LU84144A1 - MITOMYCIN ANALOGS - Google Patents

Description

t

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF A REQUEST FOR

PATENT

FORMED BY

UNIVERSITY PATENTS, INC

for

Mitomycin analogues.

The present invention relates generally to antibiotic mitosanes and their use for the treatment of neoplastic conditions in animals.

United States Patent No. 4,268,676 and United States Patent Application No. 206,529 (November 13, 1980) relate to polycyclic compounds.

In summary, the two memories mentioned above describe the search for new useful compounds which are related by their structure to mitomycins, which have antibiotic activity, which are not very toxic and which have a .CD.MJ SY-9269 activity notable antitumor in animals. In particular, these memories relate to new compounds of formula I: e î I CHo0CNHo x-Yt_i / 2 2 ßl I λλ: η, where Y represents a hydrogen atom or a lower alkyl radical, and X represents a radical thiazolamino, furfurylamino or of formula: R R1 II 3

-N-C -R

12 ". in which R, R and R, identical or different, represent hydrogen atoms or lower alkyl radicals 3 and R represents a lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thi-enyl, formamyl, tetrahydrofuryl radical or benzenesulfonamide.

They also describe new methods of treating neoplastic conditions in animals, according to which a compound of formula la 1 1 Z CH 2ocnh 2 H T la A is administered in therapeutically effective amount.

H-CI

J 11 'Tny 0 - ^ where Y represents a hydrogen atom' or an alkyl radical in-CD.MJ - 2 - ...

lower and Z represents a thiazolamino, furfurylamino, cyclopropylamino, pyridylamino radical or of formula: R4 R5

I I

- N- C-R

i6 4 5 6 in which R, R and R, identical or different, represent hydrogen atoms or lower alkyl radicals and R represents a lower alkenyl, halo-lower alkyl-radical, lower alkynyl, lower alkoxycarbonyl, halo-alkyl lower, lower hydroxyalkyl, py-ridyl, thienyl, formamyl, tetrahydrofuryl, benzyl or benzenesulfonamide.

The subject of the present invention is new compounds of formula II

? 9 _ cu2ocm2 ^ v N ^ \ 0CH3 3 T l_J * where Y represents a hydrogen atom or a lower alkyl radical, X represents a quinoline linylamino alkoxy (lower) -substituted radical, pyrazolylamino cyano-substituted or thiazolamino mono- or dialkyKinower) -substituted, or a heterocyclic nitrogen radical chosen from the 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl and N-thiomorpholinyl radicals, or a 1-aziridinyl cyano-, phenyl-, carboxamido- or (lower) alkoxycarbonyl -substituted radical, or a 1-piperazinyl alkyl (lower) -, CD.MJ - 3 - formyl- or acetylphenyl-substituted radical, or a 1-piperidyl hydroxy- or piperidyl-substituted radical, or a pyridylamino alkoxy (lower) radical,, substituted amino- or halo, or a substituted anilino carboxamido-, mercapto- or methylenedioxy radical, or

a radical of formula -N

"" VR

(in which R represents a hydrogen atom or a lower alkyl radical and R 'represents a nitrogen heterocyclic radical chosen from the radicals quinuclidinyl, pyrazolyle, 1-tri-azolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadia-zolyl and benzothiadiazolyl and their (lower) and halo-substituted alkyl derivatives, or a butyrolactonyl radical, or an adamantyl radical, or a substituted lower alkyl radical chosen from lower mercaptoalkyl, mono-, di- and trialkoxy (lower) lower alkyl, lower alkylthioi) alkyl radicals lower and their lower (alkoxy) -carbonylated, lower cyanoalkyl, mono-, di- and trialkoxy (lower) phenylalkyl lower, phenylcyclo-lower alkyl, lower 1-pyrrolidinyl lower alkyl, N-alkyl- (lower) pyrrolidinyl lower alkyl and N-morpholinyl derivatives -lower alkyl).

The subject of the invention is also new methods of treating neoplastic affections in animals, according to which a compound of formula II is administered in therapeutically effective quantity CD.MJ - 4 - P I I ch9ocnh9 Zy-'V_ / 2 I_ÛCH- IIa

H3C T> NY

0 _ / where Y represents a hydrogen atom or a lower alkyl radical, Z represents a quinolinylamino alkoxy (lower) -substituted radical, cyano-substituted pyrazolylamino or thiazolamino mono- or dialky (lower) -substituted, or a heterocyclic nitrogen radical chosen from 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl radicals, or a 1-aziridinyl cyano-, phenyl-, carboxamido- or (lower) -substituted alkoxycarbonyl radical, or a substituted 1-piperazinyl alkyl (lower) -f ormyl- or acetylphenyl-radical, or a 1-piperidyl hydroxy- or piperidyl-substituted radical, or a pyridylamino alkoxy (lower) -amino- or halo-substituted radical, or a anilino carboxamido-, mercapto-or methylenedioxy-substituted radical, or / R "

a radical of formula -N

(in which R represents a hydrogen atom or a lower alkyl radical and R "represents a nitrogen heterocyclic radical chosen from the radicals quinuclidinyl, pyrazolyle, 1-tri-azolyl, isoquinoüinyle, indazolyle, benzoxazolyle, thiadia-zolyle and benzothiadiazolyle and their substituted (lower) alkyl and halo derivatives, or CD.MJ - 5 - a butyrolactonyl radical, or an adamantyl radical, or an inono-alkoxy (lower) - substituted phenyl radical, or a substituted lower alkyl radical chosen from mercaptoalkyl radicals lower, mono-, di- and tri -alkoxy (lower) lower alkyl, lower alkylthio (lower) -alkyl and their derivatives alxoxy (lower) -carbonylated, lower cyanoalkyl, mono-, di- and tri-alkoxy (lower) phenylalkyl lower, lower phenylcycloalkyl, lower 1-pyrrolidinylalkyl, lower N-alkyl-lower pyrrolidinyl-nylalkyl, lower N-morpholinylalkyl and lower (lower) aminoalkyl)

Unless otherwise indicated, the term "lower" qualifying an "alkyl" radical designates such a radical in both a straight and branched chain containing 1 to 6 carbon atoms. For example, "lower alkyl radicals" means methyl, ethyl, propyl, butyl, pentyl and hexyl radicals, in addition to isopropyl, t-butyl, etc.

Likewise, the term "lower" qualifying an "alkoxy" radical designates such a radical of 1 to 6 carbon atoms.

It should be noted that the compounds of formula II are all included in the definition of formula IIa. In other words, the new antibiotic mitomycins of formula II are useful for the application of new antineoplastic therapeutics by administration of the compounds of formula IIa.

The mitomycins which are the subject of the invention are obtained by reaction of mitomycin A with suitable amines. The N-alkylmitomycins (for example N-methyl-mitomycin) are likewise obtained by reaction of an appropriate amine with an N-alkylmitomycin A prepared from CD.MJ - 6 - of mitomycin C, for example according to the methods described by Cheng et al.f J. Med. Chem., 20, no. 6, 767-770 (1977).

The preparation reactions generally give the desired product in the form of a crystalline solid easily soluble in alcohol.

The therapeutic methods in accordance with the invention comprise the administration of effective quantities of one or more of the compounds of formula IIa, as active principle, with pharmaceutically acceptable excipients, adjuvants or diluents to an animal suffering from a neoplastic disease. . The unit doses of the compounds administered according to the invention can range from approximately 0.001 to 5.0 mg and preferably from approximately 0.004 to 1.0 mg. These unit doses can be administered up to a daily dose of about 0.1 to 100 mg per kg and preferably about 0.2 to 51.2 mg per kg of body weight. Parenteral and especially intraperitoneal administration is the preferred mode for administration for the purposes of the invention.

Other aspects and advantages of the invention will emerge from its more detailed description below.

Examples 1 to 42 illustrate the invention without limiting it. Unless otherwise indicated, the reactions are carried out at ambient temperature (20 ° C.) without the addition of heat and all the thin layer chromatographies (TLC) carried out to check the progress of the reactions are carried out on a ready-made silica gel plate. developed using a mixture of methanol and chloroform (2: 8 by volume).

