JP2003246787A - Discorhabdine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound excellent in antitumor action. <P>SOLUTION: A compound represented by formula (1) (wherein R<SP>1</SP>is a 1-6C alkyl; R<SP>2</SP>is H or the like; R<SP>3</SP>and R<SP>4</SP>are each H or the like; R<SP>5</SP>and R<SP>6</SP>are each H, a halogen or the like; R<SP>7</SP>is H, a 1-6C alkyl or the like; B<SP>1</SP>, B<SP>2</SP>, and B<SP>3</SP>are each independently a single or double bond; and X is O, S, NH or N substituted by a 1-6C alkyl) or its pharmacologically allowable salt is provided. <P>COPYRIGHT: (C)2003,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] TECHNICAL FIELD The present invention has a novel structure
It relates to a discohabudin derivative. [0002] 2. Description of the Related Art Discorhabdin
Lukaloids are New Zealand sponge genus Latrun
from culia and Okinawan sponge Prianos melanos
Pyrroloinominoquinone alkaloid determined, high
Has many anti-tumor activities and has many naturally occurring to date
Analogs are known. [0003] However, despite its high antitumor activity,
Until now, discohabudin has been used in clinical practice
I couldn't. The reason is that
Supply is essential for clinical development, such as toxicity testing, and
This is probably because the amount required for use on the floor is insufficient. [0004] Therefore, in order to obtain compounds for clinical use,
Requires the development of natural synthetic methods and the synthesis of various derivatives
However, building such a complex structure has been extremely difficult,
In the synthesis example is not known, natural synthesis example and
No derivatives other than the natural type were known. [0005] The present inventors have proposed N, S-A
Build important synthetic precursors when building the cetal structure
And by using intramolecular Michael addition,
First successful synthesis of cohabudin A
Inducers with novel antitumor activity not previously known
The conductor was successfully synthesized. [0006] Means for Solving the Problems The present invention provides the following general formula:
(I) [0007] Embedded image (Where R¹Is a hydrogen atom, C₁-C₆Alkyl
Group, C substituted with a hydroxyl group₁-C₆Alkyl group (the hydroxyl group
May be protected), hydroxyl group (the hydroxyl group is protected
Or a mercapto group (the mercapto group
The lactate group may be protected), and R^TwoIs a hydrogen source
Indicates a child or R^TwoIs R¹Together with the ether group
Or a sulfide group, and R^ThreeAnd R^FourAre the same or different
Is a hydrogen atom, a halogen atom, a hydroxyl group (the hydroxyl group is
Protected) or a mercapto group (the
The rucapto group may be protected) and R^FiveAnd R⁶
Are the same or different and represent a hydrogen atom, a halogen atom,
Group (the hydroxyl group may be protected) or
Capto group (the mercapto group may be protected)
And R⁷Is a hydrogen atom, C₁-C₆Alkyl group or amino
A protecting group for the group, B¹And B^TwoAre the same or different,
X represents an oxygen atom, a sulfur atom, NH
Group or C₁-C₆Indicates a nitrogen atom substituted with an alkyl group
You. ) Or a pharmaceutically acceptable compound
Salt. In the above general formula (I), “C₁-C₆Archi
`` Group '' means, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl
Tert-butyl, n-pentyl, isopentyl, 2-
Methylbutyl, neopentyl, 1-ethylpropyl, n
-Hexyl, isohexyl, 4-methylpentyl, 3-
Methyl pentyl, 2-methyl pentyl, 1-methyl pen
Chill, 3,3-dimethylbutyl, 2,2-dimethylbuty
1,1-dimethylbutyl, 1,2-dimethylbutyl
1,3-dimethylbutyl, 2,3-dimethylbutyl
Or a straight chain having 1 to 6 carbon atoms such as 2-ethylbutyl.
Or a branched-chain alkyl group.
It is a linear or branched alkyl group having 1 to 4 prime numbers. In the above general formula (I), “halogen atom”
"Child" means a fluorine atom, a chlorine atom, a bromine atom or iodine
Atom, preferably a fluorine atom or a chlorine atom. In the above general formula (I), “hydroxyl group is retained.
The protecting group for the hydroxyl group when `` may be protected '' is hydrogenated
Chemical methods such as decomposition, hydrolysis, electrolysis and photolysis
Cleavage by biological methods such as hydrolysis or hydrolysis in the human body
Refers to the protective groups that are obtained, such protective groups include:
For example, methyl, ethyl, n-propyl, isopropyl
, N-butyl, isobutyl, sec-butyl, tert-butyl
Tyl, n-pentyl, isopentyl, 2-methylbutyi
, Neopentyl, 1-ethylpropyl, n-hexyl
, Isohexyl, 4-methylpentyl, 3-methylpe
Methyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
"Lower alkyl groups" such as ethylbutyl;
, Acetyl, propionyl, butyryl, isobutylyl
Pentanoyl, pivaloyl, valeryl, isovaleri
Octanoyl, nonanoyl, decanoyl, 3-methyl
Lunanoyl, 8-methylnonanoyl, 3-ethyloctane
Tanoyl, 3,7-dimethyloctanoyl, undecano
Il, dodecanoyl, tridecanoyl, tetradecanoy
, Pentadecanoyl, hexadecanoyl, 1-methyl
Pentadecanoyl, 14-methylpentadecanoyl, 1
3,13-dimethyltetradecanoyl, heptadecanoy
, 15-methylhexadecanoyl, octadecanoy
, 1-methylheptadecanoyl, nonadecanoyl, a
Alkyls such as icosanoyl and henicosanoyl
Rubonyl group, succinoyl, glutaroyl, adipoyl
Carboxylated alkylcarbonyl groups such as
Cetyl, dichloroacetyl, trichloroacetyl, tri
Halogeno lower alkylcarbo such as fluoroacetyl
Lower alkoxy lower such as nil group and methoxyacetyl
Alkylcarbonyl group, (E) -2-methyl-2-buteno
Fatty acids such as unsaturated alkylcarbonyl groups such as yl
Aliphatic acyl group "; benzoyl, α-naphthoyl, β-na
Arylcarbonyl group such as futoyl;
Halogenoants such as nzoyl and 4-chlorobenzoyl
Carbonyl group, 2,4,6-trimethylbenzoy
Lower alkylated arylca such as 4-toluoyl
Lower alkoxylation such as rubonyl group and 4-anisoyl
Arylcarbonyl group, 2-carboxybenzoyl, 3
-Carboxybenzoyl, of 4-carboxybenzoyl
A carboxylated arylcarbonyl group, such as 4-nitro
Nitrated compounds such as benzoyl and 2-nitrobenzoyl
Reel carbonyl group; 2- (methoxycarbonyl) ben
Lower alkoxycarbonylated arylca such as zoyl
Aryl such as rubonyl group and 4-phenylbenzoyl
An "aromatic acyl group" such as an arylcarbonyl group;
Tetrahydropyran-2-yl, 3-bromotetrahydro
Pyran-2-yl, 4-methoxytetrahydropyran-4-
Yl, tetrahydrothiopyran-2-yl, 4-methoxy
"Tetrahydrido, such as tetrahydrothiopyran-4-yl
A lopyranyl or tetrahydrothiopyranyl group "; tetra
Hydrofuran-2-yl, tetrahydrothiofuran-2-i
"Tetrahydrofuranyl or tetrahydrothiane
Oflanyl group "; trimethylsilyl, triethylsilyl
, Isopropyldimethylsilyl, t-butyldimethylsilyl
Ryl, methyldiisopropylsilyl, methyldi-t-butyi
Tri-lower alcohols such as luciryl and triisopropylsilyl
Lucylsilyl group, diphenylmethylsilyl, diphenyl
Butylsilyl, diphenylisopropylsilyl, phenyl
One or two aryls, such as rudiisopropylsilyl
Group substituted tri-lower alkylsilyl group, triphenyl
Tri-substituted with three aryl groups such as lucylyl
"Silyl group" such as arylsilyl group; methoxymethyl
, 1,1-dimethyl-1-methoxymethyl, ethoxy
Methyl, propoxymethyl, isopropoxymethyl,
"Lower alcohols, such as toxicmethyl and t-butoxymethyl
Xymethyl group "; such as 2-methoxyethoxymethyl
"Lower alkoxylated lower alkoxymethyl group"; 2,
2,2-trichloroethoxymethyl, bis (2-chloroethoxy
Toxic) "halogeno lower alkoxymethyl, such as methyl
1-ethoxyethyl, 1- (isopropoxy)
A "lower alkoxylated ethyl group" such as tyl;
"Ethyl halides, such as 2-trichloroethyl
Group "; benzyl, α-naphthylmethyl, β-naphthylme
Tyl, diphenylmethyl, triphenylmethyl, α-na
Like phthyldiphenylmethyl, 9-anthrylmethyl
A "methyl group substituted with 1 to 3 aryl groups";
4-methylbenzyl, 2,4,6-trimethylbenzyl
3,4,5-trimethylbenzyl, 4-methoxy
Benzyl, 4-methoxyphenyldiphenylmethyl, 4,
4'-dimethoxytriphenylmethyl, 2-nitroben
Jyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-
"Lower amino acids such as bromobenzyl and 4-cyanobenzyl
Aryl with alkyl, lower alkoxy, halogen and cyano groups
Substituted with 1 to 3 substituted aryl groups
Methyl group "; methoxycarbonyl, ethoxycarbonyl
, T-butoxycarbonyl, isobutoxycarbonyl
Such as “lower alkoxycarbonyl group”; 2,2,2-
Trichloroethoxycarbonyl, 2-trimethylsilyl
"Halogen or tri-lower radicals such as ethoxycarbonyl
Lower alkoxycarbonyl substituted with rukysilyl group
Group ”; vinyloxycarbonyl, aryloxycarbo
An “alkenyloxycarbonyl group” such as nyl; ben
Ziroxycarbonyl, 4-methoxybenzyloxyca
Rubonyl, 3,4-dimethoxybenzyloxycarbonyl
, 2-nitrobenzyloxycarbonyl, 4-nitro
One or two "lower" such as benzyloxycarbonyl
The aryl ring is substituted by an alkoxy or nitro group
Good aralkyloxycarbonyl group "
And preferably “aliphatic acyl group”, “aromatic acyl group”
Group "," methyl substituted with 1 to 3 aryl groups "
Group "," lower alkyl, lower alkoxy, halogen,
1 to 3 aryl having an aryl ring substituted with an ano group
A methyl group or a silyl group substituted with a group,
More preferably, acetyl, benzoyl, benzyl
Group, p-methoxybenzoyl group, dimethoxytrityl
Group, monomethoxytrityl group or tert-butyldimethyl
A silyl group. In the above general formula (I), “mercapto
Protection of mercapto groups when the group can be protected "
The groups are hydrogenolysis, hydrolysis, electrolysis and photolysis.
Chemical methods or biological methods such as hydrolysis in the human body
Refers to a protecting group that can be cleaved by
In the case where the "hydroxyl group may be protected"
The same thing as the protecting group of a hydroxyl group can be mentioned. In the above general formula (I), “the amino group
"Protecting group" means hydrogenolysis, hydrolysis, electrolysis and light
Chemical methods such as decomposition or organisms such as hydrolysis in the human body
A protecting group that can be cleaved by a chemical method.
