JP3536574B2 - Antineoplastic indolopyrrolocarbazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention is useful in the field of medicine, and more particularly, relates to a novel indolopyrrolocarbazole derivative which inhibits the growth of tumor cells and exhibits an antitumor effect, a method for producing the same, and a use thereof. .

[0002]

2. Description of the Related Art In the field of cancer chemotherapy, many compounds have already been put into practical use as medicaments. However, its effect on various types of tumors is not always satisfactory, and the problem of tumor cell resistance to these drugs also complicates clinical use [47th Annual Meeting of the Japanese Cancer Society, 12-15 (1988)].

[0003] Under such circumstances, in the field of cancer treatment, there is a constant demand for the development of new regulated cancer substances. In particular, there is a need for a substance that overcomes resistance to existing anticancer substances and is effective against cancers of a type in which the existing anticancer substances are not sufficiently effective.

In view of such circumstances, the present inventors have screened a wide range of microbial metabolites and found that a novel compound BE-13793C (12,13) having antitumor activity was obtained.
-Dihydro-1,11-dihydroxy-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole-
5,7 (6H) -dione) (see EP-A-0388956A2).

[0005] Thereafter, BE-13793C was chemically modified to create a compound having more excellent antitumor activity.
528030A1, European Patent Publication 05451
95A1, WO95 / 30682 and WO96 / 042
93).

[0006]

The problem to be solved by the present invention is to chemically modify the indolopyrrolocarbazole-based antitumor substance disclosed in the previous patent application to create a compound having more excellent antitumor activity. This is an issue to be tried.

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have widely synthesized indolopyrrolocarbazole derivatives and studied their antitumor activity. The present invention has been completed by finding that the compound exhibits an even better antitumor effect than the indolopyrrolocarbazole compound disclosed in the above-mentioned patent application.

That is, the present invention relates to the general formula

[0009]

Embedded image [Wherein, R represents a phenyl group, a pyridyl group, a furyl group, or a thienyl group having one or two substituents selected from the group consisting of a hydroxy group, a lower alkoxy group, a hydroxy lower alkyl group and a hydroxy lower alkenyl group; ,
When it has a lower alkoxy group as a substituent, it has another substituent selected from the group consisting of a hydroxy group, a lower alkoxy group, a hydroxy lower alkyl group and a hydroxy lower alkenyl group), and m is 1 to
3 represents an integer, G represents a β-D-glucopyranosyl group, and the substitution position of the hydroxy group on the indolopyrrolocarbazole ring is 1-position and 11-position or 2-position and 10-position]. The present invention relates to pharmaceutically acceptable salts and uses thereof.

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

The indolopyrrolocarbazole derivatives of the present invention are disclosed in European Patent Publication No. 0528030A1, European Patent Publication No. 0545195A1, WO95 /
30682 and known compounds described in WO96 / 04293,

[0012]

Embedded image [Wherein A represents NH or H, and G has the above-mentioned meaning]

[0013]

Embedded image Wherein R and m have the above-mentioned meanings, or

[0014]

Embedded image Wherein G has the meaning described above, and a compound represented by the general formula:

[0015]

Embedded image Wherein R ¹ has the same meaning as R or a group in which the hydroxyl group contained in R is protected, and m has the above-mentioned meaning, condensed, then reduced, and If necessary, the compound is produced by removing a protecting group, or a compound of the general formula IV]

[0016]

Embedded image [Wherein L represents a leaving group, and R ¹ and m have the same meanings as described above], and the protective group is removed if necessary. be able to.

The reaction between the compound represented by the general formula [II] and the compound represented by the general formula [III] is a reaction between an imide or an acid anhydride widely known in the field of chemistry and a hydrazine derivative. This reaction can be carried out usually using a solvent which does not adversely influence the reaction, for example, tetrahydrofuran, N, N-dimethylformamide and the like, and the compound [II
The amount of I] to be used is generally a small excess to 5 molar equivalents relative to compound [II], but if necessary, a large excess can be used.

The reaction temperature is usually in the range of -50 ° C. to the boiling point of the solvent, and a higher or lower temperature can be selected as necessary. The reaction time is usually in the range of 30 minutes to 2 days, but may be longer or shorter as necessary.

The reaction of condensing the compound represented by the general formula [IV] and the compound represented by the general formula [V] and then reducing the same to produce the compound [I] may be carried out in the same reaction system. However, in some cases, the intermediate product, the Schiff base, can be isolated once. That is, it can be generally carried out by mixing the compound [IV] and the compound [V] in an appropriate solvent, and then adding a reducing agent. At this time, the reaction is preferably performed in the presence of an acid such as acetic acid or hydrochloric acid. Examples of the solvent that can be used here include alcohol solvents such as methanol and ethanol, and aprotic polar solvents such as N, N-dimethylformamide. The Schiff base can be reduced using a metal hydride complex such as sodium cyanoborohydride or the like, but can also be performed by a catalytic reduction method.

The compound of the general formula [IV] and the compound of the general formula [V
The reaction of I] is an alkylation reaction of an amine, and can be performed by a known method, for example, a reaction with an alkyl halide, an alkyl mesylate, an alkyl tosylate, or the like.

The product of the above reaction can be obtained by a known method in the field of synthetic organic chemistry, for example, a precipitation method, a solvent extraction method,
It can be purified by recrystallization, chromatography or the like.

The present invention further includes a pharmaceutically acceptable salt of the compound obtained by the above method. Such salts include, for example, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium,
Or salts with basic organic compounds such as ethylamine and arginine, for example, salts with inorganic acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acetic acid, citric acid and maleic acid.

The compound represented by the formula [I] of the present invention has an excellent antitumor effect.

Effect on human gastric cancer MX-1 The MX-1 solid tumor which had been transplanted in advance into nude mice subcutaneously and proliferated was cut into small pieces, and 3 mm squares were subcutaneously transplanted into test mice. After transplantation, each amount of the test drug was injected into the tail vein of the mouse once a day for 5 consecutive days from the time when the tumor grew to 0.3 cm ³ , and then injected for another 5 days after 2 days off (treatment schedule:
5 / w × 2) or 4 injections every 3 to 4 days (treatment schedule: 2 / w × 2) for treatment. Twenty or 32 days after the start of treatment, the major axis (L) and minor axis (W) of the tumor were measured, and the volume (V) was determined (V = （× L ×
W ² ). The tumor growth inhibition rate was calculated from this volume, and the total dose (GID ₇₅ , mg / kg) that inhibited tumor growth by 75%
I asked. As a reference compound, the compound of formula

[0025]

Embedded image Was used. The results are shown in Table 1.

[0026]

[Table 1] The compounds provided by the present invention have a
As shown in the above-mentioned pharmacological test results, it shows more excellent antitumor activity.

As is apparent from the results of the above pharmacological tests, the compounds of the present invention exhibit excellent antitumor activity and are useful as antitumor agents for the prevention and treatment of diseases, particularly for the treatment of cancer. is there. When the compound of the present invention is used as an antitumor agent, various forms can be selected, for example, oral preparations such as tablets, capsules, powders, granules or liquids, or sterilization such as solutions or suspensions. Liquid parenteral preparations.

The solid preparation can be prepared as it is in the form of tablets, capsules, granules or powder, but can also be prepared using appropriate additives. Such additives include, for example, sugars such as lactose or glucose, starches such as corn, wheat or rice, fatty acids such as stearic acid, inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate, such as polyvinyl chloride Synthetic polymers such as pyrrolidone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose And other commonly used additives such as water, gelatin, talc, vegetable oil, and gum arabic.

The solid preparations such as tablets, capsules, granules and powders generally contain 0.1 to 100% by weight, preferably 5 to 100% by weight of the active ingredient.

The liquid preparation is prepared by using an appropriate additive usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil or sesame oil, and is used as a suspension, syrup or injection. And so on.

Suitable solvents for parenteral administration by intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological saline, Examples thereof include an aqueous glucose solution, ethanol, polyethylene glycol, a liquid for intravenous injection (for example, an aqueous solution of citric acid and sodium citrate) or an electrolyte solution (for intravenous drip and intravenous injection), and a mixed solution thereof.

These injections have been previously dissolved,
It may be in the form of a powder or a solution to which an appropriate additive is added, which is dissolved at the time of use. These injections are usually 0.1 to
It contains 10% by weight, preferably 1-5% by weight, of active ingredient.

A liquid preparation such as a suspension or syrup for oral administration contains 0.5 to 10% by weight of an active ingredient.

It should be noted that the actual preferred dosage of the compounds of the present invention will vary with the type of compound used, the type of composition formulated, the frequency of application and the particular site to be treated, the host and the tumor. It is. For example, the daily dose per adult is 10% for oral administration.
Parenteral administration, preferably 10 to 100 mg per day for intravenous injection.
The number of administrations varies depending on the administration method and symptoms.
Times to 5 times. In addition, administration methods such as intermittent administration such as alternate day administration and alternate day administration can also be used.

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION

[0036]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

The compounds having the following structural formulas used as raw materials in the examples are abbreviated as follows.

