JPH0687746A - Antitumor agent - Google Patents

Abstract

PURPOSE:To obtain a water-soluble antitumor agent having excellent antitumor activity and high safety, comprising a six-membered ring camptothecin derivative. CONSTITUTION:An antitumor agent comprises a compound of the formula (R1 and R2 are H, hydroxyl, alkyl, etc.; R3 is 1-6C alkyl; R4 is H, amino, etc.; Z is O, S, CR5R6 or NR7; R5 and R6 are H or 1-6C alkyl; R4 is H, amino, etc.; Z is O, S, CR5R6 or NR7; R5 and R6 are H or 1-6C alkyl; R7 is H, 1-6C alkyl, etc.; m and n are 0-2) such as (9S)-1-acetylamino-9-ethyl-2,3-dihydro-9-hydroxy- I-1H, 12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13(9H,15H)- dione. The antitumor agent is useful for treating various kinds of cancers such as lung cancer, digestive system cancer, ovarian carcinoma, uterine cancer, mammary cancer, cancer of the liver, head and neck cancer and blood cancer. A dose is 0.5-50mg based on 1m<2> surface area of body daily.

Description

Detailed Description of the Invention

[0001]

The present invention relates to blood cancer, gastric cancer, lung cancer,
The present invention relates to an antitumor agent useful for treating various cancers such as ovarian cancer.

[0002]

BACKGROUND OF THE INVENTION Camptothecin isolated from the bark, roots, fruits and leaves of Camptotheca acuminata is a pentacyclic alkaloid and inhibits nucleic acid synthesis. Therefore, it is known to exhibit antitumor activity. However, as a result of a clinical trial conducted in the United States, there is a problem in terms of toxicity, and development as a drug has been discontinued. Since then, research on camptothecin derivatives for the purpose of reducing toxicity and enhancing activity has been advanced worldwide.
There is nothing that has been put into practical use as a medicine.

By the way, since camptothecin is poorly soluble in water, there is a problem in administering it as a medicine. One known method of making camptothecin water-soluble is to cleave the lactone ring to form the sodium salt of a carboxylic acid, but this method has the disadvantage that its antitumor activity is reduced to a fraction. Therefore, a camptothecin derivative that can be water-solubilized without cleaving the lactone ring is desired.

[0004]

Under the circumstances, the present inventors have conducted various studies to obtain a camptothecin derivative having excellent action, high safety, and desirable physical properties for administration as a drug. The present inventors have completed the present invention by discovering that a hexacyclic compound in which one ring having a water-soluble group is added to camptothecin has properties superior to camptothecin and is useful as a therapeutic agent for various cancers.

That is, the present invention provides an antitumor agent containing a compound represented by the following general formula (1) or a salt thereof as an active ingredient.

[0006]

[Chemical 3]

[Wherein R ₁ and R ₂ are each a hydrogen atom; a hydroxyl group; a hydroxyl group, a halogen atom,
1 carbon atom which may have nitro group or cyano group
An alkyl group having 1 to 6 carbon atoms; an alkenyl group having 1 to 6 carbon atoms; an alkynyl group having 1 to 6 carbon atoms; an alkoxyl group having 1 to 6 carbon atoms; an aminoalkoxyl group having 1 to 6 carbon atoms; a halogen atom; a nitro group; cyano Group; mercapto group; alkylthio group; amino group which may have a protecting group; amino group which may have a protecting group or an alkyl group having 1 to 6 carbon atoms in the amino part; An aminoalkylamino group having 1 to 6 carbon atoms which may have a protecting group or an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms,
An amino group, a halogen atom, a heterocycle which may have a nitro group or a cyano group, and an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an amino group, A carbonyl group having a heterocycle which may have a halogen atom, a nitro group or a cyano group; an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an amino group which may have a protecting group, a halogen atom , A nitro group, a cyano group or a heterocyclic ring which may have a protecting group, and an alkylamino group having 1 to 6 carbon atoms; a nitrogen atom or an amino part of the heterocycle having a protecting group or an alkyl group having 1 to 6 carbon atoms A heterocyclic amine which may have a protecting group or an alkyl group having 1 to 6 carbon atoms at the nitrogen atom or amino portion of the heterocycle. Group; or a protecting group or 1 carbon atoms
6 represents a carbamoyl group which may have an alkyl group of 6, R ₃ represents an alkyl group having 1 to 6 carbon atoms, and R ₄ represents
Hydrogen atom; amino group which may have a protecting group; alkylamino group having 1 to 6 carbon atoms which may have a protecting group;
An aminoalkyl group having 1 to 6 carbon atoms which may have a protecting group; an alkylaminoalkyl group having 1 to 6 carbon atoms which may have a protecting group; a sulfonic acid group; or a carboxyl group, and Z is an oxygen atom Sulfur atom; CR ₅ R ₆ (R
₅ and R ₆ each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms); or NR ₇ (R ₇ is a hydrogen atom; 1 carbon atom)
~ 6 alkyl group; 1 carbon atom which may have a protecting group
~ 6 aminoalkyl group; an alkylaminoalkyl group having 1 to 6 carbon atoms which may have a protecting group; or an amino group protecting group), and m and n are each 0,
It means 1 or 2. ]

In the general formula (1), R ₁ or R ₂ is preferably methyl group, ethyl group, hydroxymethyl group, hydroxyl group, methoxyl group, fluorine atom, chlorine atom, bromine atom, nitro group, Examples thereof include an amino group, a cyano group, an aminomethyl group, a dimethylhydrazino group, a morpholin-1-yl group and a piperazin-1-yl group. R
Preferred examples of ₃ include an ethyl group and the like.
R ₄ is preferably an amino group or a carbon number of 1
~ 6 alkylamino group, aminoalkyl group or alkylaminoalkyl group, especially methylamino group, dimethylamino group, aminomethyl group, methylamino group, dimethylamino group, aminoethyl group, methylaminoethyl group, dimethylaminoethyl Groups and the like. Preferred examples of Z include methylene, oxygen atom, sulfur atom,
Examples thereof include imino and alkylimino. Preferred examples of the amino-protecting group include a formyl group, acetyl group, trityl group, tertiary butoxycarbonyl group, benzyl group, p-methoxybenzyloxycarbonyl group, phthaloyl group and trifluoroacetyl group. Preferred examples of the heterocyclic group include groups derived from azetidine, pyrrolidine, piperidine, imidazole, thiazole, oxazole, pyridine and the like.

In the compound (1) of the present invention, ring A has 6
The compound (1A) having a member ring is particularly preferable.

[0010]

[Chemical 4]

Further, among the compounds (1) of the present invention, a compound in which the configuration regarding the asymmetric carbon atom at the 9-position (substituent of the F ring) is S type is preferable from the viewpoint of action.

Of these, the following formula

[0013]

[Chemical 5]

(9S) -1-amino-9-ethyl-5- represented by
Fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 1
2H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b]
Quinoline-10,13 (9H, 15H) -dione or salts thereof are particularly preferred.

The compound of the general formula (1) can be produced by the method exemplified in the following reaction scheme.

[0016]

[Chemical 6]

That is, the compound (1) is obtained by condensing the aminoketone compound (2) and the pyranoindolizine compound (3) by a Friedlander reaction.

The aminoketone compound (2) is a known compound or a compound easily prepared according to a known method. The conditions for the condensation ring closure reaction of the compounds (2) and (3) are appropriately selected from the conditions of normal temperature or heating in the presence of an acid or a base. The solvent that can be used is not particularly limited as long as it is inert to the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; diethyl. Ether, diisopropyl ether, tetrahydrofuran, dimethyl cellosolve,
Ethers such as diethyl cellosolve and diglyme; lower alcohols such as methanol, ethanol, propanol and tertiary butanol; amides such as acetamide, dimethylacetamide, N, N-dimethylformamide; acetic acid and the like, Particularly preferred are benzene, toluene, acetic acid and the like.

The acid that can be used may be either an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid and sulfuric acid. Examples of the organic acid include sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pyridine-paratoluenesulfonate; carboxylic acids such as acetic acid, but especially p-toluenesulfone. Acids, pyridine paratoluene sulfonate, acetic acid and the like are preferable. Here, when acetic acid is used, it can also serve as a solvent.

The base that can be used may be either an inorganic base or an organic base. Examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, and other alkali metal hydroxides, carbonates, and carbonates. Examples thereof include hydrogen salt and hydride. Examples of the organic base include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide; triethylamine,
Tertiary alkylamines such as N, N-diisopropylethylamine; N, N-dimethylaniline, N, N-diethylaniline,
Aromatic tertiary amines such as N, N-dimethylaminopyridine;
Examples thereof include pyridine and 1,8-diazabicycloundecene, and potassium carbonate and triethylamine are particularly preferable.

Some of the starting compounds (3) are unstable to bases. In such a case, it is preferable to pay attention to the setting of reaction conditions, such as ice-cooling. Consideration should be given to conducting the reaction at a relatively low temperature, shortening the reaction time, and conducting the reaction under acidic conditions. The reaction temperature is
It is preferably in the range of 20 to 150 ° C, particularly 80 to 120 ° C. However, as described above, depending on the nature of the raw material, the temperature under ice cooling may be preferable. Reaction time is 1
It may be in the range of 48 hours and is usually completed in 1 to 24 hours. As a typical condition, for example, a method of heating under reflux in benzene, toluene or acetic acid in the presence of pyridine paratoluene sulfonate can be mentioned.

When R ₁ , R ₂ , R ₄ or the substituents they have are amino groups having a protecting group, the protecting group can be removed by hydrolysis or reduction reaction with an acid or alkali. . A compound having an alkoxyl group can be treated with aluminum chloride, aluminum bromide or the like in an inert solvent such as toluene or benzene, or heated in a hydrobromic acid solution to give a corresponding hydroxy compound. it can. Further, the compound having a nitro group can be led to the corresponding amino compound by catalytic reduction using platinum or palladium.
Furthermore, the compound having an amino group can be converted to the corresponding hydroxy compound by treating with sodium nitrite or the like in an acidic solvent at low temperature to form a diazo compound and hydrolyzing the resulting diazonium salt solution. Furthermore,
A compound having an amino group can be converted into a corresponding halogen compound by introducing it into a diazonium salt by the same method as described above and then performing a Sandmeyer reaction. The Sandmeyer reaction may be performed using a reagent such as cuprous chloride or cuprous bromide under commonly used conditions.

The compound (1) is an alkali metal, if desired.
In the case of a basic compound having an amino group or the like converted to a salt thereof by using a hydroxide of an alkaline earth metal or the like, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or formic acid, acetic acid, methanesulfonic acid, etc. Can be converted to a salt of an organic acid to give a physiologically acceptable salt.

Next, the experimental examples will show the antitumor effect and safety of the compound (1) obtained as described above. Experimental Example 1 P388 mouse leukemia cells were seeded on a 96-well microplate at 2.5 × 10 ³ cells / well, and 24 hours later, a sample was added, and the MTT method [J. Immunol. Methods, 65 , 55- 63 (1
983)] to determine the cell growth inhibition rate. That is, after culturing at 37 ° C. for 3 days in 5% CO ₂ , contact with the drug was completed.
MTT 〔3- (4,5-Dimethylthiazol-2-yl) -2,5-diph
enyl-2H-tetrazolium bromide] was added. 0.04N HC
Add isopropyl alcohol containing 200 μl / ml to
The absorbance was measured at m to determine the 50% cell growth inhibitory concentration (IC ₅₀ ) value. The results are shown in Table 1.

[0025]

[Table 1]

Experimental Example 2 P388 (mouse leukemia), MKN28 (human gastric cancer), QG56 (human
Lung cancer) or HOC21 (human ovarian cancer) 2.5 × 10³cells / w
96-well wells-seeding to ell
24 hours later, the compound of Example 50 was added, and the MTT method [J.I.
mmunol.Methods,65, 55-63 (1983)].
I asked for control. That is, after that, 5% CO ₂Below, at 37 ℃
Incubate for 3 days, 4 hours before the end of drug contact, MTT [3- (4,5-Di
methylthiazol-2-yl) -2,5-dipheny-2H-tetrazolium bro
mide] was added. Isopropyl alcohol containing 0.04N HCl
Add 200 μl / ml of call and measure the absorbance at 540 nm.
% Cell growth inhibitory concentration (IC₅₀Value) was calculated. The results are shown in Table 2.
Shown in.

[0027]

[Table 2]

Experimental Example 3 BALB / c mice were subcutaneously implanted with 1 × 10 ⁶ mouse fibrosarcoma Meth A subcutaneously in the left groin, and 7 days later, the compound of Example 50 was administered once into the tail vein. After 14 days, the mice were sacrificed and the tumor weight was measured to determine the tumor growth inhibition rate. The results are shown in Table 3.

[0029]

[Table 3]

Experimental Example 4 The compound of Example 50 was dissolved in distilled water for injection and then administered once into the tail vein of male BALB / c mice, and the number of deaths and symptoms were observed for 14 days to examine acute toxicity. As a result, the compound of Example 50 had an LD ₅₀ of 90 mg / kg.

As is clear from the results of Experimental Examples 1 to 4, the compound (1) has excellent antitumor activity, high safety and water solubility, and is useful as an antitumor agent.

The antitumor agent of the present invention comprising the compound (1) as an active ingredient is, for example, lung cancer, digestive organ cancer, ovarian cancer, uterine cancer, breast cancer,
It can be used as a therapeutic agent for various cancers such as liver cancer, head and neck cancer, blood cancer, renal cancer, Komaru tumor and the like.

The antitumor agent of the present invention can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration and transdermal administration. Among these administration methods, intravenous administration by an aqueous preparation and oral administration are preferable. The aqueous preparation can be prepared by forming an acid adduct with a pharmacologically acceptable acid or by using an alkali metal salt such as sodium. In the case of oral administration, it may be in a free form or a salt form. As a method for preparing the preparation, an appropriate preparation can be selected according to the administration method, and the preparation can be prepared by various commonly used preparation methods. Among the dosage forms of the antitumor agent of the present invention, examples of oral preparations include tablets, powders, granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions. In the case of injections, stabilizers, preservatives,
A solubilizing agent or the like can also be used. A solution which may contain these auxiliary agents may be stored in a container and then freeze-dried to prepare a solid preparation, which may be prepared at the time of use. Examples of liquid preparations include solutions, suspensions, emulsions, etc., and when preparing these preparations, suspending agents, emulsifiers, etc. can be used as additives.

The antitumor agent of the present invention can be used for the treatment of cancer in mammals, particularly humans. When administered to humans, when administered parenterally, it is generally about 0.5 mg to 50 mg per 1 m ² of body surface area per day, preferably Is preferably administered once in the range of about 1 mg to 20 mg and repeated every 3 to 4 weeks. Approximately 1 m ² of body surface area per day for oral administration
It is desirable to administer once in the range of 0.5 mg to 50 mg, preferably about 1 mg to 20 mg, and to repeat at appropriate intervals.

[0035]

The present invention will be described in more detail with reference to the following examples.

Example 1 (9S) -1-Acetylamino-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino Synthesis of [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0037]

[Chemical 7]

(1) 8-acetylamino-1-tetralone: 1-
Acetylaminotetralin 10 g, acetone 400 ml and 15%
After dissolving in a mixed solvent of 40 ml of magnesium sulfate aqueous solution,
42 g of potassium permanganate was added while maintaining at 0 ° C., and the mixture was further stirred at the same temperature for 20 minutes. 800 ml of water was added to the residue obtained by concentrating the solvent, and the precipitate was extracted with chloroform. The extract was washed with saturated saline and dried over magnesium sulfate,
The solvent was concentrated and the obtained residue was subjected to silica gel column chromatography, developed with chloroform and the fraction containing the desired product was concentrated to obtain 5.46 g of the title compound. NMR (in CDCl ₃ ) δ: 2.08-2.14 (2H, m), 2.23 (3H, s), 2.
70 (2H, t, J = 6.8Hz), 2.97 (2H, t, J = 6.8Hz), 6.93 (1H, d, J =
6.8Hz), 7.44 (1H, t, J = 8.3Hz), 8.59 (1H, d, J = 8.3Hz)

(2) 8-Acetylamino-2-hydroxyimino-1-tetralone: 316 mg of potassium tertiary butoxide was suspended in 18 ml of tetrahydrofuran (hereinafter abbreviated as THF) and then cooled to 0 ° C. under a nitrogen stream to obtain the product. To the reaction solution, a solution prepared by dissolving 500 mg of the compound obtained in (1) in 2 ml of THF was added little by little. After stirring at the same temperature for 10 minutes, 0.35 ml of butyl nitrite was added, and the mixture was heated and stirred at 50 ° C. for 1 hour. After adding diethyl ether to the reaction solution, the precipitate is filtered and the resulting powder is 10%.
It was suspended in a hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the residue obtained by concentrating the solvent was subjected to silica gel column chromatography and developed with a mixed solvent of ethyl acetate-hexane (1: 1) to obtain the desired product. 320 mg of the title compound was obtained by concentrating the fractions containing. IRν _max ^KBr cm ^-1 : 3440, 1698, 1678, 1608, 1580,
1518 NMR (in CDCl ₃ ) δ: 2.26 (3H, s), 3.08 (4H, s), 6.98 (1
H, d, J = 7.4Hz), 7.53 (1H, t, J = 7.7Hz), 8.64 (1H, d, J = 8.5H
z) MASS m / z: 232 (M ⁺ )

(3) 2,8-Diacetylamino-1-tetralone: 300 mg of the compound obtained in (2) was added to 10 ml of acetic acid and acetic anhydride.
1 g of zinc dust was added to the solution dissolved in 10 ml of the mixed solvent at room temperature, and the mixture was stirred at the same temperature for 40 minutes. Insoluble matter was removed by filtration, and the residue obtained by concentrating the filtrate was recrystallized from ethyl acetate and hexane to give 263 mg of the title compound.
Got IRν _max ^KBr cm ^-1 : 3280, 1660, 1596, 1516 NMR (in CDCl ₃ ) δ: 1.6-2.0 (1H, m), 2.11 (3H, s), 2.23
(3H, s), 2.6-3.0 (1H, m), 3.1-3.4 (2H, m), 4.6-4.8 (1H,
m), 6.93 (1H, d, J = 6.8Hz), 7.49 (1H, t, J = 8.3Hz), 8.59 (1H,
d, J = 8.3Hz) MASS m / z: 260 (M ⁺ )

(4) 2-Acetylamino-8-amino-1-tetralone: 245 mg of the compound obtained in (3) was added to 40 ml of 3N aqueous hydrochloric acid solution.
And was heated and stirred at 60 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate, and the residue obtained by concentrating the solvent was recrystallized from ethyl acetate and hexane to give 150 mg of the title compound. IRν _max ^KBr cm ^-1 : 3424, 3304, 1668, 1632, 1558,
1508 NMR (in CDCl ₃ ) δ: 1.6-2.0 (1H, m), 2.09 (3H, s), 2.6-
3.2 (3H, m), 4.41-4.67 (1H, m), 6.47-6.71 (2H, m), 7.12-
7.26 (1H, m) MASS m / z: 218 (M ⁺ )

(5) (9S) -1-Acetylamino-9-ethyl-2,3
-Dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano
[3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15
H) -dione: 300 mg of the compound obtained in (4) and 200 ml of toluene
(S) -4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano [3,4-f] indolizine-3,6,10 (4H) -trione (hereinafter referred to as trione Abbreviated) 361 mg was added, and the mixture was heated under reflux for 10 minutes using a Dean Stark apparatus, and then pyridinium p-
Add 1 mg of toluene sulfonate (hereinafter abbreviated as PPTS),
The mixture was heated under reflux for another 24 hours. After cooling, the toluene was concentrated and the resulting residue was suspended in 300 ml of a mixed solution of chloroform-methanol (10: 1), and insoluble matter was removed by filtration. The residue obtained by concentrating the filtrate was triturated with methanol to obtain 336 mg of the title compound. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3452, 1750, 1660 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.83-1.9
2 (2H, m), 1.94 (3H, d, J = 4Hz), 2.09-2.17 (2H, m), 3.14-3.
31 (2H, m), 5.21 (2H, d, J = 5.6Hz), 5.42 (2H, d, J = 5.6Hz),
5.58-5.61 (1H, d), 6.50 (1H, br s), 7.35 (1H, d, J = 2.4Hz),
7.52 (1H, d, J = 7.2Hz), 7.79 (1H, t, J = 7.2Hz), 8.02 (1H, d, J
= 8.7Hz), 8.52 (1H, t, J = 9.5Hz) MASS m / z: 445 (M ⁺ )

Example 2 (9S) -1-Amino-9-ethyl-2,3-dihydro-9-hydroxy
-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,
Synthesis of 2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0044]

[Chemical 8]

300 N of the compound obtained in Example (1) was added to 6N-
The reaction solution obtained by adding 100 ml of a hydrochloric acid aqueous solution was heated under reflux for 4 hours. After allowing to cool, the reaction mixture is concentrated and water is added to the resulting residue.
100 ml was added, insoluble matter was removed using FALCON 7105 (0.22 μm), and the residue obtained by concentrating the filtrate was subjected to reverse phase high performance liquid chromatography [CAPCELL PAK C18 (manufactured by Shiseido); acetonitrile: water: 1N hydrochloric acid (20 : 80: 2)] and two diastereoisomers were separated. The residue obtained by concentrating the first-eluting fraction was reprecipitated with methanol and acetonitrile to obtain 74 mg of the title compound (isomer A). Then, the second eluting fraction was treated in the same manner to obtain 90 mg of the title compound (isomer B). In the following examples, similarly, the isomer that elutes first in the reversed-phase high-performance liquid chromatography is A, and the isomer that elutes later is B. Isomer A: Melting point: 240 ° C or higher (decomposition) [α] _D ²⁰ = + 178 ° (c = 0.25, in H ₂ O) IRν _max ^KBr cm ⁻¹ : 3440, 1738, 1658 NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.2Hz), 1.85-1.94
(2H, m), 2.17-2.23 (1H, m), 3.20-3.23 (1H, m), 3.36-3.43
(1H, m), 5.12 (1H, br s), 5.42-5.46 (3H, m), 5.94 (1H, d, J
= 19Hz), 6.53 (1H, s), 7.38 (1H, s), 7.61 (1H, d, J = 7.2Hz),
7.85 (1H, t, J = 7.2Hz), 8.09 (1H, d, J = 8.8Hz), 8.77 (3H, br) MASS m / z: 403 (M ⁺ ) [α] _D ²⁰ = -38 ° ( c = 0.25, in H ₂ O) Isomer B: Melting point: 240 ° C. or higher (decomposition) IRν _max ^KBr cm ⁻¹ : 3444, 1740, 1658 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.84-1.93
(2H, m), 2.16-2.23 (1H, m), 3.21-3.24 (1H, m), 3.38-3.45
(1H, m), 5.13 (1H, br s), 5.42-5.49 (3H, m), 5.98 (1H, d, J
= 19Hz), 7.38 (1H, s), 7.61 (1H, d, J = 7.2Hz), 7.86 (1H, t, J =
7.2Hz), 8.09 (1H, d, J = 8.8Hz), 8.77 (3H, br) MASS m / z: 403 (M ⁺ )

Example 3 (9S) -1-Acetylamino-9-ethyl-2,3-dihydro-9-hydroxy-4-methoxy-1H, 12H-benzo [de] pyrano [3 ', 4':
Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0047]

[Chemical 9]

(1) 2-hydroxyimino-5-methoxy-8-
Nitro-1-tetralone: In Example 1- (2), 1.5 g of 5-methoxy-8-nitro-1-tetralone was used in place of 8-acetylamino-1-tetralone. By reacting in the same manner as described above and performing post-treatment, the title compound 74
0 mg was obtained. IRν _max ^KBr cm ^-1 : 3428, 3256, 1696, 1604, 1580,
1534 NMR (in DMSO-d6) δ: 2.95 (4H, s), 3.94 (3H, s), 7.32
(1H, d, J = 8.7Hz), 7.78 (1H, d, J = 8.7Hz) MASS m / z: 251 (M ⁺ )

(2) 2,8-diacetylamino-5-methoxy-1-
Tetralone: 8-acetylamino in Example 1- (3)
-2-hadoxyimino-1-tetralone instead of above (1)
225 mg of the title compound was obtained by reacting 500 mg of the compound obtained in 1. with the same reaction as in Example 1- (3) and performing post-treatment.
Got IR ν _max ^KBr cm ⁻¹ : 3432, 1696, 1642, 1532 NMR (in CDCl ₃ ) δ: 1.6-2.0 (1H, m), 2.11 (3H, s), 2.21
(3H, s), 2.6-3.2 (3H, m), 3.85 (3H, s), 4.5-4.8 (1H, m), 7.
09 (1H, d, J = 9.2Hz), 8.55 (1H, d, J = 9.2Hz) MASS m / z: 290 (M ⁺ )

