FR2540500A1 - DERIVATIVES OF MITOMYCIN AND ITS APPLICATION TO THE TREATMENT OF NEOPLASTIC DISEASES - Google Patents

Abstract

THE INVENTION CONCERNS THE COMPOUND ACCORDING TO FORMULA IIIA: (CF DRAWING IN BOPI) IN WHICH Y IS HYDROGEN OR A LOWER ALKYL AND Z IS: -A RADICAL 1 PYRROLIDINYL HYDROXY SUBSTITUT OR -UN RADICAL PIPERIDYL SUBSTITUTES BY AN ALKURIDYL SUBSTITUT, OR -UN RADICAL 1 PIPERAZINYL OR -A RADICAL ANILINE SUBSTITUTED BY A GROUP OF ACETAMINO, ACETYL, CARBAMIDO, CYANO, CARBOXY ALKYL INFERIEUR AMINO, DI-ALKOXY INFERIEUR, NITRO, SULFAMYL OR ALKINURULE DE ALKINURULE-RADICAL (CF) BOPI) IN WHICH R IS HYDROGEN OR LOWER ALKYL AND R IS A RADICAL CONTAINING HETEROCYCLIC NITROGEN, OR A SUBSTITUTE LOWER ALKYL RADICAL. APPLICATION TO THE PREPARATION OF THERAPEUTIC COMPOSITIONS FOR THE TREATMENT OF NEOPLASIC DISORDERS IN ANIMALS.

Description

The present invention relates to mitomycin derivatives.

  antibiotics and the use of such derivatives for the treatment of neoplastic disease states in animals.

  Mention is made in this patent specification

  US Pat. No. 4,268,667, to the divisional patent application

  No. 206,529 and US divisional patent application No. 264,187 corresponding to the French patent application No. 82 08 163, which provide essential data or not in connection with the present invention.

  Summarized summaries, the aforementioned US Patent No.

  No. 4,268,676 and US Application No. 206,529 indicate the background of ongoing research in the field of new useful compounds, which by their structure are close to mitomycins, possess antibiotic properties, are of low toxicity, and exhibit high activity.

  antitumor important in animals.

  More particularly, these documents describe novel compounds of formula I, ## STR2 ##

2 2540500

  Wherein Y is hydrogen or a lower alkyl radical; X is a thiazole-amine radical, a furfuryl-amine radical or a radical of formula

R R

I I R 3

-N CR

  Wherein R, R 1 and R 2 are the same or different elements selected from the group consisting of hydrogen and lower alkyl radicals, and R 3 being selected from the group consisting of lower alkenyls, lower haloalkenyls, lower alkynyls, alkoxycarbonyls

  lower, thienyls, formamyls, tetrahydrofuran

ryles and sulfonamides benzenes.

  These patents and patent application also relate to a novel method for treating neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of formula Ia, c 0 t -O & 2 g> CH 2 OCNU 2 {ll D ROCH 3 The

H 3 NY

  wherein, Y is hydrogen or lower alkyl; Z is a thiazole-amine radical, a furfuryl-amine radical, a cyclopropyl-amine radical, a pyridyl-amine radical or a radical of formula:

R 5

R 6

3 2540500

  Wherein R 4, B 5 and R 6 are the same or different members selected from the group consisting of hydrogen and lower alkyls, R 7 being selected from the group consisting of lower alkenyls, lower haloalkenyls, lower alkynyls, lower alkoxycarbonyls, lower haloalkyls, lower hydroxyalkyls, pyridyls, thienyls, formamyls, tetrahydrofuryls, benzyls and benzenesulfonamides. U.S. Patent Application No. 264,187, corresponding to French Patent Application No. 82 08 163, also discloses compounds having a sensitive antitumor activity in animals and having the formula I Ia o o

Z 2 'CH 20 OCNI 12

lia 3 C

3 3 3 I

  Y is hydrogen or a lower alkyl radical; and Z is a lower alkoxy substituted quinolinylamino radical, a substituted cyano pyrazolylamine radical, or a mono- or di-lower alkyl substituted thiazolamine radical, or a nitrogen-containing heterocyclic radical selected from the group consisting of 1-pyrrolinyl radicals, 1 indo: linyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyl and Nthiowdorpholinyl, or a substituted 1-aziridinyl cyano, phenyl, carboxamide or lower alkoxycarbonyl radical, or

4 2540500

  a substituted 1-piperazinyl lower alkyl, formyl, or acetylphenyl radical, or a substituted 1-piperidyl hydroxy or piperidyl radical, or a lower alkyl, pyridylamine, amino or substituted halo radical, or a substituted aniline carboxamido, mercapto or methylenedioxy radical, or a radical of formula R

-N-R '

  R is hydrogen or a lower alkyl radical and R 'is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl and benzoxazolyl; , thiadiazolyl and benzothiadiazolyl and the substituted lower alkyl and halo derivatives thereof or a butyrolactonyl radical, or an adamantyl radical, or a mono-lower alkoxy substituted phenyl radical, or a lower alkyl substituted radical selected from the group consisting of mercapto lower alkyls, lower alkyl lower alkyls, di and trialkoxy lower alkyls, lower alkylthio-lower alkyls and substituted lower alkoxycarbonyl derivatives thereof, lower cyanoalkyls, mono-, di and trialkoxy lower 1 phenyl-lower alkyls, lower phenyl-cycloalkyls, lower 1-pyrrolidinyl-alkyls, lower N-alkyls lower pyrrolidinyl-lower alkyls, lower N-morpholinyl-alkyls and lower lower alkyl dialkylamines - Cosulich and others: Matsui and others: Nakano and others: Matsui and others o Remers Matsui and others: -Matsui and others:

Imai and others -

  to illustrate the scope of the following documents: US Patent No. US Patent No. US Patent No. US Patent No. US Patent No. 3,332,310,431; 4,229,428;

Gann 71 page 560-562 (1980).

  The present invention relates to novel compounds of the formula wherein Y is hydrogen or lower alkyl and X is: a substituted 1-pyrrolidinyl hydroxy radical, or a substituted piperidyl radical lower alkyl, or an aniline, acetamino, acetyl, carbamido, cyano, carboxyl, amino lower alkyl, di-lower alkoxy, nitro or substituted sulfamyl radical, or

6 2540500

  1 a radical of formula R wherein R is hydrogen or lower alkyl and R1 is a heterocyclic nitrogen-containing radical selected from the group consisting of triazolyl substituted amino, isothiazolyl substituted by lower alkyl, benzothiazolyl, and nitro derivatives and substituted halo benzothiazolyl, or R 1 is: a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, amino alkyl

  lower alkyl lower, hydroxy lower alkyl -

  amino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted nitro, mono and di-hydroxy phenyl lower alkyl, pyridylamino lower alkyl

  substituted nitro and piperazinyl lower alkyl.