EXAMPLE 1 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyano-1-aziridinyl) -azirino carbamate [2 ', 3': 3,4 ~ j-pyrrolo [1,2-ajindole-4,7-dione CD.MJ - 7 -

A solution of mitomycin A (100 mg or 0.286 millimole) in 8 ml of anhydrous methanol is reacted at room temperature, under a nitrogen atmosphere, with 2-cyano-aziridine (38.9 mg or 0.572 millimole) and 30 mg of potassium carbonate. When the thin layer chromatography on silica gel (methanol-chloroform 2: 8 as solvent) indicates that the starting compound is used up, the mixture is diluted with 50 ml of methylene chloride, the whole is filtered and the filtrate is evaporated under pressure scaled down. The residue is purified by preparative thin layer chromatography on silica gel with a mixture of methanol and chloroform (2: 8 by volume) as solvent. 33 mg (yield of 30%) of the desired compound are thus obtained having a melting point of 87-89 ° C (decomposition) and giving rise to the following analysis: NMR (CDClg, TS) t "û" in ppm : disappearance of a singlet at 4.02 (due to the 6-methoxy radical of the starting compound) and appearance of new signals at 2.13 (d, 2) and 2.53 (s broad, 1) EXAMPLE 2 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thiomorpholinyl) -azirino carbamate [21,31: 3,4jpyrrolo- [1,2 -a] indole-4,7-dione

This compound is prepared according to the method of Example 1, but omitting the potassium carbonate. From 52 mg of mitomycin A and 500 mg of thiomorpholine, 14 mg (22% yield) of the desired compound is obtained having a melting point of 90-91 ° C (decomposition) and giving rise to the following analysis : NMR (CDCl 4, TS), the "5" in ppm: absence of the 6-methoxy peak at 4.02 and accentuation of the peaks at 2.8 (m, increase by 4) and 3.6 (m, increase of 4).

CD.MJ - 8 - EXAMPLE 3 -

1,1,8,2a Carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-indolinyl) -azirino [21,31: 3,4 Hpyrrolo- [ 1,2-aJindole-4,7-dione

This compound is prepared according to the method of Example 1, but omitting the potassium carbonate. From 100 mg of mitomycin A and 69 mg of indoline, 45 mg (36% yield) of the desired compound is obtained, having a melting point of 127-135 ° C. (decomposition) and giving rise to the analysis. following: NMR (CDClg, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.85-3.7 (group, 4) and 6.15- 7.5 (group, 4).

EXAMPLE 4 -

Carbamate of 1, la, 2,8,8a 8b-hexahydro-8- (hydroxymethyl) -8a-methcxy-5-methyl-6 - [(6-methoxy-3-pyridyl) amino] -azirino [21,31: 3,4 J-pyrrolo [1,2-ajindole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate. From 100 mg of mitomycin A and 2 drops of 3-amino-6-methoxypyridine, 96 mg (76% yield) of the desired compound are obtained, having a melting point of 260-262eC (decomposition) and giving rise to the following analysis: NMR (CDCl 4, TS), the "6" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.93 (s, 3), 6.77 ( s, 1), 7.26 (d, 1), 7.60 (d, 1) and 7.87 (s, 1).

EXAMPLE 5 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a ~. methoxy-5-methyl-6 - [(6-methoxy-8-quinolinyl) aminoJ-azirino- [2 ', 3': 3,4] -pyrrolo [1,2-ajindole

This compound is prepared according to the method described in Example 1. From 60 mg of mitomycin A and 54 mg of 8-amino-6-methoxyguinoline, 26 mg (yield of 32%) of the desired compound having a melting point of 135-145 ° C (decomposition) and giving rise to the following analysis: CD.MJ - 9 - NMR (CDCl ^, TS), the "5 ·· in ppm: absence of the peak of 6- methoxy at 4.02 and appearance of new peaks at 6.4 (d, 1), 6.67 (d, 1), 7.30 (dd, 1), 8.0 (dd, 1) and 8.90 (dd, 1).

EXAMPLE 6 -

1, 1a carbamate, 28.8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxv-5-methyl-6- (3-quinuclidinylamino) -azirinoL21,31: 3,4j-pyrrolo- [1,2 -ajindole-4,7-dione -

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 100 mg of mitomycin A and 3-aminoquinuclidine (prepared by reaction of an aqueous solution of 73 mg of 3-aminoquinuclidine hydrochloride with sodium hydroxide), 86 mg (yield of 54¾) of the compound are obtained. sought having a melting point of 138-146eC (decomposition) and giving rise to the following analysis: NMR (CDClg, TS), the "8" in ppm: absence of the 6-methoxy peak at 4.02, accentuation of peaks at 2.8 and 3.8 and appearance of new broad peaks at 1.2 and 2.5.

EXAMPLE 7 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2-Cy-butyrolactonyl) aminoJ-azirino [2 ', 31: 3, 4] pyrrolo- [l, 2-a] indole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 100 mg of mitomycin A and 60 mg of amino-amino-y-butyrolactone hydrochloride, 68 mg (yield of 57¾) is obtained of the desired compound having a melting point of 87-89 ° C (decomposition) and giving rise to the following analysis: NMR (DMSO-dg, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.90-2.87 ( m, 2), 3.80-4.70 (m, 3) and 8.3-9.2 (broad s, 1).

EXAMPLE 8 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-carboxamido-anilino) -azirinoL21,3 ': 3,4jpyrrolo- [ l, 2-ajindole-4,7-dionë CD.MJ - 10 -

This compound is prepared according to the method described in Example 1. From 100 mg of mitomycin A and 82 mg of 4-aminobenzamide, 36 mg (yield of 28%) of the desired compound having a melting point of 167 ~ 169 ° C (decomposition) and giving rise to the following analysis: NMR (acetone-dg, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.67 (d, 3) and 7.73 (d, 2).

EXAMPLE 9 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxybenzylamino) -azirino carbamate [21.3 1: 3.4 jpyrrolo- [l, 2-aJindole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 29 mg of mitomycin A and 69.4 mg of 3,4-dimetho-xybenzylamine, 29 mg (72% yield) of the desired compound are obtained, having a melting point of 112 ° C. (decomposition) and giving place for the following analysis: NMR (CDC13, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.9 (s, 6), 4.65 -4.75 (d, 2), 6.55 (wide s, 1) and 6.86 (s, 3).

EXAMPLE 10 -

1, 1a carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(1-ethyl-2-pyrrolidino) methylaminoJ-azi-rino [2 ' , 3 ': 3,4] -pyrrolo [1,2-aJindole-4,7-dionê ~

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 150 mg of mitomycin A and 2 drops of 2-amino-methyl-1-ethylpyrrolidine, 78 mg (41% yield) of the desired compound is obtained, decomposing above 300 ° C. and giving rise to following analysis: NMR (CDCl 4, TS), the "S" in ppm: absence of 6-methoxy peak at 4.02 and appearance of new peaks at 1.07 (t, 3), 1.4-2, 33 (m, 5), 2.36-3.03 (m, 4), 3.3-3.83 (m> 2), and 6.77-7.20 CD.MJ - 11 - (s large , 1).

EXAMPLE it -

1.la Carbamate, 2,8,8a 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(1-methoxycarbonyl-3-methylthio) propyl-aminoJ-azirino- [21, 3 ': 3,4JpyrroloÎ1,2-ajindole-4,7-dione

This compound is prepared according to the method described in Example 1, but replacing the potassium carbonate with 0.5 ml of triethylamine. From 150 mg of mitomycin A and of 110 mg of methyl ester hydrochloride of L-methionine ester, 64 mg (30% yield) of the desired compound having a melting point of 83-85 ° C. are obtained ( decomposition) and giving rise to the following analysis: NMR (CDC13, TS), the "&" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.63-2.40 (m, 3), 2.10 (s, 3), 2.43-3.0 (m, 2), 3.80 (s, 3) and 8.3, 9.3 (s wide, 1) .

EXAMPLE 12 -

1,1,8,2,8a8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-phenylcyclopropylamino) -azirino- [2 ', 3': 3,4 Jpyrrolo- carbamate [l, 2-aJindole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 125 mg of mitomycin A and 85 mg of 2-phenyl-cyclopropylamine, 70 mg (yield of 63%) of the desired compound are obtained, decomposing above 250 ° C. and giving the following analysis: NMR ( CDC13, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 0.6-1.53 (m, 4), 6.20-6.50 ( s wide, 1) and 7.18 (s broad, 5).

