NL8200839A - MITOSAN CONNECTIONS. - Google Patents

Description

If -.? VO 3077

Mitosan compounds.

The invention generally relates to antibiotic active mitosan compounds and their use in the treatment of neoplastic disease states in animals.

Reference may be made to United States Patent No. H,268,676 and United States Patent Application No. 206,529, which has been spun off from this. Briefly stated, these older pieces are new and useful compounds which are structurally related to the mitomycins and exhibit antibiotic activity, have low toxicity and exhibit marked anti-tumor activity in animals.

Briefly, the earlier documents deal with compounds of the formula I, wherein Y is hydrogen or alkyl, and X is a thiazolamino group, a 1 2 furfurylamino group, or a group of the formula I ', wherein R, R, and R are the same or different, and hydrogen or alkyl, and.

15 represents alkenyl, haloalkenyl, alkynyl, alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl or benzenesulfonamide.

This earlier application also relates to new methods of treating neoplastic conditions in animals for which a therapeutically effective amount of a compound of formula Ia 20 is administered, wherein Y is hydrogen or alkyl and Z is a thiazole amino group, a furfurylamino group, a represents cyclopropylamino group, a pyridylamino group or a group of the formula I ", wherein R, R, R and R are the same or different and represent hydrogen or alkyl, and R 7 represents alkenyl, haloalkenyl, alkynyl, alkoxycarbonyl, haloalkyl, hydroxyalkyl, pyridyl , thienyl, formamyl, tetrahydrofuryl, benzyl or benzenesulfonamide.

The invention, however, relates to compounds of the formula II of the formula sheet wherein Y is hydrogen or alkyl, and X is an alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylamino group, or a mono- or dialkyl-substituted thiar-8200839-2 - zoolamino group, or a nitrogen-containing heterocyclic ring in the form of 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl or N-thiomorpholinyl, or a cyano, phenyl, earhoxamido or alkoxycarbonyl-substituted 1-aziri-5 dinyl group, or alkyl, fonryl or acetylphenyl-substituted piperazinyl group, or a hydroxyl or piperidyl-substituted piperidyl group, or an alkoxy, amino or halogen-substituted pyridylamino group, or an carboxamido, mercapto or methylenedioxy-substituted anilane group, or a group of the formula NR-R ', where R is hydrogen or alkyl and R' is a nitrogen-containing heterocyclic ring in the form of quinuclidinyl, pyrazolyl, 1-t riazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thia-diazolyl or benzothiadiazolyl, and derivatives of alkyl and halogen substituted thereof, either a butyrolactonyl group, or an adamantyl group, or a substituted alkyl group from the mercaptoalkyl, mono- series alkoxyalkyl, alkylthioalkyl and alkoxycarbonyl-substituted derivatives thereof, cyanoalkyl, mono-, di- and tri-alkoxyphenylalkyl, phenyl cycloalkyl, 1-pyrrolidinylalkyl, N-alkylpyrrolidinylalkyl and N-mor-folinylalkyl.

The invention also relates to new methods of treating neoplastic disease states in animals, which method comprises the administration of a therapeutically active amount of a compound of the formula Ha, wherein Y is hydrogen or alkyl, and Z is an alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylaoino group, or a mono- or di-alkyl-substituted thiazolamino group, or a nitrogen-containing heterocycle in the form of 1-pyrrolinyl, 1-indolinyl, R-thiazoladinyl, R-morpholinyl, 1-piperazinyl and N-thiomorpholiny1 or 35 a cyan, phenyl, carboxamido or alkoxycarbonyl substituted 1-8200839 - * - 3 - aziridinyl group, or an alkyl, phenyl or acetylphenyl substituted 1-piperazinyl group, or a hydroxyl or piperidyl-substituted piperidyl group, or an alkoxy, amino or halogen-substituted pyridylamino group, or a carboxamido, mercapto or methylenedioxy-substituted anilino group, or a group of the formula -HB-B ", wherein E represents hydrogen or alkyl and B" 10 a nitrogen-containing heterocyclic ring in the form of quinuclelidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl or benzothiadiazolyl, and the alkyl or halogen-substituted derivatives thereof, or a butyrolactonyl group or an adamantyl group, or a monoalkoxy-substituted phenyl group, or a substituted alkyl group in the form of mercaptoalkyl, mono-, di- or tri-alkoxyalkyl, alkylthioalkyl or alkoxycarbonyl-substituted derivatives thereof, cyanoalkyl, mono-, di- and tri-alkoxyphenylalkyl, phenylcycloalkyl, 1-pyrrolidinylalkyl, N-alkylpyrrolidinylalkyl, ï-morfolinylalkyl or dialkylaminoalkyl.

Unless otherwise stated below, the alkyl groups always have 1 to 6 carbon atoms and are straight or branched. Suitable examples include methyl, ethyl, propyl, butyl, pentyl and hexyl, as well as isopropyl, tert-butyl and the like. The same goes for the alkoxy groups.

It will be understood that the compounds of formula II all fall within the specification for formula Ha. In other words, all new antibiotic active mitomycin derivatives of the formula II are useful for combating neoplastic phenomena using compounds of the formula Ila.

The present mitomycin derivatives can be prepared by. a reaction of mitoaycine A with appropriate amine compounds. The If-alkyl-mitomycins (e.g. H-methylmitomycin) derivatives are otherwise prepared by reaction of an appropriate amine with 1-alkylmitomycin A, obtained from mitomycin C, e.g. according to the method of Cheng et al., in J. Med. Chem. 20, No. 6, 7, 7, 770 (1977). The preparation reactions yield the desired product, usually in the form of a crystalline solid material which is readily soluble in alcohol.

The therapeutic methods according to the invention comprise the administration of effective amounts of one or more compounds of the formula Ha as an active substance, together with suitable pharmaceutically acceptable diluents, excipients and carriers, namely to an animal suffering from neoplastic symptoms. Unit-10 doses of the present compound contain about 0.001-5.0 mg, most preferably 0.001-1.0 mg of active compound. Such amounts can be given up to daily doses of 0.1 to about 100 mg per kg and preferably about 0.2 to about 51.2 mg per kg of body weight of the animal to be treated. Parenteral administration, especially intraperitoneal administration, is the preferred form of the present invention.

The invention is explained in more detail below with the aid of a number of examples. Examples I - XLII show a number of preparation methods, in which the reactions were carried out at room temperature (approx. 20 ° C) unless otherwise indicated. Unless otherwise indicated, all thin layer chromatograms on coated silica gel plates and a mixture of methanol and chloroform (2: 8. Volumina) were used as the running liquid.

Example I

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-25 cyano-1-aziridinyl) -azirino / * 2 ', 3': 3,17-pyrrolo-1,2-a-7-indole-7-dione carbamate.

O

A solution of 100 mg or 0.286 mmol of mitomycin A in 8 car anhydrous methanol was treated with 38.9 mg or 0.572 mmol of 2-cyanaziridine and 30 mg of potassium carbonate at room temperature under nitrogen. When a starting material was no longer detectable on a thin layer chromatography on silica gel (2: 8 methanol / chloroform), the mixture was diluted with 50 ml of methylene chloride, filtered and dried under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel with a mixture of methanol and chloroform (2: 8 volumes) as a solvent. This procedure yielded 33 mg (30 # yield) of the desired product, m.p. 87 DEG-89 DEG C. with decomposition; analyzed jfers: HMR (CDCl 3, TS): "£" values in ppm.

The disappearance of a singlet at 4.02 (the 6-methoxy group of the starting material) and the appearance of new signals at 2.13 (d, 2) and 2.53 (broad s, 1).

Example II

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thio-morpholinyl) -azirino / * 2 *, 3 *: 314 J pyrrolo £ 1 , 2-a Jindole-4,7-dione carlo-banat.

This compound was prepared analogously to Example 11 with the difference that no potassium carbonate was used. 14 mg {22%) of the desired product, m.p. 90 DEG-91 DEG (dec.), Was obtained from 52 mg of mitomycin A and 500 mg of thiomorpholine with the following analysis: 15 µM (CDCl 3, TS) values in ppm.

Disappearance of the 6-methoxy peak at 4.02 and enhancement of the peaks at 2.8 (m, increase by 4) and 3.6 (m, increase by 4).

Example III

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-in-20 dolinyl) -azirinoZ * 2 ', 3': 3.4 J7pyrrolo / T1,2-a-7indole-4,7-dione carbamate.

This compound was prepared analogous to Example I except that the potassium carbonate was omitted. From 100 mg of mitomycin A and 69 mg of indoline, 45 mg ($ 36) of the desired product was obtained, which had a melting point of 1.7 DEG-135 DEG C. (dec.) And showed the following analyzes: BMR (CDCl3) , TS) "J" values in ppm.

Disappearance of the 6-methoxy peak at 4.02 and new peaks occur at 2.85-3.7 (group, 4) and 6.15-7.5 (group, 4).

Example IV

1,1 a, 2,8,8a, 8b-hexahydro-8- (hydromoxymethyl) -8a-methoxy-5-methyl-6-P (6-methoxy-3-pyriclyl) amino. J-azirinoZ 2 ', 3': 3,4,7-pyrrolo C1,2-indole-4,7-dione carbamate.

