DK161890B - MITOMYCIN ANALOGS AND PHARMACEUTICAL PREPARATIONS THEREOF, WITH ANTINEOPLASTIC EFFECT - Google Patents

MITOMYCIN ANALOGS AND PHARMACEUTICAL PREPARATIONS THEREOF, WITH ANTINEOPLASTIC EFFECT Download PDF

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DK161890B
DK161890B DK052484A DK52484A DK161890B DK 161890 B DK161890 B DK 161890B DK 052484 A DK052484 A DK 052484A DK 52484 A DK52484 A DK 52484A DK 161890 B DK161890 B DK 161890B
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alkyl
hydroxymethyl
azirino
methyl
pyrrolo
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William A Remers
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University Patents Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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Description

DK 161890 BDK 161890 B

Opfindelsen angår generelt antibiotiske mitosan-forbindelser og deres anvendelse ved behandling af neo-plastiske sygdomstilstande hos dyr eller mennesker.The invention generally relates to antibiotic mitosan compounds and their use in treating neoplastic disease states in animals or humans.

I US patentskrifterne nr. 4.268.676 og 4.460.599 5 redegøres der for baggrunden af den igangværende forskning efter nye og nyttige forbindelser, der strukturelt er beslægtet med mitomycinerne, har antibiotisk virkning og lav toksicitet og udviser en væsentlig antitumorvirkning hos mennesker eller dyr. Deri beskrives specielt 10 hidtil ukendte forbindelser med formlen IU.S. Patent Nos. 4,268,676 and 4,460,599 5 disclose the background of the ongoing research for novel and useful compounds structurally related to the mitomycins, having antibiotic activity and low toxicity and exhibiting significant antitumor effects in humans or animals. Specifically, 10 novel compounds of formula I are disclosed therein

X ch2ocnh2 15 JL X JUocH3 i o | l\f 20 hvori Y er hydrogen eller lavere alkyl? og X er en thiazolaminogruppe, en furfurylaminogruppe eller en gruppe med formlen 25 R R1X ch2ocnh2 15 JL X JUocH3 i o | l \ f 20 wherein Y is hydrogen or lower alkyl? and X is a thiazolamino group, a furfurylamino group or a group of the formula R

lir3 -N--9-Rlir3 -N - 9-R

R2 1 2 i hvilken R, R og R er ens eller forskellige og er valgt blandt hydrogen og lavere alkyl, og R3 er valgt 30 blandt lavere alkenyl, halogen-lavere-alkenyl, lavere alkynyl, lavere alkxocarbonyl, thienyl, formamyl, tetra-hydrofuryl og benzynsulfonamid.R 2 is wherein R, R and R are the same or different and are selected from hydrogen and lower alkyl, and R 3 is selected from lower alkenyl, halo-lower-alkenyl, lower alkynyl, lower alkoxocarbonyl, thienyl, formamyl, tetra hydrofuryl and benzene sulfonamide.

I nævnte US patentskrifter beskrives også nye metoder til behandling af neoplastiske sygdomstilstande 33 hos dyr eller mennesker, hvilke fremgangsmåder omfatter administrering af en terapeutisk effektiv mængde af en forbindelse med formlen la, 2The aforementioned US patents also disclose novel methods for treating neoplastic disease states 33 in animals or humans, which include administering a therapeutically effective amount of a compound of formula Ia, 2

DK 161890 BDK 161890 B

OISLAND

O tf z I ch2ocnh2 I l| (oCH3 laO tf z I ch2ocnh2 I l | (oCH3 la

LJ>NYLJ> NY

hvori Y er hydrogen eller lavere alkyl; og Z er en thiazolamino-, furfurylamino-, cyclopropylamino- eller pyridylaminogruppe eller en gruppe med formlen R4 R5 — N-C-R7 15 >6wherein Y is hydrogen or lower alkyl; and Z is a thiazolamino, furfurylamino, cyclopropylamino or pyridylamino group or a group of the formula R4 R5 - N-C-R7> 6

RR

4 5 G4 5 G

hvori R , R og R er ens eller forskellige og valgt 7 blandt hydrogen og lavere alkyl, og R er valgt blandt lavere alkenyl, halogen-lavere-alkenyl", lavere alkynyl, 20 lavere alkoxycarbonyl, halogen-lavere-alkyl, hydroxy-lavere-alkyl, pyridyl, thienyl, formamyl, tetrahydro-furyl, benzyl eller benzensulfonamid.wherein R, R and R are the same or different and selected from among hydrogen and lower alkyl, and R is selected from lower alkenyl, halo-lower-alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower -alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl or benzenesulfonamide.

I US patentskrift nr. 4.617.389 beskrives også forbindelser, der har en væsentlig antitumorvirkning hos 25 dyr eller mennesker, og som har følgende formel IlaU.S. Patent No. 4,617,389 also discloses compounds having a substantial antitumor effect in 25 animals or humans and having the following formula IIa

0 O0 O

ch2ocnh2 I _^-0CH3 30ch2ocnh2 I _ ^ - 0CH3 30

________________________ o |_UNY________________________ o | _UNY

hvori Y er hydrogen eller lavere alkyl; og Z er en 35 lavere alkoxysubstitueret quinolinylaminogruppe, en cyanosubstitueret pyrazolylaminogruppe, en mono- eller di-lavere-alkylsubstitueret thiazolaminogruppe, eller en nitrogenholdig heterocyclisk gruppe valgt blandt 3wherein Y is hydrogen or lower alkyl; and Z is a lower alkoxy-substituted quinolinylamino group, a cyano-substituted pyrazolylamino group, a mono- or di-lower-alkyl-substituted thiazolamino group, or a nitrogen-containing heterocyclic group selected from 3

DK 161 890 BDK 161 890 B

1-pyrrolinyl-, 1-indolinyl-, N-thiazolidinyl-, N-morpholinyl-, 1-piperazinyl- og N-thiomorpholinyl-grupper, eller en cyano-, phenyl-, carboxamido- eller lavere alkoxy-5 carbonylsubstitueret 1-aziridinylgruppe, eller en lavere alkyl-, formyl- eller acetylphenylsubstitueret 1-piperazinylgruppe, eller en hydroxy- eller piperidylsubstitueret 1-piperidyl-gruppe, eller 10 en lavere alkoxy-, amino-eller halogensubstitueret pyridylaminogruppe, eller en carboxamido-, mercapto- eller methylendioxy- substitueret anilinogruppe, eller1-pyrrolinyl, 1-indolinyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyl and N-thiomorpholinyl groups, or a cyano, phenyl, carboxamido or lower alkoxy carbonyl substituted 1-aziridinyl group , or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl group, or a hydroxy or piperidyl substituted 1-piperidyl group, or a lower alkoxy, amino or halogen substituted pyridylamino group, or a carboxamido, mercapto or mercapto substituted anilino group, or

RR

15 en gruppe med formlen -N-R' hvori R er hydrogen eller lavere alkyl, og R1 er en nitrogenholdig heterocyclisk gruppe valgt blandt quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl og benzothiadia-20 zolyl, samt lavere-alkyl-og halogensubstituerede derivater deraf, eller en butyrolactonylgruppe, eller en adamantylgruppe, eller en mono-lavere-alkoxy-substitueret phenylgruppe, eller 25 en substitueret lavere alkylgruppe valgt blandt mercapto-lavere-alkyl, carboxy- lavere-alkyl, mono-, di- og tri-lavere-alkoxy-lavere-alkyl, lavere-alkylthio-lavere-alkyl og lavere-alkoxycarbonylsubstituerede derivater deraf, cyano-lavere-alkyl, mono-, di- og tri-30 lavere-alkoxyphenyl-lavere-alkyl, phenylcyclo-lavere-alkyl, 1-pyrrolidinyl-lavere-alkyl, N-lavere-alkyl-pyrrolidinyl-lavere-alkyl, N-morpholinyl-lavere-alkyl og lavere-dialkylamino-lavere-alky1.Wherein R is hydrogen or lower alkyl and R 1 is a nitrogen-containing heterocyclic group selected from quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl -and halogen-substituted derivatives thereof, or a butyrolactonyl group, or an adamantyl group, or a mono-lower-alkoxy-substituted phenyl group, or a substituted lower alkyl group selected from mercapto-lower-alkyl, carboxy-lower-alkyl, mono-, di- and tri-lower-alkoxy-lower-alkyl, lower-alkylthio-lower-alkyl, and lower-alkoxycarbonyl-substituted derivatives thereof, cyano-lower-alkyl, mono-, di- and tri-lower-alkoxyphenyl-lower-alkyl, phenyl-cyclo lower-alkyl, 1-pyrrolidinyl-lower-alkyl, N-lower-alkyl-pyrrolidinyl-lower-alkyl, N-morpholinyl-lower-alkyl and lower-dialkylamino-lower-alkyl.

De følgende referencer er også relevante i for-35 bindelse med den foreliggende opfindelse: US patentskrifterne nr. 3.332.944, nr. 3.410.867, nr. 4.231.936,nr. 3.429.894, nr. 4.268.676, nr. 3.450.705 og nr. 3.514.452, samt Imai, et al., Gann, 71, pp. 560-562 (1980).The following references are also relevant in connection with the present invention: U.S. Patent Nos. 3,332,944, 3,410,867, 4,221,936, Nos. 3,429,894, 4,268,676, 3,450,705 and 3,514,452, and Imai, et al., Gann, 71, pp. 560-562 (1980).