Such protecting groups include methoxycarbonyl, ethoxy
Rubonyl, 2-phenylethoxycarbonyl, aryl
Oxycarbonyl, benzyloxycarbonyl, cyclo
"Carbamate formation such as hexyloxycarbonyl
Group "; the above-mentioned" aliphatic acyl group ";
A cyclic group such as phthaloyl and dimethylpyrrolyl
Imide-forming group "; substituted with one to three aryl groups as described above
Methyl group "; methanesulfonyl, ethanesulfoni
A "lower alkylsulfonyl group" such as
"Halogen-substituted lower alkyls, such as
Rusulfonyl group ”; p-toluenesulfonyl, benzenes
List "arylsulfonyl groups" such as rufonyl
And preferably a carbamate-forming group or an aryl
It is a rusulfonyl group. The compound (I) of the present invention has an asymmetric carbon atom in the molecule.
Optical isomers based on elemental atoms (including diastereomers)
Exists, and the geometric isomer based on the ring structure exists
However, each of these isomers is also included in the present invention. The "pharmacologically acceptable salt" is defined as
The clear compound (I) can be converted into a salt,
Salt, preferably such a salt as sodium
Alkali metal salts such as salts, potassium salts, lithium salts,
Alkaline earth gold like calcium salt, magnesium salt
Genus salt, aluminum salt, iron salt, zinc salt, copper salt, nickel
Metal salts such as salts and cobalt salts;
Organic salt, t-octylamine salt, dibenzylamine salt,
Rufoline salt, glucosamine salt, phenylglycine alk
Ester salt, ethylenediamine salt, N-methylgluca
Min salt, guanidine salt, diethylamine salt, triethyl
Amine salt, dicyclohexylamine salt, N, N'-dibe
Ethylenediamine salt, chloroprocaine salt, pro
Caine salt, diethanolamine salt, N-benzyl-fe
Netylamine salt, piperazine salt, tetramethylammonium
Salt, tris (hydroxymethyl) aminomethane salt
Amine salts such as organic salts; hydrofluoric acid, hydrochloride, odor
Halogen atom hydride such as hydrochloride and hydroiodide
Inorganic acids such as acid salts, nitrates, perchlorates, sulfates and phosphates
Salt; methanesulfonate, trifluoromethanesulfone
Alkane sulfo, such as acid salt, ethane sulfonate
Acid, benzenesulfonic acid, p-toluenesulfonic acid
Salt-like aryl sulfonates, acetates, malic acid
Salt, fumarate, succinate, citrate, tartaric acid
Salt, oxalate, maleate, trifluoroacetate, etc.
Acid salts; and glycine salts, lysine salts, arginine salts,
Ornithine, glutamate and aspartate
Amino acid salts, and more preferably,
It is a carbonate. The compound (I) of the present invention is
Can still exist. [0017] BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention is described below.
It can be produced by method A. [0018] Embedded imageIn the above, R¹Or R⁷, B¹Or B^Three,as well as
X is as defined above, and Prot is a protecting group for the amino group.
Show. The amino-protecting group in Prot is represented by the general formula described above.
Listed are the same as the “protecting group for amino group” in (I).
And preferably a trityl group. Hereinafter, each step of the method A will be described in detail. (Method A) (Step A-1) Is this Step Known or Known Compound
Compound (II) and Compound (III) easily obtained from
Accordingly, this is a step of producing a compound (IV). Examples of the solvent used in this reaction include, for example,
For example, methanol, ethanol, n-propanol, iso-
Propanol, n-butanol, isobutanol, t-
Butanol, isoamyl alcohol, diethylene glycol
, Glycerin, octanol, cyclohexanol
And alcohols such as methylcellosolve.
And preferably methanol. Used for this reaction
Reagents must be selected according to the amino-protecting group.
It is important to note that for trityl-protected substrates, deprotection continues
In the condensation reaction, as an acid catalyst in a normal reaction
There is no particular limitation as long as it is used, but preferably a salt
Inorganic acids such as acids, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid
And more preferably hydrochloric acid. The reaction temperature depends on the starting compound and the reaction reagent.
Performed at 0 ° C. to 100 ° C., preferably at 10 ° C.
To 40 ° C. The reaction time is determined by the reaction temperature, starting compound, reaction
Depending on the type of reagent or solvent used,
Usually 10 minutes to 2 days, preferably 1 hour to 24
Time. After completion of the reaction, the target compound of this reaction is, for example,
The reaction mixture is concentrated and
Add immiscible organic solvents such as water and ethyl acetate.
After washing with water, the organic layer containing the target compound is separated and
After drying over magnesium acid, etc., the solvent is distilled off.
It is. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step A-2) In this step, compound (IV) obtained in step A-1
Compound (Ia) is obtained by an oxidative cyclization reaction
This is the manufacturing process. The solvent used in this reaction is acetoacetate.
Nitriles such as nitriles and isobutyronitrile;
Like trifluoroethanol, trifluoroethanol
And halogen-substituted alcohols.
Is trifluoroethanol. The reagents used in this reaction are those commonly used
There is no particular limitation as long as it can be used.
Jinbis (trifluoroacetate) (PIFA), phenyl
Luozin diacetate (PIDA), iodosylbenze
Like hydroxy (tosyloxyiodo) benzene
Trivalent iodine compound; Pb (IV), Hg (II), Fe (III), V (V),
Oxidizing agents such as metal salts such as Cu (II), or anodic acid
Chemical oxidation method (electrolytic oxidation), preferably PIFA
is there. Although this reaction proceeds without a catalyst, it is used.
In this case, the catalyst used in this reaction is
Fluoride, trimethylsilyl trifluoromethanesulfur
Lewis acids such as phonate; trifluoroacetic acid, trif
Organic acids, such as fluoromethanesulfonic acid; Montmorillona
Such as K10 (MK10) and Montmorillonite KSF (MKSF)
Body acid: silicotungstic acid, phosphotungstic acid,
Heteropoly such as immolybdic acid and silicomolybdic acid
Acids can be mentioned, preferably MK10. The reaction temperature depends on the starting compound and the reaction reagent.
At -50 ° C to 100 ° C, preferably 10 ° C
C. to 40C. The reaction time depends on the reaction temperature, starting compound, reaction
Depending on the type of reagent or solvent used,
Usually in 5 minutes to 12 hours, preferably in 10 minutes to 1 hour
is there. After completion of the reaction, the target compound of this reaction is, for example,
If the reaction mixture is filtered and concentrated,
Alternatively, use an immiscible organic solvent such as water and ethyl acetate.
After washing with water, the organic layer containing the target compound is separated and dried.
After drying with magnesium sulfate etc., the solvent is distilled off.
Can be The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. The compound obtained in this step is a desired compound
In some cases, the reaction is performed without going through the next (Step A-3).
It may be terminated. In order to obtain a desired compound, a deprotection reaction is performed.
If necessary, use well-known methods (eg, “Protec
tive Groups in Organic Synthesis "(Theodora W. Gre
ene, Peter G. M. Wuts, 1999, A Wiley-Interscie
nce Publication issued)
be able to. Further, if necessary to obtain a desired compound,
Oxidative dehydroxymethylation can also be performed. Used for oxidative dehydroxymethylation
The oxidizing agent is phenyliodin bis (trifluoroacetate).
(PIFA), phenyliodin diacetate (PID)
A), iodosylbenzene, hydroxy (tosiroxyyo)
E) trivalent iodine compounds such as benzene; Pb (IV), H
Like metal salts like g (II), Fe (III), V (V), Cu (II)
Oxidizing agents or anodic oxidation (electrolytic oxidation)
And preferably lead tetraacetate. Solvent used for reaction
As R¹Group or acyloxy to be introduced into
Alcohol or carboxylic acid corresponding to
Methylene chloride, THF,
Suitable examples include organic solvents such as cetonitrile.
Is a mixed solvent of methylene chloride and alcohol. This reaction is carried out according to a well-known method.
You. (Step A-3) In this step, the compound (I) obtained in step A-2
For a), a) cyclization reaction, b) C = X ketone group sulfidation reaction, c)
The enamication reaction of the C = X ketone group is performed in any order.
This is the step of producing compound (I). a) Cyclization reaction In this reaction, the compound (Ia) was dissolved in a solution (1).
Add the drug and acid, then (2) add the base
Done by As the solvent used in this reaction, for example,
For example, methylene chloride, chloroform, carbon tetrachloride,
Chloroethane, chlorobenzene, dichlorobenzene
Halogenated hydrocarbons such as diethyl ether, diiso
Propyl ether, tetrahydrofuran, dioxane,
Dimethoxyethane, diethylene glycol dimethyl ate
Ethers such as ter can be mentioned, and preferably
Methylene chloride. The acid used in this reaction includes, for example,
Boron trifluoride, trimethylsilyl trifluoro
Lewis acids such as methanesulfonate; hydrogen bromide-butyrate
Acids, organic fatty acids including inorganic acids such as hydrogen bromide-acetic acid
And hydrogen bromide-acetic acid. Book
As the reagent used for the reaction, for example, benzylthio
And p-methoxybenzylthiol
Alls can be mentioned, preferably p-methoxybenzyl
It is ruthiol. As the base used in this reaction, for example,
Sodium carbonate, potassium carbonate, lithium carbonate
Alkaline metal carbonates; sodium bicarbonate, carbonic acid
Alkali metals such as potassium hydrogen and lithium hydrogen carbonate
Bicarbonates: N-methylmorpholine, aqueous methylamine
Solution, triethylamine, tripropylamine, trib
Tylamine, diisopropylethylamine, dicyclohexane
Xylamine, N-methylpiperidine, pyridine, 4-
Pyrrolidinopyridine, picoline, 4- (N, N-dimethyl)
Ruamino) pyridine, 2,6-di (t-butyl) -4-
Methylpyridine, quinoline, N, N-dimethylanily
, N, N-diethylaniline, 1,5-diazabicyclo
B [4.3.0] Non-5-ene (DBN), 1,4-
Diazabicyclo [2.2.2] octane (DABC
O), 1,8-diazabicyclo [5.4.0] undeca
List organic bases such as -7-ene (DBU)
And preferably an aqueous solution of methylamine. The reaction temperature depends on the starting compound and the reaction reagent.
(1) performed at -100 ° C to 10 ° C
And preferably between -78 ° C and 4 ° C, (2)
Is performed at 0 ° C to 50 ° C, preferably at 0 ° C to 30 ° C.
is there. The reaction time depends on the reaction temperature, the starting compound, and the reaction.
Depending on the type of reagent or solvent used,
Usually, (1) is preferably in 30 minutes to 2 days
Is 1 hour to 36 hours, and (2) is 5 minutes
From 12 minutes to 12 hours, preferably from 10 minutes to 1 hour. After completion of the reaction, the target compound of this reaction is, for example,
If necessary, concentrate the reaction mixture and mix with water and ethyl acetate.
Organic solvent containing the target compound after washing with water.
Separate the layers, dry over anhydrous magnesium sulfate, etc.
Obtained by distillation. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. The target compound has an ether bond.
If the compound is
(For example, The Chemistry of Ether Linkage, Wi
ley, New York, 446-450, 460-468 (1967))
Therefore, it can be easily obtained. b) C = X ketone sulfidation reaction This reaction is performed using Lawesson's reagent (2,4-bis (4-methoxyphenyl).