  The present invention also relates to novel methods of treating neoplastic infections in animals by administering a therapeutically active dose of the compound of formula III wherein Y is hydrogen or a lower alkyl and Z is a substituted 1-pyrrolidinyl hydroxy radical or a lower alkyl-substituted piperidyl radical, or a 1-piperazinyl radical or an aniline radical substituted by an acetamino, acetyl, carbamido, eyano, lower alkyl carboxy group; amino, di-lower alkoxy, nitro, sulfamyl or lower alkyl, or a radical of formula 11 wherein R is hydrogen or lower alkyl and R 1 is a heterocyclic nitrogen-containing radical selected from the group consisting of substituted azolylamino, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro derivatives and substituted halo benzothiazolyl, or R 1 e st is a substituted lower alkyl radical selected from the group consisting of lower alkyl, lower alkyl amino alkyl, lower alkyl hydroxy lower alkyl, lower alkoxy hydroxy lower alkyl, lower imidazolyl alkyl, lower alkyl limidazolyl 1 nitro substituted, mono and di = hydroxy phenyl lower alkyl, pyridylamino lower alkyl substituted nitro, piperazinyl

  lower alkyl and ethyl pyridyl.

  Unless otherwise stated, the term "lower", applied to alkyl radicals, refers to straight or branched chain radicals having from one to six carbon atoms. By way of illustration, "lower alkyl" means and includes methyl radicals, Ethyl, propyl, butyl, pentyl and hexyl, as well as isopropyl, tert-butyl and the like. Similarly, the term "lower alkoxy" applied to the radical refers to a radical having one to six carbon atoms. that the compounds of formula III are all inclusive of the compounds of formula II Ia. In other words, all the new antibiotic derivatives of mitomycin of formula III can be used in the implementation of new methods of antineoplastic therapy

  administering compounds of the formula

  The mitomycin derivatives according to the invention are prepared by reacting mitomycin A with appropriate amine compounds. The N-alkyl-mitomycin derivatives (for example N-methylmitomycin) are likewise prepared by reacting a selected amine. with N-alkyl-mitomycin A prepared from mitomycin C, according to, for example, the methods generally disclosed in the article by CHENG et al in J Med Chem, 20, No. 6, 767-770 (1977) Preparative reactions generally give the desired product in the form of a crystalline solid easily

soluble in alcohol -

  The therapeutic methods according to the invention comprise the administration of effective doses of one or more compounds of formula II Ia, as active agent, together with diluents, adjuvants and pharmaceutically acceptable carriers.

  acceptable to an animal suffering from neoplastic disease.

  Unit doses of compounds, administered according to the

9 2540500

  1 method of the invention ranges from about 0.001 mg to about 5.0 mg, preferably from about 0.004 mg to about 1.0 mg. These dosed amounts are given to provide a daily dose of from about 0.1 mg to about 100 mg, preferably between 0.2 mg and 51.2 mg, per kilogram of weight of the animal being cured Parenteral administration, and more particularly by intraperitoneal route, is the preferred form when it is used.

  of the method according to the invention.

  Other aspects and advantages of the invention will emerge from

the following description.

  The following Examples 1 to 32, describing the preparation of certain currently preferred compounds according to the invention, are cited by way of illustration and in no way limit the scope of the invention. Unless otherwise indicated, all reactions have occurred at temperature

  ambient temperature (200 C) without heat input.

  cations, thin layer chromatographic (TLC) processes used to control the evolution of the reactions involve the use of a pre-coated silica gel lamella and a mixture (2 to 8 volume) of methanol and chloroform, as developing solvent Exeple 24 a, 8 E, as 8-e Mayro S (hydroxymethyl> 8α-methoxy-1- (3-hydroxy-rolidinyl) -aziri) 32 -3A 3,4 A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanohydroxide was treated with 13 ml of 3-pyrrolidinol under a nitrogen atmosphere and at room temperature when the chromatography was complete. in a thin layer on silica gel (with a solvent consisting of a mixture of two parts of methanol 1 to 8 parts of chloroform) showed that the starting reagents were no longer present, the mixture was filtered and evaporated under pressure reduced The residue is purified by preparative thin layer chromatography The same solvent yielded 23 mg (yield = 40%) of the desired product having a melting point at 82 85 C (decomposition temperature) and having the following data for analysis:

  NMR (DSMSO-d 6, TS): values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 1.6 2.2 (m, 2), 2.8-3.1 (wide s, 5) and

4.0-4.3 (m, 1).

Ex Mple 2

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

  5-methyl-6- (3-methylpiperdyl) azirinol 2 ', 13': 3,4-pyrrolo [1,2-alindole-4,7-dione carbamate This process was prepared according to the method described for Example 1 From 70 mg of mitomycin A and 200 mg of 3methyl piperidine, 46 mg (55% yield) of the desired product having a melting point of 75 ° -88 ° C. (decomposition temperature) were obtained and having the following data: to analysis:

  NMR (CDC L 13 TS): values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 0.85 (d, 3), 1.10-2.15 (m, 5) and

2.15-3.32 (m, 4).

  Exemplary 3 1 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Samethoxy -methyl-6- (1-piperazinyl) -azirinol 2 ', 3': 3,4 This compound was prepared according to the method described for example 1. From 60 mg of mitomycin A and 30 mg of anhydrous piperazine, 23 mg (yield 34%) was obtained. %) of the desired product with a melting point above 2000 C (decomposition) and having the following characteristics when analyzed:

  ES (DMSO-d 6TS): r values in ppm.

  Absence of the 6-methoxy peak at 4.0 02 and appearance of

  new peaks at 1.9 (wide s, l) and 2.9 (s, 8).

Example 4

  2.8 8 α, β-Exahydro-8-hydroyl-methyl-5-methoxy-methyl 64- (acetylamino) anilino-azirinol 2,3-: 3,4 l Pyrrolo 1,2-alindole-4,7-dione carbamate This compound has Prepared according to the method described for Example 1 Starting from 100 mg of mitomycin A and a 4- (acetylamino) aniline excess, 102 mg (yield of 76%) of the product having a melting point were obtained.

143 -

  1450 C (decomposition) and providing the following data for analysis:

  NMR (CD C 13, TS): 6 values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of new magpies at 2.1 (s, 3), 7, 4 (d, 2), 7.6 (s, 1) and

8.9-9.3 (s, 1).

12 2540500

  EXAMPLE 1 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-methyl-6-1-(acetylamino) anilinolazirinol 2 ', 3': 3, This compound was prepared according to the method described for Example 1 with the difference that a small amount of potassium carbonate in the solid state was added. of 70 mg of mitomycin A and 150 mg of 3- (acetylamino) aniline, 67 mg (72% yield) of the product were obtained).

  desired having a melting point at 140 o 0143 o C (decomposition

  position) and providing the following data for analysis:

  NMR (Acetone-d 6, TS): 2 values in ppm.

  Absence of the 6-methoxy peak at 4902 and appearance of new peaks at 2.1 (s, 3), 6.7-7.5 (m, 4), 8.0

(large s, l) and 9.3 (s, l).

Example 6

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

  -methyl-6- (4-acetylanilino) = azirylol 2 ', 3', 34-pyrrololo-1,2-alindole-4,7-dione carbamate This compound was prepared according to the method described for Example 1 with this difference that a small amount of

  Potassium carbonate in the solid state was added.