(3) 2-Acetylamino-8-amino-5-methoxy-1-tetralone: In Example 1- (4), the above (2) is used instead of 2,8-diacetylamino-1-tetralone. Using 200 mg of the obtained compound, a reaction was carried out in the same manner as in Example 1- (4),
Post-treatment was carried out to obtain 130 mg of the title compound. IR ν _max ^KBr cm ⁻¹ : 3444, 2940, 1632, 1564, 1534 NMR (in CDCl ₃ ) δ: 1.6-2.0 (1H, m), 2.08 (3H, s), 2.6-
3.4 (3H, m), 3.77 (3H, s), 4.52-4.61 (1H, m), 6.52 (1H, d, J
= 9.2Hz), 6.98 (1H, d, J = 9.2Hz) MASS m / z: 248 (M ⁺ )

(4) (9S) -1-Acetylamino-9-ethyl-2,3
-Dihydro-9-hydroxy-4-methoxy-1H, 12H-benzo
[de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-1
0,13 (9H, 15H) -dione: 125 mg of the compound obtained in (3) and 133 mg of trione were reacted for 24 hours in the same manner as in Example 1- (5) and post-treated to give 207 mg of the title compound. Got Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3448, 1748, 1660, 1600 NMR (in DMSO-d ₆ ) δ: 0.88 (3H, dt, J = 3.2,7.2Hz), 1.84
-1.89 (2H, m), 1.92 (3H, d, J = 4.8Hz), 2.06-2.07 (2H, m), 3.
07-3.08 (2H, m), 4.00 (3H, s), 5.20 (2H, d, J = 4.8Hz), 5.41
(2H, d, J = 4.8Hz), 5.52-5.54 (1H, m), 6.48 (1H, d, J = 1.6H
z), 7.28 (1H, d, J = 2.4Hz), 7.77 (1H, d, J = 9.5Hz), 8.08 (1
H, d, J = 9.5Hz), 8.44 (1H, t, J = 9.5Hz) MASS m / z: 475 (M ⁺ )

Example 4 (9S) -1-Amino-9-ethyl-2,3-dihydro-9-hydroxy
Of 4--4-methoxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione ・ hydrochloride :

[0053]

[Chemical 10]

102 mg of the compound obtained in Example 3- (4) was reacted for 6 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (50 mg) and isomer B (44 mg). Got each. Isomer A: Melting point: 240 ° C or higher (decomposition) [α] _D ²⁰ = + 78 ° (c = 0.25, in H ₂ O) IRν _max ^KBr cm ⁻¹ : 3448, 2936, 1740, 1658, 1598 NMR (DMSO- d ₆ middle) δ: 0.90 (3H, t, J = 7.2Hz), 1.84-1.93
(2H, m), 2.07-2.12 (1H, m), 2.94-3.00 (1H, m), 3.25-3.33
(1H, m), 4.03 (3H, s), 5.07 (1H, br), 5.40-5.44 (3H, m),
5.91 (1H, d, J = 19Hz), 7.32 (1H, s), 7.83 (1H, d, J = 9.5Hz),
8.15 (1H, d, J = 8.8Hz), 8.75 (3H, br) MASS m / z: 433 (M ⁺ ) Isomer B: Melting point: 240 ° C or higher (decomposition) [α] _D ²⁰ = -34 ° (c = 0.25, H ₂ O) IRν _max ^KBr cm ⁻¹ : 3448, 1744, 1654 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.84-1.91
(2H, m), 2.06-2.12 (1H, m), 2.95-3.01 (1H, m), 4.03 (3H,
s), 5.07 (1H, br), 5.41-5.44 (3H, br s), 5.93 (1H, d, J = 19H
z), 7.32 (1H, s), 7.84 (1H, d, J = 9.5Hz), 8.16 (1H, d, J = 8.8H
z), 8.78 (3H, br) MASS m / z: 433 (M ⁺ )

Example 5 (9S) -1-Amino-9-ethyl-2,3-dihydro-4,9-dihydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7 ] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0056]

[Chemical 11]

90 mg of the compound obtained in Example 3- (4) was added to 47
% Hydrobromic acid aqueous solution (30 ml), the mixture was heated under reflux for 3 hours, the solvent was concentrated under reduced pressure, 30 ml of water was added to the obtained residue, and the insoluble matter was removed using FALCON 7105 (0.22 μm). The residue obtained by concentrating the filtrate was subjected to reverse phase high performance liquid chromatography [CAPCELL PAK C18 (manufactured by Shiseido); acetonitrile:
The product was purified with water: 1N hydrochloric acid (20: 80: 2)] to give the title compound as isomer A (34 mg) and isomer B (35 mg), respectively. Isomer A: Melting point: 240 ° C or higher (decomposition) [α] _D ²⁰ = + 135 ° (c = 0.2, in H ₂ O) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz) ), 1.83-1.92
(2H, m), 2.04-2.09 (1H, m), 2.88-2.95 (1H, m), 3.20-3.24
(1H, m), 5.04 (1H, br), 5.43 (3H, m), 5.89 (1H, d, J = 19Hz),
7.29 (1H, s), 7.61 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 9.5Hz),
8.71 (3H, br), 10.5 (1H, br) MASS m / z: 419 (M ⁺ ) Isomer B: Melting point: 240 ° C or higher (decomposition) [α] _D ²⁰ = -6.0 ° (c = 0.2, H ₂ (In O) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.84-1.91
(2H, m), 2.07-2.09 (1H, m), 2.88-2.95 (1H, m), 3.21-3.24
(1H, m), 5.05 (1H, br), 5.39-5.47 (3H, m), 5.88 (1H, d, J = 1
9Hz), 7.29 (1H, s), 7.61 (1H, d, J = 8.7Hz), 7.98 (1H, d, J = 8.
7Hz), 8.68 (3H, br), 10.5 (1H, br) MASS m / z: 419 (M ⁺ )

Example 6 (9S) -9-Ethyl-2,3-dihydro-9-hydroxy-4-methoxy
-3- (1,3-dioxoisoindoline-2-yl) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline
Synthesis of -10,13 (9H, 15H) -dione:

[0059]

[Chemical 12]

(1) 4-hydroxy-5-methoxy-8-nitro-1
-Tetralone: 5-methoxy-8-nitro-1-tetralone (Japanese Patent Laid-Open No. 1-279891) 2.0 g and N-bromosuccinimide
After adding 2.05 g to 50 ml of carbon tetrachloride, a catalytic amount of benzoyl peroxide was added and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, 50 ml of chloroform was added, and the mixture was washed successively with 10% sodium hydroxide, water and saturated saline,
It was dried over anhydrous sodium sulfate. To the residue obtained by concentrating the solvent, tetrahydrofuran 5 ml, ethanol 5 ml,
8 ml of water and 250 mg of calcium carbonate were added, the mixture was heated under reflux for 16 hours, and the solvent was concentrated. 50 ml of water was added to the residue and the mixture was extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated to obtain 1.49 g of the title compound as a pale yellow powder. NMR (in CDCl ₃ ) δ: 2.2-2.4 (2H, m), 2.5-2.7 (2H, m),
3.0-3.2 (1H, m), 4.00 (3H, s), 5.29 (1H, s), 7.09 (1H, d, J =
8.8Hz), 7.52 (1H, d, J = 8.8Hz)

(2) 8-amino-5-methoxy-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: 424 mg of the compound obtained in (1), 288 mg of phthalimide, triphenyl Phosphine (517 mg) was added to 20 ml of dry THF, and a solution of 0.34 ml of diethyl azodicarboxylate (hereinafter abbreviated as DEAD) in THF was gradually added while cooling in an ice bath. After stirring at the same temperature for 30 minutes, 30 ml of water was added and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 50 ml of dioxane and 50 ml of ethanol were added to the residue, and 280 mg of 10% palladium-carbon was added for catalytic hydrogenation. Then, the catalyst was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-ethyl acetate (9: 1), and the fractions containing the target compound were concentrated to obtain 306 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.1-3.2 (4H, m), 3.36 (3H, s), 5.70
(1H, m), 6.56 (1H, d, J = 9Hz), 6.86 (1H, dJ = 9Hz), 7.6-7.8
(4H, m)

(3) (9S) -9-Ethyl-2,3-dihydro-9-hydroxy-4-methoxy-3- (1,3-dioxoisoindoline-2-
Yl) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione: toluene 30
306 mg of the compound obtained in (2) and 220 mg of trione were added to ml, and a catalytic amount of PPTS was added, and the mixture was heated under reflux for 6 hours using a Dean Stark apparatus. The reaction liquid was cooled and the precipitate was filtered to obtain 390 mg of the title compound. NMR (in CDCl ₃ ) δ: 1.04 (3H, t, J = 7.6Hz), 1.8-2.0 (2H,
m,), 2.3-2.4 (1H, m), 2.5-2.56 (1H, m), 3.1-3.2 (1H, m),
3.3-3.41 (1H, m), 3,87 (3H, s), 5.25 (2H, s), 5.31,5.75 (2
H, ABq, J = 15.9Hz), 6.05 (1H, m), 7.52 (1H, d, J = 9.5Hz), 7.
6-7.8 (5H, m), 8.28 (1H, d, J = 9.5Hz)

Example 7 (9S) -3-Amino-9-ethyl-2,3-dihydro-9-hydroxy-4
Synthesis of -Methoxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0064]

[Chemical 13]

224 mg of the compound obtained in (3) of Example 6 was dissolved in 14 ml of chloroform, and 10 ml of methanol was added.
1.2 ml of hydrazine monohydrate was added and stirred for 2 hours. After concentrating the solvent, 7 ml of 5N hydrochloric acid was added to the residue and the mixture was heated under reflux for 1 hour. After cooling, 10 ml of water was added to remove insoluble matter by filtration, and the residue obtained by concentrating the filtrate was subjected to high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-1N hydrochloric acid (20: 80: 1). Development] to obtain the title compound as isomer A (94 mg) and isomer B (80 mg). Isomer A: mp: 215 ° C. or higher (decomposed) NMR (CD ₃ in 0D) δ: 1.00 (3H, t, J = 7.2Hz), 1.95 (2H, m),
2.4-2.5 (1H, m), 2.5-2.6 (1H, m), 3.2-3.4 (2H, m), 4.12
(3H, s), 5.17 (1H, m), 5.23,5.32 (2H, ABq, J = 19.1Hz), 5.3
7,5.55 (2H, ABq, J = 16.7Hz), 7.62 (1H, s), 7.85 (1H, d, J = 9.
5Hz), 8.28 (1H, d , J = 9.5Hz) Isomer B: mp: 180 ° C. or higher (decomposed) NMR (CD ₃ in 0D) δ: 1.01 (3H, t, J = 7.1Hz), 1.97 (2H, m),
2.3-2.45 (1H, m), 2.5-2.6 (1H, m), 3.2-3.4 (2H, m), 4.16
(3H, s), 5.18 (1H, m), 5.25,5.38 (2H, ABq, J = 19.1Hz), 5.3
9,5.57 (2H, ABq, J = 16.7Hz), 7.67 (1H, s), 7.89 (1H, d, J = 9.
5Hz), 8.31 (1H, d, J = 9.5Hz)

Example 8 (9S) -3-Amino-9-ethyl-2,3-dihydro-4,9-dihydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] Indian lizino
Synthesis of [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0067]

[Chemical 14]

94 mg of the isomer A obtained in Example 7 was added to acetic acid 25
After being dissolved in 20 ml of 47% hydrobromic acid, the mixture was heated to reflux for 30 hours. After the solvent was distilled off, 10 ml of water was added to remove insoluble matter. High performance liquid chromatography [CAPC
ELL PAK C18; acetonitrile-water-1N hydrochloric acid (20: 8
0: 1)], the fraction containing the desired product was concentrated, and the residue was reprecipitated using methanol-ethanol-ethyl acetate to give the title compound as isomer A.
(17 mg), and in the same manner as the above, the title compound was obtained from the isomer B (68 mg) of Example 7 as isomer B (11 mg).
Got as. Isomer A: Melting point: 170 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.82 (2H,
m), 2.1-2.2 (1H, m), 2.4-2.6 (1H, m), 3.15-3.35 (2H, m),
4.93 (1H, m), 5.21,5.33 (2H, ABq, J = 19.1Hz), 5.41,5.45 (2
H, ABq, J = 15.9Hz), 7.28 (1H, s), 7.64 (1H, d, J = 9.5Hz), 8.
20 (1H, d, J = 9.5Hz), 8.25-8.35 (3H, m) Isomer B: mp: 195 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.89} (3H, t, J = 7.6 Hz), 1.8-2.0 (2
H, m), 2.1-2.2 (1H, m), 2.4-2.6 (1H, m), 3.15-3.35 (2H,
m), 4.94 (1H, m), 5.21,5.34 (2H, ABq, J = 19.1Hz), 5.43 (2
H, s), 7.28 (1H, s), 7.65 (1H, d, J = 9.5Hz), 8.10 (1H, d, J = 9.
5Hz), 8.25-8.35 (3H, m)

Example 9 (9S) -2-Acetylamino-9-ethyl-2,3-dihydro-9-hydroxy-4-methoxy-1H, 12H-benzo [de] pyrano [3 ', 4':
Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0070]

[Chemical 15]

(1) 2-Acetylamino-8-methoxytetralin: 8-methoxy-2-tetralone [J. Chem. Soc., 2636
(1965)] To a solution of 5.18 g dissolved in 100 ml of methanol was added sodium cyanoborohydride (560 mg) and ammonium acetate (4.86 g), and the mixture was stirred at room temperature for 89 hours. The reaction solution was ice-cooled, adjusted to pH 1 or less with concentrated hydrochloric acid, added with 500 ml of water and washed with ether, the aqueous layer was adjusted to pH 10 or more with potassium hydroxide, and extracted with ether. After the extract was dried over magnesium sulfate, the solvent was concentrated and the resulting residue was washed with methylene chloride.
After dissolving in ml, 2 ml of pyridine and 2.4 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is a 10% aqueous hydrochloric acid solution,
The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in that order, dried over magnesium sulfate, the solvent was concentrated, and the residue was recrystallized from ethyl acetate and hexane to give 2.47 g of the title compound.
Got NMR (in CDCl ₃ ) δ: 1.75-2.11 (2H, m), 1.98 (3H, s), 2.
49-2.58 (1H, m), 2.79-3.32 (3H, m), 3.80 (3H, s), 4.21-4.
37 (1H, m), 6.62-6.76 (2H, m), 7.12 (1H, t, J = 7.9Hz)

(2) 2-Acetylamino-8-methoxy-5-nitrotetralin: 20 ml of acetic anhydride was cooled to 0 ° C., and fuming nitric acid was added.
2.2 g of the compound obtained in (1) was added little by little to a solution obtained by slowly adding 1.75 ml and further adding 1 drop of concentrated sulfuric acid, and stirring for 20 minutes. Next, 40 ml of 25% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, the organic layer was dried over magnesium sulfate, the solvent was concentrated, and the resulting residue was subjected to silica gel column chromatography and developed with a mixed solvent of chloroform: methanol = 80: 1. The fraction containing the desired product was concentrated to obtain 770 mg of the title compound. Melting point: 207-210 ° C NMR (in CDCl ₃ ) δ: 1.6-2.2 (2H, m), 2.01 (3H, s), 2.3-
2.6 (1H, m), 3.10-3.24 (3H, m), 3.89 (3H, s), 4.26 (1H, m),
6.76 (1H, d, J = 9.1Hz), 7.96 (1H, d, J = 8.9Hz)

(3) 2,5-Diacetylamino-8-methoxytetralin: 320 mg of the compound obtained in (2) was dissolved in a mixed solvent of 5 ml of acetic acid and 5 ml of acetic anhydride, and then 80 mg of 10% palladium carbon was added.
Is added and catalytic hydrogenation is carried out for 5 hours. The catalyst was removed by filtration, and the residue obtained by concentrating the filtrate was recrystallized from chloroform to obtain 190 mg of the title compound. NMR (in CDCl ₃ ) δ: 1.6-2.2 (2H, m), 1.96 (3H, s), 2.16
(3H, s), 2.4-2.9 (4H, m), 3.80 (3H, s), 4.0-4.4 (1H, m), 6.
68 (1H, d, J = 8.5Hz), 7.18 (1H, d, J = 8.5Hz)

(4) 3,8-Diacetylamino-5-methoxy-1-
Tetralone: 190 mg of the compound obtained in (3) and 16 ml of acetone
And 15% magnesium sulfate aqueous solution (4 ml) were suspended in the mixture, potassium permanganate (543 mg) was added, and the mixture was stirred at room temperature for 1.5 hr. 150 ml of water was added to the reaction solution, followed by extraction with chloroform. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was concentrated and the resulting residue was recrystallized from ethyl acetate and hexane to give the title compound 12
4 mg was obtained. NMR (in CDCl ₃ ) δ: 1.96 (3H, s), 2.21 (3H, s), 2.6-3.4
(4H, m), 3.84 (3H, s), 4.4-4.7 (1H, m), 7.11 (1H, d, J = 9.2H
z), 8.61 (1H, d, J = 9.2Hz)

(5) 3-Acetylamino-8-amino-5-methoxy-1-tetralone: 102 mg of the compound obtained in (4) was added to 3N-
It was added to 20 ml of an aqueous hydrochloric acid solution, and the mixture was heated with stirring at 60 ° C. for 2 hours. The reaction mixture was cooled to 0 ° C., neutralized with sodium carbonate, extracted with chloroform, and the extract was dried over magnesium sulfate. The residue obtained by concentrating the solvent was subjected to silica gel column chromatography, developed with chloroform-methanol (40: 1), and the fractions containing the target compound were concentrated to obtain 66 mg of the title compound. NMR (in CDCl ₃ ) δ: 1.94 (3H, s), 2.51-3.34 (4H, m), 3.
76 (3H, s), 4.06-4.75 (1H, m), 6.55 (1H, d, J = 9.0Hz), 7.00
(1H, d, J = 9.0Hz)

(6) (9S) -2-Acetylamino-9-ethyl-2,3
-Dihydro-9-hydroxy-4-methoxy-1H, 12H-benzo
[de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-1
0,13 (9H, 15H) -dione: 126 mg of the compound obtained in (5) and 134 mg of trione were reacted for 24 hours in the same manner as in Example 1- (5) and post-treated to give 103 mg of the title compound. It was IRν _max ^KBr cm ^-1 : 3392,1748,1660,1600 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.85 (3H,
s), 1.87-1.93 (2H, m), 2.67-2.81 (1H, m), 3.02-3.09 (1H,
m), 3.97 (3H, s), 4.22 (1H, br), 5.09-5.25 (2H, m), 5.37-
5.46 (2H, m), 6.47 (1H, br s), 7.29 (1H, s), 7.71 (1H, d, J =
9.3Hz), 8.03 (1H, d, J = 9.3Hz), 8.13 (1H, br) MASS m / z: 475 (M ⁺ )

Example 10 (9S) -2-Amino-9-ethyl-2,3-dihydro-9-hydroxy
Of 4--4-methoxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione ・ hydrochloride :

[0078]

[Chemical 16]

48 mg of the compound obtained in Example 9 was used in Example 2
The reaction was carried out for 6 hours in the same manner as in, and post-treatment was carried out to obtain 42 mg of the title compound. Mp: 240 ° C. or higher _{^{(decomposed) IRν max KBr cm -1: 3440,1744,1658,1592}} NMR ( in _{DMSO-d 6) δ: 0.89} (3H, t, J = 7.3Hz), 1.83-1.93
(2H, m), 2.95-3.02 (1H, m), 3.26-3.33 (1H, m), 3.76 (1H, b
r), 4.00 (3H, s), 5.15-5.26 (2H, m), 5.43 (2H, s), 7.30 (1
H, s), 7.77 (1H, d, J = 9.3Hz), 8.09 (1H, d, J = 9.3Hz), 8.55
(3H, br) MASS m / z: 433 (M ⁺ )

Example 11 (9S) -2-Amino-9-ethyl-2,3-dihydro-4,9-dihydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,7 ] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0081]

[Chemical 17]

46 mg of the compound obtained in Example 9 was used in Example 5
By reacting in the same manner as above and post-treating, the title compound
18 mg was obtained. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3420,1742,1658,1590 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.85-1.92
(2H, m), 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.75 (1H, b
r), 5.23 (2H, d, J = 6.4Hz), 5.42 (2H, s), 7.27 (1H, s), 7.55
(1H, d, J = 9.3Hz), 7.93 (1H, d, J = 8.8Hz), 8.48 (3H, br s),
10.5 (1H, br s) MASS m / z: 419 (M ⁺ )

Example 12 (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy-4
-Methyl-12H-thiino [4,3,2-de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride Synthesis of:

[0084]

[Chemical 18]

(1) 3,5-Diacetylamino-8-methyl-4-thiochromanone: TH containing 153 mg of potassium-t-butoxide
5-acetylamino-8-methyl-4-thiochromanone [J. Heterocyc
lic Chem., 11, 515 (1974)] (291 mg) in THF solution (9 ml) was added, the mixture was stirred for 5 min, n-butyl nitrite (0.22 ml) was added, and the mixture was stirred at room temperature for 1 hr. Add 20 ml of ether to the reaction mixture and
After stirring for hours, the precipitate was filtered and washed well with ether. The precipitate was dissolved in a mixed solution of 20 ml of acetic acid and 20 ml of acetic anhydride, and while stirring at room temperature, about 200 mg of zinc powder was gradually added, and the mixture was further stirred for 0.5 hours. The insoluble material was removed by filtration, the solvent was evaporated, 20 ml of chloroform was added, the mixture was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fraction containing the target compound was concentrated to obtain 109 mg of the title compound. It was NMR (in CDCl ₃ ) δ: 2.12 (3H, s), 2.23 (3H, s), 2.26 (3
H, s), 3.06 (1H, dd, J = 12.5Hz, 13.7Hz), 3.60 (1H, dd, J = 4.4H
z, 12.5Hz), 4.94 (1H, ddd, J = 4.4Hz, 4.9Hz, 13.7Hz), 6.82
(1H, m), 7.29 (1H, d, J = 8.8Hz), 8.39 (1H, d, J = 8.8Hz)

(2) 3-acetylamino-5-amino-8-methyl-
4-Thiochromanone: 109 mg of the compound obtained in (1) was added to 10 ml of 6N hydrochloric acid, and the mixture was stirred at 90 ° C for 20 minutes. After cooling, the mixture was made alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated to give 51 mg of the title compound. Got NMR (in CDCl ₃ ) δ: 2.09 (3H, s), 2.16 (3H, s), 2.98 (1
H, m), 3.60 (1H, m), 4.6-5.0 (1H, m), 6.33 (1H, d, J = 9Hz),
702 (1H, d, J = 9Hz)

(3) (9S) -1-Amino-9-ethyl-1,2-dihitoro-9-hydroxy-4-methyl-12H-thiino [4,3,2-de] pyrano [3 ', 4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H,
15H) -dione hydrochloride: 45 mg of the compound obtained in (2) and 47 mg of trione were added to 10 ml of toluene, a catalytic amount of PPTS was added, and the mixture was heated under reflux for 15 hours using a Dean Stark apparatus. The reaction solution was cooled, the solvent was distilled off, the residue was subjected to silica gel column chromatography, developed with chloroform-methanol (98: 2), and the fraction containing the target compound was concentrated to obtain a residue. , 6N hydrochloric acid (10 ml) was added, and the mixture was stirred for 4 hours. After concentrating the solvent, 10 ml of water was added to remove insoluble materials by filtration, and the filtrate was filtered by high performance liquid chromatography [CAPCELL PAK
C18; developed with acetonitrile-water-1N hydrochloric acid (20: 80: 1)] to obtain the title compound as isomer A (37 mg) and isomer B (36 mg). Isomer A: Melting point: 210 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.8-1.95
(2H, m), 3.5-3.65 (2H, m), 5.38 (1H, m), 5.43,5.89 (2H, AB
q, J = 19.5Hz), 5.44 (2H, s), 6.53 (1H, s), 7.34 (1H, s), 7.
78 (1H, d, J = 8.3Hz), 7.96 (1H, d, J = 8.3Hz), 8.88 (3H, m) Isomer B: mp: 224 ° C. or higher (decomposed) NMR (in DMSO-d ₆₎ δ : 0.89 (3H, t, J = 7.3Hz), 1.8-1.95
(2H, m), 3.54 (1H, dd, J = 14.2Hz, 1.5Hz), 3.63 (1H, dd, J = 14.
2Hz, 3.4Hz), 5.39 (1H, m), 5.45 (2H, m), 5.47,5.92 (2H, AB
q, J = 19.5Hz), 6.54 (1H, s), 7.36 (1H, s), 7.79 (1H, d, J = 8.
8Hz), 7.97 (1H, d, J = 8.8Hz), 8.94 (3H, m)

Example 13 (9S) -3-Amino-4-fluoro-9-ethyl-2,3-dihydro-9-
Synthesis of hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0089]

[Chemical 19]

(1) 2-Fluorocinnamic acid methyl ester: 15 g of 2-fluorocinnamic acid in 100 ml of methanol
Suspended in and kept at 0 ° C., 1.7 g of thionyl chloride was added slowly. After the dropping was completed, the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 4 hours. By subjecting the residue obtained by concentrating the solvent to silica gel column chromatography and developing with chloroform to concentrate the fraction containing the target substance,
17.8 g of the title compound was obtained. NMR (in CDCl ₃ ) δ: 3.82 (3H, s), 6.54 (1H, d, J = 16.2H
z), 6.97-7.63 (4H, m), 7.82 (1H, d, 16.2Hz)