[0038]

Embedded image In the formula, G represents a β-D-glucopyranosyl group. The same applies to the following examples. Example 1 Structural formula

[0039]

Embedded image A compound represented by the formula:

Compound A (25 mg) and (2-tert-butyldimethylsilyloxymethyl) benzyl bromide (90 mg) were dissolved in N, N-dimethylformamide (1 ml) and stirred at room temperature overnight. The residue obtained by drying the reaction solution under reduced pressure was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target substance is concentrated, and Sephadex L
The product was applied to a H-20 chromatography column and eluted with methanol. The fraction containing the desired compound was concentrated to dryness, and the residue was washed with chloroform to give the compound of the title formula 3.6m
g was obtained. FAB chromatography MS (m / z): 655 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.78 (1H,
s), 9.75 (1H, s), 8.86 (1H, d, J
= 8.6 Hz), 8.78 (1H, d, J = 8.2H)
z), 7.44 (1H, d, J = 7.2 Hz), 7.3
7 (1H, d, J = 7.6 Hz), 7.13-7.28
(3H, m), 6.98 (1H, s), 6.78-6.
88 (2H, m), 5.95-6.05 (2H, m),
5.85 (1H, br), 5.33 (1H, d, J =
3.2Hz), 5.10-5.17 (2H, m), 4.
92 (1H, d, J = 4.0 Hz), 4.28 (2H,
d, J = 5.2 Hz), 3.72-4.10 (4H,
m), 3.45-3.55 (2H, m) Example 2 Structural formula

[0041]

Embedded image A compound represented by the formula: 30 mg of Compound A and 30 mg of (5-tert-butyldimethylsilyloxymethylthiophene) -2-carboxaldehyde were dissolved in 6 ml of methanol, 30 ml of acetic acid was added, and the mixture was stirred at 80 ° C. for 4 hours. Cool the reaction to room temperature and add sodium cyanoborohydride 2
0 mg, 200 ml of 10% methanolic hydrochloric acid solution were added,
Stirred at room temperature for 30 minutes. The residue obtained by drying the reaction solution under reduced pressure was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 27 mg of the compound represented by the title formula. Rf value: 0.37 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 660 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.19 (1H, s), 9.79 (1H,
s), 9.75 (1H, s), 8.86 (1H, d, J
= 9.3 Hz), 8.78 (1H, d, J = 9.0H)
z), 7.17 (1H, d, J = 2.1 Hz), 6.9
7 (1H, d, J = 2.1 Hz), 6.89 (1H,
d, J = 3.6 Hz), 6.82 (1H, dd, J =
2.1, 9.3 Hz), 6.79 (1H, dd, J =
2.1, 9.0 Hz), 6.73 (1H, d, J = 3.
3 Hz), 6.10 (1H, t, J = 4.5 Hz),
5.97 (1H, d, J = 8.1 Hz), 5.86 (1
H, t, J = 3.3 Hz), 5.35 (1H, t, J =
6.0Hz), 5.32 (1H, d, J = 4.8H)
z), 5.12 (1H, d, J = 4.8 Hz), 4.9
2 (1H, d, J = 5.4 Hz), 4.52 (2H,
d, J = 5.7 Hz), 4.40 (2H, d, J = 4.
2Hz), 4.02 (1H, m), 3.91 (2H,
m), 3.78 (1H, m), 3.50 (2H, m) Example 3 Structural formula

[0042]

Embedded image A compound represented by the formula: 100 mg of Compound A and 131.2 mg of 3,5-dihydroxybenzaldehyde were dissolved in 10 ml of N, N-dimethylformamide and stirred at 80 ° C. for 48 hours. After the reaction solution was concentrated under reduced pressure, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 90.3 mg of the intermediate compound. 20 mg of this intermediate compound was suspended in 5 ml of methanol, and 10 ml of sodium cyanoborohydride was suspended.
g, a few drops of 10% methanolic hydrochloric acid solution,
Stirred for 0 minutes. After methanol was distilled off under reduced pressure, water was added.
Extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated, and the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound was concentrated to dryness to give the compound 18 represented by the title formula.
mg was obtained. Rf value: 0.30 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 657 (M + H ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.19 (1H, s), 9.77 (2H, b
r), 9.11 (2H, s), 8.87 (1H, d, J
= 8.6 Hz), 8.79 (1H, d, J = 8.6H)
z), 7.17 (1H, s), 6.97 (1H, s),
6.78-6.84 (2H, m), 6.34 (2H,
s), 6.06 (1H, s), 5.96 (1H, d, J
= 8.3 Hz), 5.83 to 5.87 (2H, m),
5.34 (1H, s), 5.12 (1H, s), 4.9
2 (1H, d, J = 3.9 Hz), 4.04 (2H,
d, J = 4.5 Hz), 3.91 to 3.99 (3H,
m), 3.75 to 3.88 (1H, m), 3.49 (2
H, s) Example 4 Structural formula

[0043]

Embedded image A compound represented by the formula: Compound A (30 mg) and 4-hydroxybenzaldehyde (14 mg) were dissolved in methanol (6 ml), acetic acid (14 ml) was added, and the mixture was stirred at 80 ° C. for 2 hours. Cool the reaction to room temperature and add sodium cyanoborohydride 2
0 mg, 200 ml of 10% methanolic hydrochloric acid solution were added,
Stirred at room temperature for 1 hour. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to give 31 mg of the compound represented by the title formula. Rf value: 0.41 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 640 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.17 (1H, s), 9.77 (1H,
s), 9.74 (1H, s), 9.24 (1H, s),
8.86 (1H, d, J = 8.4 Hz), 8.78 (1
H, d, J = 8.4 Hz), 7.25 (2H, d, J =
8.7 Hz), 7.17 (1H, d, J = 1.8H)
z), 6.97 (1H, d, J = 1.8 Hz), 6.8
3 (1H, dd, J = 1.8, 8.7 Hz), 6.80
(1H, dd, J = 1.8, 8.7 Hz), 6.67
(2H, d, J = 8.1 Hz), 5.96 (1H, d,
J = 8.1 Hz), 5.87 (1H, t, J = 4.8H)
z), 5.85 (1H, t, J = 3.9 Hz), 5.3
2 (1H, d, J = 4.5 Hz), 5.10 (1H,
d, J = 5.1 Hz), 4.91 (1H, d, J = 4.
8Hz), 4.12 (2H, m), 4.03 (1H,
m), 3.91 (2H, s), 3.78 (1H, m),
3.50 (2H, m) Example 5 Structural Formula

[0044]

Embedded image A compound represented by the formula: Compound A (30 mg) and 3,5-dihydroxymethylbenzaldehyde (20 mg) were dissolved in methanol (6).
The mixture was dissolved in acetic acid (20 ml), acetic acid (20 ml) was added, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was returned to room temperature, 10 mg of sodium cyanoborohydride and several drops of a 10% methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol.
The fraction containing the desired product was concentrated to dryness to obtain 22 mg of the compound represented by the above formula. Rf value: 0.35 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 684 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.19 (1H, s), 9.79 (1H,
s), 9.76 (1H, s), 8.88 (1H, d, J
= 8.7 Hz), 8.80 (1H, d, J = 8.7H)
z), 7.32 (2H, s), 7.18 (2H, s),
6.98 (1H, d, J = 1.8 Hz), 6.81 (2
H, dt, J = 1.8, 8.7 Hz), 5.97 (1
H, d, J = 8.7 Hz), 5.93 (1H, t, J =
4.8 Hz), 5.87 (1H, t, J = 3.2H)
z), 5.34 (1H, d, J = 4.2 Hz), 5.1
5 (2H, t, J = 6.3 Hz), 5.12 (1H,
d, J = 4.8 Hz), 4.92 (1H, d, J = 4.
8 Hz), 4.49 (2H, s,), 4.47 (2H,
s), 4.22 (2H, d, J = 5.1 Hz), 4.0
3 (1H, m), 3.92 (2H, s), 3.78 (1
H, m), 3.50 (2H, m) Example 6 Structural formula

[0045]

Embedded image A compound represented by the formula: 53 mg of Compound B and 69 mg of 3,5-dihydroxybenzaldehyde were dissolved in 3 ml of N, N-dimethylformamide and stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, dissolved in 10 ml of methanol, an excess amount of sodium cyanoborohydride, 0.5 ml of a 10% methanol solution of hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes.
After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with a mixed solvent of ethyl acetate / methyl ethyl ketone. The organic layer was washed with saturated saline, and then dried and concentrated. Residue is Sephadex LH-2
This was eluted with methanol by applying to a chromatography column of No. 0. The fraction containing the desired product was concentrated to dryness to obtain 4.8 mg of the compound represented by the title formula. Rf value: 0.2 (Merck Kieselgel 60
F ₂₅₄ , developing solvent; chloroform: methanol = 3:
1) FAB chromatography MS (m / z): 657 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 10.89 (1H, s), 10.33 (1H, b
r), 9.97 (1H, br), 9.11 (1H,
s), 8.70 (1H, d, J = 6.8 Hz), 8.5
2 (1H, d, J = 7.7 Hz), 7.15 to 7.21
(2H, m), 6.98-7.06 (3H, m), 6.
36 (2H, d, J = 1.9 Hz), 6.06 (1H,
s), 5.91 (1H, t, J = 5.4 Hz), 5.4
1 (1H, d, J = 5.6 Hz), 5.30 to 5.45
(1H, m), 5.20 (1H, d, J = 4.6H)
z), 4.87 (1H, m), 3.94-4.10 (4
H, m), 3.56 to 3.77 (3H, m), 3.38.
~ 3.43 (2H, m) Example 7 Structural formula

[0046]

Embedded image A compound represented by the formula: Compound C (30 mg) and 3- (3-hydroxypropenyl) benzylhydrazine trifluoroacetate (30 mg) were added to N, N-dimethylformamide (2 m).
, and several drops of triethylamine were added, followed by stirring at 80 ° C. overnight. After the reaction solution was concentrated to dryness, the residue was subjected to preparative thin-layer chromatography (developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.
5: 0.1). 8.2 mg of the compound represented by the title formula was obtained. Rf value: 0.51 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.18 (1H, s), 9.50-10.00
(2H, br), 8.86 (1H, d, J = 8.1H)
z), 8.78 (1H, d, J = 8.5 Hz), 7.5
9 (1H, s), 7.20 to 7.40 (3H, m,),
7.16 (1H, s), 6.97 (1H, s), 6.7
3 to 6.89 (2H, m), 6.42 (1H, d, J =
3.6 Hz), 6.31 to 6.48 (1H, m),
10 (1H, t, J = 4.0 Hz), 5.95 (1H,
d, J = 7.9 Hz), 5.88 (1H, br,),
5.36 (1H, br), 5.13 (1H, br),
4.91 (1H, br), 4.84 (1H, br),
4.26 (2H, s), 4.09 (2H, s), 3.7
0 to 4.10 (4H, m), 3.41 to 3.58 (2
H, m) Example 8 Structural formula