EXAMPLE 13 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(5-chloro-2-benzoxazolyl) aminoj-azirino- [2 ', 3 ': 3,4j-pyrrolo [l, 2-a] indole-4,7-dione

This compound is prepared according to the method described in Example 1. From 100 mg of mitomycin A and 50 mg CD.MJ - 12 - of 2-amino-5-chlorobenzoxazole, 35 mg is obtained (yield of 25% ) of the desired compound having a melting point of 118-120 ° C. (decomposition) and giving rise to the following analysis: NMR (CDCl 4, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks in the region of 6.70- 7.63 (m, 4).

EXAMPLE 14 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [5-methy1-2- (1,3,4-thiadiazolyl) aminoj- carbamate azirino- [21,31: 3,4] pyrrolo [l, 2-aJindole-4,7-dione

This compound is prepared according to the method described in Example 1. From 100 mg of mitomycin A and 53 mg of 2-amino-5-methyl-1,3,4-thiadiazole, 31 mg are obtained (yield of 25%) of the desired compound having a melting point of 91-93 ° C (decomposition) and giving rise to the following analysis: NMR (CDC 1 ^, TS), the n S ·· in ppm: absence of the peak 6-methoxy at 4.02 and appearance of new peaks at 2.68 (s, 3) and 7.47- 7.63 (broad s, 1).

EXAMPLE 15 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8 - ((hydroxymethyl) -8a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) -azirinoC 2 ', 3': 3, 4jpyrrolo- [l, 2-ajindole-4,7-dione

This compound is prepared according to the process described in

Example 1, but omitting the potassium carbonate. AT

starting from 60 mg of mitomycin A and from 35 mg of 2,2-dimethoxyethylamine, 60 mg (yield of 83%) of the desired compound are obtained which decomposes beyond 220 ° C. and giving rise to the following analysis: NMR (CDCl 4, TS), the "" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.45 (s, 6), 3.33-3.93 (m, 2), 4.33-4.85 (wide s, 1) and 6.15-6.66 (wide s, 1).

* ", CD.MJ - 13 - EXAMPLE 16 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-mercaptoethylamino) -azirino [2 1, 3 ': 3,4] -pyrrolo- [1,2-a] -indole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 150 mg of mitomycin A and 100 mg of 2-mercaptoethylamine hydrochloride, 50 mg is obtained (yield of 44%) of the desired compound having a melting point of 152-154 ° C (decomposition) and giving place for the following analysis: NMR (DMSO-dg, TMS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.53-3.10 (m, 4), 7.30-7.50 (wide s, 1).

EXAMPLE 17 -

1,1,8,2a Carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(4-methyl-2-thiazolyl) aminoj-azirino- [2 ', 3 ': 3,4lpyrrolo- [l, 2-2jindole-4,7-dione

This compound is prepared according to the method described in Example 1. From 150 mg of mitomycin A and 96 mg of 2-amino-4-methylthiazole, 85 mg (yield of 59%) of the desired compound having a melting point of 116-118 ° C (decomposition) and giving rise to the following analysis: NMR (CDC13, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02, and appearance of new peaks at 2.23 (s, 3), 6.30- 6.60 (wide s, 1) and 7.30 (s, 1).

EXAMPLE 18 -

1, 1a carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-mercapto-anilino) -azirinot2 ', 3': 3.4 d - ~ pyrrolo [l, 2-aJindole-4,7-dione

This compound is prepared according to the process described in

Example 1, but omitting the potassium carbonate. AT

starting from 200 mg of mitomycin A and from 143 mg of 4-mercaptoaniline, 120 mg (yield of 47%) of the compound re- CD.MJ - 14 - sought having a melting point of 97-99 ° C. are obtained. (decomposition) and giving rise to the following analysis: NMR (CDClg, TS) "les" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.53 (d, 2) and 7.0-7.7 (m, 3).

EXAMPLE 19 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-methylenedioxyanilino) -azirino [21,31: 3,4jpyrrolo- [1.2-a] indole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate. From 80 mg of mitomycin A and 0.1 ml of 3,4-methylene-dioxyaniline, 50 mg (48% yield) of the desired compound is obtained having a melting point of 86-88 ° C (decomposition) and giving rise to the following analysis: NMR (CDClg, TS), the "in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 5.97 (s, 2), 6.0- 6.7 (m, 3), 7.27 (s, 1).

EXAMPLE 20 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (l-pyrrolidino) ethylamino3-azirino [2 ', 3': 3,4] pyrrolo- [l, 2-aJindole-4,7-dione ~

This compound is prepared according to the process described in

Example 1, but omitting the potassium carbonate. AT

starting from 100 mg of mitomycin A and from 0.2 ml of 2- (l-pyrrolidino) ethylamine, 7.5 mg (61% yield) of the desired compound are obtained, decomposing above 200 ° C. and giving place for the following analysis: NMR (CDCl 4, TS), the "é" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.57-1.93 (m, 4 ), 2.33 - 3.03 (m, 8), and 6.92 (t, 1).

CD.MJ - 15 - EXAMPLE 21 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a methoxy-5-methyl-6- (5-isoquinoleinylamino) -azirino [21,31: 3,4Jpyrrolo- [1, 2-aJindole-4,7-dione

This compound is prepared according to the method described in Example 1. From 90 mg of mitomycin A and 810 mg of 5-aminoisoquinoline, 28 mg (24% yield) of the desired compound having no dot is obtained of fusion below 340 ° C. and giving rise to the following analysis: NMR (CDClg, TS), the "6" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6 , 8-7.65 (m, 3), 7.85 (d, 1) and 8.55 (d, 1).

EXAMPLE 22 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-indazolylamino) -azirino [2 ', 3': 3,4 J -pyrrolo [l, 2-aJ-indole-4,7-dione

This compound is prepared according to the method described in Example 1. From 90 mg of mitomycin A and 666 mg of 5-amino-indazole, 35 mg is obtained (yield of 30%) of the desired compound not having melting point below 340 ° C and giving rise to the following analysis: NMR (CDC13, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.8-7.65 (m, 3) and 8.0 (s, 1).

EXAMPLE 23 -

Carbamate de l.la ^ .S.Sa.Sb-hexanydro-B-ChydroxyméthyD-Sa-metnoxy-5-methyl-6- [4- (2,1,3-benzothiadiazolyl) aminoj-azirino-L 2 ', 3 ': 3,4J-pyrrolo [l, 2-aJindole-4,7-dione

This compound is prepared according to the process described in Example 1. The reaction does not reach its end in 19 hours despite the excess of amine used. From 50 mg of mitomycin A and 300 mg of 4-amino-2,1,3-ben-zothiadiazole, 32 mg (48% yield) of the desired compound having a melting point of 139-140 ° are obtained. C (decomposition) and giving rise to the following analysis: CD.MJ - 16 - NMR (CDClg + CD ^ OD, TS), the "&" in ppm: absence of the 6-methoxy peak at 4fo2 and appearance of new peaks at 6.6 (m, 1), 7.6 (m, 2) and 8.25 (s, wide, 1).

EXAMPLE 24 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a ~ methoxy-5-methyl-6- (N-glycinyl) -azirino [21,31: 3,4Jpyrrolo- [1 , 2-a] indole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 40 ml of methanol and replacing the potassium carbonate with 10 ml of triethylamine. From 100 mg of mitomycin A and 600 mg of glycine, 47.4 mg (yield of 42%) of the desired compound is obtained which has no melting point below 350 ° C. and gives rise to l 'following analysis: NMR (CDCl ^ + CD ^ OD, TS), the "" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of a new peak at 3.45 (s, 2). EXAMPLE 25 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl ^ Same thoxy-5-methyl-6 - (2-cyanoethylamino) -azirino [2 ', 3': 3,4j-pyrroloEl, 2-aJ-indole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 210 mg of mitomycin A and 90 mg of 3-aminopropionitrile fumarate, 151 mg (65% yield) of the desired compound are obtained having a melting point of 68-70 ° C (decomposition) and giving rise to the following analysis: NMR (CDClj, TS), the "^" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.1-2.77 (m, 4) and 6 , 57 (t, 1).

EXAMPLE 26 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-fluoroethylamino) -azirino carbamate [2 ', 3': 3,4J- pyrroloEl, 2-aJ-indole-4,7-dione

This compound is prepared according to the process described CD.MJ - 17 - in Example 1, but by neutralizing the 2-fluoroethylamine hydrochloride (220 mg) using sodium methylate (119 mg) in 2 ml of methanol at 5 ° C before adding mitomycin A (77 mg) and not using potassium carbonate. 62 mg are obtained (yield 74%) of the desired compound having no melting point below 340 ° C. and giving rise to the following analysis: NMR (CDCl 4, TS), the "in ppm: absence from the 6-methoxy peak at 4.02 and appearance of new peaks at 3.3-3.9 (m, 2), 4.2 (t, 2) and 6.5 (broad s, 1).

