CA1252789A - Mitomycin analogs - Google Patents
Mitomycin analogsInfo
- Publication number
- CA1252789A CA1252789A CA000446811A CA446811A CA1252789A CA 1252789 A CA1252789 A CA 1252789A CA 000446811 A CA000446811 A CA 000446811A CA 446811 A CA446811 A CA 446811A CA 1252789 A CA1252789 A CA 1252789A
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- Prior art keywords
- lower alkyl
- methoxy
- methyl
- indole
- hydroxymethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic 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
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
Novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula IIIa, IIIa wherein: Y is hydrogen or lower alkyl; and Z
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula,
Novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula IIIa, IIIa wherein: Y is hydrogen or lower alkyl; and Z
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula,
Description
252~
"MITOMYCIN ANALOGS"
BACKGROUND
The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
The disclosures of my U.S. Letters Patent No.
4,268,676; No. 4,460,529; and my co-pending Canadian Patent Application Serial No. 3B9,102 filed March 11, 1982 may provide material relating to the present invention.
Briefly summarized, said UOS. Patents set forth a statement of the background of the ongoing search in the art for new and useful compounds which are structurally related to the mitomycins, which possess antibiotic activity, which have low toxicity and which display a substantial degree of antitumor activity in animals. More particularly, they disclose new compounds of the formula I, H ~ NH 2 wherein: Y is hydrogen or lower alkyl; and X
is a thiazolamino radical, a furfurylamino radical or a radical of the formula, R ~1 ---N - C - R
in which R, Rl and R2 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R3 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuxyl and benzene sulfonamide.
Said U.S. patents also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, Ia, ~ ~ CH2OCNH2 \,/\
II I 10CH3 Ia H3C~/ ~b o wharein: Y is hydro~en or lower alkyl; and Z
is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula, I i 7 - N ~ - R
R
~' ~2~
in which R4, R5, and R6 are the sa~e ox different and selected from the group consistin~ of hydrogen and lower alkyl, and R7 is selçcted from the group consist-ing of lower alkenyl, halo-lower alken~l, lower alkynyl, 5 lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
~ .S. Patent NoO 4,460,529 also discloses compounds with a substantial degree of antitumor activity 10 in animals of the following formula IIa, O O
~JI~ / CH20CNH2 lS ~ IIa wherein: Y is hydrogen or lower alkyl; and Z
is a lower alkoxy substituted quinolinylamino radical, a cyano substituted pyrazolylamino radical or a mono-or di-lower alkyl substituted thiazolamino radical, or a nitrogen-containing heterocyclic radical 25 selected rom the group consistin~ of l-pyrrolinyl, 1-indolinyl, N-thiazolidinyl, N-morpholinyl, l-piperazinyl, and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxy-carbonyl substituted l-aziridin~l radical, or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydrox~ or pipe~idyl substituted l-piperidyl radical, or a lower alkoxy, amino or halo substituted 35 pyridylamino radical, or `
a c~rboxamido, mercapto ox ~ethylenedioxy substituted anilino radical, or R
a radical of the for~ula, -N-R1 wherein R is hydro~en or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consistin~ of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and 10 halo substituted derivatives thereof, or a butyrolactonyl radical, or an adamantyl radical, or a mono-lower alkoxy substituted phenyl radical, or a substituted lower alkyl radical selected from the ~roup consisting of mercapto lower alkyl, carboxy lower alkyl, mono-, di~ and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted derivatives thereof, cyano 20 lower alkyl, mono-, di- and tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, l-pyrrolidinyl lower alkyl, N-lower alkyl pyrrolidinyl lower alkyl, N-morpholinyl lower alkyl, and lower dialkylamino lower alk~l.
Also pertinent to the back~round of the present invention are the followin~ references: Cosulich, et al., U.S. Patent No. 3,332,944; Matsui, et al., U.S.
Patent No. 3,410,867; ~akano, et al., U.SO Pate~t No.
4,231,936; Matsui, et al., U.S. Patent No. 3,429,894;
30 Remers, U.S. Patent No~ 4,268,676; ~atSui, et al., U.S.
Patent No. 3,450,705i Matsui, et al., U.S. Patent No~
3,514,452; and I~ai, et al., Gann, 71, pp. 560-562 (1980).
~5~
BRIEF SUMMARY
Accordin~ to the present invention, there are provided no~el compounds of the formula, III, O
Il 11 ~CE~20CNH ;~
¦ OCH3 ~ ~ NY III
wherein: Y is hydro~en or lower alkyl; and X
15 is an hydroxy substituted l-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamyl substitu~ed anilino radical, or a radical of the formula, -N-R
wherein R is hydrogen or lower alkyl and Rl is a nitrogen containing heterocyclic radical selected from the group consisting o~ amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo- 0 thiazolyl, or Rl is a substituted lower alkyl radical selected from the group consisting of amino lowex alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamlno lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl 35 lower alkyl, nitro substituted imidazolyl lower alkyl, ~2~
nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
Also provided according to the invention are novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, IIIa, ~ / ~ ~--CH20CNH2 l ~ CH3 H3 ~ ~ ~ IIIa wherein: Y is hydrogen or lower alkyl; and Z
is an hydroxy substituted l-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or R
a radical of the formula, -N-Rl wherein R is hydrogen or lower alkyl and Rl is a n.itrogen containing heterocyclic radical selected ~rom the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo-thiazolyl, or Rl is a substituted lower alkyl radical selected from the group consisting of amino lower al]cyl, lower ~2~
alkylamino lower alkyl, hyd~oxy lower alkylamino lower alkyl, hydroxy lower alkoxy, lower alkyl, imidazolyl lower alkyl, nitro substi~uted imidazolyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alXyl, and pyridyl ethyl.
Unless otherwise indicated, the term "lower", applied to "alkyl" radicals shall designate such straight or branched chain radicals as to include from one to six carbon atoms. By way of illustration, "lower alkyl" shall mean and include methyl, ethyl, propyl, butyl, pentyl and hexyl radicals as well as isopropyl radicals, t-butyl radicals and the like. Similarly, "lower" as applied to "alkoxy" shall designate a radical having one to six carbon atoms.
It will be apparent that the compounds of formula III are all comprehended by the specifications of formula IIIa. Put another way, all the novel anti-biotic mitomycin derivatives of formula III are useful in practice of the novel antineoplastic therapeutic ~0 methods which involve administration of compounds of formula IIIa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with the appropriately selected amine compounds. The N-alkyl-~5 mitomycin (e.g., N-methylmitomycin) derivatives are similarly prepared by the reaction of a selected amine with N-alkylmitomycin h prepared from mitomycin C, e.g., according to the methods generally disclosed in Cheng, et al., J.Med.Chem., 20, No. 6, 767-770 (1977). The preparative reactions generally yield the desired product as a crystalline solid which is readily soluble in alcohol.
Therapeutic methods of the invention compre-hend the administration of effective amounts of one or more of the compounds of formula IIIa, as an active ingredient, . . . . . . . . . . . . . . . . . . . . .
._ together with desired pharmaceutically acceptable diluents, adjuvants and carrie~s, to ~n animal suffering from a neoplastic disease state. Unit dosa~e forms of compounds administered according to the methods of -the 5 invention may range from about 0.001 to about 5.0 mg and preferably from about 0.00~ to about 1.0 mg, of the compounds. Such unit dosage quantities may be given to provide a daily dosage of from about 0.1 to about 100 mg per kg, and preferably from a~out 0.2 to about 51.2 10 mg per kg, of body weight o~ the animal treated.
Parenteral administration, and especially intraperitoneal administration, is the preferred route for practice of the inventive methods.
Other aspects and advantages of the present 15 invention will become apparent upon consideration of the following description.
DESCRIPTIO~ OF INVENTION
The following Examples 1 through 32, descri~ing preparation of certain presently preferred compounds according to the invention, are for illustrative purposes only and are not to be construed as limiting the invention.
Unless otherwise indicated, all reactions were carried ~5 out at room temperature (20QC), without added heat.
Unless otherwise indicated, all thin layer chromato-graphic (TLC) procedures emplo~ed to check the progress of reactions involved the use of a pre-coated silica-gel plate and a mixture o~ methanol and chloroform (2~8 30 by volume~ as a developin~ solvent~
E~
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-5-methyl-6- 3-hydroxy-1-pyrrolidinyl)-azirino~2',3':3,4]
pyrrolo[l~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) under nitrogen at room temperature. W~en thin-layer chromatography on silica gel (2:8 methanol-chloroform as solvent) showed that staxting material no 10 longer was present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography using the same solvent system. This procedure gave 23 mg (40% yield) of the desired product having a melting point of 82-5 85C (decomposition) and providing the following analysis:NMR (DMSO-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.6-2.2 (m,2),
"MITOMYCIN ANALOGS"
BACKGROUND
The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
The disclosures of my U.S. Letters Patent No.
