JPS6237632B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel mitomycin derivatives. For more details, please refer to the general formula () [In the formula, R ₁ represents an alkoxy group, a substituted alkoxy group or a substituted carbamoyloxy group,
R ₂ is CH ₂ R ₃ (wherein R ₃ represents a hydrogen atom, a substituted alkyl group, an alkoxycarbonyl group, or an acyloxy group) or

[Formula] (wherein R ₄ represents a substituted amino group). However, R ₁ =
Except for the case where OCH ₃ , R ₂ =CH ₃ (Mitomycin F: JP-A-55-45322). ] and its salts. Mitomycins are generally known as compounds having antibacterial and antitumor properties. For example, Japanese Patent Publication No. 34-7597, Publication No. 35-17897, Publication No. 38 of the same
Publication No. -23097, USP3226393, JP-A-122797
No. 55-15408, No. 55-45322, Japanese Patent Application No. 54-26752, No. 54-28250, No. 54-
No. 80809, No. 54-107069, etc.) As a result of research on new mitomycin derivatives, the present inventors found that the general formula () The present invention was completed based on the discovery that a compound represented by the formula (wherein R ₁ and R ₂ have the same meanings as defined above) has excellent antibacterial activity. The present invention will be explained in detail below. In the compound represented by the general formula ()
In the definition of R ₁ , the alkoxy group represents an alkoxy group having 1 to 4 carbon atoms, including methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-
Examples include groups such as butoxy. Examples of substituents for substituted alkoxy groups include alkoxy groups and alkylthio groups, and specific examples include groups such as methoxymethyloxy, methylthiomethyloxy, and methoxyethoxymethyloxy. Examples of the group include alkyl groups, and specific examples include groups such as dimethylcarbamoyloxy, methylethylcarbamoyloxy, and diethylcarbamoyloxy. In the definition of R ₃ , substituents for the substituted alkyl group include hydroxy group and halogenoalkyl group, and specific examples include hydroxyethyl, hydroxypropyl, chloromethyl, bromomethyl, iodomethyl, chloroethyl, bromoethyl, iodoethyl, and formylethyl. Examples of the alkoxycarbonyl group include groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl,
Examples of the acyloxy group include groups such as pivaloyloxy. In the definition of R ₄ , an alkyl group can be mentioned as a substituent of the substituted amino group, and specific examples include groups such as methylamino, ethylamino, dimethylamino, and diethylamino. Examples of the salts include alkali metal salts such as sodium salts and potassium salts. Next, the method for producing the compound of the present invention will be shown in a process diagram. (In the formula, R ₁ , R ₃ and R ₄ have the same meanings as above, R ₅ represents an alkyl group or a substituted alkyl group, and M represents an alkali metal.) In the compound that is the raw material compound, R ₁ is The compound mitomycin A, which is a methoxy group, is a known compound. (Special Publication No. 34-7597, Publication No. 35-
17897, etc.) Also, compounds in which R ₃ is a hydrogen atom in the compound as a raw material compound, 7-O-
Demethylmitomycin F is also a known compound.
