DD233844A5 - METHOD FOR PRODUCING MITOMYCIN ANALOGIC COMPOUNDS - Google Patents

Abstract

Described are novel methods of treating neoplastic disease states in animals, wherein a therapeutically effective amount of a compound of formula IIIa wherein Y denotes hydrogen or a lower alkyl and Z represents a hydroxy-substituted 1-pyrrolidinyl radical or a lower alkyl substituted one Piperidyl radical or a 1-piperazinyl radical or an anilino radical substituted by acetamino, acetyl-carbamido, cyano, carboxy-lower-alkyl-amino, di-lower-alkoxy, nitro, sulfamyl or lower-alkyl or a radical of the formula -R - N-R1, wherein R is hydrogen or lower alkyl and R 1 is a nitrogen-containing heterocyclic radical selected from the group consisting of amino-substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R 1 is a substituted lower one Alkyl radical selected from amino-lower alkyl, lower alkylamines no lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxyphenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl and pyridylethyl group.

Description

Mitomyein-analogous compounds

Field of application of the invention

The present invention relates generally to antibiotic see Hitosan compounds and their use in the treatment of neoplastic disease states in animals! »

Characteristic of the known technical solutions

As to the background of the present invention, U.S. Patent No. 4,268,676 ₃ discloses co-pending U.S. Patent Application Ser. No. 206,529 filed on Aug. 13, 1980, as well as co-pending US patent application Serial Uo. 264,187, filed on Nov. 15, 1981, (DE-OS 3,217,769). US Pat. No. 4,276,676 and co-pending US patent application Ser. No. Uo. 206,529 contain comments on the current search for new and suitable mitomycins structurally related compounds having antibiotic activity, have low toxicity and have a considerable extent antitumor activity in animals * in the applications mentioned in particular novel compounds of the formula I.

τ. ^ CH ₂ OCi ₅ H ₂

revealed in the

- "ts -

Y denotes hydrogen or lower alkyl and X denotes a thiazolamino radical, a furfurylamino radical or a radical of the formula

R f

-N-

R "

R ²

in which

1 2 R, R and R are the same or different

and are selected from the group consisting of hydrogen and lower alkyl, and R is selected from the group consisting of lower alkenyl, halo lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl and benzenesulfonamide.

The U.S. patent and application also discloses novel methods of treating neoplastic disease conditions in animals which are characterized in that a therapeutically effective amount of a compound of formula Ia

CH ₂ OCNH ₂

is administered in the

Y denotes hydrogen or lower alkyl and

Z is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical or a radical of the formula

in which

4 5 6 R, R and R are the same or different

and are selected from the group consisting of hydrogen and lower alkyl and

7 R is selected from lower alkenyl,

halogeno-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl,

Thienyl, formamyl, tetrahydrofuryl, benzyl

and benzenesulfonamide existing group.

The co-pending US patent application serial no. 264,187 discloses other compounds having a considerable degree of antitumor activity in animals corresponding to formula Ha

Z 0 0 I! y CH ₂ OCNII ₂ _J -JL ^H 3 ^C 0 NY

Ha

in the

Y denotes hydrogen or a lower alkyl and

Z is a substituted by a lower alkoxy quinolinylamino radical, a cyano-substituted pyrazolylamino radical or a mono- or di-substituted by lower alkyl thiazolamino radical, or

a nitrogen-containing heterocyclic radical selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl radicals, or a radical substituted by cyano, phenyl, carboxamido or lower alkoxycarbonyl; Aziridinyl radical, or

a substituted by lower alkyl, formyl or acetylphenyl 1-piperazinyl radical, or a substituted by hydroxy or piperidyl 1-piperidyl radical, or

a pyridylamino radical substituted by lower alkoxy, amino or halogen, or an aniline radical substituted by carboxamido, mercapto or methylenedioxy, or a radical of the formula R

-NR ¹ in the

R is hydrogen or lower alkyl and

R ¹ for a nitrogen-containing heterocyclic

A radical selected from among quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, as well as those from lower

Alkyl and halogen substituted derivatives

existing group, or a butyrolactonyl radical, or an adamantyl radical, or a mono-lower alkoxy-substituted phenyl radical or a substituted

lower alkyl radical selected from the mercapto-ep-lower alkyl, carboxy-lower alkyl, mono-, di- or tri-lower alkoxy-lower alkyl, lower alkylthio-lower alkyl and its lower alkoxycarbonyl-substituted derivatives, cyano-lower alkyl, mono-, di- or tri-lower alkoxyphenyl Hiederalkyl, phenyl cyclo-lTiederalkyl, - _{1-pyrrolidinyl-s} Mederalkyl H-lower alkyl-pyrrolidinyl-Hiederalkyl, N ~ morpholinyl JMiederalkyl and Mederdialkylamino-lower alkyl group are existing, designated "

The following U.S. Patent Nos. 3,332,944, 3,410,867, 4,231,936, 3,429,894, 4,268,676, 3,450,705 and 3,514,452, as well as the publication of Imai et al., Are also related to the background of the present invention. , Gann 21> p. 560-562 (1980) a