4,268,676; No. 4,460,529; and my co-pending Canadian Patent Application Serial No. 3B9,102 filed March 11, 1982 may provide material relating to the present invention.
Briefly summarized, said UOS. Patents set forth a statement of the background of the ongoing search in the art for new and useful compounds which are structurally related to the mitomycins, which possess antibiotic activity, which have low toxicity and which display a substantial degree of antitumor activity in animals. More particularly, they disclose new compounds of the formula I, H ~ NH 2 wherein: Y is hydrogen or lower alkyl; and X
is a thiazolamino radical, a furfurylamino radical or a radical of the formula, R ~1 ---N - C - R
in which R, Rl and R2 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R3 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuxyl and benzene sulfonamide.
Said U.S. patents also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, Ia, ~ ~ CH2OCNH2 \,/\
II I 10CH3 Ia H3C~/ ~b o wharein: Y is hydro~en or lower alkyl; and Z
is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula, I i 7 - N ~ - R
R
~' ~2~
in which R4, R5, and R6 are the sa~e ox different and selected from the group consistin~ of hydrogen and lower alkyl, and R7 is selçcted from the group consist-ing of lower alkenyl, halo-lower alken~l, lower alkynyl, 5 lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
~ .S. Patent NoO 4,460,529 also discloses compounds with a substantial degree of antitumor activity 10 in animals of the following formula IIa, O O
~JI~ / CH20CNH2 lS ~ IIa wherein: Y is hydrogen or lower alkyl; and Z
is a lower alkoxy substituted quinolinylamino radical, a cyano substituted pyrazolylamino radical or a mono-or di-lower alkyl substituted thiazolamino radical, or a nitrogen-containing heterocyclic radical 25 selected rom the group consistin~ of l-pyrrolinyl, 1-indolinyl, N-thiazolidinyl, N-morpholinyl, l-piperazinyl, and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxy-carbonyl substituted l-aziridin~l radical, or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydrox~ or pipe~idyl substituted l-piperidyl radical, or a lower alkoxy, amino or halo substituted 35 pyridylamino radical, or `
a c~rboxamido, mercapto ox ~ethylenedioxy substituted anilino radical, or R
a radical of the for~ula, -N-R1 wherein R is hydro~en or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consistin~ of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and 10 halo substituted derivatives thereof, or a butyrolactonyl radical, or an adamantyl radical, or a mono-lower alkoxy substituted phenyl radical, or a substituted lower alkyl radical selected from the ~roup consisting of mercapto lower alkyl, carboxy lower alkyl, mono-, di~ and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted derivatives thereof, cyano 20 lower alkyl, mono-, di- and tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, l-pyrrolidinyl lower alkyl, N-lower alkyl pyrrolidinyl lower alkyl, N-morpholinyl lower alkyl, and lower dialkylamino lower alk~l.
Also pertinent to the back~round of the present invention are the followin~ references: Cosulich, et al., U.S. Patent No. 3,332,944; Matsui, et al., U.S.
Patent No. 3,410,867; ~akano, et al., U.SO Pate~t No.
4,231,936; Matsui, et al., U.S. Patent No. 3,429,894;
30 Remers, U.S. Patent No~ 4,268,676; ~atSui, et al., U.S.
Patent No. 3,450,705i Matsui, et al., U.S. Patent No~
3,514,452; and I~ai, et al., Gann, 71, pp. 560-562 (1980).
~5~
BRIEF SUMMARY
Accordin~ to the present invention, there are provided no~el compounds of the formula, III, O
Il 11 ~CE~20CNH ;~
¦ OCH3 ~ ~ NY III
wherein: Y is hydro~en or lower alkyl; and X
15 is an hydroxy substituted l-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamyl substitu~ed anilino radical, or a radical of the formula, -N-R
wherein R is hydrogen or lower alkyl and Rl is a nitrogen containing heterocyclic radical selected from the group consisting o~ amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo- 0 thiazolyl, or Rl is a substituted lower alkyl radical selected from the group consisting of amino lowex alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamlno lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl 35 lower alkyl, nitro substituted imidazolyl lower alkyl, ~2~
nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
Also provided according to the invention are novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, IIIa, ~ / ~ ~--CH20CNH2 l ~ CH3 H3 ~ ~ ~ IIIa wherein: Y is hydrogen or lower alkyl; and Z
is an hydroxy substituted l-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or R
a radical of the formula, -N-Rl wherein R is hydrogen or lower alkyl and Rl is a n.itrogen containing heterocyclic radical selected ~rom the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo-thiazolyl, or Rl is a substituted lower alkyl radical selected from the group consisting of amino lower al]cyl, lower ~2~
alkylamino lower alkyl, hyd~oxy lower alkylamino lower alkyl, hydroxy lower alkoxy, lower alkyl, imidazolyl lower alkyl, nitro substi~uted imidazolyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alXyl, and pyridyl ethyl.
Unless otherwise indicated, the term "lower", applied to "alkyl" radicals shall designate such straight or branched chain radicals as to include from one to six carbon atoms. By way of illustration, "lower alkyl" shall mean and include methyl, ethyl, propyl, butyl, pentyl and hexyl radicals as well as isopropyl radicals, t-butyl radicals and the like. Similarly, "lower" as applied to "alkoxy" shall designate a radical having one to six carbon atoms.
It will be apparent that the compounds of formula III are all comprehended by the specifications of formula IIIa. Put another way, all the novel anti-biotic mitomycin derivatives of formula III are useful in practice of the novel antineoplastic therapeutic ~0 methods which involve administration of compounds of formula IIIa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with the appropriately selected amine compounds. The N-alkyl-~5 mitomycin (e.g., N-methylmitomycin) derivatives are similarly prepared by the reaction of a selected amine with N-alkylmitomycin h prepared from mitomycin C, e.g., according to the methods generally disclosed in Cheng, et al., J.Med.Chem., 20, No. 6, 767-770 (1977). The preparative reactions generally yield the desired product as a crystalline solid which is readily soluble in alcohol.
Therapeutic methods of the invention compre-hend the administration of effective amounts of one or more of the compounds of formula IIIa, as an active ingredient, . . . . . . . . . . . . . . . . . . . . .
._ together with desired pharmaceutically acceptable diluents, adjuvants and carrie~s, to ~n animal suffering from a neoplastic disease state. Unit dosa~e forms of compounds administered according to the methods of -the 5 invention may range from about 0.001 to about 5.0 mg and preferably from about 0.00~ to about 1.0 mg, of the compounds. Such unit dosage quantities may be given to provide a daily dosage of from about 0.1 to about 100 mg per kg, and preferably from a~out 0.2 to about 51.2 10 mg per kg, of body weight o~ the animal treated.
Parenteral administration, and especially intraperitoneal administration, is the preferred route for practice of the inventive methods.
Other aspects and advantages of the present 15 invention will become apparent upon consideration of the following description.
DESCRIPTIO~ OF INVENTION
The following Examples 1 through 32, descri~ing preparation of certain presently preferred compounds according to the invention, are for illustrative purposes only and are not to be construed as limiting the invention.
Unless otherwise indicated, all reactions were carried ~5 out at room temperature (20QC), without added heat.
Unless otherwise indicated, all thin layer chromato-graphic (TLC) procedures emplo~ed to check the progress of reactions involved the use of a pre-coated silica-gel plate and a mixture o~ methanol and chloroform (2~8 30 by volume~ as a developin~ solvent~
E~
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-5-methyl-6- 3-hydroxy-1-pyrrolidinyl)-azirino~2',3':3,4]
pyrrolo[l~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) under nitrogen at room temperature. W~en thin-layer chromatography on silica gel (2:8 methanol-chloroform as solvent) showed that staxting material no 10 longer was present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography using the same solvent system. This procedure gave 23 mg (40% yield) of the desired product having a melting point of 82-5 85C (decomposition) and providing the following analysis:NMR (DMSO-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.6-2.2 (m,2),
2.8-3.1 (broad s,5) and 4.0-4.3 (m,l).
0 Example_2 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethy1)-8a-methox~t-5-methyl-6-(3-meth=ylpiperdyl)-azirino[2',3':3,4]pyrrol~o [1,2-a~indole-4,7-dione carbamate
5 This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 200 mg of 3-methyl piperdine was obtained 46 mg (55~
yield) of the desired pxoduct having a melting point of 30 75-88C (decomposition) and p~oviding the following analysis:
NMR (CDC13, TS)~ alues in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 0.85 (d,3), 1.10-2.15 (m,5) and 2.15-3.32 (m,4).
s Example 3 1,la,2,S,8a,3b~Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6~ piperazinyl)-azirino[2',3':3,4]pyrxolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 ~g of mitomycin A and 30 mg of anhydrous piperazine was obtained 23 mg (34%
yield) of the desired product having a melting point 15 greater than 200C (decomposition) ~nd providin~ the following analysis:
NMR (DMSO-d6, TS): '~' values in ppm.