[J.of Medical Chemistry, 20 , 767 (1977)] Next, each step will be explained in detail. Step 1 Compound ₁ combines a compound and a halogenated alkyl or halogenated substituted alkyl represented by XCH ₂ R ₃ (wherein, X represents a halogen atom and R ₃ has the same meaning as above) in the presence of a base. It can be obtained by reacting in an inert solvent. As the alkyl halide, iodomethane, bromoethane, iodoethane, chloropropane, bromopropane, iodopropane, chlorobutane, bromobutane, iodobutane, etc. are used. Examples of the halogenated substituted alkyl include chlorohydrin, bromohydrin, iodohydrin, 1-chloro-2-propanol, 3-chloro-1-propanol, 1-bromo-2-propanol, 3-
Bromo-1-propanol, 1-iodo-2-propanol, 3-iodo-1-propanol, methyl chloroacetate, methyl bromoacetate, methyl iodoacetate, ethyl chloroacetate, ethyl bromoacetate,
Ethyl iodoacetate, propyl chloroacetate, propyl bromoacetate, propyl iodoacetate, 1,2-dichloroethane, 1,2-dibromoethane, 1,2
-diiodoethane, 1,3-dichloropropane,
1,3-dibromopropane, 1,3-diiodopropane, 1,2-dichloropropane, 1,2-dibromopropane, 1,2-diiodopropane,
1,4-dichlorobutane, 1,4-dibromobutane, 1,4-diiodobutane, 2-chloroethyl ethyl ether, chloromethyl ethyl ether, chloromethyl methyl ether, 2-
Bromoethyl ethyl ether, bromomethyl ethyl ether, bromomethyl methyl ether, 2-iodoethyl ethyl ether,
iodomethyl ethyl ether, iodomethyl methyl ether, chloroethyl acetate,
Bromoethyl acetate, iodoethyl acetate, chloromethyl bivalate, etc. are used. As the base, inorganic bases such as sodium carbonate and potassium carbonate, and tertiary amines such as triethylamine and pyridine are used. As the solvent, aprotic polar solvents such as acetone, dimethylformamide, dimethylsulfoxide, acetonitrile, etc. are used. The halogenated alkyl and the halogenated substituted alkyl are used in a molar amount of 1 to 30 times the amount of the compound, and the base is used in a molar amount of 1 to 30 times the amount of the compound. The reaction proceeds at a temperature of 0 to 50°C and is usually completed in a few hours to a few days, depending on the solvent base used, reaction temperature, etc. After the reaction is completed, the solvent is distilled off under reduced pressure, or water and an organic solvent are added for extraction, and the solvent is distilled off under reduced pressure. The obtained residue is purified by purification methods commonly used in the field of synthetic chemistry, such as column chromatography, preparative thin layer chromatography, recrystallization, and the like. Step 2 Compound ₂ is a compound

By reacting a halogenated alkyl formate or dialkylcarbamoyl halide represented by the formula (wherein X and R ₄ have the same meanings as above) in an inert solvent in the presence of a base. can get. Examples of halogenated alkyl formates include methyl chloroformate,
Ethyl chloroformate, propyl chloroformate, methyl bromoformate, ethyl bromoformate, propyl bromoformate, methyl iodoformate, ethyl iodoformate, propyl iodoformate, and the like are used. Examples of dialkylcarbamoyl halides include dimethylcarbamoyl chloride, methylethylcarbamoyl chloride, diethylcarbamoyl chloride, dimethylcarbamoyl bromide, methylethylcarbamoyl bromide, diethylcarbamoyl bromide,
Dimethylcarbamoyl iodide, methylethylcarbamoyl iodide, diethylcarbamoyl iodide, etc. are used. As the base, inorganic bases such as sodium hydrogen carbonate, sodium carbonate, and potassium carbonate, and tertiary amines such as triethylamine and pyridine are used. Examples of solvents include ethers (ethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, etc.), hydrocarbons (n-hexane, benzene, etc.),
Organic solvents such as amides (dimethylformamide, etc.), esters (ethyl acetate, etc.), ketones (acetone, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), dimethyl sulfoxide, and the like are used. In some cases, an organic base is used as a solvent. The halogenated alkyl formate, dialkyl carbamoyl halide is 1 to 5
The base is used in 1 to 30 times the molar amount. The reaction proceeds at a temperature of 0 to 30°C, and varies depending on the solvent, base, reaction temperature, etc. used, but usually 1