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Der tilvejebringes ifølge opfindelsen hidtil ukendte forbindelser med formlen IIIAccording to the invention, novel compounds of formula III are provided

° ( 5 ^-CH2OCNH2 I II ^^°CH3 111 ' S I_]> 10 hvori Y er hydrogen eller lavere alkyl; og X er en hydroxysubstitueret 1-pyrrolidinylgruppe, en lavere alkylsubstitueret piperidylgruppe, en acetamino-, acetyl-, carbamido-, cyano-, 15 carboxy-lavere-alkylamino-, di-lavere-alkoxy-, nitro-eller sulfamylsubstitueret anilinogruppe, ellerWherein Y is hydrogen or lower alkyl; and X is a hydroxy-substituted 1-pyrrolidinyl group, a lower alkyl-substituted piperidyl group, an acetamino, acetyl, carbamido , cyano, carboxy-lower-alkylamino, di-lower-alkoxy, nitro- or sulfamyl-substituted anilino group, or

RR

, - . * 1 en gruppe mea rormien -N-R, -. * 1 a group of mea rormien -N-R

hvori R er hydrogen eller lavere alkyl, og Rx er en 20 nitrogenholdig heterocyclisk gruppe valgt blandt amino-substitueret triazolyl, lavere-alkyl-substitueret isothiazolyl, benzothiazolyl oa nitro- og halogensubstituerede derivater af benzothiazolyl, eller R1 er 25 en substitueret lavere alkylgruppe valgt blandt mono-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitrosubstitueret imidazolyl-lavere-alkyl, nitrosubstitueret pyridyl-30 amino-lavere-alkyl og piperazinyl-lavere-alkyl.wherein R is hydrogen or lower alkyl and Rx is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower-alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives of benzothiazolyl, or R1 is a substituted lower alkyl group selected from mono-lower-alkylamino-lower-alkyl, hydroxy-lower-alkylamino-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, imidazolyl-lower-alkyl, nitrosubstituted imidazolyl-lower-alkyl, nitrosubstituted pyridyl-amino-lower -alkyl and piperazinyl-lower-alkyl.

Specielle forbindelser blandt de omhandlede er angivet i krav 2.Specific compounds of the present invention are given in claim 2.

Opfindelsen angår også anvendelse af en forbindelse ifølge det ovenstående til fremstilling af et læge-35 middel med virkning mod neoplastiske sygdomstilstande, til administrering af en terapeutisk effektiv mængde af en forbindelse med formlen Illa , 5 ?The invention also relates to the use of a compound of the above for the preparation of a medicament effective against neoplastic disease states, for the administration of a therapeutically effective amount of a compound of formula IIa, 5

DK 161890 BDK 161890 B

5 5 Jl Jl L--0®^ H Cy Illa S I_U> · hvori Y er hydrogen eller lavere alkyl; og Z er 10 en hydroxysubstitueret 1-pyrrolidinylgruppe, en lavere alkylsubstitueret piperidylgruppe, en 1-piperazinylgruppe, en acetamino-, acetyl-, carbamido-, cyano-, carboxy-lavere-alkylamino'> di-lavere-alkoxy-, nitro-, sulfamyl-15 eller lavere-alkylsubstitueret anilinogruppe, eller5 5 Jl Jl L - 0® ^ H Cy Illa S I_U> · wherein Y is hydrogen or lower alkyl; and Z is a hydroxy-substituted 1-pyrrolidinyl group, a lower alkyl-substituted piperidyl group, a 1-piperazinyl group, an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl-15 or lower-alkyl-substituted anilino group, or

RR

' 1'1

en gruppe med formlen -N-Ra group of formula -N-R

hvori R er hydrogen eller lavere alkyl,og R^ er en nitrogenholdig heterocyclisk gruppe valgt blandt amino-20 substitueret triazolyl, lavere alkylsubstitueret isothiazolyl, benzothiazolyl og nitro- og halogensubstituerede derivater af benzothiazolyl, eller R^ er en substitueret lavere alkylgruppe valgt blandt mono-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-25 alkylamino-lavere-alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitrosubstitueret imidazolyl-lavere-alkyl, nitrosubstitueret pyridylamino-lavere-alkyl, piperazinyl-lavere-alkyl og pyridylethyl.wherein R is hydrogen or lower alkyl and R 1 is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives of benzothiazolyl, or R 2 is a substituted lower alkyl group selected from mono lower-alkylamino-lower-alkyl, hydroxy-lower-alkylamino-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, imidazolyl-lower-alkyl, nitrosubstituted imidazolyl-lower-alkyl, nitrosubstituted pyridylamino-lower-alkyl, piperazinyl -lower alkyl and pyridylethyl.

Med mindre andet er angivet, skal udtrykket 30 "lavere" i forbindelse med "alkyl"-grupper betegne lige-kædede eller forgrenede alkylgrupper med fra 1-6 carbon-atomer. Til illustration skal "lavere alkyl" betyde og omfatte methyl-, ethyl-, propyl-, butyl-, pentyl- og hexylgrupper samt isopropylgrupper, t-butylgrupper og 35 lignende. Tilsvarende skal "lavere" i forbindelse med "alkoxy" betegne en gruppe med 1-6 carbonatomer.Unless otherwise indicated, the term "lower" in connection with "alkyl" groups should mean straight-chain or branched-chain alkyl groups having from 1-6 carbon atoms. By way of illustration, "lower alkyl" means and includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups as well as isopropyl groups, t-butyl groups and the like. Similarly, "lower" for "alkoxy" should mean a group of 1-6 carbon atoms.

Det ses tydeligt, at forbindelserne med formlen III alle er omfattet af specifikationerne for formelIt is clearly seen that the compounds of formula III are all included in the specifications of formula

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66

Illa. Sagt på en anden måde, er alle de hidtil ukendte antibiotiske mitomycinderivater med formlen III anvendelige til praktisk fremstilling af de nye antineo-plastiske lægemidler, som involverer administrering af 5 forbindelser med formlen Illa.IIIa. Stated another way, all the novel antibiotic mitomycin derivatives of formula III are useful for the practical preparation of the novel antineoplastic drugs which involve the administration of 5 compounds of formula IIa.

Mitomycinderivater ifølge opfindelsen fremstilles ved omsætning af mitomycin A med passende valgte aminforbindelser. N-alkylmitomycinderivaterne (f.eks. N-methylmitoJtyciner) fremstilles på samme måde ved at om-10 sætte en udvalgt amin med N-alkylmitomycin A fremstillet ud fra mitomycin C, f.eks. i overensstemmelse med de fremgangsmåder, der generelt er beskrevet af Cheng, et al., J. Med. Chem., 20, No. 6, 767-770 (1977). Fremgangsmåderne til fremstilling af forbindelserne 15 ifølge opfindelsen giver generelt det ønskede produkt som et krystallinsk fast stof, der er let opløseligt i alkohol.Mitomycin derivatives of the invention are prepared by reacting mitomycin A with suitably selected amine compounds. The N-alkylmitomycin derivatives (e.g., N-methylmitoyltycins) are prepared in the same way by reacting a selected amine with N-alkylmitomycin A prepared from mitomycin C, e.g. in accordance with the methods generally described by Cheng, et al., J. Med. Chem., 20, no. 6, 767-770 (1977). The processes for preparing the compounds 15 of the invention generally yield the desired product as a crystalline solid which is readily soluble in alcohol.

Den terapeutiske anvendelse af forbindelserne ifølge opfindelsen omfatter administrering af effektive 20 mængder af en eller flere forbindelser med formlen Illa som aktiv komponent, sammen med ønskede farmaceutisk acceptable fortyndingsmidler, adjuvanser og bærere, til et dyr eller menneske, der lider af en neoplastisk sygdom.The therapeutic use of the compounds of the invention comprises administering effective amounts of one or more compounds of formula IIa as active component, together with desired pharmaceutically acceptable diluents, adjuvants and carriers, to an animal or human suffering from a neoplastic disease.

25 Et farmaceutisk præparat ifølge opfindelsen indeholder et farmaceutisk acceptabelt opløsningsmiddel, fortyndingsmiddel, adjuvans eller bærer og, som den aktive komponent, fra ca. 0,001 til ca. 5 mg af en forbindelse med formlen III. Enhedsdoserne af forbindelserne, 30 som administreres ifølge opfindelsen,kan variere fra ca. 0,001 til ca. 5,0 mg og fortrinsvis fra ca. 0,004 til ca. 0,1 mg. Sådanne enhedsdoser kan indgives i en sådan mængde, at den daglige dosis udgør fra ca. 0,1 til ca. 100 mg per kg og fortrinsvis fra ca. 0,2 til 35 ca. 51,2 mg per kg legemsvægt af det behandlede dyr eller menneske. Parenteral administrering, især intra-peritoneal administrering, er den foretrukne indgivelsesvej ved den praktiske udøvelse af opfindelsen.A pharmaceutical composition according to the invention contains a pharmaceutically acceptable solvent, diluent, adjuvant or carrier and, as the active ingredient, from ca. 0.001 to approx. 5 mg of a compound of formula III. The unit doses of the compounds administered in accordance with the invention may vary from ca. 0.001 to approx. 5.0 mg and preferably from ca. 0.004 to approx. 0.1 mg. Such unit doses may be administered in an amount such that the daily dose is from about 0.1 to approx. 100 mg per kg and preferably from ca. 0.2 to 35 approx. 51.2 mg per kg body weight of the treated animal or human. Parenteral administration, especially intraperitoneal administration, is the preferred route of administration in the practice of the invention.

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Andre aspekter og fordele af opfindelsen vil fremgå af den følgende beskrivelse.Other aspects and advantages of the invention will become apparent from the following description.

De følgende eksempler 1-29, der tjener til. nærmere belysning af opfindelsen, beskriver fremstillingen af visse på 5 nuværende tidspunkt foretrukne forbindelser ifølge opfindelsen. Med mindre andet er angivet, blev alle reaktioner udført ved stuetemperatur (20°C) uden varmetilførsel. Med mindre andet er angivet, involverer alle de tyndtlagschromatografiske (TLC) fremgangsmåder, 10 der blev anvendt til at kontrollere reaktionernes forløb, brugen af i forvejen belagte silicagelplader og en blanding af methanol og chloroform (2:8 på volumenbasis) som udviklende opløsningsmiddel.The following Examples 1-29 serve. Further elucidation of the invention discloses the preparation of certain currently preferred compounds of the invention. Unless otherwise indicated, all reactions were carried out at room temperature (20 ° C) without heat supply. Unless otherwise indicated, all of the thin layer chromatographic (TLC) methods 10 used to control the course of the reactions involve the use of pre-coated silica gel plates and a mixture of methanol and chloroform (2: 8 by volume) as developing solvent.