(2) 3- (2-Fluorophenyl) propanoic acid methyl ester: the compound obtained in (1) 17.
Dissolve 8 g in 200 ml of methanol and add 6 g of 10% palladium-
Catalytic hydrogenation was performed using carbon as a catalyst. The catalyst was filtered off and the solvent was distilled off to obtain 14.7 g of the title compound. NMR (in CDCl ₃ ) δ: 2.53-2.72 (2H, m), 2.8-3.1 (2H, m),
3.67 (3H, s), 6.97-7.28 (4H, m)

(3) 3- (2-fluorophenyl) propanol: 110 ml of 2.2 g of lithium aluminum hydride
After suspending in the dry THF of 1. and stirring at room temperature for 1 hour, a THF solution (40 ml) of 5 g of the compound obtained in (2) was added over 15 minutes. After stirring at room temperature for 12 hours, 20 ml of ethyl acetate was added and the mixture was further stirred for 3 hours. Saturated ammonium chloride solution
After adding 5 ml and stirring for 30 minutes, the precipitate was filtered off. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (4.27 g). NMR (in CDCl ₃ ) δ: 1.6-2.1 (2H, m), 2.75 (2H, t, J = 7.5H
z), 3.68 (2H, t, J = 6.34Hz), 6.8-7.6 (4H, m)

(4) 3- (2-Fluorophenyl) propyl tosylate: Compound 1 obtained in (3) in 200 ml of dry pyridine.
7.75g was melt | dissolved, Tosyl chloride 24.25g was slowly added at 0 degreeC, and it stirred at room temperature for 3 hours. After adding 300 ml of ether and washing with water, 6N hydrochloric acid was added until it showed acidity, washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off to obtain 31.3 g of the title compound. NMR (in CDCl ₃ ) δ: 1.8-2.2 (2H, m), 2.45 (3H, s), 2.68
(2H, t, J = 7.8Hz), 4.04 (2H, t, J = 6.2Hz), 6.8-7.4 (4H.m),
7.33 (2H, d, J = 8Hz), 7.79 (2H, d, J = 8Hz)

(5) 4- (2-Fluorophenyl) butanonitrile: 9.89 in 35 ml of dimethyl sulfoxide (hereinafter abbreviated as DMSO)
g of sodium cyanide was dissolved, 70 ml of DMSO solution of 31.2 g of the compound obtained in (4) at room temperature was added dropwise, and the mixture was stirred for 12 hours. After adding 500 ml of water and extracting twice with 200 ml of ether,
15.4 g of the title compound was obtained by successively washing with water and saturated saline and drying over anhydrous sodium sulfate, and then distilling off the solvent.
Got NMR (in CDCl ₃ ) δ: 1.8-2.2 (2H, m), 2.15-2.42 (2H, m),
2.81 (2H, t, J = 7.65Hz), 6.8-7.3 (4H.m)

(6) 4- (2-Fluorophenyl) butanoic acid: 15.4 g of the compound obtained in (5) was added to a mixed solution of 400 ml of a 5% sodium hydroxide aqueous solution and 400 ml of diethylene glycol monoethyl ether, and the mixture was added for 3.5 hours. After heating to reflux,
It was cooled to room temperature and washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted twice with 500 ml of ethyl acetate, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. Compound 1
5.9 g was obtained. NMR (in CDCl ₃ ) δ: 1.75-2.15 (2H, m), 2.28-2.55 (2H,
m), 2.71 (2H, t, J = 7.43Hz), 6.8-7.4 (4H.m)

(7) 5-Fluoro-1-tetralone: 200 g of polyphosphoric acid was heated to 80 ° C. and stirred, and 15.9 g of the compound obtained in (6) was added over 1 hour. Stir for hours. The reaction solution was poured into ice water and extracted with chloroform, and then the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound 14.1 got g. NMR (in CDCl ₃ ) δ: 2.16 (2H, m), 2.67 (2H, t, J = 6.3Hz),
2.96 (2H, t, J = 6.3Hz), 7.20-7.31 (2H, m), 7.84 (1H, d, J =
7.81Hz)

(8) 5-Fluoro-8-nitro-1-tetralone:
After dissolving 14 g of the compound obtained in (7) in 100 ml of concentrated sulfuric acid and cooling to -5 ° C, 80 ml of concentrated sulfuric acid solution of 9.05 g of potassium nitrate was added.
The mixture was added dropwise while keeping the internal temperature at 5 ° C or lower. After stirring for 30 minutes after the addition was completed, the reaction solution was poured into ice water and extracted with chloroform.The extract solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was added. Distilled off. The residue was recrystallized from methanol to obtain 9.15 g of the title compound. NMR (in CDCl ₃ ) δ: 2.18-2.24 (2H, m), 2.74 (2H, t, J = 6.
3Hz), 2.99 (2H, t, J = 6.3Hz), 7.29 (1H, t, J = 8.3Hz), 7.38 (1
(H, dd, J = 4.4Hz, 8.8Hz)

(9) 5-Fluoro-8-nitro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: carbon tetrachloride 2
323 mg of the compound obtained in (8), 323 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added to 0 ml, and the mixture was heated under reflux for 4.5 hours. After cooling to room temperature, chloroform 30 ml
Was added, and the mixture was washed successively with cold 3% aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was added to 15 ml of dimethylformamide (hereinafter
After dissolving in DMF) and cooling to 0 ° C, 100 mg of sodium azide was added little by little, and at 0 ° C for 30 minutes at room temperature
After stirring for 30 hours, 30 ml of water was added. After extracting twice with ether, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fraction containing the desired product was concentrated to obtain 308 mg of 4-position azide. 10 ml of benzene and 39 of triphenylphosphine were added to the obtained azide.
After adding 0 mg and phthalic anhydride 220 mg and heating under reflux for 7 hours, 37 mg of tetra-n-butylammonium cyanide was added and further heating under reflux for 12 hours. After cooling to room temperature, 20 ml of ethyl acetate was added, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (2: 1), and the fractions containing the target compound were concentrated to obtain 395 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.51-2.62 (2H, m), 2,78-2.84 (1H,
m), 3.06-3.10 (1H, m), 5.87 (1H, t, J = 5.0Hz), 7.28 (1H, t,
J = 8.8Hz), 7.51 (1H, dd, J = 4.4Hz, 8.8Hz), 7.74-7.78 (2H,
m), 7.82-7.87 (2H, m)

(10) 8-Amino-5-fluoro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: 320 mg of the compound obtained in (9), 9 ml of dioxane and 15 ml of ethanol. Was added, and 290 mg of 10% palladium-carbon was added for catalytic hydrogenation, the catalyst was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and hexane-
The mixture was developed with a mixed solvent of ethyl acetate (2: 1), and the fractions containing the target compound were concentrated to obtain 206 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.3-2.55 (2H, m), 2.61-2.70 (1H,
m), 2.85-2.30 (1H, m), 5.78 (1H, m), 6.59 (1H, dd, J = 4.4H
z, 8.8Hz), 6.96 (1H, t, J = 8.8Hz), 7.65-7.75 (2H, m), 7.75-
7.85 (2H.m)

(11) (9S) -9-Ethyl-4-fluoro-2,3-dihydro-9-hydroxy-3- (1,3-dioxoisoindoline-2-
Ill) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione: toluene 10
The compound (74 mg) obtained in (10) and trione (66 mg) were reacted in ml in the same manner as in Example 1- (5) for 15 hours, and post-treated to give 120 mg of the title compound. NMR (in _{DMSO-d 6) δ: 0.90} (3H, t, J = 7.3Hz), 1.89 (2H,
m), 2.36 (1H, m), 2.45-2.5 (1H, m), 3.25-3.4 (2H, m), 5.3
4 (2H, s), 5.45 (2H, s), 5.99 (1H, m), 7.36 (0.5H, s), 7.37
(0.5H, s), 7.69 (1H, t, J = 9.3Hz), 7.86 (4H, s), 8.18 (1H, d
(d, J = 5.4Hz, 9.3Hz)

(12) (9S) -3-Amino-4-fluoro-9-ethyl
-2,3-Dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H,
15H) -dione hydrochloride: 120 mg of the compound obtained in (11) was dissolved in a mixture of 7 ml of chloroform and 5 ml of methanol, 0.7 ml of hydrazine monohydrate was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness, 7 ml of 4N hydrochloric acid was added to the residue, and the mixture was heated under reflux for 1 hr. After the reaction mixture was concentrated to dryness, 10 ml of water was added to the residue.
Was added and the insoluble matter was filtered off. The filtrate was purified in the same manner as in Example 7 to obtain the title compound as isomer A (32 mg) and isomer B (20 mg). Isomer A: Melting point: 196 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.87 (2H,
m), 2.15-2.30 (1H, m), 2.4-2.6 (1H, m), 3.3-3.5 (2H, m),
5.08 (1H, m), 5.26,5.40 (2H, ABq, J = 19.0Hz), 5.44 (2H, s),
7.35 (1H, s), 7.88 (1H, t, J = 9.3Hz), 8.30 (1H, dd, J = 5.5Hz,
9.3Hz), 8.70 (3H, m) isomer B: Melting point: 215 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.88 (2H,
m), 2.15-2.30 (1H, m), 2.4-2.6 (1H, m), 3.3-3.4 (2H, m),
5.08 (1H, m), 5.28,5.40 (2H, ABq, J = 19Hz), 5.45 (2H, s),
7.36 (1H, s), 7.89 (1H, t, J = 9.3Hz), 8.30 (1H, dd, J = 5.4Hz,
9.3Hz), 8.65 (3H, m)

Example 14 (9S) -3-Amino-4-chloro-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6, 7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0103]

[Chemical 20]

(1) 5-chloro-8-nitro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: carbon tetrachloride 20 m
5-Chloro-8-nitro-1-tetralone (403 mg), N-bromosuccinimide (412 mg) and a catalytic amount of benzoyl peroxide were added to 1 and the mixture was heated under reflux for 6 hours. After cooling to room temperature, 30 ml of chloroform was added, and cold 3% sodium hydroxide aqueous solution, water,
The organic layer was washed successively with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was dissolved in 10 ml of DMF, cooled to 0 ° C, 140 mg of sodium azide was added little by little, and the mixture was stirred at 0 ° C for 30 minutes and further at room temperature for 1 hour, and then water 30 ml.
Was added. The mixture was extracted twice with ether, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fraction containing the desired product was concentrated to obtain 450 mg of 4-position azide. Benzene 20m in the obtained azide
l, triphenylphosphine 487mg, phthalic anhydride 275mg
Was added, the mixture was heated under reflux for 7 hours, 40 mg of tetra-n-butylammonium cyanide was added, and the mixture was further heated under reflux for 12 hours, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (2: 1), and the fractions containing the desired product were concentrated to obtain 356 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.40-2.48 (1H, m), 2.56-2.67 (1H,
m), 2.75-2.83 (1H, m), 2.96-3.75 (1H, m), 5.83 (1H, dd, J =
2.9Hz, 4.9Hz), 7.46 (1H, d, J = 8.3Hz), 7.63 (1H, d, J = 8.3H
z), 7.74-7.78 (2H, m), 7.82-7.84 (2H, m)

(2) 8-Amino-5-chloro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: 320 mg of the compound obtained in (1), 9 ml of dioxane and 15 ml of ethanol. Was added thereto, 200 mg of 10% palladium-carbon was added to carry out catalytic hydrogenation, the catalyst was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and hexane-
The mixture was developed with a mixed solvent of ethyl acetate (2: 1), and the fractions containing the desired product were concentrated to obtain 176 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.4-3.3 (4H, m), 5.72 (1H, m), 6.60
(1H, d, J = 8.3Hz), 7.17 (1H, d, J = 8.3Hz), 7.6-7.9 (4H, m)

(3) (9S) -3-Amino-4-chloro-9-ethyl-2,
3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano
[3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15
H) -dione hydrochloride: To 15 ml of toluene, 176 mg of the compound obtained in (2) and 135 mg of trione were reacted for 16 hours in the same manner as in Example 1- (5) and post-treated to give (9S) -9. -Ethyl-4-
Chloro-2,3-dihydro-9-hydroxy-3- (1,3-dioxoisoindoline-2-yl) -1H, 12H-benzo [de] pyrano [3 ',
4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H)-
193 mg of dione were obtained as a mixture of 3-position isomers. 171 mg of the obtained mixture was treated in the same manner as in Example 13- (12) to give the title compound as isomer A (63 mg) and isomer B (59 mg). Isomer A: Melting point: 190 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.86 (2H,
m), 2.24 (1H, m), 2.61 (1H, m), 3.2-3.5 (2H, m), 5.09 (1H,
m), 5.23,5.39 (2H, ABq, J = 19.5Hz), 5.44 (2H, s), 7.35 (1H,
s), 7.98 (1H, d, J = 9.3Hz), 8.23 (1H, d, J = 9.3Hz), 8.69 (3
H, m) Isomer B: Melting point: 215 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz), 1.88 (2H,
m), 2.24 (1H, m), 2.54 (1H, m), 3.3-3.5 (2H, m), 5.12 (1H,
m), 5.27,5.42 (2H, ABq, J = 19.0Hz), 5.45 (2H, s), 7.36 (1H,
s), 8.00 (1H, d, J = 9.3Hz), 8.26 (1H, d, J = 9.3Hz), 8.56 (3
H, m)

Example 15 (9S) -1-Acetylaminomethyl-4-chloro-9-ethyl-2,3-
Dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano
[3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15
H) -Dione synthesis:

[0108]

[Chemical 21]

(1) 8-Acetylamino-5-chloro-2-hydroxymethylene-1-tetralone: 8 ml of ethyl formate was added with 960 mg of 60% sodium hydride under stirring with ice cooling, and after warming to room temperature, 5 minutes later, 8-acetylamino-5-chloro-1-tetralone
A solution prepared by dissolving 1.43 g in 30 ml of dimethoxyethane was gradually added, 0.06 ml of ethanol was further added, and the mixture was stirred for 30 minutes. Pour the reaction solution into 300 ml of 14% aqueous sodium chloride solution,
Ethyl acetate was added for extraction, washed with 10% aqueous citric acid solution, saturated brine, dried over anhydrous sodium sulfate and concentrated, ether was added to the residue, and the precipitate was collected by filtration to give the title compound 1.30.
got g. IRν _max ^KBr cm ^-1 : 1650, 1574, 1502, 1194 NMR (in CDCl ₃ ) δ: 2.23 (s, 3H), 2.49 (t, 2H, J = 7Hz),
3.03 (t, 2H, J = 7Hz), 7.50 (d, 1H, J = 9Hz), 8.56 (d, 1H, J = 9H
z) MASS m / z: 265 (M ⁺ ), 267 (M ⁺ +2)

(2) 9-Acetylamino-6-chloro-4,5-dihydronaphtho [1,2-d] isoxazole: 1.29 g of the compound obtained in (1) was dissolved in 30 ml of acetic acid to give hydroxylamine.・
The hydrochloride (339 mg) was added, and the mixture was heated with stirring at 120 ° C for 10 minutes. After cooling the reaction solution, water was added and the precipitate was collected by filtration and washed with water and hexane to obtain 1.1 g of the title compound. IRν _max ^KBr cm ⁻¹ : 1664, 1524, 1390, 1288 NMR (in CDCl ₃ ) δ: 2.29 (s, 3H), 2.80 (t, 2H, J = 8Hz),
3.18 (t, 2H, J = 8Hz), 7.37 (d, 1H, J = 9Hz), 8.25 (s, 1H), 8.3
0 (d, 1H, J = 9Hz), 8.80 (s, 1H) MASS m / z: 262 (M ⁺ ), 264 (M ⁺ +2)

(3) 8-Acetylamino-5-chloro-2-cyano
-1-Tetralone: Dissolve 1.54 g of the compound obtained in (2) in 20 ml of absolute ethanol and stir it with sodium methoxide 460 m.
A solution prepared by dissolving g in 50 ml of absolute ethanol was gradually added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added 1N hydrochloric acid (10 ml) and water, the mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 1.36 g of the title compound. IRν _max ^KBr cm ^-1 : 2251, 1702, 1658, 1598, 1522 NMR (in CDCl ₃ ) δ: 2.26 (s, 3H), 2.3-2.7 (m, 2H), 2.9-
3.5 (m, 2H), 3.83 (dd, 1H, J = 12Hz, 5Hz), 7.61 (d, 1H, J = 9H
z), 8.70 (d, 1H, J = 9Hz), 11.56 (s, 1H) MASS m / z: 262 (M ⁺ ), 264 (M ⁺ +2)

(4) 8-acetylamino-2-acetylaminomethyl-5-chloro-1-tetralone: the compound obtained in (3)
Using 1.36 g, the reaction was carried out in the same manner as in Example 28- (3), and post-treatment was carried out to obtain 1.20 g of the title compound. NMR (in CDCl ₃ ) δ: 2.01 (s, 3H), 2.25 (s, 3H), 1.7-2.4
(m, 2H), 2.6-3.0 (m, 2H), 3.1-3.6 (m, 2H), 3.6-3.8 (m, 1
H), 6.23 (br.s, 1H), 7.52 (d, 1H, J = 9Hz), 8.60 (d, 1H, J = 9H
z), 11.89 (s, 1H) MASS m / z: 308 (M ⁺ ), 310 (M ⁺ +2)

(5) 2-Acetylaminomethyl-8-amino-5-
Chlor-1-tetralone: In Example 1- (4), the compound 1.20 g obtained in the above (4) was used in place of 2,8-diacetylamino-1-tetralone, and The same reaction and post-treatment gave 823 mg of the title compound. NMR (in CDCl ₃ ) δ: 1.98 (s, 3H), 1.7-2.3 (m, 2H), 2.5-
3.0 (m, 2H), 3.0-3.5 (m, 2H), 3.7-3.9 (m, 1H), 6.37 (br.s,
2H), 6.48 (d, 1H, J = 9Hz), 7.23 (d, 1H, J = 9Hz) MASS m / z: 266 (M ⁺ ), 268 (M ⁺ +2)

(6) (9S) -1-Acetylaminomethyl-4-chloro-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione: 820 mg of the compound obtained in (5)
And 808 mg of trione were reacted for 24 hours in the same manner as in Example 1- (5), the reaction solution was concentrated, 20 ml of acetic acid was added to the residue, and the mixture was heated with stirring at 110 ° C. for 6 hours. The reaction mixture was concentrated, the obtained residue was subjected to silica gel column chromatography, and the fraction containing the desired product was concentrated by developing with a mixed solvent of chloroform-methanol (40: 1) to obtain 420 mg of the title compound. It was NMR (in _{DMSO-d 6) δ: 0.88} (t, 3H, J = 7Hz), 1.87 (s, 3H),
1.7-2.0 (m, 2H), 2.2-3.6 (m, 7H), 5.37 (s, 2H), 5.45 (s,
2H), 6.52 (br.s, 2H), 7.34 (s, 1H), 7.88 (d, 1H, J = 9Hz), 8.
04 (d, 1H, J = 9Hz) MASS m / z: 493 (M ⁺ ), 495 (M ⁺ +2)

Example 16 (9S) -1-Aminomethyl-4-chloro-9-ethyl-2,3-dihydro
-9-Hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7]
Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione
Hydrochloride synthesis:

[0116]

[Chemical formula 22]

100 mg of the compound obtained in Example 15- (6) was reacted for 8 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (25 mg) and isomer B (22 mg), respectively. Obtained. Isomer A: mp: 230-240 ° C. (decomposition) NMR (in _{DMSO-d 6) δ: 0.88} (t, 3H, J = 7Hz), 1.8-2.0 (m, 2
H), 1.9-3.8 (m, 7H), 5.32,5.48 (ABq, 2H, J = 17Hz), 5.46
(s, 2H), 6.56 (br.s, 1H), 7.35 (s, 1H), 7.91 (d, 1H, J = 9H
z), 8.07 (d, 1H, J = 9Hz), 8.14 (s, 3H) MASS m / z: 451 (M ⁺ ), 453 (M ⁺ +2) Isomer B: Melting point: 250-255 ° C (decomposition) NMR (in DMSO-d ₆ ) δ: 0.88 (t, 3H, J = 7Hz), 1.8-2.0 (m, 2
H), 1.9-3.8 (m, 7H), 5.32,5.48 (ABq, 2H, J = 19Hz), 5.45
(s, 2H), 6.57 (br.s, 1H), 7.35 (s, 1H), 7.90 (d, 1H, J = 9H
z), 8.06 (d, 1H, J = 9Hz) MASS m / z: 451 (M ⁺ ), 453 (M ⁺ +2)

Example 17 (9S) -1-Acetylamino-9-ethyl-1,2-dihydro-9-hydroxy-4-methyl-3H, 12H-pyrano [3 ′, 4 ′: 6,7] indolidino [1,2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15
H) -Dione synthesis:

[0119]

[Chemical formula 23]

(1) 1-Acetyl-5-acetylamino-8-methyl-2,3-dihydroquinolin-4-one: 5-amino-8-methyl-
After dissolving 7.0 g of 2,3-dihydroquinolin-4-one (JP-A 1-279891) in a mixed solvent of 30 ml of dichloromethane and 80 ml of dioxane, 15 ml of acetyl chloride was added,
The mixture was heated under reflux for 2 hours. 200 ml of ethyl acetate was added to the residue obtained by concentrating the solvent, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated, and the residue was recrystallized from ether. Thus, 7.45 g of the title compound was obtained. NMR (in CDCl ₃ ) δ: 1.95 (s, 3H), 2.23 (s, 3H), 2.27 (s,
3H), 2.0-5.5 (m, 5H), 7.45 (d, 1H, J = 8Hz), 8.59 (d, 1H, J = 8
Hz)

(2) 1-Acetyl-5-acetylamino-3-hydroxyimino 8-methyl-2,3-dihydroquinolin-4-one: In Example 1- (2), 8-acetylamino-1 -Using 2.6 g of the compound obtained in (1) above instead of tetralone, the reaction was carried out in the same manner as in Example 1- (2), and post-treatment was carried out to obtain 2.89 g of the title compound. Melting point: 195-205 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1674, 1590, 1518, 1404 NMR (in CDCl ₃ ) δ: 2.24 (s, 9H), 1.8-5.5 (m, 3H), 7.54
(d, 1H, J = 8Hz), 8.62 (d, 1H, J = 8Hz) MASS m / z: 289 (M ⁺ )

(3) 1-Acetyl-3,5-diacetylamino-8-
Methyl-2,3-dihydroquinolin-4-one: In Example 1- (3), instead of 8-acetylamino-2-hydroxyimino-1-tetralone, 2.89 g of the compound obtained in (2) above was used. The reaction was carried out in the same manner as in Example 1- (3), and post-treatment was carried out to obtain 1.65 g of the title compound. Melting point: 216-221 ° C IRν _max ^KBr cm ^-1 : 1662, 1594, 1518 NMR (in CDCl ₃ ) δ: 2.12 (s, 3H), 2.23 (s, 6H), 2.54 (s,
3H), 3.3-5.0 (m, 1H), 6.1-6.6 (br.s, 1H), 7.44 (d, 1H, J = 8
Hz), 7.60 (d, 1H, J = 8Hz) MASS m / z: 317 (M ⁺ )

(4) 3-Acetylamino-5-amino-8-methyl
-2,3-Dihydroquinolin-4-one: In Example 1- (4), 1.40 g of the compound obtained in the above (3) was used instead of 2,8-diacetylamino-1-tetralone. By reacting in the same manner as in 1- (4) and performing post-treatment, the title compound
79g was obtained. NMR (in CDCl ₃ ) δ: 2.01 (s, 3H), 2.08 (s, 3H), 3.0-4.5
(m, 3H), 5.89 (d, 1H, J = 8Hz), 6.95 (d, 1H, J = 8Hz), 5.7-6.8
(br.s, 2H) MASS m / z: 233 (M ⁺ )

(5) (9S) -1-Acetylamino-9-ethyl-1,2
-Dihydro-9-hydroxy-4-methyl-3H, 12H-pyrano
[3 ', 4': 6,7] Indolizino [1,2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15H) -dione: Compound obtained from (4)
After adding 900 mg of trione, 3 mg of PPTS and 20 ml of acetic acid to 790 mg, the mixture was heated and stirred at 100 ° C. for 7 hours in a nitrogen stream. The reaction solution was concentrated, the residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (20: 1), and the fractions containing the target compound were concentrated to obtain 210 mg of the title compound. _{^{Mp: 225-235 ℃ IRν max KBr cm -1}} : 1746, 1658, 1596, ( in _{DMSO-d 6) 1156 NMR δ} : 0.87 (t, 3H, J = 7Hz), 1.8-2.0 (m, 2
H), 1.90,1.91 (each s, 3H), 2.30 (s, 3H), 5.16,5.25 (ABq,
2H, J = 18Hz), 5.42 (s, 2H), 5.3-5.6 (m, 1H), 6.17 (br.s, 1
H), 7.26 (s, 1H), 7.36 (d, 1H, J = 8Hz), 7.52 (d, 1H, J = 8Hz) MASS m / z: 460 (M ⁺ )

Example 18 (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy
-4-methyl-3H, 12H-pyrano [3 ', 4': 6,7] indolizino [1,2
Synthesis of -c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15H) -dione hydrochloride:

[0126]

[Chemical formula 24]

