DE3403922A1 - MITOMYCIN ANALOG COMPOUNDS - Google Patents

Description

Mitomycin Analog Compounds

The present invention relates generally to antibiotic Mitosan compounds and their use in the treatment of neoplastic disease states Animals.

For the history of the present invention, reference is made to U.S. Patent 4,268,676, co-pending U.S. patent application Ser. 206,529, filed 11/13/1980 and copending U.S. patent application serial no. 264 187, submitted May 15.
1981, (DE-OS 32 17 769) referenced. In the US PS
4,268,676 and copending U.S. patent application Ser. 206 529 there are statements on the current search for new and suitable compounds structurally related to the mitomycins, which have antibiotic activity, have low toxicity and develop a considerable amount of antitumor activity in animals. In the applications mentioned, in particular new compounds of the formula I

CH ₂ OCNH ₂

revealed in the

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

R ²

denotes where

1 2
R, R and R are identical to or different from one another

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

The US patent and the cited application also disclose novel methods of treating neoplastic Disease conditions disclosed in animals, which are characterized in that a therapeutically effective Amount of a compound of formula Ia

is administered in the

Y denotes hydrogen or lower alkyl and

Z is a thiazolamino residue, a furfurylamino residue, a cyclopropylamino residue, a pyridylamino

Radical or a radical of the formula

denotes where

4 5 6
R, R and R are identical to or different from one another

and are selected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting of lower alkenyl,

halogeno-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halogeno-lower alkyl, hydroxy-lower alkyl, pyridyl,
Thienyl, formamyl, tetrahydrofuryl, benzyl and benzenesulfonamide.

Co-pending U.S. patent application serial no. 264 187 discloses further connections with a significant level of antitumor activity in animals conforming to formula Ha

Ha

in the

Y denotes hydrogen or a lower alkyl and

Z is a quinolinylamino radical substituted by a lower alkoxy, a cyano-substituted one Pyrazolylamino radical or one through lower Alkyl mono- or disubstituted 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-thioraorpholinyl radicals, or
a 1-aziridinyl radical substituted by cyano, phenyl, carboxamido or lower alkoxycarbonyl, or

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

-NO ¹
in the

R represents hydrogen or lower alkyl and

R ^{1 is} a nitrogen-containing heterocyclic

Radical selected from the group consisting of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl,
Indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl as well as their through lower

Alkyl and halogen substituted derivatives

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

lower alkyl radical selected from Mercapto-lower alkyl, carboxy-lower alkyl, mono-, di- or tri-lower alkoxy-lower alkyl, lower alkylthio-lower alkyl and its substituted by lower alkoxycarbonyl Derivatives, cyano-lower alkyl, mono-, di- or tri-lower alkoxyphenyl-lower alkyl, Phenylcyclo-lower alkyl, 1-pyrrolidinyl-lower alkyl, N-lower alkyl-pyrrolidinyl-lower alkyl, N-morpholinyl lower alkyl and lower dialkylamino-lower alkyl consisting of a group.

In connection with the background of the present The following U.S. Patents 3,332,944, 3,410,867, 4,231,936, 3,429,894, 4,268,676, and 3,450,705 are also available and 3,514,452 and the Imai et al., Gann 2if pp. 560-562 (1980).

The present invention relates to new compounds of the formula III

CH ₂ OCNH ₂

III

in the

Y denotes hydrogen or a lower alkyl and X denotes a hydroxy-substituted 1-pyrrolidinyl radical or

a piperidyl radical substituted by lower alkyl or

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

-ά-R ¹

referred to in the

R represents hydrogen or lower alkyl and

R for a nitrogen-containing heterocyclic

Radical selected from amino-substituted triazolyl, lower alkyl-substituted Isothiazolyl, benzothiazolyl and nitro- and halogeno-substituted derivatives of benzo-

thiazolyls existing group or

R is selected a substituted lower alkyl radical from the 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,

designated.

The present invention also relates to new methods for treating a neoplastic disease state in an animal, which are characterized in that one suffers from such a disease
suffering animal a therapeutically effective amount of a compound of formula IHa

IHa Ö

is administered in the

Y denotes hydrogen or a lower alkyl and Z is a hydroxy-substituted 1-pyrrolidinyl radical, or

a piperidyl radical substituted by lower alkyl 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.