  From 70 mg of mitomycin Aet 510 mg of 4-acetyla-

  niline, 25 mg (28% yield) of the product was obtained.

  with a melting point of 1030-104 ° C (decompose

  sition) and presenting the following data to the analysis:

  NMR (CDC 13, TS): 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).

13: 2540500

Example 7

  1a, 2p 8.8a, 8b Hexahydro-8 (hydroxymethyl) -8a-methoxy-5-

  This carbamido-substituted compound has been prepared according to a process of the present invention, which is described in US Pat. No. 3,136,61,4-triolol-6-yl-4-yl-anilinolazol-2-ol, 3,4-diisopropylcarbamate. the method described for Example 1 Starting with 50 mg of mitomycin A and 227 mg of 4- (1-ureido) aniline, 49 mg (67% yield) of the desired product having a melting point of 930 was obtained. -95 C (decomposition) and providing the

following data to the analysis.

  NMR (CDC 13, TS): tl values in ppm.

  Absence of 6-methoxy magpies at 4.02 and appearance of new magpies at 5.03 (s, 2), 6.9 (d, 2), 7.3 (d, 2),

8.0 (s, 1) and 8.4 (s, 1).

Ex Mle 8

  1, lag 2,8,8 asbexah dro 8 (hydroxymethyl) -8 a-methox-5-

  methyl-6- (4-cyanoanilino) -alcohol 13.4 lpyrrolid, 2-alindole-4,7-dione carbamate This compound was prepared according to the method described in Example 1 with the difference that a small amount of potassium carbonate in the solid state has been added A

  from 70 mg of mitomycin A and 472 mg of 4-aminobenzonitrile

  trile, 23 mg (24% yield) of the product was obtained having a melting point at 124-126 ° C (decomposition) and providing the following data for analysis:

  NMR (CD C 139 TS)): values in ppm.

  Absence of 6-methoxy magpie at 4.02 and appearance of new magpies at 6.6 (d, 2), 7.4 (d, 2) and

7.0 o 7.3 (wide sl).

2540500 o

1 Example 9

  1a, 1a, 8a, 8a-8-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-

  methyl-6- (3-cyanoanilino) azirinol 2 '3: 3,4 lpyrrololl, 2-alindole-4,7dione carbamate This compound was prepared according to the method described for Example 1 with the difference that a small number of

  Potassium carbonate in the solid state was added.

  From 7 mg of mitomycin A and 500 mg of 3-aminobenzonitrile, 30 mg (34% yield) of the desired product having a melting point of 970-980 ° C (decomposition) was obtained and providing the following data for analysis:

NMR (CDC 13, TS): values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of

new peaks at 7.2-7.8 (m, 4).

Exeemle 10

  1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-

  methyl-6-1 4- (N-glycyl) anilinol-azirinol 2 ', 3': 3,4-pyrrolo [1,2-indindol-4,7-dione carbamate This compound was prepared according to the method described for Example 1 From 50 mg of mitomycin A and 249 mg of 4 (N-glycyl) aniline, 62 mg was obtained (90% yield).

  Researched product having a melting point at 83 ° -85 ° C.

  (decomposition) and providing the following data to the analysis:

  NMR (DMSO-d 6, TS): 'S' values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.1 (s, 2), 6.3-6.6 (wide s, 2)

  6.6-6.8 (broad s, 2) and 6.6-7.1 (broad s, 2).

2540500

  1 Exei 1 ipleil 1, lae 22.8, has 28 bH hexahydro-8 (hydroxymethyl) -8 amethoxy 5 methyl-6 (3,4-dimethoxyanilino) azirinol 2 23 'p -3,41 pyrrole This compound was prepared according to the procedure described in Example 1. From 50 mg of mitomycin A and 229 mg of 3, 4-dimethoxyvani-line, it was prepared according to the procedure described in Example 1. obtained 61 mg (91% yield) of the desired product having a melting point of 11140-1160 [decomposition] and providing the following data for RM analysis, (CDC 13, TS) '16 ppm values' Absence from 6-methoxy peak to 4.02 and appearance

  new magpies at 3.8 (s, 6), 6.3-6.9 (m, 3) and.

7.7 (s, l).

  This compound was prepared according to the method described for Example 1. From 50 mg of mitomycin A and 229 mg of 3,5-dimethoxyaniline, 60 mg (88% yield) was obtained. melting at 980-10000 C (decomposition) and presenting the following data to the analysis

RMM (CDC 13, TS) values in ppm.

  Absence of 6-methoxy magpie at 4.02 and appearance of new magpies at 3.8 (s, 6), 5.9- = 6.4

(broad S, 3) and 7.6 (s, l).

Example 13

  1α, 2,8,58α, Sb-Hexahydro-8- (hydroxymethyl) -8α-methoxy-5-

  methyl-6- (4-nitroanilino) azirinol 2 '3': 3,4 lpyrrololl, 2-alindole-4,7-dione carbamate This compound was prepared according to the method described in. example 1 with this difference that a small amount

  Potassium carbonate in the solid state was added.

  From 70 mg of mitomycin A and 276 mg of 4 = nitro-

  niline, 16 mg (9% yield) of the desired product having a melting point of 132-134 ° C (decomposition) was obtained and providing the following data for analysis:

  NMR (Acetone-d 6, TS) d values in ppm.

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

and 7.9-8.4 (wide s, l) -

lxe14

  1, la, 2,8,8 Sa, 8b-Hexahydro-8- (hydroxymethyl) -8-amethoxy-5-

  methyl-6- (4-sulfamylanilino) azirinol 2 '3': 3,4-pyrrolo-11,2-alindole-4,7-dione carbamate This compound was prepared according to the method described for Example 1 with this difference that small amount of

  Potassium carbonate in the solid state was added.

  From 70 mg of mitomycin A and 688 mg of sulfanilamide, 25 mg (26% yield) of the desired product having a melting point of 113 ° -115 ° C. (decomposition) was obtained and having the following data analyzed:

  NMR (CD C 13, TS): '' values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance

  new peaks at 7.0 (d, 2), 7.5 (s, 1) and 7.9 (d, 2).

EX Mn P 1 e 1-5

  1, la, 2,8, 8a-Sb-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-

  methyl-6- (4-methylanilino) azirinol 2 ', 3': 3,4 lpyrrolol 1,2-alindole4,7-dione carbamate This compound was prepared according to the method described in Example 1. From 60 mg of mitomycin A and an excess of 4-methylaniline, there was obtained 63 mg (86% yield) of the recovered product having a melting point of 1130-1150 ° C (decomposition) and having the following data for analysis:

  NMR (CDC 13, TS): 6 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, 2 e 8 e 8 a Sboexahydro 2 '8 hydrox ethy l 8 a-methoxy5 th {3 Ext 2 ivlaril irano la> -3 no 1 3 vyrrolol, indo-40,7 dione carbamate Ce This compound was prepared according to the method described for Example 1. Starting from 70 mg of mitomycin A and 276 mg of 3-methylaniline, 66 mg (78% yield) of the desired product having a melting point of 890 ° C. was obtained. 910 C (decomposition) and providing the following data for analysis:

  RMI (CDC 13, TS): 1 values in ppm.

