KR900006854B1 - Mitomycin analoges - Google Patents

Abstract

6-Amino mitomycin derivs. of formula (I) are prepd. by reacting a amine cpd. of formula-NRR1 with mitomycin A or N-alkyl mitomycin A. In (I), Y= H or lower alkyl; X= anilino substd. with acetamino, acetyl, carbamido, CN or carboxy, or -NRR1; R= H or lower alkyl; R1= N contg. heterocyclic radical or substd. lower alkyl. (I) are useful for treatment of neoplastic disease in animals, with structures simimar to mitomycins and has antibiotic activity as well as antitumour activity.

Description

Mitomycin analogues and methods for their preparation

The present invention relates to an antibiotic mitosan compound, which is a mitomycin analogue useful for the treatment of neoplastic disease in an animal, and a method for preparing the same. Published US Patent No. 4,268,676, filed November 13, 1980, co-pending US Patent Application No. 206,529: and commonly pending US Patent Application No. 264,187, filed May 15,1981 Reference is made throughout this specification to provide the necessary and non-essential materials related to the invention.

In summary, the aforementioned U.S. Patent No. 4,268,676 and co-pending U.S. Patent Application No. 206,529 are structurally related to mitomycin, have antibiological activity, are low in toxicity, and exhibit significant antitumor activity in animals. It describes the ongoing research in the art for new and useful compounds.

In more detail, published US patents and patent applications describe new compounds having the structure of Formula (I):

Wherein Y is hydrogen or lower alkyl and X is a thiazoleamino radical, a furfurylamino radical or a radical of the formula:

Wherein R, R ¹ and R ² may be the same or different and are selected from hydrogen and lower alkyl, R ³ is lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxy carbonyl, thienyl, form Amyl, tetra hydrofuryl and benzenesulfonamide).

The aforementioned U.S. patents and pending patent applications also show new methods for treating neoplastic diseases in animals, which administer a compound of formula (Ia) in an effective amount from a therapeutic point of view.

Wherein Y is hydrogen or lower alkyl: Z is a thiazoleamino radical, furfurylamino radical, cyclopropylamino radical, pyridyl amino radical or a radical of the formula

Where R ⁴ .R ⁵ and R ⁶ may be the same or different and are selected from hydrogen and lower alkyl, R ⁷ is lower alkenyl, halo-low alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower Alkyl, hydroxy-loweralkyl, pyridyl, thienyl, formyl, tetrahydrofuryl, benzyl and benzene sulfonamide).

Co-pending US patent application No. 264,187 also describes compounds having significant antitumor activity in animals, which have the structure of Formula (IIa).

의 라디칼 (

식에서 R은 수소나 저급알킬이고, R¹는 퀴누클리디닐, 피라졸릴,1-트리아졸릴, 이소퀴놀리닐, 인다졸릴, 벤즈 옥사졸릴, 티아디아졸릴 및 벤조티아디아졸릴 중에서 선택된 질소를 함유하고 있는 헤테로고리 라디칼과, 저급 알킬 및 할로가 치환된 이들의 유도체 이다)이거나, 또는 부티로락토닐 라디칼, 또는 아다만틸(adamantyl) 라디칼, 또는 모노-저급 알콕시가 치환된 페닐 라디칼, 또는 메르캅토 저급알킬, 카르복시 저급알킬, 모노-저급 알콕시 저급알킬, 디 -저급알콕시 저급알킬, 트리 -저급 알콕시 저급알킬, 저급 알킬 티오 저급알킬 및 저급 알콕시카르보닐이 치환된 이들의 유도체, 시아노 저급알킬, 모노-저급 알콕시 페닐 저급알킬, 디-저급 알콕시 페닐 저급알킬, 트리-저급 알콕시 페닐 저급알킬, 페닐 시클로 저급알킬,1-피클리디닐 저급 알킬, N-저급알킬 피롤리디닐 저급알킬, N-프로폴리닐 저급알킬 및 저급 디알킬아미노 저급 알킬 중에서 선택한 치환된 저급 알킬 라디칼이다.Wherein Y is hydrogen or lower alkyl: Z is a quinolinylamino radical substituted with lower alkoxy, a pyrazolylamino radical substituted with cyano or a thiazoleamino radical substituted with mono- or di-lower alkyl, or 1 A heterocyclic radical, or cyano, containing a nitrogen selected from -pyrrolinin, 1-indolinin, N-riazolidinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl radicals, 1-aziridinyl radicals substituted with phenyl, carboxadona or lower alkoxy carbonyl, or 1-piperazinyl radicals substituted with lower alkyl, formyl or acetylphenyl, or 1- substituted with hydroxy or piperidyl Piperidyl radicals or pyridyl amino radicals substituted with lower alkoxy, amino or halo, or anilin radicals substituted with carboxado, mercapto or methylenedioxy, or a formula

Radicals (

Wherein R is hydrogen or lower alkyl, R ¹ contains nitrogen selected from quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benz oxazolyl, thiadiazolyl and benzothiadiazolyl Heterocyclic radicals and derivatives thereof substituted with lower alkyl and halo), or butyrolactyl radicals, or adamantyl radicals, or phenyl radicals substituted with mono-lower alkoxy, or mercapto Lower alkyl, carboxy lower alkyl, mono-lower alkoxy lower alkyl, di-lower alkoxy lower alkyl, tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and derivatives substituted by lower alkoxycarbonyl, cyano lower alkyl, Mono-lower alkoxy phenyl lower alkyl, di-lower alkoxy phenyl lower alkyl, tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, 1-picridinyl lower alkyl, N- Lower alkyl pyrrolidinyl lower alkyl, N-propolinyl lower alkyl, and lower dialkylamino lower alkyl.