-NO ¹

referred to in the
R represents hydrogen or lower alkyl and

R for a nitrogen-containing heterocyclic

Radical selected from the group consisting of amino-substituted

ated triazolyl, lower alkyl-substituted a

Isothiazolyl / Benzothiazolyl and nitro- and halogeno-substituted derivatives of benzo-

thiazolyls existing group or
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 consisting group.

Unless otherwise stated, the term “ ^{lower 11”} as used in connection with “alkyl” radicals denotes straight-chain or chain-branched radicals with one to six carbon atoms
"Lower alkyl" 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 conjunction with "alkoxy" denotes a radical having one to six carbon atoms.

It can be seen that the compounds of the formula III in their entirety by the details of the formula IHa can be detected. In other words, all of the new antibiotic mitomycin derivatives are of the formula III for the practice of the new antineoplastic thera-

therapeutic methods which rely on the administration of compounds of Formula IHa are of value.

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

Mitomycin (e.g. N-methylmitomycin) derivatives are described in similarly by reacting selected amines with N-alkylmitomycin A, which is produced from mitomycin C. , for example, using the general procedures described by Cheng et al, J. Med.Chem. 2jO, No. 6, 767-770 (1977). The preparative

Reactions generally provide the desired product in the form of a crystalline solid in alcohol is easily soluble.

The therapeutic methods of the present invention involve the administration of effective amounts one or more compounds of the formula IHa as active ingredient, together with suitable pharmaceutically acceptable ones Diluents, adjuvants and carriers, to an animal suffering from a neoplastic disease state suffers. The dosage units of the compounds when administered according to the method of : Invention can contain from about 0.001 to about 5.0 mg, preferably from about 0.004 to 1.0 mg, of the compounds be. Such dosage units can be administered in such a way that a daily dose, based on the body weight of the animal being treated, from about 0.1 to 100 mg / kg, preferably from about 0.2 to 51.2 mg / kg is administered. In the practice of the methods of the invention, parenteral administration is particularly important intraperitoneal administration, the preferred route.

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

The following Examples 1 to 32, which describe the preparation of certain currently preferred compounds according to the present invention, are intended to illustrate the same, but are not intended to be limiting. Unless otherwise stated, sämtliehe reactions were carried out without supplying heat at room temperature (2O ⁰ C). Unless otherwise stated,

All thin layer chromatography (TLC) operations to check the progress of the reaction involved the use of a precoated silica gel plate and a mixture of methanol and chloroform
(2: 8 parts by volume) as a developing solvent.

example 1

1.1a, 2.8.8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-

5-methyl-6 - (- 3-hydroxy-l-pyrrolidinyl) azirino

/ 2 ', 3': 3.4 / pyrrolo / 1,2-a / indole-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 solvent) indicated 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 yielded 23 mg (yield: 40%) (dec.) Of the desired product having a melting point of 82-85 ⁰ C and the following analytical data:

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

——— D

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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-methylpiperidy 1) azirino / 2 ', 3': 3.4 7pyrrolo / 1,2-α-7indole-4,7-dione carbamate

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 was added 46 mg (yield: 55%) of the desired product having a melting point of 75-88 ⁰ C and obtained the following analytical data (dec.):

NMR (CDCl-, TS) <T-values in ppm: Absence of 6-methoxy peak at 4.02 and occurrence new peaks at 0.85 (d, 3), 1.10-2.15 (m, 5) and 2.15-3.32 (m, 4).

Example 3

1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (1-piperazinyl) 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 60 mg of mitomycin A and 30 mg of anhydrous piperazine were 23 mg (yield: 34%) of the desired product having a melting point of more than 200 ⁰ C and obtained the following analytical data (dec.):

NMR (DMSO-d,., TS); <£ values in ppm: Absence of 6-methoxy peak at 4.02 and occurrence 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 / -azirino- / ~ 2 ', 3': 3 , 4 7ρνΓΓθ1ο / "Ί, 2-3 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 100 mg of mitomycin A and excess 4- (acetylamino) aniline, 102 mg (yield: 76%) of the desired product with a melting point of 143-145 ° C. (decomp.) And the
receive the following analysis data:

NMR (CDCl ,, TS)? i-values in ppm:

Absence of 6-methoxy peak at 4.02 and occurrence 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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-

5-methyl-6- / 3- (acetylamino) anilino / -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, with the difference that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 150 mg of 3- (acetylamino) aniline, 67 mg (yield: 72%) (dec.) Of the desired product having a melting point of 140-143 ⁰ C and obtained the following analytical data:

':' 3A03922

- 2-4 -

NMR (acetone-d ,, TS); ο values in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.1 (s, 3), 6.7-7.5 (ra, 4), 8.0 (broad s , 1) and 9.3 (s, 1).