  Absence of 6-methoxy magpies at 4.02 and appearance of new magpies at 2.4 (s, 3), 6.7-7.5 (m, 4) and 7.8 (s, 1). Example 17 2540500

  1, la, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-

  methyl-6-1 (5-amino-1,2,4-triazol-3-yl) aminolazirino] 2 ', 3': 3,4-pyrrolol 1,2-alindole-4,7-dione carbamate This compound was prepared according to the procedure described for Example 1 with the difference that a small amount of

  Potassium carbonate in the solid state was added.

  From 50 mg of mitomycin A and 30 mg of 3,5-diamino-

  1,2,4-triazole gave 13 mg (5.5% yield) of the desired product having a melting point of 1170-1200 c (decomposition) and providing the following data for analysis

  NMR (DMSO-d 6, TS): '' values in ppm.

  Absence of the 6-methoxy magpie at 4.02 and appearance

a new magpie at 5.37 (s, 3).

Example 18

  1a, 1a, 8a, 8a-8-Hexahydro-8- (hydroxyl) methyl-8-methoxy-5-

  methyl-6-l (3-methylisothiazol-5-yl) aminolazirinol 2 ', 3: 3,41 pyrrolol 1,2-alindole-4,7-dione carbamate This compound was prepared according to the method described for

  Example I with the difference that 0.5 ml of triethylamine

  After 60 mg of mitomycin A and 5 mg of 5-amino-3-methylisothiazole hydrochloride were obtained, 4.5 mg (8.5% yield) of the desired product with a melting point of 870 was obtained. - 90 C (decomposition) and providing the following data for analysis

  NMR (CDC 13, TS): '6' values in ppm.

  Absence of the 6-methoxy magpie at 4.02 and appearance of

  new magpies at 2.3 (s, 3), 6.1 (s, 1) and 6.4 (s, 1).

Example 19 2540500

1 E 254050 0

  1a, 2.8, 8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy 5-

  This compound was prepared according to the method described for Example I 1 with the difference that methyl-6-1 (2-benzothiazolyl) aminolaazirinol 2 '3': 314 lpyrrolo 1 -2 al indole-4,7-dione carbamate. a small amount of

  Potassium carbonate in the solid state was added.

  From 50 mg mitomycin A and 25 mg 2-aminobenzoate

  thiazole, 12 mg (18% yield) of the product was obtained.

  with a melting point of 820-850 C (decomposed

  tion) and providing the following data for analysis:

  NMR (CD C 13, TS): Values in ppm.

  Absence of the 6-methoxy magpie at 4.02 and appearance of

new peaks at 7.1-8.0 (m, 5).

Example 20

  1a, 2.8, 8a, b-Hexahydro = 8 = (hydro: x / methy 1) -8a-methoxy-

  This compound has been prepared according to the method described for the preparation of this invention. This compound has been prepared in accordance with the method described above for the preparation of this compound. example 1 with this difference that a small amount of

  Potassium carbonate in the solid state was added.

  From 50 mg of mitomycin A and 30 mg of 2-amino-6-

  nitrobenzothiazole, 20 mg (27% yield) of the desired product having a melting point of 86 ° -89 ° C. (decomposition) was obtained and providing the following data for analysis.

MIN (DMSO-d 6, 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) o 1 Example 21 2540500

  11a, 2,8,8a, 8b-Hexahydro-= - (hydroxymethyl) a-methoxy-5-

  methyl-6-1 (4-chlorobenzothiazol-2-yl) aminol azirino] 2 ', 3': 3,4-pyrrololl, 2-alindole-4,0-dicarboxylate This compound was prepared according to the method of Example 1 with this difference that a small amount of

  Potassium carbonate in the solid state was added.

  From 150 mg of mitomycin A and 27 mg of 2-amino

  chlorobenzothiazole, 30 mg (14% yield) was obtained with a melting point of 89 ° -91 ° C (decomposition) and providing the following data:

NMR (CDC 13, TS): i values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of

  new peaks at 7.1-8.0 (wide s, 4).

Example 22

  1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-mathoxy-5-

  This compound was prepared according to the procedure described in Example 1 with the difference that the 2-methyl-6-l (2-aminoethyl) aminol-azirinol 2 ', 3: 3,4 lprolo 2-alindole-4,7dione carbamate. The solvent used was dichloromethane. Starting from 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane, 35 mg (65% yield) of the desired product having a melting point of 202 ° -205 ° C. (decomposition) were obtained. providing the following data to the analysis:

  NMR (CDC 13, TS): Values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance

  new peaks at 1.5 (wide s, 2) and 3.5 (wide s, 4).

1 Example 23 2540500

  la, 0 a, 8 b-hexah ydro (h dro x seth 1) -8 a-methox'-5-

  1methyl (2-methylaminoethyl) aminolazirino [2 ', 3']: 3,4-pyrrolol 1,2-alindole-4,7-dione carbamate This compound was prepared according to the method described in Example 1 with this difference that a small amount of potassium carbonate in the solid state was added. Starting from 50 mg of mitomycin A and 25 mg of yidimethylethylenediamine, 28 mg (50% yield) of the desired product having been obtained was obtained. a melting point of 990-101 ° C (decomposition) and providing the following data for analysis: NMR (CDC 13, TS): 6 values in ppmo Absence of pie 6 fmethoxy at 4.02 and appearance

  new peaks at 1.3 (s, 1), 2.5 (s, 6), and 2.7 (s, 4).

Example 24

  la, 2,3 G, Gab-Hexahydro-8 = (hydroxyethyl) sa-methoxy-5-

  This compound was prepared by following the method described in Example 1 with this difference that the solvent was used in the following manner: ## STR5 ## was from 50 mg of mitomycin A and 18 mg of 2 (2-aminoethylamino) ethanol, 35 mg (in 58% yield) of the desired product having a melting point of 1150-118 ° C was obtained ( decomposition) and providing the following data for analysis: HMN (CDC 13, TS): '6 values in ppm

  Absence of the 6-methoxy magpie at 4.02 and appearance.

  new magpies at 2.7 (wide s, 7) and 3.7 (t, 3) o Exemplary 25 2540500

  IIa, 2.8.8 a, Sb Hexahydro 8 (hy drox thyl) -a methoo-5-

  This compound was prepared according to the method described for Example 1 with the difference that the solvent was dichloromethane From 60 mg of mitomycin A and 20 mg of 2- (2-aminoethoxy) ethanol, 30 mg (42% yield) of the desired product having a melting point of 990-102 ° C (decomposition) was obtained. and providing the following data to the analysis:

  NMR (CDC 13, TS): '6' values in ppm.

  Absence of the 6-methoxy peak at 4.02 and appearance of new peaks at 3.3-3.9 (wide s, 9)

and 6.4-6.8 (broad s, 1).

Example 26

  1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Sa-methoxy-5-

  Methyl-6-l-2- (4-imidazolyl) ethylaminolazirinol 2 'o 3: 3, 4 l pyrrolol 1,2-alinidol-4,7-dione carbamate This compound was prepared by the method described in accordance with the present invention. Example 1 with the difference that 128 mg of sodium methoxide was added. Starting from 70 mg of mitomyein A and 368 mg of histamine dihydrochloride, 61 mg (71% yield) of the desired product having one point was obtained. Merging 720-730 C (Decomposition) and providing the following data to the analysis:

  NMR (DMSO-d 6, TS): '6' values in ppm.