15 Eksempel 1 1, la, 2,8,8a, 8b-'Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-hydroxy-l-pyrrolidinyl) -azirino[2', 3': 3,4] -pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 1 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.

En opløsning af mitomycin A (50 mg) i 6 ml vand-20 frit methanol blev behandlet med 3-pyrrolidinol (13 mg) under nitrogenatmosfære ved stuetemperatur. Da tyndtlagschromatograf i på silicagel (2:8 methanol-chloroform som opløsningsmiddel) viste at udgangsmaterialet ikke laaigere var tilstede, blev opløsningen filtreret og 25 inddampet under reduceret tryk. Remanensen blev renset ved preparativ tyndtlagschromatografi ved brug af det samme opløsningsmiddelsystem. Denne fremgangsmåde gav 23 mg (40% udbytte) af det ønskede produkt med et smeltepunkt på 82-85°C (dekomponering) og med 30 den følgende analyse: NMR (DMSO-dg, TS): '5' værdier i ppm.A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3-pyrrolidinol (13 mg) under nitrogen atmosphere at room temperature. When thin layer chromatograph on silica gel (2: 8 methanol-chloroform as solvent) showed that the starting material was no longer present, the solution was filtered and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography using the same solvent system. This procedure yielded 23 mg (40% yield) of the desired product, mp 82-85 ° C (decomposition) and with the following analysis: NMR (DMSO-dg, TS): '5' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 1,6-2,2 (m,2), 2,8-3,1 (bred s, 5) og 4,0-35 4,3 (m,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 1.6-2.2 (m, 2), 2.8-3.1 (wide s, 5) and 4.0-35 4, 3 (m, l).

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Eksempel 2 1/ la,2/8/8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy- 5-methyl-6- (3-methylpiperLdyl) -azirino [2', 3 * : 3,4 ] — pyrrolo [1,2-a]-indol-4,7-dion-carbamat.Example 2 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.

5 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 70 mg mitomycin A og 200 mg 3-methylpiperidin blev der opnået 46 mg (55% udbytte) af det ønskede produkt med et smeltepunkt på 75-88°C (dekomponering) og med følgende 10 analyse: NMR (CDCl^/ TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 200 mg of 3-methylpiperidine, 46 mg (55% yield) of the desired product was obtained, mp 75-88 ° C (decomposition) and with the following analysis: NMR (CDCl3 / TS ): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 0,85 (d,3), 1,10-2,15 (m,5) og 2,15-3,32 15 (m,4) .Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 0.85 (d, 3), 1.10-2.15 (m, 5) and 2.15-3.32 (m, 4) ).

Eksempel 3 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxv- 5-methyl-6-(1-piperazinyl)-azirino[2', 3':3,4]pyrrolo-20 [1,2-a]indol-4,7-dion-carbamat.Example 3 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (1-piperazinyl) -azirino [2 ', 3': 3,4] pyrrolo-20 [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 60 mg mitomycin A og 30 mg vandfri piperazin blev der opnået 23 mg (34% udbytte) af det ønskede produkt med et 25 smeltepunkt, der var større end 200°C (dekomponering), og med den følgende analyse: NMR (DMSO-dg, TS): ’6' værdier i ppm.This compound was prepared by the procedure described in Example 1. From 60 mg of mitomycin A and 30 mg of anhydrous piperazine, 23 mg (34% yield) of the desired product was obtained with a melting point greater than 200 ° C (decomposition) and with the following analysis: NMR (DMSO -dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 1,9 30 (bred s, 1) og 2,9 (s,8).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 1.9 30 (wide s, 1) and 2.9 (s, 8).

Eksempel 4 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl) -8a-methoxy- 5-methyl-6-[4-(acetylamino)anilino]-azirino[21,3':3,4]-35 pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 4 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (acetylamino) anilino] azirino [21,3 ': 3, 4] -35 pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 100 mg af mitomycin A og overskud af 4-(acetylamino)anilin blevThis compound was prepared by the procedure described in Example 1. From 100 mg of mitomycin A and excess of 4- (acetylamino) aniline were obtained

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9 der opnået 102 mg (76% udbytte) af det ønskede produkt med et smeltepunkt på 143-145°C (dekomponering) og med følgende analyse: NMR (CDCl^, TS): '6' værdier i ppm.9 obtained 102 mg (76% yield) of the desired product, m.p. 143-145 ° C (decomposition) and with the following analysis: NMR (CDCl3, TS): '6' values in ppm.

5 Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 2,1 (s,3), 7,4 (d,2), 7,6 (s,l) og 8,9-9,3 (s,l).5 Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 2.1 (s, 3), 7.4 (d, 2), 7.6 (s, 1) and 8.9-9, 3 (s, l).

10 Eksempel 5 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy- 5-methyl-6-[3-(acetylamino)anilino]-azirino[2,,3*;3,4]— pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 5 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [3- (acetylamino) anilino] -azirino [2,3,3 *; 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i 15 eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde fast kaliumcarbonat blev tilsat. Ud fra 70 mg mitomycin A og 150 mg 3-(acetylamino)anilin blev der opnået 67 mg (72% udbytte) af det ønskede produkt med et smeltepunkt på 140-143°C (dekomponering) og med 20 følgende analyse: NMR (acetone-dg, TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1 except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 150 mg of 3- (acetylamino) aniline, 67 mg (72% yield) of the desired product was obtained, mp 140-143 ° C (decomposition) and with the following analysis: NMR (acetone -dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 2,1 (s,3), 6,7-7,5 (m,4), 8,0 25 (bred s,l) og 9,3 (s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 2.1 (s, 3), 6.7-7.5 (m, 4), 8.0 (wide s, 1) and 9 , 3 (s, l).

Eksempel 6 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy- 5-methyl-6-(4-acetylanilino)-azirino[2',3':3,4]pyrrolo-30 [l,2-a]indol —4,7-dion-carbamat.Example 6 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-acetylanilino) -azirino [2 ', 3': 3,4] pyrrolo-30 [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde fast kaliumcarbonat blev tilsat. Ud fra 70 mg mitomycin A og 510 mg 4-acetylanilin blev der op-35 nået 25 mg (28% udbytte) af det ønskede produkt med et smeltepunkt på 103-104°C (dekomponering) og med følgende analyse:This compound was prepared by the procedure described in Example 1 except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 510 mg of 4-acetylaniline, 25 mg (28% yield) of the desired product was obtained, mp 103-104 ° C (decomposition) and with the following analysis:

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10 NMR (CDCl^f TS): '6' værdier i ppm.10 NMR (CDCl3 + TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye topppe ved 2,1 (s,3), 6,6(d,2), 7,3 (d,2) og 5 7,0-7,3 (bred s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peak at 2.1 (s, 3), 6.6 (d, 2), 7.3 (d, 2) and 5 7.0-7, 3 (wide s, l).

Eksempel 7 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[4-(l-ureido)anilino]-azirino[2',3':3,4]pyrrolo-10 [1,2-a]indo1-4,7-dion-carbamat.Example 7 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [4- (1-ureido) anilino] -azirino [2 ', 3' : 3,4] pyrrolo-10 [1,2-a] indole-4,7-dione carbamate.

Denne carbamidosubstituerede forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde.This carbamido substituted compound was prepared by the procedure described in Example 1.

Ud fra 50 mg af mitomycin A og 227 mg af 4-(1-ureido)-anilin blev der opnået 49 mg (67% udbytte) af det 15 ønskede produkt med et smeltepunkt på 93-95°C (dekomponering) og med følgende analyse: NMR (CDCl^f TS): '6' værdier i ppm.From 50 mg of mitomycin A and 227 mg of 4- (1-ureido) -aniline, 49 mg (67% yield) of the desired product was obtained with a melting point of 93-95 ° C (decomposition) and with the following analysis: NMR (CDCl3 + TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 5,03 (s,2), 20 6,9 (d,2), 7,3 (d,2), 8,0 (s,l) og 8.4 (s,1).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 5.03 (s, 2), 20 6.9 (d, 2), 7.3 (d, 2), 8.0 (s, l) and 8.4 (s, 1).

Eksempel 8 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-25 methyl-6-(4-cyanoanilino)-azirino[21,3':3,4]pyrrolo-[1,2-a]indol-4,7-dion-carbamat.Example 8 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-cyanoanilino) -azirino [21,3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksenpel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde kaliumcarbcnat blev tilsat. Ud fra 70 mg af mitcenrycin A og 30 472 mg af 4-aminobenzonitril blev der opnået 23 mg (24% udbytte) af det ønskede produkt med et smeltepunkt på 124-126°C (dekomponering) og med følgende analyse: NMR (CDClg, TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1, except that a small amount of potassium carbonate was added. From 70 mg of mitcenrycin A and 30,472 mg of 4-aminobenzonitrile, 23 mg (24% yield) of the desired product was obtained, mp 124-126 ° C (decomposition) and with the following analysis: NMR (CDCl TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og 35 forekansfc af nye toppe ved 6,6 (d,2) , 7.4 (d,2) og 7,0-7,3 (bred s,l).Lack of 6-methoxy peak at 4.02 and 35 precedence of new peaks at 6.6 (d, 2), 7.4 (d, 2) and 7.0-7.3 (wide s, l).

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1 i1 i

Eksempel 9 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-cyanoanilino)-azirino[2',3’:3,4]pyrrolo-[1,2-a]indol-4/7-dion-carbamat.Example 9 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.