Example 6

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

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

NMR (CDCl ₃ , TS); <T values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.1 (s, 3), 6.6 (d, 2), 7.3 (d, 2) and 7.0-7.3 (broad s, 1).

Example 7

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

The designated compound was according to that in Example 1 described method of operation. From 50 mg of mito-

- 25 -

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

NMR (CDCl-, TS); (£ values in ppm:

Absence of 6-methoxy peak at 4.02 and occurrence 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 f la, 2,8,8a, 8b-hexahydro-8- (hydroxymethy1) -8a-methoxy-5-methyl-6- (4-cyanoanilino) azirino / 2 ', 3': 3,4 / pyrrole, 2- α-7indole-4,7-dione carbamate

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

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

keep:

NMR (CDCl ₃ , TS); <f-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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy "5-methyl-6- (3-cyanoanilino) azirino / 2 ', 3': 3.4 7pyrro- 1 , 2-a 7indole-4,7-dione carbamate

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

NMR (CDCl ₃ , TS); «T values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 7.2-7.8 (m, 4).

Example 10

1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a ~ methoxy-

5-methyl-6- / 4- (N-glycyl) anilino 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. From 50 mg of mitomycin A and 249 mg of 4- (N-glycyl) aniline, 62 mg (yield: 90%) (dec.) Of the desired product having a melting point of 83-85 ⁰ C and obtained the following analytical data:

NMR (DMSO-dg, TS); <£ values in ppm:

Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.1 (ε, 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, la, 2,8,8a, 8b-Hexahydro ~ 8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3,4-dimethoxyanilino) 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 50 mg of mitomycin A and 229 mg of 3,4-dimethoxyaniline were 61 mg (yield: 91%) (dec.) Of the desired product having a melting point of 114-116 ⁰ C and the out below

receive the analysis data:

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

Absence of 6-methoxy peak at 4.02 and occurrence 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) -8a-methoxy-5-methyl-6- (3,5-dimethoxyanilino) ~ azirino / ~ 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 50 mg of mito-

ν ■ * -ύ

: "O ^: t403922

- -2-β -

mycin A and 229 mg of 3,5-dimethoxyaniline was added 60 mg (yield: 88%) (dec.) of the desired product having a melting point of 98-100 ⁰ C and obtained 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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-nitroanilino) azirino / 2 ', 3': 3.4 jpyrrolo / ~ 1,2-a 7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, with the difference that a small amount of potassium carbonate was added. From 70 mg of mitomycin A and 276 mg of 4-nitroaniline, 16 mg (yield: 9%) of the desired product having a melting point of 132-134 ⁰ C (dec.), And obtained the following analytical data:

NMR (acetone-dg, 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 (broad s, 1).

3A03922

Example 14

1, la, 2 , 8,8a, 8b-Hexahydro-8- (hydroxymethvl) -Sa-methoxy-5-methyI-6- (4-sulfamylanilino) azirino / 2 ', 3': 3,4 / pyrrolo / ~ l, 2- a 7indole-4 ₇ 7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, with the difference that a small amount of potassium carbonate was added. From 70 mg of mitomycin A and 688 mg SuIfanilamid were 25 mg (yield: 26%) of the desired product having a melting point of 113-115 ⁰ C and obtained the following analytical data (dec.):

NMR (CDCI. ,, TS); <i-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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethy1) -8a-methoxy-5-methy1-6- (4-methylanilino) azirino / 2 ', 3': 3.4 7pyrrolo / 1 , 2-α-7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1. From 60 mg of mitomycin A and excess 4-methylaniline was added 63 mg (yield: 86%) of the desired product having a melting point of 113-115 ⁰ C (dec.) And the out below

receive the analysis data:

- 343 -

NMR (CDCI- ,, TS); cf 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

1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (3-methylanilino) 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. From 70 mg of mitomycin A and 276 mg of 3-methylaniline was added 66 mg (yield: 78%) of the desired product having a melting point of 89-91 ⁰ C and the following analytical data obtained (dec.):