This compound was prepared analogously to Example I with the difference that the potassium carbonate was omitted. From 100 mg of mitomycin A and 2 8200839 6 drops of 3-amino-β-methoxypyridine, 96 mg (76%) of the desired product, m.p. 2 - 262 ° C (dec.), Were obtained. This yielded the following analysis figures: UMR (CDClg, TS): "£" values in ppm.

5 Absence of the 6-methoxy peak he U, 02, and occurrence of new peaks he 3.93 (s, 3), 6.77 (s, 1), 7.26 (d, 1), 7.60 (d , 1) and 7.87 (s, 1).

Example V

1,1 a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - / * (6-10 with hoxy-8-quinolinyl) amino - / - azirino / "2 ', 3': 3, 7pyrrolo [1,2-a] Jinol carhamate.

This compound was prepared analogously to Example I. 26 mg or 32 # of the desired product, m.p. 135 DEG-5 DEG C. (dec.), Was obtained from 60 mg of mitomycin A and 5 mg of 8-amino-6-methoxyquinoline. This showed the following analysis figures: KMR (CDCl 3, TS) "£" values in ppm.

Absence of the 6-methoxy peak at kt02, and occurrence of new peaks at 6tk (d, 1), 6.67 (d, 1), 7.30 (dd, 1), 8.0 (dd, 1) and 8 90 (dd, 1).

Example VI

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-quinuclidinyiamino) -azirino / '2', 3 ': 3, 4' pyrrolo / * 1,2-a Jindole - ^, 7-di-one carbamate.

This compound was prepared analogously to Example I, except that no potassium carbonate was used. From 100 mg of mitomycin A and 3-aminoquinuclidine (prepared by treating an aqueous solution of 73 mg of 3-aminoquinuclidine hydrochloride with sodium hydroxide), 86 mg (5W of the desired product, mp 138-1.6 ° C with decomposition, was obtained This showed the following analysis-30 digits: UMR (CDClg, TS) values in ppm.

Absence of the 6-methoxy peak at U, 02, amplification of the peaks at 2.8 and 3.8, and appearance of new broad peaks at 1.2 and 2.5 · Pre-VII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- "2- 8200839

t> V

- 7 -

Onion-butyrolactonyl) amino-7-azirino / "2,3" 3,4-Zpyrrolo / 1,2-a-Jindole-4,7-dione carbamate.

This compound was prepared analogously to Example I with the difference that no potassium carbonate was used. 68 mg (51%) of the desired product, m.p. 87 DEG-89 DEG (dec.), Were obtained from 100 mg of mitomycin A 5 and 6θ mg of oE-amino-T-butyrolactone hydrochloride.

This showed the following analysis figures: NMR (DMSO-dg.TS) "/" values in ppm.

Absence of the β-methoxy peak at 4.02, but new 10 peaks occur at 1.90 - 2.87 (m. 2), 3.80 - 4.70 (m, 3), and 8.3 - 9 , 2 (broad s, 1).

Example VIII

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-carboxamidoanilino) -azirino / -2 ', 3': 3,4-pyrrolo / 1,2-a J7 indole-4,7-15 dione carbamate.

This compound was prepared analogously to Example I. From 100 mg of mitomycin A and 82 mg of 4-aminobenzamide, 36 mg (28%) of the desired product, m.p. 167 DEG-169 DEG C. (dec.). This showed the following analysis figures: HMR (acetone-dg, TS): "/" values in ppm.

Absence of the 6-methoxy peak at 4.02, and emergence of new peaks at 6.67 (d, 3), and 7.73 (d, 2).

Example IX

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-25 dimethoxybenzyland.no) -azirino / T 21.3 ': 3 .4 J-pyrrolo C1,2-a J indole-4,7-dione carbamate.

This compound was prepared analogous to Example I except that no potassium carbonate was used. 29 mg (72%) of the desired product was obtained from 29 mg mitomycin A and 69¼ mg 3,4-dimethoxybenzylamine. This had a melting point of 112 ° C under decomposition and gave the following analysis figures: MR (CDClg, TS): "/" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 3.9 (s, 6), 4.65 - 4.75 (d, 2), 6.55 (wide s, 3) and 6, 86 (s, 35-3).

8200839 - 8 -

Example X.

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl 1-6- /. (1-ethyl-2-pyrrolidino) methylamino-7-azirino / T 21,31: 3,1 * pyrrolo / 1,2-a J-indol-1,7-dione carbamate.

This compound was prepared in analogous example I. With the difference that no potassium carbonate was used. From 150 mg of mitomycin A and 2 drops of 2-aminomethyl-1-ethylpyrrolidine, j8 mg (1 + 1/0 of the desired product was obtained, which decomposed at temperatures above 300 ° C. The analytes read as follows: 20 MR ( CDCl 3, TS): "<f 'values in ppm.

Absence of the 6-methoxy peak at 1 +, 02, and occurrence of new peaks at 1.07 (t, 3), 1.1 H - 2.33 (m, 5), 2.36 - 3.03 (m, 4), 3.3-3.83 (m, 2) and 6.77-7.20 (broad s, 1).

Example XI

1.1a, 2.8, 8a, 8b-Hexahydro-8- (.hydroxymethyl) -8a-methoxy-5-methyl-6 - / * (1-methoxycarbonyl-3-methylthio) propyl amino. azirino- / T 2 ', 3' = 3.1 + 7-pyrrolo / -1,2-a-7indole - 7, 7-dione carbamate.

This compound was prepared analogously to Example I with this difference

O

that potassium carbonate was replaced with 0.5 cm triethylamine. 61 mg (30% yield) of the desired product was obtained from 150 mg of mitomycin A and 110 mg of L-methionine methyl ester hydrochloride. This had a melting point of 83 - 85 ° C (dec.) And showed the following analysis figures: mm. (CDC13, TS): "/" values in ppm.

25 Absence of the 6-methoxy peak at 1 +, 02, and occurrence of new peaks at 1.63 - 2.1 * 0 (m, 3), 2.10 (s, 3), 2.1 * 3 - 3 .0 (m, 2), 3.80 (s, 3) and 8.3, 9.3 (wide s, 1).

Example XII · 1.1a, 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-30 phenylcyclopropylamino) -azirinOyT 2 ^ 3 ^ 3,1 + JpyrroloZ -1,2-a Jindole-1 *, 7-dione carbamate

This compound was prepared analogous to Example I except that the potassium carbonate was omitted. 70 mg (63%) of the desired product was obtained from 125 mg of mitomycin A and 85 mg of 2-phenylcyclopropylamine. This decomposed at temperatures above 250 ° C and yielded the following 8200839-9 analysis figures: HMR (CDClg, TS): values in ppm.

Absence of the 6-methoxy peak "at b, 02 and occurrence of new peaks at 0.6 - 1.53 (m, 1»), 6.20 - 6.50 ("wide s, 1) and 7.18 ( "wide s, 5) ·

5 Example XEII

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / f (5-chloro-2-benzoxazolyl) amino-7-azirinoZ * 21.3 3,1-pyrrolo [1,2-a-7-indol-1,3-7-dione carbamate.

This compound was prepared by analogous example I. From 100 mg of mi-10 tomycin A and 50 mg of 2-amino-5-chlorobenzoxazole, 35 mg (25%) of the desired product, mp 118-120 ° C, were obtained ( dec.) and showed the following analysis figures: HMR (CDCl ^, TS): "^" values in ppm.

Absence of the 6-methoxy peak at 1.02 and occurrence of new peaks in the range 6.70-7.63 (m, h).

Example XIV

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methyl-5-methyl-6-i-5-methyl-2- (1,3-thiadiazolyl) amino. -azirino / "2 *, 3 *: 3, 7-pyrrolo /" 1,2-a-jindole-1 +, 7-dione carbamate.

This compound was prepared analogous to Example I. 31 mg (25%) of the desired product had a melting point of 91 DEG-93 DEG C. (decomposition) of 100 mg mitonycin A and 53 mg 2-amino-5-methyl-1,3,1-thiadiazole. ) and showed the following analysis figures: HMR (CDCl ^, TS): "^" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 2.68 (s, 3) and 7.47 - 7 * 63 (broad s, 1).

Example XV * 1.1 a, 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) azirino ^ 2 ', 3'; 3,4-pyrrolo [1,2-a] indole-4,7-30 dione carbamate.

This compound was prepared analogously to Example I except that no potassium carbonate was used. From 6q mg of mitomycin A and 35 mg of 2,2-dimethoxyethylamine, 60 mg (83%) of the desired product was obtained. This decomposed at temperatures above 220 ° C and showed the following analysis figures: 8200839 "* * - 10 - MR (CDCl 3, TS):" & "values in ppm.

Absence of the 6-methoxy peak he 4.02 and occurrence of new peaks he 3.45 (s, 6), 3.33 - 3.93 (m, 2), 4.33 - 4.85 (hreed s, 1 ) and 6.15-6.66 (hreed s, 1).

Example XVI

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-mercaptoethylamino) -azirino [2 ', 3': 3,4_pyrrolo / i 2-α-7indole-4,7-dione carhamate.

This compound was prepared analogously to Example I with the difference that 0.5 cm of triethylamine was used instead of the potassium carbonate. 50 mg (44%) of the desired product was obtained from 150 mg mitomycin A and 100 mg 2-mercaptoethylamine hydrochloride. This had a melting point of 152-154 ° C (dec.) And showed the following analysis figures: 15 MR (DMSO-d, TIE): "^" "values in ppm.