Besides this. Reference is made to the following for reference to the present invention. US Patent No. 3,332,944 to Cosulich et al., US Patent No. 3,410,867 to Matsui et al .; US Patent No. 4,231,936 to Nakano et al .; US Patent No. 3,429,894 to Matsui et al .; US Patent No. 4,268,676 to Remers et al .; US Patent No. 3,450,705 to Matsui et al .; US Pat. Nos. 3,514,452 to Matsui et al. And Gann, 71, PP. 560-562 (1980) to Imai et al.

(이 식에서 R 및 R¹은 아래에서 정의하는 바와같다)의 아민과 반응시켜 일반식(III)의 화합물을 생성시킨 후 반응 혼합물로 부터 이를 분리함으로써 얻을 수 있다.The present invention relates to mitomycin analogs of general formula (III) and methods for their preparation, which formulate mitomycin A or N-alkyl mitomycin A

It can be obtained by reacting with an amine of the formula in which R and R ¹ are as defined below to give the compound of formula III, and then separating it from the reaction mixture.

의 라디칼이다.In which Y is hydrogen or lower alkyl; X is a hydroxycar substituted 1-pyrrolidinyl radical, or a piperidyl radical substituted with lower alkyl, or acetoamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro or The sulfur mill is a substituted anilino radical, or

Is a radical.

중에서 R은 수소나 저급 알킬이고, R¹은 아미노가 치환된 트리아졸릴, 저급 알킬이 치환된 이소티아졸릴, 벤조티아졸릴 및 니트로와 할로가 치환된 벤조티아졸릴의 유도체 중에서 선택한 질소를 함유하고 있는 헤태로 고리 라디칼이거나, 또는 아미노 저급알킬. 저급 알킬아미노, 저급 알킬, 히드록시 저급알킬아미노 저급 알킬, 히드록시 저급알콕시 저급 알킬, 이미다졸릴 저급 알킬, 니트로가 치환된 이미다졸릴 저급알킬, 모노-히드록시페닐 저급알킬, 디-히드록시 페닐 저급알킬, 니트로가 치환된 피리딜아미노 저급알킬 및 피페라지닐 저급알킬 중에서 선택한 치환된 저급 알킬 라디칼이다).(expression

Wherein R is hydrogen or lower alkyl, and R ¹ contains nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl and derivatives of benzothiazolyl substituted with nitro and halo. Heterocyclic ring radicals or amino lower alkyl. Lower alkylamino, lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro-substituted imidazolyl lower alkyl, mono-hydroxyphenyl lower alkyl, di-hydroxy Phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.

In addition, a therapeutically effective amount of a compound of formula (IIIa) in the compound of the present invention may be administered to treat an animal's neoplastic disease.

의 라디칼이다.(식

에서 R은 수소나 저급 알킬이고, R¹은 아미노가 치환된 트리아졸릴, 저급 알킬이 치환된 이소티아졸릴, 벤조티아졸릴 및, 니트로와 할로가 치환된 벤조티아졸릴의 유도체 중에서 선택된 질소를 함유하고 있는 헤테로고리 라디칼이거나, 또는 아미노 저급 알킬, 저급 알킬아미노 저급알킬, 히드록시 저급 알킬아미노 저급알킬, 히드록시 저급 알콕시 저급알킬, 이미다졸릴 저급 알킬, 니트로가 치환된 이미다졸릴 저급알킬, 모노-히드록시 페닐 저급알킬, 디-히드록시 페닐 저급알킬, 니트로가 치환된 피리딜아이노 저급알킬, 피페라지닐 저급알킬 및 피리딜 에틸 중에서 선택하는 치환된 저급 알킬 라디칼이다).Wherein Y is hydrogen or lower alkyl, Z is hydroxy substituted 1-pyrrolidinyl radical, or lower alkyl substituted piperidyl radical, or 1-piperazinyl radical, but acetamino, acetyl, car Bamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfur or formula

Is a radical.

In which R is hydrogen or lower alkyl, R ¹ contains nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl and derivatives of benzothiazolyl substituted with nitro and halo; Heterocyclic radical or amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted with nitro, mono- Hydroxy phenyl loweralkyl, di-hydroxy phenyl loweralkyl, nitro-substituted pyridylino loweralkyl, piperazinyl loweralkyl, and pyridyl ethyl.

Unless otherwise indicated. An "alkyl" radical to which the term "lower" is attached refers to a straight or branched chain radical containing 1-6 carbon atoms. Specifically, by way of example, the term "lower alkyl" already refers to methyl, ethyl, propyl, butyl, pentyl and hexyl radicals as well as isopropyl radicals, t-butyl radicals and the like. Similarly, "alkoxy" with the term "lower" also denotes a radical containing 1-6 carbon atoms.

