmax (cm-
) :1665, 1635. 1590. 14
70. 1440. 1310. 1270°1245
, 1110. 1075. 10100 PMR spectrum (in CDC1y) (ppm): 2.57 (
3H, s), 2.83 (LH, d, J=5.8),
2.93 (IH, d, J = 5.8), 3.45 (3
H,s), 3.63(3H,s), 3.76(
3)1. s).

4,00(3)1. s), 4.73(if,
s), 4.92 (LH, d, J=4.0).

5.18(1)1. d, J=4.0), 7.28(
IH, d, J = 9.5), 7.33 (IH, d, J
=9.5), 7.70(IH,s), 13.1
6 (IH, 5) QC! , lRspect/I' (CD[
l: A, medium) (ppm): 20.1 (q>,
48.0(t), 52.9(q), R6,7(q)
, 56.9(q), 57.2(q), 68J
(d), 69.0(s), 71.5(d).

99.8(d), 102.4(s), 105.
0(s), 116.7(s).

118.0s), 118.7(s), 122.
3(d), 122.4(d).

123.2(s), 126.8(d), 137
．． 0(s), 147.7(s).

151.6(s), 153.8(s), 156.9
(s), 181.2(s).

187,5 (S) Compound 8 oRf(a O,50(chloroform:methanol-
40:1) 0 Melting point 195-197℃ 0 Ultraviolet absorption spectrum (in methanol) λ,,, (n
m) (ε) 203 (24,300), 229 (3
9,300), 26N17,300).

423 (5,500) 0 Infrared absorption spectrum (KO2 tablets) νmax (cm-
) :1670, 1600.1570.1475.
1410.1330.1270°1190, 1075.
9900 PMR spectrum (in CDCl2) (ppm)
:2.55(3H,s), 2.93(IH,d,J=
5.7), 2.98 (IH, d, J=5.7>,
3.45(3)1. s), 3.62 (3H, s),
3.78 (3 fl, s).

3.95 (3H, s), 3.98 (3ft, s),
4.73 (LH, s), 4.86 (LH, d,
J=4.0), 5.17 (LH, d, J=4.0)
, 7.25 (IH.

d, J=9.2>, 7.30 (111, d, J=9
．． 2>, 7°63 (IH, s) OCMR spectrum (in CDC1y) (ppm): 19.8 (q)
, 48.0(t), 52.9(q), 56
．． 7(q), 56.9(q), 57.1(q)
, 57.2(q), 68.5(d), 68
．． 8(s).

71.2(d), 99.8(d), 102.3
(s), 105.0(s).

118.5(d), 120.2(d), 121
．． 2(d), 121.5(s).

122.4(s), 122.8(s), 125
．． 3(s), 136.6(s).

145.4(s), 150. Hs), 152.
8(s), 153.4(s>181.6(s),
183. Hs) Example 3 In formula (I), R, =R, =I
(,R,=Ko,R,=CH.

Compound 9 Compound 2 obtained in Reference Example 2 (Y+=Y2=Y*=
HY4-CH3) 100mg to methylene chloride 1Qm
PCC100a+g was added, stirred at room temperature for 3 hours, filtered, washed with water, and dried over anhydrous sulfuric acid.

The residue was concentrated under reduced pressure to obtain a residue (YI=Y3=H, Y4=CH
3. The compound with x=0) is directly dissolved in 1Qml of acetone without isolation or purification, and 100mg of p-toluenesulfonic acid is added.

After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water and dried over anhydrous sodium sulfate. - Pass through, concentrate under reduced pressure, and subject the residue to silica gel chromatography in the usual manner (eluent; chloroform:methanol = 80
: After subjecting to 1), vacuum drying is performed to obtain 928 mg of an orange powdery compound.

ORfj direct 0.59 (chloroform: methanol 10
:1) OPMR spectrum (in CDCf3) (ppm)
:2.62(3H,s), 2.85(LH,d,J
=5.5), 2.95 (III, d, J=5.
5), 3.46 (3H, s), 3.64<38. s
), 3.80 (3H, s).

4.88 (LH, cl, J=4.3), 5.20 (
IH, d, J=4J), 7.26 (18, d, J=9.
2), 7.30 (LH, d, J=9.2), 7.8
9 (LH.

s), 12.78(1)1. s), 13.27 (I
H, 5) QC! JR spectrum (in CDCf3) (p
pm): 20, Hq), 48.0 (U, 53.0
(q), 56.8 (q), 57.3 (Q>, 68
．． 2 (cl), 69. Hs), 71.6(d),
99.8(d).

102.5(s), 105.0s), 112.6
(s), 113.4(s).

118°9(s), 122. Hd), 124.6
(s), 128.1(d).

130, Hd), 135.4(s), 147.7(
s), 152.4(s).

157.5 X2 (s, s), 186.0 (s),
186.3(s) Example 4 In formula (I), R1=H, R2
-0CH3, R3”DH.

Compound 10 of R,=CH, Compound 5 obtained in Reference Example 4 (Y+=Y3=Y<=C
H3X=0) 100n+g in chloroform 10m
Add 100 mg of pyridinium perbromide and bromide, stir overnight at room temperature, wash with water, and dry with anhydrous sulfuric acid. After filtration, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (eluent; chloroform:
After subjecting the mixture to methanol=80+1), it is vacuum dried to obtain 1036 mg of a compound in the form of an orange powder.

oRf value 0.62 (chloroform: methanol = 40
:1) OPMR spectrum (in CDCf3) (ppm)
:2.59(3H,s), 2.85(1)1. d, J
= 5.5), 2.94 (IH, d, J = 5.5),
3.46 (3H, s), 3.63 (3H, s), 3
．． 80(31(,s).