NMR (CDCl ₃ , 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, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Ba-methoxy-5-methyl-6- / (5-amino-1,2,4-triazol-3-yl) amino 7 -azirino / ~ 2 ', 3': 3.4 7pyrrolo / "l, 2-a 7indole-4,7-dione carbamate

The designated compound was according to the procedure described in Example 1, but with the difference that a small amount of potassium carbonate has been added,

- ai -

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

NMR (DMSO-d ₆ , TS); S values in ppm:

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

Example 18

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

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

that 0.5 ml of triethylamine was added prepared. From 60 mg of mitomycin A and 30 mg of 5-amino-3-methylisothiazole hydrochloride, 4.5 mg (yield: 8.5%) (dec.) Of the desired product with a ski stimulus point of 87-9O ⁰ C and the following analysis data

obtain:

NMR (CDCl ₃ , 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).

- -52 - Example 19

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-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, with the difference that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 25 mg of 2-aminobenzothiazole was added 12 mg (yield: 18%) of the desired product having a melting point of 82-85 ⁰ C and obtained the following analytical data (dec.):

NMR (CDCl ₃ , TS); cT 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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (6-nitrobenzothiazol-2-yl) amino / -azirino- / 2 ', 3 ': 3,4-pyrrolo / 1,2-α-7indole-4,7-dione carbamate

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

- 33 -

NMR (DMSO-d, -, TS); ^ 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, la, 2,8, 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-ynethoxy ~ 5-methyl-6- / (4-chlorobenzothiazol-2-yl) amino-azirino- / 2 ', 3': 3,4-pyrrolo / 1,2-α-7indole-4,7-dione carbamate

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

NMR (CDCI, TS); <£ values in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 7.1-8.0 (broad s, 4).

Example 22

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

The designated compound was according to the procedure described in Example 1, but with the difference that the solvent was dichloromethane. 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane became

- 34 -

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

NMR (CDCl ₃ , TS); <f 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, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / methyl (2-methylaminoethyl) amino 7-azirino- / ~ 2 ', 3': 3,4 ypyrrolo / "!, 2-a_7indole-4,7-dione carbamate

The designated compound was prepared according to the procedure described in Example 1, with the difference that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 25 mg of sym-dimethylethylenediamine was added 28 mg (yield: 50%) (dec.) Of the desired product having a melting point of 99-101 ⁰ C and obtained the following analytical data:

NMR (CDCl ₃ , TS); <i values in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.3 (s, 1), 2.5 (s, 6) and 2.7 (s, 4).

- 35 Example 24

1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (2-hydroxyethylamino) 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, with the exception 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 with a melting point of 115-118 ⁰ C (decomp.) And the following analysis data were obtained:

NMR (CDCl-, TS); £ values in ppm:

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

Example 25

1, la, 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 according to the procedure described in Example 1, but with the difference that the solvent was dichloromethane. From 60 mg mitomycin A and 20 mg 2- (2-aminoethoxy) ethanol were 30 mg (yield: 42%) of the desired product

product with a melting point of 99-102 ⁰ C (decomp.) and the following analysis data:

~ ir.

NMP (CDCl ₃ , TS); cf 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- (hydroxymethy 1) -8a-ntethoxy-5-methyl-6- / 2- (4-imidazolyl) ethylamino / -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, with the difference that 128 mg of sodium methoxide were added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride were 61 mg (yield: 71%) of the desired product having a melting point of 72-73 ⁰ C and the following analytical data obtained (dec.):

NMR (DMSO-d ₆ , TS); (f-values in ppm: absence of the 6-methoxy peak at 4.02 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-l-imidazolyl) ethylamino / -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. From 72 mg of mitomycin A and excess 1- (2-aminoethyl) -2-nitro-

'33 -

imidazole, 60 mg (yield: 70%) (dec.) of the desired product having a melting point of 83-85 ⁰ C and obtained the following analytical data:

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

Absence of 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, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethy1) -8a-methoxy-5-methyl ~ 6- / 2- (4-hydroxyphenyl) ethylamino 7-azirino- / ~ 2 ' _f 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. 130 mg mitomycin A and 510 mg tyramine became 138 mg (yield:
. 81%) of the desired product having a melting point of 120-125 ⁰ C (dec) and with the following analysis data obtained:

NMR (CDCl-, TS); (Γ 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), 6.7 (d, 2), 7.0 (d, 2) and 8.0 (s, 1).