  Absence of 6-methoxy magpie at 4.02 and appearance of new peaks at 3.0-3.27 (m, 4), 7.5 (s, 1),

8.0-8.7 (wide s, 2) and 8.1 (s, l) -

23 2540500

  Exe Mple 27-methyl-6-l (2-nitro-1-imidazolyl) ethylaminolazirino [2 ', 3']: 3,4-pyrrolol 102 = ejindole-4,7-dione carbamate This compound was prepared according to the method described for Example 1 Starting from 72 mg of mitomycin A and an excess of 1- (2'-aminoethyl) -2-nitroimidazole, 60 mg (70% yield) of the desired product having one point was obtained. melting point of 830-850 C (decomposition) and providing the following data for analysis

  NMR (CDC 13, TS) values in ppm.

  Absence of the 6-methoxy peak at 14.02 and appearance of new peaks at 3.14 (t, 2), 14.6 (t, 2), 7.3

(, broad s, 2) and 7.6 (s, l).

  Exanp 1 e 28 me h 18 2 4 oyhnlehlaminol-azirino l 2 ', 3': 3.41 This compound was prepared according to the method described for example 1 from 130 mg of mitomycin A and 510 mg of tyramine, 138 mg (81% yield) of the product was obtained having a melting point of 1200 = 1250 C (decompensation) and providing the following data for analysis.

  RIMW (CD Cl 3, TS): l values in ppm.

  Absence at the 6-methoxy peak at 14.02 and appearance of new peaks at 296 (t D 2), 298 (t 92) 9 6.7 (d, 2), 7.0 (d, 2) and 8.0 (s, l) 1- Example 29 2540500

  1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8-methoxy-5-

  methyl-6- [2- (3,4-dihydroxyphenyl) ethyl] amino] azirino [2 ', 3']: 3,4-pyrrolol 1,2-alindoleo 4,7-dione carbamate This compound was prepared according to the method described for Example 1 with the difference that 138 mg of sodium methoxide was added. Starting from 110 mg of mitomycin A and 660 mg of 3-hydroxytyramine hydrobromide, 60 mg (40% yield) of the product was obtained. searched decomposing without fusion above 125 C and providing the following data for analysis:

* NMR (CDC 13, TS): '' values in ppm.

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

and 8.3 (broad s, 2).

Example 30

  1, 1a, 2,8,8a, 8b-Hexahydro-8 (h-hydroxymethyl) -8α-methoxy met {2α-nitro-2α-ethylaminoazolin-3 ': 3,4-pyrrolol 1,2-alindole-4,7 -dione carbamate This compound was prepared according to the method described for Example 1 with the difference that the solvent was dichloremethane From 50 mg of mitomycin A and 30 mg of 2- (2-aminoethylamino) -5-nitropyridine, 40 mg (56% yield) of the desired product having a melting point of 76 ° -79 ° C. (decomposition) was obtained and providing the following data for analysis:

  NMR (CDCl 3, TS): values in ppm.

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

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

Exemnp 31 2540500

  l, la, 2,8,8 Sa, Sb-He: xahydro-8 (hydroxymethyl) -Sa-methethoxy-5-

  Ethyl-6-2- (1-piperazinyl) ethylamino 1-azirio 2 3: 4 pyrrolo [1,2-indol-4,7-dione carbamate This compound was prepared according to the procedure described for Example 1 with this difference that the solvent was dichloromethaned. Starting from 50 mg of mitomycin A and 20 mg of N- (2-aminoethyl) piperazine, 23 mg (yield of 36%) of the desired product having a melting point of 138 ° C. were obtained. 141 o C (decomposition) and providing the following data for analysis

  R M (CD Cl Y TS): values in ppm.

  Absence of 6-methoxy magpie at 4.02 and appearance of new peaks at 1.6-2.1 (broad s, ll> 2.2-2.6 (broad s, 8), 2.6-2.8 (large s, 4) and 6.9 (t, l)>

yo llÄa noe-4,7-d: ione case: te-

  This compound was prepared in accordance with the procedure described for Example 1, starting from the addition of mitoylcin A and the addition of 2- (2-ethyl) pyridine, to give 51 mg. of 56 51) of the desired product having a melting point of 641-770 C (deseomspositon) and providing the following data for the analysis

  RW (CDC 13 v TS) W 6 Values in PPS.

  Absence of the 6-msathoxy peak at 4.02 and appearance of new peaks at 2.8 (m, 4), 7.0-7.8 (M, 3) and

and 8.5 (d, l).

  Referring to the compounds covered by formula II Ia,

  the examples above illustrate the structural variants

hereinafter:

  1 / Compounds in which Z is a 1-pyrrolidine radical

  dinyl substituted with a hydroxy group, are represented

by example 1.

  2 / Compounds in which Z is a lower alkyl-substituted piperidyl radical are illustrated by

Example 2

  3 / compounds in which Z is a 1-piperazinyl radical or an aniline radical substituted by an acetamino, acetyl, carbamido, cyano, lower carboxyalkylamine, di-lower alkoxy, nitro, sulfamyl or lower alkyl group,

  are respectively represented by Examples 3 to 16.

  The compounds wherein Z is a radical wherein R 1 is a nitrogen-containing heterocyclic radical selected from the group consisting of triazolyl substituted amino, lower alkyl substituted isothiazolyl, benzothiazolyl and nitro derivatives; substituted halo of benzothiazolyl, are respectively represented

  by Examples 17, 18, 19, 20 and 21.

  Compounds in which Z is an O-R radical and R 1 is a substituted lower alkyl radical selected from the group consisting of lower alkyl, lower alkyl amino alkyl, lower hydroxy alkyl lower alkyl amino, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted nitro, mono and di-hydroxy phenyl lower alkyl, pyridylamino lower alkyl substituted nitro, piperazinyl lower alkyl and ethyl pyridyl, are represented respectively by the examples

22 to 32.

  Although none of the foregoing examples have referred to compounds where Y is other than hydrogen, compounds in which Y is lower alkyl are none the less within the scope of the invention and in this regard, reference will be made to compounds having a similar substitution and which are mentioned in US Pat. No. 4,268,676 and US Patent Applications 206,529 and 264,187.

  corresponding to the French requests mentioned above.

  The compounds according to the present invention are believed to possess antibacterial properties against gram-positive and gram-negative microorganisms in the same manner that has been observed for natural mitomycins and its compounds are potentially useful as agents.

  therapeutics for the treatment of bacterial diseases

  in humans and animals.

  The usefulness of the compounds of the formula Ia in the antineoplastic therapeutic methods according to the invention is demonstrated by the results of the in vivo tests in which the compounds of the invention were administered according to the various assays to mice at The procedures were conducted according to the document "Lymphocytic Leukemia P 388 Protocol 1 o 200" published in Cancer Chemothera L Reports, Part 3, Vol 3, No. 2, page 9 September 1972). Briefly

  the test procedures include the administration of

  The examined compounds were administered on the first day of the tests only and the animals were monitored and monitored with respect to the test compound in CDF-1 female mice previously challenged with intraperitoneally implanted ascitic cells.

  especially their vitality over a period of 35 days.