It is evident that all compounds of formula (III) are included in the description of formula (IIIa). In other words, all of the new antibiotics, mitomycin derivatives of Formula III, are useful for implementing new antitumor therapy methods of administering compounds of Formula lIIa.

Mitomycin derivatives of the present invention are prepared by reacting mitomycin A with a selected amine compound. N-alkylmitomycin (eg N-methylmitomycin) derivatives include N-alkylmitomycin A prepared from selected amines and mitomycin C, for example Cheng, et al., J. Med. Chem., 20 , No. 6, 767-770 (1977) by analogy. This preparation generally yields the desired product, which is readily soluble in alcohol as a crystalline solid.

A method of treatment with the present compounds is the administration of one or more compounds of formula (IIIa) to an animal suffering from a tumor as an active ingredient together with pharmaceutically usable diluents, adjuvants and carriers.

In the method of treatment using the compound, the unit dosage of the compound prepared by the preparation method of the present invention is administered is about 0.001-5.0 mg, preferably about 0.004-1.0 mg. The daily dosage administered in such a unit dosage is about 0.1-100 mg / kg according to the weight of the animal to be treated, preferably 0.2-51.2 mg / kg. Parenteral administration, particularly intraperitoneal administration, is preferred as a route for administering the compounds prepared by the methods of the present invention.

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

The following Examples 1 to 32 describe methods for preparing preferred compounds of the present invention, which are intended for the purpose of detailed description of the invention and are not intended to limit the invention. Unless otherwise indicated, all reactions take place at room temperature (20 ° C) without heating. Thin layer chromatography (TLC) is used to check the reaction process unless otherwise indicated, using a pre-coated silica gel plate and a mixture of medanol and chloroform (volume ratio 2: 8) as the developing solvent.

Example 1

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

A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3-pyrrolidinol (13 mg) at room temperature in nitrogen. Thin membrane chromatography on silica gel (methanol and chloroform were used at a ratio of 2: 8 as solvent) and when the starting material was no longer present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thin membrane chromatography using the same solvent. This reaction yielded 23 mg of the desired product (40% yield). The melting point of this product was 82 ° -85 ° C. (decomposition).

NMR (DMSO-d ₆ , TS): 'δ Value (ppm). There was no 6-methoxy peak at 4.02 and new peaks appeared at 1.6-2.2 (m, 2), 28-3.1 (wide range s, 5) and 4.0-4.3 (m, 1).

Example 2

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

This compound was prepared by the method described in Example 1. From 70 mg of mitomycin A and 200 mg of 3-methyl piperidine, 46 mg (55% yield) of the desired product were obtained, which had a melting point of 75-88 ° C. (decomposition).

NMR (CDCl ₃ , TS): 'δ value (ppm). There was no 6-methoxy peak at 4.02 and new peaks appeared at 0.85 (d, 3), 1.10-215 (m, 5) and 2.15-3.32 (m, 4).

Example 3

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1) -pyrazinyl) -azirino [2 ', 3 '.3,4] pyrrolo [1,2-a] indole-4,7-dione carbaate

This compound was prepared by the method described in Example 1. From 60 mg of mitomycin A and 30 mg of anhydrous piperazine, 23 mg of the desired product was obtained (3496, yield 1 of 3496). The melting point of the product was 200 ° C. (decomposition) and the results were analyzed as follows.

NMR (DMSO-d ₆ , TS): 'δ Value (ppm). There was no 6-methoxy peak at 4.02 and new peaks appeared at 1.9 (broad range s, 1) and 2.9 (s, 8).

Example 4

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 [4-(acetylamino) anilino] -azirino [2 ' , 3'.3, [2 ', 3'.3,4] pyrrolo [1,2-a] indole-4,7-dione carbaate

This compound was prepared by the method described in Example 1. From 100 mg of mitomycin A and excess 4- (acetylamino) aniline, 102 mg (76% yield) of the desired product were obtained, the melting point of which was 143-145 ° C. (decomposition) and the results of these analyzes were as follows. Same as

NMR (CDCl ₃ , TS): 'δ value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks appeared at 2.1 (s, 3), 7.4 (d, 2), 7.6 (s, 1) and 8.9-9.3 (s, 1).

Example 5

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

This compound was prepared by the method described in Example 1, except that only a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 150 mg of 3- (acetylamino) aniline, 67 mg (72% yield) of the desired product was obtained. The melting point of this product was 140-143 ° C. (decomposition). :

NMR (acetone-d ₆ , TS): '∂' value (ppm).

There was no 6-ethoxy peak at 4.02 and new peaks appeared at 2.1 (s, 3), 6.7-7.5 (m, 4), 8.0 (wide range s, 1) and 9.3 (s, 1).

Example 6

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

This compound was prepared by the method described in Example 1, except that only a small amount of solid potassium carbonate was added. With mitomycin A 70mg. 25 mg (28% yield) of the desired product were obtained from 510 mg of 4-acetylaniline, which had a melting point of 103 ° -104 ° C. (decomposition) and analyzed as follows:

NMR (CDCl ₃ , TS): 'δ value (ppm).

There was no 6-methoxy peak car at 4.0 and new peaks appeared at 2.1 (s, 3), 6.6 (d, 2) 7.3 (d, 2) and 7.0-7.3 (wide range s, 1).