Object of the invention

The aim of the invention is to provide new, structurally related mitomycin compounds which have antibiotic activity, are low in toxicity and have considerable anti-tumor activity. "

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties · According to the invention, novel compounds of formula III

CH ₂ GCIlH ₂

III

provided in the

Y denotes hydrogen or a lower alkyl and

Σ a hydroxy-substituted 1-pyrrolidinyl radical or

a substituted by lower alkyl piperidyl radical or

an anilino radical or a radical of the formula R which is substituted by acetamino, acetyl, carbamido, cyano, carboxy-lower-alkyl-amino, di-lower-alkoxy, nitro or sulfamyl

-NR ¹

designated in the

R is hydrogen or lower alkyl and

R is a nitrogen-containing heterocyclic radical selected from the group consisting of amino-substituted triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro and halogenoubstituted derivatives of benzothiazolyl or

R is a substituted lower alkyl radical selected from among amino-lower alkyl, lower alkylamino-lower alkyl, hydroxy-lower alkylamino-lower alkyl, hydroxy-lower alkoxy

lower alkyl, imidazolyl-lower alkyl, nitro-substituted imidazolyl-lower alkyl, mono- and di-hydroxyphenyl-lower alkyl, nitro-substituted pyridylamino-lower alkyl and piperazinyl-lower alkyl group.

The present invention furthermore relates to novel methods for treating a neoplastic disease state in an animal, which are characterized in that an animal suffering from such a disease is a therapeutically effective amount of a compound of the formula IIIa

CH ₂ OCNH ₂

is administered in the

Y is hydrogen or a lower alkyl and Z is a hydroxy-substituted I-pyrrolidinyl radical, or

a substituted by lower alkyl piperidyl radical or

a 1-piperazinyl radical or an anilino radical substituted by acetamino, acetyl, carbamido, cyano, carboxy-lower alkyl-amino, di-lower-alkoxy, nitro, su-amyl or lower-alkyl;

a remainder of the formula

-NR ¹

designated in the

R for. Hydrogen or lower alkyl and

R is a nitrogen-containing heterocyclic radical selected from dsr consisting of amino-substituted triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogeno-substituted derivatives of benzothiazolyl group or

R is a substituted lower alkyl radical selected from among amino-lower alkyl, lower alkylamino-lower alkyl, hydroxy-lower alkylaraino-lower alkyl, hydroxy-lower alkoxy-lower alkyl, imidazolyl-lower alkyl, nitro

substituted imidazolyl-lower alkyl, mono- and di-hydroxyphenyl-lower alkyl, nitro-substituted pyridylamino-lower alkyl, piperazinyl-lower alkyl and pyridylethyl existing group.

Unless otherwise specified, the term "lower" as used in connection with "alkyl" radicals denotes straight-chain or chain-branched radicals having one to six carbon atoms. Thus, "lower alkyl" refers to and includes methyl, ethyl, propyl, butyl, pentyl, and hexyl radicals as well as isopropyl radicals, t-butyl radicals, and the like. Similarly, the term "lower" in connection with "alkoxy" refers to a radical having one to six carbon atoms.

It can be seen that the compounds of the formula III are detected in their entirety by the individual details of the formula IIIa. In other words, all new mitomycin antibiotic derivatives of Formula III are useful in the practice of new antineoplastic therapies.

of value based on the administration of compounds of the formula IIIa.

Mitomycin derivatives according to the present invention are prepared by reacting mitomycin A with appropriately selected amine compounds. The N-alkyl

Mitomycin (e.g., N-methylmitomycin) derivatives are similarly prepared by reacting selected amines with N-alkylmitomycin A prepared from mitomycin C, e.g. by the general methods as described by Cheng et al, J. Med. _2_0, No. 6, 767-770 (1977). The preparative

Reactions generally provide the desired product in the form of a crystalline pesticide that is readily soluble in alcohol.

The therapeutic methods of the present invention include the administration of effective amounts of one or more compounds of Formula IIIa as the active ingredient, together with suitable pharmaceutically acceptable diluents, adjuvants and carriers, to an animal suffering from a neoplastic disease state of the administration according to the methods of the invention may be from about 0.001 to about 5.0 mg, preferably from about 0.004 to 1.0 mg, of the compounds. "Such dosage units may be administered in such a manner that a daily dose of dosiSj is Body weight of the treated animal is administered from about 0.1 to 100 mg / kg, preferably from about 0.2 to 51-2 mg / kg. In the practice of the methods of the invention, parenteral administration, in particular intrapetitoneal administration, is the preferred way «

Other aspects and advantages of the present invention will become apparent from the following description

The invention will be explained in more detail below with reference to some examples.

The following Examples 1 to 32, which describe the preparation of certain presently preferred compounds according to the present invention, are merely illustrative of the same but are not intended to be limiting thereof. Unless otherwise stated, all reactions were carried out without heat at room temperature (20 ^° C.). Unless otherwise stated.