Absence of the 6-~ethoxy peak at 4.02 and the appearance of new peAks at 1.9 (broad s,l) and 2.9 (s,8).
Example 4 1,la,2,8,8a,8b-Hexahydro-8-(h dxoxymethyl~-8a-methoxy-5-methYl-6-[4-(acetylamino)anilino]-azirino[2',3':3,4]
25 Eyrrolo[1,2-a]indole-4,7-dlone carbamate This compound was p~epaxed by the procedure described in Example 1. ~xom 100 m~ of mitomycin A and excess 4-(acetylamino)aniline ~s obtained 102 ~g (76%
30 yield~ of the desired pxoduct haYin~ a melting point of 143q-145C (decomposition) and pxo~iding the ~ollowin~
analysis:
~25~
NMR (CDC13, TS): '~' values in ppm.
Absence of th~ 6-~ethoxy peak at 4.02 and the appearance o~ new peaks at 2,1 ~,s,3), 7.4 (d,2~, 7.6 's,l) and 8.9-9.3 (s,l).
Example 5 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[3-(acetylamino)anilino]-aæirino[2l,3':3,4]
rrolo[l 2-a]indole-4,7-dione caxbamate F ,~ r 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 was 15 obtained 67 mg (72% yield) of the desired product having a melting point o~ 140-143~C (decomposition) and providing the following analysis:
N~R (Acetone-d , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 6.7-7.5 (m,4), 8.0 (broad s,l~ and 9.3 (s,l).
Example 6 25 1,la,2,8,8a,8b-Hexahydro-8-(hYdroxYmethyl)-8~-methoX -5-methvl-6-('4-acetYlanilino)-azirinoL2',3':3-,4]pyrrolo Ll,2-a~indole-4,7-dione caxbamate This compound wa~ prep~red by the procedure 30 described in Example 1, except that a small amount of solid potassium carbonate was ~dded. From 70 mg o mitomycin A and 510 mg of 4-acet~Ylaniline was obtained 25 mg (28~ yield) of the desired product having a melting point o 103-104C (decomposition~ and providing -- 3i the o}1Owing analysis:
NMR (CDC13, TS), I~ valu~s in pp~.
~bsence of the 6-methoxy peak at 4.02 and the ~ppearance of ne~ peaks at 2.1 (s,3~, 6.6(d,2), 7.3 (d,2) and 7.0-7.~ (broad s,l~.
Ex'amp1e 7 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-me'thoxy-5 meth~l-6-[4-(1-ureido)anilino]-azirino[~',3':3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate _ ' This carbamido-substituted compound was prepared by the procedure described in ~xample 1. From 50 mg of mitomycin ~ and 227 mg o~ 4-(1-ureido)aniline was obtained 49 mg (67% yield) of the desired p~oduct having a melting 15 point of ~3-95C (decomposition) and providing the fol-lowing analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 5.03 (s,2), 6.9 (d,2), 7.3 (d,2), 8.0 (s,l) and 8.4 (s,l).
Example 8 1,la,2,8,8a,8b-Hexahydro-8-(h~d~oxymeth 1~-8a-methox -5-methyl-6-(4--cyanoanilino)-azirino[2',3l:3r4]pyrrolo[1,2-a3 25 indole-4,7-dione carb'amate This compound wa~ prepared by the procedure described in Example l, except that a small amount of solid potassium carbonate waS added. From 70 m~ of 30 mitom~cin A and 472 mg of 4-aminobenzonitxile was obt~ined 23 mg (24% ~ield~ of the desi~ed product having a melting point of 124-126QC (decomposition~
and providing the following anal~sis:
NMR (CDC13, TS): '~ ' values in ppm.
Absence of the 6-methoxY peak at 4.02 and the appearance of new peaks at 6.6 (d,2), 7.4 (d,2) and 7.0-7.3 (broad s,l~.
Exam~le 9 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5~
methyl-6-(3-cyanoanilino)-azirino[2',3':3,4]pyrroloEl,2-a]
indole-4,7-dione carbamate _ _ _ _ This compound was prepared by the procedure described in Example 1, except tha-t a small amount of solid potassium carbonate was added. From 71 mg of mitomycin A and 500 mg of 3-aminobenzonitrile was 1~ obtained 30 mg (34% yield) of the desired product having a melting point of 97-98C (deoomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the ~0 appearance of new peaks at 7.2-7.8 (m,4).
Example 10 1,la,2,8,8a-,8b-Hexahvdro-8 (hYdroxYmethyl)-8a-methoxY-5-~- methyl-6-[4-(N-glycv ~ ,3':3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate ~~~
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 was obtained 62 mg (90~
yield) of the desired product having a melting point of 83-85C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): '~' values ln ppm.
~bsence of the 6-methoxy peak at 4.02 ~nd the appearance of new peaks at 3.1 (s,2~, 6.3-6.6 (broad s,2), 6.6-6.8 (broad s,2) and 6.6-7.1 (broad s,2).
E ample 11 1,la,2,8,8a,8b-Hexahydro-8-(h~droxymethyl)-8a-methoxy-5-methyl-6-(3,4-''dimethoxyanilino)-azirlno[2',3':3,4~pyrrolo [1,2-a]indole-4,7'-dione carbamate .... . . .
This compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 229 mg of 3,4-dimethoxyaniline was obtained 61 mg (91~ yield) of 15 ~he desired product having a melting point of 114-116C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Aksence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6), 6.3-~.9 (m,3) and 7.7 (s,l).
Example 12 1,la,'2,8,8a,3b-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 procedure described in Example 1. F~om 50 mg of mitomycin A and 30 229 mg of 3,5-dimethoxy~niline was obtained 60 mg (88~
yield) of the desired product having a meltin~ point of 98-100C ~decomposition) and providing the following analysis:
-- NMR tcDcl3~ TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6~, 5.9-6.4 (broad s,3) and 7.6 (s,l~.
Example 13 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methox~-5-meth~l-6-(4-nitroanilino)-a~irino~2',3':3,4~p~rrolo[1,2--a]
indole-4,7-dione carbamate Th.is 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 was obtained 16 mg (9% yield) of the desired product having a melting point of 132-134 C (decomposition) and providing the 5 follo~ing analysis:
NMR (Acetone-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-7.3 (d,2), 7.4-i.9 (d,2) and 7.9-8.4 (broad s,l).
Example 14 1,la,2,8 t 8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5 methyl-6-(4-sulfamylan lino)-azirlno[2' ! 3' 3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate ~5 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 o mitomycin A and 688 mg of sul~anilamide was obtained 25 mg (26% yield) of the desired product having a melting point of 113-115C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance o~ new peaks at 7.0 (d,2), 7.5 (s,l) and 7.9 (d,2).
~2~'7~5~
Example 15 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-~ethoxy-5-metnyl~6-(4-methylanilino~-azirino[2',3':3,4]pyrrolo[1,2-a]
indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 mg of mitomycin A and excess 4-methylaniline was obtained 63 mg (86% yield) of the desired product having a melting point of 113-115C (decomposition) and providing the followinganalysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3), 6.5-7.3 (broad s,4) and 7.6 (broad s,l).
Example 16 1,la,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-di`one carbamate This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 276 mg of 3-methylaniline was obtained 66 mg (78%
~5 yield) of the desired product having a melting point of 89-91C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methox~ peak at 4.02 and the appearance o~ new peaks at 2.4 (s J 3), 6.7-7.5 ~m,4) and 7.8 (5,1).
Example 17 1,la,2,8,8a,'8b-Hexahydro-8-(hydroxymet~lyl~-8a-methoxv-5-methvl-6-[(5-amino-1,2,4-triazol-3-yl~amino]-a~irino [2',3':3',4~pyrro'lo['1,'2-a'lindole-4,7-dione carbamate '7 This compound was prepared by the pro-edure described in Example 1, exce~t that a sm~11 amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 3,5-diamino-1,2,4-tria~ole was obtained 13 mg (5.5O- yield) of the desired product having a melting point of 117-120C (decomposition) and providing the following analysis:
NMR (DMSO-d I TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of a new peak at 5.37 (s,3).
Example 18 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methox~
methx1-6-[(3-methylisothiazol-5-yl)amino]-azirino[2',3':3,4]
pyrrolo[l,2-a]indole-4,7-dione caxbamate 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-a~ino-3-methylisothiazole hydrochloride was obtained ~.5 mg (8.5~ yield) of the desired product having a melting point of 87-90C (decomposition) and providing the following analysis:
N~R (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3~, 6.1 ~s,l) and 6.4 (s,l).