Example 7

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

Compounds substituted with carbamido were prepared by the method described in Example 1. From 50 mg of mitomycin A and 227 mg of 4- (1-ureido) aniline, 49 mg (67% yield) of the desired compound were obtained. The melting point of this product was 93-95 ° C. (decomposition). Same as

NMR (CDCl ₃ , TS): 'δ value (ppm).

There is no 6-methoxy pig at 4.02 and new at 5.03 (s, 2), 6.9 (d, 2), 7.3 (d, 2), 8.0 (s, 1) and 8.4 (s, 1) Peaks appeared.

Example 8

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

This compound was prepared by the method described in Example 1 except that a small amount of solid potassium carbonate was added. From 70 mg of matomycin A and 472 mg of 4-aminobenzonitrile, 23 mg (24% yield) of the desired product were obtained, which had a melting point of 124 ° -126 ° C. (decomposition) and analyzed as follows:

NMR (CDCl ₃ , TS): 'δ value (ppm).

There was no 6-ethoxy peak at 4.02 and new peaks appeared at 6.6 (d, 2), 7.4 (d, 2) and 7.0-7.3 (wide range s, 1).

Example 9

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

This compound was prepared by the method described in Example 1 except that a small amount of solid potassium carbonate was added. From 71 mg of mitomycin A and 500 mg of 3-aminobenzonitrile, 30 mg (34% yield) of the desired product were obtained, which had a melting point of 97 ° -98 ° C. (decomposition) and analyzed as follows:

NMR (CDCl ₃ , TS): 'δ value (ppm).

There is no 6-methoxy peak at 4.02 and a new peak at 7.2-7.8 (m, 4).

Example 10

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxy methyl) -8a-methoxy-5-methyl-6- [4- (N-glycol) anilino] azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1. From 50 mg of mitomycin A and 249 mg of 4- (N-glycyl) aniline, 62 mg (90% yield) of the desired product were obtained, which had a melting point of 83 ° -85 ° C. (decomposition). As follows.

NMR (DMSO-d ₆ , TS): '∂' value (ppm).

There are no 6-methoxy peaks at 4.02 and new peaks at 6.6-6.8 (broad s, 2) and 6.6-7.1 (broad s, 2) in 3.1 (s, 2), 6.3-6.6 (broad s, 2). appear.

Example 11

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxyanilino) -azirino [2 ' , 3 ': 3.4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1. From 50 mg of mitomycin A and 229 mg of 3.4-dimethoxyaniline, 61 mg (91% yield) of the desired product were obtained. The melting point of this product was l 14 ° -116 ° C. (degradation).

NlVlR (CDCl ₃ , TS) ∵∂ ′ value (ppm).

There is no 6-methoxy peak at 4.02 and new peaks at 3.8 (s, 6), 6.3-6.9 (m, 3) and 7.7 (s, 1)

Example 12

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

This compound was prepared by the method described in Example 1. From 50 mg of mitomycin A and 229 mg of 3.5-dimethoxyaniline, 60 mg (88% yield) of the desired product were obtained, which had a melting point of 98 ° -100 ° C. (decomposition). 98 ° -100 ° C (decomposition) and the results are as follows.

NMR (CDC1 ₃ , TS) '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks at 3.8 (s, 6) 5.9-6.4 (broad s, 3) and 7.6 × 1).

Example 13

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

This compound was prepared by the method described in Example 1, except for a small amount of solid potassium carbonate. From 70 mg of mitomycin A and 276 mg of 4-nitroaniline, 16 mg (9% yield) of the desired product were obtained. The melting point of this product is 132 ° -l34 ° C (decomposition) and the results are as follows.

NMR (acetone-d ₆ , TS). '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks appeared at 6.9-7.3 (d, 2), 7.4-7.9 (d, 2) and 7.9-8.4 (wide range s, 1).

Example 14

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

This compound was prepared by the method described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 688 mg of sulfinylamide, 25 mg (26% yield) of the desired product were obtained. The melting point of this product was 113 ° -1l5 ° C. (decomposition) and the results were analyzed as follows.

NMR (CDC1 ₃ , TS) '∂' value (ppm)

There is no 6-methoxy peak at 4.02 and new peaks at 7.0 (d, 2), 7.5 (s, 1) and 7.9 (d, 2)

Example 15

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

This compound was prepared by the method described in Example 1. From 60 mg of mitomycin A and an excess of 4-methylaniline, 63 mg (86% yield) of the desired product was obtained, which had a melting point of 113 ° -115 ° C. (decomposition).

NMR (CDC1 ₃ , TS) '∂' value (ppm)

There is no 6-methoxy peak at 4.02 and new peaks at 2.3 (s, 3), 6 5-7.3 (wide s, 4) and 7.6 (wide s, 1)

Example 16

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

This compound was prepared by the method described in Example 1. From 70 mg of mitomycin A and 276 mg of 3-.methylaniline, 66 mg (78% yield) of the desired product was obtained. The melting point of this product was 89 ° -91 ° C. (decomposition).

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There is no 6-methoxy peak at 4.02 and new peaks at 2.4 (d, 3), 6.7-7.5 (m, 4) and 7.8 (s, 1).