Absence of the 6-methoxy peak at 4.02 and emergence of new peaks at 2.53-3.10 (m, 4) and 7.30-7.50 (broad s, 1).

Example XVII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-20 methyl-2-thiazolyl) amino-7-azirino / T21.3 3.4-7 pyrrolo / 1,2-Jindole-4,7-dione carbamate.

This compound was prepared analogously to Example I. From 150 mg of mitomycin A and 96 mg of 2-amino-4-methylthiazole, 85 mg (59%) of the desired product, m.p. 166 DEG-118 DEG (dec.), Were obtained.

25 The analysis figures are as follows: MR (CDClg, TS): ”&“ values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 2.33 (s, 3), 6.30 - 6.60 (broad s, 1) and 7.30 (s, 1).

Example XVIII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-mercaptoanilino) -azirino ƒ "2 ', 3': 3,4_pyrrolo / 1,2-a7-indole-4,7-dione carbamate.

This compound was prepared analogously to Example I with the difference that no potassium carbonate was used. From 200 mg of mitomycin A and 143 mg of 4-mercaptoaniline, 120 mg (47%) of the desired product with 8200839-11 - melting point 97 DEG-99 DEG (dec.) Was obtained. This yielded the following analyzes: IMR (CDCl 3, TS): "<1" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 6.53 (d, 2) and 7.0-7.7 (m, 3).

Example XIX

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-methylenedioxyanilino) -azirino 2 ~ 3 ', 3' pyrrolo / 1,2-α-indole-4,7-dione carbamate.

This compound was prepared analogous to example I with the difference that no potassium carbonate was used. From 80 mg of mitomycin. A and 0.1

O

cm-3 3,4-methylenedioxyaniline, 50 mg (48 $) of the desired product, m.p. 86 DEG-88 DEG (dec.), were obtained with the following analyzes: 15 HMR (CDCl 3, TS): "<f" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 5.97 (s, 2), 6.0 - 6.7 (m, 3), 7.27 (s, 1).

Example XX

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- "2-20 (1-pyrrolidino) ethylamino] -azirinoZ * 2", 3 ': 3,4-pyrrolo2-1,2-a-indole-4,7-dione carbamate.

This compound was prepared analogous to Example I except that no potassium carbonate was used. From 100 mg of mitomycin A and 0.2

O

car 2- (1-pyrrolidino) ethylamine, 7.5 mg or 6.1% of the giving compound was obtained, which decomposed at temperatures above 200 ° C and gave the following analysis figures: NMR (CDCl 3, TS): "j values in ppm.

Absence of the 6-methoxy peak at 4.02 and emergence of new peaks at 1.57 - 1.93 (m, 4), 2.33 - 3.03 (m, 8) and 6.92 (t, 1) .

30 Example XXI

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-isoquinolinylamino) -azirino 2 2 ', 3': 3,4 'pyrrolo / * 1,2-a-7indole-4,7-di-one carbamate.

This compound was prepared analogously to Example I. From 90 mg of mito-35 mycine A and 810 mg of 5-aminoisoquinoline, 28 mg (2%) of 8200839-12 was obtained - the desired product having a melting point below 3 ° C and the following analyzed: MR (CDCl 3, TS): "" values in ppm.

-Absence of the 6-methoxy peak "at k, 02 but occurrence of new peaks 5 he 6.8 - 7.65 (m, 3), 7.85 (d, 1) and 8.55 (d, 1 ).

Example XXII

1, 1a, 2,8,8a, 8b-Hexahydro-8- (ihydroxymethyl) -8a-methoxy-5-methyl-6- (5-indazolylamino) -azirino / T2 ', 3': 3 Λ Jpyrrolo ƒ "1 2-a-Jindole-7-dione carbamate.

This compound was prepared analogous to example 1. From 90 mg mitp-mycine A and 666 mg 5-aminoindazole, 35 mg (30%) of the desired product, m.p. This showed the following analysis figures: MR (CDClg, TS): "<f" values in ppm.

Absence of the 6-methoxy peak at ^, 02, and occurrence of new peaks at 6.8 - 7.65 (m, 3) and 8.0 (s, 1).

Example XXIII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T k- (2,1,3-benzothiadiazolyl) amino ^ -azirinoZ * 2 ' .3 ': 3,4-pyrrolo / Tl, 2-a-J-20 indole-1, 7-dione carbamate.

This compound was prepared analogous to example I. The reaction also did not proceed completely in 19 hours despite the use of excess amine. From 50 mg of mitonycin A and 300 mg of -amino-2,1,3-benzothiadiazole, 32 mg (b8%) of the desired product, m.p. 139 DEG-25 DEG C. (dec.) And the following analysis figures obtained: MR (CDC13 + CD30D, TS): "/" values in ppm.

Absence of the 6-methoxy peak at U, 02 and occurrence of new peaks at 6.6 (m, l), 7.6 (m, 2) and 8.25 (wide s, 1 *).

Example XXIV

30 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-ethylethyl-6- (glyglycinyl) -azirino *2], 3 ': 3, ¼ Jyyrrolo 1,2-a-Jindole-1,7-dione carbamate.

This compound was prepared analogously to Example I with this difference

O Q

that cm cm of methanol was used as well as 10 cm 3 of triethylamine in place of the potassium carbonate. From 100 mg of mitomycin A and 600 mg of glycine - 13200839 - 13 - cine, 47.4 mg (42 $) of the desired product was obtained, which did not melt below 350 ° C and had the following analysis figures: HMR (CDClg + CD OD, TS): "values in ppm.

Absence of the 6-methoxy peak at 1 +, 02 and occurrence of a new 5 peak at 3.45 (s, 2).

Example XXV

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyanoethylamino) -azirinoiT2 ', 3L: 3.4 Jpyrrolo / fl, 2- aJindole-4,7-dione carbamate. This compound was prepared according to example I with the difference that 0.5 cm triethylamine was used instead of the potassium carbonate. From 210 mg of mitomycin A and 90 mg of 3-aminopropionitrile fumarate, 151 mg ($ 75) of the desired product was obtained, which had a melting point at 68 - 70 ° C (dec.) And showed the following analysis figures: 15 NMR (CDCl3, TS) : ”£ 'values in ppm.

Absence of the 6-methoxy peak at 4.02 and emergence of new peaks at 2.1 - 2.77 (m, 4) and 6.57 (t, 1).

Example XXVI

1,1 a, 2,8,8a, 8b-hexahyro-8- (hydroxymethyl) -8a * methoxy-5-methyl-6- (2-flu-20-orethylamino) -azirino2T2f, 3 ': 3,4-pyrroloZT1, 2-a_7indole-4,7-dione caramate.

This compound was prepared analogously to Example I with the difference that the 2-fluoroethylamine hydrochloride (220 mg) was neutralized with 119 mg sodium methoxide in 2 methane at 5 ° C before adding the 77 mg mitomycin A; potassium carbonate was not used. There was thus obtained 62 mg, or 74%, of the desired product, melting point above 340 ° C and the following analysis figures: NMR (CDCl 3, TS): "cf" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks at 3.3-3.9 (m, 2), 4.2 (t, 2) and 6.5 (broad s, 1).

Example XXVII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T1- (3-pyrrolinyl) -7-azirino / ~ 2r, 31: 3.4 Jf-pyrroloC1,2-a-7 indole-4,7-dione carbamate.

This compound was prepared analogous to example I with the difference 8200839-111 + - that no potassium carbonate was used and a change was required due to the presence of pyrrolidine impurities in the technical 3-pyrroline. The pyrrolidine formed a crystalline derivative with mitomycin A which was filtered out of the mixture. The filtrate was then worked up as described in Example 1. From 100 mg of mitomycin A and 1 g of technical 3-pyrroline, 30 mg (27%) of the desired product was obtained with a partial decomposition temperature of 85 - 90 ° C but no melting point below 250 ° C; this product had the following analysis figures: 10 NMR (CDCl 3, TS): "^" values in ppm.

Absence of the 6-methoxy peak at 1 +, 02 and occurrence of a new peak at 5 »9 (s, 2). It was not possible to distinguish the 2 proton peak in the 3.1 + region from other absorption.

Example XXVIII

1.1 a, 2.8,8a, .8b-Hexahydro-8- (hydroxymethyl) -8-methoxy-5-methyl-6- (3-thiazolidino) -azirinoC2 ', 3': 3.1+ J7pyrrolo 1,2-a-Jindole-l +, 7-dione carbamate.

This compound was prepared analogously to Example I with the difference that no potassium carbonate was used. From 250 mg mitomycin A and

O

0.5 cm of thiazolidine 125 mg of 0 + 3/0 of the desired product with a melting point of 105 - 107 ° CT (dec.) And the following analysis figures were obtained: NMR (CDCl 3, TMS): "<f" - values in ppm.

Absence of the 6-methoxy peak at 1 +, 02, and occurrence of new peaks at 2.62 (wide s, 2), 2.68 - 3.02 (wide s, 2) and 3.32 - 1 +, 02 (broad s, 2).

Example XXIX

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-1-1- (1 + -methylpiperazino) -7-azirino / ~ 2 *, 3r: 3.1 + 7-pyrrolo [1,2-a] -indole-1 +, 7-30 dione carbamate.