EXAMPLE 27 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [l- (3-pyrrolinyl) 3-azirino [2 ', 3': carbamate: 3,4] -pyrrolo [l, 2-a] -indole-4,7-dione

This compound is prepared according to the method described in Example 1, but omitting the potassium carbonate and making a modification made necessary by the presence of pyrrolidine in commercial grade 3-pyrroline. Pyrrolidine forms with mitomycin A a crystalline derivative which is separated from the mixture by filtration.

The filtrate is then treated as described in Example 1.

From 100 mg of mitomycin A and from 1 g of commercial 3-pyrroline, 30 mg (yield of 27%) of the desired compound are obtained having a partial decomposition temperature at 85-90eC, but not melting below at 250 ° C. and giving rise to the following analysis: NMR (CDCl 4, TS), the "<5" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of a new peak at 5, 9 (s, 2) It is not possible to discern the peak of proton 2 in region 3,4 from the rest of the absorption.

EXAMPLE 28

1.1a, 2.8.8a carbamate, 8b-hexahydro-8- (hydroxymethyl) -8-me-thoxy-5-methyl-6- (3-thiazolidino) -azirinoL 2 ', 3': 3.4 Jpyrrolo- [l, 2-ajindole-4,7-dione CD.MJ - 18 -

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 250 mg of mitomycin A and 0.5 ml of thiazoli-dine, 125 mg (yield of 43%) of the desired compound is obtained having a melting point of 105-107 ° C (decomposition) and giving rise to the following analysis: NMR (CDC13, TMS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.62 (broad s, 2), 2.68- 3.02 (wide s, 2) and 3.32-4.02 (wide s, 2).

EXAMPLE 29 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [1- (4-methylpiperazino) il-azirino [2 ', 3': carbamate 3 ~, 4] -pyrrolo- [l, 2-ajindole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 100 mg of mitomycin A and 0.2 ml of N-methylpiperazine, 50 mg (yield of 42%) of the desired compound is obtained having a melting point of 84-87 ° C (decomposition) and giving place for the following analysis: NMR (CDClg, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.27 (s, 3), 2.47 (t, 4) and 2.92 (t, 4).

EXAMPLE 30 -

Carbamate of 1, la, 2,8,8 a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [3- (pyrazolyl) amino] -azirino [2 ', 3': 3.4 J - pyrroloC1,2-aJ-indole-4.7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 100 mg of mitomycin A and 48 mg of 3-amino-pyrazole, 50 mg (yield of 44%) of the desired compound is obtained having a melting point of 142-145 ° (decomposition) and giving rise to l following analysis: NMR (CDCl 4, TMS), the "(5" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 6.50 (d, 2), 6.67- 6.83 CD.MJ - 19 - (s broad, 1) and 8.07 (s, 1).

EXAMPLE 31 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (N-morpholino) ethylamino J-azirino- [2 ', 3 1: 3,4 jpÿrrolo-Îl, 2-ajindole-4,7-dioiïe

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate.

From 100 mg of mitomycin A and 0.5 ml of N- (2-amino-ethyl} -morpholine, 70 mg (yield of 55¾) is obtained of the desired compound having a melting point of 74-76 ° C. (decomposition) and giving rise to the following analysis: NMR (CDCl 4, TS) * the "at" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.27-2, 73 (wide, 8), 3.47-4.03 (wide, 4) and 7.27 (t, 1).

EXAMPLE 32 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (ethylthio) ethylaminoJ-azirinoL 2 ', 31: 3.4] carbamate pyrrolo- [l, 2-a] indole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 250 mg of mitomycin A and 101.5 mg of 2- (ethylthio) - ethylamine hydrochloride, 220 mg (yield of 73%) of the desired compound are obtained, having a melting point of 103-106 ° C ( decomposition) and giving rise to the following analysis: NMR (CDC13, TS), the "6" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.27 (t, 3) , 2.40-2.90 (m, 4), 3.40-3.93 (m, 2) and 6.56 (t, 1).

EXAMPLE 33 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1, 5-dimethyl-6- (2-mercaptoethylamino) -azirino [21,3 ': 3,4 jpyrrolo- [1,2-aJindole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 250 mg of CD.MJ - 20 - N-methylmitomycin A and from 78 g of 2-mercapto-ethylamine hydrochloride, 150 mg (yield of 54%) of the desired compound having a melting point of 85- are obtained. 87 ° C (decomposition) and giving rise to the following analysis: NMR (CDC13, TS), the "> 5" in ppm: absence of the 6-methoxy peak at 4.05 and appearance of new peaks at 2.57 -3.10 (wide s, 4) and 6.20-6.93 (wide s, 1) EXAMPLE 34 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8 a-methoxy-5-methyl-6- (2-methoxyethylamino) azirinoL2 ', 3': 3,4J - pyrrolo [ l, 2-aJ-indole-4,7-dione

This compound is prepared according to the process described in

Example 1, but omitting the potassium carbonate. AT

starting from 120 mg of mitomycin A and 0.2 ml of 2-methoxyethylamine, 99 mg (yield of 73%) of the desired compound are obtained, having a melting point of 106-109 ° C (decomposition) and giving rise to in the following analysis: RMNiCDClg, TS), the "&" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.42 (s, 3), 3.5-3, 9 (broad s, 4), 6.27-6.77 (broad s, 1).

EXAMPLE 35 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-methoxyanilino) -azirino carbamate [2 ', 3': 3,4J- pyrrolo [l, 2-al] -indole-4,7-dione

This compound is prepared according to the process described in

Example 1, but omitting the potassium carbonate. AT

starting from 77 mg of mitomycin A and 27 mg of 4-methoxyaniline, 70 mg (yield of 74%) of the desired compound is obtained having a melting point of 103-108 ° C (decomposition) and giving rise to the following analysis : NMR (CDCl 4, TS), the "<$" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.8 (s, 3), 6.8 (s, 4 ) and 7.7 (s, 1).

CD.MJ - 21 - EXAMPLE 36 -

Carbamate of l, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-roethoxy -5-methyl-6- (1-adamantylaroino) -azirinoL 21.31: 3.4 J - pyrroloLl, 2-aJ-indole-4,7-dione

This compound is prepared according to the method described in Example 1. The reaction does not reach its end in 48 hours despite the excess of amine used. From 147 mg of mitomycin A and 666 mg of 1-aminoadamantane, 60 mg (30% yield) of the desired compound is obtained having a melting point of 149-150 ° C (decomposition) with partial decomposition at 85- 90 ° C and giving rise to the following analysis: NMR (CDCl ^ + CD ^ OD, TS), the "S" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1, 55-2.3 (m, 15).

EXAMPLE 37 -

Carbamate 1, la, 2,8,8a, 8b-hexahydro-8- (hvdroxvmethyl) 8a-methoxy-5-methyl-6- [l- (1,3,4-triazolyl) amino] -azirino [2, , 3 ': 3,4JpyrroloÇl, 2-aj-indole-4,7-dione

This compound is prepared according to the method described in Example 1. From 100 mg of mitomycin A and 80 mg of 1-amino-1,3,4-triazole, 35 mg are obtained (yield 30%) of the desired compound having a melting point of> 250 ° C (decomposition) and giving rise to the following analysis: NMR (CDCl 4, TMS), the "0" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 8.00 (s, 2).

EXAMPLE 38 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4,5-trimethoxybenzylamino) -azirino- [2 ', 31: 3,4jpyrrolo- [l, 2-a] indole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate. From 65 mg of mitomycin A and from 437 mg of 3,4,5-trimé-thoxybenzylamine, 55 mg (yield of 57%) of the desired compound having a melting point of 94-95 ° C (decomposition) are obtained. and giving rise to the following analysis: CD.MJ - 22 - NMR (CDClg, TS), the "<%" in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.85 (s, 9), 4.46-4.76 (d, 2) and 6.45 (s, 2).