[0047]

Embedded image A compound represented by the formula: Compound 45.5 mg and 3-hydroxymethylbenzylhydrazine trifluoroacetate 6
Dissolve 7.2 mg in 3 ml of N, N-dimethylformamide, add a few drops of saturated aqueous sodium hydrogen carbonate solution,
Stirred at 70 ° C. overnight. The reaction solution was diluted with methyl ethyl ketone, washed with dilute hydrochloric acid, water, and saturated saline, and dried and concentrated. The residue was roughly purified by preparative thin-layer chromatography (developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.1) and then applied to a Sephadex LH-20 chromatography column. Eluted with methanol. By concentrating and drying the fraction containing the target substance,
1.6 mg of the compound represented by the title formula was obtained. Rf value: 0.40 (Merck Kieselgel 60F)
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 654 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.18 (1H, s), 8.86 (1H, d,
J = 8.4 Hz), 8.78 (1H, d, J = 8.7H)
z), 7.42 (1H, s), 7.40 (1H, d, J
= 7.5 Hz), 7.27 (1H, t, J = 7.2H)
z), 7.18 (1H, d, J = 7.5 Hz), 7.1
7 (1H, s), 6.98 (1H, d, J = 1.8H)
z), 6.81 (2H, dt, J = 1.8, 8.1H
z), 6.00 (1H, dt, J = 1.5, 4.8H)
z), 5.95 (1H, d, J = 8.7 Hz), 5.4
3 (1H, br), 5.16 (2H, br), 4.93
(1H, br), 4.47 (2H, s), 4.25 (1
H, d, J = 4.8 Hz), 4.10 (1H, br),
4.02 (1H, d, J = 10.8 Hz), 3.90
(2H, m), 3.76 (1H, m) Example 9 Structural formula

[0048]

Embedded image A compound represented by the formula: Compound D (30 mg) and 3- (3-hydroxypropenyl) benzylhydrazine trifluoroacetate (40 mg) were added to N, N-dimethylformamide (1 ml).
And triethylamine (0.5 ml) was added,
Stirred at 0 ° C. for 1.5 hours. The reaction solution was diluted with a mixed solvent of ethyl acetate / methyl ethyl ketone, washed with dilute hydrochloric acid and saturated saline, and dried and concentrated. Residue is separated by Sephadex LH
It was eluted with methanol on a -20 chromatography column. The fraction containing the target substance was concentrated, applied again to a Sephadex LH-20 chromatography column, and eluted with ethanol. The fraction containing the desired product was concentrated to dryness to obtain 7.8 mg of the compound represented by the title formula. Rf value: 0.48 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 10.89 (1H, s), 10.35 (1H, b
r), 9.95 (1H, br), 8.70 (1H, d,
J = 7.8 Hz), 8.52 (1H, d, J = 7.8H)
z), 7.60 (1H, s), 6.91 to 7.40 (8
H, m), 6.53 (1H, d, J = 16.2 Hz),
6.39 (1H, td, J = 4.6, 16.2 Hz),
6.16 (1H, t, J = 5.6 Hz), 5.41 (1
H, d, J = 5.6 Hz), 5.35 (1H, br),
5.20 (1H, d, J = 4.9 Hz), 4.86 (1
H, t, J = 3.6 Hz), 4.84 (1H, t, J =
5.6 Hz), 4.28 (2H, s), 3.89-4.
12 (4H, m), 3.30 to 3.78 (4H, m) Example 10 Structural Formula

[0049]

Embedded image A compound represented by the formula: Compound C (100 mg) and 4-hydroxymethylbenzylhydrazine hydrochloride (100 mg) were added to N,
It was dissolved in 5 ml of N-dimethylformamide, and 0.5 ml of a saturated aqueous solution of sodium hydrogencarbonate was added. The mixture was stirred at room temperature for 1 hour and at 80 ° C. for 30 minutes. The reaction solution was diluted with methyl ethyl ketone, washed with 2N hydrochloric acid and saturated saline, and dried and concentrated. The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound is concentrated to dryness to give the compound 3 represented by the title formula.
3 mg were obtained. Rf value: 0.47 (manufactured by Merck, Kieselgel 60F)
_254, developing solvent; chloroform: methanol: tetrahydrofuran = 2: 1: 1) FAB chromatography MS (m / z): 655 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.10 (1H, br), 8.83 (1H,
d, J = 9.3 Hz), 8.73 (1H, d, J = 8.
4 Hz), 7.44 (2H, d, J = 8.4 Hz),
7.23 (2H, d, J = 7.8 Hz), 7.11 (1
H, s), 6.94 (1H, s), 6.78 (2H, d
t, J = 9.0, 2.1 Hz), 6.02 (1H, t,
J = 4.8 Hz), 5.92 (1H, d, J = 8.1H)
z), 4.80-5.23 (2H, br), 4.43.
(2H, s), 4.24 (2H, s), 4.03 (1
H, m), 3.90 (2H, m), 3.77 (1H,
m), 3.50 (2H, m), 3.25 to 3.42 (3
H, m) Example 11 Structural Formula

[0050]

Embedded image A compound represented by the formula: 52 mg of compound C and 61.4 mg of 3-methoxy-4-hydroxybenzylhydrazine hydrochloride
Was dissolved in 2 ml of N, N-dimethylformamide, and 0.5 ml of a saturated aqueous sodium hydrogencarbonate solution was added thereto.
Stirred at C for 1 hour. After the reaction solution was concentrated to dryness, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 20 mg of the compound represented by the title formula. Rf value: 0.33 (Merck Kieselgel 60F
_254, developing solvent; chloroform: methanol: tetrahydrofuran = 3: 1: 1) FAB chromatography MS (m / z) :( M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.12 (1H, s), 9.77 (1H,
s), 9.74 (1H, s), 8.86 (1H, s),
8.78 (1H, d, J = 8.6 Hz), 8.76 (1
H, s), 7.16 (2H, d, J = 8.1 Hz),
6.97 (1H, s), 6.70-6.85 (3H,
m), 6.64 (1H, d, J = 8.5 Hz), 5.8
6 to 6.04 (2H, m), 5.85 (1H, t, J =
3.6Hz), 5.32 (1H, d, J = 3.9H)
z), 5.10 (1H, d, J = 4.2 Hz), 4.9
0 (1H, d, J = 4.3 Hz), 4.11 to 4.21
(2H, m), 3.86-4.10 (4H, m), 3.
77 (3H, m), 3.35 to 3.52 (2H, m) Example 12 Structural Formula

[0051]

Embedded image A compound represented by the formula: Compound C (40 mg) and 3-hydroxy
31 mg of benzylhydrazine hydrochloride was added to N, N-dimethyl
Dissolve in 2 ml of tylformamide and add saturated sodium bicarbonate
0.5 ml of an aqueous solution of sodium chloride and stirred at 80 ° C. overnight.
Was. Dilute the reaction solution with ethyl acetate, add 2N hydrochloric acid,
After washing with aqueous sodium hydrogen solution and saturated saline, dry concentration
did. The residue is placed on a Sephadex LH-20 chromatography column.
And eluted with methanol. Concentrate and dry fractions containing the desired product
By solidification, the compound 17.2 of the title formula is obtained.
mg was obtained. Rf value: 0.24 (Merck Kieselgel 60F
₂₅₄, Developing solvent; acetonitrile: tetrahydrofura
: Toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 641 (M + H )^{+ 1} H-NMR (300 MHz, DMSO-d₆, Δpp
m): 11.18 (1H, s), 9.76 (1H,
s), 9.73 (1H, s), 9.28 (1H, s),
8.87 (1H, d, J = 8.5 Hz), 8.79 (1
H, d, J = 9.0 Hz), 7.17 (1H, s),
7.18 (1H, dd, J = 7.5, 8.0 Hz),
6.97 (1H, d, J = 2.3 Hz), 6.78-
6.93 (4H, m), 6.60 (1H, dd, J =
1.5, 8.0 Hz), 5.96 (2H, m), 5.8
5 (1H, m), 5.30 (1H, d, J = 4.2H)
z), 5.09 (1H, d, J = 4.9 Hz), 4.9
0 (1H, d, J = 5.1 Hz), 4.15 (2H,
s), 3.72 to 4.05 (4H, m), 3.50 (2
H, m) Example 13 Structural formula

[0052]