This compound was prepared according to Example I except that no potassium carbonate was used. From 100 mg mitomycin A and 0.2 cm N-methylpiperazine, 50 mg (1 + 2/0 of the desired product, m.p. 81 DEG-87 DEG (dec.), And the following analysis figures were obtained: 8200839. -15- NMR (CDCl3, TS): "é" Values in ppm.

Absence of the 6-methoxy peak he U, 02 and occurrence of new peaks at 2.27 (s, 3), 2.1 * 7 (t, k) and 2.92 (t, M) Example XXX

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / J3- (pyrazolyl) amino J7-azirino C 2 ', 3': 3, U pyrrolo / 1,2-a 7-indole-4,7-dione carbamate.

This compound was prepared analogously to Example I, but without the use of potassium carbonate. From 100 mg of mitomycin A and 1 * 8 mg of 3-aminopyrazole, 50 mg (hh%) of the desired product was obtained. This had a melting point of 1h2 - 1 ^ 5 ° C (dec.) And yielded the following analysis numbers: NMR (CDCl 2, TIC): "£" values in ppm.

Absence of the 6-methoxy peak at U, 02 and occurrence of new peaks at 6.50 (d, 2), 6.67 - 6.83 (broad s, 1) and 8.07 (s, 1).

Example XXXI

1.1a, 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-yl 2- (N-morpholino) ethylamino 7-azirino / 2 ', 3' 3, 3-pyrrolo / T1,2-a-7indole-h, 7-dione carbamate.

This compound was prepared analogously to Example I, but the potassium carbonate was omitted. From 100 mg of mitonyeine A and 0.5 cm of N- (2-aminoethyl) -morpholine, 70 mg (55%) of the desired product, m.p. Th - 76 ° C (dec.), And the following analysis figures were obtained: NMR (CDCl 3, TS): "cf" values in ppm.

Absence of the 6-methoxy peak at U, 02 and occurrence of new peaks at 2.27 - 2.73 (wide, 8), 3. ^ 7 - M3 (“wide, H) and 7.27 (t, .1 ). Example XXXII

1,1a, 8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-i-2-2- (30 (ethylthio) ethylamino 7-azirino), 2, 3 *: 3-pyrrolo-1,2-a-Jindole-7-dione carbamate.

This compound was prepared in analogous example I with the difference that 0.5 cm triethylamine was used instead of the potassium carbonate. From 250 mg mitomvcine A and 101.5 mg 2- (ethylthio) ethylamine hydrochloride, 220 mg (73 $) of the desired product, mp 8200839-16 - 103-106 ° C (dec.) And the following analysis figures Obtained: IMR (CDCl 3 TS): "^" values in ppm.

Absence of the 6-methoxy peak at ^, 02 and occurrence of new peaks he 1.27 (t, 3), 2. U0 - 2.90 (m, U), 3. U0 - 3.93 (m, 2 ) and 6.56 (t, 1). Example XXXIII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- (2-mercaptoethylamino) -azirino / 72 *, 3 ':, Pyrrolo / 1,2-aindol-U, 7-dione carhamate.

This compound was prepared analogously to Example 1 with the difference that 0.5 cm of triethylamine was used in place of the potassium carbonate. From 250 mg of N-methylmitomyein A and 78 mg of 2-mercaptoethylamine hydrochloride, 150 mg (5W of the desired product, m.p. 85 DEG-87 DEG (dec.), And the following analysis figures were obtained: IMR (CDCl 3, TS) : "J" values in ppm.

Absence of the 6-methoxypeak at U.05 and occurrence of new peaks at 2.57-3.10 (broad s, k) and 6.20-6.93 (broad s, 1).

Example XXXIV

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-methoxyethylamino) azirino / ”21.3 *: 3J7pyrroloZT 1,2- a. Jindole-4,7-dione 20 carbamate.

This compound was prepared analogously to Example I with the difference that the potassium carbonate was omitted. From 120 mg mitomycin A and

O

0.2 cm2 of 2-methoxyethylamine, 99 mg ($ 73) of the desired product, m.p. 106 DEG-109 DEG (dec.), And the following analytical figures were obtained: WMR (CDCl 3, TS): values in ppm.

Absence of the 6-methoxy peak at U, 02 and occurrence of new peaks at 3, b2 (s, 3), 3.5 - 3.9 (hreed s, k), 6.27 - 6.77 (wide s, 1). Example XXXV

1.1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (U-methoxyanilino) -azirinoZT2 ', 3': 3, ^ Jyyrrolo £ 1,2-a Jindole-1 *, 7-dione carbamate.

This compound was prepared analogously to Example I except that the potassium carbonate was omitted. From mg of mitomycin A and 27 35 mg of -methoxyaniline, JO mg (7W of the desired product with a 8200839-17 - melting point of 103 - 108 ° C (dec.) And the following analysis figures were obtained: HMR (CDCl 3, TS ): "£" values in ppm.

Absence of the 6-methoxy group he 4.02 and occurrence of new peaks he 3.8 (s, 3), 6.8 (s, 4) and 7.7 (s, 1).

Example XXXVI

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-ada-mantylamino) -azirinoC2 ', 3': 3,4.7pyrrolo / 1,2-a-indole-4,7-dione carhamSrS.'b This compound was prepared analogously to Example 1. The reaction also did not proceed completely in 48 hours despite the use of an excess of amine. 60 mg (30%) of the desired product with a melting point of 149 DEG-150 DEG C. (dec.) With partial decomposition at 05 DEG-90 DEG C. and the following was obtained from 1 mg mg of mitomycin A and 666 mg of 1-aminoadamantane. analysis figures: NMR (CDCl3 + CD30D, 35): "/" values in ppm.

Absence of the 6-methoxy peak he 4.02 and occurrence of new peaks he 1.55 - 2.3 (m, 15).

Example XXXVII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-Z-1- (1,3,4-triazolyl) amino. 7-azirinoZ 2 *, 31: 3.4 J-pyrrolo / 1.2-a-7 indole-4,7-dione carhamate.

This compound was prepared analogously to Example I. From 100 mg of mitomycin A and 80 mg of 1-amino-1,3,4-triazole, 35 mg ($ 30) of the desired product, melting point above 250 ° C (dec.), And the following analysis figures obtained: NMR (CDCl3, T1 ©): "/" values in ppm.

Absence of the 6-methoxy peak at 4.02 and emergence of new peaks at 8.00 (s, 2).

Example XXXVIII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4,5-trimethoxybenzylamino) -azirino / "21,3 *: 3, 4-7 pyrrole / T 1,2-a J7indole-4,7-dione carhamate.

This compound was prepared analogously to Example I with the difference that no potassium carbonate was used. From 65 mg of mitomycin A and 437 8200839 - 18 mg 3, 1.5 *, 5-trimethoxybenzylamine, 55 mg (51%) of the desired product, m.p. 9-95 ° C (dec.), And the following analysis figures were obtained : 1IMR (CDCl ^, TS): "/" values in ppm.

5 Absence of the 6-methoxy peak he 1 *, 02 and occurrence of new peaks he 3.85 (s, 9), 1 *, 1 * 6 - U, 76 (d, 2) and 6.1 * 5 (s , 2).

Example XXXIX

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6-C2- (ethylthio) ethylamino J7-azirinq / "2 ', 3': 3.1 + 7-pyrrolo / 1.2-a7-indole-10 U, 7-dione carhamate.

This compound was prepared analogously to Example 1 except that 0.5 cm of triethylamine was used instead of the potassium carbonate. From 120 mg of N-methylmitomycin A and 70 mg of 2- (ethylthio) ethylamine hydrochloride, 100 mg (69% ) of the desired product with a melting point of 11U-16 ° C (dec.) and the following analysis figures were obtained: MR (CDCl 3 TS): "/" values in ppm.

Absence of the β-methoxy peak at 1 *, 02 and occurrence of new peaks at 1.27 (¾. 3), 2.1 * 0 - 2.93 (m, * 0, 3.1 * 0 - 3.93 U, 2) and 6.50 - 6.80. (20 (broad s, 1).

Example XL '* 1.1a, 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T 2- (dimethylamino) ethylamino J7-azirino f2f, 3 3.1 * 7-pyrr5b / T 1,2-a-7indole-1,7 * -dione carbamate.

This compound was prepared analogously to Example I with the difference that the potassium carbonate was omitted. From 150 mg of mitomycin A and 0.2

O

The 2- (dimethylamino) -ethylamine was obtained 130 mg (75 $) of the desired product, m.p. 72 DEG-75 DEG (dec.) and the following analysis figures: 30 MR (CDClg, TS): "/" - values in ppm.

Absence of the 6-methoxy peak at 1 *, 02 and occurrence of new peaks at 2.17 (s, 6), 2.37 - 2.63 (wide s, 2), 3.3-1) -, 0 ( wide s, 2) and 6.7 - 7 »1 (wide s, 1).

Example XII

1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- 1-8200839 -19- (3-bydroxypiperidyl) _7-azirino / Γ2 ' .3 ': 3,4-P3rrrolo / 1,2-aindol-4,7-dione carbamate.