Example 19 1,la,2,8,8a,8b-Hexah~dro-8'-(hydroxymethyl)-8a-met~oxy-5-meth~l-6-[l2-benzothiazolyl~amino]-azlrino[2',3':3,4]_yrrolo [1,2-a]indole-4,7-dione carbamate ~ .
This compound was prepared by the procedure described in Example 1, except that a small amowlt of solid potassium carbonate was added. From 50 mg of ~'~52~
mitomycin A and 5 mg of 2-aminobenz~thiazole was obtained 12 mg (18% yield~ of the desired p~oduct having a meltirIg point of 82-85PC (decomposition~ and providing the following analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6~methoxy peak at 4.02 and the appearance of new peaks at 7.1-8.0 (m,5).
Example 20 1,la,2,8,8a,8b Hexahxdro-8-(hydroxymethyl)-8a-methoxy 5-methyl-6-[(6-nitrobenzothiazol-~-~l)amlno]-azirino [2',~3i.3,4]pyrrolo[1 ! 2-a]indole-4,7-dione carbamate This compound was prepared by the procedure 15 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 was obtained 20 mg (27~ yield) of the desired product having a melting point of 86-89C (decomposition) and 0 providing the following analysis:
NMR (DMSO-d , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-8.3 (m,4).
Example 21 1,la,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 This compound was prepared by the procedure 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 was obtained 30 mg (14% yield) of the desired product 35 having a melting point of 89-91C (decomposition) and providing the following analysis:
N~R (CDC13, TS)o '~' values in pp~
Absence o~ the 6-methoxy peak at 4.02 ~nd the appearance of new peaks at 7.1-8.0 (broad s , ~ ) .
Example 22 1,la,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 a '- -~-~ ~---~~'- ~~' This compound was prepared by the procedure described in Example 1, except that the solvent was dichlorome-~hane. From 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane was obtained 35 mg (65% yield) of 1~ the desired product having a melting point of 202-205C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
A~sence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.5 (broad s,2) and 3.5 (broad s,4).
25 1llal2l8`l8al8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5 methyl-6-[methyl(2-methylaminoethyl)amino]-azirino [2',3':3,4]pyrrolol1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of 30 solid potassium carbonate was added. From 50 mg of mitomycin A and 25 ~g of sym-dimethylethylenediamine was obtained 28 mg (50~ yieldl of the desired product having a melting point of 99-101C (decomposition~ and providing the following analysis:
NMR (CDC13, TS)~ values in pp~.
Absence of the 6-methox~ peak at 4.02 and the appearance of new peaks at 1.3 (s,].), 2.5 (s,6), and 2.7 (s,4).
Exam~le 24 1,la,2,8,8a,8b-Hexah dro-8-(hydroxymethY1)-8a-methoxy-5-methyl-6-[2-(2-hydroxyethylamino)ethy-lamïno]-azirino [2'~,3'.3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate 1~
This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin ~ and 18 mg of 2-(2-aminoethylamino)ethanol was obtained 35 mg (58~
15 yield) of the desired product having a melting point of 115~-118C (decomposition) and providing the ollowing analysis:
NMR (CDCl , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the ~0 appearance of new peaks at 2.7 (broad s,7) and 3.7 (t,3~.
Exam~le 25 ~5 1,la,2,8,8a,8b-Hexahy~dro-8-(hydroxymethyl)-8a-meth~y~
methyl-6-[2-_(2-hydroxyethoxy)ethylaminol-azi_ino[2',3l:3,4]
pyrrolo[l,2-a]-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was 30 dichloromethane. From 60 mg of mitom~cin A and 20 mg of 2-t2-aminoethoxy)ethanol was obtained 30 m~ (42%
yield) of the desired product having a melting point of 99-102C (decomposition) and providing the ~ollowing analysis:
NMR (CDC13, TS): '~' values in pp~.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-3.9 (broad s,9) and 6.4-6.8 (broad s,l).
Example 26 1r la,2,8,8a,8b-Hexahy~ro-8-(hydroxymethyl)-8a-metho~y-5-methyl-6-~2-(4-imidazolyl)ethylamino]-azirino[2',3':3l4]
pyrrolo[l,2-a]ind'ole-4!7~dione carb~amate This compound was prepared by the procedure described in Example 1, except that 128 mg of sodium methox~de was added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride was obtained 61 mg (71~
15 yield) of the desired product having a melting point of 72-73C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.0-3.27 (m,4), 7~5 (s,l), 8.0-8.7 (broad s,2) and 8.1 (s,l).
E_ample 27 25 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methYl-6-[(2-nitro-1-imidazolyl)ethylamino]-aziri'no' ' '~
~2',3':3,4jpyrrolo[1,2-a]indole-4,7-dlone carbamate This compound was prepared by the procedure described in Example 1. From 72 mg o~ mitomycin A and 30 excess 1-(2-aminoethyl)-2-nitroimidazole was obta~ned 60 mg (70% yield) of the desired product havin~ a melting point of 83-85C (decomposition) and provlding the following analysis:
_ NMR (CDC13, TS): '~' values in ppm.
. 35 Absence-of the 6-methoxy peak at 4.02 and the ~5~
appearance of new peaks at 3.4 (t,2), 4.6 (t,2), 7.3 (broad s,2) and 7.6 (s,l~.
Example 28 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methy__6-[2-(4-hydrox~phenyl)ethylamino]-azirino[2',3':3,4]
pyrrolo[l,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure 10 described in Example 1. From 130 mg of mitomycin A and 510 mg of tyramine was obtained 138 mg t81% yield) of the desired product having a melting point of 120-125C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
~bsence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.6 (t,2~, 2.8 (t,2), 6.7 (d,2), 7.0 (d,2) and 8.0 (s,l).
Example 29 1,la,2,8,8a,8b-Hexah~dro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(3,4-dihydroxyphenyl)ethy~_ino]-a~irino [2',3':3,4]pyrrolo[1,2-a]indole~4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 138 mg of sodium methoxide was added. From 110 mg of mitomycin A and 660 mg of 3-hydroxytyramine hydrobromide was obtained 60 mg (40% yield) of the dssired product decomposing 30 without melting above 125C and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm 7 Absence o the 6-methoxy peak ~t 4.02 and the appearance of new peaks at 2.6 (t,2), 2.8 (t,2), 6.4-6.8 (m,3) and 8.3 (broad s,2~.
~:25~
Example 30 1,la,'2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a'-methoxy-5-methyl-5-~2-[(5-nitro-2-pyridyl~amino]ethylamino'~-azirlno [2',3':3,4~pyrrolo[1,2-a]indole-4,7~dione carbamate This compound was prepared by the procedure described in Example 1, e~cept that the solven~ was dichloromethane. From 50 mg of mitomycin ~ and 30 mg of 2-(2-aminoethylamino)-5-nitropyridine was obtained 40 10 mg (56% yield) of the desired product having a melting point of 76-79C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-4.0 (m,43, 6.2-6.7 (broad s,2), 8.1 (d,l), 8.2 (d,l) and g.0 (s,l).
Example 31 1,la,2,8,8a,8b-HexahYdro-8-(hydroxYmethyl')-8a-me`thoxy-5-methyl-6-[2-(1-pipérazinyl)ethylamino]-azir-ino[2',3'-3,4]
E~rrolo[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure ~5 described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin ~ ~nd 20 mg of N-(2-aminoethyl) piperazine was obtained 23 mg (36%
yield) of the desired product having a melting point o~
138-141C (decomposition) and providing the following 0 analysis:
N~R (CDC13, TS): '~' values in ppm.
Absence o~ the 6-methox~ peak at 4.02 and the appearance of new peaks at 1.6-2.1 (broad s,l), 2.2-2.6 (broad s,8), 2.6-2.8 (broad s,4) and 6.9 (t,l).
s~
Example 32 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy 5 methyl-6-L2 (2-pyrid~l)ethyla~ino]-azixinoE2',3':3,4 pyrrolo~l,2-a]indole-4,7-dione carbamate -This compound was prepar2d by the procedure described in Example 1. From 70 mg of mitomycin A and 250 mg excess of 2-(2-aminoethyl)pyridine was obtained 51 mg (56% yield~ o~ the desired product havin~ a 10 melting point of 64-77C (decomposition) and providing the following analysis:
NMR (CDCl , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.8 (m,4), 7.0-7.8 1~ (m,3) and 8.5 (d,l).
With specific reference to the compounds comprehended by formula IIIa, the above examples illustrate the following structural variations.
~0 1. Compounds wherein Z is a hydroxy substituted l-pyrrolidinyl radical represented by Example 1.