EXAMPLE 39 -

Carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- [2- (ethylthio) ethylamino] -azirino- [21,31: 3,4jpyrrolo- [l, 2-a] indole-4,7-dione

This compound is prepared according to the method described in Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 120 mg of N-methylmitomycin A and 70 mg of 2- (ethyl-thio) ethylamine hydrochloride, 100 mg (yield of 69¾) is obtained of the desired compound having a melting point of 114-116 ° C ( decomposition) and giving rise to the following analysis: NMR (CDClg, TS) "the" S "in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.27 (t, 3) , 2.40-2.93 (m, 4), 3.40-3.93 (m, 2) and 6.50-6.80 (wide s, 1).

EXAMPLE 40 -

1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (dimethylamino) ethylamino3-azirino- [21,31: 3,4 ] pyrrolo- [l, 2-ajindole-4,7-dione

This compound is prepared according to the process described in Example 1, but omitting the potassium carbonate. From 150 mg of mitomycin A and 0.2 ml of 2- (dimethyl-amino) ethylamine, 130 mg (yield of 75¾) of the desired compound is obtained having a melting point of 72-75 ° C (decomposition) and giving rise to the following analysis: NMR (CDCl 4, TS) / les "in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 2.17 (s, 6), 2, 37-2.63 (wide s, 2), 3.3-4.0 (wide s, 2) and 6.7-7.1 (wide s, 1) EXAMPLE 41 -

Carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [l- (3-hydroxypiperidyl) J-azirino [21,3: 3, 4] -pyrrolo [1,2-a] indole-4,7-dione

This compound is prepared according to the method described in CD.MJ - 23 “Example 1, but using 0.5 ml of triethylamine instead of potassium carbonate. From 130 mg of mitomycin A and 70 mg of 3-hydroxypiperidine hydrochloride, 80 mg (yield of 58%) of the desired compound is obtained having a melting point of 98-101 ° C (decomposition) giving rise to l 'following analysis: NMR (CDClj, TS) "the" 6 "in ppm: absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 0.97-2.13 (m wide, 4), 2 , 17-3.13 (wide m, 4), 3.3-4.33 (wide m, 1) and 4.67-5.73 (wide s, 1).

EXAMPLE 42 -

By means of mitomycin A and the appropriate starting amine, the following compounds can be prepared according to the methods of the examples above: (a) 1, la, 2,8,8a, 8b-hexahydro- carbamate 8- (hydro-xymethyl) -8a-methoxy-6- (2-phenyl-1-aziridinyl) -azirino [2 ', 31: 3,4] pyrrolo- [1,2-a] indole-4,7- dione; (b) 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxy-methyl) -8a-methoxy-6- (2-methoxycarbonyl-1-aziridinyl) -azirino- [2 ', 3 carbamate ': 3,4] -pyrrolo- [1,2-a] indole-4,7-dione; (c) 1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxy-methyl) -8a-methoxy-6- (2-carboxamido-1-aziridinyl) -azirino- [21.3 'carbamate : 3,4] -pyrrolo- [1,2-a] indole-4,7-dione; (d) 1, la, 2,8,8a, 8b-hexahydro-8- (hydro-xymethyl) -8a-methoxy-6- (N-morpholinyl) -azirinot 2 ', 3': 3.4] carbamate -pyrrolo- [1,2-a] -indole-4,7-dione; (e) carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxy-methyl) -8a-methoxy-6- (1-piperazinyl) -azirino [2 '', 3 *: 3, 4Jpyrrolo- [1,2-a] -indole-4,7-dione: (f) carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8 ~ (hydro-xymethyl) -8a-methoxy-6 - (4-formyl-1-piperazinyl) -azirinot2 ', 3': 3,4jpyrrolo- [1,2-aJindole-4,7-dione; .

CD.MJ - 24 - (g) carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hy-droxymethyl) -8a-methoxy-6- (4-acetylphenyl-1-piperazinyl) -azirino [2 ', 3': 3,4J-pyrrolo- [1,2-aJindole-4,7-dione; (h) 1,1a, 2,8,8a, 8b-hexahydro-8- (hy-droxymethyl) -8a-methoxy-6- [4- (1-piperidyl) -1-piperidyl] -azirino carbamate [2 ', 3': 3,4] -pyrrolo- [1,2-a] indole-4,7-dione; (i) carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hy-droxymethyl) -8a-methoxy-6 - [(6-chloro-3-pyridyl) aminoj-azirino- [21, 3 ': 3,4] -pyrrolo-tl, 2-aJindole-4,7-dione; (j) 1,1a carbamate, 2,8,8a, 8b-hexahydro-8- (hydro-xymethyl) -8a-methoxy-6 - [(6-amino-3-pyridyl) aminoj-azirino- [21, 31: 3,4] -pyrrolo- [1,2-aJindole-4,7-dione; (k) 1,1a, 2,8,8a, 8b-hexahydro-8- (hydro-xymethyl) _8a-methoxy-6 - [(4,5-dimethyl-2-thiazolyl) amino] -azirino- [carbamate 2 ', 31: 3,4] pyrrolo- [1,2-a] indole-4,7-dione; (l) carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8- (hydro-xymethyl) -8a-methoxy-6 - [(4-cyano-3-pyrazolyl) amino] -azirino- [2 ', 3': 3,4] -pyrrolo- [1,2-aJindole-4,7-dione.

With specific reference to the compounds of formula IIa, the examples above illustrate the structural differences detailed below.

1. In the compounds of Examples 33 and 39, Y is a lower alkyl radical and more specifically methyl.

In all the other examples, Y is a hydrogen atom.

The nature of Y is independent of that of Z. Examples 16 and 33 can be compared in this connection, where Z is identical and Y is a hydrogen atom and a lower alkyl radical, respectively. Examples 32 and 39 differ in the same way.

2. The compounds in the formula of which Z is a quinolinylamino alkoxy (lower) -substituted radical, a pyrazolamino cyano-substituted radical or a thiazolamino CD.MJ - 25 - mono- or dialkyKinterior) -substituted radical are illustrated respectively by the examples 5, 42 (1), 17 and 42 (k).

3. The compounds in the formula of which Z is a nitrogen heterocyclic radical chosen from the 1-pyr-rolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl radicals are illustrated respectively by Examples 27 , 3, 28, 42 (d), 42 (e) and 2.

4. The compounds in the formula of which Z represents a 1-aziridinyl cyano-, phenyl-, carboxamido- or alkoxycarbonyl (lower) -substituted radical are illustrated respectively by Examples 1, 42 (a), 42 (c) and 42 ( b).

5. The compounds in the formula of which Z represents a 1-piperazinyl alkyl (lower) - formyl- or acetyl-phenyl-substituted radical are illustrated by Examples 29, 42 (f) and 42 (g) respectively.

6. The compounds in the formula of which Z represents a hydroxy- or piperidyl-substituted piperidyl radical are illustrated by Examples 41 and 42 (h) respectively.

7. The compounds in the formula of which Z represents a pyridylamino alkoxy (lower) ~, amino- or halo-substi-killed radical are illustrated respectively by Examples 4, 42 (j) and 42 (i).

8. The compounds in the formula of which Z represents an anilino carboxamido-, mercapto- or methylenedioxy-substituted radical are illustrated by Examples 8, 18 and 19 respectively.

9. The compounds in the formula of which Z represents R "a radical of formula -N ^ where R" is a heterocyclic radical

nR

that nitrogen selected from the quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinoline, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl and their alkyl- (lower) - and halo-substituted derivatives are illustrated by examples CD.MJ - 26 - 6, 30 , 37, 21, 22, 13, 14 and 23.

10. The compounds in the formula of which Z is a radical of formula -N where R "is a butyrolactonyl radical, an adamantyl radical or a mono-alkoxy (lower) -substituted phenyl radical are illustrated respectively by Examples 7, 36 and 35 .

11. The compounds in the formula of which Z is a / R "radical of formula -N or R" is a lower alkyl radical-

Xr substituted substituted chosen from the radicals lower mercaptoalkyl, lower carboxyalkyl, mono-, di- and trialkoxy (lower) lower alkyl, alkylthio (lower) lower alkyl and their derivatives alkoxycarbonyl (lower) -substituted, lower cyanoalkyl, mono-, di- and trialkoxy (lower) -phenylalkyl lower, phenylcycloalkyl lower, 1-pyr-rolidinylalkyl lower, N-alkyl (lower) pyrrolidinyl-lower alkyl, N-morpholinylalkyl lower and dialkyl- (lower) aminoalkyl lower are illustrated by Examples 16, 33 , 24, 34, 15, 32, 39, 11, 25, 9, 38, 12, 20, 10, 31 and 40.