  The results of the tests relating to the compounds of Examples 1 to 32 are shown in Table 1 below. The data comprise the optimal dose (OD), that is to say the dosage in mg / kg of weight of the animal for which the maximum of therapeutic effects has been observed on a regular basis Also included in the table the average survival time (TMS), expressed as the average survival time of the test animals compared to the average time of survival

  survival of control control population (% T / C).

  In the context of the in vivo procedure P 388, the reference of which is given above, a value of (% T / C) equal to or greater than 125 denotes a sensitive anti-neoplastic therapeutic activity. The lower dose in mg / kg of weight for which the 125% T / C value is obtained is considered as the minimum effective dose (BEM) These doses are shown in Table 1 It is important to

  note that the value of the average time of exceptional survival-

  was obtained in the experiment and shown in the table is also an indication of the absence of

  the invention at the dosages that are given.

TABIEAU 1

Optimal dose mg / kg DEM

Example

  No. TI-S i -T / C> 333> 333 isi> 375 0.8 <0.2 0.2 <0.2 0.2 0.4 1.6 0.8 <0.2 0 '8 0.2 0.4> 0.2 0.2 0.4 0.4 1.6 0.8 12.0 25.6 1.6 0.4 12.8 12.8 0.4 1.6 3.2 1.6 12.8 6.4 12.3 0.2

1

Lo 6 T he M is

16

is 2 r II 21 2 2 2 3 2 4 2 5

2 6

2 8

31

  6 25.6 12 8 25.6 25.6 6.4 25.6 3.2 12 8 25.6 12 a 6.4 3 2 6 12.8 12.8 12 8 25.6 25.6 25.6 25.6 3.2 25.6 12.0 25.6 25.6 23.6 25.6 12.8 12.8 25.6 6 1 Among the compounds of the invention which are clearly preferred as anti-neoplastic active agents are those which prove to be capable of doubling the relative life-span characterizing and demonstrating sensitive therapeutic properties; these compounds are those for which the TMS ratio expressed in% T / C is greater than 2 × 125. These compounds are those given in Examples 4, 10, 11 and 32. As can be seen from Table 1, an assay initial single as low as 0.2 mg / kg, revealed a long-term sensitive anti-neoplastic activity. Accordingly, the methods of the invention may include therapeutic administration of unit dosage as low as 0.001 mg or as important as 5 mg and preferably between 0.004 mg up to 10 mg of the compound as active agent in a suitable pharmaceutical preparation These preparations may be administered in the form of daily doses of between 0.1 mg to 100 mg per kilogram and preferably between 0 and 2 to 51.2 mg per kg of body weight of the animal suffering from neoplastic disorders It is preferable that the compounds of the invention are administered parenterally. In the practice of the invention, it is possible to comprise simple solutions in water of one or more of the compounds according to formula IIa.

  and may also include pharmaceutical diluents

  are acceptable and well known, as are adjuvants or supports, particularly of the saline type, suitable for

medical use.

  Other aspects and advantages of the invention will become apparent

  those skilled in the art from the foregoing description and

  therefore the invention does not include other limitations

  than those indicated in the claims which

follow.

31 2540500

Claims (1)