Embedded image A compound represented by the formula: 43 mg of compound A and (3-t
Dimethylsilyloxymethyl) -3-pyridinecarba
Suspend 100 mg of aldehyde in 10 ml of methanol and add vinegar
After adding 18 ml of acid and stirring at 80 ° C. overnight,
Concentrate the solution and transfer it to the Sephadex LH-20 chromatography column.
And eluted with methanol. Concentrate the fraction containing the target substance to dryness
And the residue was treated with methanol / tetrahydrofuran (1:
1) Dissolve in 5 ml of a mixed solvent and add 5% palladium carbon.
Then, the mixture was stirred at room temperature for 3.5 hours under a hydrogen stream. Reaction solution
Filter through celite and dissolve the residue in 5 ml of tetrahydrofuran.
Disassembled and excess tetrabutylammonium fluoride
(1.0 M tetrahydrofuran solution), and
Stirred for 0 minutes. Concentrated Sephadex LH-20
The mixture was applied to a chromatography column and eluted with methanol. Minute including target
The mixture is concentrated to dryness to give the compound of the formula
4.3 mg of the product were obtained. Rf value: 0.1 (manufactured by Merck, Kieselgel 60)
F₂₅₄, Developing solvent; acetonitrile: tetrahydrofura
: Toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 656 (M + H )^{+ 1} H-NMR (300 MHz, DMSO-d₆, Δpp
m): 11.18 (1H, s), 9.75 (1H,
s), 9.73 (1H, s), 8.84 (1H, d, J
= 8.4 Hz), 8.77 (1H, d, J = 8.9H)
z), 8.42 (1H, d, J = 4.9 Hz), 8.3
9 (1H, s), 7.48 (1H, d, J = 4.9H)
z), 7.17 (1H, d, J = 1.1 Hz), 6.9
7 (1H, s), 6.78 to 6.83 (2H, m), 6
09 (1H, t, J = 4.7 Hz), 5.97 (1H,
d, J = 6.6 Hz), 5.84 (1H, t, J = 3.
8Hz), 5.39 (1H, t, J = 5.8Hz),
5.30 (1H, d, J = 4.8 Hz), 5.09 (1
H, d, J = 4.2 Hz), 4.95 (2H, d, J =
5.3Hz), 4.90 (1H, d, J = 3.3H)
z), 4.27 (2H, d, J = 4.2 Hz), 3.7
5 to 4.03 (4H, m), 3.47 to 3.52 (2
H, m) Example 14 Structural formula

[0053]

Embedded image A compound represented by the formula: 98 mg of compound A and 92.1 mg of 4- (3-t butoxymethyl) pyridine carbaldehyde
Was dissolved in 5 ml of methanol, and 18 ml of acetic acid was added.
After stirring at 0 ° C. overnight, the reaction solution was concentrated, and the obtained crystals were washed with chloroform. This was dissolved in a mixed solvent of methanol / tetrahydrofuran (1: 1), 5% palladium carbon was added, and the mixture was stirred under a hydrogen stream for 3 hours. After filtration through celite and concentration, the residue was dissolved in tetrahydrofuran, tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, the mixture was extracted with methyl ethyl ketone, and the organic layer was washed with saturated saline and concentrated. The mixture was applied to a Sephadex LH-20 chromatography column and eluted with methanol. . The fraction containing the desired product was concentrated and dried to give 13.5 mg of the compound represented by the above formula. Rf value: 0.10 (Merck Kieselgel 60F
_254, developing solvent; chloroform: methanol: tetrahydrofuran = 2: 1: 1) FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.78 (1H,
s), 9.75 (1H, s) 8.85 (1H, d, J =
9.1 Hz), 8.77 (1H, d, J = 9.1H)
z), 8.51 (1H, s), 8.11 (1H, d, J
= 5.1 Hz), 7.59 (1H, d, J = 4.6H)
z), 7.17 (1H, d, J = 2.1 Hz), 6.9
7 (1H, d, J = 1.8 Hz), 6.79 to 6.85
(2H, m), 6.25 (1H, t, J = 5.0H
z), 5.98 (1H, d, J = 8.3 Hz), 5.8
6 (1H, d, J = 4.5 Hz), 5.32 (1H,
d, J = 4.5 Hz), 5.23 (1H, t, J = 5.
6 Hz), 5.11 (1H, d, J = 4.4 Hz),
4.91 (1H, d, J = 4.9 Hz), 4.74 (2
H, d, J = 5.2 Hz), 4.35 (2H, d, J =
7.8 Hz), 3.73-4.05 (4H, m), 3.
43 to 3.52 (2H, m) Example 15 Structural Formula

[0054]

Embedded image A compound represented by the formula: Compound A (50 mg) and (4,5-tert-butyldimethylsilyloxymethyl) thiophene-2-carboxaldehyde (100 mg) were treated with anhydrous methanol (10).
The mixture was suspended in 100 ml of acetic acid, 100 ml of acetic acid was added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 40 mg of the intermediate compound. This was suspended in 3 ml of methanol, 12 mg of sodium cyanoborohydride and 300 ml of a 10% methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol.
The fraction containing the target substance was concentrated to dryness, and fractionated thin layer chromatography (manufactured by Merck, Kieselgel 60F254, developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0). .1)
Purification gave 26 mg of the compound of the title formula. Rf value: 0.28 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 690 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.17 (1H, s), 9.50 to 10.15
(2H, br), 8.86 (1H, d, J = 8.4H)
z), 8.78 (1H, d, J = 8.7 Hz), 7.1
6 (1H, d, J = 1.8 Hz), 6.97 (1H,
d, J = 2.1 Hz), 6.92 (1H, s), 6.8
2 (1H, dd, J = 1.8, 8.7 Hz), 6.79
(1H, dd, J = 2.1, 8.4 Hz), 6.04
(1H, t, J = 5.1 Hz), 6.04 (1H, t.
J = 5.1 Hz), 5.96 (1H, d, J = 8.1H)
z), 5.88 (1H, br), 5.35 (1H, b
r), 5.28 (1H, br), 5.15 (1H, b
r), 4.93 (2H, br), 4.53 (2H, b
r), 4.73 (2H, d, J = 4.5 Hz), 4.3
0 (1H, s), 4.00 (1H, m), 3.91 (2
H, m), 3.77 (1H, m), 3.52 (2H,
m) Example 16 Structural formula

[0055]

Embedded image A compound represented by the formula: 30 mg of Compound A and 50 mg of 2- (3-tert-butyldimethylsilyloxymethyl) pyridylcarbaldehyde are suspended in 6 ml of methanol, and acetic acid 30
After stirring for 2 hours at 80 ° C., the mixture was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated and the intermediate compound 40m
g was obtained. This was dissolved in a mixed solvent of tetrahydrofuran / methanol (2: 1), 15 mg of sodium cyanoborohydride and 3 ml of a methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated and Sephadex L
The product was applied to a H-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 27 mg of the compound represented by the title formula. Rf value: 0.12 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, br), 9, 77 (2H, b
r,) 8, 82 (1H, d, J = 9.0 Hz), 8.7
84 (1H, d, J = 9.0 Hz), 8.27 (1H,
dd, J = 1.8, 5.1 Hz), 7.83 (1H,
d, J = 8.1 Hz), 7.28 (1H, dd, J =
8.1, 5.1 Hz), 7.17 (1H, d, J = 1.
8Hz), 6.98 (1H, d, J = 1.8Hz),
6.82 (1H, dd, J = 1.8, 9.1 Hz),
6.79 (1H, dd, J = 1.8, 9.0 Hz),
6.15 (1H, t, J = 5.1 Hz), 5.97 (1
H, d, J = 8.1 Hz), 5.86 (1H, t, J =
4.2Hz), 5.33 (1H, d, J = 5.4H)
z), 5.31 (1H, d, J = 5.4 Hz), 5.1
2 (1H, d, J = 4.8 Hz), 4.93 (1H,
d, J = 4.5 Hz), 4.87 (2H, d, J = 6.
0 Hz), 4.36 (2H, d, J = 5.1 Hz),
4.03 (1H, m), 3.91 (2H, s), 3.7
9 (1H, m), 3.51 (2H, m) Example 17 Structural formula

[0056]

Embedded image A compound represented by the formula: 30 mg of compound C and (6-hydroxymethyl-3-pyridylmethyl) hydrazine hydrochloride 65
mg in 5 ml of N, N-dimethylformamide,
After adding 0.5 ml of triethylamine and stirring at 80 ° C. for 3 hours, 33 mg of (6-hydroxymethyl-3-pyridylmethyl) hydrazine hydrochloride was added.
Stirred for hours. After concentrating the reaction mixture to dryness, Sephadex L
The product was applied to a H-20 chromatography column and eluted with methanol. The fraction containing the desired product is concentrated, and the residue is again separated on Sephadex L.
The mixture was applied to a H-20 chromatography column and eluted with ethanol. The fraction containing the desired product was concentrated to dryness to obtain 7.2 mg of the compound represented by the title formula. FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.12 (1H, br), 8.81 (1H,
d, J = 8.7 Hz), 8.73 (1H, d, J = 8.
7 Hz), 8.51 (1H, s), 7.90 (1H,
d, J = 7.9 Hz), 7.39 (1H, d, J = 7.
9 Hz), 7.11 (1H, s), 6.93 (1H,
s), 6.77 (2H, t, J = 8.7 Hz), 6.2.
1 (1H, t, J = 3.8 Hz), 5.92 (1H, t, J = 3.8 Hz)
d, J = 7.9 Hz), 4.85 to 5.50 (5H, b
r), 4.48 (2H, s), 4.27 (2H, d, J
= 3.8 Hz), 3.70 to 4.05 (4H, m),
3.45 to 3.52 (2H, m) Example 18 Structural Formula

[0057]

Embedded image A compound represented by the formula: 12.5 mg of compound C and 42 mg of (5-hydroxymethyl-3-pyridylmethyl) hydrazine hydrochloride were dissolved in 1 ml of N, N-dimethylformamide, 0.1 ml of triethylamine was added, and the mixture was stirred at 80 ° C. for 2.5 hours. 0.1ml
Was added and stirred at 50 ° C. overnight. After concentrating the reaction solution to dryness,
The mixture was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound was concentrated, and the residue was again applied to a Sephadex LH-20 chromatography column and eluted with ethanol. The fraction containing the desired product was concentrated to dryness to give 2.4 mg of the compound represented by the title formula. Rf value: 0.18 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, br), 9.60 to 10.0
2 (2H, br), 8.84 (1H, d, J = 8.5H)
z), 8.76 (1H, d, J = 8.6 Hz), 8.5
5 (1H, s), 8.37 (1H, s), 7.84 (1
H, s), 7.16 (1H, s), 7.00 (1H,
s), 6.75 to 6.85 (2H, m), 6.21 (1
H, t, J = 4.7 Hz), 5.95 (1H, d, J =
7.8 Hz), 5.88 to 5.95 (1H, br),
5.40 to 5.48 (1H, br), 5.26 to 5.3
5 (1H, br), 5.15 to 5.25 (1H, b
r), 4.90-4.93 (1H, br), 4.56.
(2H, d, J = 4.7 Hz), 4.50 (2H,
s), 3.72-4.05 (4H, m), 3.45-
3.55 (2H, m) Example 19 Structural formula