This compound was prepared analogously to Example I with the difference 3 that 0.5 cm 3 of triHshylamine was used instead of the potassium carbonate. From 130 mg of mitomycin A and 70 mg of 3-bydroxypiperidine hydrochloride, 80 mg (58 $) of the desired product, m.p. 98 DEG-101 DEG (dec.), And the following analysis figures were obtained: NMR (CDCl 3, TS) : "tf" values in ppm.

Absence of the 6-methoxy peak at 4.02 and occurrence of new peaks 10 at 0.97 - 2.13 (wide m, 4), 2.17 - 3.13 (wide m, 4), 3.3 - 4 , 33 (wide m, 1) and 4.67 - 5.73 (wide s, 1).

Example XDII

By using mitomycin A and the appropriate amine starting materials, the methods shown in the previous examples can be used to prepare the following compounds: (a) 1.1a, 2.8,8a, 8b-hexahydrO “8 - (hydro2ymethyl) -8a-metho2y-6- (2-phenyl-1-aziridinyl) -azirino, 2,3 ': 3,4-pyrroloZT 1,2-a -indol-4,7-dione carbamate; (b) 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl} -8a-methoxy-6 ~ (2- 20 methoxycarbonyl-1-aziridinyl] azirino ^ 2 ', 3': 3.4 pyrrolo / T 1,2-a-7-indol-4, -7-dione carbamate; (c) 1.1a, 2.8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- ( 2-carboxami do-1-azir i dinyl) -aziri no 2 ', 3': 3,4-pyrrolo, 1,2-a-7-indole-4,7-dione carbamate; 25 (d) 1.1a, 2.8.8a 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (1-morpholinyl) -azirino £ 2 ', 3': 3.4 pyrrolidone 1,2-a 7-indole-4,7-dione carbamate; e) 1,1a, 2,8,8a, 8b-hexahydr 0-8- (hydroxymethyl) -8a-methoxy-β- (1-piperazinyl) -azirino ”2 *, 3 ': 3.4 pyrrolo / 1,2-a7indole-4,7-dione carbamate, (f) 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (4-phenyl- 1-piperazinyl) -azirino / "2 *, 3 ': 3,4-pyrrolo-1,2-aindol-4,7-dione carbamate; (g) 1.1a, 2.8 $ a, 8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy-6- (4-35 acetylphenyl-1-piperazinyl) -azirinoZT2 *, 3 ': 3.4 JpyrroloZ ”1,2-a Jindole- 8200839-20- ^ 7-dione carbamate (h) 1.1a, 2.8.8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-m ethoxy-6- / (1-pipsridyl) -1-piperidyl. 7-azirino 22,3,3: 3,4-pyrrolo / 1,2-a-7indole-1,7-dione carbamate; 5 (i) 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6- ƒ "(6-chloro-3-pyridyl) amino J7-azirinOiT2 ', 3': 3, ¾ Jpyrrolo / '1,2-a Jindole-¾, 7-dione carbamate; (j) 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- / (6-amino-3-pyridyl) amino j'-azirino / f ”21.3 ': 3,1 J 7-pyrrolo / T 1,2-a-indole-10, 7-dione carbamate; (k) 1.1a 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-

C 5-dimethyl-2-thiazolyl) amino 7-azirino / T 2, 3f: 3, -7-pyrrolo / 1,2-a.J

indole ^, 7-dione carbamate; (1) 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-15 L (¾-cyano-3-pyτazolyl) amino_7-azirino / T2 ', 3' : 3, J7pyrrolo / 1,2-a J-indole, 7- <3 ion carbate.

In connection with the general formula Ha, the above examples illustrate the following structural variations: 1. In the compounds of Examples XXXIII and XXXIX, Y is 20 alkyl and more specifically methyl. In all other examples, Y is hydrogen. The identity of Y is independent of that of Z. Compare examples XVI and XXXIII in which Z is equal but Y and respectively. hydrogen and alkyl. Examples XXXII and XXXIX also differ in this way.

2. Compounds in which Z is an alkoxy-substituted quino-linylamino group, a cyano-substituted pyrazolamino group, or a mono- or di-alkyl-substituted thiazolamino group are represented, e.g. by examples V, XLII (1), XVII and XLII (k).

3. Compounds in which Z is a nitrogen-containing hetero ring selected from 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl are represented, respectively. in examples XXVII, III, XXVIII, XLIl (d), XLIl (e) and II.

b. Compounds in which Z is a 1-aziridinyl group substituted with cyano, phenyl, carboxamido or alkoxycarbonyl are respectively represented. in examples I, XKCl (a), XLIl (c) and XLIl (b).

5. Compounds in which Z is 1-piperazinyl group substituted with alkyl, formyl or acetylphenyl 8200839-23. in the examples XXIX, XLIl (f) and XLIl (g).

6. Compounds in which Z is a hydroxy or piperidyl-substituted piperidyl group are represented, respectively. in the examples 5 XLI and XLII (h).

7 · Compounds in which Z is an alkoxy, amino or halogen-substituted pyridylamino group are represented by Examples IV, XLII (j) and XLII (i).

8. Compounds in which Z is an anilino group substituted with carboxamide, mercapto or methyl-10-dioxy are represented by

* examples VIII, XVIII and XIX. R

. 9. Compounds in which Z is a group of the formula -RR "and wherein R" is a nitrogenous heterocycle from the group of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl or benzothiadiazolyl and the alkyl and halogen substituted derivatives thereof are represented by the examples

VI, XXX, XXXVII, -XXI, XXII, XIII, XIV, and XXIII. R

,. ,. 10. Compounds in which Z is a group of the formula -HR "and in which R" is a butyrolactonyl group, an adamantyl group or a mono-alkoxy-substituted phenyl group are represented by Examples VII, XXXVI and XXXV. -3. 1 "11. Compounds in which Z is a group of the formula -NR" and R "is a substituted alkyl group selected from mercaptoalkyl, carboxyalkyl, mono-, di- or tri-alkoxyalkyl, alkylthioalkyl and alkoxycarbonyl-25 substituted derivatives thereof, cyanoalkyl, mono-, di- and tri-alkoxy-phenylalkyl, phenylcycloalkyl, 1-pyrrolidinylalkyl, R-alkylpyrrolidinyl-alkyl, isimorpholinylalkyl and dialkylaminoalkyl, are represented by examples XVI, XXXIII, XXIV, XXXIV, XV, XXXII, XXXIX, XI, XXV, IX, XXXVIII, XII, XX, X, XXXI and XL.

Finally, it is noted that the use of the compound according to Example XXVI is included in the description of the use of compounds of the formula la in the old application. This compound is not covered by the present formula Ila.

The present compounds, like the compounds known from the older application, have a good antibacterial activity against 8200339 ................

% - 22 - grain-positive and gram-negative microorganisms in the same manner as has been observed for the natural mitomycins and kuxmen, so they are used in therapeutics to combat bacterial infections in humans and animals.

The utility of the compounds of the formula Ha in combating neoplastic diseases is demonstrated by the in vivo results of some experiments in which the compounds were administered in varying amounts to mice infected with P338 leukemia. These tests were performed according to "Lymphocytic 10 Leukemia Ρ33δ - Protocol 1,200" published in Cancer Chemotherapy Reports. Vol. 3, Vol. 3, No.2, p. 9 of September 1972. Briefly, these tests included administration of the test compound to female CDF mice previously infected with 10 ascites cells implanted intraperitoneally. . The test compounds were administered only on the first day of the test and the animals were monitored for survival over a 35 day period.

The results of these tests with compounds of Examples I - XLI are shown in the following Table A. The figures include optimal doses (OD} ie dosages in mg per kg body weight of the animal with maximum therapeutic effects consistently observed. Also, the mean survival time (MST) is expressed as the survival time of the test animals compared to the survival time of controls x 100 {% T / C.). In the context of this in vivo P388 procedure, a% T / C value of 125 or more shows significant antineoplastic therapeutic activity. The lowest dose in mg per kg body weight giving a 125 #'s T / C value is known as the minimum effective dose (MED). This dose is also shown in Table A. It is important that the markedly high MST values obtained with the present P308 tests shown in Table A also indicate an absence of a heavy toxicity of these compounds at the doses shown.

8200839 - 23 -

Table A

Example Optimal dose of MST MED

mg / kg as% T / C

I 12.8 339 0.2 5 II 3.2 211 0.4 III 12.8 150 .0.8 IV 6.4 211 0.2 V. 6.4 178 0.4 vi 25.6 144 12.8 10 VII 6.4 175 0.8 VIII 25.6 255.

IX 25.6 239 x '12.8 217 0.8 XI * 6.4 131 3.2 15 XII 12.8 217 L »6 XIII 25.6 178 1.6 xrv 12.8 222 0.8 XV 6 .4 200 0.8 XVI 12.8 313 <0.2 20 XVII '6.4 172 0.4 XViii 6.4 134 1.6 XIX 3.2 167 <0.2 XX 12.8 194 0.4 XXI 12.8, I83 0.2 25 τπγγτ 25.6 206 0.2 XXIII 12.8 l6l 0.8 XXIV 6.4 261 0.4 XXV 6.4 232 0.5 XXVI 6.4> 316 0, 4 30 XXVII 12.8 2l6 0.2 XXVIII 25.6 26I 0.2 XXIX 3.2 26I <0.2 XXX 25.6> 333 0.8 ττπ 25.6 150 6.4 35 XXXII 12.8 205 ls6 8200839 - 24 -

Table A (continued) XXXIII 25.6 170 1.6 XXHV 12.8 205 0.8 XXXV 12.8> 316 0.8 '5 XXXVI 25.6 132 6.4 XXXVII 12.8 172 3 * 2 XXXVIII 25 , 6 188 1.6 XXXIX 25.6 200 6.4 XL 12.8> 211 0.4 10 XLI 12.8> 211 <0.2

It is understood that the most preferred present compounds as antineoplastic agents are each giving a relative life extension greater than two-fold of the relative life extension usually considered therapeutically significant, ie, those with an MST # T / C value greater than 2 x 125. These compounds include the compounds of Examples I, VIII, XVI, XXIV, XXVI, XXIX, XXX, and XXXV.