-71

- -24. -

All Thin Layer Chromatography (TLC) procedures to evaluate the progress of the reaction involved the use of a precoated silica gel plate and a mixture of methanol and chloroform (2: 8 by volume) as a developing solvent.

example 1

1, la, 2 , 8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6 - (- 3-hydroxy-1-pyrrolidinyl) azirino- (\ I 2 ', 3': 3, 4 / pyrrole / 1,2-a 7indole-4,7-dione carbamate

A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3-pyrrolidinol (13 mg) under nitrogen at room temperature. When thin layer chromatography on silica gel (2: 8 methanol-chloroform as solvent) revealed that no starting material was present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel using the same solvent system. The procedure provided 23 mg (yield: 40%) of the desired product. , .- a melting point of 82-85 ° C (dec.) And the next

the following analysis data:

NMR (DMSO-d,., TS) £ values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new signals at 1.6-2.2 (m, 2), 2.8-3.1 (broad s, 5) and 4.0-4.3 (m, 1).

Example 2

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-methylpiperidyl) azirino / 2 ', 3': 3,4 / pyrrolo / 1, 2-a / indole-4,7-dionecarbafnate

The designated compound was prepared according to the procedure described in Example 1. From 70 mg of mitomycin A and 200 mg of 3-methylpiperidine 46 mg (yield: 55%) of the desired product having a melting point of 75-88 ⁰ C (dec.) And the following analytical data:

NMR (CDCl ₃ , TS) ί values in ppm:

Absence of the 6-methoxy peak at 4.02 and new peaks appear at 0.85 (d, 3), 1.10-2.15 (m, '5) and 2.15-3.32 (m, 4 ).

Example 3

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (1-piperazinyl) azirino / 2 ', 3': 3,4_7pyrrolo- / 1,2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1. From 60 mg of mitomycin A and 30 mg of anhydrous piperazine, 23 mg (yield: 34%) of (dec.) Of the desired product having a melting point of more than 200 ⁰ C and obtained the following analytical data:

NMR (DMSO-dg, TS); <$ - values in ppm:

Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 1.9 (broad s, 1) and 2.9 (s, 8). ,

Example 4

1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-

5-methyl-6- / 4- (acetylamino) anilino-7-azirino

/ ~ 2 ', 3': 3,4 7pyrrolo / "1,2-a 7indole-4,7-dionecarbamate

The designated compound was after that in Example 1

described procedure produced. From 100 mg

Mitomycin A and excess 4- (acetylamino) aniline

f ⁷ ^) , 102 mg (yield: 7 6%) of the desired product

with a melting point of 143-145 ° C (dec.) and the following analytical data:

NMR _(CDCl3, TS); (T-values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.1 (s, 3), 7.4 (d, 2), 7.6 (s, 1), and 8.9-9.3 (s, 1).

Example 5

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy v.,., - ' 5-methyl-6- / 3- (acetylamino) anilino-7-azirino-

_ / 2 ', 3': 3, 4 7pyrrolo / 1, 2-a 7indpl-4,7-dione carbamate

The designated compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg mitomycin A and 150 mg 3- (acetylamino) aniline, 67 mg (yield: 72%) of the desired product having a melting point of 140-143 ° C (dec.) And the following analytical data were obtained:

NMR (acetone-dg, TS); Ppm in S : Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.1 (s, 3), 6.7-7.5 (m, 4), 8.0 ( wide s, 1) and 9,3 (s, 1). *

Example 6

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-acetylanilino) azirino / 2 ', 3': 3,4 / pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg mitomycin A and 510 mg 4-acetylaniline, 25 mg (yield 28%) of the desired product having a melting point of 103-104 ⁰ C 1-5 (dec.) And the following analytical data were obtained:

NMR (CDCl-, TS); <T-values in ppm:

Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 2.1 (s, 3), 6.6 (d, 2), 7.3 (d, 2), and 7.0-7, 3 (wide s, 1).

Example 7

1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-

5-methyl-4- (1-ureido) anilino / -azirino-

/ 2 ', 3': 3,4 / pyrrolo / 1,2-a / indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 50 mg mito

- "2s -

aniline were mycin A and 227 mg · 4- (1-ureido) 49 mg (yield: 67%) of the desired product having a melting point of 93-95 ⁰ C (dec.) and the following analytical data:

NMR (CDCl, TS); (5 values in ppm:

Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 5.03 (s, 2), 6.9 (d, 2), 7.3 (d, 2), 8.0 (s, 1) and 8,4 (s, 1).

Example 8

' 1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-cyanoanilino) azirino / 2', 3 ': 3,4 _ / pyrrolo / 1,2-a / indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, but with the difference,

that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 472 mg of 4-aminobenzonitrile 23 mg (yield: 24%) of the desired product ER with a melting point of 124-126 ⁰ C and with the following analysis data (dec.)

hold:

NMR (CDCl-, TS); cf values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.6 (d, 2), 7.4 (d, 2), and 7.0-7.3 (broad s, 1).

Example 9

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-cyanoanilino) azirino / 2 ', 3': 3,4 / pyrrolo / 1,2-a / indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of potassium carbonate was added. From 71 mg of mitomycin A and 500 mg of 3-aminobenzonitrile 30 mg (yield: 34%) of the desired product having a melting point of 97-98 ⁰ C and the following analytical data (dec.):

NMR (CDCl-, TS); <T-values in ppm: Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 7.2-7.8 (m, 4).