Compounds having the formula wherein Y is hydrogen or lower alkyl and X is: a substituted 1-pyrrolidinyl hydroxy radical, or a lower alkyl substituted piperidyl radical or an aniline, acetamino, acetyl, carbamido, cyano, carboxy, lower alkylamino, di-lower alkoxy, nitro or substituted sulfamyl radical, or - a radical corresponding to the formula R -kR 'in which -R is hydrogen or a lower alkyl and R 1 is a heterocycle-containing nitrogen radical selected from the group consisting of triazolyl substituted amino, lower alkyl-substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted benzothiazolyl derivatives, or R 1 is a substituted lower alkyl radical selected from the group consisting of lower alkyl amino, lower alkyl lower alkyl, hydroxy lower alkyl-amino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted nitro, mono and di-hydroxy phenyl lower alkyl, pyridylamino lower alkyl substituted nitro and piperazinyl lower alkyl. Compounds according to claim 1, designated 1, la, 2,8,8 a, Sb-hexahydro-8 (hydroxyl-ethyl) -α-methoxy-5-methyl-6- (3-hydroxy-1-ov-1-yl). rolidinyl) -azirino L 2 ', 3': 3,4-pyrrolo (1,2-alindol-4,7-dione-methylelcarbamate 1,1a, 2,8,8a, 8bHexahydro-B- (hydroxylmethyl) 8α-methoxy-5-methyl-6- (3-methylpiperdyl) azirinol 21.31: 3.41 pyrrolol 1,2-alindole-4,7-dionc-methyl carbamate 1, la, 2.8, $ a 8β-Hexahydro- (hydroxymethyl) -Sa 'methoxy-5-methyl-6-1 (acetylamino) anilinolazirino [21.31: 3,4] pyrrolo [1,2-alindole-4,7- dionemethyl, carbamate 1,1a, 2,8,8a, 8b-Hexahydro-S- (hydroxymethyl) -Sa-methoxy-5-methyl-6-1- (acetylamino) anilinol azirino 21.31: 3 , 4-pyrrolol, 2-aliminol-4,7-dione-methyl, carbamate 1,1a, 2,8,8a-Sb-hexahydro-8- (hydroxymethyl) -Sahoxy-5-methy 1-6- (4) -acetylanilino) -azirinol 2 ', 3': 3,41 pyrrolol 1,2alindole-4,7-dione-methylcarbamate 1, la, 2, 8, sa, 8 b-hexahydro-8 (hydroxymethyl) -Sa-methoxy- 5-methyl-6 (4 (1-ure do) anilinol-azirino 21.3 -: 3, 41 pyrrolo (1 , 2-a) -indole-4,7-dione-methyl, carbamate 1, 1a, 2, 8, Sa, Sb-Rexahydro-8 (hydroxymethyl) -Sa-methoxy-5-methyl-6 (4-cyanoanilino) 21, 31: 3,41 pyrrolotl, 2alindole-4,7-dione-methyl, carbamate 1, 2,8, Sa, Sb-hexahydro-8 (hydroxymethyl) -Sa-methoxy-5-methyl-6 ( 3-cyancaniline) -azirino E 2 ', 3': 3,41 pyrrolol 1,2-alindole-4,7-dien-methyl e 1, 1a, 2,8, Sa, Ob-aexahydro-8 (hydroxymethyl) - Sa-methoxy-5-methyl-6-yl (M-glycyl) anilinol-aztrino 2 ', V: 3, 41 pyrrolol 1,2-alindole-4,7-dione-methyl-carbamate 11a, 2,8,8a 8β-Hexahydro-8 (hydroxymethyl) -Sα-methoxy-5-methyl-6 (3,4-di-2-yloxyanilino) -azirino} 21 V: 3,41 pyxrolo l-1,2-alindole-7- d 1 one-methyl ethyl bar; 1, 1a, 2, 8, Sa 8 Sb-hexahydro-8 (hydroxymothyl) -8a-3 ': 341 methoxy-5-mothyl-6- (3,5-dimethoxyanlin) -asirinol 2 pyrrolol 1,2 -alindole-4,7-dione-methyl, carbamate 1 1 to 2,8 p 8 a, 8 b-aexahydro-S- (hydroxymathyl) -S-methoxy-5-methyl-6- (4-nitroanilino) azirinol 2 'and 3': 3 # 41 pyrrolotl, 2alindole-4,7-dione-meth Yle carbamate 3 3 1 l, la, 2,8,8 a, 8 b-Hexahydro-8- (hydrcx%, - nehyl) 8α-mathoxy-5-methyl-6- (4-sulfamylanilino) azirinol 21.3 ': 3.41 pyrrolotl, 2alindale-4,7-dione-methyl, carbamate; 1a, 2,8,8a-Sb-Hexahydro-S- (hydroxymethyl) -8α-iethoxy-5-methyl-6-1 (5-amino-1,2,4-triazol-3-yl) aminol azirinol 21, 31: 3,4 lpyrrololl, 2-alindole-4,7-dione-methyl, carbamate; 1,1a, 1α, 2,8-Sal-8β-Hexahydro-8- (hydroxymethyl) -S-mathoxy-5-methyl-6 (3-methylisothiazol-5-yl) aminolazirino] 21.3 ': 3,4-Pyrrolid, 2-alindole-4,7-dione-n-butyl acrylate 1,1'-la, 2,8,8-agb-Hexahydro-S- (hydroxymethyl) -Salam, -hoxy-5-methyl-6 ( 2-benzothiazolyl) arginine-azirino [2 ', 31-3,31] pyrrololl, 2-alindole-4,7-dione-methyl-carbamate 1α, 2,8-Ba, Sb-hexahydro-8 (hydroxymethyl) -Sa Methoxy-methyl-6 - ((6-nitrabonazothiazol-2-yl) aminolazirino] 2 ', 31: 3,4 lpyrrolotl, 2-alifidol-4,7-dion L-methyl, carbamate 1, la, 2 , 8,8-α-Hexahydro-β- (hydroxymethyl) -α-methyl-3-methyl-6-yl (4-chlorobenzothiazol-2-yl) aminolazirino, 21, V: 3.41 pyrrols 2-alindole-4,7-dione-methylcarb & met -1-1a, 2,8,8a, Bb-Hezahydro-8 (hydroxymethyl) -Sal 2-Qminoethyl) aminol-azirino 121,31,3,41 1, 1α, 2α, 9-methyl-8-hydroxy-1-hydroxymethyl-17α-hydroxy-1-ylamino-1-ylmethylaminothiocarbonyl-diisopropylcarbonylcarbonyl); (2-nitro-1-imidazolyl) ethylaminopropyl, 21, 31: 3,4 pyzralo 11,2-alindols-4,7-dion G-methyl, carb, -nate 1, la, 2,8,8a, 8b-Hexahydro-8 (hydroxymethyl) -8a-methoxy-5-methyl-6H (4-hydroxyphenyl) ethylaminolazirino] 2 ', 3': 3,4-pyrrolidol 1 , 2-alindole-4,7-di Ofyl ethyl> carbamate 1,1a, 2,8,8a, 8b-Hexahydro-8 (hydroxymethyl> -8a-methoxy-5-methyl-1) 2 (3, 4-dihydroxyphenyl) ethylaminolazirinol 2 ', 3': 34 proo 12 a-7, 7-methoxy-5-methyl-8-hydroxymethyl-8-methoxy-5-methyl 2- [2- (5-Nitro-2-pyridyl) aminolethylamino] -2-iminol 2 ', 3': 3,4-pyrrolol 1,2-alindol-4,7-dionexmethyl carbamate; , 2,8,8a, 8b-Hexahydro = (hydroxymethyl) -B-methoxy-5-methyl-6-1 (1-piperazinyl) ethylaminyl-azirino [2 ', 3': 3,4] pyrrololl, 2 -a Jindo 17-4,7-dione-8 = m-th Y 1 e) carbamnte 3 Canposition therapeutic for the treatment of neoplastic diseases in animals, characterized in that it contains a compound according to the f wherein Y is hydrogen or a lower alkyl and Z is a substituted 1-pyrrol-1-substituted hydroxy radical or a lower alkyl-substituted alkyl-substituted piperi radical, or a piperazinyl radical or an aniline radical substituted with an acetarnino, acetyl, carbamido, cyano, 1-arboxy lower alkylamino, di-lower alkoxy, nitro, suifamyl or lower alkyl group, or a radical of formula in which R is hydrogen or a lower alkyl and R 1 is a heterocycly nitrogen-containing radical selected from the group consisting of tri-azolyl substituted amino, isothiazolyl substituted by an inner alkyl, benzothiazolyl, and nitro and halo derivatives substituted benzothiazolyl, or R1 is a substituted lower alkyl radical selected from the group consisting of lower alkyl amino, inner alkyl amino alkyl, hydroxy lower alkyl amino 31, lower cyl, lower alkyl lower alkoxy lower alkyl The lower imidazolyl alikyl lower nitro, the sono and