It can be completed within one day. The target product is purified by the same operation as in step 1 below. Step 3 Compound ₄ is obtained by hydrolyzing Compound ₃ in the presence of a base, extracting it under acidic conditions, and then converting it into an alkali metal salt. As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium t-butoxide, etc. are used. As the solvent, a mixture of alcohol such as methanol, ethanol, isopropanol, etc. and water is used. The base is used in a molar amount 2 to 10 times that of Compound ₃ . The reaction proceeds at a temperature of 0 to 30°C and is usually completed in one hour to one day, although it varies depending on the solvent, base, reaction temperature, etc. used. After the reaction is completed, water and an organic solvent such as ethyl acetate are added to the reaction solution. After making the aqueous layer weakly acidic with hydrochloric acid or the like, an organic solvent such as ethyl acetate is added again for extraction. The extract is treated and purified in the same manner as in step 1. Step 4 Compound ₆ is obtained by reducing the formyl group of Compound ₅ with a metal hydride in an inert solvent. As the metal hydride, sodium borohydride, sodium cyanoborohydride, L-selectride, etc. are used. As a solvent, alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane,
Ethers such as ethylene glycol dimethyl ether can be used alone or in combination. The metal hydride is used in an amount of 1 to 5 times the mole of compound ₅ . The reaction proceeds at a temperature of -20 to 30°C, and is usually completed in a few minutes to a few hours, depending on the solvent, metal hydride, reaction temperature, etc. used. After the reaction is completed, water and an organic solvent such as ethyl acetate are added to the reaction solution. Thereafter, the target product is purified by the same operation as in step 1. Step 5 Compound ₁ is the compound XR ₃ (wherein X and
R ₃ has the same meaning as above. ) is obtained by reacting a substituted halogenated alkyl, a halogenated substituted methane, etc. represented by the following in an inert solvent in the presence of a base. Examples of substituted alkyl halides include alkoxyethyl chloride, alkyl dihalides, and more specifically, chloroethyl=ethyl=
Ether, chloroethyl methyl ether, bromoethyl ethyl ether, bromoethyl ether
Methyl ether, iodoethyl ethyl ether, iodoethyl methyl ether, 1,2
-dichloroethane, 1,2-dibromoethane,
1,2-diiodoethane, 1,3-dichloropropane, 1,3-dibromopropane, 1,3-diiodopropane, 1,2-dichloropropane, 1,
Examples include 2-dibromopropane and 1,2-diiodopropane. Examples of the halogenated substituted methane include halogenomethyl alkyl ether, halogenomethyl alkoxyalkyl ether, halogenomethyl alkyl thioether, and more specifically, chloromethyl methyl ether, bromomethyl methyl ether, etc. Ether, iodomethyl methyl ether, chloromethyl ethyl ether, bromomethyl ethyl ether, iodomethyl ethyl ether, chloromethyl propyl ether, bromomethyl propyl ether, iodomethyl propyl ether, chloromethyl methoxy Ethyl ether, bromomethyl methoxyethyl ether, iodomethyl
Methoxyethyl ether, chloromethyl ethoxyethyl ether, bromomethyl ethoxyethyl ether, iodomethyl ethoxyethyl ether, chloromethyl methoxypropyl ether, bromomethyl methoxypropyl
Ether, iodomethyl methoxypropyl ether, chloromethyl methyl thioether,
Bromomethyl methyl thioether, iodomethyl methyl thioether, chloromethyl ethyl thioether, bromomethyl ethyl thioether, iodomethyl ethyl thioether, chloromethyl propyl thioether, bromomethyl propyl thioether, iodomethyl propyl thioether, etc. can be given. As the base, inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, and silver oxide, and organic bases such as triethylamine, pyridine, diisopropyl, and methylamine are used. As a solvent, an aprotic polar solvent such as acetone, dimethylformamide, dimethylsulfoxide, acetonitrile, etc., or an organic base is used directly as a solvent. XR ₃ (wherein X and R ₃ have the same meanings as defined above) is used in a molar amount of 1 to 30 times the amount of the compound, and the base is used in a molar amount of 1 to 2 times the amount of the compound. The reaction proceeds at a temperature of 0-80°C, the solvent used,
Although it depends on the base, reaction temperature, etc., the process is usually completed in a few hours to a few days. Thereafter, the target product is purified by the same operation as in step 1. The mitomycin derivative of the present invention has a strong ability to inhibit the growth of various bacteria, as shown in Table 1, the minimum inhibitory concentration (μg/ml, agar dilution method, PH
7.0).

