JPS63243084A - Mitomycin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {X represents O, S, Se or sulfoxide; R1 represents (substituted)lower alkyl, lower cycloalkyl, formula II [R' and R'' represent (substituted)lower alkyl or lower cycloalkyl], (substituted)aryl or (substituted)pyridyl; R<2> represents H, lower alkyl, lower cycloalkyl, (substituted)aralkyl, (substituted)alkanoyl, etc.; R3 represents H, methyl or acetyl; R4 represents H or methyl; R5 represents H or carbamoyl; - represents alpha-bond or beta-bond}. USE:An antitumor agent. PREPARATION:A compound expressed by formula III [R21 represents lower alkyl, lower cycloalkyl, (substituted)aralkyl or (substituted)alkanoyl, etc.] is reacted with compounds expressed by the formula R1X1X1R1 and the formula (R9)3P (R9 represents lower alkyl, phenyl or dimethylamino) to afford a compound expressed by formula I wherein the group X is X1 and the group R2 is R21. The compound expressed by formula III as a starting raw material is a novel substance and produced from mitomycins expressed by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel mitomycin derivatives having antitumor activity.

Prior Art and Problems Mitomycins are generally known as antibiotics having antibacterial and antitumor activities. Mitomycin A is a typical mitomycin.

B, C and porphyromycin (Merck Index 1
0 edition), mitomycin D and E (Japanese Patent Application Laid-Open No. 1983-12
2797), Mitomycin F and J
45322) etc. These mitomycins have the chemical structures shown in Table 1 below, and can be obtained by culturing strains of Streptomyces cespitosa.

Table 1 Structure SA of representative mitomycins
9-10 RA RB mitomycin A
0Clb -C113ItBOCII3I 1
Group-IIC)l.

CN112 4CII3II D NH2"""' HCll 3E
Nll□ 11 Old■CI■3C■3F
0C113-" C113Cl13JOCR3- ,,,,C1hC1hPorphyromycin NHz
4CI13 CHaThe three-dimensional structure is according to the journal
Op American Chemical Society, 105.
7199 (I, 983). Furthermore, decarbamoyl mitomycins at position 10 are described in Journal of Medicinal Chemistry 2, 109 (I971).

Among these mitomycins, mitomycin C has particularly strong antitumor activity and is widely used clinically. However, it has strong toxicity and bone marrow toxicity, and various derivatives of mitomycin have been produced to enhance antitumor activity and/or reduce side effects.

Among these derivatives, various compounds in which the amino group at position 7 is substituted are also known, but mitomycin derivatives in which an atom other than a carbon atom is placed adjacent to the nitrogen atom of the amino group are known. For example, JP-A-60-1
No. 69481 contains a compound in which the 7th position is substituted with methanesulfonylamino, diethylphosphorylamino, etc., and JP-A No. 61-91189 contains a compound in which the 7th position is substituted with tert-butyldimethylsilylamino or 0-nitrophenylsulfenylamino. Mitomycin derivatives substituted with etc. are disclosed. Note that all of these derivatives retain the p-quinone ring of mitomycin. Also, the same (general formula (■) in which the 7th position is substituted with nitroso or substituted ab) (Japanese Patent Application No. 61-110395), and the same 7
An application has been filed for a compound represented by the general formula (III) (Japanese Patent Application No. 61-89546) having an alkoxyimino at the position.

(In the formula, A is ON- or R, N=N-C In the formula, R7 is a substituted heterocycle (In these formulas, R7+ is a hydrogen atom, lower alkyl or lower cycloalkyl, and R7□ is hydrogen atom, halogen atom, hydroxy, lower alkoxy,
is amino or nitro, R73 is lower alkyl or lower cycloalkyl, Y is oxygen atom, sulfur atom or imino, R? 4 is R? + is the same or different and is a hydrogen atom, lower alkyl or lower cycloalkyl)], and R6 is a hydrogen atom, lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted alkanoyl, unsubstituted or substituted Arylcarbonyl, unsubstituted or substituted lower alkanesulfonyl, arylsulfonyl or aralkylsulfonyl. R2, R3, R4+R5 and υ- have the same meanings as in general formula (I) described below. ) (In the formula, R8 is lower alkyl, cycloalkyl, or unsubstituted or substituted aralkyl, and R31 is a hydrogen atom or methyl. R4+R5 and V have the same meaning as in general formula (I) described below).

-C The compound represented by the formula (IT) has a skeleton in which the p-quinone ring of mitomycin is converted into a dihydroquinone ring and its derivatives, and the compound represented by the general formula (III) has a skeleton at the 7-position. All of them are compounds with novel structures having skeletons converted to 6,7-dihydroquinone rings having imino groups.

New and useful mitomycin derivatives are always in demand, and as a result of research on new mitomycin derivatives, mitomycin has a completely novel skeleton in which the p-quinone ring is converted to an 0-quinone imine ring, which is represented by the general formula (I). A mitomycin derivative was produced. These mitomycin derivatives have an oxygen atom, a sulfur atom, a selenium atom, or an imino group adjacent to a sulfoxide at the 7-position, and the substituents at the 7-position include alkoxyimino, aralkyloxyimino, alkylthioimino, and aralkyl. Thioimino, ruthioimino, pyridylthioimino, alkylselenoimino, aralkylselenoimino,
Examples include arylselenoimino, pyridylselenoimino, alkylsulfinyl imino, aralkylsulfinyl imino, arylsulfinyl imino, and pyridylsulfinyl imino.

The mitomycin derivative of the present invention having excellent antitumor activity is represented by the following general formula (I).

[In the formula, X is an oxygen atom, a sulfur atom, a selenium atom, and a sulfoxide, and R1 is unsubstituted or substituted (in the formula, R'
, R'' are the same or different and are unsubstituted or substituted lower alkyl or lower cycloalkyl), unsubstituted or substituted aryl, and unsubstituted or substituted pyridyl. R2 is a hydrogen atom, lower argyl, lower cycloalkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted alkanoyl, unsubstituted or substituted arylcarbonyl, unsubstituted or substituted alkanesulfonyl, arylsulfonyl or aralkylsulfonyl, R3 is a hydrogen atom, methyl or acetyl, R4 is a hydrogen atom or methyl, R5 is a hydrogen atom or carbamoyl, - represents an α bond or a β bond] The compound represented by the general formula (T) is hereinafter referred to as compound (I) (the same applies to other compounds with the number 2) ).

In the definition of R,, R2, R', and R'' in general formula (r), lower alkyl is a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl. , n-butyl, isobutyl, 5ec-butyl, t
Lower cycloalkyl includes ert-butyl, n-pentyl, neopentyl, n-hexyl, etc., and lower cycloalkyl has 3 to 6 carbon atoms.
cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and the like. Also, R1, R'
.

Examples of the substituent for the substituted lower alkyl in RJJ include hydroxy, amino, carboxyl, nitro, and the like. In the definition of R,, R2, unsubstituted or substituted aralkyl includes hensyl, phenethyl, diphenylmethyl, trityl, substituted hensyl, and the like. Here, the substituent of the substituted benzyl is a substituent of the Hensen nucleus, and is one or two of the same or different lower alkoxy (lower alkoxy herein refers to a straight or branched alkoxy having 1 to 6 carbon atoms, e.g. Methoxy, ethoxy, isopropoxy, n-
butoxy, etc.), halogen atoms (chlorine atom, fluorine atom, etc.), nitro, cyano, lower alkyl (lower alkyl referred to herein has the same meaning as in R1), and the like. Regarding the definition of R1, unsubstituted or substituted aryl includes phenyl, naphthyl, etc., and the substituents are 1 or 2.
The same or different lower alkoxy (lower alkoxy herein is synonymous with the substituent of substituted Hensyl in the definition of R), halogen atom (chlorine atom, fluorine atom), carboxyl, amino, nitro, cyano,
Lower alkyl (lower alkyl here has the same meaning as in R1), etc. are included.

Regarding the definition of R1, the substituent of substituted pyridyl is ■ or 2
The same or different lower alkoxy (lower alkoxy here has the same meaning as in the substituent of substituted Hensyl in the definition of R1), carboxyl, amino, 21.
It includes alkyl, cyano, lower alkyl (lower alkyl referred to herein is synonymous with R and niugero), and the like. Regarding the definition of R2, unsubstituted or substituted lower alkanoyl refers to straight or branched alkanoyl having 1 to 6 carbon atoms, such as polmyl, acetyl, propionyl, n-butyryl,
It includes isobutyryl, n-pentanoyl, n-hexanoyl, etc., and the substituent includes a halogen atom, such as a chlorine atom, a fluorine atom, etc.

Specific examples of substituted lower alkamyl include trichloroacetyl, trifluoroacetyl, and the like. Regarding the definition of R2, the aryl referred to in unsubstituted or substituted lower arylcarbonyl includes phenyl, naphthyl, etc., and the substituent is one or two of the same or different lower alkoxy (lower alkoxy herein refers to halogen atoms (chlorine atom, fluorine atom, etc.), nitro, cyano, lower alkyl (lower alkyl referred to herein has the same meaning as in R), etc. Regarding the definition of R2, the lower alkanesulfonyl referred to in unsubstituted or substituted lower alkanesulfonyl is a linear or branched alkanesulfonyl having 1 to 6 carbon atoms, and the substituent is a halogen atom, such as a chlorine atom, a fluorine atom, etc. include. Specific examples of unsubstituted or substituted lower alkanesulfonyl include methanesulfonyl, ethanesulfonyl, isopropanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl, and the like. Regarding the definition of R2, arylsulfonyl includes hensylsulfonyl, p-toluenesulfonyl, etc., and aralkylsulfonyl includes hensylsulfonyl, etc.

The mitomycin derivative represented by the general formula (I) can be produced by the methods shown in the following reaction formulas (a), (b), (c), (d), etc.

[]11 (n-1) (wherein, Xl is a sulfur atom or a selenium atom. R21 is lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted alkanoyl, unsubstituted or substituted arylcarbonyl, unsubstituted or substituted lower alkanesulfonyl, arylsulfonyl or aralkylsulfonyl, R1 is lower alkyl, phenyl, dimethylamino; R+, R3, R4, R
s and w have the same meanings as in general formula (I). ) Reaction formula (al) indicates a method for producing 0-quinoneimines containing thioimino or selenoimino in which X is a sulfur atom or selenium atom in the general formula (I). Here, the nitroso compound (II-1) used as a raw material can be produced from mitomycins represented by the general formula (IV), and is a new compound included in the general formula (II) that has already been filed by the present inventors, and can be obtained by the following reaction formula (a').

(TI-2) (H-1) [In formula (IV) and formula (I12), R3, R,.