[0058]

Embedded image A compound represented by the formula: Compound D (30 mg) and (6-hydroxymethyl-3-pyridylmethyl) hydrazine hydrochloride 65
mg in 5 ml of N, N-dimethylformamide,
0.5 ml of triethylamine was added, and the mixture was stirred at 80 ° C. for 1.5 hours. After the reaction solution was dried and concentrated, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated and dried to give 29 mg of the compound represented by the above formula. FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 10.89 (1H, br), 10.36 (1H, br)
br), 9.97 (1H, br), 8.67 (1H,
d, J = 7.9 Hz), 8.52 (1H, d, J = 2.
2Hz), 8.50 (1H, d, J = 7.9Hz),
7.93 (1H, dd, J = 2.2, 8.1 Hz),
7.41 (1H, d, J = 8.1 Hz), 7.18 (2
H, t, J = 7.9 Hz), 7.02 (1H, d, J =
7.9 Hz), 7.00 (2H, t, J = 7.9H)
z), 6.29 (1H, t, J = 4.5 Hz), 5.4
2 (1H, d, J = 5.6 Hz), 5.33 (1H,
d, J = 6.1 Hz), 5.32 (1H, t, J = 6.
0 Hz), 5.21 (1H, d, J = 5.3 Hz),
4.82 to 4.91 (1H, br), 4.48 (2H,
d, J = 6.0 Hz), 4.29 (2H, d, J = 4.
5Hz), 3.91 to 4.12 (2H, m), 3.52
To 3.79 (3H, m), 3.30 to 3.40 (1H,
m) Example 20 Structural formula

[0059]

Embedded image A compound represented by the formula: 30 mg of Compound B and 152 mg of 4- (t-butyldimethylsilyloxyethyl) thiophene-2-carbaldehyde were suspended in 6 ml of anhydrous methanol, 30 ml of acetic acid was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol, and the fraction containing the target compound was concentrated to dryness to obtain 31 mg of an intermediate compound. This was suspended in 3 ml of methanol, 30 mg of sodium cyanoborohydride and 300 ml of a 10% methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried and concentrated. The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 5 mg of the compound represented by the title formula. Rf value: 0.43 (manufactured by Merck, toluene: water: acetic acid =
4: 2: 2: 0.5: 0.1) FAB chromatography MS (m / z): 675 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.80 (2H, b
r), 8.86 (1H, d, J = 9.0 Hz), 8.7
8 (1H, d, J = 8.7 Hz), 7.17 (1H,
d, J = 1.8 Hz), 7.03 (1H, s), 6.9
8 (1H, d, J = 2.1 Hz), 6.95 (1H,
s), 6.80 (2H, dt, J = 2.1, 8.7H)
z), 6.08 (1H, t, J = 5.1 Hz), 5.9
6 (1H, d, J = 7.8 Hz), 5.89 (1H, b
r), 5.36 (1H, br), 5.13 (1H, b
r), 4.93 (1H, br), 4.57 (1H, b
r), 4.38 (2H, d, J = 4.2 Hz), 4.0
5 (2H, m), 3.92 (2H, s), 3.77 (1
H, m), 3.50 (5H, m) Example 21 Structural formula

[0060]

Embedded image A compound represented by the formula: 17 mg of compound D and 12 mg of 4- (2-hydroxymethyl-4-pyridylmethyl) hydrazine trifluoroacetate were dissolved in 2 ml of N, N-dimethylformamide, 0.1 ml of triethylamine was added, and the mixture was stirred at 75 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted three times with water. Salt was added to the aqueous layer, and extracted three times with methyl ethyl ketone. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 8 mg of the compound represented by the title formula. FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 10.90 (1H, br), 8.66 (1H,
d, J = 7.6 Hz), 8.50 (1H, d, J = 7.
6 Hz), 8.41 (1H, d, J = 5.0 Hz),
7.57 (1H, s), 7.48 (1H, d, J = 5.
0 Hz), 7.17 (2H, t, J = 7.6 Hz),
7.07 (1H, d, J = 7.6 Hz), 7.00 (1
H, d, J = 7.6 Hz), 6.98 (1H, t, J =
7.6 Hz), 6.32 (1H, t, J = 4.8H)
z), 5.36 (1H, t, J = 3.7 Hz), 5.1
0 to 5.50 (4H, br), 4.51 (2H, d, J
= 3.7 Hz), 4.34 (2H, d, J = 4.8H)
z), 3.91-4.12 (2H, m), 3.51-
3.80 (3H, m) Example 22 Structural Formula

[0061]

Embedded image A compound represented by the formula: Compound C (17 mg) and (2-hydroxymethyl-4-pyridylmethyl) hydrazine trifluoroacetate (12 mg) were added to N, N-dimethylformamide (1 m).
and triethylamine (0.1 ml) was added.
The mixture was stirred at 0 ° C for 3.5 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The aqueous layer was added with sodium chloride and extracted with methyl ethyl ketone. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol.
The fraction containing the desired product was concentrated to dryness to obtain 4 mg of the compound represented by the title formula. FAB-MS (m / z): 656 (M + H ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.17 (1H, br), 9.55 to 10.0
5 (2H, br), 8.85 (1H, d, J = 8.4H)
z), 8.77 (1H, d, J = 8.2 Hz), 8.4
1 (1H, d, J = 5.1 Hz), 7.56 (1H,
s), 7.47 (1H, d, J = 5.1 Hz), 7.1
5 (1H, s), 6.96 (1H, s), 6.72-
6.85 (2H, m), 6.26 (1H, t, J = 4.
9 Hz), 5.94 (1H, d, J = 8.6 Hz),
5.80 to 5.99 (1H, br), 5.30 to 5.4
2 (2H, br), 5.10 to 5.20 (1H, b
r), 4.85-4.95 (1H, br), 4.51
(2H, d, J = 1.8 Hz), 4.32 (2H, d,
J = 4.5 Hz), 3.89 to 4.04 (1H, m),
3.90 (2H, m), 3.74 to 3.78 (1H,
m), 3.50 (2H, m) Example 23 Structural Formula

[0062]

Embedded image A compound represented by the formula: Compound A (14 mg) and 5-t-butyldimethylsilyloxymethylpyridine-2-carbaldehyde (14.7 mg) were suspended in anhydrous methanol (2 ml), acetic acid (8 ml) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 15.3 mg of the intermediate compound. Sodium cyanoborohydride
75 mg was suspended in 1 ml of tetrahydrofuran, and 0.55 ml of zinc chloride (1.0 M solution in diethyl ether) was added dropwise. 15.3 mg of the intermediate compound was suspended in 3 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours.
To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with methyl ethyl ketone. After drying and concentrating the organic layer, the residue was dissolved in 3 ml of tetrahydrofuran, and an excess amount of tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) was added dropwise at 0 ° C. After stirring at room temperature for 30 minutes, water was added, and the mixture was extracted with methyl ethyl ketone. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound was concentrated to dryness to give the compound 4.5 of the title formula.
mg was obtained. Rf value: 0.1 (manufactured by Merck, Kieselgel 60)
F _254, developing solvent; chloroform: methanol: tetrahydrofuran = 3: 1: 1) FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, s), 9.77 (2H, b
r), 8.84 (1H, d, J = 8.5 Hz), 8.7
6 (1H, d, J = 8.6 Hz), 8.35 (1H,
d, J = 1.7 Hz), 7.72 (2H, s), 7.1
7 (1H, d, J = 1.7 Hz), 6.98 (1H, d, J = 1.7 Hz)
d, J = 1.9 Hz), 6.78-6.98 (2H,
m), 6.22 (1H, t, J = 4.6 Hz), 5.9
6 (1H, d, J = 8.9 Hz), 5.87 (1H, b
r), 5.35 (1H, br), 5.22 (1H, t,
J = 2.0 Hz), 5.11 (1H, br), 4.91
(1H, br), 4.46 (2H, d, J = 4.2H)
z), 4.35 (2H, d, J = 4.6 Hz), 3.7
3 to 4.09 (4H, m), 3.49 (2H, s) Example 24 Structural formula

[0063]

Embedded image A compound represented by the formula: Compound A 30mg and 3,4-bis-
(T-butyldimethylsilyloxymethyl) thiophene
-2-30 mg of carbaldehyde in 6 ml of anhydrous methanol
Acetic acid, add 30 ml of acetic acid and stir at 80 ° C for 2 hours
did. The reaction solution was applied to a Sephadex LH-20 chromatography column.
And eluted with methanol. Concentrate the fraction containing the target compound
After drying, 31 mg of the intermediate compound was obtained. This is
Suspension in 5 ml of sodium cyanoborohydride
mg and 10% hydrochloric acid in methanol (100 ml).
Stirred at warm for 30 minutes. Dilute the reaction in ethyl acetate,
Washed with water and saturated saline. After concentrating the organic layer by drying, the residue
To the Sephadex LH-20 chromatography column
Eluted with the Concentrate the fractions containing the target product to dryness
Gave 25 mg of the compound of the title formula. Rf value: 0.30 (Merck, Kieselgel 60F
₂₅₄, Developing solvent; acetonitrile: tetrahydrofura
: Toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 691 (M + H )^{+ 1} H-NMR (300 MHz, DMSO-d₆, Δpp
m): 11.19 (1H, s), 9.79 (1H,
s), 9.76 (1H, s), 8.86 (1H, d, J
= 8.4 Hz), 8.78 (1H, d, J = 8.7H)
z), 7.18 (1H, d, J = 1.8 Hz), 7.1
5 (1H, s), 6.98 (1H, d, J = 2.1H)
z), 6.82 (2H, dt, J = 8.7, 1.8H
z), 6.04 (1H, t, J = 5.4 Hz), 5.9
7 (1H, d, J = 8.1 Hz), 5.86 (1H,
t, J = 3.6 Hz), 5.33 (1H, d, J = 4.
2 Hz), 5.12 (1H, d, J = 4.2 Hz),
5.01 (1H, t, J = 6.0 Hz), 4.93 (1
H, d, J = 4.8 Hz), 4.85 (1H, t, J =
5.7 Hz), 4.52 (2H, d, J = 5.7H)
z), 4.70 (2H, d, J = 5.7 Hz), 4.4
0 (2H, d, J = 4.8 Hz), 4.01 (1H,
m), 3.92 (2H, m), 3.77 (1H, m),
3.50 (2H, m) Example 25 Structural formula