Example 17

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

This compound was prepared by the method described in Example 1 except adding a small amount of solid potassium carbonate. From 50 mg of mitomycin A and 30 mg of 3,5-diamino-1,2,4-triazole, 13 mg (5.5% yield) of the desired product were obtained, which had a melting point of 117 ° -120 ° C. (decomposition). The results of this analysis are as follows:

NMR (DMSO-d ₆ , TS): '∂' value (ppIn).

There is no 6-methoxy peak at 4.02 and a new peak at 5.37 (s, 3).

Example 18

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8-methoxy-5-methyl-6-[(3-methylisothiazol-5-yl) amino-azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1 except adding 0.5 ml of triethylamine. From 60 mg of mitomycin A and 30 mg of 5-amino-3-methylisothiazole hydrochloride, 4.5 mg of the desired product (8.5% yield) was obtained, which had a melting point of 87 ° -90 ° C. (decomposition). The analysis results are as follows.

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There is no 6-methoxy peak at 4.02 and new peaks at 2.3 (s, 3), 6 1 (s, 1) and 6 4 (s, 1)

Example 19

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-benzothiazolyl) amino-azirino [2 ', 3'.3,4] pyrrolo [1,2-a] indole-4.7-dione carbamate

This compound was prepared by the method described in Example 1 except adding a small amount of solid potassium carbonate. From 50 mg of mitomycin A and 25 mg of 2-aminobenzothiazole, 12 mg (1% yield) of the desired product were obtained. The melting point of this product was 82 ° -85 ° C. (decomposition).

NMR (CDC1 ₃ , TS). '∂' value (ppm)

There is no 6-apoxy peak at 4.02 and a new peak at 7.1-8.0 (m, 5)

Example 20

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 [(6-nitrobenzothiazol-2-yl) amino] -azide Lino [2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 2-amino-6-nitrobenzothiazole, 20 mg (27% yield) of the desired product were obtained, which had a melting point of 86-89 ° C. (decomposition). As follows.

NMR (DMSO-d ₆ , TS). '∂' value in ppm.

There is no 6-methoxy peak at 4.02 and a new peak at 6.9-8.3 (m, 4).

Example 21

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 [(4-chlorobenzothiazol-2-yl) amino] -azide Lino [2 ', 3'.3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1 except that a small amount of solid potassium carbonate was added. From 150 mg of mitomycin A and 27 mg of 2-amino-chlorobenzothiazole, 30 mg (14% yield) of the desired product were obtained, which had a melting point of 89 ° -91 ° C. (decomposition). It is like

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There is no 6-methoxy peak at 4.02 and new peak at 7.1-8.0 (broad s, 4).

Example 22

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

This compound was prepared by the method described in Example 1 except that the solvent was dichloromethane. From 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane, 35 mg (65% yield) of the desired product were obtained. The melting point of this product was 202 ° -205 ° C. (decomposition). same:

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There is no 6-methoxy peak at 4.02 and new peaks at 1.5 (wide s, 2) and 3.5 (wide s, 4)

Example 23

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

This compound was prepared by the method described in Example 1 except adding a small amount of solid potassium carbonate. From 50 mg of mitomycin A and 25 mg of sym-dimethylethylenediamine, 28 mg (50% yield) of the desired product was obtained. The melting point of this product was 99 ° -10 l ° C. (decomposition).

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks at 1.3 (s, 1), 2.5 (s, 6) and 2.7 (s, 4).

Example 24

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethylamino) ethylamino] -azide Lino [2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1 except that the solvent was dichloromethane. From 50 mg of mitomycin A and 18 mg of 2- (2-aminoethylamino) ethanol the desired product 35 mg (58% yield) The melting point of this product is l15 ° -118 ° C (decomposition) and the results are as follows.

NMR (CDC1 ₃ , TS): '∂' value ppm

There is no 6-methoxy peak at 4.02 and new peaks at 2.7 (wide s, 7) and 3.7 (t, 3).

Example 25

1,1a, 2,8,8a, 8b-hexahydro-8-hydroxymethyl-8a-methoxy-5-methyl-6 [2- (2-hydroxyethoxy) ethylamino] -azirino [2 ', 3': 3,4] e; lolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1 except 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 were obtained, which had a melting point of 99 ° -102 ° C. (decomposition). Is

NMR (CDCl ₃ , TS): '∂' value (ppm).

There was no 6-ethoxy peak at 4.02 and new peaks appeared at 3.3-3.9 (wide s, 9) and 6.4-6.8 (wide s, 1).

Example 26

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

This compound was prepared by the method described in Example 1 except adding 128 mg of sodium methoxide. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride, 6lmg (71% yield) of the desired product was obtained. The melting point of this product was 72 ° -73 ° C. (degradation).

NMR (DMSO-d ₆ , TS). '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks appeared at 3.0-3.27 (m, 4) 7.5 (s, 1), 8.0-8.7 (wide range s, 2) and 8.1 (s, 1).

Example 27

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-nitro-l-imidazolyl) ethylamino]- Azirino [2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate

This compound was prepared by the method described in Example 1. From 72 mg mitomycin A and excess 1- (2-aminoethyl-2-nitroimidazole, 60 mg (70% yield) of the desired product were obtained, which had a melting point of 83 ° -85 ° C. (decomposition). The result of analysis is as follows.

NMR (CDCl ₃ , TS): '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks appeared at 3.4 (t.2) 4.6 (t, 2), 7.3 (broad s, 2) and 7.6 (s, 1).