2. Compounds wherein Z is a lower alkyl substituted piperidyl radical represented by Example 2.
yield) of the desired pxoduct having a melting point of 30 75-88C (decomposition) and p~oviding the following analysis:
NMR (CDC13, TS)~ alues in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 0.85 (d,3), 1.10-2.15 (m,5) and 2.15-3.32 (m,4).
s Example 3 1,la,2,S,8a,3b~Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6~ piperazinyl)-azirino[2',3':3,4]pyrxolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 ~g of mitomycin A and 30 mg of anhydrous piperazine was obtained 23 mg (34%
yield) of the desired product having a melting point 15 greater than 200C (decomposition) ~nd providin~ the following analysis:
NMR (DMSO-d6, TS): '~' values in ppm.
Absence of the 6-~ethoxy peak at 4.02 and the appearance of new peAks at 1.9 (broad s,l) and 2.9 (s,8).
Example 4 1,la,2,8,8a,8b-Hexahydro-8-(h dxoxymethyl~-8a-methoxy-5-methYl-6-[4-(acetylamino)anilino]-azirino[2',3':3,4]
25 Eyrrolo[1,2-a]indole-4,7-dlone carbamate This compound was p~epaxed by the procedure described in Example 1. ~xom 100 m~ of mitomycin A and excess 4-(acetylamino)aniline ~s obtained 102 ~g (76%
30 yield~ of the desired pxoduct haYin~ a melting point of 143q-145C (decomposition) and pxo~iding the ~ollowin~
analysis:
~25~
NMR (CDC13, TS): '~' values in ppm.
Absence of th~ 6-~ethoxy peak at 4.02 and the appearance o~ new peaks at 2,1 ~,s,3), 7.4 (d,2~, 7.6 's,l) and 8.9-9.3 (s,l).
Example 5 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[3-(acetylamino)anilino]-aæirino[2l,3':3,4]
rrolo[l 2-a]indole-4,7-dione caxbamate F ,~ r 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 was 15 obtained 67 mg (72% yield) of the desired product having a melting point o~ 140-143~C (decomposition) and providing the following analysis:
N~R (Acetone-d , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 6.7-7.5 (m,4), 8.0 (broad s,l~ and 9.3 (s,l).
Example 6 25 1,la,2,8,8a,8b-Hexahydro-8-(hYdroxYmethyl)-8~-methoX -5-methvl-6-('4-acetYlanilino)-azirinoL2',3':3-,4]pyrrolo Ll,2-a~indole-4,7-dione caxbamate This compound wa~ prep~red by the procedure 30 described in Example 1, except that a small amount of solid potassium carbonate was ~dded. From 70 mg o mitomycin A and 510 mg of 4-acet~Ylaniline was obtained 25 mg (28~ yield) of the desired product having a melting point o 103-104C (decomposition~ and providing -- 3i the o}1Owing analysis:
NMR (CDC13, TS), I~ valu~s in pp~.
~bsence of the 6-methoxy peak at 4.02 and the ~ppearance of ne~ peaks at 2.1 (s,3~, 6.6(d,2), 7.3 (d,2) and 7.0-7.~ (broad s,l~.
Ex'amp1e 7 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-me'thoxy-5 meth~l-6-[4-(1-ureido)anilino]-azirino[~',3':3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate _ ' This carbamido-substituted compound was prepared by the procedure described in ~xample 1. From 50 mg of mitomycin ~ and 227 mg o~ 4-(1-ureido)aniline was obtained 49 mg (67% yield) of the desired p~oduct having a melting 15 point of ~3-95C (decomposition) and providing the fol-lowing analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 5.03 (s,2), 6.9 (d,2), 7.3 (d,2), 8.0 (s,l) and 8.4 (s,l).
Example 8 1,la,2,8,8a,8b-Hexahydro-8-(h~d~oxymeth 1~-8a-methox -5-methyl-6-(4--cyanoanilino)-azirino[2',3l:3r4]pyrrolo[1,2-a3 25 indole-4,7-dione carb'amate This compound wa~ prepared by the procedure described in Example l, except that a small amount of solid potassium carbonate waS added. From 70 m~ of 30 mitom~cin A and 472 mg of 4-aminobenzonitxile was obt~ined 23 mg (24% ~ield~ of the desi~ed product having a melting point of 124-126QC (decomposition~
and providing the following anal~sis:
NMR (CDC13, TS): '~ ' values in ppm.
Absence of the 6-methoxY peak at 4.02 and the appearance of new peaks at 6.6 (d,2), 7.4 (d,2) and 7.0-7.3 (broad s,l~.
Exam~le 9 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5~
methyl-6-(3-cyanoanilino)-azirino[2',3':3,4]pyrroloEl,2-a]
indole-4,7-dione carbamate _ _ _ _ This compound was prepared by the procedure described in Example 1, except tha-t a small amount of solid potassium carbonate was added. From 71 mg of mitomycin A and 500 mg of 3-aminobenzonitrile was 1~ obtained 30 mg (34% yield) of the desired product having a melting point of 97-98C (deoomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the ~0 appearance of new peaks at 7.2-7.8 (m,4).
Example 10 1,la,2,8,8a-,8b-Hexahvdro-8 (hYdroxYmethyl)-8a-methoxY-5-~- methyl-6-[4-(N-glycv ~ ,3':3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate ~~~
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 was obtained 62 mg (90~
yield) of the desired product having a melting point of 83-85C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): '~' values ln ppm.
~bsence of the 6-methoxy peak at 4.02 ~nd the appearance of new peaks at 3.1 (s,2~, 6.3-6.6 (broad s,2), 6.6-6.8 (broad s,2) and 6.6-7.1 (broad s,2).
E ample 11 1,la,2,8,8a,8b-Hexahydro-8-(h~droxymethyl)-8a-methoxy-5-methyl-6-(3,4-''dimethoxyanilino)-azirlno[2',3':3,4~pyrrolo [1,2-a]indole-4,7'-dione carbamate .... . . .
This compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 229 mg of 3,4-dimethoxyaniline was obtained 61 mg (91~ yield) of 15 ~he desired product having a melting point of 114-116C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Aksence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6), 6.3-~.9 (m,3) and 7.7 (s,l).
Example 12 1,la,'2,8,8a,3b-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 procedure described in Example 1. F~om 50 mg of mitomycin A and 30 229 mg of 3,5-dimethoxy~niline was obtained 60 mg (88~
yield) of the desired product having a meltin~ point of 98-100C ~decomposition) and providing the following analysis:
-- NMR tcDcl3~ TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6~, 5.9-6.4 (broad s,3) and 7.6 (s,l~.
Example 13 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methox~-5-meth~l-6-(4-nitroanilino)-a~irino~2',3':3,4~p~rrolo[1,2--a]
indole-4,7-dione carbamate Th.is 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 was obtained 16 mg (9% yield) of the desired product having a melting point of 132-134 C (decomposition) and providing the 5 follo~ing analysis:
NMR (Acetone-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-7.3 (d,2), 7.4-i.9 (d,2) and 7.9-8.4 (broad s,l).
Example 14 1,la,2,8 t 8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5 methyl-6-(4-sulfamylan lino)-azirlno[2' ! 3' 3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate ~5 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 o mitomycin A and 688 mg of sul~anilamide was obtained 25 mg (26% yield) of the desired product having a melting point of 113-115C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance o~ new peaks at 7.0 (d,2), 7.5 (s,l) and 7.9 (d,2).
~2~'7~5~
Example 15 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-~ethoxy-5-metnyl~6-(4-methylanilino~-azirino[2',3':3,4]pyrrolo[1,2-a]
indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 mg of mitomycin A and excess 4-methylaniline was obtained 63 mg (86% yield) of the desired product having a melting point of 113-115C (decomposition) and providing the followinganalysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3), 6.5-7.3 (broad s,4) and 7.6 (broad s,l).
Example 16 1,la,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-di`one carbamate This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 276 mg of 3-methylaniline was obtained 66 mg (78%
~5 yield) of the desired product having a melting point of 89-91C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methox~ peak at 4.02 and the appearance o~ new peaks at 2.4 (s J 3), 6.7-7.5 ~m,4) and 7.8 (5,1).
Example 17 1,la,2,8,8a,'8b-Hexahydro-8-(hydroxymet~lyl~-8a-methoxv-5-methvl-6-[(5-amino-1,2,4-triazol-3-yl~amino]-a~irino [2',3':3',4~pyrro'lo['1,'2-a'lindole-4,7-dione carbamate '7 This compound was prepared by the pro-edure described in Example 1, exce~t that a sm~11 amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 3,5-diamino-1,2,4-tria~ole was obtained 13 mg (5.5O- yield) of the desired product having a melting point of 117-120C (decomposition) and providing the following analysis:
NMR (DMSO-d I TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of a new peak at 5.37 (s,3).