[0064]

Embedded image A compound represented by the formula: Compound A (18 mg) and 4-hydroxymethylpyridine-2-carbaldehyde (7 mg) were suspended in anhydrous methanol (2 ml), and a few drops of acetic acid were added.
For 1.5 hours. After the reaction solution was concentrated to dryness, it was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target substance was concentrated to dryness, and the intermediate compound 22
mg was obtained. 90 mg of sodium cyanoborohydride was suspended in 1 ml of tetrahydrofuran, and zinc chloride (1.0 mg) was added.
0.66 ml (M diethyl ether solution) was added dropwise. 22 mg of the intermediate compound was suspended in 3 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 11 mg of the compound represented by the title formula. FAB chromatography MS (m / z): 656 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.21 (1H, s), 9.80 (1H,
s), 9.77 (1H, s), 8.86 (1H, d, J
= 8.6 Hz), 8.78 (1H, d, J = 8.1H)
z), 7.82-7.95 (1H, m), 7.68-
7.75 (1H, m), 7.33 to 7.43 (1H,
m), 7.19 (1H, s), 7.00 (1H, s),
6.78-6.89 (2H, m), 6.22 (1H,
t, J = 4.5 Hz), 5.97 (1H, d, J = 7.
9Hz), 5.86 (1H, t, J = 3.8Hz),
5.33 (1H, d, J = 4.2 Hz), 5.29 (1
H, t, J = 5.9 Hz), 5.11 (1H, d, J =
5.0 Hz), 4.91 (1H, d, J = 4.1H)
z), 4.42 (2H, d, J = 5.5 Hz), 4.3
3 (2H, d, J = 1.6 Hz), 3.99 to 4.09
(1H, m), 3.91 (2H, m), 3.72-3.
80 (1H, m), 3.50 (2H, m) Example 26 Structural Formula

[0065]

Embedded image A compound represented by the formula: 20 mg of compound A and 3- (3-tert-butyldimethylsilyloxyphenyl) propanal 2
0 mg was suspended in anhydrous methanol 4 ml, and acetic acid 20 ml
Was added and stirred at 80 ° C. for 8 hours. Concentrate the reaction,
The mixture was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 14 mg of the intermediate compound. This was suspended in 5 ml of methanol, and 7.5 mg of sodium cyanoborohydride, 10%
After adding 0.5 ml of a methanol solution of hydrochloric acid and stirring at room temperature for 2 hours, 0.5 ml of 2N hydrochloric acid was added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with water and saturated saline. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol.
The fraction containing the desired product was concentrated to dryness to obtain 12 mg of the compound represented by the above formula. Rf value: 0.36 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 669 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, s), 9.65 (3H, b
r), 8.87 (1H, d, J = 8.1 Hz), 8.7
9 (1H, d, J = 8.1 Hz), 7.17 (1H,
d, J = 1.7 Hz), 7.02 (1H, t, J = 8.
1Hz), 6.98 (1H, d, J = 1.7Hz),
6.81 (2H, dt, J = 1.7, 5.7 Hz),
6.64 (1H, d, J = 8.1 Hz), 6.62 (1
H, s), 6.57 (1H, dd, J = 1.8, 8.1)
Hz), 5.96 (1H, d, J = 8.1 Hz), 5.
87 (1H, br), 5.74 (1H, t, J = 4.8)
Hz), 5.35 (1H, br), 5.12 (1H, b
r), 4.92 (1H, br), 4.02 (1H, d,
J = 10.8 Hz), 3.91 (2H, m), 3.79
(1H, d, J = 9.9 Hz), 3.51 (2H, d,
J = 7.5 Hz), 3.02 (2H, m), 2.65
(2H, t, J = 7.2 Hz), 1.72 (2H, t,
J = 8.1 Hz) Example 27 Structural Formula

[0066]

Embedded image A compound represented by the formula: Compound A (15 mg) and 6-hydroxymethylpyridine-2-carbaldehyde (6.9 mg) were suspended in anhydrous methanol (1 ml), and several drops of acetic acid were added.
For 5 hours. After the reaction solution was concentrated to dryness, it was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness, and the intermediate compound 5.2
mg was obtained. Sodium cyanoborohydride 68mg
Was suspended in 2 ml of tetrahydrofuran, and zinc chloride (1.
0.5 ml of a 0 M diethyl ether solution) was added dropwise. 5.2 mg of the intermediate compound was suspended in 1 ml of tetrahydrofuran, and the mixture was stirred overnight at room temperature. Add water to the reaction solution,
The mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to give 2.0 mg of the compound represented by the title formula. Rf value: 0.29 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 656 (M + H ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.21 (1H, s), 9.80 (1H,
s), 9.77 (1H, s), 8.86 (1H, d, J
= 8.6 Hz), 8.78 (1H, d, J = 8.1H)
z), 7.82-7.95 (1H, m), 7.68-
7.75 (1H, m), 7.33 to 7.43 (1H,
m), 7.19 (1H, s), 7.00 (1H, s),
6.78-6.89 (2H, m), 6.22 (1H,
t, J = 4.5 Hz), 5.97 (1H, d, J = 7.
9Hz), 5.86 (1H, t, J = 3.8Hz),
5.33 (1H, d, J = 4.2 Hz), 5.29 (1
H, t, J = 5.9 Hz), 5.11 (1H, d, J =
5.0 Hz), 4.91 (1H, d, J = 4.1H)
z), 4.42 (2H, d, J = 5.5 Hz), 4.3
3 (2H, d, J = 1.6 Hz), 3.99 to 4.09
(1H, m), 3.91 (2H, m), 3.72-3.
80 (1H, m), 3.50 (2H, m) Example 28 Structural Formula

[0067]

Embedded image A compound represented by the formula: Compound A (40 mg) and 3,5-bis (t-butyldimethylsilyloxymethyl) thiophene-2-carbaldehyde (60 mg) in anhydrous methanol (8 ml)
And 40 ml of acetic acid was added thereto, followed by stirring at 80 ° C. for 2 hours. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 46 mg of the intermediate compound. This is suspended in 5 ml of methanol, and sodium cyanoborohydride 3
0 mg and 300 ml of a 10% methanol solution of hydrochloric acid were added.
Stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed with water and saturated saline. After drying and concentrating the organic layer,
The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 36 mg of the compound represented by the title formula. Rf value: 0.24 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 690 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.79 (1H,
s), 9.76 (1H, s), 8.86 (1H, d, J
= 8.4 Hz), 8.78 (1H, d, J = 8.4H)
z), 7.18 (1H, d, J = 1.8 Hz), 6.9
8 (1H, d, J = 1.8 Hz), 6.83 (1H,
s), 6.82 (2H, dt, J = 1.8, 8.4H)
z), 5.99 (1H, t, J = 4.8 Hz), 5.9
7 (1H, d, J = 9.0 Hz), 5.87 (1H,
t, J = 4.2 Hz), 5.35 (1H, t, J = 5.
4Hz), 5.33 (1H, d, J = 4.8Hz),
5.12 (1H, d, J = 5.1 Hz), 4.96 (1
H, d, J = 5.7 Hz), 4.94 (1H, d, J =
5.4 Hz), 4.49 (4H, t, J = 6.6H)
z), 4.34 (2H, d, J = 4.8 Hz), 4.0
3 (1H, m), 3.92 (2H, m), 3.77 (1
H, m), 3.50 (2H, m) Example 29 Structural Formula

[0068]

Embedded image A compound represented by the formula: Compound B (50 mg) and 3,5-bis- (t-butyldimethylsilyloxymethyl) thiophene-2-carbaldehyde (60 mg) were treated with anhydrous methanol / N,
It was dissolved in 12 ml of N-dimethylformamide (5: 1), 50 ml of acetic acid was added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline,
It was dried and concentrated. The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound was concentrated to dryness, and the residue was dissolved in 6 ml of a mixed solvent of tetrahydrofuran / methanol (2: 1), and 30 mg of sodium cyanoborohydride and 30% of a 10% methanol solution of hydrochloric acid were added.
0 ml was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying and concentration of the organic layer, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 37 mg of the compound represented by the title formula. Rf value: 0.31 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 690 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 10.90 (1H, s), 10.37 (1H, b
r), 9.98 (1H, br), 8.69 (1H, d,
J = 8.4 Hz), 8.52 (1H, d, J = 8.4H)
z), 7.19 (2H, dt, J = 1.5, 8.4H
z), 7.05 (1H, d, J = 8.6 Hz), 7.0
1 (2H, t, J = 8.4 Hz), 6.83 (1H,
s), 6.04 (1H, t, J = 4.8 Hz), 5.4
2 (1H, d, J = 5.7 Hz), 5.35 (2H,
t, J = 6.0 Hz), 5.21 (1H, d, J = 5.
4 Hz), 4.95 (1H, t, J = 6.0 Hz),
4.91 (1H, br), 4.50 (4H, t, J =
5.7 Hz), 4.36 (2H, d, J = 5.4H)
z), 4.00 (2H, m), 3.73 (1H, m),
3.62 (2H, m), 3.40 (1H, m) Example 30 Structural formula