Example 28

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

This compound was prepared by the method described in Example 1. From 130 mg of mitomycin A and 510 mg of tyramine, 138 mg (81% yield) of the desired product were obtained. The melting point of this product was 120 ° -125 ° C. (decomposition) and the results were analyzed as follows.

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There is no 6-methoxy peak at 4.02 and new peaks appear at 2.6 (t, 2), 2.8 (t.2), 6.7 (d, 2), 7.0 (d, 2) and 8.0 (S, 1).

Example 29

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2-(3,4-dihydroxyphenyl) ethyl Example 1 except adding 138 mg of amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate sodium methoxide This compound was prepared by the method described. 60 mg (40% yield) of the desired product were obtained from 10 mg of mitomycin A and 660 mg of 3-hydroxy tyramine hydrobromide, which was decomposed without melting at 125 ° C. or higher and analyzed as follows.

NMR (CDC1 ₃ , TS): '∂' value (ppm).

There was no 6-methoxy peak at 4.02 and new peaks appeared at 2.6 (t, 2), 2.8 (t, 2), 6.4-6.8 (m, 3) and 8.3 (wide range s, 2).

Example 30

1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-5- [2- [5-nitro-2-pyridyl) amino] ethyl The amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate solvent is described in Example 1 except that the solvent is dichloromethane. This compound was prepared by a conventional method. From 50 mg of myomycin A and 30 mg of 2- (2-aminoethylamino) -5-nitropyridine, 40 mg (56% yield) of the desired product were obtained, which had a melting point of 76 ° -79 ° C. (decomposition). The analysis results are as follows.

NMR (CDCl ₃ , TS) '∂' value (ppm)

There is no 6-methoxy peak at 4.02 and 3.3-4.0 (m, 4), 6.2-6.7 (wide ranges, 2), 8.1 (d, 1), 8.2 (d, 1) and 9.0 (s, 1) A new peak appeared at.

Example 31

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

This compound was prepared by the method described in Example 1 except that the solvent was dichloromethane. From 50 mg of mitomycin A and 20 mg of N- (2-aminoethyl) piperazine, 23 mg (36% yield) of the desired product were obtained, which had a melting point of 138 ° -141 ° C. (decomposition). Is

NMR (CDC1 ₃ , TS) '∂' value (ppm)

There is no 6-methoxy peak at 4.02 and new at 1.6-2.1 (broad range s, 1), 2.2-2.6 (broad range s, 8), 2.6-2.8 (broad range s, 4) and 6. (t, 1) Peaks appeared.

Example 32

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

This compound was prepared by the method described in Example 1. 51 mg (56% yield) of the desired product were obtained from 70 mg of mitomycin A and an excess of 250 mg of 2- (2-aminoethyl) pyridine, which had a melting point of 64 ° -77 ° C. (degradation). Is as follows.

NMR (CDCl ₃ , TS) '∂'value (ppm)

There is no 6-methoxy peak at 4.02 and new peaks at 2.8 (m, 4), 7.0-7.8 (m, 3) and 8.5 (d, 1).

The examples described above with particular reference to compounds belonging to general formula (IIIa) have described the structural modifications described below.

1. Example 1 shows a compound wherein Z is a 1-pyrrolidinyl radical substituted with hydroxy.

2. Example 2 shows a compound wherein Z is a piperidyl radical substituted with lower alkyl.

3. Examples 3,4,5,6,7,8,9,10.11, l2,13,14.15 and 16e are each Z is 1-piperazinyl radical, or acetamino, acetyl, carbamido, The compounds are cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfuryl or lower alkyl substituted anilin radicals.

의 라디칼(이식에서 R¹은 아미노가 치환된 트리아졸릴, 저급알킬이 치환된 이소티아졸릴, 벤조티아졸릴 및 니트로와 할로가 치환된 벤조티아졸릴의 유도체중에서 선택된 질소를 함유하고 있는 헤테로고리 라디칼이다)인 화합물을 나타내었다.4, in Examples 17, 18, 19, 20 and 21, Z is the formula

Radicals in which R ¹ is a heterocyclic radical containing nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl and derivatives of benzothiazolyl substituted with nitro and halo ) Is shown.

의 라디칼(이식에서 R¹은 아미노 저급알킬, 저급알킬아미노 저급알킬, 히드록시 저급알킬아미노 저급알킬, 히드록시 저급알콕시 저급알킬, 이미다졸릴 저급알킬, 니트로가 치환된 이미다졸릴 저급알킬, 모노-히드록시 페닐 저급알킬, 디-히드록시페닐 저급알킬, 니트로가 치환된 피리딜아미노 저급알킬, 피페라지닐 저급알킬 및 피리딜 에틸 중에서 선택하는 치환된 저급알킬 라디칼이다)인 화합물을 나타내고 있다.5. Formulas in Examples 22,23,24,25,26,27,28,29,30,31 and 32

Radicals in which R ¹ is amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted with nitro, mono -Hydroxy phenyl loweralkyl, di-hydroxyphenyl loweralkyl, nitro-substituted pyridylamino loweralkyl, piperazinyl loweralkyl, and pyridyl ethyl.

