JPS62142179A - Production of mitomycin derivative - Google Patents

Abstract

PURPOSE:To obtain a mitomycin derivative having antimicrobial activity and antitumor activity by a short process, in improved operation efficiency and in high yield, by reacting a mitomycin compound with a compound such as N,N-dimethylformamidine, etc., in an inert solvent. CONSTITUTION:A compound shown by formula I (R1 and R2 are H or lower alkyl) such as N,N-dimethylformamidine, etc., is reacted with a compound shown by formula II (R3 and R4 are bonded to form =CH2 or R3 is H and R4 is -CH2 OCONH2; R5 is lower alkyl; Y and Z are H or CH3: broken line is alpha or beta-bond) in an inert solvent such as acetonitrile, etc., at -30-70 deg.C for several hours-several days to give the aimed compound shown by formula III such as 7-N-dimethylaminomethylenemitomycin C, etc., in >=80% yield. The compound shown by formula I is also used in the form of hydrohalide and the compound shown by formula I is liberated by adding a tertiary amine such as triethylamine, etc., to the reaction system.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing mitomycin derivatives having antibacterial and antitumor activities.

Conventional technology Although mitomycins have excellent antitumor activity, they also have side effects such as a decrease in white blood cells. Therefore, many derivatives have been synthesized with the aim of increasing activity or reducing toxicity. properties have been investigated.

Among these mitomycin derivatives, those in which the amino group at position 7 is modified include, for example, J, Med,
Chem, 24, 975 (1981), Jl.
Med, Chem.

26, 16 (1983), J. Med, Chem.
, 26, 1453 (1983).

JoMed, Chem, 27, 70H1984)
Examples of this have been reported. These documents also state that mitomycin derivatives modified at the 7-amino group exhibit antitumor activity in vivo.
Among the mitomycin derivatives in which the amino group at position is modified, examples of compounds included in the target compounds of the method of the present invention can be found in JP-A-59-1486. Among them, 7-(dimethylaminomethylene)amino-9a-methoxymitosan (hereinafter referred to as compound A) described in Example 8 of JP-A-Shochu is said to have particularly excellent antitumor activity.

In addition, 7-dimethylaminomethylene mitomycin D (
Compound B) is also included in the target compounds of the method of the present invention and has excellent antitumor activity.

According to JP-A-59-1486, the method for producing compound A is (
Example 1 + Example 8) Mitomycin C L I (x*iυ, 1%) (recovery 44.9%), in any case the yield from mitomycin C is about 2
It remained at 0%.

Further, the method for producing Compound B is Mitomycin D (Example 3) according to Japanese Patent Application No. 60-17532, and the yield was not satisfactory as in the case of Compound B.

Problems to be Solved by the Invention As is clear from the documents cited above, compounds A and B
From the viewpoint of reaction yield, these production methods are not satisfactory simply because they use expensive raw materials, and there has been a desire to develop a production method with even higher yields. At the same time, it is desirable that the production method allows for easier reaction and isolation. As a result of repeated research aimed at developing such a manufacturing method, compound Δ was developed.

For compounds including B, etc., we have found a method for producing them that is superior in operability and has much higher yields, and have completed the present invention.

Means for Solving the Problems The present invention provides compounds of the formula (I) (wherein R, , R, are the same or different and represent a hydrogen atom or a lower alkyl group). Compound represented by [hereinafter,
It is called compound (I). The same applies to compounds with other formula numbers] and formula (II) (wherein R3, R, and R are hydrogen atoms and R4 is CH20
Represents CONH2 or R8 and R4 together =
Represents CH2. R3 represents a lower alkyl group. Y and Z
are the same or different and represent a hydrogen atom or a methyl group.

AM4ma represents α- or β-bond. ) is reacted with a compound represented by the formula (I[
[) U (wherein R,, R2, R3, R4, Y and Z have the same meanings as above).

In the definition of R1 and R2 in formula (1), the lower alkyl group includes linear or branched alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, 1-propyl, and the like.

Compound (I) in the form of hydrohalides such as hydrochloride and hydrobromide, and organic acid salts such as picric acid, substituted benzenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. May be used. When using such salts, compounds (I> and (I
In the reaction system of I), triethylamine, pyridine, N, N
- A tertiary amine such as dimethylaniline or N,N-diisopropylethylamine must be present to liberate compound (I) and neutralize the liberated acid.

Methods for synthesizing compound (I) are known, for example (CH3
) JCH=NII ・HCI is Berichte,
16.1650. Ger.

1168896 (CI, C07c, d),
April, 30. 1964. Appl.

June 16.1962 etc., (C2hs)
2NCH=N)I.

(nBu) US P26 for 2NCH=NH
15023 PatentedOct, 21.1952
etc., and can be easily synthesized.

Regarding the definition of R3 in formula (n), lower alkyl groups include straight chain or branched alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, 1-propyl, and the like. Compound (II
) are known compounds, and Mitomycif A, B, F, J
, H, mitomycins having a methoxy group at the 7-position such as la-demethylmitomycin, and 2 carbon atoms at the 7-position.
Mitomycins CC having ~5 lower alkoxy groups
8 [1rakawa et al., J. Antibi.
otics, 33, 3Q4 (193Q)']. Among these, mitomycins having a methoxy group at the 7-position are more important from the viewpoint of ease of handling, and the structures of these compounds are shown below.