As shown in Table A, initial single doses of no more than 0.2 mg per kg already show a marked long-term anti-neoplastic activity. The method of the invention therefore comprises a therapeutic administration of unit doses from 0.001 mg to e.g. 5 mg, preferably from 0.004 mg to 1.0 mg, of the compounds as an active ingredient within an appropriate pharmaceutical composition. Such formulations can be administered up to a daily dose of 0.1-100 mg per kg, most preferably 0.2-51.2 mg per kg body weight of the animal suffering from a neoplastic disease. Preferably, the compounds are administered parenterally. Pharmaceuticals suitable for use in the process of the invention may be formed by simple aqueous solutions 301 of one or more of the compounds of formula Ha, but may also contain known diluents, excipients and / or carriers, such as physiological saline solutions and of such.

The invention is further defined by the following claims.

8200839

Claims (6)

1. Compounds of the formula II of the formula sheet, wherein Y is hydrogen or alkyl, and X is an alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylamino group, or a mono- or di-alkyl-substituted thiazolamino group, or a nitrogen-containing heterocycle from the group 1-pyrrolinyl, 1-indolinyl, 1-thiazoladinyl and 1-thiomorpholinyl, or a 1-aziridinyl group substituted with cyano, phenyl, carboxamido or alkoxycarbonyl, or a 1-piperazinyl group substituted with alkyl, formyl or acetylphenyl or a hydroxyl or piperidyl-substituted 1-piperidyl group, or an alkoxy, amino or halogen-substituted pyridylamino group, or an carboxamido, mercapto or methylenedioxy-substituted or R represents a group of the formula -RR wherein-. R is hydrogen or alkyl, and R 'is a nitrogenous heterocycle from the group of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thia-diazol yl and benzothiadiazolyl, and the alkyl and halogen substituted derivatives thereof, 1S 'or a butyrolactonyl group, or an adamantyl group, or a substituted alkyl group selected from mercaptoalkyl, mono, dien trialkoxyalkyl, alkylthioalkyl and alkoxycarbonyl substituted derivatives thereof , cyanoalkyl, mono-, di- and tri-alkoxyphenyl-alkyl, phenylcycloalkyl, 1-pyrrolidinylalkyl, X-alkylpyrrolidinylalkyl and Ti-morpholinylalkyl » The following compounds according to claim 1: 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cy-30--1- aziridinyl) -azirino 2 ', 2', 3 ': 3, pyrrolol / T 1,2,2-indol-1, T-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thio-8200839 -26-morpholinyl) -azirino / * 2 ', 3': 3 JpyrroloZ "1,2-a Jindole-7,7-dione carba size; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - (1-in-dolinyl) -azirino / 2 ', 3': 3'-pyrrolo / '1,2-a-7indole-U, 7-dione carhamate; 5 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / "(6-thoxy-3-pyridyl) amino-7-azirino /" 2 3, 3, 3, pyrrolo, 1,2-a-7-indole-7-dione carhamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - / "(6-methoxy-8-quinolinyl) amino J-azirino / T2 ', 3 3,4-pyrrolo-1,2-a-J7in-10-diol-7-dione carhamate; 1.1 a, 2,8,8a, 8h-hexahy dro-8- (hydroxymethyl) -8a-meh hoxy- 5 -methyl- 6- (3-chin-nuclidinylamino) -azirino 2 ”21,3 ': 3,1'-pyrrolo / 1,2-a-Jindole, 7-dione-carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2-15 (/ * - butyrolactonyl) amino J-azirino / * 2 ' 3 ': 3,3-pyrrolo [1,2-a] indole-4,7-dione carhamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (il -carboxamidoanilinoj-azirino / * 2 ', 3': 3 'pypyrolo /' 1,2-a Jindole-U, 7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-dimethoxybenzylamino) azirino / "2 ', 3': 3, Jpyrrolo / - 1,2-a Jindole, 7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) - 8a-met hoxy-5-met hy 1-6 - / * (1-ethyl-2-pyrrolidino) methylaminoJ-azirino / "2 ', 3': 3, Jpyrrolo [1,2-a J 25 indole · ^ 7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / r (1-methoxycarhonyl-3-methylthio) propylamino J- azirino / * 2 ', 3': 3,3 Jpyrrolo / 1,2-a Jindole, 7,7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a- methoxy-5-methyl-6- (2-30-phenylcyclopropylamino) -azirino / "2 ', 3 ^ 3, 3-pyrroloβ., 2-a-indole, 7-dione carhamate; 1.1 a, 2.8,8a, 8h-hexahydro -8- (hydroxymethyl) -8a-methoxy-5-methyl 1-6- / (5-chloro-2-henzoxazolyl) amino J-azirino / 2 ', 3': 3, pypyrolo / 1,2-a Jin-1001-¾, 7-dio n carhamate; 35 1,1as2s8,8as 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-yT 5-8200839-27-methyl-2- (1,3, U-thxadiazolyl) amino 7- azirino / "2 ', 3': 3, 1/4 pyrrolo / 1,2-a J-indole-if, 7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) -azirino / '2', 3 ': 3,4¼ pyrrolo / 7 1,2-a-7indole, 7-5 dione carhamate; 1 * 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-mercaptoethylamino) -azirino / ~ 2 ', 3': 3, 7 'pyrrolo / ” 1,2-a-indole-1,7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-84-cycloxymethyl) -8a-methoxy-5-methyl-6- / "(h-10 methyl -2-thiazolyl) amino-2-azirino] -S 3, 3: 3,4-pyrrolo-1,2-indol-7,7-dione carhamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (mercaptoanilino) -azirino / 72 ', 3': 3-7 pyrrolo / Tl, 2-a J-indole, 7-dione carhamate; 1.1 a, 2.8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl6- (3'-methylenedioxyanilino) -azirino "2,3,3: 3, ¼ J7pyrrolo 1,2-a-JindoleA, 7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-i-2- (1 pyrrolidino) ethylamino J7-azirino / 2 ', 3': 3, 1/4 pyrrolo / 1,2-a-indole-20 7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahyro-8- (hydroxymethyl) -8a-methoxy-5-methyl6- (5-iso-quinolinylamino) -azirino / * 2 ', 3': 3,4¼ J7pyrrolo C 1,2-a J indole 7,7-dione carhamate; 1,1a a 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-25 indazolylamino) -azirino / "2 ^ 3 ^: 3 ^ - ^ 3 ^^) 10 / 71.2 ^ .7indole · ^, 7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahyro-8- (hydroxymethyl) -8-a-methoxy-5-methyl 1-6- / 7 ^ (2,3,3-benzothiadiazolyl) amino.7-azirino £ '2', 3 ': 3,4¼ pyrrolo * 1,2-a 1-indole ^ 7-dione carhamate 1,1a, 2s8,8a, 8h-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyanoethylamino) -azirino / ~ 2 *, 3 ^ 3, 1/4 pyrolojT 1 1,2-a. Jindole, 7,7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T 1- (3 -pyrrolinyl) _7-azirino / 72 ', 3': 3¼ Jpyrrolo / '1,2-a J indole · 7,7-dione 35 carhamate; 8200839-28-1,1a, 2,8,8a, 8b -hexahydro-8- (hydroxymethyl) -8-methoxy-5-methyl-6- (3-thiazolidino) -azirino / 72 '. 