400 mg of the compound obtained in Example 17- (5) was reacted for 4 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (80 mg) and isomer B (55 mg). Got each. Isomer A: Melting point: 230-250 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1756, 1658, 1614 NMR (in DMSO-d ₆ ) δ: 0.88 (t, 3H, J = 7Hz), 1.7-2.0 (m , 2
H), 2.35 (s, 3H), 3.50,3.87 (each d, 1H, J = 12Hz), 5.0-5.
2 (m, 1H), 5.44 (s, 2H), 5.37,5.83 (ABq, 2H, J = 10Hz), 7.31
(s, 1H), 7.44 (d, 1H, J = 8Hz), 7.59 (d, 1H, J = 8Hz), 8.77 (b
rs, 3H) MASS m / z: 418 (M ⁺ ) isomer B: Melting point: 220-240 ° C. (decomposition) IRν _max ^KBr cm ⁻¹ : 1746, 1658, 1592 NMR (in DMSO-d ₆ ) δ: 0.88 ( t, 3H, J = 7Hz), 1.7-2.0 (m, 2
H), 2.35 (s, 3H), 3.50,3.86 (each d, 1H, J = 12Hz), 5.0-5.
2 (m, 1H), 5.45 (s, 2H), 5.39,5.79 (ABq, 2H, J = 9Hz), 6.3-6.
5 (br, 1H), 6.54 (s, 1H), 7.32 (s, 1H), 7.45 (d, 1H, J = 8Hz),
7.60 (d, 1H, J = 8Hz), 8.70 (br.s, 3H) MASS m / z: 418 (M ⁺ )

Example 19 (9S) -1-Acetylamino-4-chloro-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6 ,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0129]

[Chemical 25]

(1) 2,8-Diacetylamino-5-chloro-1-tetralone: In Example 1- (2), 8-acetylamino-1
8-Acetylamino-5-chloro-1-instead of tetralone
Using 600 mg of tetralone, the reaction was carried out in the same manner as in Example 1- (2) and post-treatment was carried out to give 8-acetylamino-5-chloro-2-
Crude hydroxyimino-1-tetralone was reacted, and the obtained compound was reacted in the same manner as in Example 1- (3) and post-treated to obtain 304 mg of the title compound. IRν _max ^KBr cm ^-1 : 3296, 1652, 1574, 1464 NMR (in CDCl ₃ ) δ: 1.75-2.04 (1H, m), 2.12 (3H, s), 2.
23 (3H, s), 2.70-3.18 (3H, m), 4.55-4.83 (1H, m), 6.4 (1H,
br), 7.55 (1H, d, J = 9.0Hz), 8.61 (1H, d, 9.2Hz) MASS m / z: 294 (M ⁺ )

(2) 2-Acetylamino-8-amino-5-chloro
-1-Tetralone: In Example 1- (4), 270 mg of the compound obtained in (1) above was used in place of 2,8-diacetylamino-1-tetralone, and the same procedure as in Example 1- (4) was conducted. The reaction and post treatment were performed to obtain 160 mg of the title compound. IRν _max ^KBr cm ⁻¹ : 3448, 1614, 1458 NMR (in CDCl ₃ ) δ: 1.73-1.87 (1H, m), 2.09 (3H, s), 2.
66-3.15 (3H, m), 4.53-4.74 (1H, m) 6.50 (1H, d, J = 9.0Hz), 7.
26 (1H, d, J = 9.0Hz) MASS m / z: 252 (M ⁺ )

(3) (9S) -1-Acetylamino-4-chloro-9-
Ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
13 (9H, 15H) -dione: 130 mg of the compound obtained in (2) and 136 mg of trione were reacted for 24 hours in the same manner as in Example 1- (5),
Post-treatment was performed to obtain 174 mg of the title compound. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3416, 1660, 1494 NMR (in DMSO-d ₆ ) δ: 0.86-0.90 (3H, m), 1.85-1.89 (2
H, m), 1.91 (3 / 2H, s), 1.92 (3 / 2H, s), 2.16 (2H, br s), 3.
24 (2H, br s), 5.18-5.30 (2H, m), 5.43 (2H, s), 5.57-5.62
(1H, m), 6.52 (1H, s), 7.33 (1H, s), 7.89 (1H, d, J = 8.8Hz),
8.05 (1H, d, J = 8.8Hz), 8.46-8.50 (1H, m) MASS m / z: 479 (M ⁺ )

Example 20 (9S) -1-Amino-4-chloro-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6, 7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0134]

[Chemical formula 26]

124 mg of the compound obtained in Example 19- (3) was reacted for 6 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (8.2 mg) and isomer B (8.2 mg). ) Respectively. Isomer A: mp: 240 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.89} (3H, t, J = 6.8Hz), 1.81-1.92
(2H, m), 2.18-2.25 (1H, m), 3.16-3.25 (1H, m), 5.13 (1H, b
r), 5.45-5.49 (3H, m), 5.95 (1H, d, J = 19Hz), 6.56 (1H, s),
7.37 (1H, s), 7.97 (1H, d, J = 9.3Hz), 8.13 (1H, d, J = 9.3Hz),
8.79 (1H, br) Isomer B: Melting point: 240 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz), 1.81-1.92
(2H, m), 2.18-2.25 (1H, m), 3.16-3.25 (1H, m), 5.14 (1H, b
r), 5.46-5.50 (3H, m), 5.90 (1H, d, J = 19Hz), 6.56 (1H, s),
7.38 (1H, s), 7.98 (1H, d, J = 9.3Hz), 8.14 (1H, d, J = 9.3Hz),
8.66 (1H, br)

Example 21 (9S) -1-Acetylamino-9-ethyl-4-fluoro-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′:
Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0137]

[Chemical 27]

(1) 2,8-Diacetylamino-5-fluoro-1-
Tetralone: 8-acetylamino in Example 1- (2)
-1-Tetralone instead of 8-acetylamino-5-fluoro
Using 600 mg of -1-tetralone, the reaction was carried out in the same manner as in Example 1- (2) and post-treatment was carried out to crude 8-acetylamino-5-fluoro-2-hydroxyimino-1-tetralone, which was then obtained. The obtained compound was reacted in the same manner as in Example 1- (3) and post-treated to give 372 mg of the title compound. IR ν _max ^KBr cm ⁻¹ : 3264, 1698, 1614, 1538, 1400 NMR (in CDCl ₃ ) δ: 1.83-2.04 (1H, m), 2.11 (3H, s), 2.
22 (3H, s), 2.65-3.19 (3H, m), 4.61-4.82 (1H, m), 6.5 (1H,
br s), 7.26 (1H, t, J = 9.2Hz), 8.62 (1H, dd, J = 4.6,9.6Hz) MASS m / z: 278 (M ⁺ )

(2) 2-Acetylamino-8-amino-5-fluoro-1-tetralone: In Example 1- (4), the above (1) was used instead of 2,8-diacetylamino-1-tetralone. Using 300 mg of the obtained compound, a reaction was carried out in the same manner as in Example 1- (4),
Post-treatment was carried out to obtain 182 mg of the title compound. IRν _max ^KBr cm ⁻¹ : 3428, 2960, 1622, 1472 NMR (in CDCl ₃ ) δ: 1.73-1.88 (1H, m), 2.10 (3H, s), 2.
69-3.08 (3H, m), 4.49-4.69 (1H, m) 6.43-6.54 (1H, m), 7.06
(1H, t, J = 8.8Hz) MASS m / z: 236 (M ⁺ )

(3) (9S) -1-Acetylamino-9-ethyl-4-
Fluoro-2,3-dihydro-9-hydroxy-1H, 12H-benzo
[de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-1
0,13 (9H, 15H) -dione: 160 mg of the compound obtained in (2) and 179 mg of trione were reacted for 24 hours in the same manner as in Example 1- (5) and post-treated to give 224 mg of the title compound. Obtained. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3292, 2944, 1750, 1660, 1598 NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 8.8Hz), 1.82-1.92
(2H, m), 1.93 (3H, s), 2.09-2.14 (2H, m), 3.16-3.19 (2H,
m), 5.18-5.29 (2H, m), 5.43 (2H, s) 5.57-5.62 (1H, m), 6.51
(1H, s), 7.33 (1H, s), 7.78 (1H, t, J = 9.3Hz), 8.11 (1H, dd,
J = 5.4,9.3Hz), 8.51 (1H, d, J = 8.8Hz) MASS m / z: 463 (M ⁺ )

Example 22 (9S) -1-Amino-9-ethyl-4-fluoro-2,3-dihydro-9-
Synthesis of hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0142]

[Chemical 28]

180 mg of the compound obtained in Example 21- (3) was reacted for 5 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (10 mg) and isomer B (14 mg). Got each. Isomer A: mp: 240 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.89} (3H, t, J = 7.3Hz), 1.81-1.94
(2H, m), 2.13-2.21 (1H, m), 3.14-3.22 (1H, m), 5.13 (1H, b
r), 5.43-5.48 (3H, m), 5.92 (1H, d, J = 19Hz), 6.55 (1H, s),
7.37 (1H, s), 7.85 (1H, t, J = 9.3Hz), 8.18 (1H, dd, J = 5.4,9.
3Hz), 8.68 (1H, br) Isomer B: Melting point: 240 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.83-1.93
(2H, m), 2.16-2.20 (1H, m), 3.15-3.25 (1H, m), 5.16 (1H, b
r), 5.45-5.50 (3H, m), 5.95 (1H, d, J = 19Hz), 7.37 (1H, s),
7.85 (1H, t, J = 9.3Hz), 8.19 (1H, dd, J = 5.4,9.3Hz), 8.81 (1
H, br)

Example 23 (9S) -1-Acetylamino-4-cyano-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6 ,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0145]

[Chemical 29]

(1) 2,8-Diacetylamino-5-cyano-1-tetralone: In Example 1- (2), 8-acetylamino-1
8-acetylamino-5-cyano-1-instead of tetralone
Using 1 g of tetralone, the reaction was carried out in the same manner as in Example 1- (2), post-treatment was carried out to crude 8-acetylamino-5-cyano-2-hydroxyimino-1-tetralone, and then the obtained compound Was reacted in the same manner as in Example 1- (3) and post-treated to obtain 270 mg of the title compound. IRν _max ^KBr cm ^-1 : 3292, 2228, 1708, 1666, 1588,
1518 NMR (in CDCl ₃ ) δ: 1.71-2.05 (1H, m), 2.12 (3H, s), 2.
27 (3H, s), 2.66-3.43 (3H, m), 4.60-4.87 (1H, m), 6.3 (1H,
br), 7.77 (1H, d, J = 8.7Hz), 8.78 (1H, d, J = 9.0Hz) MASS m / z: 285 (M ⁺ )

(2) 2-Acetylamino-8-amino-5-cyano
-1-Tetralone: In Example 1- (4), 250 mg of the compound obtained in (1) above was used in place of 2,8-diacetylamino-1-tetralone, and the same procedure as in Example 1- (4) The reaction and post treatment were performed to obtain 182 mg of the title compound. IRν _max ^KBr cm ^-1 : 3428, 3336, 2216, 1652, 1614,
1542 NMR (in CDCl ₃ ) δ: 1.6-2.0 (1H, m), 2.09 (3H, s), 2.56
-3.39 (3H, m), 4.51-4.71 (1H, m), 6.59 (1H, d, J = 9.0Hz), 7.
40 (1H, d, J = 9.0Hz) MASS m / z: 243 (M ⁺ )

(3) (9S) -1-Acetylamino-4-cyano-9-
Ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
13 (9H, 15H) -dione: 165 mg of the compound obtained in (2) and 179 mg of trione were reacted for 43 hours in the same manner as in Example 1- (5),
Post-treatment was performed to obtain 135 mg of the title compound. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3296, 2940, 2228, 1752, 1662,
1602 NMR (in DMSO-d ₆ ) δ: 0.86-0.90 (3H, m), 1.81-1.91 (2
H, m), 1.93 (3 / 2H, s), 1.94 (3 / 2H, s), 2.16-2.34 (2H, m),
3.38-3.51 (2H, m), 5.20-5.31 (2H, m), 5.43-5.44 (2H, m),
5.61-5.66 (1H, m), 6.55 (1H, s), 7.37 (1 / 2H, s), 7.38 (1/2
H, s), 8.09 (1H, d, J = 8.8Hz), 8.14 (1H, d, J = 8.8Hz), 8.51-
8.54 (1H, m) MASS m / z: 470 (M ⁺ )

Example 24 (9S) -1-Amino-4-cyano-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6, 7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0150]

[Chemical 30]

124 mg of the compound obtained in Example 21- (3) was reacted for 3 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (29 mg) and isomer B (30 mg). Got each. Isomer A: Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3428, 2928, 2232, 1740, 1660,
1600 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 6.8Hz), 1.87-1.91
(2H, m), 2.2-2.4 (1H, m), 2.6-2.7 (1H, m), 3.4-3.6 (2H,
m), 5.18 (1H, br), 5.46-5.51 (3H, m), 5.96 (1H, d, J = 19H
z), 6.58 (1H, s), 7.42 (1H, s), 8.17 (1H, d, J = 8.8Hz), 8.22
(1H, d, J = 8.8Hz), 8.79 (1H, br) MASS m / z: 428 (M ⁺ ) Isomer B: Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 2884, 2228, 1754 , 1658, 1590 NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz), 1.83-1.94
(2H, m), 2.26-2.33 (1H, m), 2.54-2.68 (1H, m), 3.38-3.57
(2H, m), 5.20 (1H, br), 5.47-5.52 (3H, m), 5.97 (1H, d, J = 1
9Hz), 6.58 (1H, s), 7.38 (1H, s), 8.18 (1H, d, J = 8.8Hz),
8.23 (1H, d, J = 8.8Hz), 8.85 (1H, br) MASS m / z: 428 (M ⁺ )

Example 25 (9S) -9-Ethyl-9-hydroxy-2-sulfonyl-2,3-dihydro-1H, 12H-benzo [de] [3 ', 4': 6,7] indolizino [1 , 2-
b] Synthesis of quinoline-10,13 (9H, 15H) -dione:

[0153]

[Chemical 31]

3-Sulfonyl-8-amino-1-tetralone [An
n., 638, 43-56 (1960)] 500 mg and trione 355 mg were reacted for 16 hours in the same manner as in Example 17- (5). After allowing to cool, the reaction solution is concentrated, the residue is diluted with water, and subjected to column chromatography with Diaion HP-20, developed with 25% ethanol aqueous solution, and the fractions containing the target compound are concentrated. Thus, 220 mg of the title compound was obtained. Melting point: 190-200 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1744, 1660, 1164, 1038 NMR (in DMSO-d ₆ ) δ: 0.89 (t, 3H, J = 7Hz), 1.8-2.0 (m, 2
H), 2.9-3.6 (m, 5H), 5.1-5.4 (ABq, 2H), 5.43 (s, 2H), 6.5
0 (br, 1H), 7.31,7.32 (each s, 1H), 7.49 (d, 1H, J = 7Hz), 7.
73 (t, 1H, J = 7Hz), 7.96 (d, 1H, J = 7Hz) MASS m / z: 468 (M ⁺ )

Example 26 (9S) -1,4-Diamino-9-ethyl-1,2-dihydro-9-hydroxy-12H-thiino [4,3,2-de] pyrano [3 ′, 4 ′: Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0156]

[Chemical 32]

(1) 8-Acetylamino-5-benzyloxycarbonylamino-4-thiochromanone: To 40 ml of dichloromethane was added 570 mg of 8-acetylamino-5-amino-4-thiochromanone and 1 ml of pyridine, and the mixture was stirred at 0 ° C. While stirring, 0.69 ml of carbobenzoyl chloride was added and stirred for 1 hour. The reaction solution was washed successively with dilute hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from methanol to obtain 710 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.21 (3H, s), 3.03 (2H, m), 3.16 (2
H, m), 5.21 (2H, s), 6.97 (1H, br.s), 7.3-7.5 (5H, m), 7.7
9 (1H, d, J = 8.8Hz), 8.30 (1H, d, J = 8.8Hz), 11.60 (1H, br.s)

(2) 3,8-Diacetylamino-5-amino-4-thiochromanone: TH containing 168 mg of potassium-t-butoxide
5 ml of THF solution containing 370 mg of the compound obtained in (1) was added to 5 ml of F solution with stirring at 0 ° C. under nitrogen stream, and after stirring for 5 minutes, 0.24 ml of n-butyl nitrite was added, and the mixture was stirred at room temperature for 1 hour. Stir for hours. After adding 20 ml of ether to the reaction solution and stirring for 1 hour, the precipitate was filtered and washed well with ether. Precipitate 20
It was dissolved in a mixed solution of 20 ml of acetic anhydride and 20 ml of acetic anhydride, and while stirring at room temperature, about 200 mg of zinc powder was gradually added, and the mixture was further stirred for 30 minutes. After removing the insoluble matter by distillation, the solvent was distilled off and chloroform 20 ml
Was added, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated. The residue is dissolved in 20 ml of a mixed solvent of dioxane-methanol (1: 1) and catalytic hydrogenation is carried out using 100 mg of 5% palladium-carbon. After removing the catalyst by filtration, the solvent was evaporated, the residue was subjected to silica gel column chromatography, and developed with a mixed solvent of hexane-ethyl acetate (4: 1) to concentrate the fraction containing the target substance. This gave 23 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.10 (3H, s), 2.19 (3H, s), 2.99 (1
H, t, J = 13Hz), 3.56 (1H, dd, J = 4Hz, 12Hz), 4.79 (1H, dt, J = 4
Hz, 13Hz), 6.40 (1H, d, J = 8.8Hz) 6.85 (1H, m), 6.92 (1H, d, J
= 4Hz), 7.35 (1H, d, J = 8.8Hz)

(3) (9S) -1,4 diamino-9-ethyl-1,2-dihydro-9-hydroxy-12H-thiino [4,3,2-de] pyrano [3 ′,
4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H)-
Dione / hydrochloride: 23 mg of the compound obtained in (2) and 20 mg of trione were added to 5 ml of toluene, and a catalytic amount of PPTS was added.
It heated and refluxed for 20 hours using the Dean Stark apparatus. The reaction solution was cooled, the solvent was distilled off, the residue was subjected to silica gel column chromatography, developed with chloroform-methanol (95: 5), and the fraction containing the target compound was concentrated to obtain a residue. , 4N hydrochloric acid (4 ml) was added, and the mixture was stirred for 1.5 hours.
After concentrating the solvent, add 4 ml of water to remove insoluble matter by filtration,
High performance liquid chromatography [CAPCELL PAKC1]
8; developed with acetonitrile-water-1N hydrochloric acid (20: 80: 1)] to obtain the title compound as isomer A (10 mg) and isomer B (7.4 mg). Isomer A: mp: 220 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.88} (3H, t, J = 7.3Hz), 1.86 (2H,
m), 3.34 (1H, d, J = 14.0Hz), 3.50 (1H, dd, J = 14.0Hz, 3.2H
z), 5.29 (1H, m), 5.36,5.76 (2H, ABq, J = 19.5Hz), 5.43 (2H,
s), 6.11 (2H, s), 6.49 (1H, s), 7.22 (1H, s), 7.42 (1H, d, J
= 9.3Hz), 7.82 (1H, d, J = 9.3Hz), 8.66 (3H, m) Isomer B: mp: 220 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.88} (3H, t, J = 7.3Hz), 1.87 (2H,
m), 3.35 (1H, d, J = 13.7Hz), 3.48 (1H, dd, J = 13.7Hz, 3.0H
z), 5.28 (1H, m), 5.35,5.74 (2H, ABq, J = 19.5Hz), 5.43 (2H,
s), 6.11 (2H, s), 6.49 (1H, s), 7.22 (1H, s), 7.41 (1H, d, J
= 9.3Hz), 7.82 (1H, d, J = 9.3Hz), 8.61 (3H, m)

Example 27 (9S) -3- (2-Acetylaminoethyl) -9-ethyl-1,2-dihydro-9-hydroxy-4-methyl-3H, 12H-pyrano [3 ', 4':
6,7] Indolizino [1,2-c] benzo [ij] [2,7] naphthyridine
Synthesis of -10,13 (9H, 15H) -dione:

[0161]

[Chemical 33]

(1) 5-Acetylamino-8-methyl-2,3-dihydroquinolin-4-one: 5-amino-8-methyl-2,3-dihydroquinolin-4-one (2.0 g) was added to dichloromethane (20 ml) and It was dissolved in a mixed solvent of 1.3 ml of pyridine, 1.2 ml of acetyl chloride was added thereto with stirring under ice cooling, and the mixture was stirred for 4 hours. Water was added to the reaction solution, which was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain a residue, which was crystallized with ether to give the title compound 1.
I got 24g. NMR (in CDCl ₃ ) δ: 2.01 (s, 3H), 2.20 (s, 3H), 2.72 (t,
2H, J = 7Hz), 3.61 (t, 2H, J = 7Hz), 7.19 (d, 1H, J = 8Hz), 7.94
(d, 1H, J = 8Hz)

(2) 5-acetylamino-1-cyanomethyl-8-
Methyl-2,3-dihydroquinolin-4-one: 1.95 g of the compound obtained in (1) was dissolved in 40 ml of DMF, 6 ml of bromoacetonitrile was added, and the mixture was heated under reflux for 3 hours. The reaction solution is concentrated,
Chloroform was added to the residue, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated, and the resulting residue was subjected to silica gel column chromatography and developed with a mixed solvent of chloroform-methanol (100: 1). 605 mg of the title compound by concentrating the fractions containing the desired product.
Got Melting point: 190-193 ° C IRν _max ^KBr cm ^-1 : 1696, 1644, 1506, 1392, 1248 NMR (in CDCl ₃ ) δ: 2.22 (s, 3H), 2.29 (s, 3H), 2.93 (t,
2H, J = 6.5Hz), 3.68 (t, 2H, J = 6.5Hz), 4.01 (s, 2H), 7.38
(d, 1H, J = 8Hz), 8.43 (d, 1H, J = 8Hz) MASS m / z: 257 (M ⁺ )

(3) 5-Acetylamino-1- (2-aminoethyl) -8-methyl-2,3-dihydroquinolin-4-one: 650 mg of the compound obtained in (2) was added to 10 ml of acetic acid and acetic anhydride. It is dissolved in 30 ml of a mixed solvent, and 2 ml of Raney nickel is added for catalytic hydrogenation. The catalyst was removed by filtration, and the filtrate was concentrated. Chloroform was added to the obtained residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was recrystallized from chloroform and ether to give the title compound (510 mg). Melting point: 151-153 ° C IRν _max ^KBr cm ^-1 : 1690, 1646, 1520 NMR (in CDCl ₃ ) δ: 2.00 (s, 3H), 2.21 (s, 3H), 2.26 (s,
3H), 2.76 (t, 2H, J = 7Hz), 3.14 (t, 2H, J = 7Hz), 3.4-3.7 (m,
4H), 5.98 (br, 1H), 7.30 (d, 1H, J = 8Hz), 8.27 (d, 1H, J = 8H
z) MASS m / z: 303 (M ⁺ )

(4) 5-Amino-1- (2-aminoethyl) -8-methyl-2,3-dihydroquinolin-4-one: In Example 1- (4), 2,8-diacetylamino- By using 510 mg of the compound obtained in (3) above instead of 1-tetralone and reacting in the same manner as in Example 1- (4) and performing post-treatment, the title compound 22
0 mg was obtained. NMR (in CDCl ₃ ) δ: 1.99 (s, 3H), 2.16 (s, 3H), 2.6-2.9
(m, 4H), 3.3-3.7 (m, 4H), 5.8-6.8 (br, 1H), 6.20 (d, 1H, J
= 8Hz), 7.04 (d, 1H, J = 8Hz) MASS m / z: 261 (M ⁺ )

(5) (9S) -3- (2-acetylaminoethyl) -9-
Ethyl-1,2-dihydro-9-hydroxy-4-methyl-3H, 12H
-Pyrano [3 ', 4': 6,7] indolizino [1,2-c] benzo [ij] [2,
[7] Naphthyridine-10,13 (9H, 15H) -dione: 210 mg of the compound obtained in (4) and 230 mg of trione were reacted for 7 hours in the same manner as in Example 17- (5), and post-treatment was carried out. Title compound
195 mg was obtained. Mp: 155-165 ° C. (decomposition) NMR (in _{DMSO-d 6) δ: 0.88} (t, 3H, J = 7Hz), 1.7-2.0 (m, 2
H), 1.82 (s, 3H), 2.47 (s, 3H), 2.9−3.1 (m, 2H), 3.2-3.3
(m, 2H), 3.4-3.7 (m, 4H), 5.26 (s, 2H), 5.3-5.5 (m, 2H), 7.
34 (s, 1H), 7.67 (d, 1H, J = 7Hz), 7.74 (d, 1H, J = 7Hz), 8.0-
8.1 (br.s, 1H) MASS m / z: 488 (M ⁺ )

Example 28 (9S) -3- (2-Aminoethyl) -9-ethyl-1,2-dihydro-9-hydroxy-4-methyl-3H, 12H-pyrano [3 ', 4': 6 , 7] Indolizino [1,2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H,
15H) -Dione synthesis:

[0168]

[Chemical 34]