R5 and VV numbers have the same meaning as in general formula (I)] mitomycins represented by general formula (IV) or acid addition salts thereof, such as hydrochloride, hydrobromide, etc. 1 to 3 equivalents of base per acid addition salt of roxylamine, such as inorganic bases such as sodium carbonate and sodium hydride; Tertiary amines such as pyridine and triethylamine; Metal alkoxides such as sodium methoxide and botanical ethoxide. A compound of general formula (U) in which R2 is a hydrogen atom [hereinafter referred to as compound (II-2)] is obtained by reacting in an inert solvent such as methanol, dimethylformamide, water, etc. in the presence of the following.

0.8 to 1.2 equivalent base relative to compound (Ill-2), such as an inorganic base such as sodium hydride, sodium carbonate, silver oxide; sodium methoxide, potassium-1e
0.8 to 1.2 equivalents of an alkylating agent, such as formula R22tlaβ, relative to compound (II-2) and compound (II2) in the presence of r t-butoxide, n-butyllithium, lithium diisopropylamide, etc.

(R2□O) 2S02- CIIzNz or (R2□
) 308F4 (in each formula, R22 is lower alkyl, lower cycloalkyl, or unsubstituted or substituted aralkyl) in an inert solvent such as methanol, tetrahydrofuran, dimethylformamide, etc. A compound of formula (II) in which R2 is lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl [hereinafter referred to as compound (II-1a)] is obtained.

0.0 for compound (II-2) and compound (II-2).
8 to 1.2 equivalents of a reactive derivative of a carboxylic acid represented by R23-0w1 (wherein R23 is unsubstituted or substituted lower alkanoyl, or unsubstituted or substituted carbonyl) or an acylating agent. acylating agent and an equivalent amount of a base, such as an inorganic base such as sodium hydride, sodium carbonate, silver oxide; sodium methoxide;
n-butyllithium, lithium diisopropylamide,
The general formula (II
), a compound in which R2 is unsubstituted or substituted lower alkanoyl or unsubstituted or substituted arylcarbonyl [hereinafter referred to as compound (II-1b)] is obtained. The reactive derivatives of carboxylic acids referred to as acylating agents include acid chlorides,
Includes acid halides such as acid bromides, acid anhydrides, and the like.

0.8 for compound (II-2) and compound (n-2)
~1.2 This mouse's l? 24-011 (wherein R24 is unsubstituted or substituted lower alkanesulfonyl, arylsulfonyl or aralkylsulfonyl) (hereinafter referred to as sulfonylating agent) is an equivalent amount of the sulfonylating agent. In the general formula (II), R2 is unsubstituted or substituted lower alkanesulfonyl, arylsulfonyl or aralkylsulfonyl by reacting in an inert solvent such as acetonitrile, dimethylformamide, chloroform or a base such as pyridine in the presence of a base. A certain compound [hereinafter compound (■-
10). The reactive derivative referred to as the sulbonylating agent includes acid halides such as acid chloride and acid bromide, acid anhydrides, and the like. As the base in this sulfonylation, the same base as in the above-mentioned acylation is used.

Disulfide (RI SSRl ) or diselenite (
R + 5eSeRI) and a trivalent phosphorus compound ((R9) 3
The 0-quinone imine (I-4) can be obtained by reacting P). Here, the trivalent phosphorus compound includes trialkylphosphines such as triethylphosphine, tri-n-butylphosphine, triphenylphosphine, hexamethylposporastriamide, and the like. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but preferably alcohols such as methanol, ethanol, and isopropanol, and organic solvents such as acetonitrile, dimethylpolamide, and dimethyl sulfoxide are used. They can be used alone or in combination.

Reaction t and j+ are carried out under cooling or heating, and are preferably completed in a few minutes to several days at room temperature from 0°C. After the reaction is completed, the target compound (J-1) can be obtained by commonly used processing operations, such as extraction, chromatography, separation such as recrystallization, and loading methods.

(III) [In formula (I-2), RZI has the same meaning as in formulas (I!-1) and (I-1), Ro and R31 have the same meaning as in general formula (I), R4, R5 and ~V
has the same meaning as in general formula (I).

Reaction formula (b) shows a method for producing 〇-cow nonimines containing an alkoxyimino group in which X is an oxygen atom in general formula (I). In the formula, lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl in the definition of R8 has the same meaning as in the definition of R1 in general formula (I). Here, the raw material 6,7-cyhydroquinone (II
I) can be produced from mitomycins represented by the general formula (IV), is a new compound that has already been filed by the present inventors, and can be obtained by the following method.

1 to 3 equivalents of R80NI+□ (in the formula R
8 has the same meaning as in formula (I'1l-1)) or its acid addition salts, such as hydrochloride, hydrobromide, etc., in methanol, ethanol, acetonitrile, dimethylbormamide, tetrahydrofuran, water, etc. A 6,7-cyhydroquinone compound (III) is obtained by reacting in an inert solvent in the presence of a base if necessary. R80NI+2
When using an acid addition salt of RIIONI+□, use the amount of base necessary to liberate RIIONI+□. Examples of such bases include inorganic bases such as thorium carbonate, sodium hydrogen carbonate, and sodium hydroxide; tertiary amines such as pyridine and triethylamine; and alkali metal alkoxides such as sodium methoxide and sodium ethoxide.

The 6,7-cyhydroquinone body obtained as above (
Compound (I-2) is obtained by alkylating, acylating and sulfonylating III). The alkylation is carried out using an alkylating agent in an amount of 0.8 to 1.5 equivalents based on the 6,7-cyhydroquinone body (I[I) and compound (III), for example, (R2゜O) 2SO□, (R2□) 30
8F4 (in each formula, R2□ is lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl), CH
2N2] to the compound (ff[) from 0.8 to
1.2 The 0-quinone imine (I-2a) can be obtained by reacting in the presence of the base in question.

Bases used in this reaction include inorganic bases such as sodium hydride, lithium hydride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, silver oxide; sodium methoxide, sodium ethoxide, potassium tert.
-butoxide, n-butyllithium, 5ec-butyllithium, phenyllithium, lithium diisopropylamide, and other organic bases. The solvent used in the reaction may be any I or sQ solvent that does not participate in the reaction, but preferably alcohols such as methanol, ethanol, isopropanol, and lert-butanol, diethyl ether, tetrahydrofuran, etc. Organic solvents such as ethers, dimethylborumamide, and dimethylsulfoxide, which can be used alone or in combination. The reaction usually proceeds under cooling or heating, but is preferably completed in several minutes to several hours at 0° C. to room temperature.

After the reaction is complete, commonly used processing operations such as extraction,
The target compound (I-2a) can be obtained by separation and purification methods such as chromatography and recrystallization.

R21 is unsubstituted or substituted lower alkanoyl in formula (I-2) by reacting compound (TIT) with an acylating agent in an amount of 0.8 to 1.2 equivalents to compound (III) in the presence of a base. , unsubstituted or substituted arylcarbonyl compound (I-2b) can be produced. The acylating agent used here is RI3 0H (
In the formula, R23 is unsubstituted or substituted lower alkanoyl,
It is a reactive derivative of a carboxylic acid represented by an unsubstituted or substituted carbonyl, and includes acid halides such as acid chloride and acid bromide, acid anhydrides, and the like. Further, the base used, its usage amount, and the solvent are the same as in the case of alkylation.

In addition, in the presence of compound (Ifl) and a base, compound (In
) with 0.8 to 1.2 equivalents of a sulfonylating agent to form a compound (I-2) in which R21 is unsubstituted or substituted lower alkanoyl, arylsulfonyl, or aralkylsulfonyl. 2c) can be produced. The sulbonylating agent used here is a reactive derivative of sulfonic acid represented by R2,-0++<wherein R24 is unsubstituted or substituted alkanesulfonyl, arylsulfonyl or aralkylsulfonyl], and is an acid chloride. , acid halides such as acid bromides, acid anhydrides, and the like. Further, the base used, its usage amount, and the solvent may be the same as in the case of alkylation.

(I-1'b) (In the formula, R23 is acyl, R1, R: 1.R4゜R5 and --I have the same meaning as in general formula (I))
Reaction formula fcl shows a method for producing a compound of O-quinoneimine in which X is a sulfur atom and R2 is a hydrogen atom in the general formula (I), and the 5-position 0-acyl body (I-1'
By treating b) with a base, the 5-position -011 body N
-3> can be obtained.

The compound (r-1'b) is a compound in which X is a sulfur atom and R21 is an acyl in the above-mentioned compound (I-1), and can be synthesized according to the reaction formula (al).

In this reaction, when the base is used in an amount of 0.8 to 1.2 equivalents based on compound N-1'b), a compound in which only the acyl of R23 is converted to a hydrogen atom is obtained, and 2 to 6 equivalents of the base are obtained. When used as an example, a compound is obtained in which not only the acyl of R23 but also the acetyl when R is acetylated is converted into a hydrogen atom. Examples of bases include inorganic bases such as sodium hydride, lithium hydride, sodium carbonate, potassium carbonate, and sodium bicarbonate; sodium methoxide, sodium ethoxide, and sodium chloride;
Examples thereof include organic bases such as -butoxide, n-butyllithium, lithium diisopropylamide, diisopropylamine, and hydroxylamine. The solvent used in the reaction is alcohols such as methanol, ethanol, isopropanol, and water, either alone or in combination.

The reaction usually proceeds under cooling or heating, but is preferably completed in several minutes to several hours at room temperature from O'C. After the reaction is completed, the target compound (I-3) can be obtained by commonly used treatment operations such as separation and purification methods such as extraction, chromatography, and recrystallization.

(I-1') (I-/I) (wherein R+, Rz, R3, Ra, R5 and vV
The reaction formula (dl has the same meaning as in general formula (I)) indicates a method for producing 0-quinoneimines in which X is sulfoxide in general formula (I), and the thioimino form (I
A sulfinylimino compound (I-4) can be obtained by oxidizing the sulfur atom of -1') to a sulfoxide. Compound (I-1') is a compound in which X is a sulfur atom in the aforementioned compound (I-1), and has the reaction formula (al
It can be synthesized by Examples of the oxidizing agent include hydrogen peroxide, tert-butylhydroberoxide, benzoyl peroxide, m-chloroperbenzoic acid, etc., and the amount used is 0.8 to ([-1')]. 1.2 Fireflies. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but preferably halogenated solvents such as carbon tetrachloride and chloroform, alcohols such as methanol, ethanol, and isopropanol, and acetate, alcohol, etc. , an organic solvent such as acetonitrile, or water, which can be used alone or in combination.

The reaction usually proceeds under cooling or heating, but is preferably completed in several minutes to several hours at 0° C. to room temperature. After the reaction is completed, the target compound (I-4) can be obtained by commonly used treatment operations such as separation and purification methods such as extraction, chromatography, and recrystallization.

Table 2 lists the names of representative examples of compounds of the present invention obtained in Examples, and Table 3 lists the substituents on their structural formulas.