5 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde/ bortset fra at en lille mængde fast kaliumcarbonat blev tilsat. Ud fra 71 mg af mitomycin Λ og 500 mg af 3-aminobenzonitril blev der opnået 30 mg (34% udbytte) af det ønskede 10 produkt med et smeltepunkt på 97-98°C (dekomponering) og med følgende analyse: NMR (CDCl3, TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1 except that a small amount of solid potassium carbonate was added. From 71 mg of mitomycin Λ and 500 mg of 3-aminobenzonitrile, 30 mg (34% yield) of the desired product was obtained, mp 97-98 ° C (decomposition) and with the following analysis: NMR (CDCl TS): '6' values in ppm.

Manglende 6-methoxy-topved4,02 og forekomst af nye toppe ved 7,2-7,8 15 (m,4).Lack of 6-methoxy peak wood4.02 and occurrence of new peaks at 7.2-7.8 15 (m, 4).

Eksempel 10 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-14-(N-glycyl)anilino]-azirino[2',3':3,4jpyrrolo-20 [1,2-a]indol-4,7-dion-carbamt.Example 10 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-14- (N-glycyl) anilino] -azirino [2 ', 3': 3,4-pyrrolo-20 [1,2-a] indole-4,7-dione carbamide.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 50 mg af mitomycin A og 249 mg af 4-(N-glycyl)anilin blev der opnået 62 mg (90% udbytte) af det ønskede produkt med 25 et smeltepunkt på 83-85°C (dekomponering) og med følgende analyse: NMR (DMSO-dg, TS): '6' værdier i ppm.This compound was prepared by the procedure 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 was obtained with a melting point of 83-85 ° C (decomposition) and with the following analysis : NMR (DMSO-dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekanst af nye toppe ved 3,1 (s,2), 30 6,3-6,6 (bred s,2), 6,6-6,8 (bred s,2) og 6,6-7,1 (bred s,2).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 3.1 (s, 2), 6.3-6.6 (wide s, 2), 6.6-6.8 (wide s , 2) and 6.6-7.1 (wide s, 2).

Eksempel 11 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-35 methyl-6- (3,4-dimethoxyani 1 ino -azirino[2', 31:3,4]pyrrolo-[1,2-a]indol-4,7-dion-carbamat.Example 11 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-35-methyl-6- (3,4-dimethoxyani-1-azirino [2 ', 31: 3 , 4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 50 mg afThis compound was prepared by the procedure described in Example 1. From 50 mg of

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12 mitomycin A og 229 mg af 3,4-dimethoxyanilin blev der opnået 61 mg (91% udbytte) af det ønskede produkt med et smeltepunkt på 114-116°C (dekomponering) og med følgende analyse: 5 NMR (CDCl^, TS): '6' værdier i ppm.12 mitomycin A and 229 mg of 3,4-dimethoxyaniline 61 mg (91% yield) of the desired product were obtained, mp 114-116 ° C (decomposition) and with the following analysis: 5 NMR (CDCl ): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 3,8 (s,6), 6,3-6,9 (m,3) og 7,7 (s,1).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 3.8 (s, 6), 6.3-6.9 (m, 3) and 7.7 (s, 1).

10 Eksempel 12 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,5-dimethoxyanilino)-azirino[2',3':3,4]-pyrrolo[1,2-aJindol-4,7-dion-carbamat—Example 12 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-aJindol-4,7-dione carbamate

Denne forbindelse blev fremstillet ved den i 15 eksempel 1 beskrevne fremgangsmåde. Ud fra.50 mg af mitomycin A og 229 mg af 3,5-dimethoxyanilin blev der opnået 60 mg (88% udbytte) af det ønskede produkt med et smeltepunkt på 98-100°C (dekomponering) og med følgende analyse: 20 NMR (CDClg, TS): '6' værdier i ppm.This compound was prepared by the procedure 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 was obtained, mp 98-100 ° C (decomposition) and with the following analysis: 20 NMR (CDClg, TS): '6' values in ppm.

Manglende 6-methoxy-top i 4,02 og forekomst af nye toppe ved 3,8 (s,6), 5,9-6,4 (bred s,3) og 7,6 (s,l).Lack of 6-methoxy peak in 4.02 and occurrence of new peaks at 3.8 (s, 6), 5.9-6.4 (wide s, 3) and 7.6 (s, 1).

25 Eksempel 13 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5- methyl-6-(4-nitroanilino)-azirino[2',31:3,4]pyrrolo- [1,2-a]indol-4,7-dion-carbamat.Example 13 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-nitroanilino) -azirino [2 ', 31: 3,4] pyrrolo- [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i 30 eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille maaigcie fast kaliumcarbonat blev tilsat. Ud fra 70 mg mitomycin A og 276 mg af 4-nitroanilin blev der opnået 16 mg (9% udbytte) af det ønskede produkt med et smeltepunkt på 132-134°C (dekomponering) og med følgende 35 analyse: NMR (acetone-d.,, TS) : '6' værdier i ppm.This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 276 mg of 4-nitroaniline, 16 mg (9% yield) of the desired product was obtained, mp 132-134 ° C (decomposition) and with the following analysis: NMR (acetone-d . ,, TS): '6' values in ppm.

OISLAND

Manglende 6-methoxy-top ved 4,02 og forekomst .' af nye toppe ved 6.9- 7,3 (d,2), 7,4-7,9 (d,2) og 7.9- 8,4 (bred s,l).Lack of 6-methoxy peak at 4.02 and incidence. ' of new peaks at 6.9- 7.3 (d, 2), 7.4-7.9 (d, 2), and 7.9- 8.4 (wide s, l).

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Eksempel 14 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-sulfamylanilino)-azirino[2',3':3,4]pyrrolo-[1,2-a]indol-4,7-dion-carbamat.Example 14 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-sulfamylanilino) -azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

5 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille maengdé fast kaliumcarbonat blev tilsat. Ud fra 70 mg af mitomycin A og 688 mg af sulfanilamid blev der opnået 25 mg (26% udbytte) af det ønskede produkt med et 10 smeltepunkt på 113-115°C (dekomponering) og med følgende analyse: NMR (CDCl^f TS): 1 δ1 værdier i ppm.This compound was prepared by the procedure 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 sulfanilamide, 25 mg (26% yield) of the desired product was obtained with a melting point of 113-115 ° C (decomposition) and with the following analysis: NMR (CDCl ): 1 δ1 values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 7,0 (d,2), 15 7,5 (s,l) og 7,9 (d,2).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 7.0 (d, 2), 7.5 (s, 1) and 7.9 (d, 2).

Eksempel 15 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-methylanilino)-azirino[2',3':3,4]pyrrolo-20 [1,2-a]indol-4,7-dion-carbamat.Example 15 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-methylanilino) -azirino [2 ', 3': 3,4] pyrrolo-20 [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 angivne fremgangsmåde. Ud fra 60 mg af mitomycin A og overskud af 4-methylanilin blev der opnået 63 mg (86% udbytte) af det ønskede produkt med et 25 smeltepunkt på 113-115°C (dekomponering) og med følgende analyse: NMR (CDCl^/ TS): '6' værdier i ppm.This compound was prepared by the procedure of Example 1. From 60 mg of mitomycin A and excess 4-methylaniline, 63 mg (86% yield) of the desired product was obtained with a melting point of 113-115 ° C (decomposition) and with the following analysis: NMR (CDCl TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 2,3 (s,3), 30 6,5-7,3 (bred s,4) og 7,6 (bred s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 2.3 (s, 3), 6.5-7.3 (wide s, 4) and 7.6 (wide s, 1).

Eksempel 16 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-methylanilino)-azirino[21,3':3,4]pyrrolo-35 [1,2-a]indol-4,7-dion-carbamat.Example 16 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3-methylanilino) -azirino [21,3 ': 3,4] pyrrolo -35 [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 70 mg af j mitomycin A og 276 mg af 3-methylanilin blev der opnåetThis compound was prepared by the procedure described in Example 1. From 70 mg of j mitomycin A and 276 mg of 3-methylaniline were obtained

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14 66 mg (78% udbytte) af det ønskede produkt med smeltepunkt på 89-91°C (dekomponering) og med følgende analyse: NMR (CDCl^f TS) : '6' værdier i ppm.14 66 mg (78% yield) of the desired product, mp 89-91 ° C (decomposition) and with the following analysis: NMR (CDCl3 + TS): '6' values in ppm.

5 Manglende 6-methoxy-top ved 4,02 og forekomst· . af nye toppe ved 2,4 (s,3) , 6,7-7,5 (m,4) og 7,8 (s,1).5 Missing 6-methoxy peak at 4.02 and occurrence ·. of new peaks at 2.4 (s, 3), 6.7-7.5 (m, 4), and 7.8 (s, 1).

Eksempel 17 10 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(5-amino-l,2,4-triazol-3-yl)amino]-azirino-[2',31:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 17 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(5-amino-1,2,4-triazol-3-yl) ) amino] -azirino- [2 ', 31: 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse hlev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en 15 lille mængde fast kaliumcarbonat blev tilsat, Ud fra 50 mg af mitomycin A og 30 mg af 3,5-diamino-l,2,4- triazol blev der opnået 13 mg (5,5% udbytte) af detThis compound was prepared by the procedure 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 3,5-diamino-1,2,4-triazole, obtained 13 mg (5.5% yield) of it

ønskede produkt med et smeltepunkt på 117-120°Cdesired product having a melting point of 117-120 ° C

(dekomponering) og med følgende analyse: 20 NMR (DMSO-dg, TS): '6' værdier i ppm.(decomposition) and with the following analysis: 20 NMR (DMSO-dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 5,37 (s,3) .Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 5.37 (s, 3).

25 Eksempel 18 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]indol-4,7-dion-carbamat.Example 18 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.