【table】

[Table] Examples are shown below. Example 1 20 mg of mitomycin A is dissolved in 1 ml of dry DMF, 0.06 ml of methyl bromoacetate and 50 mg of potassium carbonate are added to the solution, and the mixture is stirred at room temperature under a nitrogen stream for 24 hours. After the reaction is completed, excess potassium carbonate in the reaction mixture is removed, and excess methyl bromoacetate and the solvent are distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a mixed solvent of chloroform:methanol (93:7v/v) as a developing solvent, the main product fractions were collected, and the solvent was distilled off under reduced pressure to give a reddish brown powder (16.4%). mg (68% yield) is obtained. The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e421. High-resolution mass spectrum: Actual value 421, 1466 (calculated value 421, 1485) ′HNMR: (δ, py−d5) 1.78 (3H, s), 2.65
(1H, dd, 4.6Hz, 2.2Hz), 2.75 (1H, d, 16.3
Hz), 2.87 (1H, d, 4.6Hz), 3.22 (3H, s),
3.52 (3H, s), 3.60 (1H, dd, 12.6Hz, 2.4
Hz), 3.95 (1H, dd, 11.3Hz, 4.4Hz), 4.01
(3H, s), 4.03 (1H, d, 16.3Hz), 4.36
(1H, d, 12.6Hz), 4.84 (1H, dd, 11.3Hz,
10.5Hz), 5.31 (1H, dd, 10.5Hz, 4.4Hz), 7.70
(2H, bs) IR: (KBr tablet method) (cm ^-1 ) 3460, 3365, 2940,
1725, 1653, 1634, 1580 Based on the above data, this substance is identified as 1a-N-methoxycarbonylmethylmitomycin A. Example 2 The procedure of Example 1 was repeated except that 30 mg of mitomycin A and 0.1 ml of ethyl bromoacetate were used instead of 20 mg of mitomycin A and 0.06 ml of methyl bromoacetate.
Obtain 24.3 mg (65% yield). The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e435. High-resolution mass spectrum: Actual value 435, 1647 (calculated value 435.1642) ′HNMR: (δ, py−ds) 1.03 (3H, t, 6.7
Hz), 1.79 (3H, s), 2.69 (1H, dd, 4.4Hz,
2.2Hz), 2.75 (1H, d, 16.6Hz), 2.88 (1H,
d, 4.4Hz), 3.21 (3H, s), 3.61 (1H, dd,
12.5Hz, 2.2Hz), 3.95 (1H, dd, 11.2Hz, 4.4
Hz), 4.00 (3H, s), 4.02 (2H, q, 6.7Hz),
4.04 (1H, d, 16.6Hz), 4.38 (1H, d, 12.5
Hz), 4.86 (1H, dd, 11.2Hz, 10.7Hz), 5.31
(1H, dd, 10.7Hz, 4.4Hz), 7.65 (2H, bs) IR: (KBr tablet method) (cm ^-1 ) 3455, 3360, 2935,
1727, 1653, 1634, 1577 Based on the above data, this substance is identified as 1a-N-ethoxycarbonylmethylmitomycin A. Example 3 Same as Example 1 except that 0.06 ml of tert-butyl bromoacetate was used instead of 0.06 ml of methyl bromoacetate, except that 18.3 mg of reddish-brown powder was obtained.
(yield 69%). The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e463. High-resolution mass spectrum: Actual value 463.1925 (calculated value 463.1954) ′HNMR: (δ, py−ds) 1.34 (9H, s), 1.80
(3H, s), 2.63 (1H, d, 1.66Hz), 2.64
(1H, dd, 4.5Hz, 2.1Hz), 2.84 (1H, d, 4.5
Hz), 3.21 (3H, s), 3.61 (1H, dd, 12.5
Hz, 2.1Hz), 3.99 (3H, s), 4.00 (1H, dd,
10.6Hz, 4.5Hz), 4.02 (1H, d, 16.6Hz), 4.40
(1H, d, 12.5Hz), 4.84 (1H, t, 10.6Hz),
5.30 (1H, dd, 10.6Hz, 4.5Hz), 7.65 (2H,
bs) IR: (KBr tablet method) (cm ^-1 ) 3465, 3370, 2940,
1732, 1654, 1635, 1579 From the above data, this substance is 1a-N-(t-
It was identified as mitomycin A (butoxycarbonylmethyl). Example 4 Mitomycin A 16.5mg in acetonitrile 0.4ml
Add 40μ of chloromethyl methyl ether in the presence of triethylamine, and stir at room temperature for 1.5 hours. After the reaction is completed, water is added to the reaction solution and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography using a mixed solvent of chloroform:acetone (6:4 v/v) as a developing solvent. mitomycin
11mg of A was recovered, and the main product was 6.4mg of black-purple needles.
Get mg. The physical properties of this main product substance are as follows. Mass spectrum: gives molecular ion peak at m/e393. High-resolution mass spectrum: Actual value 393.1500 (calculated value 393.1536) ′HNMR: (δ, py−d5) 1.84 (s), 2.67
(dd), 2.99(d), 3.22(s), 3.27(s), 3.54
(dd), 3.87(d), 3.95(dd), 4.02(s), 4.21
(d), 4.29(d), 4.80 (dd), 5.38 (dd) IR: (KBr tablet method) (cm ^-1 ) 3450, 1720, 1690,
1650, 1630, 1570, 1100, 1060 Based on the above data, this substance is identified as 1a-N-methoxymethylmitomycin A. Example 5 100 mg of mitomycin A is dissolved in 5 ml of dry DMF and 150 mg of potassium carbonate and 0.3 ml of chloromethyl pivalate are added to the solution. Then, this mixture was stirred on an ice bath under a nitrogen stream for 30 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
After drying the extract over anhydrous sodium sulfate, the solvent is removed under reduced pressure. Chloroform the resulting residue:
Fractions of mitomycin A and the product are obtained by silica gel column chromatography using a mixed solvent of methanol (93:7 v/v) as a developing solvent.
The product was further mixed with chloroform:methanol (7:
3v/v) as a developing solvent. From the reddish-purple band with the highest Rf value, 5.4 mg (7.5% yield) of a glassy reddish-purple solid is obtained. The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e463. High-resolution mass spectrum: Actual value 463.1932 (calculated value 463.1954) ′HNMR: (δ, py−d ₅ ) 1.12 (9H, s), 1.84
(3H, s), 2.84 (1H, dd, 4.9Hz, 2.2Hz),
3.18 (1H, d, 4.9Hz), 3.21 (3H, s), 3.56
(1H, dd, 12.8Hz, 2.2Hz), 3.97 (1H, dd,
11.2Hz, 4.6Hz), 4.02 (3H, s), 4.22 (1H,
d, 12.8Hz), 4.76 (1H, dd, 11.2Hz, 10.5
Hz), 4.99, 5.07 (2H, AB, 8.8Hz), 5.36
(1H, dd, 10.5Hz, 4.6Hz), 7.62 (2H, b _s ) IR: (KBr tablet method) (cm ^-1 ) 3460, 3365, 2955,
1725, 1648, 1632, 1586, 1328, 1296, 1280,
1211, 1129, 1105, 1066 Based on the above data, this substance is identified as 1a-N-pivaloyloxymethylmitomycin A. Example 6 25 mg of 1a-N-methoxycarbonylmethylmitomycin A was dissolved in a mixed solvent of 6 ml of methanol and 2 ml of water, and 15 mg of sodium methoxide was added to the solution.
Add and stir at room temperature for 1 hour. After the reaction is complete, water is poured into the reaction solution, and then ethyl acetate is added. Add dilute hydrochloric acid to the aqueous layer to adjust the pH to 4.2, and then extract with ethyl acetate. After drying, the solvent was distilled off under reduced pressure to obtain 13.3 mg (yield 55%) of a reddish-purple solid. This substance is very unstable, and mass spectra cannot be measured, but ′HNMR and IR are as follows. ′HNMR: (δ, py−d5) 1.78 (3H, s), 2.71
(1H, dd, 4.9Hz, 2.2Hz), 2.84 (1H, d, 15.8
Hz), 2.89 (1H, d, 4.9Hz), 3.23 (3H, s),
3.63 (1H, dd, 12.5Hz, 2.2Hz), 3.98 (1H,
dd, 11.2Hz, 4.9Hz), 4.01 (3H, s), 4.22
(1H, d, 15.8Hz), 4.44 (1H, d, 12.5Hz),
4.95 (1H, dd, 11.2Hz, 10.0Hz), 5.29 (1H,
dd, 10.7Hz, 4.9Hz), 7.64 (2H, b5) IR: (KBr tablet method) (cm ^-1 ) 3460, 3370, 2950,
1717, 1649, 1585 Furthermore, the substance produced by dissolving this substance in methanol and adding an ethereal solution of diazomethane was confirmed to be the starting material 1a-N-methoxycarbonylmethylmitomycin A by TLC, 'HNMR, MS, and IR. be done. From the above data, this substance is identified as 1a-N-carboxymethylmitomycin A. this
1a-N-Carboxymethylmitomycin A is dissolved in methanol, an equivalent amount of sodium bicarbonate is added, and the solvent is distilled off to obtain a dark purple powder.
The physical properties of this substance are as follows. ′HNMR: (δ CD ₃ OD) 1.84 (3H, s), 2.36
(1H, d, 15.8Hz), 2.45 (1H, dd, 4.5Hz, 2.2
Hz), 2.59 (1H, d, 4.5Hz), 3.20 (3H, s),
3.42 (1H, dd, 12.7Hz, 2.2Hz), 3.50 (1H,
d, 15.8Hz), 3.55 (1H, dd, 11.0Hz, 4.6
Hz), 3.97 (3H, s), 4.11 (1H, d, 12.7
Hz), 4.23 (1H, dd, 11.0Hz, 10.5Hz), 4.76
(1H, dd, 10.5Hz, 4.6Hz) IR: (KBr tablet method) (cm ^-1 ) 3425, 1713, 1578 From the above data, this substance was identified as the sodium salt of 1a-N-carboxymethylmitomycin A. Ru. Example 7 23 mg of mitomycin A to 1 ml of triethylamine
Add 20μ of N,N-dimethylcarbamoyl chloride and stir under reflux for 4 hours. After the reaction is completed, water is added to the reaction solution and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a mixed solvent of chloroform:methanol (93:7 v/v) as a developing solvent, and fractions of the main product were collected, and the solvent was distilled off under reduced pressure.
6 mg (yield 22%) of black-purple prismatic crystals are obtained. The physical property values of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e420. High-resolution mass spectrum: Actual value 420.1653 (calculated value 420.1645) ′HNMR: (δ, py−d5) 1.88 (3H, s), 2.77
(6H, s), 3.21 (1H, dd), 3.22 (3H, s),
3.58 (1H, dd), 4.00 (3H, s), 4.05 (2H,
m), 4.54 (1H, dd), 5.54 (1H, dd), 8.45
(2H, b _s ) IR: (KBr tablet method) (cm ^-1 ) 3350, 1720, 1650,
1580 From the above data, this substance is 1a-N-(N,
It is identified as N-dimethylcarbamoyl) mitomycin A. Example 8 30 mg of 1a-N-(2-formylethyl)mitomycin A are dissolved in 1 ml of dry THF and a solution of 15 mg of sodium borohydride in 0.2 ml of dry methanol is added to the solution on an ice bath. Under nitrogen flow
Stir for 15 minutes. After the reaction is complete, acetone and water are added to the reaction solution, and the mixture is extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was mixed with chloroform:acetone (6:
4v/v) mixed solvent as a developing solvent, the main product fractions were collected, and the solvent was distilled off under reduced pressure to obtain 22.6mg (75% yield) of a dark reddish-purple glassy solid. can get. The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e407. High-resolution mass spectrum: Actual value 407.1657 (calculated value 407.1692) 'HNMR: 1.80 (3H, s), 1.83-2.18 (3H,
m), 2.37 (1H, dd, 4.6Hz, 2.1Hz), 2.69
(1H, d, 4.6Hz), 3.01-3.12 (1H, m), 3.21
(3H, s), 3.53 (1H, dd, 12.7Hz, 2.1Hz),
3.82 (2H, t, 5.9Hz), 3.96 (1H, dd, 11.1
Hz, 4.5Hz), 4.20 (1H, d, 12.7Hz), 4.79
(1H, dd, 11.1Hz, 10.5Hz), 5.41 (1H, dd,
10.5Hz, 4.5Hz), 7.66 (2H, bs) IR: (KBr tablet method) (cm ^-1 ) 3430, 2930, 1712,
1651, 1642, 1579 From the above data, this substance is 1a-N-(3-
It was identified as mitomycin A (hydroxypropyl). Example 9 11.3 mg of 7-O-demethylmitomycin F was dissolved in 1 ml of acetonitrile, 5.0 mg of chloromethyl methyl ether was added in the presence of triethylamine, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, water is added to the reaction solution and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a mixed solvent of chloroform:acetone (6:4 v/v) as a developing solvent, the product fractions were collected, and the solvent was distilled off under reduced pressure to give 11.0 mg of reddish-purple crystals.