190 mg of the compound obtained in Example 27- (5) was reacted in the same manner as in Example 2 and post-treated to give 120 mg of the title compound. Mp: 210-230 ° C. _{^{(decomposition) IRν max KBr cm -1: 1746,1660,1594}} NMR ( in _{DMSO-d 6) δ: 0.88} (t, 3H, J = 7.5Hz), 1.8-1.9
(m, 2H), 2.49 (s, 3H), 3.1-3.5 (m, 8H), 5.26 (s, 2H), 5.43
(s, 2H), 7.32 (s, 1H), 7.69 (d, 1H, J = 9Hz), 7.78 (d, 1H, J = 9H
z), 8.1-8.3 (br.s, 3H) MASS m / z: 446 (M ⁺ )

Example 29 (9S) -4-Chloro-9-ethyl-2,3-dihydro-9-hydroxy
-3-Dimethylamino-1H, 12H-benzo [de] pyrano [3 ', 4': 6,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0171]

[Chemical 35]

44 mg of isomer B obtained in Example 14 was added to 50
35% formalin aqueous solution dissolved in 5% hydrous methanol 5 ml
Catalytic hydrogenation is carried out by adding 5 ml and 50 mg of 10% palladium-carbon. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. 4 ml of water was added to remove insoluble matter by filtration, and the filtrate was purified by high performance liquid chromatography [CAPCELL PAK C18; developed with acetonitrile-water-1N hydrochloric acid (20: 80: 1)] to obtain 8 mg of the title compound. . NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.88 (2H,
m), 2.2-2.4 (1H, m), 2.4-2.6 (1H, m), 2.67 (3H, m), 3.06
(3H, m), 3.3-3.5 (2H, m), 5.19 (1H, m), 5.21,5.43 (2H, ABq,
J = 18.6Hz), 5.45 (2H, s), 6.56 (1H, s), 7.37 (1H, s), 8.03
(1H, d, J = 9.3Hz), 8.31 (1H, d, J = 9.3Hz)

Example 30 (9S) -1-Acetylamino-4-amino-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6 ,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0174]

[Chemical 36]

(1) 2,5,8-Triacetylamino-1-tetralone: In Example 1- (2), instead of 8-acetylamino-1-tetralone, 5,8-diacetylamino-1-tetralone 1.65 The reaction was carried out in the same manner as in Example 1- (2) using g, and post-treatment was carried out to give 5,8-diacetylamino-2-hydroxyimino-1-tetralone as a crude product. The reaction was carried out in the same manner as in 1- (3) and post-treatment was carried out to obtain 950 mg of the title compound. IRν _max ^KBr cm ^-1 : 3280, 1660, 1596, 1516 NMR (in CDCl ₃ ) δ: 1.79-2.02 (1H, m), 2.11 (3H, s), 2.
18 (3H, s), 2.23 (3H, s), 2.4-3.0 (3H, m), 4.54-4.69 (1H,
m), 7.60 (1H, d, J = 9.0Hz), 8.55 (1H, d, J = 9.0Hz) MASS m / z: 317 (M ⁺ )

(2) 2-Acetylamino-5,8-diamino-1-tetralone: Obtained in the above (1) instead of 2,8-diacetylamino-1-tetralone in Example 1- (4). Compound 50
Using 0 mg of the compound, the reaction was carried out in the same manner as in Example 1- (4) and post-treatment was carried out to obtain 290 mg of the title compound. IRν _max ^KBr cm ^-1 : 3436, 3352, 3296, 2444, 1626,
1556 NMR (in DMSO-d ₆ ) δ: 1.74-1.87 (1H, m), 1.90 (3H, s),
2.14-2.16 (1H, m), 2.54-2.77 (2H, m), 4.41-4.47 (1H, m),
6.48 (1H, d, J = 8.3Hz), 6.83 (1H, d, J = 8.3Hz), 8.04 (1H, d, J
= 7.8Hz) MASS m / z: 233 (M ⁺ )

(3) (9S) -1-Acetylamino-4-amino-9-
Ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
13 (9H, 15H) -dione: 234 mg of the compound obtained in (2) and 261 mg of trione were dissolved in 30 ml of acetic acid and heated under reflux for 14 hours under a nitrogen stream. Then, post-treatment was carried out in the same manner as in Example 1- (5) to give 134 mg of the title compound. Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3380, 2984, 2940, 1748, 1662,
1602 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.82-1.92
(2H, m), 1.93 (3 / 2H, s), 1.94 (3 / 2H, s), 2.08-2.09 (2H,
m), 3.08 (2H, br), 5.16-5.26 (2H, m), 5.39-5.46 (2H, m),
5.53-5.56 (1H, m), 6.51 (1H, s), 7.32 (2H, s), 7.96 (1H, d,
J = 9.5Hz), 7.99 (1H, d, J = 8.7Hz), 8.54 (1H, t, J = 8.7Hz) MASS m / z: 458 (M ⁺ )

Example 31 (9S) -1,4-Diamino-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,7] Synthesis of indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0179]

[Chemical 37]

113 mg of the compound obtained in Example 21- (3) was reacted for 6 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (28 mg) and isomer B (28 mg). Got each. Isomer A: Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3392, 3232, 2936, 1742, 1652,
1590 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 6.8Hz), 1.82-1.92
(2H, m), 2.03-2.09 (1H, m), 2.67-2.93 (2H, m), 4.97 (1H, b
r), 5.32-5.46 (3H, m), 5.74-5.81 (1H, m), 6.47 (1H, s), 7.
21 (1H, s), 7.39 (1H, d, J = 8.8Hz), 7.83 (1H, d, J = 8.8Hz),
8.60 (1H, br) MASS m / z: 418 (M ⁺ ) isomer B: Melting point: 240 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3436, 3232, 1746, 1658, 1592 NMR (in DMSO-d ₆₎ ) δ: 0.89 (3H, t, J = 6.8Hz), 1.81-1.92
(2H, m), 2.03-2.09 (1H, m), 2.68-2.95 (2H, m), 4.99 (1H, b
r), 5.37-5.47 (3H, m), 5.81 (1H, d, J = 19Hz), 7.23 (1H, s),
7.43 (1H, d, J = 8.8Hz), 7.85 (1H, d, J = 8.8Hz), 8.64 (1H, br) MASS m / z: 418 (M ⁺ )

Example 32 (9S) -1-Acetylamino-9-ethyl-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6 ,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0182]

[Chemical 38]

(1) Methyl (2'-tolyl) acetate: 25 g of o-tolylacetic acid was dissolved in 350 ml of methanol, and then concentrated hydrochloric acid 1
ml was added and the mixture was heated under reflux overnight. 200 ml of water was added to the residue obtained by concentrating the solvent, and the precipitate was extracted with chloroform.
The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated to give the title compound (27.2 g). NMR (in CDCl ₃ ) δ: 2.30 (3H, s), 3.64 (2H, s), 3.68 (3
H, s), 7.17 (4H, s)

(2) Methyl 4- (2′-tolyl) -3-butenate: A solution of 13.1 g of the compound obtained in (1) in 100 ml of toluene was cooled to −65 ° C., and 1M diisobutylaluminum hydride was added. 80 ml of toluene solution of is added dropwise over 1 hour,
The mixture was stirred at the same temperature for 1 hour. The reaction was stopped by adding methanol. The reaction solution was diluted with ethyl acetate, 10% aqueous hydrochloric acid solution,
The mixture was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was concentrated. Methyl (triphenylphosphoranylidene) was added to a solution of the residue in 100 ml of benzene.
26.5 g of acetate was added, and the mixture was stirred at room temperature overnight. The solvent was concentrated, a mixed solvent of ethyl acetate: n-hexane (1: 9) was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated and the obtained residue was subjected to silica gel chromatography, developed with ethyl acetate: n-hexane (1: 9), and the fractions containing the target compound were concentrated to give 12.7 g of the title compound. . NMR (in CDCl ₃ ) δ: 2.27 (3H, s), 3.46-3.54 (2H, m), 3.
70 (3H, s), 5.70 (1H, d, 15.5Hz), 6.95-7.24 (5H, m)

(3) 4- (2'-tolyl) butyric acid: To a solution of 12.6 g of the compound obtained in (2) in 200 ml of methanol was added 10% palladium carbon, and catalytic reduction was carried out for 20 minutes under hydrogen flow. It was The catalyst was filtered off, and the reaction solution was concentrated to about 150 ml. 70 ml of 1N sodium hydroxide solution was added to the concentrated solution, and the mixture was heated with stirring at 50 ° C. for 1 hour. After returning to room temperature, the reaction solution was ice-cooled and adjusted to pH 1 or less with concentrated hydrochloric acid. The precipitate was extracted with chloroform, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated to give the title compound 11.4.
got g. Melting point: 54-56 ° C IRν _max ^KBr cm ^-1 : 3416, 2944, 1748, 1660, 1602 NMR (in CDCl ₃ ) δ: 1.83-1.99 (2H, m), 2.31 (3H, s), 2.
34-2.75 (4H, m), 7.12 (4H, m) MASS m / z: 178 (M ⁺ )

(4) 5-methyl-1-tetralone: polyphosphoric acid 1
20 g was heated to 70 ° C., 10.0 g of the compound obtained in (3) was added in a powder state over 30 minutes, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was poured into 600 ml of ice water, and the precipitate was collected by filtration. After washing with water,
The obtained powder was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated to give 8.19 g of the title compound. Melting point: 43-47 ° C IRν _max ^KBr cm ^-1 : 3452,2952,1676,1592,1464 NMR (in CDCl ₃ ) δ: 2.07-2.27 (2H, m), 2.31 (3H, s), 2.
57-2.93 (4H, m), 7.11-7.33 (2H, m), 7.89-7.98 (1H, m) MASS m / z: 160 (M ⁺ )

(5) 8-Nitro-5-methyl-1-tetralone:
A solution prepared by dissolving 8.1 g of the compound obtained in (4) in 70 ml of concentrated sulfuric acid was cooled to -5 ° C, and a solution of 5.37 g of potassium nitrate in 50 ml of concentrated sulfuric acid was added dropwise so that the reaction temperature did not exceed 5 ° C. And stirred at the same temperature for 30 minutes. 600 ml of ice water
The extract was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The residue was subjected to silica gel chromatography,
By developing with ethyl acetate: n-hexane (1:15) and concentrating the fraction containing the desired product, 5.82 g of the title compound was obtained. Melting point: 104-107 ° C IRν _max ^KBr cm ^-1 : 3452, 2964, 1690, 1596 NMR (in CDCl ₃ ) δ: 2.17-2.22 (2H, m), 2.37 (3H, s), 2.
69-2.72 (2H, m), 2.89 (2H, t, J = 5.9Hz), 7.25 (1H, d, J = 8.3H
z), 7.40 (1H, d, J = 7.8Hz) MASS m / z: 205 (M ⁺ )

(6) 8-Acetylamino-5-methyl-1-tetralone: 2.5 g of the compound obtained in (5) was dissolved in a mixed solvent of 50 ml of acetic acid and 50 ml of acetic anhydride, and then 10% palladium carbon was added.
800 mg was added and catalytic reduction was performed for 1 hour in a hydrogen stream. The residue obtained by filtering off the catalyst and concentrating the filtrate was subjected to silica gel chromatography, developed with chloroform and the fractions containing the target compound were concentrated to give the title compound.
Obtained 2.22 g. Melting point: 92-94 ° C IRν _max ^KBr cm ^-1 : 3512, 3176, 2940, 1690, 1650,
1604 NMR (in CDCl ₃ ) δ: 1.95-2.18 (2H, m), 2.22 (3H, s), 2.
25 (3H, s), 2.61-2.93 (4H, m), 7.33 (1H, d, J = 8.5Hz), 8.51
(1H, d, J = 8.5Hz) MASS m / z: 217 (M ⁺ )

(7) 2,8-Diacetylamino-5-methyl-1-tetralone: In Example 1- (2), 8-acetylamino-1
8-Acetylamino-5-methyl-1-instead of tetralone
Using 1 g of tetralone, the reaction was carried out in the same manner as in Example 1- (2) and post-treatment was carried out to crude 8-acetylamino-2-hydroxyimino-5-methyl-1-tetralone, and then the obtained compound Was reacted in the same manner as in Example 1- (3) and post-treated to give 476 mg of the title compound. Melting point: 195-198 ° C IRν _max ^KBr cm ^-1 : 3312, 2928, 1712, 1638, 1596,
1520 NMR (in CDCl ₃ ) δ: 1.74-1.98 (1H, m), 2.11 (3H, s), 2.
22 (3H, s), 2.24 (3H, s), 2.66-3.03 (3H, m), 4.52-4.79 (1
H, m), 6.5 (1H, br), 7.36 (1H, d, J = 8.5Hz), 8.50 (1H, d, 8.5
Hz) MASS m / z: 274 (M ⁺ )

(8) 2-Acetylamino-8-amino-5-methyl
-1-Tetralone: In Example 1- (4), 400 mg of the compound obtained in (7) above was used in place of 2,8-diacetylamino-1-tetralone, and the same procedure as in Example 1- (4) was conducted. The reaction and post treatment were performed to obtain 265 mg of the title compound. Melting point: 192-194 ° C IRν _max ^KBr cm ^-1 : 3460, 3360, 2924, 1618, 1566,
1536 NMR (in CDCl ₃ ) δ: 1.76-1.87 (1H, m), 2.10 (3H, s), 2.
16 (3H, s), 2.63-2.69 (1H, m), 2.91-2.97 (2H, m), 4.55-4.5
6 (1H, m), 6.55 (1H, d, J = 8.3Hz), 7.13 (1H, d, J = 8.3Hz) MASS m / z: 232 (M ⁺ )

(9) (9S) -1-Acetylamino-9-ethyl-2,3
-Dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
13 (9H, 15H) -dione: 200 mg of the compound obtained in (8) and 227 mg of trione were reacted for 23 hours in the same manner as in Example 1- (5),
Post-treatment was carried out to obtain 287 mg of the title compound. Melting point: 270 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3428, 2944, 1754, 1660, 1608,
1556 NMR (in DMSO-d ₆ ) δ: 0.86-0.90 (3H, m), 1.75-1.89 (2
H, m), 1.91 (3 / 2H, s), 1.92 (3 / 2H, s), 2.11-2.14 (2H, m),
2.47 (3 / 2H, s), 2.48 (3 / 2H, s), 3.08-3.11 (2H, m), 5.19-
5.21 (2H, m), 5.43 (2H, s), 5.52-5.57 (1H, m), 6.50 (1 / 2H,
s), 6.51 (1 / 2H, s), 7.31 (1H, s), 7.71 (1H, d, J = 8.3Hz), 7.
94 (1H, d, J = 8.3Hz), 8.47 (1H, t, J = 8.3Hz) MASS m / z: 459 (M ⁺ )

Example 33 (9S) -1-Amino-9-ethyl-2,3-dihydro-9-hydroxy
Of 4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione ・ hydrochloride :

[0193]

[Chemical Formula 39]

150 mg of the compound obtained in Example 32- (9) was reacted for 7 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (58 mg) and isomer B (62 mg). Got each. Isomer A: Melting point: 250 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3432, 2936, 1746, 1658, 1594 NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 6.8Hz), 1.83 -1.91
(2H, m), 2.15-2.22 (1H, m), 2.56-2.59 (1H, m), 3.12-3.28
(2H, m), 5.09 (1H, br), 5.40-5.45 (3H, m), 5.90 (1H, d, J = 1
9Hz), 6.52 (1H, s), 7.34 (1H, s), 7.76 (1H, d, J = 8.8Hz),
8.01 (1H, d, J = 8.8Hz), 8.73 (3H, br) MASS m / z: 417 (M ⁺ ) Isomer B: Melting point: 250 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3448, 2936, 1746, 1658, 1596 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 6.8Hz), 1.83-1.93
(2H, m), 2.17 (1H, br), 2.61-2.68 (1H, m), 3.10-3.21 (2H,
m), 5.10 (1H, br), 5.43-5.48 (3H, m), 5.93 (1H, d, J = 19H
z), 7.35 (1H, s), 7.78 (1H, d, J = 8.8Hz), 8.02 (1H, d, J = 8.8H
z), 8.80 (3H, br) MASS m / z: 417 (M ⁺ )

Example 34 (10S) -1-Acetylamino-10-ethyl-1,2,3,4-tetrahydro-10-hydroxy-13H-cyclohept [de] pyrano
[3 ', 4': 6,7] Indolizino [1,2-b] quinoline-11,14 (10H, 1
6H) -Dione synthesis:

[0196]

[Chemical 40]

(1) 1-Acetylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene: 1-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene [J . Am. Chem. S
oc., 5820 (1969)] (8.7 g) is dissolved in a mixed solvent of acetic anhydride (150 ml) and acetic acid (50 ml), and Raney nickel (10 ml) is added to carry out catalytic hydrogenation. After removing the catalyst by filtration, the filtrate was concentrated, chloroform was added to the residue, the mixture was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 6.17 g of the title compound. NMR (in CDCl ₃ ) δ: 1.5-1.9 (m, 6H), 2.15, 2.20 (each
s, 3H), 2.6-2.9 (m, 4H), 6.9-7.4 (m, 3H) MASS m / z: 203 (M ⁺ )

(2) 1-Acetylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-9-one: Example 1- (1)
In the above, instead of 1-acetylaminotetralin
Using 200 mg of the compound obtained in (1), the reaction was carried out in the same manner as in Example 1- (1), and post-treatment was carried out to obtain 55 mg of the title compound. Melting point: 155-162 ° C NMR (in CDCl ₃ ) δ: 1.5-2.0 (m, 6H), 2.17 (s, 3H), 2.6-
2.9 (m, 4H), 6.93 (d, 1H, J = 8Hz), 7.38 (t, 1H, J = 8Hz), 8.30
(d, 1H, J = 8Hz) MASS m / z: 217 (M ⁺ )

(3) 1,8-Diacetylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-9-one: Example 1-
In (2), instead of 8-acetylamino-1-tetralone, 270 mg of the compound obtained in (2) above was used, and Example 1- (2)
The compound obtained by post-treatment was reacted in the same manner as in 1. and further post-treatment was carried out in the same manner as in Example 1- (3) to obtain 126 mg of the title compound. Melting point: 220-223 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1722, 1682, 1616, 1548 NMR (in CDCl ₃ ) δ: 2.08 (s, 3H), 2.19 (s, 3H), 1.5-2.4
(m, 4H), 2.7-3.1 (m, 2H), 4.7-4.9 (m, 1H), 6.1-6.3 (br.s,
1H), 6.94 (d, 1H, J = 8Hz), 7.34 (t, 1H, J = 8Hz), 8.32 (d, 1H, J
= 8Hz), 9.01 (br.s, 1H) MASS m / z: 274 (M ⁺ )

(4) 8-Acetylamino-1-amino-6,7,8,9-
Tetrahydro-5H-benzocyclohepten-9-one: In Example 1- (4), instead of 2,8-diacetylamino-1-tetralone, 115 mg of the compound obtained in (3) above was used. By reacting in the same manner as 1- (4) and post-treating,
90 mg of the title compound are obtained. NMR (in CDCl ₃ ) δ: 2.04 (s, 3H), 1.5-1,7 (m, 2H), 2.0-
3.2 (m, 4H), 4.9-5.1 (m, 1H), 5.98 (br.s, 1H), 6.53 (d, 1H,
J = 8Hz), 6.54 (d, 1H, J = 8Hz), 6.72 (br.s, 1H), 7.23 (t, 1H,
(J = 8Hz)

(5) (10S) -1-Acetylamino-10-ethyl-
1,2,3,4-Tetrahydro-10-hydroxy-13H-cyclohept [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-11,14 (10H, 16H) -Dione: Compound 90m obtained in (4)
In the same manner as in Example 1- (5), g and trione (105 mg) were reacted for 21 hours and post-treated to give 72 mg of the title compound. Melting point: 203-206 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1748, 1660, 1600, 1160 NMR (in CDCl ₃ ) δ: 0.96,1.03 (each t, 3H, J = 7Hz), 1.5
-4.0 (m, 6H), 2.15,2.27 (each s, 3H), 5.0-6.0 (m, 2H), 7.
3-8.2 (m, 4H) MASS m / z: 459 (M ⁺ )

Example 35 (10S) -1-Amino-10-ethyl-1,2,3,4-tetrahydro-10-
Hydroxy-13H-cyclohept [de] pyrano [3 ', 4': 6,7]
Synthesis of indolidino [1,2-b] quinoline-11,14 (10H, 16H) -dione hydrochloride:

[0203]

[Chemical 41]

The compound (65 mg) obtained in Example 34- (5) was reacted for 4 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (17 mg) and isomer B (21 mg). Got each. Isomer A: Melting point 200-220 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1746, 1660, 1600, 1164 NMR (in DMSO-d ₆ ) δ: 0.88 (t, 3H, J = 7Hz), 1.7-2.0 ( m, 2
H), 2.0-3.5 (m, 6H), 5.15 (s, 1H), 5.46 (s, 2H), 5.53,5.7
3 (ABq, 2H, J = 19Hz), 6.56 (s, 1H), 7.35 (s, 1H), 7.63 (d, 1
H, J = 8Hz), 7.79 (t, 1H, J = 8Hz), 8.09 (d, 1H, J = 8Hz), 8.79
(br.s, 3H) MASS m / z: 417 (M ⁺ ) isomer B: melting point 210-230 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1744, 1664, 1600, 1160 NMR (in DMSO-d ₆ ) δ: 0.88 (t, 3H, J = 7Hz), 1.7-2.0 (m, 2
H), 2.0-3.5 (m, 6H), 5.0-5.2 (m, 1H), 5.46 (s, 2H), 5.54,
5.72 (ABq, 2H, J = 19Hz), 6.56 (s, 1H), 7.35 (s, 1H), 7.62
(d, 1H, J = 8Hz), 7.77 (t, 1H, J = 8Hz), 8.09 (d, 1H, J = 8Hz),
8.61 (br.s, 3H) MASS m / z: 417 (M ⁺ )

Example 36 (9S) -9-Ethyl-2,3-dihydro-3- (1,3-dioxoisoindoline-2-yl) -9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline
Synthesis of -10,13 (9H, 15H) -dione:

[0206]

[Chemical 42]

(1) 4-azido-5-methyl-8-nitro-1-tetralone: In Example 13- (9), 5-fluoro-8-nitro-
By using 410 mg of 5-methyl-8-nitro-1-tetralone instead of 1-tetralone, the reaction was carried out in the same manner as in Example 13- (9), and post-treatment was carried out to obtain 490 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.33-2.50 (2H, m), 2.55 (3H, s), 2.
69-2.75 (1H, m), 2.98-3.07 (1H, m), 5.07 (1H, t, J = 2.9Hz),
7.42 (1H, d, J = 7.8Hz), 7.54 (1H, d, J = 8.8Hz)

(2) 5-Methyl-8-nitro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: Example 13- (9)
In place of 4-azido-5-fluoro-8-nitro-1-tetralone, 490 mg of the compound obtained in (1) above is reacted in the same manner as in Example 13- (9), and post-treatment is carried out. This gave 366 mg of the title compound. Melting point: 220-223 ° C IRν _max ^KBr cm ^-1 : 3456, 3084, 2940, 1770, 1712,
1596 NMR (in CDCl ₃ ) δ: 2.26 (3H, s), 2.38-2.44 (1H, m), 2.
55-2.65 (1H, m), 2.72-2.79 (1H, m), 2.93-3.02 (1H, m), 5.7
0-5.72 (1H, m), 7.39 (1H, d, J = 8.3Hz), 7.42 (1H, d, J = 8.3H
z), 7.74-7.84 (4H, m) MASS m / z: 350 (M ⁺ )

(3) 8-Amino-5-methyl-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: Example 13- (10)
In Example 13, the compound 145 mg obtained in the above (2) was used in place of 5-fluoro-8-nitro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone. As in the case of (10), Raney nickel was used as a catalyst instead of 10% palladium carbon to react, and post-treatment was carried out to give the title compound.
Obtained 75 mg. Melting point: 163-165 ° C IRν _max ^KBr cm ^-1 : 3456, 3344, 2952, 1770, 1710,
1622 NMR (in CDCl ₃ ) δ: 2.02 (3H, s), 2.25-2.32 (1H, m), 2.
41-2.50 (1H, m), 2.58-2.64 (1H, m), 2.88-2.98 (1H, m), 5.6
0-5.62 (1H, m), 6.58 (1H, d, J = 8.3Hz), 7.05 (1H, d, J = 8.3H
z), 7.70-7.81 (4H, m) MASS m / z: 320 (M ⁺ )

(4) (9S) -9-Ethyl-2,3-dihydro-9-hydroxy-4-methyl-3- (1,3-dioxoisoindoline-2-
Il) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione: obtained with (3) The compound (62 mg) and trione (51 mg) were reacted for 18 hours in the same manner as in Example 6- (3) and post-treated to give the title compound (86 mg). Melting point: 285-290 ° C (decomposition) IRν _max ^KBr cm ^-1 : 3448, 2944, 1748, 1714, 1660,
1600 NMR (in DMSO-d ₆ ) δ: 0.89-0.93 (3H, m), 1.82-1.93 (2
H, m), 2.32 (3H, s), 2.46 (1H, br), 3.18-3.22 (2H, m), 5.2
2-5.48 (4H, m), 5.85 (1H, br), 6.49 (1 / 2H, s), 6.51 (1 / 2H,
s), 7.36 (1H, s), 7.65 (1H, d, J = 8.3Hz), 7.79-7.84 (4H,
m), 8.04 (1H, d, J = 8.3Hz) MASS m / z: 547 (M ⁺ )