Enyl) -1,3,2,4-dithiadiphosphetane-2,4-disul
Fid) and known methods (eg, Tetrahedron, 4
1, 5061-5087 (1985)). c) Enamidation of C = X ketone group This reaction is well known using amines or N-alkylamines.
Method (for example, the method described in Chem. Lett., 1371 (1985)).
This is done accordingly. Compound (I) of the present invention or its pharmacologically acceptable
The resulting salts exhibit antitumor activity. Also, the compound of the present invention
(I) shows pharmacokinetics such as absorption, biodistribution, and blood half-life
And has low toxicity to organs such as kidney and liver. Follow
Thus, the compound (I) of the present invention is useful, for example, as a medicament.
Yes, especially useful as a drug to treat or prevent cancer
It is. The compound of the present invention is used as a prophylactic or
When used as a therapeutic agent, the compound represented by the general formula (I)
Or a pharmacologically acceptable salt thereof.
Excipients or diluents, either per se or as appropriate pharmacologically acceptable
Tablets, capsules, granules, powders
Or syrup orally, or injection, suppository
Parenteral administration with a drug, patch, or external preparation
can do. These preparations contain excipients (eg, lactose,
Sugars like white sugar, glucose, mannitol, sorbitol
Derivatives: corn starch, potato starch,
α-starch, starch derivatives such as dextrin; crystalline cellulo
Cellulose derivatives such as sugar; gum arabic; dex
Tolan; organic excipients such as pullulan;
Hydrosilicic acid, synthetic aluminum silicate, calcium silicate, meta
Silicate derivatives such as magnesium silicate aluminate; phosphorus
Phosphates such as calcium hydrogen oxyacid; like calcium carbonate
Carbonates; inorganics such as sulfates such as calcium sulfate
Excipients may be mentioned. ), Lubricants (eg,
Tearic acid, calcium stearate, stearic acid
Metal salts of stearic acid such as gnesium; talc;
Id silica; wax such as beeswax and gay wax
And boric acid; adipic acid; sulfuric acid such as sodium sulfate
Salt; glycol; fumaric acid; sodium benzoate; DL
Leucine; sodium lauryl sulfate, mug lauryl sulfate
Lauryl sulfate such as nesium; silicic anhydride, hydrated silicic acid
And silicic acids such as the above-mentioned substances; and the above-mentioned starch derivatives
Can be. ), Binders (eg, hydroxypropyl
Lulose, hydroxypropyl methylcellulose, poly
Vinylpyrrolidone, macrogol, and the excipient
Similar compounds can be mentioned. ), Disintegrant (eg
Low-substituted hydroxypropylcellulose,
Cimethylcellulose, carboxymethylcellulose cal
Sodium, internally cross-linked carboxymethylcellulose sodium
Cellulose derivatives such as carboxymethyl star
H, sodium carboxymethyl starch, cross-linked polyvinyl
Chemically modified starch cells such as nilpyrrolidone
Loins can be mentioned. ), Emulsifiers (eg,
Colloidal clays such as bentonite and veegum;
Metal hydroxides such as magnesium oxide and aluminum hydroxide
Compound: Sodium lauryl sulfate, calcium stearate
Anionic surfactant such as benzalkonium chloride
Cationic surfactants such as polyoxyethylene;
Alkyl ether, polyoxyethylene sorbitan fat
Nonionic such as fatty acid ester and sucrose fatty acid ester
Surfactants can be mentioned. ), Stabilizer (methyl
Paraoxybenzoic, such as paraben and propylparaben
Acid esters: chlorobutanol, benzyl alcohol
Alcohols such as phenylethyl alcohol;
Benzalkonium chloride; like phenol and cresol
Phenols; thimerosal; dehydroacetic acid; and
Sorbic acid can be mentioned. ), Flavoring agents (eg
For example, commonly used sweeteners, acidulants, flavors and the like
Can be ), Known using additives such as diluents
Manufactured by the method. The amount used depends on the condition, age, etc.
However, in the case of oral administration, the lower limit is 1 mg per dose (preferably
Is 30 mg), the upper limit is 2000 mg (preferably 1500 m
g), in the case of intravenous administration, a lower limit of 0.5 mg
(Preferably 5 mg), upper limit 500 mg (preferably 250 mg)
mg) for adults 1 to 6 times daily depending on symptoms
Administration. [0050] EXAMPLES The following examples were all performed under a nitrogen stream.
Was. Merk 60 230-40 for flash chromatography
0 Thin-layer chromatography using mesh silica gel
Is a reagent using Merk silica gel 60F-254 glass plates.
As for, commercially available ones were used except as otherwise noted. After completion of the reaction, the organic phase is treated with magnesium sulfate or
Is dried over sodium sulfate, filtered,
It was concentrated below. IR spectrum measurement uses KBr pellet method
The NMR spectra were measured using CDCl_ThreeDuring,
TMS was measured as an internal standard. (Example) (Example 1) (Example 1a) [Racemate] [0052] Embedded image The compound obtained in Reference Example 5 (110.7 mg, 0.1
62mmol) in trifluoroethanol (10ml)
MK10 (50 mg) and PIFA (90.4 mg, 0.210 mmol)
Added warm. After stirring the reaction solution at room temperature for 30 minutes,
It was concentrated below. Flash chromatography of the residue
(N-hexane: ethyl acetate: triethylamine = 100: 5
0: 0.1) to give the desired compound (30 mg, 27%) and its
The diastereomer (20 mg, 18%) was obtained. IR (KBr): ν 3390,1660,1595,1575,1525,1460,1435,13
80 cm^-1.¹ H NMR (500 MHz): δ 0.10 (s, 3H), 0.12 (s, 3H),
0.94 (s, 9H), 1.60 (d, 1H, J = 10.0 Hz), 1.74 (t, 1H,
 J = 11.7 Hz), 2.43 (s, 3H), 2.62 (t, 2H, J = 7.3 Hz),
 3.52-3.55 (m, 2H), 3.72-3.76 (m, 1H), 3.85 (dt, 1
H, J = 8.5, 18.0 Hz), 4.09 (dt, 1H, J = 7.0, 18.0 Hz),
 6.09 (br s, 1H), 6.29 (d, 1H, J = 10.0Hz), 6.98 (d
d, 1H, J = 10.0, 2.0 Hz), 7.28 (d, 1H, J = 2.0 Hz), 7.28
32 (d, 2H, J = 8.0 Hz), 7.45 (s, 1H), 8.04 (d, 2H, J =
9.0 Hz).¹³ C NMR (125 MHz): δ -5.5, 17.4, 18.2, 21.6, 25.
8, 36.4, 43.8, 49.5, 66.0, 104.0, 118.4, 121.8, 12
5.4, 125.7, 126.0, 126.1, 128.6, 129.6, 134.6, 14
1.9, 145.7, 152.2, 152.6, 157.1, 168.3, 178.9. HR-FABMS Calcd for C₃₂H₃₇BrN_ThreeO_FiveSSi (M + H)⁺: 682.140
7; Found: 682.1392.UV / Vis (CH_TwoCl_Two): λmax (ε) 487
 (2000), 330 (11300), 234 (27800) nm. Diastereomer [0054] Embedded image IR (KBr): ν 3390,1660,1590,1575,1525,
1460,1435,1380 cm^-1.¹ H NMR (300 MHz): δ 0.10 (s, 3H), 0.12 (s, 3H),
0.95 (s, 9H), 1.60 (m, 1H), 1.73 (t, 1H, J = 12.0 H
z), 2.43 (s, 3H), 2.61 (t, 2H, J = 7.0 Hz), 3.48-3.6
0 (m, 2H), 3.74-3.86 (m, 2H), 4.07 (dt, 1H, J = 17.
7, 6.5 Hz), 6.12 (br s, 1H), 6.33 (d, 1H, J = 9.9 H
z), 6.91 (dd, 1H, J = 9.9, 2.7 Hz), 7.32 (d, 2H, J = 8.
1 Hz), 7.42 (d, 1H, J = 2.4 Hz), 7.45 (s, 1H), 8.03
(d, 2H, J = 8.4Hz).¹³ C NMR (125 MHz): δ -5.4, -5.3, 17.6, 18.4, 21.
7, 25.9, 36.8, 44.0, 49.5, 66.1, 103.9, 118.6, 12
1.9, 123.9, 125.0, 125.6, 126.1, 128.7, 129.7,134.
7, 142.2, 145.8, 152.3, 152.8, 157.1, 168.4, 179.
0. HR-FABMS Calcd for C₃₂H₃₇BrN_ThreeO_FiveSSi (M + H)⁺: 682.140
7; Found: 682.1413. UV / Vis (CH_TwoCl_Two): λmax (ε) 486 (2200), 331 (1220
0), 233 (26900) nm. (Example 1b) [Optically active substance] [0056] Embedded imageUsing the compound obtained in Reference Example 6a as a raw material
Using the same method as in Example 1a,
The desired compound was obtained. [α]_D ^{twenty five} +149.8 (c 0.46, CHCl_Three). (Example 2) (Example 2a) [Racemate] [0058] Embedded image The compound obtained in Example 1a (45.1 mg, 0.1%
0661 mmol) in methylene chloride (5 mL)._Three・ Et_TwoO
(0.13 mL, 1.04 mmol) was added at 0 ° C. under a nitrogen stream. Anti
The reaction solution was stirred at 0 ° C. for 7 hours, and then warmed to room temperature.
The reaction was terminated by adding sodium hydrogen carbonate. Filter
After that, the filtrate was concentrated under reduced pressure. Flash the residue
For chromatography (methylene chloride: methanol = 20: 1)
Thus, purification gave the target compound (33.7 mg, 90%). IR (KBr): ν 3390, 1660, 1595, 1570, 1525, 1485, 1
460, 1375 cm^-1.¹ H NMR ((CD_Three)_TwoCO, 500 MHz): δ 1.65 (dd, 1H, J = 12.
8, 2.9 Hz), 1.91 (t, 1H, J = 12.2 Hz), 2.43 (s, 3H),
 2.65 (dd, 2H, J = 7.8, 6.9 Hz), 3.59-3.68 (m, 1H),
3.71-3.84 (m, 1H), 3.84 (dd, 1H, J = 3.6, 9.9 Hz),
4.05 (dt, 1H, J = 6.8, 17.7 Hz), 6.17 (d, 1H, J = 9.6
Hz), 6.25 (br s, 1H), 7.22 (dd, 1H, J = 9.8, 2.6 H
z), 7.46 (d, 1H, J = 2.7 Hz), 7.47 (d, 2H, J = 8.1 H
z), 7.64 (s, 1H), 8.06 (d, 2H, J = 8.1 Hz).¹³ C NMR ((CD_Three)_Two(CO, 75 MHz): δ 18.0, 21.6, 37.2, 4
5.0, 50.3, 50.4, 65.3, 105.0, 119.6, 122.2, 122.6,
126.9, 127.5, 128.2, 129.4, 130.2, 130.3, 130.7, 1
35.7, 143.2, 147.1, 154.1, 158.6, 169.3, 178.8. HR-FABMS Calcd for C₂₆H_{twenty three}BrN_ThreeO_FiveS (M + H)⁺: 568.0542;
 Found: 568.0539. UV / Vis (CH_TwoCl_Two): λmax (ε) 486 (1600), 330 (1000
0), 230 (28000) nm. (Example 2b) [Optically active substance] [0060] Embedded image Using the compound obtained in Example 1b as a raw material
And using the same method as in Example 2a,
The desired compound was obtained. [α]_D ^29.5 +101 (c 0.157, CHCl_Three). (Example 3) [0062] Embedded image The compound obtained in Example 2a (27.9 mg, 0.2
0491 mmol) methylene chloride (7 mL) -methanol (3.5 m
L) In the mixed solution, add lead tetraacetate (43.5mg, 0.0981mmol)
The mixture was added at 0 ° C. under a nitrogen stream. Stir the reaction solution at 0 ° C for 1.5 hours.