The compound tooth corresponds to the example patient.

The compound names in the following tables and examples are indicated by the position number of the general formula (I), unlike in Table 1 (common names).

The names of the compounds obtained in Reference Examples 1 to 8 are listed in Table 1 as compounds No. and a to h, respectively.

Table 2 [:1aS-(Iaα, 8β, 8aα, 8bα))
8- (((aminocarbonyl)oxycomethyl l-
4,8a-dimethoxy-6-[(isopropylthio)imino) 1. Ia, 2.6, 8.8a, 8b-hebutahydro-5-methyl-azilino (2', 3':3.
4) Pyrrolo[1,2a]indol-7-one C1aS-(Iaa, 8β, 8aα, 8bα)) -8
-([(aminocarbonyl)ogishi]methyl) -4,
8a-dimethoxy-Lla, 2,6,8°8a,8b-
Hebutahydro-6-((2”-hydroxyethylthio)
imino]-5-methyl-azilino (2', 3':3
,4) pyrrolo(I,2-a)indol-7-one (
IaS (laα, 8β, 8aα, 8bα)) −8
-(((aminocarbonyl)oxycomethyl) -4,
8a-dimethoxy-1+1a+2,6,88a,8b-
Heptahydro-5-methyl-6-C(2″-nitrophenylthio)imino]-azilino(2′,3′ 73.
4]]pyrroloC1,2-a indol-7-one 1:
1aS-(Iaα, 8β, 8aα, 8bα)) -8-
(((aminocarbonyl)oxycomethyll -6-[
(4″-aminophenylthio)imino)4,8a-dimethoxy-1,Ia,2,6,8,8a,8bheptahydro-5-methyl-azilinoC2′,3′:3,4
) pyrrolo(I,2-a)indol-7-one (IaS
-(Iaα, 8β, 8aα, 8bα)) -8-(((
(aminocarbonyl)oxycomethyl) 4,8a-dimethoxy-1,la,2,6,8°8a,8b-hebutahydro-5-methyl-6-((2″-pyridylthio)imino)-azilino(2′,3 ':3,4) pyrrolo(C2-a) indol-7-one (IaS-(Iaα, 8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyll-4,8
a-dimethoxy-Lla, 2,6,8゜8a,8b-hebutahydro-6-((4''-hydroxycarbonyl-2
″-pyridylthio)imino]-5-methyl-azinori(
2', 3': 3.4) Pyrrolo[1,2-a]zeynol-7one triethylamine salt (IaS-(Iaα+8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyll-4,8
a-dimethoxy-1,Ia,2,6,8゜8a,8b-
Hebutahydro-5-methyl-6-C (4″-nitro-2
”-pyridylthio)imino]-azilino(2', 3'
:3.4] pyrrolo(C2-a) indol-7-one [1aS-(Iaα, 8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyll -6-
((diethylthiocarbamylthio)imino) -4,8
a-dimethoxy-1,la,2,6,8,8a,8bhepkhydo-5-methyl-azilino(2',3':
3.4) Pyrrolo0.2-a) Indol-7-one [
1aS (Iaα+8β, 8aα, 8bα)) 8
(((aminocarbonyl)oxycomethyl) −
4,8a-dimethoxy-1,Ia,2,6.88a,8
b-Hebutahydro-5-methyl-6-[(phenylseleno)imino]-azilino (2', 3': 3,4)
Pyrrolo[1,2a]indol-7-one (IaS (Iaα+8β, 8aa, 8bcx)]8
(((aminocarbonyl)oxycomethyl)-6-
((n-butylseleno)imino)-4,8a-dimethoxy-1,la,2,6,8,8a,8b-heptahydro-5-methyl-azilino(2',3':3.4)pyrrolo[1,2a ] Indol-7-one (las-(latx, 8β, 8aα, 8bα)) -
8-(C(aminocarbonyl)oxycomethyl)-4,
8a-dimethoxy-Lla, 2,6,8°8a,8b-
Heptahydro-5-methyl-6-((2″-pyridylseleno)imino)-azilino(2′,3′: 3,4
) pyrrolo[12-a) indol-7-one (IaS-(Iaα, 8β, 8aα, 8bα)) 8
(((aminocarbonyl)oxycomethyl)-4
,8a-dimethoxy-1,Ia,2,6,8°8a,8
b-heptahydro-5-methyl-6-((2″-pyridylsulfinyl)imino]-azilinoC2′,3′
: 3,4) Pyrrolo[1,2-a]indol-7-one (IaS-(Iaα, 8β, 8aα, 8bα)) -
8-(((aminocarbonyl)oxycomethyll-6-
((n-butylsulfinyl)imino) 4.8a-
Dimethoxy-1,1a,2,6,8.8a,8b-heptahydro-5-methyl-azilino (2', 3':
3.4) Pyrrolo (C2-a) indol-7-one (las (laa18β, 8aα, 8bα))
8 (((aminocarbonyl)oxycomethyl)
-4,8a-dimethoxy-1,Ia, 2,6,8゜8a
, 8b-hebutahydro-5-methyl-6-[(methylsulfinyl)imino]-azilino (2', 3':
3,4) Pyrrolo(C2-a) indol-7-one [1aS-(Iaα+8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyll-4,8
a-dimethoxy-Lla, 2,6,8°8a,8b-hebutahydro-5-methyl-6-[(phenylsulfinyl)imino]-azilino (2', 3': 3,4)
Pyrrolo(I,2-a)indol-7-one (IaS (laα, 3β, 8aα, 8bα)) −
8-([(aminocarbonyl)oxycomethyl)-6
-((n-butylthio)imino) -1,Ia,2,6
,8.8a,8b-heptahyto0-8a-methoxy5-
Methyl-4C(p-toluenesulfonyl)oxy]azilinoC2',3':3.4)pyrrolo(I,2-a)
Indol-7-one (IaS-(laα, 8α, 8aα, 8bα)) -4
-acetyloxy-8([(aminocarbonyl)oxycomethyl1-6=[(n-butylthio)imino)-L5-
Dimethyl~1. Ia, 2,6,8.8a8b-heptahydro-8a-hydroxy-azilino (2', 3':
3.4] Pyrrolo(I,2-a)indol-7-one [
1aS -(lacx, 8β, 8aα, 8bα)]-]
1-acetyl-4-acetyloxy8-(((aminocarbonyl)oxycomethyl) -1,1a,2,6.8
．． 8a,8b-heptahyto o-8B-methoxy5-methyl-6-[(phenylthio)imino]-azilinoC2'
, 3': 3,4) pyrrolo (L2-a) indol-7-one (IaS-(Iaα, 8β, 8aα, 8bα
)) -8-(((aminocarbonyl)oxy]methyl) Lla, 2.6,8,8a,8b-heptahydro-4-hydroxy-88-methoxy-5-methyl-6[
(phenylthio)imino]-azilinoC2',3'
: 3,4) Pyrrolo(I,2-a) indol-7-one (], aS-(Iaα, 8β, 8aα, 8bα))
-8-(((aminocarbonyl)oxycomethyl)
1+1a, 2+6.8.8a, 8b-hebutahydro-4
-Hydroxy-8a-methoxy-5-methyl-6[(methylthio)imino]-azilino[2', 3': 3
．． 4) Pyrrolo(I,2-a)indol-7-one(I
aS-(laα, 8β, 8aα, 8bα)) -8-(
((aminocarbonyl)oxycomethyl)-6-((ethylthio)imino)Lla, 2,6,8,8a,8b-
heptahydro-4-hydroxy-8a methoxy-5-methyl-azilinoC2',3': 3,4)pyrrolo(
I,2-a) Indol-7-one (IaS-(Iaα
, 8β, 8aα, 8bα)) -8-(((aminocarbonyl)oxycomethyll-6-((n-butylthio)
imino) Lla, 2.6+8+8a, 8b-hebutahydro-4-hydroxy 8a-methoxy-5-methyl-azilino (2', 3': 3,4) pyrrolo (L2-
a) Indol-7-one (laS (Iaα+8β
, 8aα, 8bα)) -8-(((aminocarbonyl)oxycomethyl) Lla, 2.6.8.8a, 8
h-heptahydro-4-hydroxy-6-((2″-hydroxyethylthio)imino)-8a-methoxy5-
Methyl-azilino (2', 3': 3.4) pyrrolo CL2-a) indol-7-one CIaS -(Ia
α, 8β, 8act, 8ba)]-8-(C(aminocarbonyl)oxycomethyll-6-((4〃-aminophenylthio)imino)-Lla, 2,6,8.8a,
8b-heptahydro-4hydroxy-8a-methoxy-
5-methyl-azilino [2'.

3': 3,4) pyrrolo[L2-a) indole-7
-on (IaS-(laα, 8β18aα, 8bα)]
-8-([(aminocarbonyl)oxycomethyl)
Lla, 2,6,8,8a,8b-heptahydro-4-
Hydroxy-8a-methoxy-5-methyl-6((2″
-pyridylthio)imino]-azilino(2', 3'
:3.4] pyrrolo(I,2-a)indol-7-one (IaS-(laα, 8α, 8aα, 8bα))
8 (((aminocarbonyl)oxycomethyll
-6-((n-butylthio)imino) -4,8a-dihydroxy-1,5-dimethyl-1,la,2,6,8
8a, 8b-hebutahydroazilino (2', 3'
: 3.4) Pyrrolo(I,2-a) indol-7-one [1aS-(Iacx, 8β, 8aα, 8bα))
8(((aminocarbonyl)oxycomethyl l-6-(
(n-butylsulfinyl)imino) 1.1a, 2
．． 6.8.8a,8b-hebutahydro-4-hydroxy-8a-methoxy-5-methyl-azilino(2',3
:3.4]pyrrolo(I,2-a)indole-7-
On (IaS-(Iaα, 8β, 8aα, 8bα))
8- [((aminocarbonyl)oxycomethyl)
-4,8a-dimethoxy-1,1a, 2.6.8°8a
, 8b-hebutahydro-6-[(methoxy)imino]-
5-methyl-azilinoC2',3':3,4]pyrrolo(L2-a)indol-7-one (IaS (laα, 8β, 8aα, 8bα)) -
8-(((aminocarbonyl)oxy)methyl l -6
-((isobutyloxy)imino) -4,8a-dimethoxy-Lla, 2,6.8.8a,8b-heptahydro-5-methyl-azilino (2', 3':3,4)
Pyrrolo(I,2-a]indol-7-one (IaS-(laα, 8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyl l-4, fusihydroxy-1.Ia, 2,8°8a, 8b-hexahydro-8-methoxy-5-methyl-6 nitrosoazilino[2',3':3 , 4) Pyrrolo (I, 2-a
) indole (IaS-(laα, 8β, 8aα, 8bα)) -8
-(((aminocarbonyl)oxycomethyl)-4,8
a-dimethoxy-1,Ia, 2,8°8a,8b-hexahydro-7-hydroxy-5-methyl-6 nitrosoazilino(2',3':3,4)pyrrolo(L2-a
ll indole (IaS (laα, 8β, 8aα, 8bα): l
1-acetyl-4-acetyloxy-8-(((aminocarbonyl)oxycomethyl)-Lla, 2,8,
8a,8b-hexahydro-7-hydroxy5-methyl-6-nidrosoazilinoC2',3':3.4'
) Pyrrolo(I,2-a)indole Table 3 Table R4 shows 11 for compounds No. 21 and 30, and C113 for the others.