Denne forbindelse blev fremstillet ved den i 30 eksempel 1 beskrevne fremgangsmåde, bortset fra at 0,5 ml af triethylamin blev tilsat. Ud fra 60 mg af mitomycin A og 30 mg af 5-amino-3-methylisothiazol-hydrochlorid blev der opnået 4,5 mg (8,5% udbytte) af det ønskede produkt med smeltepunkt på 87-90°C (dekomponering) og 35 med følgende analyse: NMR (CDC13, TS) : '5' værdier i ppm.This compound was prepared by the procedure described in Example 1, except that 0.5 ml of triethylamine was added. From 60 mg of mitomycin A and 30 mg of 5-amino-3-methylisothiazole hydrochloride, 4.5 mg (8.5% yield) of the desired product was obtained, mp 87-90 ° C (decomposition) and 35 with the following analysis: NMR (CDCl3, TS): '5' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst . af nye toppe ved 2,3 (s,3), 6,1 (s,1) og 6,4 (s,l).Lack of 6-methoxy peak at 4.02 and incidence. of new peaks at 2.3 (s, 3), 6.1 (s, 1) and 6.4 (s, 1).

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1515

Eksempel 19 1/13,2,8,83/8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-Γ(2-benzothi3zolyl)3mino]-szirino[2',3':3,4]-pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 19 1 / 13,2,8,83 / 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6-Γ (2-benzothiazolyl) 3mino] -sirino [2 ', 3': 3 , 4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

5 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde fast kaliumcarbonat blev tilsat. Ud fra 50 mg af mitomycin A og 25 mg af 2-aminobenzothiazol blev der opnået 12 mg (18% udbytte) af det ønskede 10 produkt med et smeltepunkt på 82-85 C (dekomponering) og med følgende analyse.This compound was prepared by the procedure described in Example 1 except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 25 mg of 2-aminobenzothiazole, 12 mg (18% yield) of the desired product was obtained, mp 82-85 ° C (decomposition) and with the following analysis.

NMR (CDCl^, TS): '6' værdier i ppm.NMR (CDCl3, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 7,1-8,0 15 (m,5).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 7.1-8.0 15 (m, 5).

Eksempel 20 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy- 5-methyl-6-[(6-nitrobenzothiazol-2-yl)amino]-azirino-20 [2',3':3,4jpyrrolo[1,2-ajindol-4,7-dion-carbamat.Example 20 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(6-nitrobenzothiazol-2-yl) amino] -azirino-20 [2 ', 3': 3,4jpyrrolo [1,2-ajindol-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde fast kaliumcarbcnat blev tilsat. Ud fra 50 mg af mitomycin A og 30 mg af 2-amino-6~nitrobenzothiazol 25 blev der opnået 20 mg (27% udbytte) af det ønskede produkt med et smeltepunkt på 86-89°C (dekomponering) og med følgende analyse: NMR (DMSO-dg, TS): '6' værdier i ppm.This compound was prepared by the procedure 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 25, 20 mg (27% yield) of the desired product was obtained, mp 86-89 ° C (decomposition) and with the following analysis: NMR (DMSO-dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og 30 forekomst af nye toppe ved 6,9-8,3 (m,4) .Lack of 6-methoxy peak at 4.02 and 30 occurrence of new peaks at 6.9-8.3 (m, 4).

Eksempel 21 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(4-chlorbenzothiazol-2-yl)amino]azirino-35 [2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 21 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(4-chlorobenzothiazol-2-yl) amino] azirino-35 [2 ' , 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at enThis compound was prepared by the procedure described in Example 1, except that one

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16 lille mængde fast'kaliumcarbonat blev tilsat. Ud fra 150 mg af mitomycin A og 27 mg af 2-amiiio-chlorbenzothiazol blev der opnået 30 mg (14% udbytte) af det Ønskede produkt med et smeltepunkt på 89-91°C (dekomponering) 5 og med følgende analyse: NMR (CDC13, TS): '6' værdier i ppm.16 small amounts of solid potassium carbonate were added. From 150 mg of mitomycin A and 27 mg of 2-amino chlorobenzothiazole, 30 mg (14% yield) of the desired product was obtained, mp 89-91 ° C (decomposition) 5 and with the following analysis: NMR ( CDC13, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4/02 og forekomst af nye toppe ved 7,1-8/0 (bred s,4).Lack of 6-methoxy peak at 4/02 and occurrence of new peaks at 7.1-8 / 0 (wide s, 4).

1010

Eksempel 22 I,la,2/8/8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[methyl(2-methylaminoethyl)amino]-azirino-[ 2 ’, 3': 3,4hpyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 22 I, Ia, 2/8 / 8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [methyl (2-methylaminoethyl) amino] -azirino- [2 ', 3' : 3,4hpyrrolo [1,2-a] indole-4,7-dione carbamate.

15 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at en lille mængde fast kaliumcarbonat blev tilsat. Ud fra 50 mg af mitomycin A og 25 mg af sym-dimethylethylendiamin blev der opnået 28 mg (50% udbytte) af det ønskede 20 produkt med et smeltepunkt på 99-101°C (dekomponering) og med følgende analyse: NMR (CDC13, TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1 except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 25 mg of sym dimethylethylenediamine, 28 mg (50% yield) of the desired product was obtained, mp 99-101 ° C (decomposition) and with the following analysis: NMR (CDCl TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst. af nye toppe ved 1,3 (s,l), 25 2,5 (s,6), og 2,7 (s,4).Lack of 6-methoxy peak at 4.02 and incidence. of new peaks at 1.3 (s, 1), 2.5 (s, 6), and 2.7 (s, 4).

Eksempel 23 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(2-hydroxyethylamino)ethylamino]-azirino-30 12*,31:3,4]pyrrolo[l,2-a]indol-4,7-dion-carbamat,Example 23 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethylamino) ethylamino] -azirino-12 *, 31 : 3,4] pyrrolo [l, 2-a] indole-4,7-dione carbamate,

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at opløsningsmidlet var dichlormethan. Ud fra 50 mg af mitomycin A og 18 mg af 2-(2-aminoethylamino)ethanol 35 blev der opnået 35 mg (58% udbytte) af det ønskede produkt med et smeltepunkt på 115-118°C (dekomponering) og med følgende analyse:This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 18 mg of 2- (2-aminoethylamino) ethanol 35, 35 mg (58% yield) of the desired product was obtained, mp 115-118 ° C (decomposition) and with the following analysis :

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17 NMR (CDCl^, TS): ’6' værdier i ppm.17 NMR (CDCl3, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst. af nye toppe ved 2,7 (bred s,7) og 3,7 (t,3).Lack of 6-methoxy peak at 4.02 and incidence. of new peaks at 2.7 (wide s, 7) and 3.7 (t, 3).

55

Eksempel 24 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(2-hydroxyethoxy)ethylamio]-azirino-[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 24 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- [2- (2-hydroxyethoxy) ethylamio] -azirino- [2 ', 3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

1 o Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at opløsningsmidlet var dichlormethan. Ud fra 60 mg af mitomycin A og 20 mg af 2-(2-aminoethoxy)ethanol blev der opnået 30 mg (42% udbytte) af det ønskede produkt med et smelte-1 5 punkt på 99-102°C (dekatrponering) og med følgende analyse: NMR (CDClg, TS): '6' værdier i ppm.This compound was prepared by the procedure 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 was obtained with a melting point of 99-102 ° C (decant exposure) and with the following analysis: NMR (CDCl3, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 3,3-3,9 (bred s,9) og 6,4-6,8 (bred s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 3.3-3.9 (wide s, 9) and 6.4-6.8 (wide s, l).

2020

Eksempel 25 1,la,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]indol-4,7-dion-carbamat.Example 25 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.

25 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra at 128 mg natriunmethoxid blev tilsat. Ud fra 70 mg af mitomycin A og 368 mg af histamindihydrochlorid blev der opnået 61 mg (71% udbytte) af det ønskede produkt med et 30 smeltepunkt på 72-73°C (dekomponering) og med følgende analyse: NMR (DMSO-dg, TS): '6’ værdier i ppm.This compound was prepared by the procedure described in Example 1, except that 128 mg of sodium methoxide was added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride, 61 mg (71% yield) of the desired product was obtained with a melting point of 72-73 ° C (decomposition) and with the following analysis: NMR (DMSO-dg, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 35 3,0-3,27 (m,4), 7,5 (s,l), 8,0-8,7 (bred s,2) og 8,1 (s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 3.0-3.37 (m, 4), 7.5 (s, 1), 8.0-8.7 (wide s, 2) and 8.1 (s, l).

1818

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Eksempel 26 1,la,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]indol-4,7-dion-carbamat.Example 26 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.

Denne forbindelse blev fremstillet ved den i 5 eksempel 1 beskrevne fremgangsmåde. Ud fra 72 mg af mitomycin A og overskud af 1-(2-aminoethyl)-2-nitroimidazol blev der opnået 60 mg (70% udbytte) af det ønskede produkt med et smeltepunkt på 83-85°C (dekomponering) og med følgende analyse: 10 NMR (CDCl^, TS): 'δ' værdier i ppm.This compound was prepared by the procedure described in Example 1. From 72 mg of mitomycin A and excess 1- (2-aminoethyl) -2-nitroimidazole, 60 mg (70% yield) of the desired product was obtained having a melting point of 83-85 ° C (decomposition) and with the following Analysis: 10 NMR (CDCl3, TS): 'δ' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst. af nye toppe ved 3,4 (t,2), 4,6 (t,2), 7,3 (bred s,2) og 7,6 (s,l).Lack of 6-methoxy peak at 4.02 and incidence. of new peaks at 3.4 (t, 2), 4.6 (t, 2), 7.3 (wide s, 2) and 7.6 (s, l).

15 Eksempel 27 1,la,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]indol-4,7-dion-carbamat.Example 27 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.

20 Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde, bortset fra ht opløsningsmidlet var dichlormethan. Ud fra 50 mg af mitomycin A og 30 mg af 2-(2-aminoethylamino)-5-nitropyridin blev der opnået 40 mg (56% udbytte) af det 25 ønskede produkt med et smeltepunkt på 76-79°C (dekomponering) og med følgende analyse: NMR (CDCl^, TS): 'δ* værdier i ppm.This compound was prepared by the procedure described in Example 1, except the solvent was dichloromethane. From 50 mg of mitomycin A and 30 mg of 2- (2-aminoethylamino) -5-nitropyridine, 40 mg (56% yield) of the desired product was obtained, mp 76-79 ° C (decomposition) and with the following analysis: NMR (CDCl3, TS):? δ * values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst "af nye toppe ved 3,3-4,0 30 (m,4) , 6,2-6,7 (bred s,2), 8,1 (d,l), 8,2 (d,1) og 9,0 (s,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 3.3-4.0 30 (m, 4), 6.2-6.7 (wide s, 2), 8.1 (d , l), 8.2 (d, 1) and 9.0 (s, l).