After stirring, the temperature was raised to room temperature and concentrated under reduced pressure. The residue
Rush chromatography (methylene chloride: methanol
= 50: 1) to give the desired compound (24.5 mg, 88%).
Obtained as a diastereomer mixture.¹ H NMR ((CD_Three)_TwoCO, 500 MHz): δ 1.91 (dd, 1H, J = 2.
2, 13.7Hz), 2.18 (dd, 1H, J = 3.3, 13.7 Hz), 2.43
(s, 3H), 2.65-2.72 (m, 2H), 3.35 (s, 3H), 3.85 (dt,
 1H, J = 7.9, 18.0 Hz), 4.05 (dt, 1H, J = 7.0, 18.0 H
z), 4.93 (br s, 1H), 6.11 (d, 1H, J = 10.1 Hz), 7.34
 (dd, 1H, J = 2.6, 9.9 Hz), 7.43 (d, 1H, J = 2.6 Hz),
7.47 (d, 2H, J = 8.3 Hz), 7.66 (s, 1H), 8.07 (d, 2H,
 J = 8.6 Hz).¹ H NMR ((CD_Three)_TwoCO, 500 MHz): δ 1.90 (d, 1H, J = 13.8
 Hz), 2.12 (dd, 1H, J = 3.1, 13.8 Hz), 2.43 (s, 3H),
 2.64 (t, 1H, J = 8.5 Hz), 2.68 (t, 1H, J = 7.1 Hz), 3.
36 (s, 3H), 3.77-3.85 (m, 1H), 4.05 (dt, 1H, J = 6.
8, 17.8 Hz), 4.92 (br s, 1H), 6.20 (d, 1H, J = 9.7 H
z), 7.01 (dd, 1H, J = 2.6, 9.7 Hz), 7.34 (br s, 1H),
7.46 (d, 2H, J = 8.1 Hz), 7.65 (s, 1H), 7.76 (d, 1H,
 J = 2.6 Hz), 8.07 (d, 2H, J = 8.4 Hz). HR-FABMS Calcd for C₂₆H_{twenty three}BrN_ThreeO_FiveS (M + H)⁺: 568.0542;
 Found: 568.0547. (Example 4) (Example 4a) [Racemate] [0064] Embedded image The compound obtained in Example 3 (16.7 mg, 0.02
94 mmol) in methylene chloride (1.2 mL).
Xybenzylthiol (5 μL, 0.0359 mmol) in a nitrogen stream
After dropping at -78 ° C, 30% hydrogen bromide / acetic acid (0.03 mL)
Was dropped. The temperature of the reaction solution was raised to 4 ° C while stirring, and 36
Stirred for hours. Add a 40% aqueous methylamine solution to perform the reaction.
After completion, methylene chloride was added. Add 10% hydrochloric acid
After acidification, the aqueous layer was extracted with methylene chloride. water
After adding saturated sodium bicarbonate solution,
Extracted with methylene. After mixing each organic layer, under reduced pressure
Concentrated. The residue is separated by preparative thin-layer chromatography (chloride
Purify with methylene: methanol = 30: 1) to obtain the desired compound
(Red crystals, 3.7 mg, 22%), Compound A (red crystals, 2.8 m
g, 19%) and Compound B (red crystals, 2.2 mg, 13%)
Was. mp> 300 ° C. IR (KBr): ν 3365, 1680, 1660, 1610, 1595, 1565, 15
25, 1455, 1375 cm^-1.¹ H NMR (300 MHz): δ 2.42 (s, 3H), 2.61-2.77 (m, 4
H), 2.80-2.86 (m, 2H), 3.89 (dt, 1H, J = 9.0, 18.3 H
z), 4.29 (dt, 1H, J = 18.3, 6.0 Hz), 4.62 (dd, 1H, J =
7.8, 11.7 Hz), 5.28 (t, 1H, J = 3.9 Hz), 5.93 (d, 1
H, J = 3.9 Hz), 7.33 (d, 2H, J = 8.4 Hz), 7.43 (s, 1
H), 7.49 (s, 1H), 8.02 (d, 2H, J = 8.4 Hz). ¹³ C NMR (125 MHz): δ 17.7, 21.7, 39.9, 45.5, 50.
0, 50.0, 55.9, 61.3, 116.2, 118.4, 119.6, 121.9, 1
25.1, 126.1, 128.7, 129.8, 134.5, 140.6, 146.0, 15
2.8, 154.8, 168.3, 188.0. HR-FABMS Calcd for C_{twenty five}H_{twenty one}BrN_ThreeO_FourS_Two (M + H)⁺: 570.015
7; Found: 570.0171. UV / Vis (CHCl_Three): λmax (ε) 483 (1400), 326 (1220
0), 265 (14400), 242 (18200) nm. Compound A [racemic form] [0066] Embedded image Mp> 300 ° C.¹ H NMR (300 MHz): δ 2.42 (s, 3H), 2.60-2.75 (m, 6
H), 3.75-3.86 (m, 1H), 4.24 (dt, 1H, J = 18.0, 6.0 H
z), 4.60 (dd, 1H, J = 11.7, 7.2 Hz), 5.26 (t, 1H, J =
3.5 Hz), 5.90 (d, 1H, J = 5.1 Hz), 5.99 (d, 1H, J = 1
0.23), 7.03 (d, 1H, J = 10.2 Hz), 7.33 (d, 2H, J = 8.
1 Hz), 7.48 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz). HR-FABMS Calcd for C_{twenty five}H_{twenty two}N_Three0_FourS_Two (M + H)⁺: 492.1052;
Found: 492.1049. Compound B [0068] Embedded image Mp> 300 ° C. IR (KBr): ν 3375, 1690, 1660, 1615, 1595, 1560, 1
525, 1480, 1460, 1380cm^-1.¹ H NMR (300 MHz): δ 2.42 (s, 3H), 2.63-2.70 (m, 4
H), 3.75-3.90 (m, 1H), 4.23 (dt, 1H, J = 18.0, 6.1 H
z), 4.79 (d, 1H, J = 11.7 Hz), 4.84 (d, 1H, J = 12.0 H
z), 5.30 (t, 1H, J = 3.9 Hz), 6.00 (d, 1H, J = 3.6 H
z), 6.10 (d, 1H, J = 10.2 Hz), 7.07 (d, 1H, J = 10.2 H
z), 7.33 (d, 2H, J = 8.4 Hz). 7.49 (s, 1H), 8.02 (d,
 2H, J = 8.4 Hz).¹³ C NMR (125 MHz): δ 17.7, 21.7, 41.5, 49.5, 49.
6, 60.6, 61.4, 66.6, 115.0, 118.4, 121.8, 123.5, 1
25.2, 126.0, 128.7, 129.8, 134.4, 140.5, 146.0, 15
2.9, 154.5, 168.2, 188.6. HR-FABMS Calcd for C_{twenty five}H_{twenty one}BrN_ThreeO_FourS_Two (M + H)⁺: 570.015
7; Found: 570.0142. (Example 4b) [Optically active substance] [0070] Embedded imageUsing the compound obtained in Example 2b as a raw material
Using the same method as in Example 3 and Example 4a
Optically active target compound and optical compound A
The active form was obtained. [α]_D ^24.3 -72.7 (c 0.053, CHCl_Three). Compound A [optically active form] [0072] Embedded image [Α]_D ^24.2 +134 (c 0.146, CHCl_Three). (Example 5) 5- (toluene-4-sulfonyl) -3,
5,7,8,9,10-Hexahydro-2H-1,5,7-to
Riaza-acephenanthrylene-6-one-8- (tert
-Butyldimethylsilyloxymethyl) -10-spiro
-4 '-(2'-bromo) -cyclohexa-2', 5'-di
En-1′-one hydrochloride [optically active form] [0074] Embedded image Example 5a 5- (Toluene-4-sulfur)
Fonyl) -3,5,7,8,9,10-hexahydro-2H
-1,5,7-Triaza-acephenanthrylene-6-o
8- (tert-butyldimethylsilyloxymethyl)
-10-Spiro-4 '-(2'-bromo) -cyclohexa
-2 ', 5'-diene-1'-one [optically active form] [0076] Embedded image The compound obtained in Reference Example 6a (43.4 mg, 0.
0543 mmol) of 2,2,2-trifluoroethanol (1.5 m
L) Add montmorillonite K at room temperature under a nitrogen atmosphere.
10 (MK10, 31.9mg) and PIFA (93.4mg, 0.217mmol)
And stirred for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was removed.
Flash column chromatography (n-hexane:
Purification with ethyl acetate: triethylamine = 100: 50: 0.1)
Thus, the target compound (red solid, 13.7 mg, 37%) was obtained. IR (KBr): ν 3390, 1660, 1595, 1575, 1525, 1460, 1
435, 1380 cm^-1.¹ H NMR (500 MHz): δ 0.10 (s, 3H), 0.12 (s, 3H),
0.94 (s, 9H), 1.60 (d, 1H, J = 10.0 Hz), 1.74 (t, 1H,
 J = 11.7 Hz), 2.43 (s, 3H), 2.62 (t, 2H, J = 7.3 Hz),
 3.52-3.55 (m, 2H), 3.72-3.76 (m, 1H), 3.85 (dt, 1
H, J = 8.5, 18.0 Hz), 4.09 (dt, 1H, J = 7.0, 18.0 Hz),
 6.09 (br s, 1H), 6.29 (d, 1H, J = 10.0Hz), 6.98 (d
d, 1H, J = 10.0, 2.0 Hz), 7.28 (d, 1H, J = 2.0 Hz), 7.28
32 (d, 2H, J = 8.0 Hz), 7.45 (s, 1H), 8.04 (d, 2H, J =
9.0 Hz).¹³ C NMR (125 MHz): δ -5.5, 17.4, 18.2, 21.6, 25.
8, 36.4, 43.8, 49.5, 66.0, 104.0, 118.4, 121.8, 12
5.4, 125.7, 126.0, 126.1, 128.6, 129.6, 134.6, 14
1.9, 145.7, 152.2, 152.6, 157.1, 168.3, 178.9. UV / Vis (CH_TwoCl_Two): λmax (ε) 487 (2000), 330 (1130
0), 234 (27800) nm. [α]_D ^25.0 + 150 ° (c 0.460, CHCl_Three). (Example 5b) 5- (toluene-4-sulfonyl)-
3,5,7,8,9,10-Hexahydro-2H-1,5,7
-Triaza-acephenanthrylene-6-one-8-
(Tert-butyldimethylsilyloxymethyl) -10-
Spiro-4 '-(2'-bromo) -cyclohexa-2',
5'-dien-1'-one hydrochloride [optically active substance] [0078] Embedded image The compound obtained in Example 5a (13.7 mg, 0.1%
020 mmol) in methanol (3 ml).