R5 is C0NHz (α
), and the others indicate C0N11□(β).

In the table, Me+Et+Pr+Bu+Ac and Ts are methyl, ethyl, propyl, butyl, acetyl and 1 to 1, respectively.
means luenesulponyl.

Compound (I) exhibits excellent antitumor activity. The pharmacological effects of representative compound (I) are shown below in experimental examples.

Experimental Example 1 Table 4 shows the effects of representative compound (I) on HeLa S3 cultured cells. In the table, ■C5° is the concentration of the test compound that gives 50% of the cell number when no drug is administered.

Table 4 Anti-11eLa S, cultured cell effect The test method is as follows.

Cultured 11eLa S3 cells were prepared in a MEM medium containing 10% (v/v) fetal bovine serum and 292 μ/mβ glutamine to prepare a suspension cell solution of 3×10′ cells/mβ. 24
1 ml each was dispensed into a multi-well plate and cultured at 37°C in a carbon dioxide incubator (5% carbon dioxide, 95% air).

After 24 hours, drugs dissolved or suspended in PBS or ethanol or dimethyl sulfoxide were added at various concentrations. After addition, in a 37°C carbon dioxide incubator (5% carbon dioxide, 9
5% air) for 72 hours. The culture solution in each well was removed by suction using an aspirator, 1 ml of PBS was added, and the cell surface was gently washed and removed by suction. The number of cells in each cell suspension was counted using a microcell counter (manufactured by Toa Medical Electronics Co., Ltd.), which was pipetted into PB containing 0.05% tryptocin and 0.02% EDT by pipetting 1 mj2 into each well. 5 compared to the number of cells in the non-drug control.
The concentration indicating 0% cell number (IC5o) was determined from the concentration dependence curve.

Experimental Example 2 Table 5 shows the effects of representative compound (I) on Sarcoma 180 solid tumor. In the table, C,1, means chemotherapy coefficient, and C,1,=LDso/EDs. However, for comparison with mitomycin C, the value obtained by dividing C,1 of the test compound by C,l of mitomycin C is shown here. Here, LII5o is an elephant, and the sexual toxicity value is also ED5.
o indicates the dose that reduces the Sarcoma 180 solid tumor volume to 50% of the tumor volume of the non-administered control group. WBC in table
4ooo/[1Dso value is the dose and IED that give a peripheral white blood cell count of 4000. It shows the ratio of WBC4oo of the test compound and represents the effect on peripheral leukocytes, but here for comparison with mitomycin C, the test compound WBC4oo.

/EDso to mitomycin C WBC4ooo/H
Shows the value divided by Dso.

Table 5 Effect of LDs on Sarcoma 180 solid tumor
The values of o, EDso, and WBC<ooa were determined by the methods described below.

(l) LDs.

The drug was intraperitoneally administered once to ddy mice, and the survival and death of 5 mice per group was observed for 14 days after administration, and the LDSO was calculated from the mortality rate of each administration group according to the Berens-Kerber method.

(211E　D　s.

5 x 106 Sarcoma 180Rd cells were intraperitoneally transplanted into ddy mice, cells were collected from ascites on the 7th day, washed with Il'ffl with sterile physiological saline, and suspended at 5 x 107 cells/mβ in sterile physiological saline. A liquid was prepared. This 0.
1 m6 was subcutaneously transplanted into the right lung fossa of a ddy male mouse weighing 20±2 g. The drug is physiological saline or Tween 8
24 hours after tumor implantation.
0.1 to 0.2 mg was administered through the tail vein of 5 mice in a group. Seven days after transplantation, the major axis (a) and minor axis (b) of the tumor were measured, and the value of axb2/2, which corresponds to the tumor volume, was determined.

The antitumor effect was evaluated by the ratio (T/C) of the volume (T) of the drug-administered group to the volume (C) of the control group to which no drug was administered. Plot the T/C at each dose on a graph with the normal scale on the vertical axis and the dose on the logarithmic scale on the horizontal axis, and plot the relationship between the dose and T/Cq as a straight line using the least squares method. Ta.

From the obtained linear regression equation, the dose (IEDS) at which T/C was 0.5 was calculated.

f31 WBCtoo.

5×10 6 Sarcoma 180 cells were subcutaneously transplanted into the right lung fossa of dd, yIJi mice weighing 20±2 g, 5 mice per group, and the drug was intraperitoneally administered 24 hours later. On the 4th day after drug administration, blood was collected at 0.0% from the Ul fossa venous plexus of tumor-bearing mice.
02n+I! Collected, 9.98n+j! It was dispersed in Cell Kit Seven solution. After adding one drop of Zabonin solution to dissolve red blood cells, the number of white blood cells was measured using a microcell counter. The peripheral white blood cell count was plotted on a normal scale on the vertical axis, and the dose was plotted on a logarithmic scale on the horizontal axis to determine the relationship between the dose and the peripheral white blood cell count. V2)
C4ooo) was calculated.

As mentioned above, compound (I) generally has excellent antitumor activity. Some of the compounds (+) have higher C,1 values than mitomycin C, and this term means that the possible dose range is wider than mitomycin C. Also, some compounds (I) are (Kanooo/IEDs).

ED, which has a value greater than mitomycin C and is equivalent to this term. This means that the bone marrow toxicity at administration i1, which gives mitomycin C, is reduced compared to mitomycin C.

Therefore, compound (I) can be used as an antitumor agent containing it, particularly as an antitumor agent containing an effective amount of compound (I) and a pharmaceutical adjuvant. The pharmaceutical auxiliaries herein include commonly used diluents, excipients, disintegrants, binders, lubricants, bases, and the like.

Compound (I) can be used in various dosage forms.

When used as an injection, a diluent commonly used in this field, such as ethanol, and a compound <r)
After dissolving (combining a surfactant and a solubilizer if necessary), add distilled water for injection with or without removing the ethanol by suction;
Physiological saline; prepared by mixing glucose, flux, mannitol, etc. with a solution of distilled water for injection.

In addition, injections and compounds (I
) and sodium chloride may be used as a powder injection, which is dissolved before use. These injections are administered, for example, intravenously, but intramuscular, intraarterial, intraperitoneal, and intrathoracic administration are also possible.

Preparations for oral administration are produced by mixing and molding compound (I) and appropriate excipients, disintegrants, binders, lubricants, etc. in a conventional manner to form tablets, granules, or powders.

A suppository preparation is prepared by mixing and molding compound (I) and a commonly used carrier by a conventional method.

The dosage varies depending on the administration method, type of compound (T), age, symptoms, etc., but in general, for mammals including humans,
2-150 mg/6 as compound (+) per day
0 kgMitj this teal.

Examples Examples and reference examples of the present invention are shown below. Furthermore, Mass
The spectrum is FAB (Fast Atom Bomb
ardment) method.

In the examples below, the compounds Nal~35 of Table 2.3
These correspond to Example Teeth 1 to 35, respectively, and Compound No.
a % h correspond to Reference Example Nos. 1 to 8, respectively.

Example I Compound b, 104ml! 0.5ml of methanol! Add 124m+r of diphenyl disulfide and stir at room temperature for 5 minutes. Tri-n-butylphosphine 11
8 μβ was added, and the mixture was further stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel chromatography using chloroform-methanol (9:1; v/
ν) as a developing solvent to obtain 1108rn of Compound 1 (yield: 86.0%).

'II NMR (CDCj! 3) δ; 2.28 (
31-1, s), 2.83 (lit, m).

2.96 (III, m), 3.25 (3H, s),
3.54 (III, d), 3.75 (311, s),
4.17(III, d), 4.6011+, tL
4.83 (2H, br).

4.93 (I1Ldd), 7.27 (LH, m),
7.44 (2H, m), 7.70 (2H, m) C13NMR (CDC(I3)δ, 11.1.32.4
．． 37.5.43.8゜49.5.49.6.60.3
．． 62.5.106.6.109.4゜124.6.1
27.3.128.9.130.9.143.8.14
4.8°149.9. 156.8. 157.2.
170.8IR(KBr)cm"'; 3194.2
932. 1707. 1614. 1585°142
9.1388,133L 1217,1067Mas
s 457 (CZ21124N405S molecule l 45
6.52) Molecule example 2 Compound b, 130■, dimethyl disulfide 70μl,
and tri-n-butylphosphine 0.20m7! The same method as in Example 1 was repeated except that compound 2.110 was used.
(2) is obtained (yield 78.2%).

'HNMR (CDCj! 3) δ; 2.12 (3H,s
), 2.81 (311, s).

2.83 (Ill, m), 2.95 (III, m),
3.23(3)1. s), 3.69 (IH, dd)
, 3.7H311,s), 3.52(IH,d),
C1,4(3H,s).

4.53 (IB, t), 4.88 (II, dd),
4.93(21+,br)IR(KBr)crn-'
:3462.2924.1734.1610.157B
.

1456, 1386.1331.1217.117L
1054Mass 395 (C+ 711zzNtO
ss molecule it 394.46) Example 3 Compound S, 200mg, diethyl disulfide 140μ
Compound 3.170 was prepared by repeating the same method as in Example 1, except using 295 μβ of tri-n-butylphosphine,
mg (yield 75.8%).

'It-NMR (CDCff,) δ; 1.44 (31
1,t), 2.13 (31Ls).

2.82 (Ill, m), 2.95 (IH, m),
3.04 (21+, q), 3.23 (3+1.s),
3.51 (Ill, dL 3.68 (LH, dd),
3.71 (3H, s).

4.13 (ill, cl), 4.54 (I1Lt),
4.88 (I1Ldd), 5.05 (211,br
) IR(KBr)cm-';34B0.2928.17
]4.1612.1580°1524, 1475.14
49.1384.1330.1216.1066Mas
s 409 (C18H24N40., S molecular weight 408
．． 48) Example 4 Compound b, 50 mg, di-n-butyl disulfide 10
4μ! and tri-n-butylphosphine +-35μ! The same method as in Example 1 was repeated except that compound 4.4 was used.
3 mg is obtained (yield 70.7%).

'II-NMR (CDCj2.) δ; 0.95 (311
,t), 1.48(21LmL1.79(21Lm)
, 2.12 (311, s), 2.82 (LH, m)
, 2.95 (III, d), 3.05 (2B, t)
, 3.22 (311, s), 3.51 (IH, d)
.