Example 18 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methox~
methx1-6-[(3-methylisothiazol-5-yl)amino]-azirino[2',3':3,4]
pyrrolo[l,2-a]indole-4,7-dione caxbamate 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-a~ino-3-methylisothiazole hydrochloride was obtained ~.5 mg (8.5~ yield) of the desired product having a melting point of 87-90C (decomposition) and providing the following analysis:
N~R (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3~, 6.1 ~s,l) and 6.4 (s,l).
Example 19 1,la,2,8,8a,8b-Hexah~dro-8'-(hydroxymethyl)-8a-met~oxy-5-meth~l-6-[l2-benzothiazolyl~amino]-azlrino[2',3':3,4]_yrrolo [1,2-a]indole-4,7-dione carbamate ~ .
This compound was prepared by the procedure described in Example 1, except that a small amowlt of solid potassium carbonate was added. From 50 mg of ~'~52~
mitomycin A and 5 mg of 2-aminobenz~thiazole was obtained 12 mg (18% yield~ of the desired p~oduct having a meltirIg point of 82-85PC (decomposition~ and providing the following analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6~methoxy peak at 4.02 and the appearance of new peaks at 7.1-8.0 (m,5).
Example 20 1,la,2,8,8a,8b Hexahxdro-8-(hydroxymethyl)-8a-methoxy 5-methyl-6-[(6-nitrobenzothiazol-~-~l)amlno]-azirino [2',~3i.3,4]pyrrolo[1 ! 2-a]indole-4,7-dione carbamate This compound was prepared by the procedure 15 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 was obtained 20 mg (27~ yield) of the desired product having a melting point of 86-89C (decomposition) and 0 providing the following analysis:
NMR (DMSO-d , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-8.3 (m,4).
Example 21 1,la,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 This compound was prepared by the procedure 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 was obtained 30 mg (14% yield) of the desired product 35 having a melting point of 89-91C (decomposition) and providing the following analysis:
N~R (CDC13, TS)o '~' values in pp~
Absence o~ the 6-methoxy peak at 4.02 ~nd the appearance of new peaks at 7.1-8.0 (broad s , ~ ) .
Example 22 1,la,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 a '- -~-~ ~---~~'- ~~' This compound was prepared by the procedure described in Example 1, except that the solvent was dichlorome-~hane. From 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane was obtained 35 mg (65% yield) of 1~ the desired product having a melting point of 202-205C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
A~sence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.5 (broad s,2) and 3.5 (broad s,4).
25 1llal2l8`l8al8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5 methyl-6-[methyl(2-methylaminoethyl)amino]-azirino [2',3':3,4]pyrrolol1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of 30 solid potassium carbonate was added. From 50 mg of mitomycin A and 25 ~g of sym-dimethylethylenediamine was obtained 28 mg (50~ yieldl of the desired product having a melting point of 99-101C (decomposition~ and providing the following analysis:
NMR (CDC13, TS)~ values in pp~.
Absence of the 6-methox~ peak at 4.02 and the appearance of new peaks at 1.3 (s,].), 2.5 (s,6), and 2.7 (s,4).
Exam~le 24 1,la,2,8,8a,8b-Hexah dro-8-(hydroxymethY1)-8a-methoxy-5-methyl-6-[2-(2-hydroxyethylamino)ethy-lamïno]-azirino [2'~,3'.3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate 1~
This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin ~ and 18 mg of 2-(2-aminoethylamino)ethanol was obtained 35 mg (58~
15 yield) of the desired product having a melting point of 115~-118C (decomposition) and providing the ollowing analysis:
NMR (CDCl , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the ~0 appearance of new peaks at 2.7 (broad s,7) and 3.7 (t,3~.
Exam~le 25 ~5 1,la,2,8,8a,8b-Hexahy~dro-8-(hydroxymethyl)-8a-meth~y~
methyl-6-[2-_(2-hydroxyethoxy)ethylaminol-azi_ino[2',3l:3,4]
pyrrolo[l,2-a]-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was 30 dichloromethane. From 60 mg of mitom~cin A and 20 mg of 2-t2-aminoethoxy)ethanol was obtained 30 m~ (42%
yield) of the desired product having a melting point of 99-102C (decomposition) and providing the ~ollowing analysis:
NMR (CDC13, TS): '~' values in pp~.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-3.9 (broad s,9) and 6.4-6.8 (broad s,l).
Example 26 1r la,2,8,8a,8b-Hexahy~ro-8-(hydroxymethyl)-8a-metho~y-5-methyl-6-~2-(4-imidazolyl)ethylamino]-azirino[2',3':3l4]
pyrrolo[l,2-a]ind'ole-4!7~dione carb~amate This compound was prepared by the procedure described in Example 1, except that 128 mg of sodium methox~de was added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride was obtained 61 mg (71~
15 yield) of the desired product having a melting point of 72-73C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.0-3.27 (m,4), 7~5 (s,l), 8.0-8.7 (broad s,2) and 8.1 (s,l).
E_ample 27 25 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methYl-6-[(2-nitro-1-imidazolyl)ethylamino]-aziri'no' ' '~
~2',3':3,4jpyrrolo[1,2-a]indole-4,7-dlone carbamate This compound was prepared by the procedure described in Example 1. From 72 mg o~ mitomycin A and 30 excess 1-(2-aminoethyl)-2-nitroimidazole was obta~ned 60 mg (70% yield) of the desired product havin~ a melting point of 83-85C (decomposition) and provlding the following analysis:
_ NMR (CDC13, TS): '~' values in ppm.
. 35 Absence-of the 6-methoxy peak at 4.02 and the ~5~
appearance of new peaks at 3.4 (t,2), 4.6 (t,2), 7.3 (broad s,2) and 7.6 (s,l~.
Example 28 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methy__6-[2-(4-hydrox~phenyl)ethylamino]-azirino[2',3':3,4]
pyrrolo[l,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure 10 described in Example 1. From 130 mg of mitomycin A and 510 mg of tyramine was obtained 138 mg t81% yield) of the desired product having a melting point of 120-125C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
~bsence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.6 (t,2~, 2.8 (t,2), 6.7 (d,2), 7.0 (d,2) and 8.0 (s,l).
Example 29 1,la,2,8,8a,8b-Hexah~dro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(3,4-dihydroxyphenyl)ethy~_ino]-a~irino [2',3':3,4]pyrrolo[1,2-a]indole~4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 138 mg of sodium methoxide was added. From 110 mg of mitomycin A and 660 mg of 3-hydroxytyramine hydrobromide was obtained 60 mg (40% yield) of the dssired product decomposing 30 without melting above 125C and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm 7 Absence o the 6-methoxy peak ~t 4.02 and the appearance of new peaks at 2.6 (t,2), 2.8 (t,2), 6.4-6.8 (m,3) and 8.3 (broad s,2~.
~:25~
Example 30 1,la,'2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a'-methoxy-5-methyl-5-~2-[(5-nitro-2-pyridyl~amino]ethylamino'~-azirlno [2',3':3,4~pyrrolo[1,2-a]indole-4,7~dione carbamate This compound was prepared by the procedure described in Example 1, e~cept that the solven~ was dichloromethane. From 50 mg of mitomycin ~ and 30 mg of 2-(2-aminoethylamino)-5-nitropyridine was obtained 40 10 mg (56% yield) of the desired product having a melting point of 76-79C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-4.0 (m,43, 6.2-6.7 (broad s,2), 8.1 (d,l), 8.2 (d,l) and g.0 (s,l).
Example 31 1,la,2,8,8a,8b-HexahYdro-8-(hydroxYmethyl')-8a-me`thoxy-5-methyl-6-[2-(1-pipérazinyl)ethylamino]-azir-ino[2',3'-3,4]
E~rrolo[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure ~5 described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin ~ ~nd 20 mg of N-(2-aminoethyl) piperazine was obtained 23 mg (36%
yield) of the desired product having a melting point o~
138-141C (decomposition) and providing the following 0 analysis:
N~R (CDC13, TS): '~' values in ppm.
Absence o~ the 6-methox~ peak at 4.02 and the appearance of new peaks at 1.6-2.1 (broad s,l), 2.2-2.6 (broad s,8), 2.6-2.8 (broad s,4) and 6.9 (t,l).
s~
Example 32 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy 5 methyl-6-L2 (2-pyrid~l)ethyla~ino]-azixinoE2',3':3,4 pyrrolo~l,2-a]indole-4,7-dione carbamate -This compound was prepar2d by the procedure described in Example 1. From 70 mg of mitomycin A and 250 mg excess of 2-(2-aminoethyl)pyridine was obtained 51 mg (56% yield~ o~ the desired product havin~ a 10 melting point of 64-77C (decomposition) and providing the following analysis:
NMR (CDCl , TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.8 (m,4), 7.0-7.8 1~ (m,3) and 8.5 (d,l).