Example 10

1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy- 5-methyl-6- / 4- (N-glycyl) anilino-7-azirino / ~ 2 ', 3': 3, 4 7pyrrolo / l, 2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. Aniline were composed of 50 mg of mitomycin A and 249 mg of 4- (N-glycyl) 62 mg (yield: 90%) of the desired product having a melting point of 83-85 ⁰ C (dec.) And the following analytical data:

NMR (DMSO-dg, TS); S-values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.1 (s, 2), 6.3-6.6 (broad s, 2) 6.6-6.8 (broad s, 2 ) and 6,6-7,1 (broad s, 2).

Example 11

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3,4-dimethoxyanilino) azirino / 2 ', 3': 3,4 / -pyrroles? / "!, 2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1. From mitomycin A 50 mg and 3,4-dimethoxyaniline 229 mg, 61 mg (yield: 91%) of the desired product having a melting point of 114-116 ° C (dec.) And the following analytical data were obtained:

NMR _(CDCl3, TS); cT values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.8 (s, 6), 6.3-6.9 (m, 3), and 7.7 (s, 1).

Example 12

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3,5-dimethoxyanilino) -a-zirino / 2 ', 3': 3,4 7-pyrrolo / 1,2-a-7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 5 0 mg of mitochondrial

mycin A and 229 mg of 3,5-dimethoxyaniline was added 60 mg (yield: 88%) of the desired product having a melting point of 98-100 ⁰ C (dec.) is obtained and the following analytical data:

NMR (CDCl ₃ / TS); cT values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.8 (s, 6), 5.9-6.4 (broad s, 3) and 7.6 (s, 1).

Example 13

1, 1a, 2, 8, 8a, 8b-hexahydro-8- (hydroxymethyl) -S-methoxy-5-methyl-6- (4-nitroanilino) azirino / 2 ', 3': 3,4 / pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of potassium carbonate was added. From 70 mg mitomycin A and 27 6 mg 4-nitroaniline, 16 mg (yield: 9%) of the desired product with a melting point of 132-134 ° C (dec.) • and the following analytical data were obtained:

NMR (acetone-d ,, TS); <5 "values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.9-7.3 (d, 2), 7.4-7.9 (d, 2) and 7.9-8.4 ( wide s, 1).

Example 14

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-sulfamylanilino) azirino / 2 ', 3': 3,4_ 7pyrrolo / 1 , 2-a 7indol-4 _r 7-dioncarbamat

The designated compound was prepared by the procedure described in Example 1, except that a small amount of potassium carbonate was added. From 70 mg of mitomycin A and 68 mg SuIfanilami 8 d 25 mg (yield: 26%) of (dec.) Of the desired product having a melting point of 113-115 ⁰ C obtained and the following analytical data:

NMR _(CDCl3, TS); tf values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 7.0 (d, 2), 7.5 (s, 1), and 7.9 (d, 2).

Example 15

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-methylanilino) azirino / 2 ', 3': 3,4-7pyrrolo / 1 , 2-a / indole-4,7-dioncarbama.t

The designated compound was prepared according to the procedure described in Example 1. From 60 mg mitochon- - mycin A and excess 4-methylaniline, 63 mg (yield: 86%) of the desired product having a melting point of 113-115 ⁰ C obtained and with the following analysis data: C (dec.)

LO

NMR _(CDCl3, TS); c $ "values in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.3 (s, 3), 6.5-7.3 (broad s, 4) and 7.6 (broad s, 1).

"'-. · · Example 16

_r l la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-methylanilino) -azirino / 2 ', 3': 3,4 7pyrro-: lo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1 TO. From 70 mg mitomycin A and 276 mg 3-methylaniline 66 mg (yield: 78%) of the desired product having a melting point of 89-91 ⁰ C (dec.) And the following analytical data were obtained:

MMR (CDCl3 ,, TS); X values in ppm: Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.4 (s, 3), 6.7-7.5 (m, 4); and 7.8 (s, 1).

';. ;; ..,. ^; ". ^; .; - ^ [." (: '...,. Example 17 '.

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (5-amino-1,2,4-triazol-3-yl) -amino -azirino / ~ 2 ', 3': 3,4 7pyrrolo / ~ l, 2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of potassium carbonate was added,

manufactured. From 50 mg mitomycin A and 30 mg 3,5-diamino-1,2,4-triazole were 13 mg (yield: 5.5%) of the desired product having a melting point of 117-120 ⁰ C (dec.) And the received the following analysis data:

NMR (DMSO-dg, TS); <i-values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of a new peak at 5.37 (s, 3).

Example 18

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (3-methylisothiazol-5-yl) -amino-7-azirino- / ~ 2 ', 3 ': 3,4 7pyrrolo / l, 2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, but with the difference,

that 0.5 ml of triethylamine was added. From 60 mg mitomycin A and 30 mg S-amino-S-methylisothiazole hydrochloride were added 4.5 mg (yield: 8.5%) of the desired product having a melting point of 87-9O ⁰ C (dec.) And the analytical data below

receive: ,

NMR _(CDCl3, TS); d-values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.3 (s, 3), 6.1 (s, 1), and 6.4 (s, 1).