Mitomycin R, R, Y Z
A Ha to 19
Me HβB Ha
HMe aF Ha
Me Me βJ
Ha Me Me aH
CH2=HMe− K CH,=
Me Me -Kder C
H, = Me Ha
: CH20CONH21(der:la-
In addition to demethylmitomycin, these compounds are also described in the following literature:

Mitomycin Document A Merck Index 10th edition B Same as above F JP 55-45322 J Same as above H JP 55-118396 K Same as above Kder JP 55-7787 Compound (I
) is usually used in an amount of 1 to 10 equivalents based on compound (n).

The inert solvent used in this reaction is chloroform.

Dichloromethane, diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethyl sulfoxide, dimethyl formamide, etc., and these may be used alone or in combination.

The reaction is usually carried out at -30 to 70°C and is completed in several hours to several days. After completion of the reaction, compound (III) can be isolated and purified by usually distilling off the solvent and then subjecting it to column chromatography on silica gel, alumina, or the like.

According to the method of the present invention, compound (I) can be obtained from compound (II) in a yield of usually 80% or more.

The number of operations, simplicity, and yield of the reaction in the present invention are all superior to the process of obtaining compound A of JP-A-59-1486 and the process of obtaining compound B of JP-A-60-31074. Furthermore, since mitomycin D used as a raw material for compound B is a compound that has been chemically derived and supplied from mitomycin B, the ability of the present invention to obtain compound B directly from mitomycin B without going through mitomycin D is a significant step. This has great advantages in terms of shortening the process time and making it easier to obtain raw materials.

Next, examples of the present invention will be shown.

Example 1 Synthesis of 7-N-dimethylaminomethylene mitomycin C (compound Δ) N,N-dimethylformamidine monohydrochloride ((C)13) 28 in 2.5 ml of acetonitrile
C) l=Nll-HCI) 85+ng and 70.2 ml of triethylamine are added and stirred at room temperature. After 10 minutes, 34 mg of mitomycin A was added, and stirring was continued for 64 hours.

After distilling off the solvent under reduced pressure, ethyl acetate-methanol (
It is purified by silica gel chromatography using 95:5; V/V) as a developing solvent. A green fraction having the Rf value of TLC as described below was collected, cyclohexane was added thereto, and the solvent was removed under reduced pressure to obtain 49 7-N-dimethylaminomethylene mitomycin C as a green powder.

Yield 81%.

'H-NMR (CDCI!, ): δ 1.93 (3H,
s), 2.80(1)1. dd, J=4.4.2
．． 0), 2.90(1)1. d, J=4.4).

3.04 (3H, s), 3.08 (38, s),
3.22 (3H, s).

3.50(1)1. dd, J=12.7.2.0)
, 3.61 (IH, dd.

J = 10.5.4.4), 4.20 (IH, d, J
=12.7).

4.50 (IH, dd, J=lO, 7, 10, 5),
4.74 (2H,br,).

4.78 (18, dd, J=10.7.4.4),
7.69 (IH, 5) IR (KBr): 3310
．． 2940.171B, 1624.1540°130
6, 1059c+r' MS (m/z): 389 (M''), 357.3
46.328.313° High resolution MS: M"=389.
Calculated value for 1720 (C18) 123NSO5 = 3
89.1697) TLC (Merck 8rt 5714.CH
Cj! 3-MeOH.

9: IV/V): Rr=0.40 Example 2°? Synthesis of -N-dimethylaminomethylene mitomycin D (compound B) Acetonitrile 3 ml, ) Liethylamine 0.3 ml
l.

In the same manner as in Example 1, 82 mg of 1-N-dimethylaminomethylene mitomycin D as a green powder was obtained from mitomycin 890. Yield 82%.

'H-NMR (CDCj!J: δ 1.90 (3H,
s), 2.25 (5H, s), 3.03 (311,
s), 3.08 (311, s), 3.46 (lfl
, br, d, J=12.7), 3.71 (IH,
t, J=4.2).

4.08 (IH, d, J=12.7), 4.2
0C1tl, br, ), 4.70(2N, d
, J=4.2), 4.72(2)1. br, s
), ? , 70(1)1. s) I R (KB r )
:343G, 2930.17 (13,1621,1
535°1310 cm-' MS (m/z): 389 (M, 371.
346. 328. 310°295, 273.259 High resolution MS: M"=389.1694 (CIllH2
Calculated value for 3NIl = 389.1697 > TLC (Merck Art 5714. CHCj
2s-MeOH.

19 : I V / V ) : Rf = 0.17 Effects of the Invention According to the method of the present invention, compared to the conventional method,
It can be obtained in a shorter process and with much higher yields.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedures
Amendment Document January 29, 1985 1, Description of the case Patent Application No. 280723 of 1985 2, Name of the invention Process for producing mitomycin derivatives 3, Person making the amendment Relationship to the case Patent applicant postal code 100 Address Address: 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (102) Kyowa Hakko Kogyo Co., Ltd. (Location: 03-2)
01-7211 Extension 3391) Contents of the amendment (1) ``Unexamined Japanese Patent Publication No. 55-7787J'' in 5 lines from the bottom of page 9.
Corrected to JP-A-56-7787J.

Claims (1)

[Claims] A compound represented by the formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group.) and formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)
4 together represents =CH_2. R_5 represents a lower alkyl group. Y and Z are the same or different and represent a hydrogen atom or a methyl group. ■ represents an α-bond or a β-bond. ) in an inert solvent. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1, R_2, R_3, R_4, Y and Z has the same meaning as above).