di-hydroxy phenyl 91 lower alkyl, the pyrly 1 m Inc alkyl nitro nitrate subitu the piperazinyl lower alkyl and I ethrl pyridyl. The compound according to claim 3 wherein the compound comprising Li, Cidano and the group comprising: , carbamate I, la, 2,8,8a-Sb-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-1-4 (acetylamino) anilinol-azirino 21.31: 3 4-pyrrolido (1,2-alindole-4,7-dione-thymethyl) carbamate 1a, 2,8,8a, 8b-Hexahydro-S- (hydroxymethyl) -8α-methoxy-5-methyl -6-13- (acetylamino) anilinol-azirino-21,31: 3,4-pyrrololi, 2-alindole-4,7-dioneinylated 5-ethylhexylamine, 2,8,8 a, 8b-Hexahydro-B- ( hydroxymethyl) -8α-methoxy-5-methyl-6- (4-acetylanilino) azirinof 2 1, 3 ': 3,41 pyrrolotl, 2alindole-4,7-dione-methylcarbamate, 1.1a to 2.8 α, α-β-Hexahydro-S- (hydroxymethyl) -α-methoxy-5-methyl-6-14- (1-ureido) aniline-azirincl 21.31: 3.41 pyrrolo (1,2-indolole-4,7) -dione-methyl carbamate lela, 2,8,8 a, 8 b-Rexahydro-g- (hydroxymothyl) -Sa-methogy-5-methyl-6- (4-cyanoanilinol-a zirinol 29,31: 3,41 pyrrolol 1,2-alindole-4,7-dione-methyl carbamatelela, 2,8,8 a, 8b-hexahydro-S- (hydroxymethyl) -8α-methoxy-5-methyl-6- (3-cyanoanilino) azirinol 21.31: 3.41 pyrrolofl, 2alindole-4, 7-dione-methyl, carbamate; lolao 2.8.8a # 8b-Rexahydro-S- (U-hydroxymethyl) -8α-methoxy-5-methyl-6-1,4-t N "glycyl) anilinolazirinol 21.31: 3.41 pyrrolol 1 , 2-alindole-4,7, dione-methyl carbamate ylol # 2, Oiga, 8b-Hexahydgo-S (hydroxymethyl) -8-methoxy-5-mothyl-6- (3,4-dimethoxyanilino) -azirinol 21 , 31: 3-, 41 pyrrolotl, 2-alindole-4 g 7-di-1-methyl, carbamate methoxy-methyl-G- (3,5-dimethoxyanil) -N-azir Anol 21.31 -3.41 pyrrolol 1,2-indolole 1,1a, 2,8,8a-N -hexahydro-C- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-nitroanilino-3-yl) -4,7-diene-meth-1-ylcarbamate L 2 n-Ol 2 ", 3 '- 3,41 pyrrolol 1,2-alindole-4,7-dions-methyl carbamate 1, la, 2, 8, Sa-Ob-Hexahyclo-3 (hydroxymethyl) -S-mathoxy 5-methyl-6- (4-aulfamylantlino) azirinol 29.31: 3.41 pyrr (1,2-indindole-4-yl) -diont-methyl, carbamate, lpla # 2,8,8 a, 8 b- Sexahyclo-S- (hydroxymethyl) -Sam Oth OXY-5-methyl-6- (4-methylanilino) -azrino (21,39: 3,41 pyrrolol 1,2-alindole-4,7-dione-methyl) carbamate -? 540500 1 1, la, 2,8,8 a, 8 b_Hexahydro-8 (hydroxyme thyl) -Sa-methoxy "5-methyl-6- (3-methylanilino) -azirinol 2 '3': 3,41 pyrrolol 1,2-alindole-4,7-dione-methyl carbamate 1,1a, 2,8 8a, 8b-Hexahydro-8- (hydroxymethyl) -S-methoxy-5-methyl-6-1 (5-amino-1,2,4-triazol-3-yl) aminolazirinol 21,3 ' 1,4-Pyrrolol 1,2-alindole-4,7-dione-methylcarbamate 1,1a, 2,8,8a-Sb-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- 1 (3-methylisothiazol-5-yl) aminol-azirino-1-yl 31: 3,4-pyrrolidyl-1,2-alindole-4,7-dione-in-1-yl carbonate, la, 2,8,8 a. Hexahydro-S "(hydroxymethyl) -Sa-metho-cy-5-methyl-6-1 (2-benzothiazolyl) aminol-azirino] 2 ', 31: 3, 4-pyrrolol 1,2-alindole-4,7-dione methylene chloride 1,1a, 1a, 2,8,8a, Ob-Rexahydro-8 (hydroxymethyl) -Sa-methoxy-5-methyl-6 (6-nitrobenzothiazol-2-yl) aminolazirino 21.11: 3,4-pyrrolidol 1,2-alindole-1,7-dione-1-methyl-carbamate 1,1m, 2,8,8-bis-hexahydro-S- (hydroxymethyl) -Samethoxy-5-methyl- 1 (4-Chlorobenzothiazol-2-yl) aminol-azirincl 21,31-3p4-lyrrolol 1,2-lindole-4,7-diol nm-ra 5thyle, carbmete; 1, 1a, 2, 8, Sa, Ob-Eamahydro-8 (hydroxymethyl) -Sa- (2-methylethyl) -alanine-2-amino-21, 3 's, 3,41 pyrrololl, 2-alindois-4, 7-dione-α-methylcarbamate-1α-Hezahydro-O (hydroxymatkiyl) -Sa 1, "2, 0, en, (hydroitymathyl) -S-tethanylamine 7-dione-methyl carbonate 1 ', 1α, 2,8-a, eb-α-eehydro-S -' (hydroxymethyl) -O-methyl, 1-syl-5-methyl-C E 2 (2-hydrouyathory) ettylaminol-aziz Inc. 254 È 0500   1 l, la, 2,8,8 a, 8 b-Hexahydro-8 (hydroxymethyl) -8 a-   methoxy-5-methyl-6 (2 (4-hydroxyphenyl) ethylamino) -azirino [2 ']: 3,4-pyrrololl, 2-alindole-4,7-dione-methyl-carbarnate;   i, la, 2,8,8 a, 8 b-Hexahydro-8 (hydroxymethyl> -8 a-   methoxy-5-methyl-6-1 (2 (3,4-dihydroxyphenyl) ethylamino] azirinol 2 ', 3':, yr11 12 aided, 7-dimethylated   1, la, 2,8, a, 8 b-Hexahydro-8 (hydroxymethyl) -8 a-   methoxy-5-methyl-6- {2 l (5-nitro-2-pyridyl) aminol ethylaminol -   azirinol (2 ', 3': 3,4 lpyrrolol 1,2-alindolo 2-4,7-dione-methyl, carbatnate   1, la, 2,8,8 a, b-Hexahydro-8 = - & hydroxyimethyl) -Sa   methoxy-5-methyl-6-1 (1-piperazinyl) ethylaminol-1α, 2 ', 3': 3, 41 pyrrololl, 2-alindole-4,7-dione-methyl, 1,1a, 2b, 8.8 Sa, 8Hexahydro'S (hydroxymethyl) -Sawo methoxy-5-methyl-6-1- (2-pyridyl) ethylaminolazirino [2 ', 3']: 3,4-pyrrololl, 2-a 1-indoleu-4, 7done = methyl baznte '-Composition according to claim, characterized in that the amount of compound administered is comprised of a daily dose of between 0.2 m C up to about 51.2 Mg   per kilo of Ilanimal's body weight.   6 -Pharmaceutical composition usable POUF the treat-   Neoplastic conditions in the animal, said composition comprising, in a solvent, a premature Miuant, adjuvant or carrier N acceptable, an active product consisting of an amount of between 0.001 to 5 Mg of the compound answering the formula o H 3 N   Wherein Y is hydrogen ủ a lower alkyl and Z is a substituted 1 L-yrrolidinyl hydroxy radical or a lower alkyl-substituted piperidyl radical, or a piperazinyl radical or an aniline radical substituted with an acetamino, acetyl group, carbamido, cyano, carboxy lower alkyl amino, di-lower alkoxy, nitro, sulfamyl or lower alkyl, or a radical of formula wherein R is hydrogen or lower alkyl and R 1 is a radical containing heterocyclic nitrogen selected from the group comprising substituted tri-azolylamino, lower alkyl-substituted isothiazolyl, benzotiaziazolyl, and nitro derivatives and substituted benzothiazolyl halo, or R1 is a substituted lower alkyl radical selected from the group consisting of lower alkylamines, alkyl-lower alkylamines, hydroxy lower alkyl amino lower alkyl, hydroxy lower alkyl lower alkyl, imidazolyl lower alkyl, tlimi dazolyl substituted lower alkyl nitro, monoo and di-hydroxy phenyl lower alkyl, pyridylasino lower alkyl substituted nitro, piperazinyl lower alkyl and ethyl pyridylo