[0069]

Embedded image A compound represented by the formula: Compound A (20 mg) and 2-hydroxymethylthiophene-3-carbaldehyde (20 mg) were dissolved in anhydrous methanol (4 ml), and acetic acid (20 ml) was added.
Stirred at 80 ° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target substance is concentrated to dryness, and the residue is mixed with a tetrahydrofuran / methanol mixed solvent (2: 1) 3
dissolved in sodium cyanoborohydride 30m
g, 10% hydrochloric acid in methanol (300 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 16 mg of the compound represented by the title formula. Rf value: 0.49 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 660 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, s), 9.79 (1H,
s), 9.75 (1H, s), 8.86 (1H, d, J
= 8.4 Hz), 8.78 (1H, d, J = 8.4H)
z), 7.30 (1H, d, J = 4.8 Hz), 7.1
7 (1H, d, J = 2.1 Hz), 7.09 (1H,
d, J = 5.4 Hz), 6.98 (1H, d, J = 2.
1 Hz), 6.82 (1H, dd, J = 2.1, 8.4)
Hz), 6.80 (1H, dd, J = 2.1, 8.4H)
z), 5.97 (1H, d, J = 8.1 Hz), 5.9
2 (1H, t, J = 5.1 Hz), 5.86 (1H,
t, J = 3.9 Hz), 5.37 (1H, d, J = 5.
7Hz), 5.33 (1H, d, J = 4.5Hz),
5.12 (1H, d, J = 4.8 Hz), 4.93 (1
H, d, J = 4.8 Hz), 4.76 (2H, d, J =
5.7 Hz), 4.20 (2H, d, J = 5.1H)
z), 4.00 (1H, m), 3.91 (2H, s),
3.77 (1H, m), 3.50 (2H, m) Example 31 Structural Formula

[0070]

Embedded image A compound represented by the formula: 30 mg of Compound A and 30 mg of 3-tert-butyldimethylsilyloxymethylthiophene-2-carbaldehyde were dissolved in 5 ml of anhydrous methanol, 30 ml of acetic acid was added, and the mixture was stirred at 80 ° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness, the residue was suspended in 3 ml of methanol, 30 mg of sodium cyanoborohydride and 300 ml of a 10% methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to give 24 mg of the compound represented by the title formula. Rf value: 0.40 (manufactured by Merck, Kieselgel 60F2
54, developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 660 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.78 (1H,
s), 9.75 (1H, s), 8.85 (1H, d, J
= 8.7 Hz), 8.78 (1H, d, J = 9.0H)
z), 7.31 (1 Hd, J = 4.8 Hz), 7.18
(1H, d, J = 1.8 Hz), 6.99 (1H, d,
J = 4.8 Hz), 6.97 (1H, d, J = 1.8H)
z), 6.81 (2H, ddJ = 1.8, 9.0H
z), 6.06 (1H, t, J = 4.8 Hz), 5.9
7 (1H, d, J = 8.7 Hz), 5.86 (1H,
t, J = 3.9 Hz), 5.33 (1H, d, J = 4.
5 Hz), 5.12 (1H, d, J = 4.5 Hz),
4.99 (1H, t, J = 5.4 Hz), 4.93 (1
H, d, J = 5.1 Hz), 4.53 (2H, d, J =
5.7 Hz), 4.38 (2H, d, J = 4.8H)
z), 4.02 (1H, m), 3.91 (2H, m),
3.77 (1H, m), 3.50 (2H, m) Example 32 Structural Formula

[0071]

Embedded image A compound represented by the formula: Compound A (35 mg) and 8-t-butyldimethylsilyloxymethyl-1-naphthaldehyde 6
0 mg was suspended in 2 ml of methanol, and a few drops of acetic acid were added.
Stirred at 60 ° C. for 2 hours. The reaction solution was concentrated, and the obtained solid was washed with chloroform to obtain an intermediate compound (32.5 m).
g was obtained. 68 mg of sodium cyanoborohydride was suspended in 3 ml of tetrahydrofuran, and zinc chloride (1.0 mg) was added.
M diethyl ether solution) was added dropwise. 32.5 mg of the intermediate compound was suspended in 2 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. After adding saturated saline, the mixture was extracted with a mixed solvent of ethyl acetate / methyl ethyl ketone.
The organic layer is dried and concentrated, and the residue is treated with tetrahydrofuran 1.5
and dissolve in tetrabutylammonium fluoride
0.5 ml was added. After stirring at room temperature for 1.5 hours, the mixture was diluted with a mixed solvent of ethyl acetate / methyl ethyl ketone, washed with water and saturated saline, and the organic layer was dried and concentrated, and then eluted with methanol on a Sephadex LH-20 chromatography column. The fraction containing the desired product was concentrated to dryness to obtain 3.3 mg of the compound represented by the title formula. FAB chromatography MS (m / z): 705 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.16 (1H, s), 8.84 (1H, d,
J = 7.9 Hz), 8.76 (1 H, d, J = 7.9 H)
z), 7.87 (2H, d, J = 7.4 Hz), 7.6
8 (1H, d, J = 7.4 Hz), 7.58 (1H,
d, J = 7.4 Hz), 7.49 (1H, d, J = 7.
4 Hz), 7.39 (1H, t, J = 7.4 Hz),
7.15 (1H, s), 6.97 (1H, s), 6.8
0 (2H, t.J = 7.9 Hz), 5.86 to 6.00
(3H, m), 5.42 (2H, s), 4.85 (2
H, d, J = 4.2 Hz), 4.80-5.50 (4
H, br), 3.72-4.05 (4H, m), 3.4.
5 to 3.59 (2H, m) Example 33 Structural formula

[0072]

Embedded image A compound represented by the formula: 30 mg of compound A and 30 mg of 4-tert-butyldimethylsilyloxythiophene-3-carbaldehyde were suspended in 6 ml of methanol, 30 ml of acetic acid was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target substance was concentrated to dryness, and this was dissolved in 5 ml of a tetraidrofuran / methanol mixed solvent (2: 1), and sodium cyanoborohydride 20 mg, 10 mg
A 200% methanol solution of hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried and concentrated. Residue is Sephadex L
The product was applied to a H-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 15 mg of the compound represented by the title formula. Rf value: 0.47 (manufactured by Merck, Kieselgel 60F)
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB chromatography MS (m / z): 661 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.79 (1H,
s), 9.76 (1H, s), 8.86 (1H, d, J
= 8.7 Hz), 8.78 (1H, d, J = 8.7H)
z), 7.43 (1H, d, J = 3.3 Hz), 7.3
0 (1H, d, J = 3.6 Hz), 7.17 (1H,
d, J = 2.1 Hz), 6.98 (1H, d, J = 2.
1 Hz), 6.83 (1H, dd, J = 2.1, 8.7)
Hz), 6.81 (1H, dd, J = 2.1, 8.7H)
z), 6.04 (1H, t, J = 5.1 Hz), 5.9
7 (1H, d, J = 9.0 Hz), 5.87 (1H,
t, J = 3.6 Hz), 5.34 (1H, d, J = 3.
9 Hz), 5.12 (1H, d, J = 5.1 Hz),
5.10 (1H, t, J = 5.1 Hz), 4.92 (1
H, d, J = 4.5 Hz), 4.67 (2H, d, J =
5.4 Hz), 4.23 (2H, d, J = 4.2H)
z), 4.01 (1H, m), 3.92 (2H, s),
3.77 (1H, m), 3.50 (2H, m) Example 34 Structural Formula

[0073]

Embedded image A compound represented by the formula: Compound A (38 mg) and 4-hydroxymethylthiophene-2-carbaldehyde (25 mg) were suspended in anhydrous methanol (7 ml), and acetic acid (45 ml) was added.
The mixture was stirred at 80 ° C. for 7 hours. After the reaction solution was concentrated under reduced pressure, 38 mg of crystals were collected by filtration from methanol / chloroform. The crystals are treated in tetrahydrofuran / methanol (4: 1) 10
dissolved in sodium cyanoborohydride 13m
g, 10% methanol solution of hydrochloric acid (0.5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with a saturated saline solution, and dried and concentrated. The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 21.7 mg of the compound represented by the title formula. Rf value: 0.24 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 660 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.19 (1H, s), 9.77 (2H, b
r), 8.86 (1H, d, J = 8.6 Hz), 8.7
8 (1H, d, J = 8.6 Hz), 7.17 (1H,
s), 7.14 (1H, d, J = 1.8 Hz), 6.9
8 (2H, m), 6.81 (2H, dt, J = 1.8,
6.9 Hz), 6.12 (1H, t, J = 5.1H)
z), 5.97 (1H, d, J = 8.1 Hz), 5.8
7 (1H, s), 5.35 (1H, d, J = 1.8H
z), 5.13 (1H, d, J = 2.4 Hz), 5.0
1 (1H, t, J = 5.4 Hz), 4.93 (1H,
d, J = 3.6 Hz), 4.40 (2H, d, J = 4.
5 Hz), 4.34 (2H, d, J = 4.8 Hz),
4.00 (1H, dd, J = 2.1, 11.6 Hz),
3.91 (2H, s), 3.79 (1H, m), 3.5
1 (2H, br) Example 35 Structural Formula

[0074]