Finally, it should be noted that the use of the compound of Example 26 is known from the description of the use of compounds of formula la in US Patent 4,268,676. This compound does not meet the formula IIa.

Compounds of the invention, like those of U.S. Patent No. 4,268,676, are believed to exhibit antibacterial activity against Gram-positive and Gram-negative microorganisms in a manner analogous to that observed with natural mitomycins and are therefore potentially useful as therapeutic agents for bacterial infections in humans and animals.

The usefulness of the compounds of formula IIa in the pro-CD.MJ-27- therapeutic antineoplastic drugs of the invention is demonstrated by the results of in vivo studies in which the compounds were administered in different doses to mice in which P338 leukemia was induced.

These tests are performed as described in "Lymphocytic Leukemia P338 - Protocol 1.200", published in Cancer Chemo-therapy Reports, Part 3, volume 3, n ° 2, page 9 (September 1972). In summary, the experiment consists in administering the test compound to female CDF "*" mice previously infected with 10 ascites cells implanted intraperitoneally. The compounds are administered on the first day of the test only and the animals are monitored for vitality, inter alia, for 35 days.

Table I collates the results of the test of the compounds of Examples 1 to 41. The data given are the optimal dose ("OD"), that is to say the dose, in mg / kg of body weight of The animal, for which the therapeutic effect is maximum in a reproducible manner. The table also indicates the average survival time ("TSM") expressed in the form of the average survival time of the test animals compared to the average survival time of the control animals x 100 ("% e / T").

As part of the in. in vivo on P338 leukemia, a% E / T value of more than 125 indicates significant antineoplastic therapeutic activity. The lower dose, in mg / kg body weight, for which 125% E / T is reached is called the minimum effective dose ("DEM"). These doses are also mentioned in Table I. It should be noted that the exceptionally high values of the average survival time observed against leukemia P338 which are mentioned in Table I prove the absence of appreciable toxicity of the compounds at the doses tested.

CD.MJ - 28 -

TABLE I

Example D.O., mg / kg TSM,% E / T DEM

1 12.8 339 0.2 2 3.2 211 0.4 3 12.8 150 0.8 4 6.4 211 0.2 5 6.4 178 0.4 6 25.6 144 12.8 7 6 , 4,175 0.8 8 25.6 255 1.6 9 25.6 239 1.6 10 12.8 217 0.8 11 6.4 131 3.2 12 12.8 217 1.6 13 25.6 178 1.6 14 12.8 222 0.8 15 6.4 200 0.8 16 12.8 313 <0.2 17 6.4 172 0.4 18 6.4 134 1.6 19 3.2 167 <0.2 20 12.8 194 0.4 21 12.8 183 0.2 22 25.6 206 0.2 23 12.8 161 0.8 24 6.4 261 0.4 25 6.4 232 0 , 4 26 6.4> 316 0.4 27 12.8 216 0.2 28 25.6 222 0.2 29 3.2 261 <0.2 30 25.6> 333 0.8 CD.MJ - 29 - TABLE I (continued)

Example D.O., mg / kg TSM,% E / T DEM

31 25.6 150 6.4 32 12.8 205 1.6 33 25.6 170 1.6 34 12.8 205 0.8 35 12.8> 316 0.8 36 25.6 132 6.4 37 12.8 172 3.2 38 25.6 188 1.6 39 25.6 200 6.4 40 12.8> 211 0.4 41 12.8> 211 <0.2

Obviously, the especially preferred compounds admitted as antineoplastic agents in accordance with the invention are those manifesting more than twice the relative capacity to prolong the survival of the compounds which have a significant therapeutic power, that is to say those ensuring a time of average survival, expressed in% W / T, of more than 2 x 125. The compounds are in particular those of examples 1, 8, 16, 24, 26, 29, 30 and 35.

As can be seen from Table I, initial unit doses as low as 0.2 mg / kg exhibit significant long-term antineoplastic activity. Consequently, the methods of the invention can comprise the therapeutic administration of unit doses ranging from barely 0.001 mg to 5 mg and preferably from 0.004 mg to 1.0 mg of the compounds, as active ingredient, in an appropriate pharmaceutical preparation. These preparations can be administered daily in an amount of 0.1 to 100 mg per kg and preferably about 0.2 to 51.2 mg per kg of body weight of the animal suffering from a neoplastic condition. The compounds CD.MJ - 30 - are preferably administered parenterally. The pharmaceutical preparations suitable for the application of the methods of the invention can be simple aqueous solutions of one or more of the compounds of formula IIa, but can also comprise known acceptable pharmaceutical diluents, adjuvants and / or excipients, for example physiological saline solution.

Although various embodiments and details have been described to illustrate the invention, it goes without saying that it is susceptible of numerous variants and modifications without departing from its scope.

CD.MJ - 31 -.

Claims (5)