3.68 (IILddL 3.7H311,s), 4
．． 13 (In, d), 4.50 (], tLL), 4
．． 89 (ill, dd), 5.07 (211, br)
IR(KBr)cm-';3290.2958.17
15.1614.1583゜1452.1386,13
33,1219. 1068Mass 437 (C2
011211N405S Molecule i 436.53) Example 5 Compound b, 0.80 g, diisoprobyl disulfite river, 05 mA, and tri-n-butylphosphine 2.04
The same method as in Example 1 was repeated except that m# was used to obtain 5.0.18 g of the compound (yield: 19.4%).

'II NMR (CDCI! 3) δ; 1.40 (
611, d), 2.15 (3H, s).

2.80 (LH, dd), 2.93 (LH, d),
3.23 (3H, s), 3.30 (III, q),
3.52 (III, dd), 3.69 (I1Ldd)
, 3.71 (311, s), 4.14 (III, d
), 4.55 (III, dd), 4.76 (21L
brL 4.90 (Ill, dd) IR (KBr) cm
-';3400.2950.1705.1610.1
460°1332, 1220.1065 Mass 423 (C+ Jh6N40sS molecule ff
l 422.50) Example 6 Compound b, 100 mg, 2-hydroxyethyl disulfide 90 μ and tos=n-butylphosphine 0.31
mj! The same method as in Example 1 was repeated except that 6.60 mg of the compound was obtained (yield 51.6%).

'H-NMR (CDC7!3) δ; 2.10 (31L
sL 2.84 (Ill, m).

2.96 (Ill, river) + 3.2N21+, t),
3.23 (311, s), 3.53 (IH, d),
3.68 (Ill, ddL 3.72 (31LsL 4
．． 09 (211, t).

4.14 (I1, d), 4.51 (IH, t), 4
．． 86 (III, dd), 4.98 (21 Lbr) IR (KBr) cm-'; 3266, 2928.17
14.1613.1578°1452, 1385.13
31.1218.1065Mass 425 (C10
H24N406S molecular weight 424.48) Example 7 Compound ib, 135 mg, 2-nitrophenyl disulfide 171■ and tri-n-butylphosphine 152μβ
The same method as in Example 1 was repeated except that compound 7.
100 ml was obtained (yield 53.7%).

'+1-NMR(CDCβ3)δ; 2.27(311
, s), 2.89 (LH, m).

2.99 (III, m), 3.26 (311, s),
3.57 (ill, d), 3.76 (LH, dd)
, 3.78 (3H, s), 4.17 (Ill, d)
, 4.57 (I11, tL4.88 (IILdd),
4.98 (211, br), 7.40 (I/It,
t), 7.73 (III, t), 8.26 (Il
l, d), 8.54 (IH, d) IR (KBr) c
m-' 13452. 2949. 1713. 16
14. 1593°1522, 1472. 1385
．． 1335. 1218. 1067Mass 50
2 (CzzllzJs07S molecule ffl 501. molecule ff group example 8 compound
The same method as in Example 1 was repeated except that compound 8.
70■ was obtained (yield 49.0%).

'11 NMR (CDC7!3) δ; 2.24 (3
11,s), 2.83 (IILm).

2.95 (III, m), 3.25 (311, s),
3.54 (III, d), 3.73 (3H, s),
4.17 (Ill, dL 4.58 (III, t),
4.80 (211, br).

4.95 (IH, dd), 6.74 (2+1.d),
7.47(2+1.d)IR(KBr)cm-';
3340.2924. ]715.1596.1472
゜1447, 13B5.1329.1216.11.7
5.1066Mass 472 (CzzHzsNsO
sS molecule t 471.54 molecules Decoration Example 9 Repeat the same method as Example 1 except using compound b, 0.67 g, 2.2'-dipyridyl disulfide 1.01 g, and hexamethylbosporastramide river, 18n+2 Compound 9.0.66 g is obtained (yield 78.4%)
).

'II-NMI? (CDCII,) δ; 2.2
9 (311, s), 2.85 (I1Ldd).

2.99 (IILd), 3.25 (31LsL 3.
55 (III, d), 3.71 (III, dd),
3.76 (31Ls), 4.16 (III, dL 4
．． 56 (Ill, ddL4.87 (III, dd),
4.95 (21Lbr), 7.14 (III, m),
7.75 (I, lLm), 8.01 (II (, dL
8.52 (Ili, d) IR (KBr) cm-';
3400. 1705. 1610. 1450. 1
390°1340, 1215.1140.107010
7O458 (C21112:1N50!, S molecular weight 45
7.50) Example 10 Compound b, 273■, 6,6'-cythiocinicotinic acid.
Example 1 except that 765 mg of 2-tritactic tylamine salt was used.
After reacting in the same manner as above, the compound was separated and purified by silica gel chromatography using chloroporum-methanol-triethylamine (90:10:I v/v) as a developing solution to obtain 272 ml of triethylamine salt of compound 10 (yield: 60 .1%).

'II-NMR (CDC11!3) δ: 1.27 (
911, t), 2.30 (311, s).

2.85 (III, ddL2.96 (Iff, dL3.
04 (61Lq), 3.25 (311,s), 3.
55(I)1. dd), 3.71 (I1Ldd),
3.76 (311,s), 4.17 (I1Ld
), 4.57(l)+, dd), 4.86(I
H, dd), 4.99 (2tLbr), 8.0
0 (III, d), 8.36 (IH, dd), 9.
14 (IH, dd) IR (KRr) cm-'; 342
0. 2936. 2676, 1707. 1586
゜1480.1456, 1385.1070 Example 11 Compound b, 0.75 g, 2.56 g of 2,2'-dithiobis(5-nitropyridine) and hexamethylphosphorustriamit''], 08 m7! Repeat the same method as in Example 1 to obtain 11.92 mg of the compound (
yield 8.8%).

'HNMR (d6-DMSO) δ; 2.26 (311
,s), 2.81(I1LmL2.87(III, m
), 3.19 (3tl, s), 3.46 (Ill,
dd), 3.57 (I11, d), 3.77 (3
1Ls), 3.94(III, dL 4.+1(I
ILtL4.69 (IH, dd), 6.56 (211
,br), 8.25(III, dL 8.70(ll
LddL 9.32 (III, d) IR (kBr) cm
-';31150.2924.1717.1616.
1587°1567, 1,174.1385.1340
．． +217.1,143.1098゜Mass 50
3 (C2+IIzzNbOtS molecule i 502.50
) Example 2 Compound b, 0.90 g, bis-(diethylthiocarbamyl)-disulfide 2.20 g and hydry-n-butylbosphine 2.29 md were used in the same manner as in Example]. Repeat compound 12.0.12 g are obtained (yield 9
．． 8%).

'It NMR (CDCII:+)δ; 1.3
6 (611,br), 2.41 (31Ls).

2.85 (IH, br), 2.96 (III, d),
3.23 (3tl, s), 3.55 (III, dd
), 3.67 (I11, dd), 3.75 (311
,s>, 3.86-3.90(411,br), 4
．． 18 (I1Ld), 4.54 (I1Ldd), 4
．． 78 (211, br), 4.84 (III, dd)
IR(KBr)cm= ; 3420.2920.17
10.1614.14B0゜1.155.1336.1
,270.120Ei, 1065Mass 496
(Cz+tlzJ, 0sSz molecule 1495.61)
Example 13 Compound b, 500■, diphenyldiselenide 1,07
g and hexamethylbosphorastriamide 0.62+
nj! The same method as in Example 1 was repeated except that compound 13.178 was obtained (yield: 35.4%).

'11 NMR (CDCII 3) δ; 2.3
0 (3H, s), 2.85 (IH, m).

2.98 (II (, m), 3.26 (3H, s),
3.54(II(,d), 3.76(IH,d)
d), 3.76 (3H, s), 4.18 (IH
, d), 4.57 (IH, t).

4.85(2)1. br), 4.93C1,H,d
d>, 1.28(lH, m>, 7.42(2H
, m), 7.79 (2H, m) IR (KBr) cm
-';3450.2930. 1715. 1614
．． 1580°145L 1384, 1330, 121
7.1065Mass 504 (CzzHzaNtO
5Se molecule ffi 503.42) Example 14 Compound S, 275 mg, di-n-butyl diselenide 5
62■ and hexamethylphosphorustriamide 256μ
Compound 1 was obtained by repeating the same method as in Example I except using β.
4.98 .mu. is obtained (yield 26.7%).

'HNMR (da-DMSO) δ; 0.92 (3H, t
), 1. ．． 43 (2H, m).

1.82 (2H, m), 2.10 (3H, s), 2
．． 76 (IH, m), 2.85 (It (, mL) 3.
01<2H,t), 3.16(3tl,s>, 3.
45 (I, 1Ldd).

3.70 (3H, s), 3.88 (LH, d), 4
．． 09 (I!l, t), 4.70 (Itl, dd),
6.53(2H,br)IR(KBr)cm-';
3418. 2928. 1715. 1614. 1
583°145L 1384. 1333. 121
7. 1066 gate ass 484 (CzoH2aN4
0sSe molecular weight 483.43) Example 15 Compound b, 0.45 g, 2,2'-diselenodipyridine 3.87 g and hexamethylphosphorustriamide 1.
The same method as in Example 1 was repeated except that 34 mn was used to obtain compound 15.181 (yield: 29.2%).

'H-NMR (d6-DMSO) δ; 2.28
(3H, s), 2.80 (LH, m).

2.89 (ItLm), 3.19 (3H,s), 3
．． 51 (IH, dd), 3.76 (3H, s), 3
．． 95 (IH, d), 4.11 (IH, t), 4.
73 (IH, dd).

6.56 (2H, br), 7.27 (LH, m),
7.90 (LH, m), 8.09 (LH, d), 8
．． 53 (III, d) JR (KBr) cm-'; 34
30.2924.1716.1616.1481144
7, 1417.1384.1330.1217.111
6.1066Mass 505 (Cz+1lzJsO
sSe molecular weight 504. ．． 11) Example 16 Compound 9.219■ was dissolved in 17ml of chloroform, 123■ of metachloroperbenzoic acid was added under water cooling, and the solution was dissolved at the same temperature.
After stirring for 0 minutes, 53 cm of calcium hydroxide was added, stirred at room temperature for 30 minutes, and filtered. After concentrating the filtrate under reduced pressure, it was separated and purified by silica gel column chromatography (developing solution: chloroform-methanol 9:1 v/v) to obtain compound 16.110 mg (yield: 48.4%).
). This is obtained as a mixture of optical isomers of sulfoxide from the following NMR.