AEA

Example 19

1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Ba-methoxy- 5-methyl-6- (2-benzothiazolyl) amino 7-azirino / 2 ', 3': 3, 4 7pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, but with the difference,

ΐ; From 50 mg of mitomycin A and 25 mg of 2-aminobenzothiazole were added 12 mg (yield: 18%) of the desired product having a melting point of 82-85 ° C (decomp.): a small amount of solid potassium carbonate was added. and the following analysis data:

NMR (CDCl3 ,, TS); <f-values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 7.1-8.0, (m, 5).

Example 20

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (6-nitrobenzothiazol-2-yl) amino / -azirino- : / ~ 2 ' , 3 ': 3,4 7pyrrolo / l, 2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 2-amino-6-nitrobenzothiazole 20 mg (yield: 27%) of the desired product having a melting point of 86-89 ⁰ C and the following analytical data (dec.):

NMR (DMSO-dg, TS); <5 values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.9-8.3 (m, 4).

Example 21

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (4-chlorobenzothiazol-2-yl) -amino-azirino- / 2 ', 3' : 3.4 vpyrrolo / 1,2-a-7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 150 mg mitomycin A and 27 mg 2-aminochlorobenzothiazole, there were obtained 30 mg (yield: 14%) of the desired product having a melting point of 89-91 ° C (dec.) And the following analytical data:

NMR (CDCl-, TS); ci values in ppm:

Absence of the 6-methoxy peak at 4.02 and on-V - new peaks appear at 7.1-8.0 (broad s, 4).

Example .22

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (2-aminoethyl) amino / -azirino- / 2 ', 3': 3, 4 7pyrrolo / 1 ', 2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1 ", except that the solvent was dichloromethane, and 50 mg mitomycin A and 10 mg 1,2-diaminoethane were obtained

 , '.: -. . "- 3+ - '

Obtained 35 mg (yield: 65%) of the desired product having a melting point of 202-205 ⁰ C (dec.) And the following analytical data:

NMR _(CDCl3, TS); J values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.5 (broad s, 2) and 3.5 (broad s, 4).

Example 23

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / methyl (2-methylaminoethyl) amino / -azirino- / ~ 2 ', 3': 3,4 7pyrrolo / ~ l, 2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg mitomycin A and 25 mg sym-dimethyl ethylenediamine, 28 mg (yield: 50%) of the desired product of melting point 99-101 ° C (dec.) And the following analytical data were obtained: '. ^ Λΐ, · · -. ·; ' -. '· ^J. "'

. ' - ^: NMR (CDCl ₃ , TS); cf values in ppm:

Absence of the 6-methoxy peak at 4.02 and up; . ' ·: New peaks occur at 1.3 (s, 1), 2.5 (s, 6) and

as

Example 24

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2- (2-hydroxyethylamino) ethylamino-7-azirino / ~ 2 ', 3': 3,4 7pyrrolo / ~ l, 2-a 7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 18 mg of 2- (2-aminoethylamino) ethanol, 35 mg (yield: 58%) of the desired product having a melting point of 115-118 ⁰ C and with the following analysis data (dec.):

NMR (CDCl-, TS); S values in ppm:

---- j

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.7 (broad s, 7) and 3.7 (t, 3).

Example 25

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (2-hydroxyethoxy) ethylamino-7-azirino- / 2 ', 3': 3,4 7pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that the solvent was dichloromethane. From 60 mg mitomycin A and 20 mg 2- (2-aminoethoxy) ethanol, 30 mg (yield: 42%) of the desired product were obtained.

obtained with a melting point of 99-102 ⁰ C (dec.) and the following analytical data:

a ic

NMR (CDCl-, TS); cT values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.3-3.9 (broad s, 9) and 6.4-6.8 (broad s, 1).

Example 26

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -S-methoxy-5-methyl-6- / 2- (4-imidazolyl) ethylamino-7-azirino- / ~ 2 ', 3' : 3,4 7pyrrolo / "1,2-a-7indole-4,7-dionecarbamate

The designated compound was prepared according to the procedure described in Example 1, except that 128 mg of sodium methoxide was added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride 61 mg (yield: 71%) of the desired product having a melting point of 72-73 ⁰ C and the following analytical data (dec.):

NMR (DMSO-dg, TS); (T-values in ppm:

Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 3.0-3.27 (m, 4), 7.5 (s, 1), 8.0-8.7 (broad s, 2) and 8,1 (s, 1).

Example 27

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (2-nitro-1-imidazolyl) ethylamino / -azirino7 2 ', 3 ': 3,4 7pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 72 mg mitomycin A and excess 1- (2-aminoethyl) -2-nitro-

imidazole, 60 mg (yield: 70%) of the desired product having a melting point of 83-85 ° C (dec.) and the following analytical data were obtained:

NMR (CDCl-, TS); σ values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.4 (t, 2), 4.6 (t, 2), 7.3 (broad s, 2), and 7.6 (s, 1).