2. Compounds according to claim 1, in this case: the carbamate of l, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyano -1-aziridinyl) -azirino [2 ', 3': 3,4] pyrrolo [1,2-a3indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thiomorpholinyl) -azirino [21,31: 3,4 jpyrrolotl, 2- a] -indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-indolinyl) -azirino carbamate [21.3 *: 3.4Jpyrrolotl, 2-aJindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(6-methoxy-3-pyridyl) amino] -azirino carbamate [21, 3 ': 3,4j-pyrroloCl, 2-ajindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(6-methoxy-8-quinolinyl) aminoj-azirino- [2 'carbamate , 3 ': 3,4J-pyrrolo [1,2-a] indole; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) carbamate - OI i mw.1 null .ni 4 ^ __ Γ Tl 11 · Ο Λ I pyrrolo- [l, 2-a] indole -4.7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (Ti-butyrolactonyl) amino] azirino [21.3 'carbamate: 3.4] pyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-carboxamidoanilino) -azirino [21,3 ': 3.4] pyrrolo- [1,2-a] indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxybenzylamino) -azirino- [2 ', 31: 3 carbamate , 4] pyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(1-ethyl-2-pyrrolidino) methylaminoü-azirino- [2 * , 31: 3,4] -pyrrolo [1,2-a] indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(1-methoxycarbonyl-3-methylthio) propyl-amino] -azirino- carbamate [21.31: 3.4] pyrrolo [1,2-aJindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-phenylcyclopropylamino) -azirino- [2 ', 3': 3 carbamate , 4] pyrrolo- [1,2-a] -indole-4,7-dione; the carbamate of 1.1a, 2.8.8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-C (5-chloro-2-benzoxazolyl) amino] azirino-C2 *, 3 ': 3.43 -pyrroloCl, 2-a] indole-4,7-dione; 1,1,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [5-methyl-2- (1,3,4-thiadiazolyl) amino carbamate ] -azirino- [2 ', 3': 3.4 Jpyrrolo [1,2-a! lindole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) ~ 8a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) -azirino carbamate [21.31: 3.43 - pyrrolo- [1,2-a] indole-4,7-dione; 1,1,8,2,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-mercaptoethylamino) -azirino carbamate [2 ', 3': 3.4 d -pyrrolo- [1,2-a] indole-4,7-dione; 1,1a, 2,8,8a carbamate, 8b-hexahydro-8- (hydroxymethyl) -8a- CD.MJ - 34 - methoxy-5-methyl-6 - [(4-methyl-2-thiazolyl) aminoJ -azirinot 2 ', 31: 3,4J-pyrrolo [1,2-a] indole-4,7-dione; the carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-mercaptoanilino) -azirinot2 ', 3 1: 3,4] - pyrrolotl, 2-aJ-indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-methylenedioxyanilino) -azirino- [2 ', 3 *: 3,4] pyrrolo- (1,2-aJindole-4,7-dione; l, la carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl- 6-t2- (1-pyrrolidino) ethylamino] -azirino- [21,3 ': 3,4] pyrrolo- [1,2-aJindole-4,7-dione; 1,1a, 2,8 carbamate, 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-isoquinoleinylamino) -azirinot 21.3 ': 3,4] pyrrolo-tl, 2-ajindole-4,7- dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-indazolylamino) -azirinot2 ', 3 *: 3,4 ] pyrrolo-tl, 2-a] -indole-4,7-dione; carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 -t4- (2,1,3-benzothiadiazolyl) amino] -azirino-121,31: 3,4] -pyrrolot1,2-aJindole-4,7-dione; l, la carbamate, 2,8,8a , 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyanoethylamino) -azirinot 21.31: 3.4] pyrrolo- 11.2 — a J — indole —4.7 -dione; 1,1a, 2,8,8 carbamate a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-tl- (3-pyrrolinyl) J-azirinot2 ', 3': 3,4] -pyrrolot1,2-aJ-indole- 4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl} -8-methoxy-5-methyl-6- (3-thiazolidino) -azirinot carbamate 2 ^ 3 ^ 3,4 Jpyrrolo-tl , 2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [1- ( 4-methylpiperazino)] - azirinot 2 ', 31: 3.4] - pyrrolo-tl, 2-a] indole-4,7-dione; CD.MJ - 35 - l, la, 2.8, carbamate 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [3 - (pyrazolyl) amino] azirino [2 ', 3': 3,43-pyrrolo [1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (N-morpholino) ethylaminoj -azirino- [2 ', 3': 3,4] pyrrolo [1,2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (ethylthio) ethylaminoJ-azirino [21,3 ': 3,4 J - pyrrolo- [1,2-a] indole-4,7-dione; carbamate 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- (2-mercaptoethylamino) -azirino [21,31: 3,4 3 - pyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1,1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-methoxyethylamino) azirino [21,31: 3,4j-pyrrolot1,2-a] - indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-adamantylamino) -azirino [21,31: 3,4] pyrrolo - [1,2-aJ-indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [1- (1,3,4-triazolyl) amino] -azirino carbamate 21, 3 ': 3.4 3 - pyrrolot1,2-a] -indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4,5-trimethoxybenzylamino) -azirino carbamate [21.31: 3 , 4] pyrrolo- [1,2-ajindole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- [2- (ethylthio) ethylaminoJ-azirino- [2 ', 3 ': 3.43 pyrrolo- [1,2-a0indole-4,7-dione; 1,1,8,2,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [1- (3-hydroxypiperidyl) j-azirinot 21.3: 3 carbamate, 4 J-pyrrolo [1,2-aJindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) - 8a-methoxy-6- (2-phenyl-1-aziridinyl) -azirino carbamate [2 ', 3': 3,4Jpyrrolo - CD.MJ - 36 - tl, 2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2-methoxycarbonyl-l-aziridinyl) -azirinot 2 1, 3 ^ 3,41-pyrrolo -t1,2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2-carboxamido-1-aziridinyl) -azirinot21.3 ': 3,4J— pyrrolo- tl, 2-aJ-indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (4-formyl-1-piperazinyl) -azirinot21.31: 3.4 J carbamate tl, 2-ajindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (4-acetylphenyl-1-piperazinyl) -azirinot21, 3 1: 3,4J-pyrrolo- t1,2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-t 4- (1-piperidyl) -l-piperidylJ-azirinot21.3 ': 3,4 J-pyrrolo-t1,2-aJindole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-t (6-chloro-3-pyridyl) aminoJ-azirinot21.31: 3.4] pyrrolo -tl, 2-aJ-indole-4, 7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-t (6-amino-3-pyridyl) amino] -azirino [21,31: 3, 4Jpyrrolo-tl, 2-aJ-indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-t (4,5-dimethyl-2-thiazolyl) aminoJ-azirinot2 *, 3 ': 3 carbamate , 4] -pyrrolo-t1,2-aJindole-4,7-dione and the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-t (4 -cyano-3-pyrazolyl) aminoJ-azirinot2 ', 3': 3,4J-pyrrolo- (1,2-aJ-indole-4,7-dione. 3. A method of treating a neoplastic condition in an animal, characterized in that an animal suffering from such a condition is administered a therapeutically effective amount of a compound of formula: CD.MJ - 37 - Il f _ ^ / CH2OCNH2 I _--- OCH, "3C T \ ï o - ^ where Y represents a hydrogen atom or a lower alkyl radical, Z represents a quinoline linylamino alkoxy (lower) -substituted, pyrazolylamino cyano-substituted or thiazolamino radical mono- or dialkyKinterior) -substituted, or a heterocyclic nitrogen radical chosen from the radicals 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl, or a cyano-1-aziridinyl radical, phenyl-, carboxamido- or lower alkoxycarbony) -substituted, or a 1-piperazinyl alkyl (lower) -formyl- or acetylphenyl-substituted radical, or a 1-piperidyl hydroxy- or piperidyl- substituted radical, or a pyridylamino alkoxy (lower) radical -amino- or halo-substituted, or an anilino radical ca rboxamido-, mercapto-or methylenedioxy-substituted, or a radical of formula - N (in which R represents a hydrogen atom or a lower alkyl radical and R "represents a nitrogen heterocyclic radical chosen from quinuclidinyl, pyrazolyl, 1- tri-azolyl, isoquinoline, indazolyl, benzoxazolyl, thiadia-zolyl and benzothiadiazolyl and their substituted (lower) alkyl and halo derivatives, or a butyrolactonyl radical, or CD.MJ - 38 - an adamantyl radical, or a phenyl mono-alkoxy radical (lower) - substituted, or a substituted lower alkyl radical chosen from lower mercaptoalkyl, lower carboxyalkyl, mono-, di- and tri-alkoxy (lower) lower alkyl, lower alkylthio (lower) -alkyl and their alkoxycarbonylated, cyanoalkyl derivatives lower, mono-, di- and tri-alkoxy (lower) phenylalkyl lower, phenylcycloalkyl lower, 1-pyrrolidinylalkyl lower, N-alkyl (lower) -pyrrolidi-nylalkyl lower, N-morp lower holinylalkyl and dialkyl- (lower) lower aminoalkyl). 