' It NMR (CDCj23) δ; 2.20.
2.21 (3+1. Both sL2.88 (Ill, br
L 2.96 (01, br), 3.15, 3.20 (
311° both s), 3.55 (ill, m), 3.
78 (III, m), 3.81, 3.82 (3H, both s), 4.11. ．． 4.1.4 (IH, both d),
4.41, 4.40 (Ill, both dd), 4.5
3, 4.63 (Ill, both cld).

4.93, 4.97 (211, both brL 7.31 (
IH, m), 7.80 (2H, m).

8.55, 8.56 (Ill, both d) IR (KBr)
cm-';3410.1715.1610.1530
．． 1486°1452, 1332.1220.1066
Mass 474 (Cz + Hz: +Na (I6s molecular weight 473.50) Example 17 4.120 mg of the compound was dissolved in 12 mj2 of chloroform, 51 + ng of metachloroperbenzoic acid was added, and the mixture was heated to 10 ml at room temperature.
After stirring for 10 minutes, add 40 mg of calcium hydroxide.
Stir for a minute and filter. After concentrating the filtrate under reduced pressure, it was separated and purified by silica gel column chromatography (developing solution: chloroform-methanol 9:1 ν/ν) to obtain compound 1.
7.100 mg is obtained (yield 82.0%). Note that this compound is obtained as a mixture of optical isomers of sulfoxide from the following NMR.

' II NMR (CDCj2 a) δ; 0.96
, 0.97 (311, both t).

1.51 (211, m), 1.99 (211, m),
2.15, 2.25 (311, both s) + 2.90 (
III, m), 2.94 (21Lm), 2.99 (
IH, m), 3.25 (311, s), 3.55,
3.58 (Ill, both dd), 3.62, 3.64
(I) 1° both dd), 3.80, 3.803+1.
Both s), 4.13.4.2011+.

Both d), 4.45, 4.54 (Ill, both t),
4.64, 4.79 (Ill.

Both dd), 4.88, 4.91 (2H, both br)
IR(KBr)cm-';3278.2926.17
17.1608.1477゜13B3.1330.10
61 106l 453 (C211H211N4065 molecular weight 452.53) Example 18 330 mg of compound The same method as in Example 17 was repeated except that 2.228 mg of metachloroperbenzoic acid was used to obtain 18.120 mg of compound (yield 34.8%) ).

Note that this compound is obtained as a mixture of optical isomers of sulfoxide from the following NMR.

'H-NMR (CD13) δ, 2.15, 2.16 (
3H, both s) + 2.82, 2.85 (31L both s)
, 2.90 (IH, m), 2.99, 3.00 (I
II, both d), 3.25 (311, s), 3
．． 55 (ItLm), 3.60 (IH, m), 3.
81, 3.82 (3H, both s), 4.14, 4.2
0(I, tl.

Both d), 4.4L4.47 (II (, both t),
4.64, 4.80 (III.

both dd), 5.06 (211, br) IR (KBr
)cm-';3380.1705.1602.148
3.1380°1329, 1217.1060 106O411 (C+JzzNaO6S molecular weight 410.
46) Example 19 Compound 1.430 mg, metachloroperbenzoic acid 256+
The same method as in Example 16 was repeated except that ng was used to obtain 19.220 mg of the compound (yield 49.5%).

Note that this compound is obtained as a mixture of optical isomers of sulfoxide from the following NMR.

'It-NMR (CDCf3) δ; 2.15, 2.16
(3+1. Both are s).

2.86 (ill, br), 2.94 (ill, br)
L 3.18, 3.25 (311° both s), 3.5
2 (I1Lm), 3.68 (LH, m), 3.7L
3.75 (both 31L are S), 4.09, 4.14 (I
II, both d), 4.45, 4.47 (I, IJ,
Both dd), 4.72 (Ill, m), 4.83 (
211, br), 7.41 (311, mL 8.02
(211,m)IR(KBr)cm-';3410.
2924.1703.1609.1483°1384,
13311219.1062Mass 473 (Cz
z11zJa06S molecular weight 472.51) Example 20 49 mg of compound f is suspended in 1 ml of methanol, 37 μβ of di-n-butyl disulfide is added, and the mixture is stirred at room temperature for 5 minutes. Tory n-butylbosphine 48μ! and further stirred at room temperature for 1 hour.

The solvent was distilled off under reduced pressure, and the resulting oil was purified by silica gel chromatography using chloroporum-methanol (25
: 1; v/v) as a developing solvent to obtain compound 20.27 mg (yield 49.1%).

'II-NMR(CDC12:+)δ; 0.93(
311,t), 1.44(21(,m).

1.76(2+1.m), 2.18(3)I,s)
, 2.49(31+,s), 2.79(If(
, m), 2.93 (III, d), 3.04 (
21Lt), 3.26 (31!, s).

3.47 (IH, d), 3.72 (IH, dd),
3.94 (Ill, d), 4.54 (III,
t), 4.7H2tl,br), 4.89(I
1, dd), 7.38 (2+1.d), 7.8
4(21Ld)IR(KBr)cm-'; 3280.
2968. 1716. 1618. 1453°1
388.1340, 1220, 1198.1183.1
070107O577 (CzJhzN40tSz molecule ii 576.58) Example 21 Compound e, 0.40 g, di-n-butyl disulfide 0.37 ml2 and l.so n-butylphosphine 0.
21.0.16 g of the compound was obtained by repeating the same method as in Example 1 except using 49 ml2 (yield 35.1χ)
.

'HNMR (CDC13) δ; 0.95 (311,t
L 1.47 (2H, m).

1.80 (21+, m), 2.00 (3H, s),
2.23 (3fl, s), 2.25 (III, dd)
, 2.30 (3H, s), 2.32 (IH, d),
3.07 (211,t).

3.40 (ltl, dd), 3.77 (IH, d),
3.79 (ltl, m), 4.71 (Ill, dd
), 4.76(211,br), 4.85(I,1
+, dd) IR (KBr) cm-'; 3440.2
928. 1770.1705. 1622°15B2
．． 1486. 14SL 1365. 1338.
11B1. 1054Mass 465 (C211
1211N4065 molecular weight 464. ! 54) Example 22 1500 mg of compound C was dissolved in 3 me of methanol,
Add 502+ ng of diphenyl disulfide and stir at room temperature for 1
Stir for a minute. I/IJ -n-butylphosphine 0.
Add 57 ml and stir for a further 20 minutes at room temperature. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel chromatography using chloroborum-methanol (30:
1 ; v/v) as a developing solvent, the compound 2 was separated and purified.
2.360 mg is obtained (yield 59.5%).

' H-NMR (CDCI!, 3) δ; 2.11 (3
11,s), 2.14 (3tLs).

2.39 (3+l, s), 3.19 (311, s),
3.28 (III, dd), 3.50 (IILd)
, 3.53 (III, d), 3.79 (IH, dd
), 4.04 (IILd).

4.1HI11. t), 4.86 (211, br),
5.11 (LH, dd), 7.30 (IH, t),
7.44 (2+1.t), 7.71 (2H, dd)
'3C-NMR (CDCf3)6; 11.8.
20.6.23.5.39.2゜42.2.44.0.
48.0.49.5.6L, 6.105.7.109.
4゜124.8.127.7.129. Sails 132.4.
135.6.143.4゜148.8. 154.9.
156.9.167.7.170.6.181.2IR
(KBr)cm-';3450.2924.1?71
．． 1699.1622°1449, 1374. 13
30. 1186. 1146. 1069Mass
527 (CzJIzJaOtS molecule i1526.5B
) Example 23 22.360 mg of compound was dissolved in 70 mff1 of methanol, and sodium methoxide (28% methanol solution)
After adding 1.05 g and stirring at room temperature for 4 hours, dry ice is added to quench the reaction. The solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel chromatography using chloroform-methanol (9:1; v/v) as a developing solvent, and further recrystallized from dimethylformamide-chloroform to obtain compound 23. 100
mg (yield 33.2%).

IH-NMl? (d6-DMSO) δ;2.1
7 (31i, s), 2.74 (I1Lm).

2.84 (LHlm) + 3.16 (311,s),
3.43 (ltl, dd), 4.06 (I)1. dL
4.67 (I1Ldd), 6.53 (2tl, br
), 7.28(LH,m), 7.46(21(,m
), 7.66 (2tl, m), 9.78 (III,
s)” CNMR (da-DMSO) 6:10.
8.3], 5.3G, 1°42.9. 49.0.
50.0. 60.8. 105.7. 107.7
゜117.9. 124.0. 126.8. 129
．． 0. 142.4. 143.9°150.1,15
6.7, 157.6, 169.6 II? (KBr)
cm-'; 3448. 3300. 1726.
1704. 1614°1566, 1487. 14
55. 1408. 1330. 1204. 106
2Mass 443 (C211122N40SS molecular weight 442.50) Example 24 Compound C12, 14g, dimethyl disulfide 0.67
A reddish-brown solid obtained by reacting 1.85 mj2 of mn and tri-n-butylphosphine in the same manner as in Example 22 was dissolved in 180 mA of methanol, and sodium methoxide (2
After adding 5.49 g of 8% Me01+ solution and stirring at room temperature for 3 hours, dry ice was added to quench the reaction.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (I2:1
; v/v) as a developing solvent and further recrystallized from methanol-chloroform to obtain 24.0.36 g of compound (yield 19.2%).

'II-NMR (d6-DMSO) δ; 2.01 (3
11,s), 2.68 (31Ls).

2.72 (III, m), 2.81 (LH, m),
3.13 (3H, s), 3.36 (III, d
d), 4.00 (IH, d), 4.09 (LH
,t), 4.63(lit, dd), 6.52
(21+,br), 9.65(III,5)IR(
KBr) cm-'; 346B, 1725.1699
．． 1615.1567°1484, 1408. 13
32. 1203. 1181. 1124. 106
1106l 381 (CI6112.N, O5S molecular weight 380.43) Example 25 Compound c, 450 mg, diethyl disulfide 0.24
A reddish-brown solid obtained by reacting 0.50 ml of tri-n-butylphosphine and 0.50 ml of tri-n-butylphosphine in the same manner as in Example 22 was dissolved in 50 mj2 of methanol, and sodium methoxide (28
After stirring 420 mg of %MeO (11 vol.) at room temperature for 3 hours, dry ice was added to quench the reaction.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (I2:1
;v/v) as a developing solvent and further recrystallized from dimethylformamide-chloroform to obtain compound 25.70 (yield: 17.1%).

'II-NMR(d6-DMSO)δ; 1.3
2 (31Lt), 2.02 (3H, s).

2.73 (Itlm), 2.8H1lI, m),
2.92 (21Lq), 3.13 (3tLs),
3.37 (III, dd), 4.00 (Ill
, d), 4.09 (III, t).