- 39 -

Example 29

1,1a, 2,8,8a _f 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (3,4-dihydroxyphenyl) ethylamino, / - 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, with the difference that 138 mg of sodium methoxide were added. From 110 mg of mitomycin A and 660 mg of 3-hydroxytyramine hydrobromide, 60 mg (yield: 40%) of the desired product, which ^{decomposed above 125 °} C. without melting and provided the following analytical data, were obtained:

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

• —-— j

Absence of 6-methoxy peak at 4.02 and occurrence 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, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- 2- / (5-nitro-2-pyridyl) amino 7ethylamino-azirino / ~ 2 ' , 3 ': 3.4 7pyrrolo / ~ 1.2-a 7indole-4,7-dione carbamate

The designated compound was according to the procedure described in Example 1, but with the difference that the solvent was dichloromethane. From 50 mg mitomycin A and 30 mg 2- (2-aminoethylamino) -5-nitropyridine were 40 mg (yield: 56%) of the

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

NMR (CDCl ₃ , TS); <T values in ppm:

Absence of 6-methoxy peak at 4.02 and occurrence 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

Example 31

1, la, 2,8,8ä, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (1-piperazinyl) ethylamino 7-azirino-
I. 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, with the exception that the solvent was dichloromethane.
From 50 mg of mitomycin A and 20 mg of N- (2-AminoethyDpiperazin were 23 mg (yield:. 36%) of the desired product having a melting point of 138-141 ⁰ C (dec), and obtained the following analytical data:

NMR (CDCl ₃ , TS); <f-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 ^^ fSa ^ b-Hexaliydro-S- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 2- (2-pyridyl) 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. From 70 mg of mitomycin A and 250 mg excess of 2- (2-aminoethyl) pyridine, 51 mg (yield: 56%) (dec.) Of the desired product having a melting point of 64-77 ⁰ C and. receive the following analysis data:

NMR. (CDCl_, TS); Values in ppm:

¹ J

Absence of 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 identified by Formula IHa, the above show Examples include the following variations in terms of structures:

1. Compounds in which Z is a hydroxy-substituted 1-pyrrolidinyl radical are illustrated by the example 1 represents.

2. Compounds in which Z is a lower alkyl substituted piperidyl radical are by the example 2 represents.

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

Nitro, sulfamyl or lower alkyl substituted Anilino radical is illustrated in each case by the examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16 are reproduced.

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

-NO ¹

referred to in the

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

ated triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives of the benzothiazolyl group,

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

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

-NO ¹
referred to in the

R is selected a substituted lower alkyl radical from the 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, designated,

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

■ - "Φ2- -

, 3g-

Although none of the above examples in detail Illustrated compounds in which Y is other than hydrogen, compounds in which Y is lower alkyl is, nevertheless, within the scope of the present invention, including those analogously substituted Compounds in the aforementioned U.S. Patent and U.S. Patent Applications Serial No. 206 529 and 264 187 is referred.

It is believed that the compounds according to the present Invention antibacterial effectiveness against gram-positive and gram-negative microorganisms in possess a manner similar to that observed with the naturally occurring mitomycins; the compounds are thus of potential value as therapeutic agents for the treatment of bacterial diseases Infections in humans and animals.

The value of the compounds of the formula IHa in the context of antineoplastic therapeutic methods according to Invention is demonstrated by the results of in vivo screening studies in which the compounds with variation of the dosage were administered to mice in which P388 leukemia had been induced. The investigations were carried out according to the "Lymphocytic Leukemia P388 - Protocol 1,200", published in: Cancer Chemotherapy Reports, Part 3, Volume 3, No. 2, Page 9 (September 1972). The screening examinations included briefly presented, the administration of the test compounds to female CDF mice previously treated with 10 Ascites cells had been infected by intraperitoneal implantation. The test connections were only administered on the first day of the test, and the animals were treated for a period of 35 days, among others monitored for their vitality.