Example 37 (9S) -3-Amino-9-ethyl-2,3-dihydro-9-hydroxy
Of 4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione ・ hydrochloride :

[0212]

[Chemical 43]

74 mg of the compound obtained in Example 36- (4) was reacted in the same manner as in Example 7 and post-treated to give the title compound as isomer A (14 mg) and isomer B (15 m
g) respectively obtained. Isomer A: Melting point 250 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3448, 2936, 1742, 1656, 1592 NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.84- 1.91
(2H, m), 2.13-2.20 (1H, m), 2.54-2.58 (1H, m), 2.68 (3H,
s), 5.05 (1H, br), 5.19-5.44 (4H, m), 6.50 (1H, s), 7.33 (1
H, s), 7.76 (1H, d, J = 8.8Hz), 8.10 (1H, d, J = 8.8Hz), 8.27
(3H, br) MASS m / z: 417 (M ⁺ ) isomer B: Melting point: 250 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3400, 3236, 2976, 1746, 1662,
1614 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.83-1.94
(2H, m), 2.13-2.20 (1H, m), 2.59-2.62 (1H, m), 2.69 (3H,
s), 3,27-3.42 (2H, m), 5.07 (1H, br), 5.19-5.44 (4H, m),
7.34 (1H, s), 7.78 (1H, d, J = 8.8Hz), 8.12 (1H, d, J = 8.8Hz),
8.53 (3H, br) MASS m / z: 417 (M ⁺ )

Example 38 (9S) -1-Amino-4-chloro-9-ethyl-1,2-dihydro-9-hydroxy-12H-thiino [4,3,2-de] pyrano [3 ′, 4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione-hydrochloride synthesis:

[0215]

[Chemical 44]

(1) 5-Acetylamino-8-chloro-4-thiochromanone: 5-acetylamino-8-amino-4-thiochromanone (JP-A 1-279891) (500 mg) in concentrated hydrochloric acid (12 ml), water (3 m)
A solution prepared by dissolving 153 mg of sodium nitrite in 2 ml of water was gradually added dropwise to a solution of the solution suspended in 1 liter cooled to 0 ° C. and stirred for 5 minutes. 270 mg of cuprous chloride was dissolved in 3 ml of concentrated hydrochloric acid. Pour the solution at 0 ° C. After stirring at room temperature overnight, the residue obtained by concentrating the solvent after drying with magnesium was subjected to silica gel column chromatography, and the fraction containing the target compound by developing with chloroform was concentrated to obtain 478 mg of the title compound. It was NMR (in CDCl ₃ ) δ: 2.22 (3H, s), 2.45-3.42 (4H, m), 7.
43 (1H, d, J = 9Hz), 8.50 (1H, d, J = 9Hz)

(2) 3,5-Diacetylamino-8-chloro-4-thiochromanone: obtained in (1) instead of 5-acetylamino-8-methyl-4-thiochromanone in Example 12- (1). The obtained compound (477 mg) was reacted in the same manner as in Example 12- (1) and post-treated to give 171 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.08 (3H, s), 2.20 (3H, s), 3.20 (1
H, d, J = 13Hz), 3.51 (1H, dd, J = 13,9Hz), 4.7-4.9 (1H, m), 7.
50 (1H, d, J = 9.2Hz), 8.54 (1H, d, J = 9.2Hz)

(3) 3-Acetylamino-5-amino-8-chloro
-4-Thiochromanone: The compound (171 mg) obtained in (2) was reacted in the same manner as in Example 12- (2) and post-treated to give the title compound (22 mg). NMR (in CDCl ₃ ) δ: 2.09 (3H, s), 3.07 (1H, d, J = 13Hz),
3.60 (1H, dd, J = 12.5Hz, 4.5Hz), 4.7-4.9 (1H, m), 6.36 (1H,
d, J = 9Hz), 7.00 (1H, d, J = 9Hz)

(4) (9S) -1-amino-4-chloro-9-ethyl-1,
2-dihydro-9-hydroxy-12H-thiino [4,3,2-de] pyrano
[3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15
H) -dione.hydrochloride: Compound 22 mg obtained in (3) and trione 23 mg were reacted for 11 hours in the same manner as in Example 12- (3) and post-treated to give the title compound as isomer A (12 mg).
And isomer B (11 mg). Isomer A: IRν _max ^KBr cm ⁻¹ : 3444, 1744, 1660, 1590, 1556 NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.89 (2H,
m), 3.62 (2H, d, J = 1.95Hz), 5.46 (2H, s), 5.47,5.85 (1H, A
Bq, J = 19.5Hz), 6.54-6.58 (1H, br.s), 7.39 (1H, s), 7.97
(1H, d, J = 8.8Hz), 8.06 (1H, d, J = 8.8Hz), 8.80-8.87 (3H, m) MASS m / z: 456 (M ⁺ +1) Isomer B: IRν _max ^KBr cm ^-1 : 3452, 1746, 1662, 1596, 1556 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.88 (2H,
m), 3.60-3.63 (2H, m), 5.46 (2H, s), 5.48,5.81 (2H, ABq,
J = 19.5Hz), 6.54-6.57 (1H, br.s), 7.40 (1H, s), 7.97 (1H,
d, J = 8.8Hz), 8.06 (1H, d, J = 8.8Hz), 8.75-8.82 (3H, m) MASS m / z: 456 (M ⁺ +1)

Example 39 (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy-1
2H-chiino [4,3,2-de] pyrano [3 ', 4': 6,7] indolizino
Synthesis of [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0221]

[Chemical formula 45]

(1) 3,5-Diacetylamino-4-thiochromanone: In Example 12- (1), 5-acetylamino-4-thiochromanone was replaced by 5-acetylamino-4-
Using thiochromanone (360 mg), the reaction was carried out in the same manner as in Example 12- (1), and post-treatment was carried out to obtain 133 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.11 (3H, s), 2.23 (3H, s), 3.06 (1
H, d, J = 12.7Hz), 3.52 (1H, dd, J = 12.5Hz, 4.8Hz), 4.83-5.0
9 (1H, m), 6.7-6.9 (1H, br), 6.93 (1H, dd, J = 7.9Hz, 1.3Hz),
7.2-7.4 (1H, br), 7.27-7.46 (1H, m), 8.46 (1H, dd, J = 8.4H
(z, 1.2Hz)

(2) 3-Acetylamino-5-amino-4-thiochromanone: 132 mg of the compound obtained in (1) was reacted in the same manner as in Example 12- (2), and post-treated to give the title compound 62
to obtain mg. NMR (in CDCl ₃ ) δ: 2.09 (3H, s), 3.13 (1H, d, J = 13Hz),
3.52 (1H, dd, J = 13Hz, 9Hz), 4.72-4.97 (1H, m), 6.36 (1H, d
d, J = 8.3Hz, 1Hz), 6.50 (1H, dd, J = 7.66Hz, 1.09Hz), 6.75-
7.1 (1H, br), 7.09 (1H, t, J = 8Hz)

(3) (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy-12H-thiino [4,3,2-de] pyrano [3 ′, 4 ′:
6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione-hydrochloride: 62 mg of the compound obtained in (2) and 76 m of trione
g was reacted for 10 hours in the same manner as in Example 12- (3) and post-treated to give the title compound as isomer A (19 mg) and isomer B (11 mg). Isomer A: IRν _max ^KBr cm ⁻¹ : 3444, 1746, 1660, 1596, 1502 NMR (in DMSO-d ₆ ) δ: 0.94 (3H, t, J = 7.3Hz), 1.89 (2H,
m), 3.58 (2H, ABq, J = 15Hz, 14Hz), 5.43 (2H, s), 5.49 (1H,
d, J = 16.1Hz), 5.91 (1H, d, J = 19.5Hz), 6.47-6.55 (1H, br.
s), 7.43 (1H, s), 7.69 (1H, d, J = 6.84Hz), 7.78-7.82 (1H,
m), 8.04 (1H, d, J = 8.3Hz), 8.86-8.95 (3H, br) MASS m / z: 422 (M ⁺ +1) Isomer B: IRν _max ^KBr cm ^-1 : 3420, 1746, 1660 , 1598, 1504 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.89 (2H,
m), 3.51-3.63 (1H, m), 5.39-5.52 (4H, m), 5.91 (1H, d, J = 1
9.5Hz), 6.49-6.60 (1H, br), 7.40 (1H, s), 7.71 (1H, d, J = 7.
33Hz), 7.79-7.83 (1H, m), 8.04 (1H, d, J = 8.3Hz), 8.87-9.
0 (3H, br) MASS m / z: 422 (M ⁺ +1)

Example 40 (9S) -1-Acetylamino-9-ethyl-4-chloro-1,2-dihydro-9-hydroxy-3H, 12H-pyrano [3 ′, 4 ′: 6,7] indolizino [1,2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15
H) -Dione synthesis:

[0226]

[Chemical formula 46]

(1) 1-Acetyl-5-acetylamino-8-chloro-2,3-dihydroquinolin-4-one: In Example 17- (1), 5-amino-8-methyl-2,3 5-amino-8-chloro-2,3-dihydroquinoline-4 instead of -dihydroquinolin-4-one
-ON (JP-A 1-279891) using 3.8 g, Example 17-
The reaction was carried out in the same manner as in (1) and post-treatment was carried out to obtain 2.8 g of the title compound. Melting point: 175-177 ° C NMR (in CDCl ₃ ) δ: 2.14 (s, 3H), 2.26 (s, 3H), 2.0-6.2
(m, 5H), 7.60 (d, 1H, J = 9Hz), 8.66 (d, 1H, J = 9Hz)

(2) 1-Acetyl-3,5-diacetylamino-8-
Chlor-2,3-dihydroquinolin-4-one In Example 1- (2), 1.4 g of the compound obtained in (1) above was used in place of 8-acetylamino-1-tetralone, and Example 1- The reaction was carried out in the same manner as in (2) and post-treatment was carried out. The obtained compound was further reacted in the same manner as in Example 1- (3) and post-treated to obtain 0.62 g of the title compound. Melting point: 206-210 ° C IRν _max ^KBr cm ^-1 : 1680, 1662, 1576, 1512, 1284 NMR (in CDCl ₃ ) δ: 2.06 (s, 3H), 2.12 (s, 3H), 2.25 (s,
3H), 3.5-6.5 (m, 3H), 7.5-8.7 (m, 2H), 11.44 (br.s, 1H) MASS m / z: 337 (M ⁺ ), 339 (M ⁺ +2)

(3) 3,5-Diamino-8-chloro-2,3-dihydroquinolin-4-one: 8 ml of 6N hydrochloric acid was added to 514 mg of the compound obtained in (2), and the mixture was heated with stirring at 110 ° C. for 1.5 hours. did. The reaction solution was cooled, chloroform was added thereto and 50 ml of a 1N sodium hydroxide aqueous solution was added with stirring, the chloroform layer was extracted, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 260 mg of the title compound. NMR (in CDCl ₃ ) δ: 3.2-3.5 (m, 1H), 3.6-3.8 (m, 2H) 5.0
0 (br.s, 2H), 5.89 (d, 1H, J = 9Hz), 6.37 (br.s, 2H), 7.09
(d, 1H, J = 9Hz)

(4) 3-Acetylamino-5-amino-8-chloro
-2,3-Dihydroquinolin-4-one: Compound 2 obtained in (3)
Dissolve 60 mg in a mixed solvent of 5 ml of dichloromethane and 5 ml of THF, and under stirring with ice cooling, 0.16 ml of pyridine and 0.13 ml of acetic anhydride.
Was added and stirred for 20 minutes. The reaction mixture was concentrated, chloroform was added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was triturated with ether and petroleum ether to give 287 mg of the title compound. IRν _max ^KBr cm ^-1 : 3428, 1614, 1498, 1316, 1146 NMR (in CDCl ₃ ) δ: 2.09 (s, 3H), 3.0-4.7 (m, 3H), 5.10
(br.s, 1H), 5.89 (d, 1H, J = 9Hz), 6.51 (br.s, 1H), 7.11 (d,
1H, J = 9Hz) MASS m / z: 253 (M ⁺ ), 255 (M ⁺ +2)

(5) (9S) -1-Acetylamino-9-ethyl-4-
Chlor-1,2-dihydro-9-hydroxy-3H, 12H-pyrano
[3 ', 4': 6,7] Indolizino [1,2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15H) -dione: Compound obtained from (4)
202 mg of the title compound was obtained by reacting 267 mg and 277 mg of trione in the same manner as in Example 17- (5) for 7 hours and performing a post-treatment.
Got Melting point: 250-270 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1748, 1662, 1608, 1158 NMR (in DMSO-d ₆ ) δ: 0.87 (t, 3H, J = 7Hz), 1.7-2.0 (m, 2
H), 2.50 (s, 3H), 3.4-3.6 (m, 2H), 5.19,5.27 (ABq, 2H, J = 1
9Hz), 5.43 (s, 2H), 5.4-5.6 (m, 1H), 6.52 (s, 1H), 7.29, 7.
30 (each s, 1H), 7.40 (d, 1H, J = 9Hz), 7.71 (d, 1H, J = 9Hz),
8.52 (t, 1H, J = 8Hz) MASS m / z: 480 (M ⁺ ), 482 (M ⁺ +2)

Example 41 (9S) -1-Amino-9-ethyl-4-chloro-1,2-dihydro-9-hydroxy-3H, 12H-pyrano [3 ′, 4 ′: 6,7] indolizino [ 1,
Synthesis of 2-c] benzo [ij] [2,7] naphthyridine-10,13 (9H, 15H) -dione hydrochloride:

[0233]

[Chemical 47]

190 mg of the compound obtained in Example 40- (5) was reacted for 3 hours in the same manner as in Example 2 and post-treated to give the title compound as isomer A (67 mg) and isomer B (40 mg). Got each. Isomer A: Melting point 130-150 ° C (decomposition) IRν _max ^KBr cm ^-1 : 1744, 1658, 1606, 1162 NMR (in DMSO-d ₆ ) δ: 0.88 (t, 3H, J = 7Hz), 1.7-2.0 ( m, 2
H), 3.45 (q, 1H, J = 7Hz), 3.57,3.89 (each d, 1H, J = 12Hz),
4.2-4.5 (br, 1H), 5.15 (s, 1H), 5.39,5.79 (ABq, 2H, J = 19H
z), 5.45 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.34 (s, 1H),
7.49 (d, 1H, J = 9Hz), 7.78 (d, 1H, J = 9Hz), 8.68 (br.s, 3H) MASS m / z: 438 (M ⁺ ), 440 (M ⁺ +2) Isomer B : mp 250-270 ℃ ^{_{(decomposition) IRν max KBr cm -1: 1750}} , 1600, 1608, 1160 NMR ( in _{DMSO-d 6) δ: 0.88} (t, 3H, J = 7Hz), 1.7-1.9 (m, 2
H), 3.56,3.89 (ABq, 1H, J = 12Hz), 5.16 (s, 1H), 5.41,5.78
(ABq, 2H, J = 19Hz), 5.45 (s, 2H), 6.56 (s, 1H), 6.86 (s, 1
H), 7.34 (s, 1H), 7.49 (d, 1H, J = 9Hz), 7.79 (d, 1H, J = 9Hz),
8.67 (br.s, 3H) MASS m / z: 438 (M ⁺ ), 440 (M ⁺ +2)

Example 42 (9S) -3-Amino-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,7] indolizino [1,2-b] quinoline-10,13 (9H,
Synthesis of 15H) -dione hydrochloride:

[0236]

[Chemical 48]

(1) 8-Acetylamino-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: Carbon tetrachloride 60 ml
8-acetylamino-1-tetralone 1.07 g, N- bromosuccinimide 1.28 g and a catalytic amount of benzoyl peroxide were added,
The mixture was heated under reflux for 1 hour. After cooling to room temperature, the precipitate was filtered off and the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with chloroform, and the fraction containing the desired product was concentrated. The bromide obtained was dissolved in 20 ml of DMF.
After cooling to ℃, add 440 mg of sodium azide little by little, and stir at 0 ℃ for 30 minutes, then at room temperature for 1 hour, and then add water 30
ml was added. The mixture was extracted twice with ether, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated to give 4
1.17 g of the azide body was obtained. Benzene 5 was added to the obtained azide.
0 ml, triphenylphosphine 1.38 g, phthalic anhydride 781 m
After adding g and heating under reflux for 12 hours, 40 mg of tetra-n-butylammonium cyanide was added, and after heating under reflux for another 4 hours, the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (2: 1), and the fractions containing the desired product were concentrated to obtain 1.25 g of the title compound. NMR (in CDCl ₃ ) δ: 2.26 (3H, s), 2.2-2.3 (1H, m), 2.75
-3.0 (3H, m), 5.69 (1H, dd, J = 5.4Hz, 10.8Hz), 6.74 (1H, d, J
= 7.8Hz), 7.44 (1H, t, J = 7.8Hz), 7.75-7.80 (2H, m), 7.85-
7.82 (2H, m), 8.71 (1H, d, J = 7.8Hz), 12.18 (1H, s)

(2) 8-Amino-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: Compound 339m obtained in (1)
g was added to 10 ml of 4N hydrochloric acid, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, sodium hydrogen carbonate was added to make the mixture alkaline, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated to obtain 190 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.15-2.21 (1H, m), 2.7-3.0 (3H, m),
5.60 (1H, dd, J = 4.6Hz, 11.5Hz), 6.22 (1H, d, J = 7.8Hz), 6.5
5 (1H, d, J = 7.8Hz), 7.12 (1H, t, J = 7.8Hz), 7.74-7.79 (2H,
m), 7.86-7.90 (2H, m)

(3) (9S) -3-Amino-9-ethyl-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,
7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride: 190 mg of the compound obtained in (2) and 163 mg of trione were added to 20 ml of toluene and Example 1- (5). Similarly, by reacting for 15 hours and post-treatment, (9S) -9-ethyl-2,3-dihydro-9-hydroxy-3- (1,3-dioxoisoindoline-2-yl) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino
263 mg of [1,2-b] quinoline-10,13 (9H, 15H) -dione were obtained as a mixture of 3-position isomers. The title compound was obtained as isomer A (73 mg) and isomer B (58 mg) by treating the obtained compound 223 mg in the same manner as in Example 13, (12). Isomer A: Melting point: 190 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.87 (2H,
m), 2.2-2.5 (2H, m), 3.2-3.45 (2H, m), 4.98 (1H, m), 5.30
(2H, s), 5.44 (2H, s), 7.36 (1H, s), 7.85-7.93 (2H, m), 8.1
7 (1H, d, J = 8.3Hz), 8.88 (3H, m) Isomer B: mp: 218 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.90} (3H, t, J = 7.3Hz) , 1.88 (2H,
m), 2.3-2.5 (2H, m), 3.3-3.4 (2H, m), 4.91 (1H, m), 5.32
(2H, s), 5.45 (2H, s), 7.37 (1H, s), 7.85 (1H, d, J = 6.8Hz),
7.92 (1H, dd, J = 6.8Hz, 7.7Hz), 8.19 (1H, d, J = 7.7Hz), 8.80
(3H, m)

Example 43 (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy-4
-Methyl-12H-pyrano [4,3,2-de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride Synthesis of:

[0241]

[Chemical 49]

(1) 3,5-Diacetylamino-8-methyl-4-chromanone: In Example 12- (1), 5-acetylamino-8
5-acetylamino instead of -methyl-4-thiochromanone
-8-Methyl-4-chromanone (Japanese Patent Laid-Open No. 1-279891) 1 g
Was reacted in the same manner as above and post-treated to obtain 105 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.11 (3H, s), 2.17 (3H, s), 2.22 (3
H, s), 3.98 (1H, dd, J = 12.1Hz, 15.1Hz), 4.70-5.05 (2H, m),
6.26 (1H, m), 7.34 (1H, d, J = 8.3Hz), 8.18 (1H, d, J = 8.3Hz)

(2) 3-Acetylamino-5-amino-8-methyl
-4-Chromanone: 100 mg of the compound obtained in (1) was added to 3 m of concentrated hydrochloric acid.
In addition to 1, the mixture was stirred at 80 ° C. for 1 hour. After cooling, 5 ml of ice water was added and sodium carbonate was added to make it alkaline, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-ethyl acetate (4: 1), and the fractions containing the target compound were concentrated to give 48 mg of the title compound. Got Melting point: 178-180 ° C IRν _max ^KBr cm ^-1 : 3448, 3328, 1650, 1628, 1484 NMR (in CDCl ₃ ) δ: 2.06 (3H, s), 2.08 (3H, s), 3.7-4.1
(1H, m), 4.65-5.05 (2H, m), 6.14 (1H, d, J = 8.3Hz), 7.06 (1
(H, d, J = 8.3Hz)

(3) (9S) -1-Amino-9-ethyl-1,2-dihydro-9-hydroxy-4-methyl-12H-pyrano [4,3,2-de] pyrano [3 ′, 4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H,
15H) -dione hydrochloride: 139 mg of the compound obtained in (2) and 156 mg of trione were added to 12 ml of acetic acid, and the mixture was heated under reflux for 6 hours. The reaction solution was cooled, the solvent was distilled off, the residue was subjected to silica gel column chromatography, developed with chloroform-methanol (98: 2), and the fraction containing the target compound was concentrated to obtain a residue. Then, 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 80 ° C for 2 hours. After the reaction solution was concentrated, 20 ml of water was added to the residue to remove insoluble matter by filtration, and the filtrate was purified by high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-1N hydrochloric acid (developed with 18: 82: 1)]. Then, the title compounds were obtained as isomer A (77 mg) and isomer B (93 mg). Isomer A: Melting point: 200 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3432, 1756, 1658, 1602 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 6.8Hz), 1.83-1.92
(2H, m), 2.44 (3H, s), 4.44 (1H, d, J = 12.2Hz), 4.91 (1H, d,
J = 12.2Hz), 5.20 (1H, brs), 5.39,5.78 (2H, ABq, J = 19Hz),
5.44 (2H, s), 7.37 (1H, s), 7.78 (1H, d, J = 8.8Hz), 7.80 (1
H, d, J = 8.8Hz), 8.88 (3H, br) MASS m / z: 420 (M ⁺ +1) Isomer B: Melting point: 200 ° C or higher (decomposition) IRν _max ^KBr cm ^-1 : 3444, 1746, 1658, 1596 NMR (in DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.83-1.92
(2H, m), 2.45 (3H, s), 4.44 (1H, d, J = 11.7Hz), 4.91 (1H, d,
J = 11.7Hz), 5.20 (1H, brs), 5.41,5.78 (2H, ABq, J = 19.5H
z), 5.44,5.48 (2H, ABq, J = 16.6Hz), 7.40 (1H, s), 7.78 (1H,
d, J = 8.8Hz), 7.82 (1H, d, J = 8.8Hz), 8.97 (3H, br) MASS m / z: 420 (M ⁺ +1)

Example 44 (9S) -3-Amino-9-ethyl-5-fluoro-2,3-dihydro-9-
Synthesis of hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0246]

[Chemical 50]

(1) 4- (4-Fluorophenyl) -4-oxobutanoic acid: To 79.6 g of fluorobenzene, 50 g of succinic anhydride and 133.3 g of aluminum chloride were added, and the mixture was heated under reflux for 6 hours. After distilling off excess fluorobenzene, the residue was added to 2 l of a cold 1% aqueous hydrochloric acid solution, the precipitate was collected by filtration, washed with water and dried to obtain 73 g of the title compound. NMR (in CDCl ₃ ) δ: 2.82 (2H, t, J = 6.6Hz), 3.29 (2H, t, J
= 6.6Hz), 7.1-7.2 (2H, m), 7.9-8.1 (2H, m)

(2) 4- (4-Fluorophenyl) butanoic acid methyl ester: 73 g of the compound obtained in (1) was dissolved in 600 ml of acetic acid, and 20 ml of 40% perchloric acid and 10 g of 10% palladium-carbon were dissolved. Is added and catalytic hydrogenation is carried out at 5 atm.
After distilling off the acetic acid, 100 ml of water was added, the mixture was extracted with ethyl acetate, washed successively with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, 100 ml of dichloromethane, 74 g of sodium carbonate were added to the residue,
30 ml of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and cooled to 0 ° C. After gradually adding 150 ml of methanol and stirring at room temperature for 12 hours, 300 ml of ethyl acetate was added, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 66.7 g of the title compound. Got NMR (in CDCl ₃ ) δ: 1.93 (2H, quintet, J = 7.8Hz), 2.32
(2H, t, J = 7.8Hz), 2.62 (2H, t, J = 7.8Hz), 3.66 (3H, s), 6.9
6 (2H, m), 7.13 (2H, m)