None of the examples described above describe compounds in which Y is other than hydrogen, but compounds in which Y is lower alkyl are also included in the present invention, and are described in U.S. Patent Nos. 4,268,676 and pending U.S. Patent Applications 206,529 and 264,187. Similarly substituted compounds of the arc can be mentioned by reference.

The compounds of the present invention have anti-bacterial activity against Gram-positive and Gram-negative microorganisms to some extent as observed in naturally occurring mitomycin, and thus can be used as therapeutic agents for treating humans and animals infected with bacteria.

In anti-tumor therapy using the compounds of the present invention, the usefulness of the compound of formula (IIIa) has been demonstrated by the results of an in vivo screening procedure, which has been described in mice of P388 leukemia. The compound prepared by the preparation method is administered in various dosages. This method is described in Cancer Chemotherapy Reports, Part 3, Vol. 3, No. 2, page 9 (September, 1972). P388-protoco11 200). In short, the screening method involves administering a test compound to CDF ¹ female mice that had been transplanted intraperitoneally with 10 ⁶ multi-celled cells intraperitoneally to track the animal's vitality after administering the test compound only on the first day of the test, especially for 35 days. Traced.

표시되어 있다. 앞에 기술되어 있는 생체내 P388 방법과의 관계에서, % T/C의 값이 125나 그 이상인 것은 상당한 항종양 치료 활성을 나타내는 것이다. 125 % T/C값이 얻어지는 가장 낮은 투여량(mg/kg 동물의 몸무게)은 최소 유효 토여량(''MED'')으로 알려져 있다. 최소 유효 투여량 역시 표 1에 기재하였다. 이는 표 1에 기재되어 있는 P388 선별법에서 얻어진 예외적으로 높은 MST 값 역시 지시된 투여량으로 투여할때 실질적으로 화합물이 독성을갖고있지 않음을 나타내고 있다.The results of the test of the compounds of Examples 1 to 32 by the screening method are described in Table 1 below. The data given include the optimal dose (“OD”), which is the dose at which the maximum therapeutic effect can be observed, expressed in mg per kg based on the weight of the animal. The data also includes the average survival (“MST”), which is compared to the MST of the control animal.

Is indicated. In relation to the in vivo P388 method described above, a value of% T / C of 125 or greater indicates significant antitumor therapeutic activity. The lowest dose (mg / kg animal weight) at which a 125% T / C value is obtained is known as the minimum effective dose (`` MED ''). Minimum effective doses are also listed in Table 1. This indicates that the exceptionally high MST values obtained in the P388 screening method described in Table 1 are also substantially nontoxic in the compounds when administered at the indicated doses.

Table 1

Clearly, among the most preferred compounds included as antitumor agents according to the present invention, there is usually a compound that exhibits twice or more of its ability to prolong relative life as an important evidence of characterizing potential treatment. That is, these compounds have an MST% T / C greater than 2 × 125. Such compounds are those described in Examples 4, 10, 11 and 32.

As can be seen from Table 1, even when initially administered at a small amount of 0.2 mg / kg, antitumor activity was shown for a very long time. Thus, in active pharmaceutical preparations, the compound of the invention is treated as an active ingredient in a very small amount on the order of 0.00lmg or in a large amount on the order of 5 mg, preferably in a unit dose of 0.004 mg-10 mg.

Such agents may be administered in an amount to be administered daily, in an amount of O.lmg-10 mg, preferably about 0.2-51.2 mg per kg body weight of the animal suffering from the tumor. The compound is preferably administered parenterally. Contractually suitable compositions used in administering the compounds of the invention may consist of simple aqueous solutions in which one or more compounds of formula (IIIa) are dissolved, and are well known diluents, adjuvants and And / or carriers such as salts that are pharmaceutically suitable.

Considering the foregoing, it is expected that other forms and advantages of the present invention will be possible to those skilled in the art, and the scope of the present invention is intended to be limited by the appended claims.

Claims (5)

Mitomycin analogues of general formula (III).

Wherein Y is hydrogen or lower alkyl and X is hydroxy substituted 1-pyrrolidinyl radical, lower alkyl substituted piperidyl radical, or acetamide, acetyl, carbamido, cyano, carboxy lower Alkylamino, di-lower alkoxy, nitro or sulfimyl are substituted anilin radicals, or