Tanol (0.3 mL) was added, and the reaction mixture was immediately concentrated under reduced pressure.
The compound was reduced to give the target compound (purple solid).¹ H NMR (500 MHz): δ 0.07 (s, 6H), 0.90 (s, 9H),
1.79 (dd, 1H, J = 13.5, 3.5 Hz), 2.09 (t, 1H, J = 11.5
 Hz), 2.44 (s, 3H), 2.94 (t, 2H, J = 5.5 Hz), 3.62-
3.74 (m, 2H), 3.83-3.91 (m, 3H), 6.46 (d, 1H, J = 9.
5 Hz), 7.18 (dd, 1H, J = 10.0, 3.0 Hz), 7.46 (d, 1H,
 J = 7.5 Hz), 7.50 (d, 2H, J = 3.0 Hz), 7.93 (s, 1H),
8.10 (d, 2H, J = 8.5 Hz). HR-FABMS Calcd for C₃₂H₃₇BrN_ThreeO_FiveSSi (M-Cl)⁺: 682.14
07; Found: 682.1392. Example 6 3,5,7,8,9,10-Hexahydro-2
H-1,5,7-triaza-acephenanthrylene-6
On-8- (tert-butyldimethylsilyloxymethyl
) -10-spiro-4 '-(2'-bromo) -cyclo
Kisa-2 ', 5'-dien-1'-one hydrochloride [optical activity
body] [0080] Embedded image (Example 6a) 3,5,7,8,9,10-f
Xahydro-2H-1,5,7-triaza-acephenane
Surylene-6-one-8- (tert-butyldimethylsilyl
Ruoxymethyl) -10-spiro-4 ′-(2′-bro
M) -Cyclohexa-2 ′, 5′-dien-1′-one [light
Academically active body] [0082] Embedded image The compound obtained in Example 5a (4.8 mg, 0.0
0703mmol) in anhydrous tetrahydrofuran (0.5mL)
0.1M sodium methoxide at 0 ° C under nitrogen atmosphere
/ Methanol (0.34 mL) was added dropwise, and the mixture was stirred at room temperature for 6 hours.
Was. The reaction solution is subjected to flash column chromatography (salt
Purification with methylene chloride: methanol = 10: 1)
(Black solid, 2.0 mg, 54%) was obtained.¹ H NMR (CD_ThreeOD, 300 MHz): δ 0.13 (s, 3H), 0.15 (s,
 3H), 0.94 (s, 9H), 1.84 (d, 1H, J = 13.5 Hz), 1.94
(t, 1H, J = 11.0 Hz), 2.69 (t, 2H, J = 7.0 Hz), 3.65
-3.81 (m, 4H), 3.88-3.98 (m, 1H), 6.33 (s, 1H), 7.
01 (s, 1H), 7.27 (dd, 1H, J = 10.0, 2.5 Hz), 7.56 (d,
 1H, J = 2.5 Hz). (Example 6b) 3,5,7,8,9,10-hexahydro-
2H-1,5,7-triaza-acephenanthrylene-6
-On-8- (tert-butyldimethylsilyloxymethyl
) -10-spiro-4 '-(2'-bromo) -cyclo
Kisa-2 ', 5'-dien-1'-one hydrochloride [optical activity
body] [0084] Embedded image The compound obtained in Example 6a (2.0 mg, 0.0
0380 mmol) in methanol (1 ml).
Tanol (0.05 mL) was added, and the reaction mixture was immediately concentrated under reduced pressure.
This gave the target compound (black solid).¹ H NMR (CD_ThreeOD, 300 MHz): δ 0.13 (s, 3H), 0.15 (s,
 3H), 0.95 (s, 9H), 1.84 (d, 1H, J = 13.5 Hz), 2.05
(t, 1H, J = 14.0 Hz), 2.89 (t, 2H, J = 7.0 Hz), 3.53-
4.00 (m, 5H), 6.48 (d, 1H, J = 10.0 Hz), 6.91 (s, 1
H), 7.21 (s, 1H), 7.24 (dd, 1H, J = 10.0, 2.5 Hz), 7.
59 (d, 1H, J = 2.5 Hz). HR-FABMS Calcd for C_{twenty five}H₃₁BrN_ThreeO_ThreeSi (M-Cl)⁺: 528.131
8; Found: 528.1300. (Example 7) 5- (toluene-4-sulfonyl) -3,
5,7,8,9,10-Hexahydro-2H-1,5,7-to
Riaza-acephenanthrylene-6-one-8- (hydr
Roxymethyl) -10-spiro-4 ′-(2′-bromo)
-Cyclohexa-2 ', 5'-dien-1'-one hydrochloride
[Optically active substance] [0086] Embedded image Example 7a 5- (Toluene-4-sulfur)
Fonyl) -3,5,7,8,9,10-hexahydro-2H
-1,5,7-Triaza-acephenanthrylene-6-o
8- (Hydroxymethyl) -10-spiro-4'-
(2'-bromo) -cyclohexa-2 ', 5'-diene-
1'-one [optically active substance] [0088] Embedded image The compound obtained in Example 5a (74.3 mg, 0.2%
109 mmol) in anhydrous methylene chloride (7 mL).
BF at 0 ℃_Three? Et_TwoO (0.28 mL, 2.18 mmol)
Then, the mixture was stirred for 4 hours while the temperature was raised from 0 ° C. to room temperature. Anti
Add sodium bicarbonate to the reaction solution, filter with cotton plug, and reduce
It was concentrated under pressure. The residue is flash column chromatographed.
Fee (methylene chloride: methanol: triethylamine
= 100: 5: 0.1) to give the desired compound (red solid, 54.
5 mg, 88%). IR (KBr): ν 3390, 1660, 1570, 1525, 1485, 1460, 1
375 cm^-1.¹ H NMR ((CD_Three)_TwoCO, 500 MHz): δ 1.65 (dd, 1H, J = 12.
8, 2.9 Hz), 1.91 (t, 1H, J = 12.2 Hz), 2.43 (s, 3H),
 2.65 (dd, 2H, J = 7.8, 6.9 Hz), 3.59-3.68 (m, 1H),
3.71-3.84 (m, 1H), 3.84 (dd, 1H, J = 9.9, 3.6 Hz) 4.
05 (dt, 1H, J = 17.7, 6.8 Hz), 6.17 (d, 1H, J = 9.6 H
z), 6.25 (br s, 1H), 7.22 (dd, 1H, J = 9.8, 2.6 Hz),
 7.46 (d, 1H, J = 2.7 Hz), 7.47 (d, 2H, J = 2.7 Hz),
7.64 (s, 1H), 8.06 (d, 2H, J = 8.1 Hz).¹³ C NMR ((CD_Three)_Two(CO, 75 MHz): δ 18.0, 21.6, 37.2, 4
5.0, 50.3, 50.4, 65.3, 105.0, 119.6, 122.2, 122.6,
126.9, 127.5, 128.2, 129.4, 130.2, 130.3, 130.7, 1
35.7, 143.2, 147.1, 154.1, 158.6, 169.3, 178.8. UV / Vis (CH_TwoCl_Two): λmax (ε) 486 (1600), 330 (1000
0), 230 (28000) nm. [α]_D ^24.9 + 182 ° (c 0.133, CHCl_Three). (Example 7b) 5- (toluene-4-sulfonyl)-
3,5,7,8,9,10-Hexahydro-2H-1,5,7
-Triaza-acephenanthrylene-6-one-8-
(Hydroxymethyl) -10-spiro-4 '-(2'-bu
Lomo) -cyclohexa-2 ', 5'-dien-1'-one
Hydrochloride [optically active form] [0090] Embedded image The compound obtained in Example 7a (54.5 mg, 0.
096 mmol) in methanol (3 ml).
Tanol (1.2 mL) was added, and the reaction mixture was immediately concentrated under reduced pressure.
This gave the desired compound (purple solid).¹ H NMR (CD_ThreeOD, 300 MHz): δ 1.64 (d, 1H, J = 12.0 H
z), 1.92 (t, 1H, J = 12.0Hz), 2.42 (s, 3H), 2.72 (br
 s, 2H), 3.54-3.78 (m, 5H), 6.28 (d, 1H, J = 9.5 H
z), 7.20 (dd, 1H, J = 9.5, 2.5 Hz), 7.47 (d, 1H, J =
2.5 Hz), 8.02 (d, 2H, J = 8.5 Hz). HR-FABMS Calcd for C₂₆H_{twenty three}BrN_ThreeO_FiveS (M-Cl)⁺: 568.054
2; Found: 568.0539. Example 8 5- (toluene-4-sulfonyl) -3,
5,7,8,9,10-Hexahydro-2H-1,5,7-to
Riaza-acephenanthrylene-6-one-8- (hydr
Roxymethyl) [3 ′]-10-spiro-4 ′-(2′-
Bromo) -cyclohexa-5'-en-1'-one hydrochloric acid
Salt [optically active form] [0092] Embedded image Example 8a 5- (toluene-4-sulfur)
Fonyl) -3,5,7,8,9,10-hexahydro-2H
-1,5,7-Triaza-acephenanthrylene-6-o
8- (Hydroxymethyl) [3 ']-10-spiro
-4 '-(2'-bromo) -cyclohex-5'-ene-
1'-one [optically active substance] [0094] Embedded image The compound obtained in Example 7a (24.2 mg, 0.2%
0426 mmol) in anhydrous methylene chloride (2.7 mL).
Under an atmosphere, add 30% hydrogen bromide / acetic acid (0.04 mL) at room temperature, and add
Stirred for 6 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and methyl chloride was added.
Extract with ren, dry the organic layer and concentrate under reduced pressure.