- 3β-

The results of the screening tests on the compounds of Examples 1 to 32 are shown in Table 1 below. The values given are for the optimal dose ("OD"), ie that dose, based on
on the body weight of the animal, in mg / kg, at which the maximum therapeutic effects are consistently observed. The mean survival time (“MST”), expressed as the MST of the test animals in comparison to the MST of the control animals, multiplied by 100 (“% T / C”) is also given in each case. In connection with the in vivo assay method P388 cited above, a "% T / C" value of 125 or higher signifies significant antineoplastic therapeutic activity. The lowest dose based on 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 pointed out that the results obtained in the P388 screening tests and listed in Table 1

The extraordinarily high MST values also led to the lack of any appreciable toxicity of the compounds in the Show applied dosages.

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

_ AJL _

Table 1 - continued

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

- 45 t / t

Particularly preferred compounds which are used as antineoplastic agents in accordance with the present invention undoubtedly include those which have more than twice the life-prolonging ability
those which are generally characterized as the detection variable for a significant therapeutic potential, ie the compounds which have an MST value (in% T / C) which is greater than 2 125. It can be seen that the compounds of Examples 4, 10, 11 and 32 belong to this group of compounds.

As can be seen from Table 1, initial single doses as low as 0.2 mg / kg showed significant long-term antineoplastic effect. Accordingly, the methods according to the present Invention include the therapeutic administration of dosage units of the compounds as low as are that they are only 0.001 mg, or that are so high that they are 5 mg, preferably from Do-

Sizing units in the range from 0.004 to 10 mg of the Compounds as active ingredients in the form of suitable pharmaceutical preparations. Such preparations can after a treatment regimen that, based on the body weight of the person involved in a neoplastic

see sick animal, a daily dose from about 0.1 to 100 mg / kg, preferably from about 0.2 to 51.2 mg / kg. Preferably the compounds administered parenterally. Pharmaceutical compositions suitable for practical use in

In the context of the method according to the invention are suitable, can simply from solutions of one or more compounds of the formula IUa exist in water, but they

—Φ6 -

can also include well known, pharmaceutically acceptable diluents, adjuvants and / or carriers, for example Contains saline solution for medical use.

Claims (2)