Eksempel 28 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-35 methyl-6-[2-(1-piperazinyl)ethylamino]-azirino-[21,3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat.Example 28 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-35-methyl-6- [2- (1-piperazinyl) ethylamino] -azirino- [21.3 ': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate.

Denne forbindelse blev fremstillet ved den iThis compound was prepared by the i

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19 eksempel 1 beskrevne fremgangsmåde, bortset fra at opløsningsmidlet var dichlormethan. Ud fra 50 mg af mitomycin A og 20 mg af N-(2-aminoethyl)piperazin blev der opnået 23 mg (36% udbytte) af det ønskede 5 produkt med et smeltepunkt på 138-141°C (dekomponering) og med følgende analyse: NMR (CDCl^/ TS): '6' værdier i ppm.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 was obtained, mp 138-141 ° C (decomposition) and with the following analysis : NMR (CDCl3 / TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og forekomst af nye toppe ved 1,6-2,1 10 (bred s,l), 2,2-2,6 (bred s,8), 2,6-2,8 (bred s,4) og 6,9 (t,l).Lack of 6-methoxy peak at 4.02 and occurrence of new peaks at 1.6-2.1 10 (wide s, 1), 2.2-2.6 (wide s, 8), 2.6-2 , 8 (broad s, 4) and 6.9 (t, l).

Eksempel 29 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-15 methyl-6-[2-(2-pyridyl)ethylamino]-azirino[2',3':3,4]- pyrrolo[1,2-a]indol-4,7-dion-carbamat. 'Example 29 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. '

Denne forbindelse blev fremstillet ved den i eksempel 1 beskrevne fremgangsmåde. Ud fra 70 mg af mitomycin A og 250 mg overskud af 2-(2-aminoethyl)-20 pyridin blev der opnået 51 mg (56% udbytte) af det ønskede produkt med et smeltepunkt på 64-77°C (dekomponering) og med følgende analyse: NMR (CDClg, TS): '6' værdier i ppm.This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 250 mg of excess 2- (2-aminoethyl) -20 pyridine, 51 mg (56% yield) of the desired product was obtained, mp 64-77 ° C (decomposition) and with following analysis: NMR (CDCl3, TS): '6' values in ppm.

Manglende 6-methoxy-top ved 4,02 og 25 forekomst af nye toppe ved 2,8 (m,4), 7,0-7,8 (m,3) og 8,5 (d,l).Lack of 6-methoxy peak at 4.02 and 25 occurrence of new peaks at 2.8 (m, 4), 7.0-7.8 (m, 3) and 8.5 (d, 1).

Med speciel henvisning til forbindelserne omfattet af formel Illa, illustrerer de foregående eksempler følgende strukturelle variationer.With particular reference to the compounds of formula IIla, the foregoing examples illustrate the following structural variations.

30 1. Forbindelser hvori Z er en hydroxysubstitueret 1-pyrrolidinylgruppe, repræsenteret af eksempel 1.Compounds wherein Z is a hydroxy-substituted 1-pyrrolidinyl group represented by Example 1.

2. Forbindelser hvori Z er en lavere-alkylsubstitueret piperidylgruppe, repræsenteret af eksempel 2.2. Compounds in which Z is a lower-alkyl-substituted piperidyl group represented by Example 2.

35 3. Forbindelser hvori Z er en 1-piperazinyl- gruppe eller en acetamino-, acetyl-, carbamido-, cyano-, carboxy-lavere-alkylamino-, di-lavere-alkoxy-, nitro-, sulfamyl- eller lavere-alkylsubstitueret anilinogruppe,3. Compounds wherein Z is a 1-piperazinyl group or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl or lower alkyl substituted anilino,

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20 er repræsenteret af henholdsvis eksemplerne 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 og 16.20 are represented by Examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, respectively.

4. Forbindelser, hvori Z er en gruppe med formlén RCompounds in which Z is a group of the formula R

* 1 1 5 -N-R , i hvilken R1 er en nitrogenholdig heterocyclisk gruppe valgt blandt aminosubstitueret triazolyl, lavere- alkylsubstitueret isothiazolyl, benzothiazolyl og nitro- og halogensubstituerede derivater af benzothiazolyl, er repræsenteret af henholdsvis eksemplerne 10 17, 18, 19, 20 og 21.* 1 1 5 -NR, wherein R 1 is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower-alkyl-substituted isothiazolyl, benzothiazolyl, and nitro- and halogen-substituted derivatives of benzothiazolyl, are represented by Examples 10 17, 18, 19, 20, respectively. .

5. Forbindelser, hvori Z er en gruppe med formlen RCompounds wherein Z is a group of formula R

I 1 *1 -N-R , i hvilken R er en substitueret lavere alkyl-gruppe valgt fra gruppen bestående af mono-lavere-alkyl-15 amino-lavere-alkyl, hydroxy-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitrosubstitueret imidazol-lavere-alkyl, nitrosubstitueret pyridylamino-lavere-alkyl, piperazi-nyl-lavere-alkyl og pyridylethyl, er repræsenteret af 20 henholdsvis eksemplerne 22, 23, 24, 25, 26, 27, 28 og 29.In 1 * 1 -NR, wherein R is a substituted lower alkyl group selected from the group consisting of mono-lower-alkyl-amino-lower-alkyl, hydroxy-lower-alkylamino-lower-alkyl, hydroxy-lower-alkoxy lower alkyl, imidazolyl lower alkyl, nitrosubstituted imidazole lower alkyl, nitrosubstituted pyridylamino lower alkyl, piperazinyl lower alkyl and pyridylethyl are represented by Examples 22, 23, 24, 25, 26 respectively. , 27, 28 and 29.

Selv om ingen af de foregående eksempler belyser forbindelser, hvori Y er andet end hydrogen, er forbindelser, hvori Y er lavere alkyl, ikke desto mindre omfattet af opfindelsen, idet der refereres til 25 de analogt substituerede forbindelser ifølge de tidligere nævnte US patentskrifter nr. 4.268.676, 4.460.599 og 4.617.389.Although none of the foregoing examples illustrate compounds in which Y is other than hydrogen, compounds in which Y is lower alkyl are nevertheless encompassed by the invention, with reference to the analogously substituted compounds of the aforementioned U.S. Pat. 4,268,676, 4,460,599 and 4,617,389.

Forbindelserne ifølge opfindelsen formodes at have antibakteriel virkning mod gram-positive og gram-30 negative mikroorganismer på' en måde, der ligner den, der er observeret for naturligt forekomne mitomyciner, og er således potentielt anvendelige som terapeutiske midler ved behandling af bakterielle infektioner hos mennesker og dyr.The compounds of the invention are believed to have antibacterial activity against gram-positive and gram-negative microorganisms in a manner similar to that observed for naturally occurring mitomycins, and are thus potentially useful as therapeutic agents in the treatment of bacterial infections in humans. and animals.

35 Anvendeligheden af forbindelserne med formlenThe utility of the compounds of the formula

Illa ved de antineoplastiske, terapeutiske fremgangsmåder ifølge opfindelsen demonstreres ved hjælp afIIa by the antineoplastic therapeutic methods of the invention is demonstrated by means of

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21 resultaterne af in vivo screening-tests, ved hvilke forbindelserne administreres i varierende doser til mus, i hvilke der er fremkaldt en P388 leukemitilstand. Ovennævnte tests blev udført i overensstemmelse med 5 "Lymphocytic Leukemia P388 - Protocol 1.200",offentliggjort i Cancer Chemotherapy Reports, Part 3, Vol. 3, No.21 results from in vivo screening tests in which the compounds are administered in varying doses to mice in which a P388 leukemia condition is induced. The above tests were performed in accordance with 5 "Lymphocytic Leukemia P388 - Protocol 1,200" published in Cancer Chemotherapy Reports, Part 3, Vol. 3, No.

2, side 9 (september 1972). Kort sagt involverer disse screening-tests administrering af testforbindelsen til CDF^ hunmus, der i forvejen er inficeret med 10^ 10 ascites-celler, der er implanteret intraperitonalt. Testforbindelserne blev kun administreret på den første testdag, og bl.a. dyrenes vitalitet blev overvåget i en 35 dages periode.2, page 9 (September 1972). In brief, these screening tests involve administration of the test compound to CDF 3 female mice previously infected with 10 ^ 10 ascites cells implanted intraperitoneally. The test compounds were administered only on the first test day. the vitality of the animals was monitored for a 35 day period.

Resultaterne fra screening-tests for for-15 bindeiserne fra eksemplerne 1-29 er opstillet i tabel I nedenfor. De opgivne tal omfatter optimal dosis ("O.D."), dvs. den dosis i mg/kg legemsvægt af dyret, ved hvilken de maksimale terapeutiske effekter konsistent er observeret. Median-overlevelsestiden ("MST") 20 udtrykt som MST for testdyrene sammenlignet med MST for kontrolindivider x 100 ("% T/C") er også angivet i tabellen. I forbindelse med in vivo P388 proceduren, der er angivet ovenfor, tyder en % T/C værdi på 125 eller mere på en signifikant antineoplastisk, 25 terapeutisk virkning. Den laveste dosis i mg/kg legemsvægt, ved hvilken 125% T/C værdien opnås, betegnet som den minimale effektive dosis ("MED"). Disse doser er også opstillet i tabel I. Det er bemærkelsesværdigt, at deusædvanligt høje MST værdier, der er opnået ved 30 P388 screening-tests og angivet i tabel I, også tyder på, at forbindelserne ved de angivne doser er i det væsentlige ikke toxiske.The results of screening tests for the precursors of Examples 1-29 are set forth in Table I below. The figures given include the optimal dose ("O.D."), ie. the dose in mg / kg body weight of the animal at which the maximum therapeutic effects are consistently observed. The median survival time ("MST") 20 expressed as MST for the test animals compared to MST for control subjects x 100 ("% T / C") is also given in the table. In the in vivo P388 procedure set forth above, a% T / C value of 125 or more indicates a significant antineoplastic therapeutic effect. The lowest dose in mg / kg body weight at which the 125% T / C value is obtained, designated as the minimum effective dose ("MED"). These doses are also listed in Table I. It is noteworthy that the unusually high MST values obtained by 30 P388 screening tests and listed in Table I also indicate that the compounds at the indicated doses are substantially non-toxic .