(3) 4- (4-Fluoro-2-nitrophenyl) butanoic acid methyl ester: 66.7 g of the compound obtained in (2) was added to 600 ml of cold concentrated sulfuric acid, and the internal temperature was kept at 5 ° C or lower. Meanwhile, 300 ml of a concentrated sulfuric acid solution containing 50 g of potassium nitrate was added dropwise. After the addition was completed, the mixture was stirred for another 30 minutes, poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (40: 3), and the fractions containing the target compound were concentrated to obtain 39.3 g of the title compound. NMR (in CDCl ₃ ) δ: 1.98 (2H, m), 2.40 (2H, t, 7.3Hz),
2.91 (2H, t, J = 7.8Hz), 3.69 (3H, s), 7.27 (1H, ddd, J = 2.9H
z, 7.8Hz, 8.3Hz), 7.37 (1H, dd, J = 5.3Hz, 8.3Hz), 7.66 (1H, d
(d, J = 2.9Hz, 8.8Hz)

(4) 4- (2-acetylamino-4-fluorophenyl) butanoic acid methyl ester: 39.3 g of the compound obtained in (3) and 3 g of 10% palladium-carbon were added to 200 ml of methanol for 6 hours. Perform catalytic hydrogenation. After the catalyst was filtered off and the solvent was distilled off, 50 ml of chloroform was added to the residue, and 50 ml of acetic anhydride was added with stirring at room temperature, followed by stirring for 3 hours. By concentrating the reaction solution to dryness, the title compound
42.0 g was obtained. NMR (in CDCl ₃ ) δ: 1.72-1.85 (2H, m), 2.31 (3H, s), 2.
45 (2H, m), 2.56 (2H, m), 3.76 (3H, s), 6.71 (1H, dt, J = 2.5H
z, 8.3Hz), 7.04 (1H, dd, J = 6.3Hz, 8.3Hz), 8.08 (1H, dd, J = 2.
(5Hz, 10.8Hz)

(5) 5-Acetylamino-7-fluoro-1-tetralone: 42 g of the compound obtained in (4) was dissolved in 100 ml of methanol, 200 ml of 1N sodium hydroxide was added, and the mixture was mixed at room temperature for 3 hours.
Stir for hours. After the reaction solution is concentrated to about 200 ml, it is made acidic by adding concentrated hydrochloric acid and extracted three times with 100 ml of ethyl acetate.
The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Add 100 ml of dichloromethane to the residue, and add sodium carbonate 1
After adding 7 g and 12 ml of thionyl chloride, the mixture was heated under reflux for 2 hours. After cooling to room temperature, the insoluble material was filtered off. The filtrate was concentrated, 200 ml of 1,2-dichloroethane and 40 g of aluminum chloride were added to the residue, and the mixture was stirred at 70 ° C for 3 hours and 90 ° C for 1 hour.
The reaction solution was poured into ice water and extracted with chloroform,
The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-ethyl acetate (7: 3), and the fractions containing the target compound were concentrated to obtain 17 g of the title compound. NMR (in CDCl ₃ ) δ: 2.16 (2H, m), 2.24 (3H, s), 2.66 (2
H, t, J = 6.83Hz), 2.78 (2H, t, J = 6.0Hz), 7.08 (1H, br.s), 7.
59 (1H, dd, J = 2.4Hz, 8.3Hz), 7.84 (1H, dd, J = 2.4Hz, 7.8Hz)

(6) 5-Acetylamino-7-fluoro-1,2,3,
4-Tetrahydronaphthalene: Compound 10.5 obtained from (5)
g, 10% palladium-carbon 5 g and perchloric acid 5 ml acetic acid 30
In addition to 0 ml, catalytic hydrogenation is carried out at 5 atm for 6 hours. After removing the catalyst by filtration and concentrating the reaction solution to about 50 ml, 100 ml of water was added and the mixture was extracted three times with chloroform. The chloroform layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 9.5 g of the title compound.
Got NMR (in CDCl ₃ ) δ: 1.7-1.9 (4H, m), 2.20 (3H, s), 2.52
(2H, m), 2.75 (2H, m), 6.61 (1H, d, J = 8.8Hz), 6.94 (1H, m),
7.59 (1H, d, J = 9.8Hz)

(7) 8-Acetylamino-6-fluoro-1-tetralone: 9.46 g of the compound obtained in (6) was dissolved in 420 ml of acetone, and 42 ml of 15% magnesium sulfate aqueous solution was added to
After cooling to ℃, 21.7 g of potassium permanganate was added little by little. After the addition is complete, stir at 0 ° C for 50 minutes and then at room temperature for 1
After stirring for 1 hour, the reaction solution was poured into 1 liter of water and extracted three times with chloroform. The chloroform layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (3: 1), and the fractions containing the target compound were concentrated to obtain 7.98 g of the title compound. NMR (in CDCl ₃ ) δ: 2.08 (2H, m), 2.24 (3H, s), 2.69 (2
H, t, J = 6.4Hz), 2.96 (2H, t, J = 6.1Hz), 6.64 (1H, dd, J = 2.4H
z, 8.3Hz), 8.42 (1H, dd, J = 2.4Hz, 12.0Hz), 12.35 (1H, br.
s)

(8) 6-Fluoro-8-triphenylmethylamino-1-tetralone: 4N was added to 287 mg of the compound obtained in (7).
10 ml of hydrochloric acid was added and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine,
After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (7: 3), and the fraction containing the desired product was concentrated. 5 ml of dichloromethane in the residue,
0.8 ml triethylamine, triphenylmethyl chloride
1.5 g was added and the mixture was heated under reflux for 4 hours. After cooling to room temperature, 20 ml of dichloromethane was added, and the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (3: 1), and the fractions containing the target compound were concentrated to obtain 706 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.03 (2H, m), 2.66 (2H, t, J = 6.4Hz),
2.84 (2H, t, J = 6.1Hz), 5.67 (1H, dd, J = 2.4Hz, 12.7Hz), 6.02
(1H, dd, J = 2.4Hz, 8.8Hz), 7.2-7.4 (15H, m), 11.29 (1H, s)

(9) 6-Fluoro-8-triphenylmethylamino-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: obtained in (8) in 30 ml of carbon tetrachloride. Compound 706 mg,
231 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added, and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, 30 ml of chloroform was added, 1N cold sodium hydroxide,
The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in 5 ml of DMF, cooled to 0 ° C., 160 mg of sodium azide was added little by little, and the mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 1 hour.
30 ml of water was added. After being extracted twice with ether, washed successively with water and saturated brine, dried over anhydrous sodium sulfate,
The solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (9: 1), and the fraction containing the desired product was concentrated to obtain 344 mg of 4-position azide. To the obtained azide compound, 20 ml of benzene, 205 mg of triphenylphosphine and 116 mg of phthalic anhydride were added, and the mixture was heated under reflux for 12 hours and then 40 mg of tetra-
After n-butylammonium cyanide was added and the mixture was heated under reflux for 8 hours, the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-hexane (1: 1), and the fractions containing the target compound were concentrated to obtain 440 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.15 (1H, m), 2.7-3.1 (3H, m), 5.55
(1H, dd, J = 4.40Hz, 12.2Hz), 5.75 (1H, dd, J = 2.4Hz, 7.8Hz),
5.77 (1H, dd, J = 2.4Hz, 10.2Hz), 7.2-7.4 (15H, m), 7.67 (2
H, m), 7.88 (2H, m), 11.41 (1H, s)

(10) 8-Amino-6-fluoro-4- (1,3-dioxoisoindoline-2-yl) -1-tetralone: obtained in (1) in 8 ml of formic acid cooled to 0 ° C. Compound (423 mg) was added, and one drop of concentrated hydrochloric acid was added with stirring. After stirring at room temperature for 1 hour, the solvent was distilled off. The residue was dissolved in chloroform and concentrated, then an ether-hexane mixed solvent was added, and the precipitated crystals were collected by filtration to obtain 132 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.16 (1H, m), 2.7-3.05 (3H, m), 5.56
(1H, dd, J = 4.4Hz, 11.7Hz), 5.95 (1H, dm, J = 9.8Hz), 6.21 (1
H, dd, J = 2.0Hz, 10.8Hz), 7.78 (2H, m), 7.90 (2H, m)

(11) (9S) -3-Amino-9-ethyl-5-fluoro
-2,3-Dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H,
15H) -dione hydrochloride: 125 mg of the compound obtained in (10) and (S) -4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano [3,4-f] indo in 10 ml of toluene Lysine-3,6,10 (4H) -trione 104 mg was reacted for 22 hours in the same manner as in Example 1- (5) and post-treated to give (9S) -9-ethyl-5-fluoro-2,3. -
Dihydro-9-hydroxy-3- (1,3-dioxoisoindoline-2-yl) -1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b ] Quinoline-10,13 (9H, 15H) -dione 119mg
Was obtained as a mixture of 3-position isomers. Obtained compound 119 m
g was treated in the same manner as in (12) of Example 13 to give the title compound as isomer A (31 mg) and isomer B (35
mg). Isomer A: Melting point: Gradually colored (decomposition) from 206 ° C. NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz), 1.87 (2H,
m), 2.21-2.33 (1H, m), 2.40-2.55 (1H, m), 3.25-3.40 (2H,
m), 4.92 (1H, m), 5.31 (2H, s), 5.45 (2H, s), 6.54 (1H, s),
7.35 (1H, s), 7.81 (1H, dd, J = 2.4Hz, 9.3Hz), 7.97 (1H, dd, J
= 2.4Hz, 10.3Hz), 8.70 (3H, br.s) Isomer B: Melting point: Gradual coloring from 194 ° C (decomposition) NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz ), 1.88 (2H,
m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 3.3-3.4 (2H, m), 4.
94 (1H, m), 5.31 (2H, s), 5.45 (2H, s), 7.36 (1H, s), 7.82 (1
H, dd, J = 2.4Hz, 9.3Hz), 7.98 (1H, dd, J = 2.4Hz, 10.2Hz), 8.
81 (3H, br.s)

Example 45 (9S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-3-dimethylamino-1H, 12H-benzo [de] pyrano [3 ′, 4 ′:
Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0259]

[Chemical 51]

Compound obtained in Example 44 (isomer A) 15
To mg, 35% formalin aqueous solution 1 ml, formic acid 0.08 ml and 1
After adding 0.03 ml of N sodium hydroxide and heating under reflux for 1 hour, the solvent was distilled off. After adding 2 ml of 1N hydrochloric acid to the residue and distilling off the solvent, 4 ml of water was added to remove insoluble matter by filtration, and the filtrate was filtered by high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-1N hydrochloric acid (17: 83: 1 Development in Step 5)] to obtain 9 mg of the title compound. Melting point: 182 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.3Hz), 1.87 (2H,
m), 2.3-2.7 (2H, m), 2.85 (3H, d, J = 4.4Hz), 2.87 (3H, d, J =
4.4Hz), 3.2-3.6 (2H, m), 4.99 (1H, m), 5.25,5.36 (2H, ABq,
J = 19Hz), 5.45 (2H, s), 6.55 (1H, m), 7.36 (1H, s), 8.0-8.
1 (2H, m), 10.42 (1H, m)

Example 46 (9S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-3-dimethylamino-1H, 12H-benzo [de] pyrano [3 ′, 4 ′:
Synthesis of 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0262]

[Chemical 52]

Compound obtained in Example 44 (isomer B) 20
After treating mg in the same manner as in Example 45, high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-
The product was purified with 1N hydrochloric acid (21: 79: 1)] to obtain 9 mg of the title compound. Melting point: 230 ° C or higher (decomposition) NMR (in DMSO-d6) δ: 0.88 (3H, t, J = 7.3Hz), 1.88 (2H,
m), 2.3-2.7 (2H, m), 2.86 (3H, d, J = 4.4Hz), 2.89 (3H, d, J =
4.9Hz), 3.3-3.5 (2H, m), 4.99 (1H, m), 5.26,5.37 (2H, ABq,
J = 19Hz), 5.45 (2H, s), 6.55 (1H, m), 7.36 (1H, s), 8.01 (1
H, dm, J = 9.3Hz), 8.05 (1H, dm, J = 9.8Hz), 10.25 (1H, m)

Example 47 (9S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-3-methylamino-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6 ,
7] Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0265]

[Chemical 53]

(1) 5-acetamino-7-fluoro-1-methyltrifluoroacetaminotetralone: ethanol 20 ml
To the compound obtained in Example 44 (5) in 1.02 g, 11 ml of 40% aqueous methylamine solution and 1.2 g of 10% palladium-carbon were added, and after catalytic hydrogenation for 9.5 hours, the catalyst was filtered off,
The filtrate was concentrated to dryness. The residue was dissolved in 20 ml of chloroform, 2 ml of triethylamine was added, 4 ml of trifluoroacetic anhydride was added with stirring at 0 ° C., and then the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with dilute hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography with chloroform-ethyl acetate (9: 1). After development, 1.33 g of the title compound was obtained from the fraction containing the desired product. NMR (in CDCl ₃ ) δ: 1.7-2.0 (1.6H, m), 2.0-2.3 (2.4H,
m), 2.22 (3H, s), 2.5-2.7 (2H, m), 2.71,2.84 (3H, each
s), 5.15 (0.4H, m), 5.79 (0.6H, m), 6.54 (0.6H, d, J = 8.3H
z), 6.65 (0.4H, d, J = 8.3Hz), 6.97 (1H, m), 7.65-7.75 (1H,
m)

(2) 8-acetamino-6-fluoro-4-methyltrifluoroacetamino-1-tetralone: To 1.32 g of the compound obtained in (1), 60 ml of acetone and 6 ml of a 15% aqueous magnesium sulfate solution were added, Gradually add 1.9 g of potassium permanganate while stirring at 0 ° C. 30 minutes at the same temperature after the addition is complete
After stirring for 30 minutes at room temperature, add 60 ml of water,
It was extracted three times with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography and developed with chloroform-ethyl acetate (9: 1) to obtain 748 mg of the title compound from the fraction containing the desired product. NMR (in CDCl ₃ ) δ: 2.0-2.4 (2H, m), 2.26 (3H, s), 2.7-
3.0 (2H, m), 2.84,2.97 (3H, each small m), 5.30 (0.3H, dd,
J = 4.9Hz, 11.7Hz), 5.96 (0.7H, dd, J = 4.4Hz, 11.7Hz), 6.43
(0.7H, dm, J = 7.3Hz), 6.56 (0.3H, dm, J = 7.3Hz), 8.57 (0.7
H, dd, J = 2.4Hz, 11.2Hz), 8.60 (0.3H, dd, J = 2.9Hz, 11.7Hz),
12.3 (1H, br.s)

(3) 8-Amino-6-fluoro-4-methyltrifluoroacetylamino-1-tetralone: the compound obtained in (2)
20 ml of 4N hydrochloric acid was added to 722 mg, and the mixture was heated under reflux for 5 hours.
After cooling to room temperature, saturated sodium hydrogencarbonate was added to make it weakly alkaline, and then extracted three times with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. After distilling off the solvent, 50 ml of dichloromethane and 0.29 ml of triethylamine were added to the residue, and the mixture was placed in an ice salt bath (-1
0.29m trifluoroacetic anhydride while cooling and stirring at 2 ℃)
15 ml of a dichloromethane solution containing 1 was added dropwise. After stirring at the same temperature for 1 hour, the reaction solution was mixed with water, a saturated aqueous citric acid solution,
The extract was washed with water and saturated saline solution in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography and developed with chloroform-ethyl acetate (19: 1) to obtain 421 mg of the title compound from the fraction containing the desired product. NMR (in CDCl ₃ ) δ: 2.0-2.4 (2H, m), 2.6-2.9 (2H, m), 2.
86,2.98 (3H, each s), 5.20 (0.35H, dd, J = 4.4Hz, 11.7Hz),
5.87 (0.65H, dd, J = 4.4Hz, 11.7Hz), 5.97 (0.65H, dm, J = 9.3H
z), 6.09 (0.35H, dm, J = 9.3Hz), 6.26 (0.65H, dd, J = 2.4Hz,
8.7Hz), 6.28 (0.35H, dd, J = 2.0Hz, 8.8Hz)

(4) (9S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-3-methylamino-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
13 (9H, 15H) -dione · hydrochloride: To 24 ml of toluene, 378 mg of the compound obtained in (3) and 330 mg of trione were added, and
By reacting for 19 hours in the same manner as in (5) and post-treating (9
S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-3
-Methyltrifluoroacetylamino-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,
340 mg of 13 (9H, 15H) -dione are obtained as a mixture of 3-position isomers. 30 ml of concentrated hydrochloric acid was added to 300 mg of the obtained compound, and the mixture was heated at 80 ° C.
After stirring for 2.5 hours, the solvent was distilled off. Water (15 ml) was added to the residue, insoluble materials were removed by filtration, and the filtrate was purified by high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-1N hydrochloric acid (developed with 20: 80: 1)] to give the title compound. Obtained as isomer A (83 mg) and isomer B (103 mg). Isomer A: Melting point: 230 ° C or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.87 (2H,
m), 2.3-2.6 (2H, m), 2.70 (3H, br.s), 3.3-3.5 (2H, m), 4.
81 (1H, m), 5.26,5.37 (2H, ABq, J = 19.1Hz), 5.45 (2H, s), 6.
55 (1H, s), 7.36 (1H, s), 7.90 (1H, dd, J = 2.4Hz, 9.3Hz), 8.0
3 (1H, dd, 2.4Hz, J = 9.8Hz), 9.2-9.4 (2H, m) Isomer B: mp: 230 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.88} (3H, t, J = 7.3Hz), 1.88 (2H,
m), 2.3-2.6 (2H, m), 2.70 (3H, br.s), 3.3-3.5 (2H, m), 4.
82 (1H, m), 5.26,5.37 (2H, ABq, J = 19Hz), 5.45 (2H, s), 6.54
(1H, s), 7.36 (1H, s), 7.91 (1H, dd, J = 2.4Hz, 9.3Hz), 8.03
(1H, dd, 2.4Hz, J = 10.3Hz), 9.2-9.5 (2H, m)

Example 48 (9S) -1-Amino-9-ethyl-5-fluoro-2,3-dihydro-9-
Synthesis of hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H, 15H) -dione hydrochloride:

[0271]

[Chemical 54]

(1) 2,8-Diacetylamino-6-fluoro-1-
Tetralone: To a THF solution (60 ml) was added 2.28 g of potassium-t-butoxide, and the mixture of Example 44 was stirred at 0 ° C. under a nitrogen stream.
90 ml of a THF solution containing 3 g of the compound obtained in (7) above was gradually added, and after stirring for 10 minutes, 2.44 ml of n-butyl nitrite was added,
It was stirred at room temperature for 1 hour. Pour the reaction solution into dilute hydrochloric acid aqueous solution,
It was extracted three times with chloroform. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 87 ml of acetic acid and 87 ml of acetic anhydride were added to the residue, and 11 g of zinc dust was gradually added with stirring at room temperature, and the mixture was further stirred for 10 minutes. The insoluble material was filtered off, the solvent was distilled off, the residue was dissolved in 100 ml of chloroform, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (2: 3), and the fractions containing the target compound were concentrated to give 2.82 g of the title compound. Got NMR (in CDCl ₃ ) δ: 1.8-2.0 (1H, m), 2.11 (3H, s), 2.14
(3H, s), 2.67 (1H, m), 3.02 (1H, m), 3.25 (1H, m), 4.65 (1H,
ddd, J = 4.9Hz, 5.4Hz, 13.2Hz), 6.48 (1H, br.s), 6.64 (1H, d
d, J = 8.3Hz, 2.4Hz), 8.43 (1H, dd, J = 8.2Hz, 2.4Hz)

(2) 8-Amino-6-fluoro-2-trifluoroacetamino-1-tetralone: 20 ml of concentrated hydrochloric acid was added to 1.23 g of the compound obtained in (1), and the mixture was stirred at 100 ° C. for 12 hours. After cooling to room temperature, 200 ml of water was added and washed twice with chloroform. Sodium hydroxide was added to the aqueous layer to make it alkaline, and then extracted four times with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in dry THF (50 ml), triethylamine (0.59 ml) was added, and then 0.6 ml while cooling in an ice-salt bath.
10 ml of a THF solution containing trifluoroacetic anhydride was added dropwise. After stirring at the same temperature for 1 hour, 5 ml of water was added and the solvent was distilled off. 30 ml of water was added to the residue, extracted three times with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with chloroform, and the fraction containing the desired product was concentrated to give 1.1 g of the title compound. NMR (in CDCl ₃ ) δ: 1.88 (1H, ddd, J = 4.4Hz, 13.2Hz, 25.4
Hz), 2.79 (1H, m), 2.97 (1H, m), 3.15 (1H, m), 4.50 (1H, dd
d, J = 4.4Hz, 4.9Hz, 13.2Hz), 6.21 (2H, m)

(3) (9S) -1-Amino-9-ethyl-5-fluoro-
2,3-Dihydro-9-hydroxy-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 (9H,
15H) -dione hydrochloride: 144 mg of the compound obtained in (2) and 130 mg of trione were added to 30 ml of toluene, a catalytic amount of PPTS was added, and the mixture was heated under reflux for 41 hours using a Dean Stark apparatus. The reaction solution was cooled, the solvent was distilled off, the residue was subjected to silica gel column chromatography, developed with chloroform-methanol (99: 1), and the fraction containing the target compound was concentrated to obtain a residue, Methanol (5 ml), water (5 ml) and 4N hydrochloric acid (4 ml) were added and the mixture was stirred at 80 ° C for 5 hours. After the solvent was concentrated, 4 ml of water was added to remove insoluble matter by filtration, and the residue was purified by high performance liquid chromatography [CAPCELL PAK C18; acetonitrile-water-1N hydrochloric acid (developed with 22: 78: 1)] to give the title compound. Isomer A (19 mg) and Isomer B (16
mg). Isomer A: Melting point: 200 ° C. or higher (decomposition) NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.89 (2H,
m), 2.15-2.27 (1H, m), 2.40-2.55 (1H, m), 3.20-3.45 (2H,
m), 5.07 (1H, m), 5.42,5.84 (2H, ABq, J = 19.5Hz), 5.46 (2
H, s), 6.55 (1H, s), 7.38 (1H, s), 7.60 (1H, dd, J = 2.4Hz, 9.3
Hz), 7.86 (1H, dd , J = 2.4Hz, 10.3Hz), 8.2-8.6 (3H, m) Isomer B: mp: 210 ° C. or higher (decomposed) NMR (in _{DMSO-d 6) δ: 0.88} (3H , t, J = 7.3Hz), 1.88 (2H,
m), 2.15-2.27 (1H, m), 2.45-2.60 (1H, m), 3.20-3.45 (2H,
m), 5.12 (1H, m), 5.42,5.83 (2H, ABq, J = 19.1Hz), 5.46 (2
H, s), 6.55 (1H, s), 7.38 (1H, s), 7.62 (1H, dd, J = 2.4Hz, 8.8
Hz), 7.86 (1H, dd, J = 2.4Hz, 10.2Hz), 8.4-8.6 (3H, m), 7.86
(1H, dd, J = 2.4Hz, 10.2Hz), 8.4-8.6 (3H, m)

Example 49 (9S) -1-Amino-9-ethyl-4,5-difluoro-9-hydroxy-2,3-dihydro-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,7]
Synthesis of indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione:

[0276]

[Chemical 55]

(1) 4- (3,4-Difluorophenyl) -4-oxobutanoic acid: To 57 g of difluorobenzene, 45 g of succinic anhydride and 130.7 g of aluminum chloride were added, and the mixture was heated under reflux for 4 hours. 200 ml of 1% hydrochloric acid aqueous solution was added to the reaction solution, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, chloroform-
The mixture was developed with a mixed solvent of methanol (30: 1), and the fraction containing the desired product was concentrated to obtain 30 g of the title compound. NMR (in CDCl ₃ ) δ: 2.82 (2H, t, J = 7Hz), 3.26 (2H, t, J = 7)
Hz), 7.0-7.9 (3H, m)

(2) 4- (3,4-difluorophenyl) butanoic acid: 30 g of the compound obtained in (1) was dissolved in 200 ml of acetic acid and 8 ml of 60% perchloric acid and 3 g of 10% palladium-carbon were dissolved. In addition, catalytic hydrogenation was performed at 6.5 atm. The catalyst was filtered off, the acetic acid was distilled off, 600 ml of ethyl acetate was added to the residue, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 26 g of the title compound. NMR (in CDCl ₃ ) δ: 1.8-2.1 (2H, m), 2.37 (2H, t, J = 7H
z), 2.64 (2H, t, J = 7Hz), 6.9-7.1 (3H, m)

(3) 4- (4,5-difluoro-2-nitrophenyl) butanoic acid: 500 mg of the compound obtained in (2) was added to 4 ml of cold concentrated sulfuric acid, and potassium nitrate was added while keeping the internal temperature below 5 ° C. 2.5 ml of concentrated sulfuric acid solution containing 371 mg was added dropwise. After completion of dropping, the mixture was stirred for 30 minutes, poured into ice water, and extracted with 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off.
480 mg of the title compound was obtained. NMR (in CDCl ₃ ) δ: 1.8-2.1 (2H, m), 2.48 (2H, t, J = 7H
z), 2.9-3.0 (2H, m), 7.21 (1H, dd, J = 7Hz, 10Hz), 7.90 (1H,
(dd, J = 7Hz, 10Hz)