Example 28

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (4-hydroxyphenyl) ethylamino / -azirino- / 2 ', 3': 3,4 / pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 130 mg of mitomycin A and 510 mg of tyramine 138 mg (yield: 81%) of the desired product having a melting point of 120-125 ⁰ C and with the following analysis data (dec.):

NMR _(CDCl3, TS); (Γ values in ppm:

Absence of the 6-methoxy peak at 4.0 2 and appearance of new peaks at 2.6 (t, 2), 2.8 (t, 2), 6.7 (d, 2), 7.0 (d, 2) and 8.0 (s, 1).

as

Example 29

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2- (3,4-dihydroxyphenyl) ethylamino-7-azirino / 2 ', 3' : 3.4 zpyrrolo / 1,2-a-7indole-4,7-dione carbamate

The designated compound was prepared by the procedure described in Example 1, except that 138 mg of sodium methoxide was added. From 110 mg mitomycin A and 660 mg 3-hydroxytyramine hydrobromide, 60 mg (yield: 40%) of the desired product, which decomposed above 125 ^° C. without melting and gave the following analytical data, were obtained:

NMR _(CDCl3, TS); S values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.6 (t, 2), 2.8 (t, 2), 6.4-6.8 (m, 3), and 8.3 (broad s, 2).

Example 30

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- 2- (5-nitro-2-pyridyl) amino / ethylaminoazirino / 2 ' , 3 ': 3,4 7pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that the solvent was dichloromethane

 From 50 mg mitomycin A and 30 mg 2- (2-aminoethylamino) -5-nitropyridine, 40 mg (yield: 56%) of the

desired product with a melting point of 76-79 ⁰ C (dec.) And the following analysis data obtained:

NMR (CDCl-, TS); / Values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.3-4.0 (m, 4), 6.2-6.7

(broad s, 2), 8.1 (d, 1), 8.2 (d, 1) and 9.0

(s, 1).

( ") Example 31

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -S-methoxy-5-methyl-6- / 2- (1-piperazinyl) ethylamino-7-azirino- / 2 ', 3': 3,4_ / pyrrolo / 1,2-a / indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, except that the solvent was dichloromethane

From 50 mg of mitomycin A and 20 mg of N- (2-aminoethyl) piperazine, 23 mg (yield: 36%) of (dec.) Of the desired product having a melting point of 138-141 ⁰ C obtained and the following analytical data:

NMR _(CDCl3, TS); d-values in, ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.6-2.1 (broad s, 1), 2.2-2.6 (broad s, 8), 2.6-2, 8 (broad s, 4) and 6.9 (t, 1).

Example 32

1, la / 2,8,8a, 8b-Hexahydro-8- (hydroxymethy1) -Sa-methoxy- 5-methyl-6- / 2- (2-pyridyl) ethylamino-7-azirino

/ .2 ', 3': 3, 4 / pyrrolo / 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 70 mg of mito ^ mycin A and 250 mg of excess 2- (2-aminoethyl) pyridine, 51 mg (yield: 56%) of the desired product having a melting point of 64-77 ° C (dec.) And the following analytical data were obtained :

NMR (CDCl-, TS); Values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.8 (m, 4), 7.0-7.8 (m, 3), and 8.5 (d, 1).

With particular reference to the compounds designated by the formula IIIa, the above examples show the following variations in the structures:

1. Compounds in which Z is a hydroxy-substituted 1-pyrrolidinyl radical, are represented by Example 1.

2. Compounds in which Z is a lower alkyl substituted piperidyl radical are represented by Example 2.

3. Compounds in which Z is a 1-piperazinyl radical or a radical which is substituted by acetamino, acetyl, carbamido, cyano, carboxy-lower-alkyl-amino, di-lower-alkoxy,

Nitro, SuIfamyl or lower alkyl substituted anilino radical are each represented by the examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16.

4. Compounds in which Z is a radical of the formula

-NR ¹

designated in the

R is a nitrogen-containing heterocyclic radical selected from the amino-substituted

stands triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro and halogenosubstiuxerten derivatives of benzothiazolyl existing group,

are each represented by Examples 17, 18, 19, 20 and 21.

5. Compounds in which Z is a radical of the formula

-NR ¹

designated in the

R is a substituted lower alkyl radical

('selected from amino-lower alkyl, lower

alkylamino-lower alkyl, hydroxy-lower alkylamino-lower alkyl, hydroxy-lower alkoxy

lower alkyl, imidazolyl-lower alkyl, nitro-substituted imidazolyl-lower alkyl, mono- and di-hydroxyphenyl-lower alkyl, nitro-substituted pyridylamino-lower alkyl, piperazinyl-lower alkyl and pyridylethyl group,

are each represented by Examples 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32.

Although none of the foregoing examples specifically illustrates compounds in which Y is other than hydrogen, compounds in which Y is lower alkyl nonetheless fall within the scope of the present invention, including the analogously substituted compounds in the aforementioned US Pat Patent Applications Serial No. 206 529 and 264 187.

It is believed that the compounds according to the present invention have antibacterial activity against gram positive and gram negative microorganisms in

in a way similar to that observed with naturally occurring mitomycins; the compounds are therefore of potential value as therapeutic agents for the treatment of bacterial infections in humans and animals.