DK 161890 BDK 161890 B

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Tabel ITable I

Eksempel Optimal dosis MST MEDExample Optimal dose of MST MED

Nr. mg/kg som % T/C mg/kg 1 25,6 163 0,8 2 25,6 238 <0,2 3 12,3 200 0,2 4 25,6 >333 <0,2 5 25,6 231 0,2 6 6,4 167 0,4 7 25,6 194 1,6 3 3,2 150 0,8 3 12,8 172 <0,2 10 25,6 322 0,8 11 12,8 >333 0,2 12 6,4 161 0,4 13 · 3,2 172 >0,2 14 25,6 225 0,2 15 12,8 167 0,4 16 12,8 181 0,4 17 12,8 181 1,6 18 25,6 169 0,8 19 25,6 150 12,8 20 25,6 128 25,6 21 25,6 144 1,6 22 25,6 133 12,8 23 12,8 133 12,8 24 25,6 181 0,4 25 25,6 163 * 1,6 26 25,6 150 3,2 27 12,8 144 6,4 28 25,6 138 12,8 29 -25,6 >375 0,2No. mg / kg as% T / C mg / kg 1 25.6 163 0.8 2 25.6 238 <0.2 3 12.3 200 0.2 4 25.6> 333 <0.2 5 25.6 231 0.2 6 6.4 167 0.4 7 25.6 194 1.6 3 3.2 150 0.8 3 12.8 172 <0.2 10 25.6 322 0.8 11 12.8> 333 0.2 12 6.4 161 0.4 13 · 3.2 172> 0.2 14 25.6 225 0.2 15 12.8 167 0.4 16 12.8 181 0.4 17 12.8 181 1.6 18 25.6 169 0.8 19 25.6 150 12.8 20 25.6 128 25.6 21 25.6 144 1.6 22 25.6 133 12.8 23 12.8 133 12 , 8 24 25.6 181 0.4 25 25.6 163 * 1.6 26 25.6 150 3.2 27 12.8 144 6.4 28 25.6 138 12.8 29 -25.6> 375 0.2

DK 161890 BDK 161890 B

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Det er indlysende, at de mest foretrukne forbindelser til anvendelse som antineoplastiske midler ifølge opfindelsen er de, der udviser mere end det dobbelte af den relative livsforlængende evne, der generelt karak-5 teriseres som værende tegn på signifikant terapeutisk virkning, dvs. de forbindelser, der har en MST % T/C-værdi, der er større end 2 x 125. Denne klasse forbindelser ses at omfatte forbindelserne fra eksemplerne 4, 10, 11 og 29.It is obvious that the most preferred compounds for use as antineoplastic agents of the invention are those which exhibit more than twice the relative life-prolonging ability generally characterized as being indicative of significant therapeutic efficacy, ie. those compounds having an MST% T / C value greater than 2 x 125. This class of compounds is seen to comprise the compounds of Examples 4, 10, 11 and 29.

10 Som det kan ses i tabel I, udviste så små ini tiale enkeltdoser som 0,2 mg/kg væsentlig og langvarig antineoplastisk virkning. Følgelig kan der ifølge opfindelsen administreres enhedsdoser så små som 0,001 mg eller så store som 5 mg, fortrinsvis fra 0,004 mg til 15 1,0 mg, af forbindelserne som den aktive komponent i et passende farmaceutisk præparat. Sådanne præparater kan administreres dagligt i en mængde på fra 0,1 mg til 100 mg per kg, fortrinsvis fra ca. 0,2 til ca. 51,2 mg per kg, legemsvægt af det menneske eller dyr, der har 20 en neoplastisk lidelse. Det foretrækkes at indgive forbindelserne parenteralt. Farmaceutiske præparater, der egner sig til anvendelse ved den praktiske udøvelse af opfindelsen, kan omfatte simple vandige opløsninger af en eller flere af forbindelserne med formlen Illa, 25 men kan også indeholde velkendte farmaceutisk acceptable fortyndingsmidler, adjuvanser og/eller bærere, såsom salt egnet til medicinsk brug.As can be seen in Table I, as small initial doses as 0.2 mg / kg exhibited significant and long-lasting antineoplastic effect. Accordingly, according to the invention, unit doses as small as 0.001 mg or as large as 5 mg, preferably from 0.004 mg to 1.0 mg, of the compounds can be administered as the active component in a suitable pharmaceutical composition. Such compositions may be administered daily in an amount of from 0.1 mg to 100 mg per kg, preferably from 0.2 to approx. 51.2 mg per kg, body weight of the human or animal having a neoplastic disorder. It is preferred to administer the compounds parenterally. Pharmaceutical compositions suitable for use in the practice of the invention may comprise simple aqueous solutions of one or more of the compounds of formula IIla, but may also contain well-known pharmaceutically acceptable diluents, adjuvants and / or carriers such as salts suitable for use in the invention. medical use.

Claims (7)