4. Method according to claim 3. Characterized in that the compound is chosen from: carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - {2-cyano-1-aziridinyl) -azirino [2 ^ 3 ^ 3,43 -pyrrolotl, 2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thiomorpholinyl) -azirino [21,3 ': 3,4] pyrrolo- [1,2-a] -indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-indolinyl) -azirinot carbamate 21.31: 3.4 Jpyrrolo- [ 1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(6-methoxy-3-pyridyl) amino] azirino [21,31 : 3,4] -pyrrolo [1,2-ajindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(6-methoxy-8-quinolinyl) aminoj-azirino-L2 'carbamate, 3 *: 3,4] -pyrrolo [1,2-a] indole; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a- m'ethoxy-5-methyl-6- (3-quinuclidinylamino) - azirinot 2 1, 3 ': 3, 4 3- pyrrolo- [1,2-a] indole-4,7-dione; Cü.MJ - 39 - 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- ("j-butyrolactonyl) amino) carbamate -azirino-C 21f 3 *: 3.4 Jpyrrolo- [1,2-aJ-indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 ~ (4-carboxamidoanilino) -azirinot 21.31: 3.4 Jpyrrolo-t1,2 ~ a] indole ~ 4,7-dione; the carbamate of 1, la, 2, 8.8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxybenzylamino) -azirinot21.3 ': 3,4Jpyrrolo- [1,2-a] indole- 4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(1-ethyl-2-pyrrolidino) methylamino3 -azirino- [2 ', 31: 3,4] pyrrolo- [1,2-alindole-4,7-dione; the carbamate of 1, la, 2,8,8af8b-hexahydro-8- (hydroxymethyl) -8a -methoxy-5-methyl-6 - [(1-methoxycarbonyl-3-methylthio) propylamino] -azirino- [2 ', 3': 3,4] pyrrolo [lf2-a] indole-4,7-dione; 1,1a, 2,8,8a carbamate, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-phenylcyclopropylamino) -azirino [21,3 ': 3, 4] pyrrolo - [l , 2-a] indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(5-chloro-2-benzoxazolyl) amino] -azirino- [2 ', 31: 3,4] -pyrrolo [1,2-a] indole-4,7-dione; 1,1,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [5-methyl-2- (1,3,4-thiadiazolyl) aminoj carbamate -azirino- [2 ', 3': 3,4] pyrrolo [1,2-a! lindole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) -azirino- carbamate [21.31: 3, 4Jpyrrolo- [1,2-a] indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-mercaptoethylamino) -azirinot21.3 ': 3,4] -pyrrolo carbamate - [1,2-ajindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a- methoxy-5-methyl-6 - [(4-methyl-2-thiazolyl) aminoJ-azirino- CD.MJ carbamate - 40 - [21.31: 3.4 Jpyrrolo- [1,2-a] indole-4,7-dione; 1, la, carbamate, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-mercaptoanilino) -azirinot21.31: 3.4 J - pyrrolot1, 2-aj-indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-methylenedioxyanilino) -azirino carbamate [21, 3 ': 3, 4pyrrolo- [1,2-a] indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (1-pyrrolidino) ethylaminoJ-azirino [21,3 'carbamate: 3,4Jpyrrolo-Cl, 2-a] indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-isoquinolinylamino) -azirinot2 ', 3': 3,4] carbamate -tl, 2-ajindole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-indazolylamino) -azirino carbamate [2 *, 3 *: 3.43 -pyrrolot1,2-a] -indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro ~ 8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (2,1,3-benzothiadiazolyl) amino] -azirino carbamate 21.31: 3.4] -pyrrolo [1,2-a] indole-4,7-dione; carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (N-glycinyl) -azirinot 21.3 ': 3,4] pyrrolo -tl, 2-a] indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyanoethylamino) -azirinot2 ', 3' carbamate2 ', 3': 3,4] - pyrrolotl, 2-a] -indole-4,7-dione; the carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-fl- (3-pyrrolinyl)] - azirino (2 ', 3': 3,4] -pyrrolot1,2-a] -indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8-methoxy-5-methyl carbamate -6- (3-thiazolidino) -azirino [2 ', 3': 3,4] pyrrolo-tL., 2-a] indole-4,7-dione; 1,1a, 2,8,8a carbamate , 8b-hexahydro-8- (hydroxymethyl) -8a- CD.MJ - 41 - methoxy-5-methyl-6- [l- (4-methylpiperazino) J-azirino [21,3 ': 3,4] -pyrrolo ~ [l, 2-a] indole-4,7-dione; the carbamate of l, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [ 3- (pyrazolyl) amino] -azirino [2 ', 31: 3,4J-pyrrolotl, 2-aJ-indole-4,7-dione; carbamate 1,1a, 2,8,8a, 8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy ~ 5 ~ methyl-6- [2 ~ (l-morpholino) ethylamino] -azirino [2 ', 3': 3,4 Jpyrrolo- [1,2-a] indole-4 , 7-dione; 1,1a, 2,8,8a carbamate, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5 ~ methyl-6- [2- (ethylthio) ethylamino] -azirino [21 , 31: 3,4] -pyrrolo-C1,2-aj indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahyd ro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- (2-mercaptoethylamino) -azirino [21,3 ': 3.4] pyrrolo- [1,2-a] indole-4,7- dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-methoxyethylamino) azirino carbamate [2 ', 3': 3,4] -pyrrolotl, 2-aJ-indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-methoxyanilino) -azirinoC 2 ', 3': 3,4 Jpyrrolo - [1,2-a] -indole-4,7-dione; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-adamantylamino) -azirino carbamate [21.3 ': 3.4] pyrrolo- [1,2-a] -indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- carbamate [1- (1,3,4-triazolyl) amino] -azirino [ 2 ', 3': 3.4] pyrrolo [1,2-a] -indole-4,7-dione; the carbamate of 1, la, 2,8, 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4,5-trimethoxybenzylamino) -azirino- [2 *, 3 ': 3,4] pyrrolo- [1,2-aJindole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- [2- (ethylthio) ethylaminoJ-azirino [2 *, 3 '' carbamate : 3,4Jpyrrolo- [1,2-a] indole-4,7-dione; . Cl) .MJ - 42 - the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2 - (dimethylamino) ethylamino] -azirino - [21.31: 3.4 Jpyrrolo- [1,2-aJindole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl} -8a-methoxy-5-methyl-6- [1- (3-hydroxypiperidyl)] - azirino [21.3: 3 , 4] -pyrrolo [1,2-aJ-indole-4,7-dione; carbamate 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- ( 2-phenyl-1-aziridinyl) -azirino [2 ', 3': 3,4Jpyrrolo- [1,2-aJindole-4,7-dione; carbamate del, la, 2,8,8a, 8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy-6- (2-methoxycarbonyl-1-aziridinyl) -azirinot 2 ', 3': 3,4] -pyrrolo- [1,2-a] indole-4,7-dione ; 1, la, 2,8,8a, 8b-hexahvdro-8- (hydroxymethyl) -8a-methoxy-6- (2-carboxamido-1-aziridinyl) -azirinot carbamate 21.31: 3.4Jpyrrolo - [1,2-a] -indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro ~ 8- (hydroxymethyl) -8a-methoxy-6- (N-morpholinyl ) -azirinot21.3 ': 3.4 Jpyrrolo- [1,2-aj-indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) - 8a-methoxy-6- (1-piperazinyl) -azirinot 21.31: 3.4 Jpyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (4-formyl-1-pip erazinyl) -azirinot2 *, 3 ': 3,4] pyrrolo- [1,2 — a] —indole — 4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro ~ 8- (hydroxymethyl) -8a-methoxy-6- (4-acetylpheny1-1-piperazinyl) -azirinot 21.3 ': 3,4] - pyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- [4- (1-piperidyl) -l-piperidyl] azirino [2 ', 3 *: 3.4 J pyrrolo- [1,2-a] indole-4,7-dione; the carbamate of 1.1a, 2.8.8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6 - [(6-chloro-3-pyridyl) amino] -azirino [2 *, 3 *: 3.43 - CD.MJ - 43 - pyrrolo- [1,2-a] -indole-4,7-dione; the carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6 - [(6-amino-3-pyridyl) amino] -azirino [2 ', 3': 3,4Jpyrrolo- [1,2 ~ aJ-indole-4,7-dione; 1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6 - [(4,5-dimethyl-2-thiazolyl) amino] -azirino carbamate [2 *, 3 ': 3,4] -pyrrolo- [1,2-a] indole-4,7-dione and the carbamate of 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy -6 - [(4-cyano-3-pyrazolyl) amino] -azirino [2 ', 31: 3,4J-pyrrolo- [1,2-a] -indole-4,7-dione. 5. Method according to claim 3, characterized in that the quantity of compound administered is a daily dose of approximately 0.2 mg to approximately 51.2 mg per kg of body weight of the animal. 6. Therapeutic composition for the treatment of a neoplastic disease in an animal, characterized in that it comprises a pharmaceutically acceptable solvent, diluent, adjuvant or excipient and as active principle approximately 0.001 mg to approximately 5 mg of a compound of formula : 0? z ^ ^ ch2ocnh2 I .-— OCH, l L_-NY where Y represents a hydrogen atom or a lower alkyl radical, Z represents a quinoline linylamino alkoxy (lower) -substituted radical, pyrazolylamino cyano-substituted or thiazolamino mono- or dialkyKinérieur ) -substituted, or a heterocyclic nitrogen radical chosen from the 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, CD.MJ - 44 - N-morpholinyl, 1-piperazinyl and N-thiomorpholinvl radicals, or a 1-aziridinyl cyano radical -, phenyl-, carboxamido or alkoxycarbonyl (lower) -substituted, or a 1-piperazinyl alkyl (lower) -formyl- or acetylphenyl-substituted radical, or a 1-piperidyl hydroxy- or piperidyl- substituted radical, or a pyridylamino alkoxy radical (lower) - amino- or halo-substituted, or an anilino carboxamido-, mercapto- or methylenedioxy-substituted radical, or a radical of formula -N "'' R (in which R represents a hydrogen atom or a lower alkyl radical and R "represents a chosen heterocyclic nitrogen radical i among the quinuclidinyl, pyrazolyl, 1-tri-azolyl, isoquinoline, indazolyl, benzoxazolyl, thiadia-zolyl and benzothiadiazolyl radicals and their substituted (lower) alkyl and halo derivatives, or a butyrolactonyl radical, or an adamantyl radical, or a radical substituted mono-alkoxy (lower) phenyl, or a substituted lower alkyl radical chosen from lower mercaptoalkyl, mono-, di- and tri-alkoxy (lower) radicals lower alkyl, lower alkylthio-lower alkyl and their alkoxycarbo derivatives- nylated, lower cyanoalkyl, mono-, di- and tri-alkoxy- (lower) lower phenylalkyl, phenylcycloalkyl lower, 1-pyrrolidinylalkyl lower, N-alkyl (lower) -pyrrolidi-nylalkyl lower, N-morpholinylalkyl lower and dialkyl- (lower ) lower aminoalkyl). CD.MJ - 45 -