(4) 4- (2-acetylamino-4,5-difluorophenyl) butanoic acid: the compound obtained in (3) 380 m
g was dissolved in a mixed solvent of 5 ml of acetic acid and 10 ml of acetic anhydride to obtain 10%
60 mg of palladium-carbon was added and catalytic hydrogenation was performed.
The catalyst was filtered off, the filtrate was concentrated, and the residue obtained was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (10: 1), and the fraction containing the target compound was concentrated to give the title compound. 90 mg of compound are obtained. NMR (in CDCl ₃ ) δ: 1.7-1.9 (2H, m), 2.29 (3H, s), 2.4-
2.6 (4H, m), 6.93 (1H, dd, J = 8Hz, 12Hz), 8.09 (1H, dd, J = 8H
z, 12Hz), 8.53 (1H, br s)

(5) 5-Acetylamino-7,8-difluoro-1-
Tetralone: 9.07 g of the compound obtained in (4) was added to dichloromethane 45
Dissolve in 0 ml, add 7.71 g of phosphorus pentachloride with stirring at room temperature, and
Stir for hours. The reaction mixture was concentrated, dichloromethane was added to the residue, and the mixture was evaporated again. 1,2-dichloroethane 500m in the residue
l, 9.88 g of anhydrous aluminum chloride were added, and the mixture was stirred at 70 ° C. for 1 hour and then gently heated under reflux for 15 hours. The reaction solution was poured into ice water, extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (50: 1), and the fractions containing the target compound were concentrated to obtain 2.31 g of the title compound. NMR (in CDCl ₃ ) δ: 2.1-2.2 (2H, m), 2.23 (3H, s), 2.5-
2.7 (2H, m), 2.7-2.9 (2H, m), 6.93 (1H, br s), 7.84 (1H, dd,
(J = 7Hz, 11Hz)

(6) 5-Acetylamino-7,8-difluoro-1,
2,3,4-Tetrahydronaphthalene: 1 g of the compound obtained in (5) was dissolved in 20 ml of ethanol, 166 mg of sodium borohydride was added under stirring at room temperature, and the mixture was stirred for 20 minutes. Chloroform and 10% citric acid were added to the reaction solution, and the chloroform layer was extracted. The chloroform layer was concentrated, and 20 ml of toluene was added to the residue.
And p-TsOH were added in small amounts and the mixture was heated under reflux for 1 hour. 100 ml of ethyl acetate was added to the reaction solution, washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. 20 ml of ethanol, 20 ml of dioxane and 0.2 ml of acetic acid were obtained.
Was dissolved in a mixed solvent of, platinum oxide (200 mg) was added, and catalytic hydrogenation was performed. The catalyst was filtered off, the filtrate was concentrated, ether was added to the residue, and the precipitate was collected by filtration to obtain 0.8 g of the title compound. NMR (in CDCl ₃ ) δ: 1.79 (4H, br s), 2.18 (3H, s), 2.52
(2H, br s), 2.73 (2H, br s), 6.91 (1H, br s), 7.4-7.6 (1
H, m)

(7) 8-Acetylamino-5,6-difluoro-1-
Tetralone: 810 mg of the compound obtained in (6) was dissolved in 30 ml of acetone, 3 ml of 15% magnesium sulfate was added, and 1.17 g of potassium permanganate was gradually added with stirring. After 1 hour, chloroform was added to the reaction solution for extraction, which was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 806 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.05-2.17 (2H, m), 2.23 (3H, s), 2.
68 (2H, t, J = 5.85Hz), 3.00 (2H, t, J = 5.85Hz), 8.61 (1H, d
d, J = 7.8Hz, 13.2Hz), 12.1-12.23 (1H, br s)

(8) 2,8-Diacetylamino-5,6-difluoro-1-tetralone: 300 mg of the compound obtained in (7) was added to 7.5 ml of
The solution dissolved in THF is 309 mg of tertiary potassium butoxide.
Is gradually added to a mixed solvent of 15 ml of THF and 1.5 ml of tertiary butanol under a stream of N _{2 at} 0 ° C. After stirring for 10 minutes at the same temperature, 0.22 ml of n-butyl nitrite was added dropwise at 0 ° C., and then the mixture was stirred for 1.5 hours while gradually raising the temperature to 20 ° C. 1
The pH is adjusted to 1 with N hydrochloric acid and then extracted with chloroform. After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was added with 15 ml of acetic acid and acetic anhydride.
15 ml was added, 1 g of zinc dust was further added, and the mixture was stirred at 20 ° C. for 18 hours. After removing the insoluble matter by filtration and distilling off the solvent,
The residue is extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. The mixture was developed with a mixed solvent of chloroform-methanol (97: 3), and the fractions containing the target compound were concentrated to obtain 311 mg of the title mixture. NMR (in CDCl ₃ ) δ: 1.83-1.94 (1H, m), 2.10 (3H, s), 2.
21 (3H, s), 2.59-2.67 (1H, m), 2.92-3.01 (1H, m), 3.18-3.
26 (1H, m), 4.62-4.68 (1H, m), 6.70 (1H, d, J = 5.9Hz), 8.56
(1H, dd, J = 7.3Hz, 13.2Hz), 11.64-11.67 (1H, br s)

(9) 2,8-Diamino-5,6-difluoro-1-tetralone: 300 mg of the compound obtained in (8) is added to 50 ml of 3N hydrochloric acid, and the mixture is stirred at 60 ° C. for 3.5 hours. Then add 15 ml of concentrated hydrochloric acid 9
After stirring at 0 ° C for 30 minutes, the mixture is cooled, the reaction mixture is neutralized with sodium hydrogen carbonate and extracted with 300 ml of chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 140 mg of the title compound. NMR (in CDCl ₃ ) δ: 1.79-1.93 (1H, m), 2.68-2.81 (2H,
m), 3.16-3.20 (1H, m), 3.53-3.56 (1H, m), 6.26-6.29 (2H,
m), 6.34-6.45 (2H, m), 7.28 (1H, s)

(10) 8-Amino-5,6-difluoro-2-trifluoroacetylamino-1-tetralone: 140 mg of the compound obtained in (9) was dissolved in 10 ml of THF and cooled to 0 ° C., and 75 mg of triethylamine was added. In addition, trifluoroacetic anhydride 155mg
Gradually add. After stirring for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution is added and the mixture is extracted with chloroform. After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent is evaporated and the obtained residue is subjected to silica gel column chromatography and developed with a mixed solvent of chloroform-methanol (97: 3) to contain the desired product. The fractions were concentrated to give 93 mg of the title mixture. NMR (in CDCl ₃ ) δ: 1.85 (1H, ddd, J = 4.4Hz, 13Hz, 26.1H
z), 2.75-2.84 (2H, m), 3.20-3.26 (1H, m), 4.5 (1H, dd, J =
4.9Hz, 13.7Hz), 6.31 (1H, dd, J = 6.3Hz, 11.7Hz), 6.35-6.4
4 (2H, br s), 7.54-7.6 (1H, br s)

(11) (9S) -9-Ethyl-4,5-difluoro-2,3-
Dihydro-9-hydroxy-1-trifluoroacetylamino-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolizino
[1,2-b] quinoline-10,13 (9H, 15H) -dione: 90 mg of the compound obtained in (10) was dissolved in 20 ml of toluene, 81 mg of trione and 20 mg of PPTS were added, and then 111 in a nitrogen stream. Heated to reflux for hours. The reaction mixture was concentrated, the obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (30: 1), and the fractions containing the target compound were concentrated to obtain 98 mg of the title compound. . NMR (in CDCl ₃ ) δ: 1.01 (3H, t, J = 7Hz), 1.80-1.83 (2H,
m), 2.01 (1H, s), 2.33 (1H, s), 2.96 (1H, dd, J = 6.35Hz, 7.3
2Hz), 4.32-4.36 (1H, m), 5.23 (3H, dd, J = 6.35Hz, 17.1Hz),
5.67 (1H, d, J = 17.1Hz), 7.55 (1H, s)

(12) (9S) -1-Amino-9-ethyl-4,5-difluoro-2,3-dihydro-9-hydroxy-1H, 12H-benzo [de]
Pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13
(9H, 15H) -dione hydrochloride: 1 mg of the compound (95 mg) obtained in (11)
After adding 30 ml of N hydrochloric acid and heating under reflux for 1 hour, the solvent is distilled off and 30 ml of water is added to the resulting residue to remove insoluble matter by filtration. High-performance liquid chromatography [CAPCELL PAK]
C18; acetonitrile: water: developed with 1N hydrochloric acid (20: 80: 1)] to give the title compound as isomer A (6.2 mg)
And isomer B (5.9 mg). Isomer A: IR ν _max ^KBr cm ⁻¹ : 3416,1746,1660,1602,1512 NMR (in DMSO-d ₆ ) δ: 0.87 (3H, t, J = 7.3Hz), 1.82-1.9
1 (2H, m), 2.15-2.26 (1H, m), 5.11-5.18 (1H, br s), 5.44,
5.84 (2H, ABq, J = 19Hz), 5.45 (2H, s), 7.35 (1H, s), 8.18 (1
H, dd, J = 7.8Hz, 11.5Hz), 8.55-8.64 (3H, br) MASS m / z: 439 (M ⁺ ) Isomer B: IRν _max ^KBr cm ^-1 : 2932,1750,1658,1596, 1508 NMR (in DMSO-d ₆ ) δ: 0.86 (3H, t, J = 7.3Hz), 1.83-1.9
(2H, m), 2.15-2.24 (1H, m), 5.12-5.16 (1H, br s), 5.44,5.
82 (2H, ABq, J = 19Hz), 5.45 (2H, s), 6.55 (1H, s), 7.35 (1H,
s), 8.19 (1H, dd, J = 7.8Hz, 11.5Hz), 8.53-8.66 (3H, br) MASS m / z: 439 (M ⁺ )

Example 50 (9S) -1-Amino-9-ethyl-5-fluoro-2,3-dihydro-9-
Hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ',
4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H)-
Dione hydrochloride:

[0290]

[Chemical 56]

(1) 4- (4-fluoro-3-methylphenyl) -4-
Oxobutanoic acid: 2-fluorotoluene 250m
Add 200 g of succinic anhydride and 800 g of aluminum chloride to l,
Heat at 0 ° C. for 1 hour. The reaction solution was added to cold 1% aqueous hydrochloric acid solution (5 L), extracted with ethyl acetate, washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 345 g of the title compound. NMR (in CDCl ₃ ) δ: 1.89-1.97 (2H, m), 2.24 (3H, s), 2.
36 (2H, t, J = 7.3Hz), 2.60 (2H, t, J = 7.3Hz), 6.84-6.99 (3H,
m)

(2) 4- (4-Fluoro-3-methylphenyl) butanoic acid methyl ester: 172 g of the compound obtained in (1) was dissolved in 700 ml of acetic acid, and 40 ml of 40% perchloric acid and 1
30 g of 0% palladium-carbon is added, and catalytic hydrogenation is performed at 6 atm. After removing insolubles by filtration, acetic acid was distilled off, and 2 l of water was added to the obtained residue. The mixture was extracted with chloroform, washed with saturated saline, and dried over anhydrous sodium sulfate. After distilling off the solvent, 1 l of methanol is added to the residue and cooled to 0 ° C. After slowly adding 269 g of thionyl chloride to this solution, 10 ml of dimethylformamide was added and the mixture was added at room temperature for 12 hours.
After stirring for a period of time, the reaction solution was concentrated, extracted with chloroform, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 153 g of the title compound. NMR (in CDCl ₃ ) δ: 1.91 (2H, quintet, J = 7.5Hz), 2.24
(3H, d, J = 2Hz), 2.31 (2H, t, 7.5Hz), 2.57 (2H, t, J = 7.5Hz),
3.66 (3H, s), 6.89 (1H, t, J = 9Hz), 6.93 (1H, ddd, J = 9Hz, 5H
z, 3Hz), 6.97 (1H, dd, J = 7Hz, 3Hz)

(3) 4- (4-Fluoro-3-methyl-6-nitrophenyl) butanoic acid methyl ester: 10.9 g of the compound obtained in (2) was added to 6 ml of cold concentrated sulfuric acid, and the internal temperature was 5 ° C. While maintaining the following, 15 ml of a concentrated sulfuric acid solution of 5.8 g of potassium nitrate is added dropwise. After the addition is complete, the mixture is stirred for 20 minutes, then the reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography,
Develop with a mixed solvent of hexane-ethyl acetate (90: 7),
7.1 g of the title compound was obtained by concentrating the fraction containing the desired product.
Got NMR (in CDCl ₃ ) δ: 1.97 (2H, quintet, J = 8Hz), 2.34 (3
H, d, J = 2Hz), 2.41 (2H, t, J = 8Hz), 2.90 (2H, t, J = 8Hz), 3.6
9 (3H, s), 7.18 (1H, d, J = 7Hz), 7.66 (1H, d, J = 9Hz)

(4) 7-Fluoro-8-methyl-5-nitro-1-tetralone: 7.1 g of the compound obtained in (3) was dissolved in 20 ml of methanol, 10 ml of 15% sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was concentrated, acidified by adding concentrated hydrochloric acid and extracted with chloroform.The chloroform layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate.
The solvent is distilled off. The residue is gradually added to 50 ml of polyphosphoric acid heated to 110 ° C, and then stirred for 4.5 hours. The reaction mixture is added to 100 ml of ice water, extracted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (1: 1), and the fractions containing the target compound were concentrated to obtain 1.7 g of the title compound. NMR (in CDCl ₃ ) δ: 2.11 (2H, quintet, J = 7Hz), 2.60 (3
H, d, J = 2Hz), 2.72 (2H, t, J = 7Hz), 3.14 (2H, t, J = 6.0Hz), 7.
74 (1H, d, J = 9Hz)

(5) 5-Acetylamino-7-fluoro-8-methyl-1,2,3,4-tetrahydronaphthalene: the compound obtained in (4)
1.35 g was dissolved in 5 ml of ethanol and 15 ml of THF, 114 mg of sodium borohydride was added under stirring at room temperature, and the mixture was stirred for 20 minutes. The reaction solution was concentrated, 25 ml of toluene was added to the residue, and
840 mg of p-TsOH was added and the mixture was heated under reflux for 30 minutes. 100 ml of ethyl acetate was added to the reaction solution, washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 20 ml of ethyl acetate, 400 mg of platinum oxide was added, and catalytic hydrogenation was carried out for 4 hours. The catalyst was filtered off, the filtrate was concentrated, and 10 ml of dichloromethane was added to the resulting residue, 1.2 ml of triethylamine and 0.81 ml of acetic anhydride were added, and the mixture was stirred for 40 minutes. The reaction solution was diluted with 50 ml of chloroform, washed successively with diluted hydrochloric acid, saturated sodium hydrogen carbonate solution, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.23 g of the title compound. NMR (in CDCl ₃ ) δ: 1.79 (4H, s), 2.10 (3H, s), 2.19 (3
H, s), 2.53 (2H, s), 2.62 (2H, s), 7.46 (1H, d, J = 9Hz)

(6) 8-Acetylamino-6-fluoro-5-
1.2 g of the compound obtained from methyl-1-tetralone (5) was dissolved in 80 ml of acetone, 8 ml of 15% magnesium sulfate was added, and 2.63 g of potassium permanganate was gradually added with stirring. After 1 hour, chloroform was added to the reaction solution for extraction, which was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 825 mg of the title compound. NMR (in CDCl ₃ ) δ: 2.08 (2H, quintet, J = 7Hz), 2.15 (3
H, d, J = 2Hz), 2.22 (3H, s), 2.66 (2H, t, J = 7Hz), 2.88 (2H,
t, J = 6Hz), 8.42 (1H, d, J = 13Hz)

(7) 2,8-Diacetylamino-6-fluoro-5-
Methyl-1-tetralone: 4.7 g of the compound obtained in (6)
A solution of 1 l of THF in a solution of tertiary potassium butoxide 4.
Slowly add to a mixed solvent of 200 ml of THF and 10 ml of tertiary butanol containing 48 g at 0 ° C. under N ₂ stream. After stirring for 10 minutes at the same temperature, 4.79 ml of n-butyl nitrite was added dropwise at 0 ° C., and then the mixture was stirred for 1.5 hours while gradually raising the temperature to 20 ° C. The pH is adjusted to 1 with 1N hydrochloric acid and then extracted with chloroform. After washing with saturated saline and drying over anhydrous sodium sulfate, 80 ml of acetic acid and 60 ml of acetic anhydride are added to the residue obtained by distilling off the solvent, 15 g of zinc dust is further added, and the mixture is stirred at 20 ° C for 18 hours. The insoluble material was removed by filtration, the solvent was evaporated, the residue was extracted with chloroform, washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent is distilled off and the resulting residue is subjected to silica gel column chromatography. Develop with a mixed solvent of chloroform-methanol (97: 3),
By concentrating the fractions containing the target compound, 3.85
got g. NMR (in CDCl ₃ ) δ: 1.7-1.9 (1H, m), 2.11 (3H, s), 2.15
(3H, s), 2.23 (3H, s), 2.7-2.8 (1H, m), 2.9-3.1 (2H, m),
4.5-4.7 (1H, m), 6.53 (1H, br s), 8.43 (1H, d, J = 13Hz), 11.
76 (1H, s)

(8) 2,8-Diamino-6-fluoro-5-methyl-1
-Tetralone: 3.85 g of the compound obtained in (7) was added to 6N-hydrochloric acid 100
Add to ml and stir at 80 ° C for 6 hours. The reaction mixture is poured into 100 ml of water, adjusted to pH 10 with 15% aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 1.66 g of the title compound. NMR (in CDCl ₃ ) δ: 1.83 (1H, dq, 13Hz, 4Hz), 2.04 (3H,
s), 2.25-2.4 (1H, m), 2.75 (1H, ddd, J = 14Hz, 13Hz, 4Hz), 2.
98 (1H, ddd, J = 14Hz, 4Hz, 3Hz), 3.53 (1H, dd, J = 13Hz, 4Hz),
6.20 (1H, d, J = 12Hz), 6.42 (1H, br s)

(9) 8-Amino-6-fluoro-5-methyl-2-trifluoroacetylamino-1-tetralone: A solution prepared by dissolving 1.66 g of the compound obtained in (8) in a mixed solvent of 70 ml of ethanol and 10 ml of THF. Triethylamine (2 ml) and ethyl trifluoroacetate (1.51 ml) were added to and the mixture was stirred at 20 ° C. for 20 hours. The reaction solution was added to diluted hydrochloric acid water, extracted with chloroform,
It is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography, developed with chloroform, and the fractions containing the desired product were concentrated to give 1.79 g of the title compound. NMR (in CDCl ₃ ) δ: 1.81 (1H, dq, J = 13Hz, 5Hz), 2.06 (3
H, d, J = 0.5Hz), 2.8-3.1 (3H, m), 4.48 (1H, dt, 13Hz, 4Hz),
6.26 (1H, d, J = 13Hz), 7.64 (1H, br s)

(10) (9S) -9-Ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1-trifluoroacetylamino-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione: 4.0 g of the compound obtained in (9) was dissolved in 900 ml of toluene to give trione 4.5.
After adding 7 g and 4.9 g of PPTS, the mixture was heated under reflux in a nitrogen stream for 71 hours. The reaction mixture was concentrated, the obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (30: 1), and the fraction containing the desired product was concentrated to obtain 4.21 g of the title compound. . NMR (in MeOH-d ₄ + CDCl ₃ ) δ: 0.94, 0.96 (3H, t, J = 7Hz),
1.75-1.95 (2H, m), 2.36 (3H, s), 2.3-2.5 (2H, m), 3.05-3.
35 (2H, m), 5.05-5.75 (5H, m), 7.30 (0.5H, d, J = 11Hz), 7.4
5 (0.5H, s), 7.56 (0.5H, d, J = 11Hz), 7.57 (0.5H, s)

(11) (9S) -1-Amino-9-ethyl-5-fluoro
-2,3-Dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-10,13 (9H , 15H) -Dione hydrochloride: Compound 6 obtained in (10)
25 mg was added to a mixed solution of concentrated hydrochloric acid 7.5 ml, methanol 18 ml and water 12 ml, and the mixture was stirred at 80 ° C for 7 hours. Insoluble matter is removed by filtration, and the filtrate is subjected to high performance liquid chromatography [CAPCELL
PAK C18; acetonitrile: water: 1N hydrochloric acid (20:80:
1)]] and the title compound was converted to isomer A (13
8 mg) and isomer B (143 mg). Isomer A: Melting point: 220-250 ° C. (decomposition) [α] _D ²⁰ = + 198 ° (c = 0.42, in H ₂ O) IRν _max ^KBr cm ⁻¹ : 3400,1748,1660,1592 NMR (D ₂ O Middle) δ: 0.73 (3H, t, J = 7.3Hz), 1.74 (2H, q, J =
7.3Hz), 2.13 (3H, s), 2.45-2.55 (1H, m), 2.6-2.7 (1H, m),
2.85-3.0 (1H, m), 3.2-3.3 (1H, m), 5.11 (1H, m), 5.18,5.
25 (2H, ABq, J = 19Hz), 5.18, 5.32 (2H, ABq, J = 16Hz), 7.05
(1H, s), 7.09 (1H, d, J = 11Hz) Isomer B: Melting point: 220-230 ° C (decomposition) NMR (in D ₂ O) δ: 0.82 (3H, t, J = 7.3Hz), 1.83 (2H, q, J =
7.3Hz), 2.13 (3H, s), 2.1-2.3 (1H, m), 2.5-2.6 (1H, m),
2.9-3.1 (1H, m), 3.1-3.3 (1H, m), 4.97 (1H, br s), 5.06,5.
32 (2H, ABq, J = 19Hz), 5.24,5.37 (2H, ABq, J = 16Hz), 6.99 (1
H, d, J = 11Hz), 7.16 (1H, s)

[0302]

The compound (1) or a salt thereof has excellent antitumor activity, is highly safe, and is water-soluble, and the antitumor agent of the present invention comprising this as an active ingredient is a lung cancer, a digestive organ cancer, an ovarian cancer, Uterine cancer,
It is useful for the treatment of various cancers such as breast cancer, liver cancer, head and neck cancer, blood cancer, renal cancer, Komaru tumor and the like.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ikuo Mitsui 1-16-13 Kitakasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Central Research Institute

Claims (2)

[Claims] 1. An antitumor agent comprising a compound represented by the following general formula (1) or a salt thereof as an active ingredient. [Chemical 1] [In the formula, R ₁ and R ₂ are each a hydrogen atom; a hydroxyl group; an alkyl group having 1 to 6 carbon atoms which may have a hydroxyl group, a halogen atom, a nitro group or a cyano group; an alkenyl having 1 to 6 carbon atoms. Group; alkynyl group having 1 to 6 carbon atoms; alkoxyl group having 1 to 6 carbon atoms;
6 aminoalkoxyl group; halogen atom; nitro group;
Cyano group; mercapto group; alkylthio group; amino group which may have a protecting group; carbon group which may have a protecting group or an alkyl group having 1 to 6 carbon atoms in the amino part
~ 6 aminoalkyl group; 1 carbon atom which may have a protecting group or an alkyl group having 1 to 6 carbon atoms in the amino part
~ 6 aminoalkylamino group; alkyl group having 1 to 6 carbon atoms, alkoxyl group having 1 to 6 carbon atoms, amino group, halogen atom, nitro group or C1 to C having a heterocycle which may have a cyano group 6 alkyl group; 1 carbon atom
A carbonyl group having a heterocycle which may have an alkyl group having from 6 to 6, an alkoxyl group having from 1 to 6 carbon atoms, an amino group, a halogen atom, a nitro group or a cyano group;
To C6 alkyl group, C1 to C6 alkoxyl group, amino group which may have a protecting group, halogen atom, nitro group, cyano group or C1 to C6 which has a heterocycle which may have a protecting group. Alkylamino group; protecting group or 1 carbon atom on the nitrogen atom or amino part of the heterocycle
An aminoheterocyclic group which may have an alkyl group of 6;
A heterocyclic amino group which may have a protecting group or an alkyl group having 1 to 6 carbon atoms on a nitrogen atom or an amino part of the heterocyclic ring; or a carbamoyl group which may have a protecting group or an alkyl group having 1 to 6 carbon atoms. R ₃ represents an alkyl group having 1 to 6 carbon atoms, R ₄ represents a hydrogen atom; an amino group which may have a protecting group; an alkylamino group having 1 to 6 carbon atoms which may have a protecting group An aminoalkyl group having 1 to 6 carbon atoms which may have a protecting group; an alkylaminoalkyl group having 1 to 6 carbon atoms which may have a protecting group; a sulfonic acid group; or a carboxyl group, Z
It represents an oxygen atom; a sulfur atom; CR ₅ R ₆ (meaning R _5, R ₆ are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms); or NR ₇ (R ₇ is a hydrogen atom; a carbon number 1 to An alkyl group having 6; an aminoalkyl group having 1 to 6 carbon atoms, which may have a protecting group;
And an aminoamino-protecting group), and m and n respectively represent 0, 1 or 2. ] 2. The following formula: Represented by (9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4': 6,7] Indolizino [1,2-b] quinoline-10,13 (9
An antitumor agent comprising (H, 15H) -dione or a salt thereof as an active ingredient.