Is a radical. (

Wherein R is hydrogen or lower alkyl, R ¹ contains nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl, and derivatives of benzothiazolyl substituted with nitro and halo Heterocyclic radical or amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted with nitro, mono -Hydroxy phenyl lower alkyl, di-hydroxy phenyl lower alkyl, substituted lower alkyl radicals selected from nitro-substituted pyridylamino lower alkyl and piperazinyl lower alkyl) The mitomycin analogue according to claim 1 which is named as follows: 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-hydroxy-1-pyrrolidinyl) -azirino [ 2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-methylpiperidyl) -azirino [2 ', 3 '3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (acetylamino) anilino] -azirino [2 ' , 3 '3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [3-(acetylamino) anilino] -azirino [2 ' , 3 '3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-acetylanilino) -azirino [2 ', 3' : 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (1-ureino) anilino] -azirino [ 2 ', 3'3,4] pyrrolo [1,2-a] indole-4,7-dionecarbamate; 1,1a, 2,8,8a, 8b-hexahydro-8-(hydroxymethyl ) -8a-methoxy-5-methyl-6- (4-cyanonilino) -azirino [2 ', 3'3,4] pyrrolo [1,2-a] indole-4,7-dionecarb Barmate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-cyanoylino) -azirino [2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- [N-glycyl) anilino] -azirino [ 2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxyanilino) -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,5-dimethoxyanilino) -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-nitroanilino) -azirino [2 ', 3' 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-sulpymilanilino) -azirino [2 ', 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(5 amino-1,2,4-triazole-3- Yl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(3-methylisothiazol-5-yl) amino]- Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 3, pyrrolo [1,2-a] indole-4,7- Dioncarbamate, 3, pyrrolo [1,2-a] chile-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-benzothiazolyl) amino] -azirino [2 ' , 3 ';. 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate: 1,1a, 2,8,8a, 8b-hexahydro-8-(hydroxymethyl ) -8a-methoxy-5-methyl-6-[(6-nitrobenzothiazol-2-yl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a ] Indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(4- Chlorobenzothiazol-2-yl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-animoethyl) amino] -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [methyl (2-methylaminoethyl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethylamino) ethylamino] -azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethoxy) ethylamino] -azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8-( Hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (4-imidazolyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2- a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2 -Itro-1-imidazolyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (4-hydroxyphenyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (3,4-dihydroxyphenyl) ethylamino] Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8 -(Hydroxymethyl) -8a-methoxy-5-methyl-6- {2-[(5-nitro-2-pyridyl) amino] ethylamino} -azirino [2 ', 3': 3,4 ] Pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (1-piperazinyl) ethylamino] -azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate. Formulating mitomycin A or N-alkyl mitomycin A

Mitomycin of general formula (III), characterized by reacting with an amine of formula (R and R ¹ as defined below) to form a compound of general formula (III) and then separating it from the reaction mixture Method of Preparation of Analogs.

Wherein Y is hydrogen or lower alkyl: X is hydroxy substituted 1-pyrrolidinyl radical, lower alkyl substituted piperidyl radical, or acetamide, acetyl, carbamido, cyano, carboxy Lower alkylamino, di-lower alkoxy, nitro or sulfimyl is a substituted alino radical, or

Is a radical. (

Wherein R is hydrogen or lower alkyl, R ¹ contains nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl, and derivatives of benzothiazolyl substituted with nitro and halo Imidazolyl lower alkyl, mono-, or a heterocyclic radical, or substituted with amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl nitro A substituted lower alkyl radical selected from hydroxy phenyl lower alkyl, di-hydroxy phenyl lower alkyl, nitro-substituted pyridyl amino lower alkyl and piperazinyl lower alkyl.) 4. The method of claim 3, wherein the mitomycin analogue is named as follows. 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-hydroxy-1-pyrrolidinyl) -azirino [ 2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate: 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxy Methyl) -8a-methoxy-5-methyl-6- (3-methylpiperidyl) -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7 -Dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (acetylamino) anilino] -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [3- (acetylamino) anilino] -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-acetylanilino) -azirino [2 ', 3' : 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (1-ureido) anilino] -azirino [ 2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-cyanoanilino) -azirino [2 ', 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-cyanoanilino) -azirino [2 ', 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a -Methoxy-5-methyl-6- [4- (N-glysyl) anilino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7 -Dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxyanilino) -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,5-dimethoxyanilino) -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-nitroanilino) -azirino [2 ', 3' : 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-sulmilylanilino) -azirino [2 ', 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(5 amino-1,2,4-triazole-3- Yl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(3-methylisosolazol-5-yl) amino]- Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-benzothiazolyl) amino] -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(6-nitrobenzothiazol-2-yl) amino]- Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(4-chlorobenzothiazol-2-yl) amino]- Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-animoethyl) amino] -azirino [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [methyl (2-methylaminoethyl) amino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethylamino) ethylamino] -azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethoxy) ethylamino] -azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (4-imidazolyl) ethylamino])-azide Lino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-[(2-nitro-1-imidazolyl) ethylamino]- Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (4-hydroxyphenyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydr Oxymethyl) -8a-methoxy-5-methyl-6- [2- (3,4-dihydroxyphenyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1, 2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2-[(5-nitro-2-pyridyl) amino] Ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1,1a, 2,8,8a, 8b-hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (1-piperazinyl) ethylamino] -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate. A pharmaceutical composition for use in the treatment of neoplastic disease in an animal, comprising about 0.001-5 mg of an active ingredient mitomycin analog of the following formula and a pharmaceutically acceptable solvent, diluent adjuvant, or carrier Pharmaceutical adjustments for use in the treatment of neoplastic disease in animals:

Wherein Y is hydrogen or lower alkyl: Z is hydroxy substituted 1-pyrrolidinyl radical, lower alkyl substituted piperidyl group radical, 1-piperazinyl radical, acetamino, acetyl, Carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfyl or lower alkyl are substituted anilin radicals, or

Is a radical, (

Wherein R is hydrogen or lower alkyl, R ¹ contains nitrogen selected from triazolyl substituted with amino, isothiazolyl substituted with lower alkyl, benzothiazolyl and benzothiazolyl substituted with nitro and halo; Heterocyclic radical or amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, imidazolyl lower alkyl substituted with nitro, mono- A substituted lower alkyl radical selected from hydroxy phenyl lower alkyl, di-hydroxy phenyl lower alkyl, nitro-substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.)