FROM KREISLER SCHONWALD EISHOLD FUES FROM KREISLER KELLER SELTING WERNER University Patents, Inc. Norwalk, Conn. 6851 U.S.A. PATENT LAWYERS Dr.-Ing. by Kreisler 11973 Dr.-lng.K.W. Ice Hold ti981 Dr.-Ing. K. Schönwald Dr. J. F. Fues Dipl.-Chem. Alek von Kreisler Dipl.-Chem. Carola Keller Dipl.-Ing. G. felting Dr. H.-K. Werner DEICHMANNHAUS AT THE MAIN RAILWAY STATION D-5000 COLOGNE Ί February 3rd, 1984 AvK / GF 72 Claims ( 1. jCompounds of the formula CH ₀ OCNH- ΊΙΙ in the Y denotes hydrogen or a lower alkyl and X is a hydroxy-substituted 1-pyrrolidinyl radical or a piperidyl radical substituted by lower alkyl or one through acetamino, acetyl, carbamido, cyano, Carboxy-lower alkyl-amino, di-lower alkoxy, nitro or sulfamyl substituted anilino radical or a radical of the formula R. -NO ¹ referred to in the R represents hydrogen or lower alkyl and R stands for a nitrogen-containing heterocyclic radical selected from the group consisting of amino-substituted a Triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogenosubstiuierten derivatives of benzothiazolyl existing group or R is selected a substituted lower alkyl radical from the 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 consisting group. 2. Compounds according to claim 1, characterized in that they are designated by the following names: 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- (3-hydroxy-l-pyrrolidinyl) -azirino- / 2 ', 3': 3,4_7pyrrolo / 1,2-α_7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy- 5-methyl-6- (3-methylpiperidyl) azirino / 2 ', 3': 3,4_7- pyrrolo / 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy- 5-methyl-6- / 4- (acetylamxno) anilino_7-azirino- / ~ 2 ', 3': 3,4_7pyrrolo / ~ 1,2-a_7indole-4,7-dione carbamate; 1,13,2,8,8a, 8b-Hexahydro-8- (hydroxymethy1) -8a-methoxy-5-methyl-6- / 3- (acetylamino) anilino 7-azirino- / 2 ', 3': 3, 4__7pyrrolo / 1,2-a_7indole-4, 7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethy1) -Sa-methoxy-5-methyl-6- (4-acetylanilino) azirino / 2 ', 3': 3,4_7pyrrolo / 1, 2-a_ / indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / 4- (1-ureido) anilino_7-azirino- / 2 ', 3': 3 , 4-7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- (4-cyanoanilino) azirino / 2 ', 3': 3,4_7pyrrolo / 1, 2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-cyanoanilino) azirino / 2 ', 3': 3,4_ / pyrro- Io / 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / 4- (N-glycyl) anilino_7-azirino- / ~ 2 ', 3': 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1 _r la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxyanilino) azirino / 2 ¹ , 3 ': 3,4_γ- pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- (3,5-dimethoxyanilino) -azirino / 2 ¹ , 3 ': 3,4_7- pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- (4-nitroanilino) azirino / 2 ', 3': 3,4_ / pyrrolo / 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- (4-sulfamylanilino) -azirino / 2 ', 3': 3,4_7-pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / (5-amino-l, 2,4-triazol-3-yl) amino_7- azirino / 2 ', 3': 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / (3-methylisothiazol-5-yl) amino_7-azirino- / ~ 2 ', 3 ': 3, 4_7pyrrolo / 1, 2-a__7indole ~ 4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / (2-benzothiazolyl) amino_7-azirino- / ~ 2 ', 3': 3, 4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / (6-nitrobenzothiazol-2-yl) amino__7-azirino- / ~ 2 ·, 3 ': 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / (4-chlorobenzothiazol-2-yl) amino_7-azirino / 2 ', 3': 3,4_7pyrrolo / "" 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / (2-aminoethyl) amino_7-azirino- / ~ 2 ', 3': 3, 4__7pyrrolo / ~ 1,2-a_7indole-4, 7-dione carbamate, 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / methyl (2 -methylaminoethyl) amino _ / - azirino- / ~ 2 ', 3': 3,4_7pyrrolo / ~ 1,2-a_7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2- (2-hydroxyethylamino) ethylamino_7-azirino / 2 ', 3': 3, 4__7pyrrolo / 1,2-a / indole-4, 7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2- (2-hydroxyethoxy) ethylamino__7-azirino- / ~ 2 ', 3': 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / 2- (4-imidazolyl) ethylamino_7-azirino- / 2 ', 3': 3 , 4_ / pyrrolo / 1,2-α-7indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-methyl-6- / (2-nitro-l-imidazolyl) ethylamino__7-azirino / ~ 2 ', 3' : 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Ba-methoxy-5-methyl-6- / 2- (4-hydroxyphenyl) ethylamino_ _- 7-azirino- / 2 ', 3' : 3,4_7pyrrolo / ~ 1,2-α-7indole-4,7-dione carbamate; l, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl- €> 7 / ~ * 2- (3,4-dihydroxyphenyl) ethylamino_7-azirino / 2 ', 3 ': 3,4_7pyrrolo / "1,2-a_7indole-4,7-dione catbamate; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- ) 2- / "" (5-nitro-2-pyridyl) amino_7ethylaminolazirino / "2 ^f , 3 ·: 3,4_7pyrrolo /" 1,2-a_7indole-4,7-dione- "carbamate; 1, la, 2,8,8a _r 8b-Hexahydro-8- (hydroxymethyl) -ea-methoxy-5-methyl-6- / ~ 2- (1-piperazinyl) ethylamino__7-azirino- / 2 ', 3: 3,4_7pyrrolo / "1,2-α-7indole-4,7-dione carbamate. B. Pharmaceutical composition for use in Treatment of neoplastic disease in an animal, enr.hsltend '-in pharmaceutically acceptable solvents , Diluent, adjuvant or carrier material and, as an active ingredient, an amount of about 0.001 to about 5 mg of a compound of the formula > β - CH ₂ OCNH ₂
OCH ₃ in the Y denotes hydrogen or a lower alkyl and Z denotes a hydroxy-substituted 1-pyrrolidinyl radical, or a piperidyl radical substituted by lower alkyl or a 1-piperazinyl radical or one by acetamino, Acetyl, carbamido, cyano, carboxy-lower-alkyl-amino, Di-lower alkoxy, nitro, sulfamyl or Lower alkyl substituted anilino radical or a remainder of the formula -NO ¹ referred to in the R represents hydrogen or lower alkyl and R stands for a nitrogen-containing heterocyclic radical selected from the group consisting of amino-substituted Triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogenosubstiuierten derivatives of benzothiazolyl existing group or R is selected a substituted lower alkyl radical from the 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, designated.