3.99 (3H, s), 4.74 (1M, s), 4
．． 9HIH, d, J=4.3).

5, 18 (LH, d, J = 4.3), 6.62 (I
H,s), 7.82 (IH,s).

13.45(1)1. s), 13.87(ltl, s
)OCUR spectrum (in CDCf3) (ppm)
:20, Hq), 48.0(t), 53. Hq)
, 56.7(q), 56.8(q), 57.3(
q), 68.2(d), 69.0(s>, 71.
5(d).

99.8 (+j), 102.5 (s), 105.1
(s), 105.8(d).

106.0(s), 112.9(s), 118.7
(s), 121.9(d).

123.8(s), 136.1(s), 147.7
(s), 150. Hs).

152.4(s), 158.3(s), 160.6
(s), 183.4 (S).

186,2 (s> Example 5 Formula (I> with R,=L=)l SR,=OCH
,,R,=C1-13 Compound 11 200 mg of N-chloroscunnimide was dissolved in methylene chloride 5
ml of dimethyl sulfide under water cooling.
After adding, it was further cooled to -20°C, and compound 3 obtained in Reference Example 2 (Yl=Y4=CH3, Y2=Yj=H)1
Add a solution of 3 ml of methylene chloride in which 00 mg of
Stir at the same temperature for 4 hours. Then triethylamine 0,
Add 1 ml and let stand under water cooling day and night. After washing with water and drying with anhydrous sodium sulfate, it was filtered and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography in the usual manner (eluent: chloroform;
Methanol = 60:1) and then crystallized with chloroform-ether-n-hexane to give a clear-colored compound 11.
Obtain 26 mg.

0RfiO,60 (chloroform:methanol=40:
1) OPMR spectrum (in CDCf3) (ppm)
:2.58(3H,s), 2.87(II(,d,J
=5.5>, 2.96 (IH, d, J=5.5),
3.46 (3H, s), 3.63 (3H, s), 3
．． 81 (3H, s).

4.01 (3H, s), 4.74 (IH, s), 4
．． 90 (III, d, J=4.1).

5, 19 (IH, d, J=4.1), 7.12 (1
)1. d, J=8.5), 7.78(LH, d,
J=8.5), 7.79(LH,s), 13.4
1(LH,s)○C1JRx Vector (CDCf3 medium) (ppm): 20.1(q), 48.0(t
), 53.0(q), 56.4(q), 56.8
(s>, 57.3(s), 68.3(d), 69
．． 0(s>, 71.4(d).

99, 8(d), 102.6(s), 105.0s
), 115.2(d).

116.7(s), 118.8(s), 120.
4(+J), 122.5(d).

123.9(s), 124.5(s), 136
．． 0(s), 147.9(s).

152.3(s), 152.7(s), 154
．． 5(s), 181.0(s).

188,0 (S) Example 6 In formula (1), R, =R, =CH3, R2・0C
Compound 12 with II3, R,=H Compound 11 obtained in Example 5 (R, ・R3=H,
R, -QC)1. , R4=CH3) was dissolved in 75ml of acetate, 500mg of silver(I) oxide and 1ml of methyl iodide were added, and the mixture was refluxed for 1 hour. Thereafter, 12,100 mg of a yellow compound was obtained using the same method as in Reference Example 2.

oRfl 0.52 (chloroform: methanol = 4
0: 1) 0 melting point = 210-212℃ ○Ultraviolet absorption spectrum (in methanol) λmax (
nm) (ε): 229 (33,400), 270 (
27,900), 37N10,200)O infrared absorption spectrum (KBr tablet) max (cm-'): 1
675, 1600. 1580. 1485. 14
50. 1340. 1265°1090, 985 0 PMR spectrum (COCl, medium) (ppm)
:2,55 (3)1. s), 2.93 (LH
, d, J=5.5), 2.96(1)1. d, J=
5.5>, 3.46 (3H, s), 3.62 (3H
,s), 3.79(3H,s).

3.97 (3H, s), 3.99 (3) 1. s),
4.73 (IH, s), 4.88 (LH, d, J=4
．． 0), 5.18(1)1. d, J=4.0), 7
．． 20 (III, d.

J=8.8), 7.71 (IH, s), 8.02.
(LH, d, J=8.8)QC)4R spectrum (CD
(in Cl2) (ppm): 19.8(q), 48
．． 1(t), 52.9(q), 56.3(q),
56.7(q), 57.2(q), 61.
6(q), 68.5(d), 68.9(s).

71.3(d), 99.8(d), 102.3
(s), 105.0(s).

115.3(d), 121.4(d), 122
．． 0(s), 123.6(s).

124.6(d), 126.4(s), 129
．． Hs), 135. Hs).

L45.7 X2 (s, s), 150.9 (
s), 159.2(s).

181.3(s), 182. Hs) Effects of the Invention Compound (I) has excellent antitumor activity and is useful as an antitumor agent.

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_4 are the same or different and represent a hydrogen atom or a methyl group, and R_2 and R_3 are the same or different. Differently indicates a hydrogen atom, hydroxyl group, or methoxy group (except when R_2 and R_3 are hydrogen atoms at the same time)
A novel DC-45 derivative represented by