Was. The residue was purified by flash column chromatography (n-
Hexane: ethyl acetate = 1: 1)
(Red crystals, 19.4 mg, 80%) was obtained.¹ H NMR (CDCl_Three, 300 MHz): δ 1.85 (d, 1H, J = 12.5 H
z), 1.94 (dd, 1H, J = 13.0, 2.0 Hz), 2.40 (br s, 3
H), 2.64 (t, 2H, J = 7.5 Hz), 3.67 (br s, 1H), 3.69-
3.87 (m, 2H), 3.83 (s, 2H), 4.12 (td, 1H, J = 20.0,
6.0 Hz), 4.22 (d, 1H, J = 12.5 Hz), 5.06 (d, 1H, J = 1
2.5 Hz), 5.95 (br s, 1H), 6.07 (d, 1H, J = 10.0 Hz),
 7.12 (d, 1H, J = 10.0 Hz), 7.31 (d, 2H, J = 8.5 Hz),
7.46 (s, 1H), 7.98 (d, 2H, J = 8.5 Hz). [α]_D ^26.5 -10 ° (c 0.266, CHCl_Three). (Example 8b) 5- (toluene-4-sulfonyl)-
3,5,7,8,9,10-Hexahydro-2H-1,5,7
-Triaza-acephenanthrylene-6-one-8-
(Hydroxymethyl) [3 ']-10-spiro-4'-
(2'-bromo) -cyclohex-5'-ene-1'-o
Hydrochloride [optically active substance] [0096] Embedded image The compound obtained in Example 8a (19.4 mg, 0.1%
0341mmol) in methanol (3ml)
/ Methanol (0.5 mL), and immediately the reaction mixture was
Concentration gave the target compound (purple solid).¹ H NMR (300 MHz, CD_ThreeOD): δ 1.85 (d, 1H, J = 12.5 H
z), 2.27 (d, 1H, J = 13.5Hz), 2.43 (s, 3H), 2.86 (br
 s, 2H), 3.75-4.10 (m, 5H), 4.15 (d, 1H, J = 12.5 H
z), 5.62 (d, 1H, J = 12.0 Hz), 6.22 (d, 1H, J = 10.0 H
z), 7.09 (d, 1H, J = 10.0 Hz), 7.43 (d, 2H, J = 8.0 H
z), 7.80 (br s, 1H), 8.06 (d, 2H, J = 8.5Hz). HR-FABMS Calcd for C₂₆H_{twenty three}BrN_ThreeO_FiveS (M-Cl)⁺: 568.054
1; Found: 568.0549. (Example 9) 5- (toluene-4-sulfonyl) -3,
5,7,8,9,10-Hexahydro-2H-1,5,7-to
Riaza-acephenanthrylene-6-one-8-sulf
Anil [5 ']-10-spiro-4'-cyclohexa-
2'-en-1'-one hydrochloride [0098] Embedded image Example 9a 5- (toluene-4-sulfur)
Fonyl) -3,5,7,8,9,10-hexahydro-2H
-1,5,7-Triaza-acephenanthrylene-6-o
8-Methoxy-10-spiro-4'-cyclohexa
-2'5'-diene-1'-one [0100] Embedded image 3- (4-hydroxyphenyl) -2-a
Starting from minopropionic acid methyl ester,
Example 2a, Reference Example 3, Reference Example 5, Example 1, Example 2 and
The reaction was carried out sequentially according to the same method as in Example 3.
Thus, the target compound (yellow solid) was obtained.¹ H NMR (CDCl_Three, 300 MHz): δ 1.90 (d, 1H, J = 13.8 H
z), 2.02 (dd, 1H, J = 13.8, 3.1 Hz), 2.43 (s, 3H),
2.63 (t, 1H, J = 7.5 Hz), 3.32 (s, 3H), 3.88 (dt, 1
H, J = 18.0, 8.5 Hz), 4.10 (dt, 1H, J = 18.5, 7.0 Hz),
 4.74 (br s, 1H), 6.17 (dd, 1H, J = 10.0, 2.0 Hz),
6.25 (dd, 1H, J = 10.0, 2.0 Hz), 6.49 (br s, 1H), 6.7
1 (dd, 1H, J = 10.0, 3.0 Hz), 7.27 (d, 2H, J = 3.0 H
z), 7.34 (d, 1H, J = 8.5 Hz), 7.47 (s, 1H), 8.03 (d,
2H, J = 8.5 Hz). (Example 9b) 5- (toluene-4-sulfonyl)-
3,5,7,8,9,10-Hexahydro-2H-1,5,7
-Triaza-acephenanthrylene-6-one-8-ose
Ruphanyl [5 ']-10-spiro-4'-cyclohex
Sa-2'-en-1'-one [0102] Embedded image The compound obtained in Example 9a (17.5 mg, 0.1%
0357 mmol) in anhydrous methylene chloride (2.0 mL).
Under an atmosphere at -78 ° C, 4-methoxybenzylthiol (5
μL, 0.0359 mmol) and 30% hydrogen bromide / acetic acid (0.03 mL).
And raise the temperature from -78 ° C to 4 ° C while stirring for 40 hours.
did. A 40% aqueous methylamine solution (0.5 mL) was added to the reaction solution.
After stirring for 3 minutes, the reaction solution was extracted with methylene chloride.
The organic layer was dried and concentrated under reduced pressure. Residue
Ram chromatography (n-hexane: ethyl acetate =
2: 1) to give the desired compound (dark pink solid, 1.8 mg, 10 mg
%). mp> 300 ° C. IR (KBr): ν 3375, 1650, 1595, 1555, 1520, 1475, 1
460, 1380 cm^-1.¹ H NMR (CDCl_Three, 300 MHz): δ 2.42 (s, 3H), 2.60-2.7
5 (m, 6H), 3.75-3.86 (m, 1H), 4.24 (dt, 1H, J = 18.
0, 6.0 Hz), 4.60 (dd, 1H, J = 11.7, 7.2 Hz), 5.26
(t, 1H, J = 3.5 Hz), 5.90 (d, 1H, J = 5.1 Hz), 5.99
(d, 1H, J = 10.2 Hz), 7.03 (d, 1H, J = 10.2 Hz), 7.33
(d, 2H, J = 8.1 Hz), 7.48 (s, 1H), 8.03 (d, 2H, J = 8.
4 Hz).¹³ C NMR (CDCl_Three, 75 MHz): δ 17.7, 21.7, 41.0, 45.
9, 47.3, 49.7, 56.3, 61.0, 116.9, 118.4, 121.9, 12
5.3, 125.4, 125.8, 129.8, 134.5, 140.8, 145.9, 15
3.1, 154.6, 168.5, 196.2. HR-FABMS Calcd for C_{twenty five}H_{twenty two}N_ThreeO_FourS_Two (M + H)⁺: 492.1052;
Found: 492.1049. UV / Vis (CH_TwoCl_Two): λmax (ε) 489 (1500), 327 (1330
0), 237 (27300) nm. (Example 9c) 5- (toluene-4-sulfonyl)-
3,5,7,8,9,10-Hexahydro-2H-1,5,7
-Triaza-acephenanthrylene-6-one-8-ose
Ruphanyl [5 ']-10-spiro-4'-cyclohex
Sa-2'-en-1'-one hydrochloride [0104] Embedded image The compound obtained in Example 9b (1.8 mg, 0.0
0357 mmol) in methanol (1 ml).
Tanol (0.05 mL) was added, and the reaction mixture was immediately concentrated under reduced pressure.
This gave the desired compound (green solid).¹ H NMR (CD_Three(OD, 300 MHz): δ 2.43 (s, 3H), 2.50-2.9
6 (m, 6H), 3.70-3.78 (m, 1H), 3.90 (dt, 1H, J = 18.
0, 6.0 Hz), 4.40 (dd, 1H, J = 12.0, 7.0 Hz), 5.33
(t, 1H, J = 3.0 Hz), 6.28 (d, 1H, J = 10.0 Hz), 6.97
(d, 1H, J = 10.0 Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.88
(s, 1H), 8.07 (d, 2H, J = 8.5 Hz). (Reference example) (Reference Example 1) (Reference Example 1a) [Racemate] [0106] Embedded image The compound obtained in Example 4a (1.7 mg, 0.0
0298 mmol) in tetrahydrofuran (0.25 mL) solution
Sodium methoxide / methanol (0.08 mL)
The solution was added at 0 ° C under flowing. The reaction solution was stirred at 0 ° C. for 1 hour
Afterwards, preparative thin-layer chromatography (methyl chloride
Purified with ren: methanol = 10: 1) to obtain the target compound (red
Colored crystals, 0.8 mg, 65%) were obtained. mp> 300 ° C. IR (KBr): ν 3345, 1680, 1650, 1605, 1555, 1525, 1
475, 1445, 1400, 1385,1310 cm^-1.¹ H NMR (300 MHz): δ 2.70-2.89 (m, 6H), 3.95 (dt, 1
H, J = 17.7, 8.7 Hz), 4.26 (dt, 1H, J = 18.0, 6.6 Hz),
 4.70 (dd, 1H, J = 7.7, 11.4 Hz), 5.33 (br s, 1H),
5.91 (br s, 1H), 6.86 (s, 1H), 7.55 (s, 1H), 9.00
(br s, 1H).¹³ C NMR ([D₆] DMSO, 125 MHz): δ 17.9, 39.0, 45.2,
50.2, 50.3, 55.9, 61.2, 115.2, 117.4, 118.1, 121.
1, 122.5, 124.1, 141.4, 154.2, 157.5, 170.0, 188.3. HR-FABMS Calcd for C₁₈H₁₅BrN_ThreeO_TwoS (M + H)⁺: 416.0068;
 Found: 416.0071. UV / Vis (MeOH): λmax (ε) 469 (1000), 334 (9900) n
m. (Reference Example 1b) [Optically active substance, hydrochloride] [0108] Embedded image The compound obtained in Example 5a was used as a starting material.
Example 2a, Example 3, Example 4a, Reference
Following the same procedure as in Example 1a and Example 5b,
The reaction is carried out and the optically active target compound (green solid, hydrochloric acid
Salt). IR (KBr): ν 3650, 2400, 1680, 1610, 1580, 1525, 1
435, 1410, 1390 cm^{? 1}.¹ H NMR (300 MHz, CD_ThreeOD): δ 2.60 (d, 1H, J = 12.0 H
z), 2.88 (dd, 1H, J = 17.0, 6.5 Hz), 2.94-3.03 (m, 3
H), 3.07 (dd, 1H, J = 17.1, 12.3 Hz), 3.79 (dt, 1H, J
= 14.3, 9.6 Hz), 3.93 (dt, 1H, J = 14.1, 5.4 Hz), 4.5
1 (dd, 1H, J = 12.0, 6.6 Hz), 5.37 (dd, 1H, J = 3.8,
1.1 Hz), 7.19 (s, 1H), 7.57 (s, 1H).¹³ C NMR ([D₆] DMSO, 125 MHz): δ 18.4, 40.8, 44.2,
44.8, 49.9, 54.2, 59.1, 104.2, 120.3, 123.6, 123.
7, 126.1, 127.6, 148.3, 150.7, 154.1, 166.3, 187.2 HR-FABMS Calcd for C₁₈H₁₅BrN_ThreeO_TwoS (M-Cl)⁺: 416.006
8; Found: 416.0071. UV / Vis (MeOH): λmax (ε) 558 (800), 349 (7000), 2
49 (17100) nm. [α]_D ^24.4 +388 (c 0.06, CH_ThreeOH). (Reference Example 2) 3- (3-bromo-4-hydroxyphenyl)
M) -2-Tritylaminopropionic acid methyl ester (Reference Example 2a) 3- (4-hydroxyphenyl) -2-
Methyl tritylaminopropionate 3- (4-hydroxyphenyl) -2-aminopropio
Acid methyl ester (511mg, 2.21mmol)
To a solution of lumamide (20 mL) at 0 ° C, triethylamine
(0.62 mL, 4.44 mmol) and trityl chloride (617
mg, 2.21 mmol). Reaction solution at room temperature for 3 hours
After stirring, water was added to terminate the reaction, and ethyl acetate was added.
I got it. Separate the mixture and extract the aqueous layer twice with ethyl acetate.