1. Mitomycinforbindelse, kendetegnet ved, at den har formlen O O1. Mitomycin compound, characterized in that it has the formula O0 2. Forbindelse ifølge krav 1, kendetegnet ved, at den er 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy- 5-methyl-6-(3-hydroxy-l-pyrrolidinyl)-azirino-[2',3';3,4]pyrrolo[1,2-a]indol -4,7-dion-carbamat; 35 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-methyl-6- (3-methylpiperidy]) -azirino[2^31:3,4]-pyrrolo[1,2-a]indol-4,7-dion-carbamat; DK 161S90B 1,13,2,8,83/8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[4-(acetylamino)anilino]-azirino-[ 2 ', 3' : 3,4 ]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-5 methoxy-5-methyl-6-[3-(acetylamino)anilino]-azirino-[2',31:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-acetylanilino)-azirino[2',3':3,4] -pyrrolo[l,2-a]indol-4,7-dion-carbamat; 10 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a- methoxy-5-methyl-6-[4-(1-ureido)anilino]-azirino-[2',31:3,4]pyrrolo(1,2-a)indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-me thy 1-6- (4-cyanoanilino)-azirino[2',3':3,4]-15 pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,1a, 2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-me thy 1-6- (3-cyanoanilino)-azirino[2',31;3,4]-pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-20 methoxy-5-methyl-6-[4-(N-glycyl)anilino]-azirino-[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-dimethoxyanilino)-azirino-[2',31:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 25 l/la^/S/Sa/Sb-Hexahydro-S*- (hydroxymethyl)-8a- methoxy-5-methyl-6-(3,5-dimethoxyanilino)-azirino-[21,3':3:4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-nitroanilino)-azirino-30 [2',3';3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-sulfamylanilino)-azirino-[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat ; DK 161890 B 1,13,2,8,83,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(5-amino-l,2,4-triazol-3-yl)amino]-azirino[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 5 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Sa me thoxy-5-methy 1-6- [ (3-methylisothiazol-5-yl) amino]-azirino[2',31:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-10 methoxy-5-methyl-6-[(2-benzothiazolyl) amino]-azirino-[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 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]indol-4,7-dion-15 carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(4-chlorbenzothiazol-2-yl)-amino]-azirino[2',31:3,4]pyrrolo(1,2-a]indol-4,7-dion-carbamat · 20 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a- methoxy-5-methy1-6-[methyl(2-methylaminoethyl)amino]-azirino[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-25 methoxy-5-methyl-6-[2-(2-hydroxyethylamino)ethylamino]-azirino[2*,3*:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(2-hydroxyethoxy)ethylamino]-azirino[21,31:3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; 30 1,la,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]indol-4,7-dion-aarbamat; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy- 5 -methyl- 6- [(2-nitro-l-imidazolyl)ethylamino]-35 azirino[2',3':3,4]pyrrolo[1,2-a]indol-4,7-dion-carbamat; DK 161890 B 1,13,2,8,83,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-methy1-6-{2-[(5-nitro-2^pyridyl)amino]-ethylamino}-azirino [2', 3': 3,4] pyrrolo [ 1,2-a] indol-4,7-dion-carbamat ? 5 1, la, 2,8,8a, 8b-Hexahydro*-8~ (hydroxymethyl) *-8a- methoxy-5-methyl-6-[2~(1-piperazinyl)ethylaminoj-azirino-[2*,3* s3,4]pyrrolo[1,2-a)indol-4,7-dion-carbamat.Compound according to claim 1, characterized in that it is 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) -Same thoxy-5-methyl-6- (3-methylpiperidyl]) -azirino [2 ^ 31: 3,4] pyrrolo [ 1,2-a] indole-4,7-dione carbamate; DK 161S90B 1,13,2,8,83 / 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-5-methoxy-5-methyl-6- [3- (acetylamino) anilino] -azirino- [2 ', 31: 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 [l, 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 ', 31: 3,4] pyrrolo (1,2-a) indole-4,7-dione carbamate; 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Same thoxy-5-methyl-1-6- (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) -Same thoxy-5-methyl-1-6- (3-cyanoanilino) -azirino [2 ', 31; 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-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (3,4-dimethoxyanilino) -azirino- [2 ', 31: 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1 / 1a / S / Sa / Sb-Hexahydro-S * - (hydroxymethyl) -8-methoxy-5-methyl-6- (3,5-dimethoxyanilino) -azirino- [21,3 ': 3: 4 a] 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-30 [2 ', 3'; 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6- (4-sulfamylanilino) -azirino- [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; B 1,13,2,8,83,8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(5-amino-1,2,4-triazol-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) -Same methoxy-5-methyl 1-6- [(3-methylisothiazol-5-yl) amino] -azirino [2 ', 31: 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-nitro-benzothiazol-2-yl) amino] -azirino [2 *, 3 ' : 3,4] pyrrolo [1,2-a] indole-4,7-dione-carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5-methyl-6 - [(4-Chloro-benzothiazol-2-yl) amino] -azirino [2 ', 31 : 3,4] pyrrolo (1,2-a] indole-4,7-dione carbamate · 1, 1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5 methyl6- [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] -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-hydroxyethoxy) ethylamino] -azirino [21,31: 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; 1, 1a, 2,8,8a, 8b-Hexahydroxy 8- (hydroxymethyl) -8-methoxy-5-methyl-6- [2- (4-imidazolyl) ethylamino] -azirino- [2 *, 3 *: 3,4] pyrrolo [1,2-a] indole 4,7-dione aarbamate; 1,1a, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Same thoxy-5-methyl-6- [(2-nitro-1-imidazolyl) ethylamino] - Azirino [2 ', 3': 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate; DK 161890 B 1,13,2,8,83,8b-Hexahydroxy 8- (hydroxymethyl) -Same thoxy-5-methyl-6- {2 - [(5-nitro-2-pyridyl) amino] -ethylamino} -azirino [2 ', 3': 3,4] pyrrolo [1, 2-a] indole-4,7-dione carbamate? 5 1, 1a, 2,8,8a, 8b-Hexahydro * -8 ~ (hydroxymethyl) * -8a-methoxy-5-methyl-6- [2- (1-piperazinyl) ethylamino] -azirino- [2 *, 3 * s3,4] pyrrolo [1,2-a) indole-4,7-dione carbamate. 3. Forbindelse ifølge krav 1 eller 2 til anvendelse ved behandling af neoplastiske sygdomstilstande 10 hos et dyr eller menneske.A compound according to claim 1 or 2 for use in the treatment of neoplastic disease states 10 in an animal or human. 4. Forbindelse ifølge krav 1 eller 2, kendetegnet ved, at den anvendes i en daglig dosis på mellem ca. 0,2 mg og ca. 51,2 mg per kg legemsvægt ved behandling af neoplastiske sygdomstilstande hos et dyr 15 eller menneske.A compound according to claim 1 or 2, characterized in that it is used in a daily dose of between 0.2 mg and approx. 51.2 mg per kg body weight in the treatment of neoplastic disease states in an animal or human. 5. Farmaceutisk præparat, kendetegnet ved, at det indeholder et farmaceutisk acceptabelt opløsningsmiddel, fortyndingsmiddel, adjuvans eller bærer og, som den aktive komponent, fra ca. 0,001 til ca. 5 mg 20 af en forbindelse med formlen 0 « ^ch2ocnh2 i il L- 00113 ni hvori Y er hydrogen eller lavere alkyl; og X er en hydroxysubstitueret 1-pyrrolidinylgruppe, 30 en lavere-alkylsubstitueret piperidylgruppe, en acetamino-, acetyl-, carbamido-, cyano-, carboxy-lavere-alkylamino-, di-lavere-alkoxy-, nitro- eller sulfamyl-substitueret anilinogruppe, eller R 1 1 35 en gruppe med formlen -N-R hvori R er hydrogen eller lavere alkyl, og R^ er en nitrogenholdig heterocyclisk gruppe valgt blandt amino-substitueret triazolyl, lavere-alkylsubstitueret DK 161890 B isothiazolyl, benzothiazolyl og nitro- og halogensubstituerede derivater af benzothiazolyl, eller R^ er en substitueret lavere alkylgruppe valgt blandt mono-lavere-alkylamino-lavere-alkyl, hydroxy-lavere -5 alkylamino-lavere-alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitro-substitueret imidazolyl-lavere-alkyl, nitro-substitueret pyridyl-amino-lavere-alkyl og piperazinyl-lavere-alkyl.Pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable solvent, diluent, adjuvant or carrier and, as the active component, from 0.001 to approx. 5 mg 20 of a compound of the formula 0 «^ ch2₂₂₂n₂₂ in I il L-00113 ni wherein Y is hydrogen or lower alkyl; and X is a hydroxy-substituted 1-pyrrolidinyl group, a lower-alkyl-substituted piperidyl group, an acetamino, acetyl, carbamido, cyano, carboxy-lower-alkylamino, di-lower-alkoxy, nitro or sulfamyl-substituted anilino group or R 1 is a group of the formula -NR wherein R is hydrogen or lower alkyl and R 1 is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower-alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives is a substituted lower alkyl group selected from mono-lower-alkylamino-lower-alkyl, hydroxy-lower-5-alkylamino-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, imidazolyl-lower-alkyl, nitro-substituted imidazolyl-lower-alkyl, nitro-substituted pyridyl-amino-lower-alkyl and piperazinyl-lower-alkyl. 5. CH2oInH2 i I T_.och3 10 hvori Y er hydrogen eller lavere alkyl; og X er en hydroxysubstitueret 1-pyrrolidinylgruppe, en lavere-alkylsubstitueret piperidylgruppe, en acetamino-, acetyl-, carbamido-, cyano-, aarboxy-lavere-alkylamino-, di-lavere-alkoxy-, nitro-15 eller sulfamylsubstitueret anilinogruppe, eller R I i en gruppe med formlen -N-R hvori R er hydrogen eller lavere alkyl, og R* er en nitrogenholdig heterocyclisk gruppe valgt blandt amino-20 substitueret triazolyl, lavere-alkyl-substitueret isothiazolyl, benzothiazolyl og nitro- og halogensubstituerede derivater af benzothiazolyl, eller R^" er en substitueret lavere alkylgruppe valgt blandt 25 mono-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkylamino-lavere—alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitro-substitueret imidazolyl-lavere-alkyl, nitro-substitueret pyridyl-amino-lavere-alkyl og piperazinyl-lavere-alkyl.5. CH 2 O H 2 in I T 1 and 3 wherein Y is hydrogen or lower alkyl; and X is a hydroxy-substituted 1-pyrrolidinyl group, a lower-alkyl-substituted piperidyl group, an acetamino, acetyl, carbamido, cyano, aarboxy-lower-alkylamino, di-lower-alkoxy, nitro-or sulfamyl-substituted aniline or R 1 in a group of the formula -NR wherein R is hydrogen or lower alkyl and R * is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower-alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives of benzothiazolyl, or Is a substituted lower alkyl group selected from mono-lower alkylamino-lower-alkyl, hydroxy-lower-alkylamino-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, imidazolyl-lower-alkyl, nitro-substituted imidazolyl-lower-alkyl, nitro-substituted pyridyl-amino-lower-alkyl and piperazinyl-lower-alkyl. 6. Farmaceutisk præparat ifølge krav 5, til an-10 vendelse ved behandling af neoplastiske sygdomstilstande hos et dyr eller menneske.The pharmaceutical composition of claim 5, for use in treating neoplastic disease conditions in an animal or human. 7. Anvendelse af en forbindelse med formlen l ^ 15 .^CH2OCNH2 I I _____OCHj !3c ιτΛ 11Ia o I_lx« 20 hvori Y er hydrogen eller lavere alkyl? og Z er en hydroxysubstitueret 1-pyrrolidinylgruppe, en lavere-alkylsubstitueret piperidylgruppe, en 1-piperazinylgruppe, 25 en acetamino-, acetyl-, carbamido-, cyano-, carboxy-lavere-alkylamino-, di-lavere-alkoxy-, nitro-, sulfamyl-eller lavere-alkylsubstitueret anilinogruppe, eller R ' i en gruppe med formlen -N-R 30 hvori R er hydrogen eller lavere alkyl,og R^ er en nitrogenholdig heterocyclisk gruppe valgt blandt amino-substitueret triazolyl, lavere-alkylsubstitueret isothiazolyl, benzothiazolyl og nitro- og halogen- substituerede derivater af benzothiazolyl, eller R er 35 en substitueret lavere alkylgruppe valgt blandt mono-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkylamino-lavere-alkyl, hydroxy-lavere-alkoxy-lavere-alkyl, imidazolyl-lavere-alkyl, nitro-substitueret DK 101890 B imidazolyl-lavere-alkyl, nitro-substitueret pyridylami.no-lavere-alkyl, piperazinyl-lavere-alkyl og pyridylethyl, til fremstilling af et lægemiddel med virkning mod neo-plastiske sygdomstilstande.Use of a compound of formula I ^ 15. CH2OCNH2 I I _____OCHj! 3c ιτΛ 11Ia o I_lx «20 wherein Y is hydrogen or lower alkyl? and Z is a hydroxy-substituted 1-pyrrolidinyl group, a lower-alkyl-substituted piperidyl group, a 1-piperazinyl group, an acetamino, acetyl, carbamido, cyano, carboxy-lower alkylamino, di-lower alkoxy, nitro , sulfamyl or lower alkyl substituted anilino group, or R 'in a group of the formula -NR 30 wherein R is hydrogen or lower alkyl and R 1 is a nitrogen-containing heterocyclic group selected from amino-substituted triazolyl, lower-alkyl-substituted isothiazolyl, benzothiazolyl and nitro- and halogen-substituted derivatives of benzothiazolyl, or R is a substituted lower alkyl group selected from mono-lower-alkylamino-lower-alkyl, hydroxy-lower-alkylamino-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, imidazolyl-lower-alkyl, nitro-substituted DK-101890 B lstande.
DK052484A 1983-02-07 1984-02-06 MITOMYCIN ANALOGS AND PHARMACEUTICAL PREPARATIONS THEREOF, WITH ANTINEOPLASTIC EFFECT DK161890C (en)

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