With specific reference to the compounds comprehended by formula IIIa, the above examples illustrate the following structural variations.
~0 1. Compounds wherein Z is a hydroxy substituted l-pyrrolidinyl radical represented by Example 1.
2. Compounds wherein Z is a lower alkyl substituted piperidyl radical represented by Example 2.
3. Compounds wherein Z is a 1-piperazinyl 25 radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lo~er alkoxy, nitro, sulfamyl or lower alkyl substituted anilino radical are represented, respectively, by Examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
4. Compounds ~herein Z is a radical of the formula R
_N_~l and wherein Rl is a nitro~en containin~ heterocylic radical selected from the group consistin~ o~ amino 35 substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl and nitro and halo substituted derivatives ~25~
of benzothiazolyl are represented, respectively, ~y Examples 17, 18, 19, 20 and 21.
_N_~l and wherein Rl is a nitro~en containin~ heterocylic radical selected from the group consistin~ o~ amino 35 substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl and nitro and halo substituted derivatives ~25~
of benzothiazolyl are represented, respectively, ~y Examples 17, 18, 19, 20 and 21.
5. Compounds wherein Z is a radical of the formula R
-N-Rl and wherein Rl is a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alk~l, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alXyl, piperazinyl lower alkyl and pyridyl ethyl are represented, respectively, by Examples 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32.
While none of the foregoing examples are illustrative of compounds wherein Y is other than hydrogen, compounds wherein Y .is lower alkyl are nonetheless within the comprehension of the invention, reference being made to analogously substituted compounds of my aforesaid U~S. Patent No. 4,268,676 and U.S. Patent Nos. 4,460,599 and 4,617,389.
Compounds according to the present invention are believed to possess anti-bacterial activity against gram-positive and gram-negative microorganisms in a manner similar to that observed for the naturally occurring mitomycins and are thus potentially useful as therapeutic agents in treating bacterial infections in humans and animals.
Usefulness of compounds of formula IIIa in the antineoplastic therapeutic methods of the invention is demonstrated by the results of in vivo screening procedures wherein the compounds are administered in varying dosage amounts to mice in which a P388 leukemic condition is induced. The procedures were carried out according to "~ymphocytic Leukemia P388 - Protocol g.~;
1.200", published in Cancer Chemotherapy Repoxts, Part 3, Vol. 3, No. 2, page 9 (September, 1972). Briefly put, the screening procedures involved administration of the test comp~und to CDFl female mice previously 5 infected with 106 ascites cells implanted intraperitoneally.
Test compounds were administered on the first day of testing only, and the animals were monitored for vitality, inter alia, over a 35-day period.
Results of screening of compounds of Examples 10 1 through 32 are set forth in Table I below. Data given includes optimal dose ("O.D."), i.e., that dosage in mg/kg of body weight of the animal at which the maximum therapeutic effects are consistently observed.
Also included is the median survival time ("MST") 15 expressed as the MST of the test animals compared to the MST of controls x 100 ~"% T/C"). Within the context of the _ vivo P388 procedure noted above, a % T/C
value of 125 or greater indicates significant anti-neoplastic therapeutic activity. The lowest dose in 20 mg/kg of body weight at which the 125% T/C value is obtained is known as the minimum effective dose ("MED").
These doses also are listed in Table I. It is worthy of note that the exceptionally high ~ST ~alues obtained in the P388 screenings reported in Table I are also 25 indicative of the absence of substantial toxicity of the compounds at the dosages indicated.
~2~d~9 ExampleOptimal Dose~lST MED
No.mg/kg as % T/C
1 25.6 153 0.8 2 25.6 238 ~0.2 3 12.8 200 0.2 4 25.6 ~333 ~0.2 ~5.6 231 0.2
-N-Rl and wherein Rl is a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alk~l, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alXyl, piperazinyl lower alkyl and pyridyl ethyl are represented, respectively, by Examples 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32.
While none of the foregoing examples are illustrative of compounds wherein Y is other than hydrogen, compounds wherein Y .is lower alkyl are nonetheless within the comprehension of the invention, reference being made to analogously substituted compounds of my aforesaid U~S. Patent No. 4,268,676 and U.S. Patent Nos. 4,460,599 and 4,617,389.
Compounds according to the present invention are believed to possess anti-bacterial activity against gram-positive and gram-negative microorganisms in a manner similar to that observed for the naturally occurring mitomycins and are thus potentially useful as therapeutic agents in treating bacterial infections in humans and animals.
Usefulness of compounds of formula IIIa in the antineoplastic therapeutic methods of the invention is demonstrated by the results of in vivo screening procedures wherein the compounds are administered in varying dosage amounts to mice in which a P388 leukemic condition is induced. The procedures were carried out according to "~ymphocytic Leukemia P388 - Protocol g.~;
1.200", published in Cancer Chemotherapy Repoxts, Part 3, Vol. 3, No. 2, page 9 (September, 1972). Briefly put, the screening procedures involved administration of the test comp~und to CDFl female mice previously 5 infected with 106 ascites cells implanted intraperitoneally.
Test compounds were administered on the first day of testing only, and the animals were monitored for vitality, inter alia, over a 35-day period.
Results of screening of compounds of Examples 10 1 through 32 are set forth in Table I below. Data given includes optimal dose ("O.D."), i.e., that dosage in mg/kg of body weight of the animal at which the maximum therapeutic effects are consistently observed.
Also included is the median survival time ("MST") 15 expressed as the MST of the test animals compared to the MST of controls x 100 ~"% T/C"). Within the context of the _ vivo P388 procedure noted above, a % T/C
value of 125 or greater indicates significant anti-neoplastic therapeutic activity. The lowest dose in 20 mg/kg of body weight at which the 125% T/C value is obtained is known as the minimum effective dose ("MED").
These doses also are listed in Table I. It is worthy of note that the exceptionally high ~ST ~alues obtained in the P388 screenings reported in Table I are also 25 indicative of the absence of substantial toxicity of the compounds at the dosages indicated.
~2~d~9 ExampleOptimal Dose~lST MED
No.mg/kg as % T/C
1 25.6 153 0.8 2 25.6 238 ~0.2 3 12.8 200 0.2 4 25.6 ~333 ~0.2 ~5.6 231 0.2
6 6.4 167 0.4
7 25.6 194 1.6
8 3.2 150 0.8
9 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 ~002
14 25.6 225 0.2
15 12.8 167 0.4 ~0 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 3.2 178 0.4 23 25.6 133 12.8 24 12.8 133 12.
25 25.6 181 0.4 26 25.6 ~ 63 1.6 27 25.6 150 3. ~
28 25.6 218 1.6 29 12.8 139 12.8 30 12.8 144 6.4 _ 35 31 25.6 138 12.8 32 25.6 > 375 0.2 ~2~
Clearly amon~ the most preferred compounds employed as antineoplastic agents accoxding to the invention are those exhibiting moxe than twice the relative life-extending capacity generally characterized 5 as evidencing significant therapeutic potential, i.e., those having an MST ~ T/C value greater than 2 x 125.
The elass of such compounds is seen to include the eompounds of Examples 4, 10, 11 and 32.
As may be noted from Table I, initial single 10 dosa~es of as little as 0.2 mg/kg showed substantial long term antineoplastic activity. Accordingly, the methods of the invention may involve ~herapeutic administra-tion of unit dosages of as little as 0.001 mg or as much as 5 mg, preferably from 0.004 mg to 10 mg, of the 15 compounds as the active ingredient in a suitable phar-maceutical preparation. Such preparations may be administered in a daily regimen calling for from 0.1 mg to 100 mg per kg, preferably from about 0.2 to about 51.2 mg per kg, of the body weight of the animal ~0 suffering from neoplastic disease. It is preferred that the compounds be administered parenter~lly.
Ph~rmaceutical compositions suitable for use in practice o~ methods o~ the invention may eomprise simple water solutions of one or more o~ the compounds of formula ~5 ~IIa, but may also include ~ell known pharmaceutieally acceptable diluents, adjuvants and/or carriers sueh as saline suitable for medicinal use.
Further aspects and advanta~es o~ the present invention are expected to oecur to those skilled in the 30 ar~ upon consideration of the ~oregoin~ descxiption and consequently only sueh limitations ~s appeax in the appended claims should be pl~ced thereon.
_ 35
25 25.6 181 0.4 26 25.6 ~ 63 1.6 27 25.6 150 3. ~
28 25.6 218 1.6 29 12.8 139 12.8 30 12.8 144 6.4 _ 35 31 25.6 138 12.8 32 25.6 > 375 0.2 ~2~
Clearly amon~ the most preferred compounds employed as antineoplastic agents accoxding to the invention are those exhibiting moxe than twice the relative life-extending capacity generally characterized 5 as evidencing significant therapeutic potential, i.e., those having an MST ~ T/C value greater than 2 x 125.