Was. After mixing the organic layers, washing with saturated saline and drying,
It was concentrated under reduced pressure. Flash chromatography of the residue
-(N-hexane: ethyl acetate = 3: 1)
Compound (colorless crystals, 1.003 g, quantitative) was obtained. IR (KBr): ν 3345, 1715, 1615, 1595, 1515, 1445 cm
^-1.¹ H NMR (300 MHz): δ 2.59 (d, 1H, J = 10.8 Hz), 2.88
 (dd, 2H, J = 6.9, 4.2 Hz), 3.04 (s, 3H), 3.50 (dt,
1H, J = 10.8, 6.9 Hz), 4.78 (s, 1H), 6.76 (d, 2H, J =
8.4 Hz), 7.06 (d 2H, J = 8.4 Hz), 7.11-7.26 (m, 9
H), 7.40 (d, 6H, J = 7.5 Hz).¹³ C NMR (75 MHz): δ 41.4, 51.4, 58.4, 70.9, 115.
1, 126.3, 127.7, 128.7,129.2, 130.8, 145.8, 154.5,
 175.3. HR-FABMS Calcd for C₂₉H₂₈NO_Three (M + H)⁺: 438.2069; Fou
nd: 438.2073. (Reference Example 2b) 3- (3-bromo-4-hydroxyphene)
Nyl) -2-tritylaminopropionate methyl ester
Le Compound (3.28 g, 7.5 mmol) obtained in Reference Example 2a
N-bromosuccinyl solution was added to the tilformamide solution (40 mL).
Amide (1.34 g, 7.5 mmol) in dimethylformamide
Was slowly added dropwise at room temperature under a nitrogen stream. Reaction solution
After stirring for 2.5 hours, water was added to terminate the reaction.
Ethyl ether was added. Separate the mixture, and remove the aqueous layer
Extracted twice with chill ether. Combine the organic layers and mix with water 2
Once, washed with saturated saline once, dried, and concentrated under reduced pressure.
did. The residue was subjected to flash chromatography (n-hex
Purification with sun: ethyl acetate = 4: 1) yields the desired compound (none
Colored crystals, 2.546 g, 65%) were obtained. IR (KBr): ν 3500, 1730, 1605, 1595, 1495, 1445 cm
^-1.¹ H NMR (300 MHz): δ 2.57 (d, 1H, J = 10.8 Hz), 2.85
 (d, 2H, J = 6.6 Hz), 3.06 (s, 3H), 3.49-3.52 (m, 1
H), 5.43 (s, 1H), 6.95 (d, 1H, J = 8.4 Hz), 7.04 (d
d, 1H, J = 8.4, 1.8 Hz), 7.12-7.31 (m, 9H), 7.32 (d,
 1H, J = 1.8 Hz), 7.39 (d, 6H, J = 7.5 Hz).¹³ C NMR (75 MHz): δ 40.9, 51.4, 58.0, 70.9, 109.
7, 115.7, 126.4, 127.8,128.7, 130.5, 131.0, 133.1,
 145.7, 151.1, 174.7. HR-FABMS Calcd for C₂₉H₂₇BrNO_Three (M + H)⁺: 516.1174; F
ound: 516.1166. Reference Example 3 [2- (3-bromo-4-tert-butyldi)
Methylsilyloxyphenyl) -1- (tert-butyldi
Methylsilyloxymethyl) ethyl] tritylamine (Reference Example 3a) [2- (3-Bromo-4-hydroxyf
Enyl) -1- (hydroxymethyl) ethyl] trityl
Amine Salt of the compound obtained in Reference Example 2 (1.3749 g, 2.66 mmol)
In a methylene chloride (50 mL) solution under a nitrogen stream at -78 ° C,
1.0M diisobutylaluminum hydride / hexane
(8.6 mL, 8.6 mmol) was added dropwise. Heat the reaction solution to room temperature
After stirring for 5 hours, water was added to terminate the reaction.
Was. After the reaction solution was filtered through celite, the filtrate was washed with saturated bicarbonate.
Wash sequentially with an aqueous sodium solution and saturated saline, dry
After that, the mixture was concentrated under reduced pressure. Flash chromatography of the residue
Raffy (n-hexane: ethyl acetate = 2: 1)
Thus, the target compound (colorless crystals, 1.246 g, 96%) was obtained. IR (KBr): ν 3505, 3330, 1595, 1495, 1445 cm^-1.¹ H NMR (300 MHz): δ 1.96 (br s, 1H), 2.15 (dd, 1
H, J = 13.2, 4.8 Hz), 2.42 (dd, 1H, J = 13.2, 9.6 Hz),
 2.70-2.74 (m, 1H), 2.97 (dd, 1H, J = 10.8, 4.2Hz),
3.10 (dd, 1H, J = 10.8, 2.7 Hz), 6.76 (dd, 1H, J = 8.
4, 1.8 Hz), 6.81 (d, 1H, J = 8.4 Hz), 6.98 (d, 1H, J =
1.8 Hz), 7.17-7.31 (m, 9H), 7.54 (d, 6H, J = 7.5 H
z).¹³ C NMR (75 MHz): δ 37.8, 55.2, 62.3, 71.3, 109.
9, 115.7, 126.6, 127.9, 128.6, 130.1, 132.6, 132.7,
 146.4, 150.6. HR-FABMS Calcd for C₂₈H₂₇BrNO_Two (M + H)⁺: 488.1225; F
ound: 488.1257. (Reference Example 3b) [2- (3-bromo-4-tert-butyl)
Dimethylsilyloxyphenyl) -1- (tert-butyl
Dimethylsilyloxymethyl) ethyl] tritylamine Salt of the compound obtained in Reference Example 3a (1.246 g, 2.55 mmol)
1,8-diazabicyclo in methylene chloride (20 mL) solution
[5.4.0] Undec-7-ene (DBU, 1.90 mL, 12.
7 mmol) and tert-butyldimethylsilyl chloride
(1.166g, 7.74mmol) in a nitrogen stream at 0 ° C
Was. After stirring the reaction solution at 0 ° C. for 2 、 hours, saturated hydrogen carbonate
The reaction was terminated by adding sodium solution. Methyle chloride
After extraction with water, the organic layer is washed with saturated saline, dried,
It was concentrated under reduced pressure. Flash chromatography of the residue
-(N-hexane: ethyl acetate = 20: 1)
Compound (colorless oil, 1.583 g, 87%) was obtained. IR (KBr): ν 3320, 1600, 1495, 1470, 1460, 1390, 1
360 cm^-1.¹ H NMR (300 MHz): δ -0.13 (s, 3H), -0.11 (s, 3H),
 0.20 (s, 6H), 0.85 (s, 9H), 1.02 (s, 9H), 2.14
(d, 1H, J = 6.3 Hz), 2.46-2.61 (m, 3H), 2.68 (brs, 1
H), 2.90 (dd, 1H, J = 9.6, 3.0 Hz), 6.69 (d, 1H, J =
8.4 Hz), 6.80 (dd, 1H, J = 8.4, 1.8 Hz), 7.18 (d, 1H,
 J = 1.8 Hz), 7.15-7.29 (m, 9H), 7.56 (d, 6H, J = 7.5 H
z).¹³ C NMR (75 MHz): δ -5.5, -5.4, -4.3, 18.1, 18.3,
 25.7, 25.9, 37.7, 55.2, 62.3, 71.1, 114.8, 119.7,
 126.3, 127.8, 128.7, 129.3, 133.9, 134.3, 147.2,
150.6. HR-FABMS Calcd for C₄₀H₅₅BrNO_TwoSi_Two (M + H)⁺: 716.295
5; Found: 716.2942. (Reference Example 4) 7-methoxy-1- (toluene-4-sul)
Honyl) -3,4-dihydro-1H-pyrrolo [4,3,2
-De] quinolin-8-one 3- (2-azidoethyl) -6,7-dimethoxy-1-
(4-methylphenylsulfonyl) indole (215.4m
g, 0.538 mmol) of hexafluoroisopropanol (15
ml)-water (0.3 mL) mixed solution with trimethylsilyl
Fluoromethane sulfonate (0.23mL, 1.271mmo
l) was added dropwise at 0 ° C under a nitrogen stream, and then PIFA (277.4 mg,
 0.645 mmol). The reaction solution was stirred at 0 ° C for 1.5 hours.
After that, the reaction was terminated by adding a saturated aqueous sodium hydrogen carbonate solution.
And stirred for 15 minutes. After extraction with methylene chloride,
The organic layer was washed with saturated saline, dried, and concentrated under reduced pressure.
did. Flash chromatography of the residue (methyl chloride
Len: methanol: triethylamine = 100: 5: 0.1)
Purification gives the desired compound (yellow oil, 144.9mg, 76%)
Was. IR (KBr): ν 1670, 1620, 1595, 1580, 1535 cm^-1.¹ H NMR (270 MHz): δ 2.40 (s, 3H), 2.78 (t, 2H, J =
7.6 Hz), 3.78 (s, 3H), 4.18 (t, 2H, J = 7.6 Hz), 6.09
 (s, 1H), 7.31 (d, 2H, J = 8.2 Hz), 7.51 (s, 1H), 8.0
8 (d, 2H, J = 8.2 Hz). HR-MS m / z Calcd for C₁₈H₁₆N_TwoO_FourS (M⁺): 356.0831; Fo
und: 356.0825. (Reference Example 5) 7- [2- (3-bromo-4-hydroxy)
Phenyl) -1- (tert-butyldimethylsilyloxy
Methyl) ethylamino] -1- (toluene-4-sulfo
Nyl) -3,4-dihydro-1H-pyrrolo [4,3,2-
de] quinolin-8-one (Reference Example 5a) [2- (3-Bromo-4-hydroxyf
Enyl) -1- (tert-butyldimethylsilyloxime
Tyl) ethyl] tritylamine Tet of the compound obtained in Reference Example 3 (1.577 g, 2.20 mmol)
In a solution of lahydrofuran (35 mL) at 0 ° C under a nitrogen stream
Trabutylammonium fluoride (TBAF, 2.2 mL (1.0 M
Trahydrofuran solution), 2.20 mmol). Reaction
After the solution was stirred at 0 ° C. for 30 minutes, saturated aqueous ammonium chloride was added.
The reaction was terminated by adding a solution, and extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried, and concentrated under reduced pressure.
did. The residue was subjected to flash chromatography (n-hex
Purification with sun: ethyl acetate = 10: 1) yields the desired compound (none
Color oil, 1.330 g, quantitative). IR (KBr): ν 3520, 3325, 1595, 1495, 1470, 1450 cm
^-1.¹ H NMR (300 MHz): δ -0.13 (s, 3H), -0.11 (s, 3H),
 0.85 (s, 9H), 2.10 (br s, 1H), 2.47-2.61 (m, 3H),
 2.69 (br s, 1H), 2.88 (dd, 1H, J = 9.6, 3.0 Hz), 5.
40 (br s, 1H), 6.85-6.86 (m, 2H), 7.13 (d, 1H, J =
1.8 Hz), 7.12-7.29 (m, 9H), 7.56 (d, 6H, J = 7.5 H
z).¹³ C NMR (75 MHz): δ -5.5, -5.4, 18.1, 25.9, 37.6,
 55.1, 62.3, 71.1, 109.7, 115.5, 126.3, 127.8, 12
8.7, 130.3, 132.9, 133.3, 147.1, 150.3. HR-FABMS Calcd for C₃₄H₄₁BrNO_TwoSi (M + H)⁺: 602.2090;
 Found: 602.2075. (Reference Example 5b) 7- [2- (3-bromo-4-hydroxy)
Cyphenyl) -1- (tert-butyldimethylsilyloxy)
Cimethyl) ethylamino] -1- (toluene-4-sul
Honyl) -3,4-dihydro-1H-pyrrolo [4,3,2
-De] quinolin-8-one To the compound obtained in Reference Example 5a (312.4 mg, 0.518 mmol)
0.1M hydrogen chloride / methanol (5.2mL) under nitrogen stream at room temperature
And stirred for 30 minutes. The resulting solution was obtained in Reference Example 4.