Embedded image A compound represented by the formula: 107 mg of compound A and 126 mg of 5-hydroxymethylfurfural were suspended in 2 ml of methanol, several drops of acetic acid were added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was concentrated, and the obtained solid was washed with chloroform.
This was dissolved in 5 ml of a methanol / tetrahydrofuran mixed solvent (1: 2), and 62.8 mg of sodium cyanoborohydride and 5 ml of a 10% methanol solution of hydrochloric acid were added.
Was added and stirred at room temperature for 30 minutes. The reaction solution was diluted with a mixed solvent of ethyl acetate / methyl ethyl ketone, and washed with water and saturated saline. The organic layer was dried and concentrated, applied to a Sephadex LH-20 chromatography column, and eluted with methanol.
The fraction containing the desired product was concentrated to dryness to obtain 103 mg of the compound represented by the above formula. FAB chromatography MS (m / z): 644 (M) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.19 (1H, s), 9.77 (2H, b
r), 8.85 (1H, d, J = 8.5 Hz), 8.7
7 (1H, d, J = 8.6 Hz), 7.18 (1H,
d, J = 2.1 Hz), 6.98 (1H, d, J = 1.
7 Hz), 6.75 to 6.86 (2H, m), 6.31
(1H, d, J = 3.1 Hz), 6.15 (1H, d,
J = 3.1 Hz), 6.03 (1H, t, J = 4.7H)
z), 5.97 (1H, d, J = 8.3 Hz), 5.8
7 (1H, t, J = 3.6 Hz), 5.34 (1H, t, J = 3.6 Hz)
d, J = 3.9 Hz), 5.08 to 5.15 (2H,
m), 4.93 (1H, d, J = 4.5 Hz), 4.2
8 (2H, d, J = 5.6 Hz), 4.20 (2H,
d, J = 4.7 Hz), 3.72 to 4.05 (4H,
m), 3.45 to 3.55 (2H, m) Example 36 Structural Formula

[0075]

Embedded image A compound represented by the formula: Compound A (39 mg) and 3-hydroxy-4-hydroxymethylbenzaldehyde (33 mg) were suspended in methanol (8 ml), acetic acid (150 μl) was added, and the mixture was stirred at room temperature for 3 nights. The reaction solution was filtered, and the obtained solid was washed with chloroform. This was dissolved in 5 ml of a mixed solvent of methanol / tetrahydrofuran (1: 2), 9 mg of sodium cyanoborohydride and several drops of 10% hydrochloric acid in methanol were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, applied to a Sephadex LH-20 chromatography column, and eluted with methanol. The fraction containing the target compound was concentrated to dryness to give 3.5 mg of the compound represented by the title formula.
Got. FAB-MS (m / z): 670 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.18 (1H, s), 9.77 (1H,
s), 9.76 (1H, s), 9.28 (1H, b
r), 8.87 (1H, d, J = 8.5 Hz), 8.7
8 (1H, d, J = 8.5 Hz), 7.18 (1H,
d, J = 7.9 Hz), 7.17 (1H, s), 6.9
7 (1H, d, J = 2.0 Hz), 6.77 to 6.93
(4H, m), 5.96 (1H, d, J = 8.2H
z), 5.92 (1H, t, J = 5.0 Hz), 5.8
6 (1H, t, J = 3.2 Hz), 5.33 (1H,
d, J = 4.3 Hz), 5.12 (1H, d, J = 4.
6 Hz), 4.92 (1H, d, J = 5.0 Hz),
5.83 (1H, br), 4.41 (2H, d, J =
3.2Hz), 4.14 (2H, d, J = 5.0H)
z), 4.00 (1H, m), 3.90 (2H, m),
3.78 (1H, m), 3.50 (2H, m) Example 37 Structural Formula

[0076]

Embedded image A compound represented by the formula: 30 mg of Compound A and 24.9 mg of 3- (2-hydroxyethyl) benzaldehyde were suspended in 1 ml of methanol, and several drops of acetic acid were added, followed by stirring at 80 ° C. for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was washed with chloroform. This was suspended in 2 ml of methanol, 9.0 mg of sodium cyanoborohydride and several drops of a 10% methanol solution of hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by drying the reaction solution under reduced pressure was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 20.7 mg of the compound represented by the title formula. FAB chromatography MS (m / z): 669 (M + H) + 1 H over NMR (300 MHz, DMSO over d _6,? Pp
m): 11.18 (1H, s), 9.78 (1H,
s), 9.75 (1H, s), 8.87 (1H, d, J
= 8.5 Hz), 8.79 (1H, d, J = 8.6H)
z), 7.36 (1H, s), 7.32 (1H, d, J
= 7.6 Hz), 7.15 to 7.25 (2H, m),
7.07 (1H, d, J = 7.6 Hz), 6.97 (1
H, d, J = 2.0 Hz), 6.75 to 6.85 (2
H, m), 6.02 (1H, d, J = 5.2 Hz),
5.96 (1H, d, J = 8.2 Hz), 5.86 (1
H, t, J = 3.3 Hz), 5.33 (1H, d, J =
4.3 Hz), 5.11 (1H, d, J = 4.9H)
z), 4.90 (1H, d, J = 5.4 Hz), 4.6
1 (1H, t, J = 5.3 Hz), 4.23 (2H,
d, J = 4.5 Hz), 3.72-4.05 (4H,
m), 3.45 to 3.60 (4H, m), 2.69 (2
(H, t, J = 7.3 Hz) Example 38 Structural Formula

[0077]

Embedded image A compound represented by the formula: Compound A (40 mg) and 5-hydroxymethylthiophene-3-carbaldehyde (40 mg) were suspended in methanol (8 ml), and acetic acid (40 ml) was added.
For 3 hours. The reaction solution was cooled to room temperature, chloroform was added, and the powder was collected by filtration. 5 ml of methanol
Sodium cyanoborohydride 20 mg, 1
200 ml of 0% methanolic hydrochloric acid solution was added, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. The reaction solution was diluted with a mixed solvent of ethyl acetate / methyl ethyl ketone, washed with water and saturated saline, and dried and concentrated. The residue was applied to a Sephadex LH-20 chromatography column and eluted with methanol. The fraction containing the target compound was concentrated to dryness to give the compound 21 represented by the title formula.
mg was obtained. Rf value: 0.29 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): 660 (M ⁺ ) ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 11.19 (1H, s), 9.80 (2H, b
r), 8.86 (1H, d, J = 9.0 Hz), 8.7
9 (1H, d, J = 8.7 Hz), 7.34 (1H,
s), 7.17 (1H, d, J = 1.5 Hz), 7.0
4 (1H, s), 6.97 (1H, d, J = 1.5H
z), 6.82 (1H, dd, J = 1.5, 9.0H)
z), 6.80 (1H, dd, J = 8.7, 1.5H
z), 5.97 (2H, t, J = 5.1 Hz), 5.8
7 (1H, br), 5.40 (1H, t, J = 6.0H)
z), 5.35 (1H, br), 5.13 (1H,
s), 4.91 (1H, d, J = 3.9 Hz), 4.5
7 (2H, d, J = 4.2 Hz), 4.20 (2H,
d, J = 4.8 Hz), 3.88-4.10 (3H,
m), 3.78 (1H, m), 3.50 (2H, m) Example 39 Structural Formula

[0078]

Embedded image A compound represented by the formula: Compound A (38 mg) and 3-hydroxymethyl-4-hydroxybenzaldehyde (91 mg) were dissolved in N, N-dimethylformamide (2 ml).
Drops were added and the mixture was stirred at 80 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was washed with chloroform. This is suspended in 3 ml of methanol, and sodium cyanoborohydride 4
0 mg and several drops of 10% methanolic hydrochloric acid solution were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was applied to Sephadex LH-20.
And eluted with methanol. The fraction containing the desired product was concentrated to dryness to obtain 8.9 mg of the compound represented by the title formula. Rf value: 0.15 (Merck Kieselgel 60F
₂₅₄ , developing solvent; acetonitrile: tetrahydrofuran: toluene: water: acetic acid = 4: 2: 2: 0.5: 0.
1) FAB-MS (m / z): ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp)
m): 11.19 (1H, s), 9.75 (1H, b
r), 9.74 (1H, br), 9.23 (1H, b
r), 8.87 (1H, d, J = 8.6 Hz), 8.7
9 (1H, d, J = 8.6 Hz), 7.37 (1H,
s), 7.12 to 7.20 (2H, m), 6.98 (1
H, d, J = 2.1 Hz), 6.75 to 6.85 (2
H, m), 6.70 (1H, d, J = 8.3 Hz),
5.97 (1H, d, J = 8.3 Hz), 5.86 (1
H, t, J = 4.4 Hz), 5.76 (1H, t, J =
5.3Hz), 5.33 (1H, d, J = 4.4H)
z), 5.10 (1H, d, J = 3.4 Hz), 4.8
9 to 4.98 (2H, m), 4.44 (2H, d, J =
4.5 Hz), 3.72 to 4.15 (6H, m),
48 to 3.55 (2H, m)

[0079]

The compounds of the present invention have excellent antitumor effects and are therefore useful as antitumor agents in the field of medicine.

[0080]

────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Hiroyuki Suda 3rd Okubo Tsukuba City, Ibaraki Prefecture Banyu Pharmaceutical Co., Ltd. Tsukuba Research Laboratories (56) References JP-A-6-128283 (JP, A) International Publication 95/30682 (WO, A1) WO 91/18003 (WO, A1) WO 96/04293 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07H 19/23 A61K 31/7056 REGISTRY (STN) CA (STN) CAOLD (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula [Wherein, R represents a pyridyl group, a furyl group, or a thienyl group having one or two substituents selected from the group consisting of a hydroxy lower alkyl group and a hydroxy lower alkenyl group, and m represents an integer of 1 to 3. , G represents a β-D-glucopyranosyl group, and the substitution position of the hydroxy group on the indolopyrrolocarbazole ring is 1-position and 11-position or 2-position and 10-position.
Or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula 2. The compound according to claim 1, wherein R and G have the meaning described in claim 1, or a pharmaceutically acceptable salt thereof. 3. A compound of the general formula 2. The compound according to claim 1, wherein R and G have the meaning described in claim 1, or a pharmaceutically acceptable salt thereof. 4. An antitumor agent comprising the compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof.