HU201074B - Process for producing mitomycine-a-amalogues - Google Patents

Abstract

The present invention relates to a process for the preparation of the novel mitomycin A analogs of the formula (I): wherein R 6 is C 1-6 alkyl or monosubstituted C 1-4 alkyl in which the substituent is a C 1-4 alkoxy group, benzylthio, morpholino. , pyridyl, 1,3-dioxolyl-2- or (C1-C4) alkanoylamino (C1-C4-alkyldithiocarbon). The novel process of the present invention is characterized in that the mitosane of formula (II) is \ t Reaction with Triazene III, wherein R @ 2 is as defined herein and Ar is a derivative derived from a diazotizable aromatic amine, the process being preferably used to produce antibiotic, known alkoxy and novel substituted alkoxy compounds. - NN-NH-R6 (III) HU 201074 BA description: 8 pages, 4 drawings, Figure 33

Description

The present invention relates to a process for the preparation of novel mitornicin analogs. The compounds prepared are mitomycin A analogues in which the 7-oxy moiety of mitosan-water is unsubstituted (they are already partially known) or has 5 substituted alkyl substituents (which are new). Mitomycin-A has been shown to have antibiotic activity and other 7-substituted-mitosan analogues have such activity. 10

The process of the present invention is a supplement to and continuation of U.S. Patent Application No. 646,888, filed September 4, 1984, in the United States.

The name of mitomycin A according to Chemical Abstract, as last amended (Shirhata et al., J. Ara. Chem. Soc., 105, 7199 (1983)), is as follows: [laS- (labeta, 8beta, 8abeta)] - 8 - [(aminocarbonyloxy) methyl] -6,8a-dimethoxy-1,1a, 2,8,8a, 8b-hexahydro-20 -5-methylazirino [2 ', 3', 3,4 ] pyrrolo [1,2-a] indole-4,7-dione, numbered on the azirino-pyrroloindole ring system according to formula (A).

In the trivial name widely used in the mitomycin literature, the above ring system, which contains many characteristic mitomycin substituents, is referred to as mitozane, and this numbering is shown in formula (B). 30

According to the name mitomycin A is a 7,9-dimethoxymitosan and mitomycin C 7-amino-9a-methoxymitosan. In terms of stereochemistry, the compounds of the present invention, when given according to the mitotic name or described by structural formula, may be characterized by the stereochemistry of mitomycin A (represented by formula C).

40 other 7-alkoxy-substituted mitosans, which are derivatives of mitomycin A, have been found to be active in experimental, animal, cancerous diseases, Urakava et al., J. Antibiotics, 33, 804-809 (1980).

Mitomycin C is a major mitomycin species produced by fermentation and is commercially available. The known technology used to convert mitomycin-C to mitomycin-A has several disadvantages. The methylation of 7-hydroxy-9α-50-methoxy-mitosane obtained by hydrolysis of mitomycin C requires the use of diazomethane, which is a very hazardous substance for large-scale application. In addition, the 7-hydroxy intermediate product is very unstable (Matsui et al., J. Antibiotics, XXI, 189-198 (1968)) .These difficulties are avoided by the use of 7-acyloxy-mitosans [Kyowa Hakko Kogyo KK, Japanese Patent Application J5 6073-085, Farmdoc No. 56227 D / 31). However, mitomycin A-alcoholysis, described by Urakawa et al., 60 J. Antibotics, 1980, 33, 804-809, allows only 7-alkoxy compounds having the appropriate alcohol component to be reactive. 65

The present invention relates to a novel process for the preparation of a known compound of the formula I wherein:

R ^f1 is C 1-6 alkyl or monosubstituted C 1-4 alkyl in which the substituent is C 1-4 alkoxy, benzylthio, morpholino, pyridyl, 1,3-dioxolyl-2- or (C 1-4) alkanoyl; amino (C1-C4) alkyldithio.

Many of the compounds of formula (I) produced by the process of the invention have inhibitory activity in vivo in experimental animal tumors. Many of the novel compounds of formula (I) have been prepared by the process of the present invention and are also provided. the compounds of Examples 3, 4, 5 and 8 of the present invention also exhibit antitumor activity in experimental animal tumors, which are used in a manner similar to mitomycin C; if they are less toxic than mitomycin C, their dose can also be used.

As used herein, the term halogen means chlorine, fluorine, bromine or iodine.

In the preparation of the compounds of formula (I) according to the invention, the compound of formula (II) is reacted with a triazene of formula (III):

R ⁶ is as defined above, and

Ar is an aryl group of a diazotizable aromatic amino group.

The 1-substituted-3-aryl-triazenes of the formula (III), more particularly the 1-alkyl-3-aryl-triazenes, are a group of compounds which are known to be reacted with carboxylic acids to prepare the corresponding lower alkyl esters. 1-Methyl-3- (4-methylphenyl) triazene Ε. H. White et al., Org. Syn., 48, 102-105 (1968) and in our Examples, may be prepared by the method described in Preparation 1. This method of preparation gives good results only with the use of water-soluble amines of formula R ⁶ NHz. Ε. Another preparation method is known from H. White et al., Tetrahedron Letters, No. 21, p. Such a procedure is described in our examples a

Preparation 2.

The 1-methyl-3- (4-methylphenyl) triazene reagent, prepared by the above procedure, was used to prepare methyl esters of carboxylic acids, such as 2,4-dinitrobenzoic acid [Ε. H. White et al., Org. Syn. 48, 102-105 (1968)] for the preparation of methyl ester or cephalosporinic acid methyl ester (Mangia, Teterahedron Letters, No. 52, p. 5219-20 (1978)], so that

EN 201074 Β only the desired delta ³ isomer was formed, no isomerization to the delta ³ isomer occurred. The reagent was also used to convert 3-hydroxy-3-cephem-4-carboxylate in benzene at reflux to 3-methoxy-cephalosporin spray (Wiederkehr et al., U.S. Pat. No. 4,069,324, issued Jan. 17, 1978). description).

Other 1- (lower alkyl) -3-aryl-triazenes of formula (III) may be prepared by the above process by reaction of other lower alkylamines and aryl diazonium salts optionally substituted as indicated. Any diazonium salt which can be readily formed can be used in the preparation of the 1,3-disubstituted triazene to introduce the aryl group from 6 to 12 carbon atoms. Examples of triazenes produced by the method include:

l-butyl-3- (4-methylphenyl) triazene;

l- (l-methylethyl) -3- (4-methylphenyl) triazene;

3- (4-methylphenyl) -l-2- (4-morpholinyl) ethyl) triazene;

3- (4-methylphenyl-1- (2- (2-pyridyl) ethyl) triazene;

l- (2-benzylthio-ethyl) -3- (4-methylphenyl) triazene;

3- (4-chloro-phenyl) -l- (2-methoxyethyl) triazene;

3- (4-chlorophenyl) -1- (1,3-dioxol-2-ylmethyl) triazene.

Other triazenes described in the literature are also useful in the process of the present invention for the preparation of 7- (substituted alkoxy) monomers (I), such as those described by TA Daniels et al., 1977, Can. J. Chem., 55, 3751-3754. ) of the general formula (D).

The following triazenes of formula (III) may also be suitably used in the process of the invention:

l-butyl-3- (alpha-naphthyl) triazene;

l-hexyl-3-phenyl-triazene;

l-ethyl-3- (2,4-dimethyl-phenyl]) - triazene;

L-1-methylethyl) -3- (4-methoxyphenyl) triazene.

Preferably, 3-methyl-1- (4-methylphenyl) triazene is used as the methylating agent for the preparation of mitomycin A. In the process, at least two moles of the above reagent are used per 7-hydroxy-9a-methoxymethyl moiety, and preferably, the 7-hydroxy-9a-methoxy-mitosane starting material is in a well-soluble liquid lower alkanol, lower alkanoic acid lower alkyl ester, di- (lower alkyl ether, cyclic aliphatic ether or lower polyhalogenated aliphatic) Such solvents may contain from 1 to 6 carbon atoms, but are preferably boiling below 100 ° C. For example, particularly preferred solvents are dichloromethane, methanol, diethyl ether, ethyl acetate and mixtures thereof. at reflux temperature, up to a maximum of 4 at about 60 ° C. The reaction is preferably carried out at room temperature or below, for example, 0-25 ° C.

Suitably, the completion of the reaction can be monitored by thin-layer chromatography. Mitomycin A is a dark purple material and is easily distinguishable from starting material and by-products. Using a dichloromethane: methanol (90: 10) solvent mixture, the Rf of mitomycin A is 0.36. Chromatography on neutral alumina may be used to purify the product.

The preparation of other ^7-R6 0 mitozónok [Formula (I)] of the present invention may also be carried out as described above.

The antitumor therapeutic utility of the compounds of formula (I) produced by the method of the invention was demonstrated by an in vivo assay in which the compounds were administered at various doses to mice infected with Ρ-388-leukemia or B16-melanone.

The compounds of the present invention also possess antibacterial activity against Gram-positive and Gram-negative microorganisms, with the same mechanism of action as that observed for naturally occurring mitomycins. thus, they may be potential therapeutic agents for bacterial infections in humans and animals,

P-388 (mouse) anti-leukene effect

Table I summarizes the results of laboratory tests inoculated intraperitoneally with an inoculum containing 10® P-388 (mouse) leukemia ascites cells and different formulations of the compound of formula (I) and mitomycin-C produced by the method of the present invention. mice. The compounds of the invention are administered by intraperitoneal injection. For each dose, groups of six mice were treated and one dose was used on the day after inoculation. In a series of experiments, control groups of 10 mice were treated with physiological saline. The mitomycin-C treated group was used as a positive control. A 30-day protocol was run in which the mean survival values for each group on each day and the number of survivors on day 30 were reported. Mice were weighed before and 6 days after treatment. Weight change was considered as a measure of toxicity. Mice weighing 20 grams were used and weight loss of about 2 g was not considered excessive. Results are given in% T / C,

-3H 201074 Β which is the mean survival rate of the treated group (T) relative to the survival rate (C) of the saline control group (C). Control animals treated with saline usually died within 9 days. The .maximum effect value is given in the table as% T / C and the dose triggering it is also given. Values in parentheses are those of the same experiment as mitomycin-C positive control. Thus, comparisons can be made between the compounds of the present invention and mitomycin C in terms of activity. At% T / C, a minimum effect of 125 was considered. The minimum effective dose in the table is the dose that results in 125% T / C. Values under "mean weight change" are the mean weight changes observed for the individual mice at the maximum effective dose and the minimum effective dose.

Table 1

Inhibition of P-388 (murine) leukemia is a compound of formula (I)

Example number of compound R ⁶ Maximum effect Minimum Effect Dose * Average súlyváltozés ² % T / C Dose* P n-Bu 167 (306) ⁴ 1.6 (3.2) ⁴ 0.2 +0.1; -0.4 2 ³ i-Pr 167 (306) 1.6 (3.2) 0,005 -0.7; +0.1 3 (the) 222 (306) 6.4 (3.2) 0.05 -1.7; -0.5 4 (B) 233 (306) 3.2 (3.2) 0.05 -2.4; +0.2 5 (C) 156 (306) 6.4 (3.2) 0.2 -.07; +0.3 6 (D) 183 (306) 6.4 (3.2) 0.1 -1.2; -0.3 7 (E) 211 (172) 0.4 (3.2) 0.05 -0.6; +1.3 8 (F) 267 (172) 0.4 (3.2) 0.05 +0.9; +1.7

1. mg / kg body weight;

2. average grams / day for maximum and minimum effective doses;

3. Urakawa et al., J. Antibiotics,

23: 804-809 (1980);

4. values in brackets in the same row refer to mitomycin-C.

The following examples illustrate the invention.

In the examples, the temperatures are given in ° C, the melting points are not corrected. Proton nuclear magnetic resonance (1 H-NMR) spectra were measured on a Varian XL100, Joel FX-900 or Bruker WM 360 spectrometer, or in pyridine-ds or DIO. If the delta = 8.57 resonance value was used as an internal reference, when DzO is used the internal reference is TSP. Chemical shifts are given in delta values, coupling constants in Hz. The symbols are described by the following symbols: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sz, broad; dd, doublet of doublets; dt, doublet of triplets. The infrared spectrum or a Beckman Model 4240 spectrometer or a Nicolet FT-IR was measured using a spectrophotometer and set the ^cm-1 values. Ultraviolet (UV) spectra were determined on a Cary Model 290 spectrometer or on a Hewlitt Packard 8450A spectrometer equipped with a multi-diode detector. Thin layer chromatography (TLC) was performed on 0.25 mm Analtech silica gel GF plates. Flash chromatography was performed on Woelm neutral alumina (DCC grade) or Woelm silica gel (32-63 micrometers) using the indicated eluents. All the solvent evaporators were performed under vacuum at temperatures below 40 ° C.

1-Alkyl-3-aryl-triazenes form a known group of molecules which, by reaction with carboxylic acids, are suitable for the preparation of their corresponding lower alkyl esters. The 1-methyl-3- (4-methylphenyl) triazene was prepared as follows.

Preparation 1

Ε. H. White et al., Org. Syn., 48, 102-105 (1968)):

l ~ methyl-3- (p-tolyl) triazene

50.2 g (0.47 mole) of p-toluidine were weighed into a 1 mL 200 mL dropping funnel and immersed in an ice-salt bath at about -10 ° C. A solution of 46.8 g (0.55 mol) of potassium nitrite in 150 ml of water was placed in a dropping funnel and 250 g of crushed ice and 140 ml of concentrated hydrochloric acid were added to the p-toluidine with stirring. The potassium nitrite solution is added dropwise with stirring over a period of about 1 to 2 hours, until a positive starch test is obtained (Note 1).

HU 201074 Β

The reaction mixture was stirred for an additional hour to ensure complete reaction of toluidine.

The solution of p-tolyldiazonium chloride is then adjusted to pH 6.8-7.2 with concentrated aqueous sodium carbonate at 0 ° C while the solution turns red to orange and a small amount of precipitate forms. The cold, neutral solution is placed in a dropping funnel and added to a vigorously stirred mixture of 150 g of sodium carbonate, 300 ml of 30-35% aqueous methylamine (Note 2) and 100 g of crushed ice in a 3 L flask, in a slow stream. The temperature of the reaction mixture was maintained at about -10 ° C during the addition, which required about 45 minutes (Note 3). The reaction mixture was extracted three times with an equal volume of ether. The ether extracts were dried over anhydrous sodium sulfate and evaporated at room temperature on a rotary evaporator. 65 g of crude 1-methyl-3- (p-tolyl) triazene are obtained (Note 4). This was placed in a water-cooled sublimation apparatus and the triazene was sublimated at 30 ° C under a pressure of 133.3 Pa. Yield: 43.3 g (0.29 mol, 62%) of yellow crystalline sublimate; 77-80 ° C (note 5). The sublimate can be recrystallized from hexane to give a white mirror crystalline triazene; mp: 80.5-81.5 ° C. More preferably, the sublimate is dissolved in a minimal amount of ether and twice the volume of hexane is added and then cooled to 0 ° C to give a white precipitate with a yellowish color; mp 79-81 ° C. The pure triazene yield was 33-37 g (47-53%) (Note 6).

Notes:

1. The starch-potassium iodide tests should be performed 1 to 2 minutes after stopping potassium nitrite addition.

2. Replaced with 40% aqueous methylamine.

3. The reaction is complete when the drop of the reaction mixture does not give a red level in an aqueous solution of sodium carbonate beta-naphthol.

4. The major impurity is 1,5-di- (p-tolyl) -3-methyl-1,4-pentazadiene (m.p. 148 ° C). This can be removed by fractional crystallization but the sublimation of the triazene is simpler.

5. The sublimate contains trace amounts of 1,3-di- (p-tolyl) triazene as detected by TLC analysis. Recrystallization affords pure 1-methyl-3- (p-tolyl) triazene.

6. The process is well carried out only with water soluble amines. Preparation 2 below is more applicable to water-insoluble amines.

Preparation 2

Ε. H. White et al., Tetrahedron Letters, No. 21, p. 761 (1961):

l- (n-butyl) -3- (p-chlorophenyl) triazene

A solution of p-chlorophenyl diazonium hexafluorophosphate in dimethylformamide, free from recrystallized from 2.87 g (10.1 mmol) of acetone-methanol in dimethylformamide, was slowly cooled to 0.73 g. 10.0 mmol) of butylamine, 15 g of powdered sodium carbonate and 30 ml of dimethylformamide. The diazonium salt may be added with stirring at room temperature, but a purer product may be obtained if the diazonium salt is prepared in a separate separating funnel at -5 ° C and is used there for the reaction. The reaction mixture is then warmed to 0 ° C and stirred until a negative probe with 2-naphthol (usually a few minutes is sufficient). Ether was then added, the reaction mixture was filtered, and the filtrate was washed with water and dried. (The triazene can be isolated at this point and recrystallized from pentane at low temperature.)

Preparation 3

7-Hydroxy-9a-me toxic toxin

2.2 g (6.6 mmol) of mitomycin-C are dissolved in 140 ml of 0.1 N sodium hydroxide (50%) and the reaction mixture is stirred for 30 hours at room temperature. The solution was adjusted to pH 4.0 with 1N hydrochloric acid and extracted with ethyl acetate (4 x 500 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated in vacuo at 30-35 ° C. A solid residue is obtained which is dissolved in ether and treated with excess hexane. A peach precipitate was obtained which was filtered and dried to give a fine peach powder product (1.4 g, 63%). ¹ H-NMR (pyridine-d 5, delta): 2.05 (s, 3H), 2.14 (bs, 1H), 2.74 (bs, 1H), 3.13 (d, 1H), 3.24 (s, 3H), 3.56 (d,

1H), 4.00 (dd, 1H), 4.37 (d, 1H), 5.05 (t, 1H), 5.40 (dd, 1H), 5.90 (br s, 2H).

Preparation 4

The mitomycin

7-Hydroxy-9α-methoxymitosan (100 mg, 0.30 mmol) and 1-methyl-3- (p-tolyl) triazene (100 mg, 0.67 mmol) were dissolved in dichloromethane (2 mL).

EN 201074 Β ml in diethyl ether. The reaction mixture is refluxed gently for 6 hours and then stirred at room temperature for 18 hours. TLC (dichloromethane: methanol (90: 10)) showed a purple spot of Rf = 0.36 and a trace of impurity Rf = 0.41. The reaction mixture was evaporated to dryness and chromatographed on Woelm neutral alumina using dichloromethane and dichloromethane-methanol (30: 1) as eluent. Fractions containing Rf = 0.36 were combined and evaporated to dryness. The dry residue was precipitated from dichloromethane with hexane to give an amorphous purple powder (25 mg, 24%); mp 161 ° C, m.p.

Elemental Analysis for: C 19 H 19 N 3 O 6 Calculated: C, 54.96; H, 5.44; N, 12.02%;

Found: C, 53.96; H, 5.37; N, 11.99%.

IR (KBr), max, cm ^-1 : 3400, 3300, 2950, 1700, 1630, 1575, 1200, 1060.

1 H-NMR (pyridine-d 5, delta): 1.82 (s, 3H), 2.74 (dd, 1H), 3.12 (d, 1H), 3.24 (s, 3H),

3.54 (dd, 1H, 3.96 (dd, 1H), 4.02 (s, 3H), 4.22 (d, 1H), 4.84 (broad s, 2H), 5.02 (t , 1 H, 5.38 (dd, 1H).

The yield of Preparation 4 can be increased to 63% using a dichloromethane reaction solvent and a reaction time of 24 hours at room temperature.

Preparation 5

To a 250 mL one-necked round bottom flask was placed solid sodium carbonate, 35% aqueous amine solution (amount given in Preparation 1) and ice, and the suspension was stirred at -5 ° C (ice-salt bath). A cold aqueous suspension of p-chlorophenyl diazonium hexafluorophosphate (Aldrich Chemical Co., Aldrich Chemical Co., pH 4) was added dropwise to the suspension. Upon completion of the addition, the reaction mixture was extracted with diethyl ether. The ether extracts were combined, washed with water, dried over magnesium sulfate and evaporated. The yellowish solid residue was purified by column chromatography over Woelm alumina, hexane: dichloromethane (1: 1). ('H-NMR measurement is performed.)

6-13. production

II. Most of the triazenes listed in the Table are prepared by the method of Preparation 1. The triazenes were purified by column chromatography on Woelm alumina.

3Q See sections 12 and 13 of Table II.

Triazenes are prepared by the method of Preparation 5.