The value of the compounds of the formula IIIa in the context of antineoplastic therapeutic methods according to the invention is demonstrated by the results of in vivo screening studies in which the compounds were administered with variation of the dosage to mice in which P388 leukemia had been induced. The studies were performed according to the "Lymphocytic Leukemia P388 - Protocol 1,200", published in: Cancer

Chemotherapy Reports, Part 3, Volume 3, No. 2, page 9 (September 1972). Briefly, the screening studies involved administering the test compounds to female CDF mice previously infected with 10 ascites cells by intraperitoneal implantation.

had been fished. The test compounds were administered only on the first day of the test and the animals were monitored for their vitality, inter alia, over a period of 35 days.

The results of the screening studies of the compounds of Examples 1 to 32 are shown in Table 1 below. The values given for the optimal dose ("OD"), ie the dose, based on the body weight of the animal, in mg / kg, at which the maximum therapeutic effects are consistently observed, are given. Also indicated is the mean survival time ("MST"), expressed as the MST of the test animals compared to the MST of the control animals multiplied by 100 ("% T / C"). In connection with f '' \ cited above in vivo test method P388

" ^y means a"% T / C "value of 125 or higher is a sig

significant antineoplastic therapeutic activity. The lowest dose, in terms of body weight, in mg / kg at which the T / C value of 125% is reached is known as the minimum effective dose ("MED"). Their numerical values are also given in Table 1. It should be noted that the results obtained in the P388 screening tests and listed in Table 1

0 "exceptionally high MST values also indicated the lack of significant toxicity of the compounds at the dosages used.

25

30

Table 1 MST MED example Optimal dose O.D. % TC mg / kg No. mg / kg 163 0.8 238 <0.2 1. 25.6 200 0.2 2 25.6 > 333 <0.2 3 12.8 231 0.2 4 25.6 5 25.6

of

Table 1 - continued

example Optimal dose MST MED O.D. No. mg / kg % TC mg / kg 6 6.4 167 0.4 7 25.6 194 1.6 8th 3.2 150 0.8 9 12.8 172 <0.2 10 25.6 322 0.8 11 12.8 > 333 0.2 12 6.4 161 0.4 13 3.2 172 > 0.2 14 25.6 225 0.2 15 12.8 167 0.4 16 12.8 181 0.4 17 12.8 181 1.6 18 25.6 169 0.8 19 25.6 150 12.8 20 25.6 128 25.6 21 25.6 144 1.6 22 3.2 178 0.4. 23 25.6 133 12.8 24 12.8 , 133 12.8 25 25.6 181 0.4 26 25.6 163 1.6 27 25.6 150 3.2 28 25.6 218 1.6 29 12.8 139 12.8 30 12, C 144 6.4 31 25.6 138 12.8 32 25.6 > 375 0.2

The most preferred compounds used as antineoplastic agents according to the present invention are undoubtedly those having more than twice the life-prolonging ability of those generally characterized as a measure of significant therapeutic potential, ie, the compounds, which have an MST value (in% T / C) that is greater than 2 χ 125. It can be seen that the compounds of Examples 4, 10, 11 and ''' ^Λ 32 belong to this group of compounds.

As can be seen from Table 1, such low initial unit doses as only 0.2 mg / kg showed a significant long-term antineoplastic effect. Accordingly, the methods of the present invention may include the therapeutic administration of dosage units of the compounds that are low enough to be as low as 0.001 mg, or as high as 5 mg, preferably of dosage units in the range of 0.004 to 10 mg of the compounds as active ingredients in the form of suitable pharmaceutical preparations. Such preparations can be administered according to a treatment protocol which, based on the body weight of the neoplastic

disease of suffering animal, a daily dosage of about 0.1 to 100 mg / kg, preferably from about 0.2 to 51.2 mg / kg sets. Preferably, the compounds are administered parenterally. Pharmaceutical compositions suitable for practical use in the

0 are suitable for the process according to the invention, can simply consist of solutions of one or more compounds of the formula IHa in water, but they

3Q

may also contain well known pharmaceutically acceptable diluents, adjuvants and / or carriers, for example, saline for medical use.

Claims (2)