4.63(lILdd), 6.53(211,br
), 9.45(IILs)IR(KBr)c+n-
';3482,1721,1697,1615,15
69°1483, 1407. 1334. 1200
．． 1180. 1057Mass 395 (C, l
7H22N40. S molecular weight 394.46) Example 26 Compound C 11,00 g, di-n-butyl disulfide 0
．． 88'mI! , and tri-n-butylphosphine 0.
A reddish-brown solid obtained by reacting 95mff1 in the same manner as in Example 22 was dissolved in 100 nl of methanol, 2.15 g of sodium methoxide (28% Merit solution) was added, and the mixture was stirred at room temperature for 9 hours, then dry ice was added. to quench the reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography using chloroborum-methanol (9:1; v/v) as a developing solvent, and further recrystallized from dimethylformamide-chloroform to obtain compound 26. Obtain 190+ng (yield 1
9.5%).

'II NMR (d6-DMSO) δ; 0.91 (3
H,t), 1.42(2H,m).

7j+
--1.72 (2tl, m), 2.01 (
311,s), 2.72(ILm), 2.81
(IH, m), 2.94 (2H, t), 3.13 (3H
, s), 3.38 (III, dd).

4.00 (III, d), 4.09 (LH, t),
4.63 (III, dd), 6.52 (21L
br), 9.44(III,5)IR(KBr)c
m-'; 3470, 2952, 1713, 1699,
1615°1563.1486,1455,1405,
1332,1,178,1056Mass 423 (
C19H26N405S molecular weight 422.51) Example 2
7 Compound C10, 41g, 2-hydroxyethyl disulfide 244μ! and tri-n-butylbosphine 391
A yellow-brown solid obtained by reacting μρ in the same manner as in Example 22 was dissolved in 30 mff of methanol, 0.75 g of sodium methoxide (28% MeO 1 l solution) was added, and the mixture was stirred at room temperature for 6 hours, and then placed on dry ice. Quench the reaction by adding The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (6
: l ; v/v) as a developing solvent to obtain 27.50 mg of the compound (yield 12.9%)
.

'H=NMR(d6-DMSO)δ; 2.01
(31+, s), 2.72 (IH, m).

2.8H111,m), 3.02(31Lt),
3.13 (311, s), 3.73 (3H, t)
, 4.00 (Ill, d), 4.09 (ill
, t), 4.63 (I1Ldd).

6, 52 (21+, br) IR (KBr) cm-'; 3290.2918. 1
701. 1607.1568°1482, 1401
．． 1337. 1223. 1198. 1058M
ass 411 (CI7112ZN4055 molecular weight 4
10.46) Example 28 Compound C1450+ng, 4-aminophenyl disulfide 500+ng and tri-n-butylphosphine 0.
48ml! The dark purple solid obtained by reacting in the same manner as in Example 22 was dissolved in 65 ml of methanol, 400+ ng of sodium methoxide (28% methanol solution) was added, stirred at room temperature for 12 hours, and then dry ice was added. Quench the reaction. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (9:1; v/v) as a developing solvent to obtain compound 28.70.
．． 8%).

'+1-NMR(d6-DMSO)δ; 2.1
0 (31!, s), 2.73 (III, m).

2.82 (IH, m), 3.15 (31Ls), 3
．． 45 (LH, d), 4.02 (I8, d), 4
．． 08(I1(,t), 4.67(Ill, dd)
, 6.53 (2H, br), 6.65 (2H,
d), 7.28 (211, d) IR (KBr) cm
-';3340. 1715. 1695. 159
8. 1483°1414.1331,1290,12
02.1176.1059Mass 458 (Cz+
1IzJsOsS Molecular weight 457.51) Example 29 Compound C10, 50g, 2,2'-dipyridyl disulfide 0.76g and trilobylphosphine 0.
A reddish-brown solid obtained by reacting 99mff1 in the same manner as in Example 22 was dissolved in 10mj2 of methanol, 0.19 g of sodium methoxide (28% methanol solution) was added, and the mixture was stirred at room temperature for 23 hours, and then poured with dry ice. addition to quench the reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography using chloroform-methanol (9:1; ν/v) as a developing solvent to obtain compound 29.97■ (yield 19.0
%).

'II-NMR (d6-DMSO) δ; 2.20 (3
H, s), 2.76 (III, m).

2.85 (IH, d), 3.16 (311, s),
3.44 (Ill, dd), 4.06 (Ill, d)
, 4.12(ill,t), 4.67(I14,d
d), 6.52 (211, br), 7.25 (I
ILm), 7.9H11(,m), 8.00(
ill, d).

8.50 (ill, d) IR (KBr) cm-'; 3430.2920.17
04.1576, 1486°1447.1418,13
32,1214.1065Mass 444 (CZ0
1121N5053 molecular weight 443.48) Example 30 Compound 21187mg was added to methanol L5mj! Sodium methoxide (28% methanol solution) dissolved in 0.23
After stirring at room temperature for 15 minutes, dry ice was added to remove excess sodium methoxide. After concentrating the reaction solution, it is separated and purified by silica gel chromatography (developing solution: chloroform to methanol 9:1 v/v) to obtain 1 g of compound 30.126rr (yield 74.6%).

'ItNMR(CDCI23-CD30D)δ;0.9
2 (31Lt).

1.38~1.8H411,m), 2.20(3t
l, s), 2.21-2.26 (2t(, mL 2
．． 27 (311, sL 3.02 (21+, t), 3
．． 51 (ILdd).

3.70 (Ill, dd), 4.04 (I1Ld),
4.65(2)1. m) [CKBr) cm-';3
400.2954.1697.1609.1560゜1
486, 1451.1344.1209.1153.1
114.1063Mass 423 (CIQH26N
4055 molecular weight 422.51) Example 31 Compound 26.91 was mixed with chloroform-methanol 2:3
25 mj of v/v mixed solvent! After adding 59 mg of metachloroperbenzoic acid under water cooling and stirring at the same temperature for 15 minutes, 36 mg of calcium hydroxide was added, stirred at room temperature for 1.5 hours, and filtered. After concentrating the filtrate under reduced pressure, it is separated and purified by silica gel chromatography (developing solution: chloroform-methanol 20:Iv/v) to obtain 31.90 mg of the compound (yield: 95.5%). This compound is obtained as a mixture of optical isomers of sulfoxide from the following NMR.

'HNMR (CDCI!, 3) δ; 0.99 (3H, t
), 1.52 (2tl, m).

1.78 (2H, m), 2.06 (311, s),
2.90 (IH, m).

2.94, 2.99 (Ill, both d), 3.03 (
211, m), 3.2L3.22 (3H1 both s),
3.5NI11. d), 3.64, 3.65 (II
I, both dd).

4.15 (III, d), 4.53, 4.55 (I)
I, both t), 4.6B, 4.74 (I 11, both dd), 4.8B, 4.89 (2+1. both br)
IR(KBr)c+n-violet;3275.2956.17
17.1620.1574°MOS, 1325.
1212. 1060106O439 (C+ 9112
6N4063 molecular weight 438.51) Example 32.33 Compound g, 898 mg was dissolved in dimethylformamide 32.5
Botacium tert-butoxide 369 was dissolved in a mixed solvent of mj2 and tert-butanol 32.5 mff.
After adding +ng and stirring at room temperature for 10 minutes, dimethyl sulfate was added.
Add 0.28 mβ and stir at room temperature for 30 minutes. Add a small amount of dry ice to the reaction mixture to remove excess boxium.
After treating t-butoxide, the reaction solution is concentrated and extracted with chloroform-water. After drying and concentrating the chloroform extract, it is separated and purified by silica gel chromatography (developing solution: chloroborum-methanol 20:1 v/v) to obtain compound 32.33.300+ng (yield 32.1%).

In addition, these were determined by silica gel thin layer chromatography.
Indicates that it is a component. (Developing solution: chloroform-methanol 9:1. Rf=0.22.0.25) Therefore, it was separated by silica gel thin layer chromatography using the above-mentioned developing solution, and NMI? When we measured the NOE of
The methoxy group at the 6-position (methoxy)imino group is in the syn form with respect to the methyl group at the 5-position (Rf = 0.22 product, N0H = 8%) and the anti-form (Rf-0,
25 products; N0E=O%) were found.

These products are compound 32 (syn), compound 33
(anti), respectively 252mg and 52m
get g.

Compound 32 (syn)' II-NMR (CDCff 3) δ; 2.18 (
311, s), 2.81 (I8, br).

2.92 (IH, d), 3.22 (3H, s), 3
．． 49 (IH, dd), 3.6] (III, dd),
3.69 (311, s), 4.09 (IH, d),
4.20 (311, s).

4.53 (III, dd), 4.76 (211, br
), 4.82(ill, dd)IR(KBr)cm-
';3430.2938.1715.1623.15
41°1480, 1455.1331.1, 218.1
051105l 379 (CI?1122N401.
Molecular weight 378.38) Compound 33 (anti) 'HNMR (CDCj23) δ; 2.20 (31+,
s), 2.81(]H, dd).

2.93 (IH, d), 3.23 (31, s), 3
．． 48 (Ill, dd), 3.62 (LH, dd),
3.69 (3H, s), 4.00 (LH, d),
4.17 (3+1.s).

4.54 (III, dd), 4.73 (Hl, dd)
, 4.91(211,br)IR(KBr)c+c'
;3420.2938.1706.1616.154
9°1480, 1452. 1333. 1218.
1067Mass 379 (C+ 71122N4
06 Molecular weight 378.38) Example 34.35 Compound 700 mg, Botacium tert-butoxide 25B+ng and dimethyl sulfate 0.20+nI!
The same operation as in Example 32.33 was repeated except that 35.429 mg of compound 34 was obtained (yield 52.5%).
). Similar to Example 32.33, these were shown to be two components with Rf = 0.43 and 0.48 by silica gel thin layer chromatography (developing solution: chloroborum-methanol 6:1 ν/ν), and by preparative separation. 244 each
mg (Rf=0.43), 67+ng (Rf=0
．． 48) is obtained. By NMR, the product with Rf = 0.43 was identified as Compound 35 (anti), and the product with Rf = 0.48 was identified as Compound 34 (syn).

Compound 35 (anti)' II-NMR (CDCff 3) δ; 0.96
(611, d), 2.10 (ltl, m).

2.24 (311, s), 2.82 (Itl, br)
, 2.94 (IH, d), 3.23 (3H, s),
3.48 (I1Ld), 3.62 (III, dd)
, 3.69 (311, s).

4.00 (Ill, d), 4.19 (2+1.d),
4.50 (IH, dd), 4.72 (ltl, dd
), 5.12(211,br)TR(KBr)δ;
3420. 2932. 1717. 1615. 1
554°1452.1387,1335,1216,1
067.101910l9421 (C2oHzJ40
6 Molecular weight 420.46) Compound 34 (syn)' H-NMR (CDCI!, 3) δ; 0.69 (
6H, d), 2.02 (311, s).