(Yield 86%) is obtained. The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e393. High-resolution mass spectrum: Actual value 393.1527 (calculated value 393.1536) ′HNMR: (δ, py−d5) 1.93 (3H, s), 2.17
(1H, dd), 2.23 (3H, s), 2.53 (1H, d),
3.18 (3H, s), 3.45 (3H, s), 3.45 (1H,
dd), 3.91 (1H, dd), 4.12 (1H, d), 4.71
(1H, dd), 5.29 (1H, dd), 5.47 (1H, d),
5.57 (1H, d), 7.60 (2H, s) IR: (KBr tablet method) (cm ^-1 ) 3450, 3350, 1720,
1650, 1630, 1330, 1290, 1060 From the above data, this substance is identified as 7-O-demethyl-7-O-methoxymethylmitomycin F. Example 10 4.9 mg of 7-O-demethylmitomycin F is dissolved in 0.25 ml of pyridine, 15 µ of N,N-dimethylcarbamate chloride is added, and the mixture is stirred at room temperature for 20 hours. After the reaction is completed, water is added to the reaction solution and extracted with ethyl acetate. The solvent of the extracted layer is removed under reduced pressure.
The obtained residue was mixed with chloroform:acetone (6:
4v/v) mixed solvent as a developing solvent, collect the product fractions,
The solvent is distilled off under reduced pressure to obtain 3.9 mg (66% yield) of a reddish-purple powder. The physical properties of this substance are as follows. Mass spectrum: gives molecular ion peak at m/e420. High-resolution mass spectrum: Actual value 420.1666 (calculated value 420.1645) ′HNMR: (δ, py−d5) 1.90 (3H, s), 2.14
(1H, dd), 2.21 (3H, s), 2.52 (1H, d),
2.87 (3H, s), 3.04 (3H, s), 3.12 (3H,
s), 3.41 (1H, dd), 3.98 (1H, dd), 4.05
(1H, d), 4.74 (1H, t), 5.35 (1H, dd),
7.60 (2H, s) IR: (KBr tablet method) (cm ^-1 ) 3450, 1720, 1660,
1630, 1580 From the above data, this substance is 7-O-demethyl-7-O-(N,N-dimethylcarbamoyl)
Identified as mitomycin F. Example 11 14.5 mg of 7-O-demethylmitomycin F is dissolved in 1 ml of acetonitrile, 15 µ of chloromethyl methyl sulfide is added in the presence of triethylamine, and the mixture is stirred at 50°C for 3 hours. After the reaction is completed, water is added to the reaction solution and extracted with ethyl acetate. The solvent of the extracted layer is removed under reduced pressure. The obtained residue was mixed with chloroform:acetone (6:
4v/v) mixed solvent as a developing solvent, collect the product fractions,
When the solvent was distilled off under reduced pressure, 4.6 mg of reddish-purple powder (yield
27%). The physical properties of this substance are as follows. The mass spectrum gives m/e394 (M-15) ⁺ . ′HNMR: (δ, py−d ₅ ) 1.94 (3H, s), 2.08
(1H, dd), 2.16 (3H, s), 2.21 (3H, s),
2.51 (1H, d), 3.17 (3H, s), 3.44 (1H,
dd), 3.92 (1H, dd), 4.11 (1H, d), 4.73
(1H, d), 5.31 (1H, d), 5.68 (1H, d),
5.74 (1H, d), 7.60 (2H, s) IR: (KBr tablet method) (cm ^-1 ) 3450, 3350, 1720,
1650, 1630, 1570, 1420, 1300 From the above data, this substance is 7-O-demethyl-7-O-methylthiomethylmitomycin F.
It is identified as

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ represents an alkoxy group, a substituted alkoxy group or a substituted carbamoyloxy group,
R ₂ represents CH ₂ R ₃ (in the formula, R ₃ represents a hydrogen atom, a substituted alkyl group, an alkoxycarbonyl group, or an acyloxy group) or [Formula] (in the formula, R ₄ represents a substituted amino group) . However, R ₁ =
Except when OCH ₃ , R ₂ = CH ₃ . ] A novel mitomycin derivative and its salt.