3': 3-Pyrrolo-T 1,2-a-7indole-k, 7-dione carbamate 1.1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - / - 1 - 5 (--methylpiperazino) -azirino / * 2 ', 3' : 3, ^ - 7pyrrolo / T 1,2-a-7indole - ^, 7-dione carbamate; 1.1a, 2, 8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 73-pyrazolyl) amino J7-azirino "21,3": 3-pyrrolo / 1,2-a-7-indole -U, 7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-Z "2- (N-morpholino) ethylamino ^ 7-azirino /" 2 ", 3 ': 3 Jpyrrolo, 1,2-a, J-indole-4,7-dione carbamate; 1.1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl -β -, / Γ 2- (ethylthio) ethylamino -7-azirino / T2 *, 3 ': 3, ^ _ 7pyrroloZ ”1,2-a Jindole- 15 U, 7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-with goxy-5-methyl-6- (2-methoxyethylamino) -azirino * 2 ′, 3 ′: 3, ZJZpyrroloZ "1,2-a J-indole - ^, 7-dione carbamate; 1.1 a, 2.8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6-20 (2-mercaptoethylamino) -azirinoZ ~ 2 ', 3': 3'-Pyrrolo'-1,2-a-Jindole-U, 7-dione carbamate; 1,1a, 2,8,8a-8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-ada-mantylamino-azirino] 2 ', 3': 3,3 '/ pyrrolo-1,2-aindol-1 +, 7-dione carbamate; 1.1a, 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-Z71- (1,3% triazolyl) amino J7-azirino £ 2 ', 3' 3, ^ pyrroloC1,2-a-7indole-7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3, ^ 5-trimethoxybenzylamino) -azirino / T 2 ', 3': 3, J 7 pyrrolo [1,2-a-7 indole-U, J-30 dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy-1,5- = dimethyl-6-C2- (ethylthio) ethylamino J-azirinoZT2 ', 3': 3, ¾ J'pyrroloZ "1,2-a Jindole-h97- dione carbamate, 1.1a, 2.8,8a, 8b-hexahydro -8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-35 (3-hydroxypiperidyl) J-azirino / T2 ', 3': 3, 3'pyrroloi '1,2-a JindoleTU, 7-8200839-29-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2-phenyl-1-aziridinyl) -azirino 2 ', 3': 3, U Pyrrolo / 1,2-a Jindole-U, 7-dione earbane; 5 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2-methoxycar- bonyl-1-aziridinyl) -azirinoΖΓ2 ', 3': 3½-7pyrrolo / T 1,2-a Jindool-il, 7-cli-one carbamate; 1.1 a, 2.8,8a, 8b-hexahydro-8 - (hydroxymethyl) -8a-methoxy-6- (2-arboxami-do-1-aziridinyl) -azirino 2 ', 3 ^ 3, ½-7pyrrolo / * 1,2-a_7indole- ^ 7-dione 10 carbamate; 1.1 a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (U-formyl-1-piperazinyl) -azirino / f2f, 3 ': 3, ½_7pyrrolo 1,2 1.2- a7indole-it, 7-dione carbamate; 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6-acetylphenyl-15 l-piperazinyl] -azirino, 3 ': 3, 1/2 pyrrolo / 1 , 2-a-7indole, 7, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (1-piperidyl) -1-piperidyl) J-azirino / "2 '93' 1,3,5-pyrrolo [1,2-a] indole - - di-one carbamate; 20 l, 1a, 2,8,8a, 8b-hex8hydro-8- (hydroxymethyl) -8a-methoxy-6- / '( 6-chloro-3-pyridyl) amino .J-azirino / T 21.31: 3, ½ .pyrrolo ^ T 1,2-a Jindole-4,7-dione carbamate; 1.1a, 2.8; 8a, 8b- hexahydro-8- (hydroxymethyl) -8a-metropyl-6- (6-amino-3-pyridyl) amino-7-azirino 2, 3, 3, ½ Jpyrrolo / "1,2-a. jindole · ^ 7-dione carbamate; 1.1 a ^ 2,8,8a, 8b-Hexabydro-8- (hydroxymethyl) -8a-methoxy-6-, 1,5-dimethyl-2-thiazolyl) amino J7-azirino * 2,3 '* : 3.5 Jpyrrolo / T1,2-α-7indole-½, 7-dione carbamate; 1,1a, 2,8; 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-metboxy-6-i "(4-cyano-3-30 pyrazolyl) amino, 7-azirino * 2 ', 3 1,3-pyrrolo [1,2-a] indole, 7-dione carbamate. 3- A method of treating a neoplastic disease condition in an animal, characterized in that the animal with such a disease is administered with a therapeutically effective amount of a compound of the formula Ha, wherein Y is hydrogen or alkyl, and Z 8200839-30 - an alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylamino group, or a mono- or di-alkyl-substituted thiazolamino group, or a nitrogen-containing heterocyclic group in the form of 1-pyrrolinyl, 5-indolinyl, N- thiazoladinyl, N-morpholinyl, 1-piperazinyl or N-thio-morpholinyl, or a cyano, phenyl, carboxamido or alkoxycarbonyl substituted 1-aziridinyl group or an alkyl, formyl or acetylphenyl substituted 1-piperazinyΙ-ΙΟ group or a hydroxyl or piperidyl substituted 1-piperidyl group or an alkoxy, amino or halogen substituted pyridylamino group, or a carboxamido, mercapto or methylenedioxy substituted the anilil 15 group, or R represents a group of the formula -NR ", wherein R represents hydrogen or alkyl, and R" represents a nitrogen-containing heterocycle in the form of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thia -diazolyl or benzothiadiazolyl and the alkyl or rhalo-substituted derivatives thereof is either a butyrolactonyl group, or an adamantyl group, or a monoalkoxy-substituted phenyl group or a substituted alkyl group in the form of mercaptoalkyl, carboxyalkyl, mono-, di- and Trialkoxyalkyl, alkylthioalkyl and alkoxycarbonyl substituted derivatives thereof, cyanoalkyl, mono-, di- and tri-alkoxyphenylalkyl, phenyl-cycloalkyl, 1-pyrrolidinylalkyl, N-alkylpyrrolidinylalkyl, 1-morpholinylalkyl or di-alkylaminoalkyl. U. Method according to claim 3, characterized in that the compound used is selected from one of the following compounds: 1, 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5 -methyl-6- (2-cy-on-1-aziridinyl) -azirino2 * 2r, 3 ': 3, J 7 pyrrolo,, 1,2-a Jindol, 7-dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (thio-35-morpholinyl) -azirinoZ "2 ', 3': 3, 7'-pyrrolo. 1,2-a IJ indole, T-dione carba- 8200839-31 - size; 1.1a, 2.8,8a, 8b-hexahydro-8- (hydroxymethyl) -o-methoxy-5-methyl-6- (1-in-dolinyl) -azirino £ ”2 ', 3': 3 'b J-pyrrolof 1,2-a-7indole-1), 7-dione carba size; 5 1, 1a, 2,8,8a 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-; f (6-methoxy-3-pyridyl) amino J7-azirino / * 2 ', 3 ^ 3, Jpyrrolo * 1 1,2-a'indole-7,7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-, (6 -methoxy-8-quinolinyl) amino .J-azirinoZ '2', 3 ': 3, -7-pyrrole / 1,2-a 7in-10 maze-4,7-dione carhamate, 7.1a, 2, 8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-quinuclidinylamino) -azirinoZ 2 *, 3 ^ 3, 7-pyrrolo-1,2-a Jindole- U, 7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T 2-15-butyrolactonyl) amino J7-azirinoZ * 2 *, 3 ': 3-7 pyrrolo2 * 1,2-a-7indole-7-dione carhamate; 1.1 a, 2.8 9 8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-carboxamidoanilino) -azirino - / ”2 ', 3f: 3, - 7-pyrrolo / 1,2-a-7indole-7,7-dione carhamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,3dimethoxyhenzylamino) -azirino / ,2,3 *; 3,3- 7pyrrolO) T 1,2-a Jindole-H, 7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahy dro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-jT (1-ethyl-2-pyrrolidino) methylamino J7-azirino / T 2 * 3 ': 3, 7-pyrrolo-1,2-a-J-25 indole-U, 7-dione carhamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (faydroxymethylJ-8a-methoxy-5-methyl-6-Z '(1-methoxycarhonyl-3-methylthio) propylamino-7-azirinoZ ~ 2 *, 3 * : 3, 7-pyrro-10Z * 1,2-a7-indole-7,7-dione carhamate; 1,1a, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-with hyl- 6- (2-30 phenylcyclopropylamino) -azirino ^ 2 ', 3': 3, J'pyrrolo / 1,2-a 7indole - ^ 7-dione carhamate; 1.1 a, 2.8,8a, 8h- hexahy dro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-chloro-2-henzoxazolyl) amino7-azirino / '2 *, 3 *: 3, pypyrolo or 1,2- α-7-dole-4,7-dione carhamate; 1,1 α, 2,8,8a, 8h-hexahydro-8- (hydroxymethyl] -8a-methoxy5-methyl-6- 5-5-me-82 0 0839 ..............