Of the obtained compound (144.9 mg, 0.407 mmol) in methanol (1.
0 mL) solution was added dropwise at room temperature under a nitrogen stream. Reaction solution
After stirring for 16 hours, the mixture was concentrated under reduced pressure. Flush the residue
Chromatography (methylene chloride: methanol:
Triethylamine = 100: 5: 0.1)
(Red solid, 149.8 mg, 54%). IR (KBr): ν 3370, 1665, 1610, 1580, 1550, 1535, 1
495, 1460, 1445, 1380cm^-1.¹ H NMR (CD_ThreeOD, 500 MHz): δ 0.01 (s, 3H), 0.02 (s,
 3H), 0.90 (s, 9H), 2.42 (s, 3H), 2.74-2.8 1 (m, 4
H), 3.55 (br s, 1H), 3.58 (dd, 1H, J = 10.0, 4.0 H
z), 3.65 (dd, 1H, J = 10.0, 4.0 Hz), 3.98 (t, 2H, J =
7.5 Hz), 5.51 (s, 1H), 6.76 (d, 1H, J = 8.5 Hz), 7.00
 (dd, 1H, J = 8.5, 2.0 Hz), 7.29 (d, 1H, J = 2.0 Hz),
7.39 (d, 2H, J = 8.5 Hz), 7.66 (s, 1H), 8.00 (d, 2H,
 J = 8.5 Hz). ¹³ C NMR (CD_Three(OD, 75 MHz): δ -5.4, -5.3, 19.1, 21.
7, 26.4, 30.8, 36.1, 38.7, 47.7, 55.4, 66.5, 95.5,
 110.8, 110.9, 117.3, 117.4, 119.7, 128.0, 129.8,
130.4, 130.4, 130.9, 131.7, 131.8, 134.7, 134.8, 1
35.8, 147.6, 154.2. HR-FABMS Calcd for C₃₂H₃₉BrN_ThreeO_FiveSSi (M + H)⁺: 684.156
3; Found: 684.1586. (Reference Example 6) 7- [2- (3-bromo-4-tert-butyl)
Dimethylsilyloxyphenyl) -1- (tert-butyl
Dimethylsilyloxymethyl) ethylamino] -1-
(Toluene-4-sulfonyl) -3,4-dihydro-1
H-pyrrolo [4,3,2-de] quinolin-8-one salt
Acid salt [optically active substance] [0110] Embedded image Reference Example 6a 7- [2- (3-bromo-
4-tert-butyldimethylsilyloxyphenyl) -1
-(Tert-butyldimethylsilyloxymethyl) ethyl
Amino] -1- (toluene-4-sulfonyl) -3,4
-Dihydro-1H-pyrrolo [4,3,2-de] quinoline
-8-one [optically active substance] [0112] Embedded image (2S) -3- (4-hydroxyphenyl)
M) 2-aminopropionic acid methyl ester as a raw material
And used in the same manner as in Reference Examples 2 and 3.
The optically active compound of Reference Example 3b thus obtained (11
8.1mg, 0.165mmol) in 0.1M hydrogen chloride / methanol (2.5m
L) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 30 minutes.
This reaction solution was treated with the compound obtained in Reference Example 4 (58.7 mg, 0.1%).
165 mmol) in methanol (4.0 mL).
And stirred for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was removed.
Flash column chromatography (n-hexane:
Purified with ethyl acetate: triethylamine = 100: 100: 0.1)
Thus, the target compound (red solid, 88.7 mg, 67%) was obtained.¹ H NMR (CD_ThreeOD, 500 MHz): δ 0.02 (s, 6H), 0.14 (s,
 3H), 0.16 (s, 3H), 0.90 (s, 9H), 0.99 (s, 9H), 2.
40 (s, 3H), 2.75-2.91 (m, 4H), 3.58-3.60 (m, 2H),
3.67 (dd, 1H, J = 10.0, 4.0 Hz), 3.97 (br s, 2H), 5.
47 (s, 1H), 6.77 (d, 1H, J = 8.5 Hz), 7.04 (dd, 1H, J
= 8.0, 2.0 Hz), 7.35 (d, 1H, J = 1.5 Hz), 7.38 (d, 2
H, J = 8.5 Hz), 7.63 (s, 1H), 8.00 (d, 2H, J = 7.5 H
z). [α]_D ^{twenty four} -83 (c 0.113, CHCl_Three). (Reference Example 6b) 7- [2- (3-bromo-4-tert-butyl)
Tyldimethylsilyloxyphenyl) -1- (tert-butyl
Tyldimethylsilyloxymethyl) ethylamino] -1
-(Toluene-4-sulfonyl) -3,4-dihydro-
1H-pyrrolo [4,3,2-de] quinolin-8-one
Hydrochloride [optically active form] [0114] Embedded image The compound obtained in Reference Example 6a (88.7 mg, 0.
111 mmol) in methanol (3 ml).
Tanol (1.2 mL) was added, and the reaction mixture was immediately concentrated under reduced pressure.
The resulting product was purified to give the desired compound (purple solid).¹ H NMR (CD_ThreeOD, 300 MHz): δ 0.04 (s, 6H), 0.14 (s,
 3H), 0.16 (s, 3H), 0.89 (s, 9H), 0.99 (s, 9H), 2.
43 (s, 3H), 2.70-2.96 (m, 4H), 3.60-3.85 (m, 5H),
5.39 (s, 1H), 6.72 (d, 1H, J = 8.0 Hz), 7.04 (dd, 1
H, J = 8.5, 2.0 Hz), 7.30 (d, 1H, J = 2.0 Hz), 7.44
(d, 2H, J = 8.5 Hz), 7.79 (s, 1H), 8.07 (d, 2H, J = 8.5
 Hz). HR-FABMS Calcd for C₃₈H₅₃BrN_ThreeO_FiveSSi_Two (M-Cl)⁺: 798.2
428; Found: 798.2418. (Formulation example) (Formulation Example 1) Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg
Compound of Example 1 in powder form, 150 mg lactose, 50 mg
 Cellulose and 6 mg magnesium stearate
By filling, produce unit capsules, after washing,
dry. (Formulation Example 2) Soft capsule Digestible oils such as soybean oil, cottonseed oil or olive oil
A mixture of the compound of Example 2 was prepared and placed
Pump into the gelatin with an exchange pump to get 100 mg of the active ingredient.
The resulting soft capsule is obtained, washed and dried. (Formulation Example 3) Tablet In a conventional manner, 100 mg of the compound of Example 3 and 0.2 mg of
Loidal silicon dioxide, 5 mg magnesium stearate
275 mg microcrystalline cellulose, 11 mg starch and
And 98.8 mg of lactose. [0116] If desired, a coating is applied. (Formulation Example 4) Suspension In 5 ml, 100 mg of the finely divided compound of Example 2, 100 mg
mg of sodium carboxy group methylcellulose, 5 mg
Sodium benzoate, 1.0 g sorbitol solution (Japan
Manufactured to contain 0.025 ml of vanillin
I do. (Formulation Example 5) Cream 40% white petrolatum, 3% microcrystalline wax,
10% lanolin, 5% span 20, 0.3% tween 20
100mg fines in 5g cream consisting of 41.7% water
By mixing the compound of Example 1
You. (Test example) Antitumor activity test Human colorectal cancer cells WiDr (American Type Culture Collecti
on) into a 96-well plate (Nunc)^Three/ Well
And sowed. 10% fetal calf serum for cancer cell culture
DMEM / F-12 (GIBCO) was used as a culture solution. Cellular
Simultaneous seeding with dimethyl sulfoxide (DMSO, Dojin Chemical
Test compounds dissolved in a laboratory) to a final concentration of 0.001, 0.0
1, 0.1, 1, and 10 μM (final concentration of DMSO)
Degree is 0.1%). In the control group, only DMSO was 0.1%.
Was added. Cancer cells with test compound added are 5% carbon dioxide
The cells were cultured at 37 ° C. for 72 hours under elemental concentration. Cultured cells
Uses 10% final concentration of trichloroacetic acid (Wako Pure Chemical Industries)
Add, leave at 4 ° C for 1 hour to fix, then wash with water
Later, it was air-dried. Next, 0.4% sulfolodamine B (Molec
ular Probes Inc.)-1 50% acetic acid (Wako Pure Chemical Industries) solution
μl to each well and leave at room temperature for 30 minutes to remove cells.
Stained. Wash stained cells with 1% acetic acid solution, 150 μl
Add Tris solution to each well and add
The absorbance was measured. This test was performed with n = 4 per group.
Test was carried out. Absorbance equivalent to 1/2 of the average absorbance of the control group
2 points indicating the average absorbance closest to and sandwiching that value
Find the concentration of, and approximate a linear function from the absorbance of the two points
Test to show half the absorbance of the control group
The compound concentration was calculated. This concentration is the IC of the test compound.₅₀Value and
did. Test compound IC₅₀The values are shown in Table 1. [0117] [Table 1] _______________________ Test compound IC₅₀Value (μM) ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣ Compound of Example 5b 0.29 Compound of Reference Example 6b 3.0 _______________________ As shown in Table 1, the compounds of the present invention showed good antitumor
It has tumor activity and is useful as a prophylactic or therapeutic agent for cancer.
You. [0118] The compound of the present invention has a novel structure,
Moreover, it is useful as a compound having excellent antitumor activity.
You.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 495/22 C07D 495/22 C07F 7/18 C07F 7/18 V // C07M 7:00 C07M 7:00 F-term (reference) 4C050 AA04 AA08 BB04 CC07 DD02 EE03 FF01 GG02 GG03 HH01 4C065 AA16 AA19 BB09 CC03 DD03 HH01 HH04 JJ01 JJ03 KK01 KK04 LL02 LL03 LL04 PP03 4C071 AA04 AA03 BB03 A03 BB03 CC03 DD03 GA16 MA01 MA04 NA14 ZB26 4H049 VN01 VP01 VQ60 VR23 VR41 VU07

Claims (1)

[Claim 1] The following general formula (I): (In the formula, R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group substituted with a hydroxyl group (the hydroxyl group may be protected), a hydroxyl group (the hydroxyl group is protected. Or a mercapto group (the mercapto group may be protected), R ² represents a hydrogen atom, or R ² together with R ¹ represents an ether group or a sulfide. R ³ and R ⁴ are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group (the hydroxyl group may be protected), or a mercapto group (the mercapto group may be protected) And R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group (the hydroxyl group may be protected), or a mercapto group (the mercapto group may be protected) ) And R
⁷ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a protecting group for an amino group, B ¹ , B ² and B ³ are the same or different and represent a single bond or a double bond, and X is an oxygen atom , Sulfur atom, NH group or C
Shows the ₁ -C ₆ nitrogen atoms substituted with an alkyl group. However, Disco Hub Din A is excluded. ), A compound represented by
Or a pharmacologically acceptable salt thereof.