The elass of such compounds is seen to include the eompounds of Examples 4, 10, 11 and 32.
As may be noted from Table I, initial single 10 dosa~es of as little as 0.2 mg/kg showed substantial long term antineoplastic activity. Accordingly, the methods of the invention may involve ~herapeutic administra-tion of unit dosages of as little as 0.001 mg or as much as 5 mg, preferably from 0.004 mg to 10 mg, of the 15 compounds as the active ingredient in a suitable phar-maceutical preparation. Such preparations may be administered in a daily regimen calling for from 0.1 mg to 100 mg per kg, preferably from about 0.2 to about 51.2 mg per kg, of the body weight of the animal ~0 suffering from neoplastic disease. It is preferred that the compounds be administered parenter~lly.
Ph~rmaceutical compositions suitable for use in practice o~ methods o~ the invention may eomprise simple water solutions of one or more o~ the compounds of formula ~5 ~IIa, but may also include ~ell known pharmaceutieally acceptable diluents, adjuvants and/or carriers sueh as saline suitable for medicinal use.
Further aspects and advanta~es o~ the present invention are expected to oecur to those skilled in the 30 ar~ upon consideration of the ~oregoin~ descxiption and consequently only sueh limitations ~s appeax in the appended claims should be pl~ced thereon.
_ 35
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Compounds of the formula, III
wherein: Y is hydrogen or lower alkyl; and X
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamyl substituted anilino radical, or a radical of the formula, wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo-thiazolyl, or R1 is a substituted lower alkyl radical selected from the group consistiny of 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, nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
wherein: Y is hydrogen or lower alkyl; and X
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamyl substituted anilino radical, or a radical of the formula, wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzo-thiazolyl, or R1 is a substituted lower alkyl radical selected from the group consistiny of 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, nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
2. The Compounds according to Claim 1 named:
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-methylpiperdyl)-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-glycyl)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-sulfamylanilino)-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-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)-8a-methoxy-5-methyl-6-[(3-methylisothiazol-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-aminoethyl)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]-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 [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-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-[(5-nitro-2-pyridyl)amino]-ethylamino]azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carhamate;
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.
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-methylpiperdyl)-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-glycyl)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-sulfamylanilino)-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-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)-8a-methoxy-5-methyl-6-[(3-methylisothiazol-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-aminoethyl)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]-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 [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-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-[(5-nitro-2-pyridyl)amino]-ethylamino]azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carhamate;
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.
3. A pharmaceutical composition for use in treatment of a neoplastic disease in an animal, said composition comprising a pharmaceutically acceptable solvent, diluent, adjuvant or carrier and, as the active ingredient, from about 0.001 to about 5 mg of a compound of the formula wherein Y is hydrogen or lower alkyl; and Z
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula, wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro, and halo substituted derivatives of benzo-thiazolyl, or R1 is a substituted lower alkyl radical selected from the group consisting of 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, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula, wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro, and halo substituted derivatives of benzo-thiazolyl, or R1 is a substituted lower alkyl radical selected from the group consisting of 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, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46461283A | 1983-02-07 | 1983-02-07 | |
| US464,612 | 1983-02-07 |
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| CA1252789A true CA1252789A (en) | 1989-04-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA000446811A Expired CA1252789A (en) | 1983-02-07 | 1984-02-06 | Mitomycin analogs |
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| JP (1) | JPS59152384A (en) |
| KR (1) | KR900006854B1 (en) |
| AT (1) | AT385509B (en) |
| AU (1) | AU571193B2 (en) |
| BE (1) | BE898856A (en) |
| CA (1) | CA1252789A (en) |
| CH (1) | CH658658A5 (en) |
| DD (1) | DD233844A5 (en) |
| DE (1) | DE3403922A1 (en) |
| DK (1) | DK161890C (en) |
| ES (1) | ES8607305A1 (en) |
| FI (1) | FI80698C (en) |
| FR (1) | FR2540500B1 (en) |
| GB (1) | GB2134514B (en) |
| GR (1) | GR81455B (en) |
| HU (1) | HU190236B (en) |
| IE (1) | IE56814B1 (en) |
| IL (1) | IL70897A (en) |
| IT (1) | IT1178855B (en) |
| LU (1) | LU85199A1 (en) |
| NL (1) | NL8400338A (en) |
| NO (1) | NO161374C (en) |
| NZ (1) | NZ206932A (en) |
| OA (1) | OA07654A (en) |
| PH (1) | PH20249A (en) |
| PT (1) | PT78067B (en) |
| SE (1) | SE461982B (en) |
| YU (1) | YU44984B (en) |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4487769A (en) * | 1982-06-04 | 1984-12-11 | Bristol-Myers Company | Amidines |
| CA1282069C (en) * | 1985-09-12 | 1991-03-26 | Damon L. Meyer | Antibody complexes of hapten-modified diagnostic or therapeutic agents |
| JPS63150282A (en) * | 1986-12-13 | 1988-06-22 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative |
| JPS63246379A (en) * | 1987-03-31 | 1988-10-13 | Kyowa Hakko Kogyo Co Ltd | 7-n,8-n-ethylenemitomycin 8-imines |
| EP0485904B1 (en) * | 1990-11-13 | 1997-08-20 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin derivatives |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3332944A (en) * | 1964-11-02 | 1967-07-25 | American Cyanamid Co | Antibiotic derivatives of mitomycins a, b, c and porfiromycin |
| JPS5439098A (en) * | 1977-08-31 | 1979-03-24 | Kyowa Hakko Kogyo Co Ltd | Mitomycin c derivatives |
| US4268676A (en) * | 1979-12-05 | 1981-05-19 | University Patents, Inc. | Mitomycin analogs |
| JPS5686184A (en) * | 1979-12-17 | 1981-07-13 | Kyowa Hakko Kogyo Co Ltd | Novel mitomycin c derivative |
| NZ199617A (en) * | 1981-05-15 | 1985-08-30 | University Patents Inc | Azirino(2',3',:3,4)pyrrolo(1,2-a)indole-4,7-dione derivatives and pharmaceutical compositions |
| US4487769A (en) * | 1982-06-04 | 1984-12-11 | Bristol-Myers Company | Amidines |
| US4642352A (en) * | 1983-12-23 | 1987-02-10 | Bristol-Myers Company | Acylamino mitosanes |
-
1984
- 1984-01-25 NZ NZ206932A patent/NZ206932A/en unknown
- 1984-01-27 GB GB08402233A patent/GB2134514B/en not_active Expired
- 1984-02-02 ZA ZA84788A patent/ZA84788B/en unknown
- 1984-02-03 NL NL8400338A patent/NL8400338A/en not_active Application Discontinuation
- 1984-02-03 AU AU24073/84A patent/AU571193B2/en not_active Ceased
- 1984-02-04 DE DE19843403922 patent/DE3403922A1/en not_active Withdrawn
- 1984-02-06 PT PT78067A patent/PT78067B/en not_active IP Right Cessation
- 1984-02-06 NO NO840433A patent/NO161374C/en unknown
- 1984-02-06 ES ES529478A patent/ES8607305A1/en not_active Expired
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- 1984-02-06 IE IE272/84A patent/IE56814B1/en not_active IP Right Cessation
- 1984-02-06 DD DD84259885A patent/DD233844A5/en not_active IP Right Cessation
- 1984-02-06 PH PH30204A patent/PH20249A/en unknown
- 1984-02-06 HU HU84483A patent/HU190236B/en not_active IP Right Cessation
- 1984-02-06 DK DK052484A patent/DK161890C/en active
- 1984-02-06 CH CH550/84A patent/CH658658A5/en not_active IP Right Cessation
- 1984-02-06 CA CA000446811A patent/CA1252789A/en not_active Expired
- 1984-02-06 GR GR73720A patent/GR81455B/el unknown
- 1984-02-07 FR FR8401845A patent/FR2540500B1/en not_active Expired
- 1984-02-07 YU YU217/84A patent/YU44984B/en unknown
- 1984-02-07 FI FI840502A patent/FI80698C/en not_active IP Right Cessation
- 1984-02-07 OA OA58227A patent/OA07654A/en unknown
- 1984-02-07 IL IL70897A patent/IL70897A/en unknown
- 1984-02-07 IT IT67113/84A patent/IT1178855B/en active
- 1984-02-07 LU LU85199A patent/LU85199A1/en unknown
- 1984-02-07 SE SE8400628A patent/SE461982B/en not_active IP Right Cessation
- 1984-02-07 BE BE0/212351A patent/BE898856A/en not_active IP Right Cessation
- 1984-02-07 KR KR1019840000574A patent/KR900006854B1/en not_active IP Right Cessation
- 1984-02-07 JP JP59021505A patent/JPS59152384A/en active Pending
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