-- - 32 - thyl-2- (1,3, Wfchiadiazolyl) amino J7-azirinoZ ”21,3 ': 3, b J7pyrrolo Γ1,2-a J indool-i), 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8 a-methoxy-5-methyl-6- (2,2-dimethoxyethylamino) azirinoZ ~ 2 ', 31: 3, b_7pyrrolo / ~ 1,2-a. 7indole-4,7-5 dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethylJ-8a methoxy-5-methyl-6- (2-mercapto thylamino-azirino * 2 ', 3': 3'-pyrxol [2 -7-indole-U, 7-di-one carbamate; 1,1a, 2,8,8a, öb-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / T (11-10 methyl-2-thiazolyl) amino J-azirinoZ "2 ' 31: 3 Pyrrolo [1,2-a-7 indol-7-di-on arbamate; 1.1 a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-mercaptoanilino) -azirino / T2 ', 3': 3, 7-pyrroloZTl, 2- a Jindole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl-8a-methoxy-5-methyl-6- (3'-methylenedioxyanilino) -azirinoZ * 2 ', 3': 3 ' 1,2-a-Indole-1,2-dione-carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxyethyl) -8a-methoxy-5-methyl-6- / 2- ( 1-pyrrolidino) ethylamino J7-azirino / 2 ', 3': 3-7pyrroloZ "1,2-a-indole-20 µl, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy- 5-methyl-6- (5-isoquinolinylamino) -azirino £2 ', 3 ′: 3,4 ¼ J7pyrroloZ 1,2 1,2-a-7 indole-i +, 7-dione carbamate 1.1 a. 2.8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (5-25 indazolylamino] azirinoZ "2 ', 3': 3, ¼-7pyrrolo /" 1 1,2-a-Jindole-7,7-dione carbamate; 1.1 a, 2.8,8a, b-hexahydro-8- (hydroxymethyl} -8a-methoxy-5-methyl 1-6- / "U- (2, 1,3-benzothiadiazolyl) amino.J-azirinoj 2 ', 3': 3,1¼ J7-pyrrolo, 1,2-a 7-indol-U, 7-dione carbamate; 1.1 a, 2.8 8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (N-glycinyl) -azirino £2,, 3 ′: 3, ¼Jpyrrolo / T 1,2-αindole -li, 7-dione carbam aat; 1.1 a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (2-cyanethylamino) -azirinoZT2r, 3 ': 3, ¼-7pyrrolo 1, 2-alpha-indole, 1,5-dione carbamate; 8200839 - 33 - 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Oa-methoxy-5-methyl-6-, 1- (3-pyrrolinyl) J-azirino / "2 ^ 3 ^ 3, ¾- / pyrrolo / -1,2-a Jindole-4,7-dione carbamate; 1 µl 1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -o-methoxy- 5-Methyl-6- (3-5 thiazolidino) -azirinoZT2 ', 3': 3 'pyrrolo [1,2-a] indol-1, 7' - (1-carbamate; 1,1a, 2, 8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-β - (^ methylpiperazino; J'-azirino / T 2 ', 3': 3, ¼ Jfcyrrolo / '1, 2-a-J-indole - ^, 7-dione carbamate; 10 1,1 a, 2,8,8a, 8b-hexahyro-8- (hydroxymethyl) -8a-metboxy-5-methyl-6-yl-3 - (pyrazolyl) amino J-azirino / T 2 ', 3 *: 3-7-pyrrolo / T 1,2-a-7indole-U, 7-dione carbamate; 1.1 a, 2.8,8a-8b-hexahydro- 8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - / - 2- (1-morpholino) ethylamino JT-azirinoZ * 2 ', 3': 3 ', JpyrroloZ. ”1,2-a Jindole- 4.7-15 dione carbamate; 1.1 a, 2.8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methyloxy-5-ethylethyl 1-6- / "2- (ethylthio) ethylamino J-azirino £ * 2 *, 3 ': 3, Jpyrrolite 1,2-a Jindole-4,7-dione carbamate; 1.1 a, 2,8,8a, 8b-hexahyro-8- (hydroxymethyl) -8a-methoxy-1,5-dimethyl-6- 20 (2-mercaptoethylamino) -azirinoΖΓ 2 ', 3': 3, ¼ J7pyrrolo 1,2-a-Jindole-7,7-dione carbamate; 1.1 a, 2,8,8a, 8b-hexahyro-8- (hydroxymethyl J-8a-methoxy-5-methyl-6- (2-methoxyethylamino} azirino) 2 T, 3 ^ 3, ¼ J7pyrrolo ƒ "1,2-a" 7indole-k, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl J-8a-methoxy-5-methyl-6- (i +) methoxyanilino) -azirino / T2 ', 3': 3'-7-pyrroline 1,2-a-zindole - ', 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl J -8a-methoxy-5-methyl-6- (1-adamantylamino) -azirino / T2 ', 3': 3, 7-pyrrolo 2 "1,2-a] indol- * 5-dione 30 carbamate. 1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-meth.oxy-5-methyl-6-1-(1,3,3-triazolyl) amino J7-azirino "2", 3 ': 3,3-pyrrolo-1,2-a-7indole-7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl] -8a-methoxy-5- methyl-6- (3,4,5-, trimethoxybenzylamino) -azirinoC 2 ', 3': 3, 3'-pyrrolo / "1,2-a. jindole-U, 7- 82 0 0 8 3 9. .............. - 3fc - dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (HycLroxymethyl) -8a-methoxy-1,5-dimethyl- 6 - ^ - (ethylthiojethylamino J-azirino ^ 2 ', 3': 3, ^ 7 pyrrolo / "1,2- a Jindole-7-dione carbamate; 5 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 2- (dimethylamino) ethylamino-7-azirinoZ "2 ', 3': 3 J 7 pyrrolo [1,2-a] J indol-if 7,7-one-carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- / 1- (3-hydroxypiperidyl) / -azirino / "2 ', 3' : 3, 7-pyrrolo2-1,2-a-indole-U, 7-10 dione carbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2-phenyl-1-azidridinyl) -azirino * 2 ', 3': 3, 1/4 Pyrrolo 1,2-a-indole-k, 7-dione carbamate; 1.1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl} -8a-methoxy-6- (2-methoxycarolyl-1-az iridinyl) -az irino / "2", 31: 3 U * 7pyrrolo / 1,2-a Jindole-U, 7-di-one carbamate; 1.1 a, 2.8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (2- c arb oxami do-1-aziridinyl) -azirino 2 ', 3': 3, 3 pyrrolo / T 1,2-a-7indole-U, 7-dione carbamate; 1.1 a, 2.8,8a, 8b- hexahy dro-8- (hydroxymethyl) -8a-methoxy-6- (N-morpholinyl) -20 azirino / 2 ', 31: 3, 7-pyrrolo / T 1,2-a-7indole-1 *, 7-dione cabbamate; '1.1a, 2 »8.8a, 8b-hexahydr o-ö- (hydroxymethyl) -8a-methoxy-6- (1-piperazinyl) -azirino /" 2', 3 ': 3, 1/4 PyrroloZ " 1,2-a7indole-i +, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- (Uf ormyl-1-piperazinyl) -azirino 2 ”2 ', 373, ¼ JpyrroloZT 1,2-a Jindole-U, 7-dion carba-25 gauge; 1.1 a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6 - (4-acetylphenyl-1-piperazinyl) -azirinOif2?, 3 ': 3, - 7-pyrroloZr1,2-a-7indole - ^, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8 - (hydroxymeth yl J-8a-methoxy-6- / T ^ - (1-piperi-30 dyl) -1-piperidyl-7-azirino / T 2 ', 3 ^ 3, 1/4 pyrrolo / - 1,2-a-indole-H, 7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl-8a-methoxy-6- (6-chloro-3-pyridyl) aminoJ7-azirinOiT 2 ', 3': 3, ¼-7pyrrolo 1,2-a-7 indole-7,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- / T (6- amino-3- 8200839 -35- ✓ - ft pyriityl) amino JZ-azirino ^ 2 ^ 31: 3, U-7 pyrrolo / 1,2-a indole-4,7-dione carbamate; 1,1a, 2,8 , 8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6- / r (^, 5-dime-thyl-2-thiazolyl) aminoI7-azirino - / "2 ', 3': 3, ^ _ 7ρυγγο1οΖ 1,2-a-7indole-5 T-dione carbamate and 1,1a, 2,0,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-6-, r (i + -cyano-3-pyrazolyl) amino-7-azirino / T2 ', 3': 3, 4J-pyrrolo / T 1,2-a Jindole-1, 7-dione carbamate. Method according to claim 3, characterized in that the amount to be administered corresponds to a daily dose of about 0.2 mg to about 51.2 mg per kg body weight of the animal. 6. Pharmaceutical composition for the treatment of a neoplastic disease in an animal, characterized in that this composition contains a pharmaceutically suitable solvent, diluent, excipient or carrier, and as active ingredient 0.001-5 mg of a compound of the formula III of the formula sheet, wherein Y is hydrogen or alkyl, and 2 is an alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylamino group or a mono- or di-alkyl-substituted thiazolamino group, or a nitrogen-containing heterocycle in the form of 1-pyrrolinyl, 1-indolynyl, 1-thiazoladinyl, 1-morpholinyl, 1-piperazinyl and N-thiomorpholinyl, or 1-aziridinyl group substituted with cyano, phenyl, carboxamido or alkoxycarbonyl, or one with alkyl, forayl or acetylphenyl-substituted 1-piperazinyl group or a hydroxyl or piperidyl-substituted 1-piperidyl group, or an alkoxy, amino or halogen-substituted pyridylamino group, or a carboxamido, mercapto or methylenedioxy substituted anilane group, or R represents a group of the formula -NR ", wherein R is hydrogen or alkyl and R" is a nitrogen-containing heterocycle in the form of ehinuclidinyl, pyrazolyl, 1-triazolyl, isoehinolinyl, indazolyl , benzoxazolyl, thia-diazolyl and benzothiadiazolyl as well as the 8200839 tr e. - 36 - substituted derivatives thereof, or a butyrolactonyl group, or an adamantyl group, or a monoalkoxy-substituted phenyl group, or a substituted alkyl group, the latter in the form of mercaptoalkyl, mono-, di- and tri-alkoxyalkyl, alkylthioalkyl and alkoxy carbonyl-substituted derivatives thereof, cyanoalkyl, mono-, di- and tri-alkoxyphenylalkyl, phenylcycloalkyl, 1-pyrrolidinylalkyl, N-alkyl-pyrrolidinylalkyl, N-morpholinylalkyl and dialkylaminoalkyl. 10 8200839