2.09 (LH, m), 2.8H111, br),
2.92 (lit, d), 3.22 (3H, s
), 3.48 (Ill, d), 3.61 (IH
, dd), 3.69 (311, s).

4.08 (III, d), 4.17 (2+1.d)
, 4.49 (III, dd), 4.83 (Il
l, dd), 4.99 (2H, br) IR (KBr
) δ , 3420. 2932. 1.7]8. 16
14. 1550°1456.1388,1334,1
218.1044Mass 421 (C2oHzJ4
06 Molecular weight 420.46) Reference example 1 2.38 g of hydroxylamine hydrochloride was added to 10 mj2 of water.
2.18 g of anhydrous sodium carbonate while stirring
Slowly increase your strength. this? Add mitomycin A6 to the solution.
．． 00 g dissolved in 400 mff1 of methanol was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography using chloroform-methanol (9:1; v/v) as a developing solvent to obtain 5.21 g of compound a (yield: 86.
5%).

'If NMR (db-DMSO) 6 F 2.0
6(31(,s), 2.76(]1Ldd).

2.89 (LH, d), 3.16 (311, s), 3.
45 (I1LddL 3.53(I)1.dd),
4.09 (IH, clc+), 4.17 (I11, d
), 4.63 (III, dd), 6.55 (211
,br), 10.17(Ill,s), 19.17
(III, s) “C-NMI?(d6-DMSO)δ:9.5.31.
2.35.5.41.6゜49.3.49.6.60.
Sail 105.9.107.7.120.9.139.01
48.2. 156.5. 160.1. 169.0
IR(KIlr)cm-'; 3400.2940.
1705. 1590. 1480°133 (I, 12
10,1060 106O351 (C+5H+eN<06 Molecular weight 35
0.34) Reference Example 2 Compound a, 3.00g, dimethylformamide 50n+
Dissolve j2 and ter in 50me of t-butanol,
Add 0.86 g of rt-butoxy potassium and
Stir for a minute. Methyl iodide 0.69n+j! Add
The mixture is further stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, chloroform and water were added to the obtained oil, and the extracted chloroform layer was dried over anhydrous sodium sulfate, the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to extract chloroform- Methanol (I5:
I; v/v) as a developing solvent to obtain 1.32 g of compound b (yield 42.3%).

'HNMR (CDCj2 s) δ; 2.30 (3H,
s), 2.87 (I!Ldd).

2.98 (IH, d), 3.24 (311, s),
3.57(Ill, dd), 3.72(31(,sL
3.74 (lLddL 4.24 (I11, d),
4.51 (I8, dd), 4.84 (ill, dd)
, 19.01(IH,5)IR(KBr)cm-'
;3400.2930.1?15.1605.1480
゜1335, 1220.1065 Mass 365 (CI6H2ON406 Molecular weight 364.37) Reference example 3 N1-acetyl mitomycin A (Special Publication No. 40-181
(I) obtained in the same manner as in Reference Example 1 using 17) as a raw material
aS-(la α, 8β, 8aα, 8bcy)) −
1-acetyl-8~(((aminocarbonyl)oxycomethyl)=4,7-cyhydroxy-1.la, 2,8.
8a, 8b-hexahydro-88-methoxy-5-methyl-6-nidrosoazilino (2', 3': 3,4
) Pyrrolo (I,2-a: 1.03 g of l indole was dissolved in 110 mI of pyridine, and 0.3 mff of acetic anhydride was added.
1 and stirred at room temperature for 10 hours.

The solvent was distilled off under slight pressure, and the resulting oil was subjected to silica gel chromatography using chloroform-methanol (I5:
1; v/v) as a developing solvent to separate and purify compound C.
31,00 g are obtained (yield 87.6%).

' It NMR (CDCQ 3) δ; 2.14 (3
11,s), 2.32(3H,s).

2.40(3)1. s), 3.19(3)1. s),
3.30 (Ill, dd), 3.48 (I1Ldd
), 3.53 (III, dL 3.77 (Ill, d
), 4.01 (LH, dd).

4.09 (IH, d), 4.99 (III, dd),
15.80(01,5)IR(KBr)cm-';
3400.2950.1710.1620.14B0゜1340, 1210.11.90.1070107O4
35(C+, l1zzN40e molecule IH434,
40) Reference Example 4 By the same method as in Reference Example 1, compound dO, 88
g (yield 73.2%).

'HNMR (d6-DMSO) δ; 2.04 (3H,
s), 2.24 (311, s).

2.35 (ILdd), 2.49 (III, d),
3.63 (Ill, dd), 3.72 (IH,
dd), 4.08(LH,d), 4.15(i
ll, dd), 4.74 (IH, dd), 6.
38(21(,brL 6.62(ItLbr),
9.52 (I8,s), 19.34 (IH,5)
IR (KBr) cm-'; 3400. 2950.
1705. 1595. 1480°1345.122
0.1055 Mass 351 (C+stl+sN<06 Molecular weight 350.34) Reference example 5 Compound d, 1.25 g was added to 50 mj of pyridine! Add 0.42 ml of acetic anhydride while cooling with water and stir for 30 minutes. The solvent was distilled off under slight pressure, and the resulting oil was subjected to silica gel chromatography using chloroform-methanol (9:
1. ν/v) as a developing solvent to separate and purify the compound e,
Obtain 0.95 g (yield 68.7%).

'HNMR(CDC13-CD3-CD30D-d6-
Dδ; 2.21 (3tL s).

2.31(311,s), 2.34(II(,d),
2.36(3)1. s), 2.40 (I1, dd)
, 3.54 (IH, dd), 3.76 (LH, dd
), 3.87(I1(, dL 4.49(II,
dd), 4.86 (IH, ddon Reference Example 6 Compound a, 0.33 g was dissolved in tetrahydrofuran 40 mj2
Triethylamine 0.121if! was dissolved in water and cooled with water.
, and 0.15 g of p-1-luenesulfonic acid chloride are added, and the mixture is stirred at the same temperature for 30 minutes. The reaction solution was poured into saturated brine, and the tetrahydrofuran layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (30:
1. v/ν) as a developing solvent to separate and purify the compound f,
Obtain 0.11 g (yield 22.8%).

'It NMR (CDC42a) δ; 2. ], 7
(3H, s), 2.49 (3tl, s).

2.88 (Ill, ddL 2.98 (IH, d),
3.3], (311,s), 3.66(ill,dL
3.72 (IH, dd), 4.12 (III, d)
, 4.48 (III, dd), 4.70 (21Lb
r), 4.83 (III, dd), 7.40 (2t
l, d), 7.82 (2H, d), 18.43 (I
)1,5)IR(KBr)cm-';3460.29
30. 1715. 1620. 1460°1390
, 1335.1195.1180Mass 505 (
CzzHzJ40++S molecular weight 504. ．． 16) Reference Example 7 0.097 g of sodium methoxide was added to 3 mn of methanol.
0.154 g of methoxyamine hydrochloride in a suspension of
and stir at room temperature for 10 minutes. There methanol 9
ml and 0.30 g of mitomycin A were added, and the mixture was further stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography.
Separation and purification was carried out using methanol (I5: 1, v/v) as a developing solvent to obtain 0.17 g of compound g (yield: 54
．． 2%).

'HNMR(CDCj2:+)δ;1. ．． 40,1
．． Old (3H, both d).

2.84 (IH, m), 2.93 (Ift, m),
3.21, 3.24 (311, both sL3.45 (II
I, m), 3.73, 3.77 (III, both dd)
, 3.83, 4.24 (IH, both d), 4.09
(3H, s), 4.16 (III, m).

4.59, 4.65 (IH, both dd), 4.75.
4.79 (Ill, both dd).

4,89 (2H,br)'' C-NMR (CDCβ3)δ; 17.5+ 18.
1.32.4.32.6゜36.6.43.3.43.
9.44.0.49.1. ,49.2.49.9゜61
．． 8.62.2.63.6.105.7.105.8.
125.8.126.0゜152.2.152.7.1
52.9.154.3.156.7.156.8°17
6.4. 176.8. 190.7. 191.1T
R(KBr)cm-'; 3450. 2940. 1
705. 1640. 1565°1450.1340
,1070.1020102O365(C+6]1z
oN406 Molecular weight 364.37) Reference example 8 0.24 g of isobutyloxyamine hydrochloride was added to a solution of 0.30 g of mitomycin A dissolved in 30 mβ of methanol.
and then 0.50m of triethylamine! ! , and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (20:1; v/v) as a developing solvent to obtain 0.11 g of compound h (yield: 29. 6%).

'II-NMR (CDC13) δ; 1.01,1
．． 03 (611, both d).

1.45.1.49 (3 + 1. both d), 2.12 (
II(,m), 2.95(Itlm).

3.06 (LH, m), 3.30, 3.33 (3H,
Both s), 3.74 (Ill, m).

3.77.3.85 (I+1. both ad), 3.98
, 4.29 (LH, both d).

4.08 (ill, m), 4.12, 4.14 (21
1, both d), 4.70 (ItlmL4.80(lt
l, m) IR (KBr) cm-'; 3400.2950. 1
710. 1640.1570°1460, 1340
．． 1070. 1020102O407 (CI9H2
6N406 Molecular weight: 406.45) Reference Example 9 Injection 10 mg of the compound obtained in Example 35 is dispensed into a sterile brown vial to form a sterile powder preparation. Sterilize this for 50 minutes before use.
Add 5 ml of % ethanol water and stir thoroughly to dissolve and prepare an injection solution.

Reference example 10 tablet 20 mg of the compound of Example 9, 1.70 mg of lactose.

Tablets are prepared in a conventional manner using 20 mg of potato starch, 4 mg of hydroxypropyl cellulose, and 1 mg of magnesium stearate.

Reference Example 11 Suppository 20 mg of the compound of Example 13, Witepsol H-15
A suppository is prepared in a conventional manner using a blending ratio of 750 mg and 320 mg of Witepsol E-75.

Effects of the Invention Compound (I) has excellent antitumor activity and can be used as an active ingredient of an antitumor agent or as an intermediate for producing a compound having further useful antitumor activity.

Claims (1)

[Claims] General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. Cycloalkyl, ▲numerical formula, chemical formula, table, etc.▼ (in the formula, R', R'' are the same or different and are unsubstituted or substituted lower alkyl or lower cycloalkyl), unsubstituted or substituted aryl, and unsubstituted or Substituted pyridyl. R_2 is a hydrogen atom, lower alkyl, lower cycloalkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted alkanoyl, unsubstituted or substituted arylcarbonyl, substituted or substituted lower alkanesulfonyl, arylsulfonyl or aralkylsulfonyl. , R_3 is a hydrogen atom, methyl or acetyl, R_4 is a hydrogen atom or methyl, R_5
is a hydrogen atom or carbamoyl, ■ is an α bond or β
A mitomycin derivative represented by [representing a bond].