II. spreadsheet

triazenes

Production number Amin formula Diazonium salt formula Triazene formula 1 (ARC) (XIV) (XVI) 6 (V) (XIV) (XVII) 7 (VI) (XIV) (XVIII) 8 (VII) (XIV) (XIX) 9 (VIII) (Xiv) (XX) 10 (IX) (XIV) (XXI) 11 (X) (XIV) (XXII) 12 (XI) (XV) (XXIII) 13 (XII) (XV) (XXIV) 1-6. example General Procedure 7-Alkoxy-9a-methoxy mitozánok followed by TLC (10% methanol in dichloromethane as eluent). 7-Alkoxy-9a-methoxymitosan is dark purple (1-6) 55 the patch of aluminum oxide appears

A solution of triazene (2.4 equivalents) in dichloromethane / methanol (4: 1) was added to a solution of 7-hydroxy-9a-methoxymitosan (60) in dichloromethane / methanol (60: 4). The reaction mixture was stirred at room temperature and the progress of the reaction was by thin layer chromatography. The reaction mixture, when considered complete by TLC analysis, is chromatographed on Woelm alumina. 7-Alkoxy-9a-methoxy-mitosane is obtained as an amorphous solid. The product obtained is prepared as described in Table III. Table 1-6. below.

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HU 201074 Β 1Π. Spreadsheet

7-Alkoxy-9a-methoxy-mitosans are compounds of formula (1)

Example No. ⁶ R ⁶ * ¹ H-NMR δ KCnr ¹ ) Elemental analysis (pyridine-ds, delta) ppm

l ^b butyl 0.80 (t, 3H), 1.44 (m, 4H), 1.84 (s, 3H), 2.08 (s broad, 1 H), 3.20 (s, 3 H 2, 3.52 (d, 1 H), 4.00 (dd, 1H), 4.28 (m, 3H), 5.04 (t, 1H), 5.44 (dd, 1H), 7.64 (wide s, 211) Elvi: C, 58.30; H, 6.44; N, 10.74%; Found: C, 58.34; H, 6.25; N, 10.80%. 2 ^b isopropyl 1.20 (d, 3H), 1.28 (d, 3H), 1.88 (s, 3H), 2.20 (s, 1H), 2.76 (s, 1H), 3.16 (s, 1H), 3.24 (s, 3H), 3, 56 (d, 1H), 4.00 (dd, 1H), 4.24 (d, 1H), 5.00 (m, 2H), 5.44 (dd, 1H) 3 ^c - ^d (the) 1.96 (s, 3H), 2.40 (m, 4H), 3480, 3260, Elvi: C, 52.60; 2.56 (t, 211), 2.76 (wide s, 2940, 1725, H, 5.95; 1H), 3.16 (d, 1H), 3.24 (s, 1620, 1210, N, 11.41%; 3H), 3.54 (d, 1H), 3.68 1055 Found: C, 52.75; H (m, 4H), 4.00 (dd, 1H), 4.26 6.00; N, 11.44%. (d, 1H) 4.60 (m, 2H), 5.04 (Corrected (t, 1H), 5.44 (dd, 1H). 0.5 mol% to CHCl3) 4 <B) 1.68 (s, 3H), 1.96 (s broad, 3430, 3500, Elvi: C, 59.99; H 1H), 2.72 (broad s, 1H), 2930, 1715, 5.49; N, 12.72%; 3.08 (bs, 1H), 3.20 1625, 1210, Found: C, 59.94; H (t, 3H), 3.50 (d, 1H), 3.92 (dd, 1H), 4.16 (d, 1H), 4.92 (m), 5.36 (dd, 1H). 1060 5.66; N, 12.63%. 5 (C) 1.92 (s, 3H), 2.12 (broad, s 3420, 3280, Elvi: C, 59.37; H 1H), 2.76 (br s, 1H), 2.84 2930, 1895, 5.60; N, 8.65; (t, 2H), 3.16 (broad s, 1H), 1620, 1210, S, 6.60%; 3.26 (s, 3H), 3.56 (d, 1H), 1065 Found: C, 59.26; 3.86 (s, 2H), 4.04 (dd, 1H), H, 5.66; N, 8.63; 4.28 (d, 1H), 4.60 (m, 2H), 5.12 (t, 1H), 5.48 (dd, 1H), 7.46 (ni), 7.76 (broad s). S, 6.66%. 6 (D) 1.88 (s, 3H), 2.04 (s, 3H), 2.24 3300, 2920, (wide s, 1H), 2.76 (wide s, 1710, 1625, - 1H), 3.08 (m, 5H), 3.24 (s, 3H), 1210, 1065