63 526 11 invention claim 1. A process for the preparation of mitomycin-analogous compounds of the formula III in the Y denotes hydrogen or a lower alkyl and X denotes a hydroxy-substituted 1-pyrrolidinyl radical or a lower alkyl radical Piperidyl radical or an anilino radical substituted by aceto-amino, acetyl, carbamido, cyano, carboxy-lower alkyl-amino, di-lower alkoxy, nitro or sulfamyl R a remainder of the formula, _Λ designated in the R is hydrogen or lower alkyl and R is a nitrogen-containing heterocyclic radical selected from amino-substituted. Isothiazolyl, benzothiazolyl and nitro- and halogeno-substituted derivatives of benzothiazolyl existing group or R is a substituted lower alkyl radical selected from the group consisting of amino-lower alkyl, lower-alkylamino-lower alkyl, hydroxy-lower alkylamino-lower alkyl, Hydroxy-lower alkoxy-lower alkyl, imidazolyl-lower alkyl, nitro-substituted imidazolyl-lower alkyl, mono- and di-hydroxyphenyl-naphthyl, nitro-substituted pyrodylamino-lower alkyl and piperazinyl-lower alkyl group, characterized in that mitomycin A or N-alkylmitomycin A with appropriately selected amine Connections is implemented. 2. according to item 1, characterized in that the following compounds are prepared: 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-hydroxy-1-pyrrolidinyl) azirino- ^ ^f , 3 ': 3 , 47- pyrrolo ^ T, 2-a7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-methylpiperidyl) azirino / 2 ', 3': 3,47pyrrolo- β , 2-a7indol-4 '7-dioncarbamat; 1,1a, 2,8,8 _a , 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 -> - (acetylamino) anilino-7-azirino- / 2 ^l , 3 ': 3 » 47-pyrrolo ^ T, 2-a7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 5- (acetylamino) anilino-7-azirino- / 2 ', 3': 3,47pyrrolo / T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-acetylanilino) azirino ^ S * 3 ·: 3 »47pyrrolo £ \ , 2-a7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -S-a-methoxy-5-methyl-b - ^ - - (1-ureido) anilino-7-azirino- / 5 ^f , 3 3,47pyrrolo β, 2-a7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-cyanoanilino) -azirino ^ 2 ', 3': 3 '47pyrro-, 2 -a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-cyanoanilino) azirino / 2 * ^f , 3 ': 3.47pyrrolo / T , 2-a7indole-4,7-dione carbamate; 1,1a, 2,8,8a, Sb-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6 - / - (N-glycyl) -α-nilino-7-azirino- 1% ', 3' i3,47pyrrolo / T, 2-a7indole-4,7-dionecarbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3 »4 -dimethoxyanilino) azirino / 2 ^f , 3 ': 3,47-pyrrolo / T, 2-a7indole-4,7-dionecarbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydromethyl) - 8a-methoxy-5-methyl-6- (3> 5-dimethoxyanilino) azirino (jL ', 3': 3 »47-pyrrolo) T, 2-a7indole-4,7-dionecarbamate; 1,1a, 2, 8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-nitroanilino) -azirino ^, 3 ': 3,47pyrrolo / f, 2-a7indole-4 , 7-dioncarbamat; 1, ia, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-sulfamylanilino) -azirino / 2 · 3 ': 3 »47-pyrrolo 2 ~ 1,2-a7indol-4,7-dioncarbamat; 5-methyl-6/75-amino-1,2,4-triazol-3-yl) amino7-azirino ^ 2 ', 3': 3,47pyrrolo / T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-methylisothiazol-5-yl) -amino-7-azirino- 2-W : 3, 47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 12-benzothiazolyl) -amino-7-azirino-2 ', 3': 3,47pyrrolo / T, 2-a7indol, 4,7-dioncarbamat; 1,1a, 2,8,8a, 3b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / T6-nitrobenzothiazol-2-yl) -amino7-azirino » is ', 3': 3 , 47pyrrolo / T, 2-a7indol, 4,7-dioncarbamat; 1,1a, 2,8,8a-, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- ^ X4-chlorobenzothiazole-2-yl) amino7-aziridine • ^f 3: 3, 47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1 a, 2,8,8a, 81d-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (12-aminoethyl) amino-7-azirino-j / 2 ¹ , 3 ': 3, 47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-S-methyl-o-methyl (2-methylaminoethyl) amino-7-azirino- / 2 ', 3': 3, 47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-met3hoxy-5-methyl-6-5- (2-hydroxyethylamino) -ethylamino7-aziri-JQO [I ', 3' : 3,47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6-5- (2-hydroxyethoxy) ethylamino-7-azirino-5 ', 3': 3 , 47pyrrolo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy- -6- ^ 5- (4-imidazolyl) ethylamino-7-azirino-: 3,47pyrrolo- / 7,2-a7indole-4,7-dionecarbamate; 1,1a, 2,8,8a, Sb-hexahydro-S-hydroxymethyl-S-methoxy-5-methyl-6- ₍ / 12-nitro-1-imidazolyl) ethylamino-7-azirino / 2 ', 3': 3, 47pyrrolo / T, 2-a7indol-4i7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 5- (4-hydroxyphenyl) ethylamino-7-azirino- / 2 ', 3 ¹ : 3 , 47pyrrolo / T, 2-a7indol ~ 4,7-dioncarbamat; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- ^ 5- (3 > 4-dihydroxyphenyl) ethylamino-7-azirineOj / 2 ', 3' : 3,47pyuDlo ^ T, 2-a7indol-4,7-dioncarbamat; 1,1a, 2,8,8a, Sb-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- ^ 2- ^ X5-nitro-2-pyridyl) amino / ethylamino] azirino- 5 ''3': 3,47pyrroloVi, 2-a7indole-4,7-dionecarbamate; 1,1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy -6- ^ 5- (1-piperazinyl) ethylamino7- <azirino-3,47pyrrolo / T, 2-a7indol-4,7-dioncarbamat.