3.52 (d, 1H), 3.76 (t, 2H), 3.98 (dd, 1H), 4.24 (d, 1H), 4.72 (t, 2H),

5.04 (t, 1H), 5.40 (dd, 1H). 7 ^b (E) 1.88 (s, 311), 2.00 (broad, s 1H), 3440, 3280, Elvi: C, 54.96; H 2.72 (broad s, 1H), 3.08 (d, 1H), 2950, 1700, 5.89; N, 10.68%; 3.20 (s, 3H), 3.24 (s, 3H), 3.52 1630, 1200 Found: C, 54.45; (m, 3H), 3.96 (dd, 1H, 4.20 (d, 1065 H, 5.85; N, 10.42%. 1H), 4.56 (m, 2H), 5.04 (t, 1H), 5.40 (dd, 1H). 8 <F) 1.92 (s, 3H), 2.72 (m, 1H), 3.08 3460, 3360, Elvi: C, 54.15; H (d, 1H), 3.20 (s, 3H), 3.52 (dd, 3200, 2960, 5.50; N, 9.97%; (1H), 3.84 (m, 4H), 3.94 (dd, 1H), 1720, 1625, Found: C, 53.44; H 4.20 (d, 1H), 4.60 (m, 2H), 4.96 1210, 1060 5.46; N, 9.74%.

(t, 1H), 5.28 (m, 1H), 5.36 (dd,

1H), 7.52 (br s, 2H).

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HU 201074 Β

b) Urakawa et al., J. Antibotics,

23: 804-809 (1980);

c) Molecular ion detected (+) and (-, CIMS;

d) It can also be produced by the alcoholysis of mitomycin A, following the procedure described by Urakawa et al.

Claims (10)

PATENT CLAIMS A process for the preparation of mitomycin A analogs of formula (I) wherein R ⁶ is C 1-6 alkyl or monosubstituted C 1-4 alkyl wherein the substituent is a C 1-4 alkoxy, benzylthio, morpholino, pyridyl. -, 1,3-dioxolyl-2- or (1-4C) alkanoylamino- (1-4C) alkyldithio, characterized in that the mitosane (II) is reacted with a triazene (III), wherein in the general formulas, R ^s is as defined in the foregoing and Ar is a group derived from a diazotizable aromatic amine. Process according to claim 1, characterized in that the triazene (III) is 1-methyl-3- (4-methylphenyl) -triazene. 3. A process according to claim 1, wherein at least 2 molar equivalents of triazene are used per mitosane of formula II. 4. A process according to claim 1, wherein the reaction medium is an inorganic liquid organic solvent which is soluble in mitosane (III). The process according to claim 1, wherein the reaction mixture is selected from the group consisting of lower alkanol, lower alkanoic acid alkyl ester, lower dial5 alkyl ether, lower polyhalogenated aliphatic hydrocarbon and cyclic aliphatic ether, wherein the maximum number of carbon atoms is eight. . The method of claim 1, wherein Characterized in that the reaction medium is dichloromethane, methanol, diethyl ether, ethyl acetate or a mixture of two or more thereof. The method of claim 1, wherein Characterized in that the reaction is carried out at a temperature of 0-25 ° C. 8. A process according to claim 1 for the preparation of compounds of formula I wherein R ⁶ is 2- (benzoethylthio) ethyl, wherein the starting materials are suitably substituted. 9. A process according to claim 1 for the preparation of compounds of formula I: Wherein R ⁶ is 2- (2-pyridyl) ethyl, wherein the starting materials are suitably substituted. The method of claim 1 30 for the preparation of compounds of formula I wherein R ⁶ is 2- (4-morpholinyl) ethyl, characterized in that the starting materials are suitably substituted. 35 11. The method of claim 1, formula (I) compounds of formula, in which R ⁶ represents a (l, 3-dioxol-2-yl) methyl group, characterized in that correspondingly substituted starting 40 materials are used.