GB2134514A - Mitomycin analogs - Google Patents
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- 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
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Abstract
Mitomycin derivatives useful for treatment of neoplastic disease states in animals have the formula IIIa, <IMAGE> wherein: Y is hydrogen or lower alkyl; and Z is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or a 1-piperazinyl 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, <IMAGE> wherein R is hydrogen or lower alkyl and R<1> is a nitrogen containing heterocyclic radial selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R<1> is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
Description
SPECIFICATION
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; my co-pending U.S. Patent
Application Serial No. 206,529 filed November 13, 1980; and my co-pending U.S. Patent
Application Serial No. 264,187 filed May 15, 1 981, are specifically incorporated by reference herein to the extent that they may provide essential and nonessential material relating to the present invention.
Briefly summarized, said U.S. Patent No. 4,268,676 and co-pending application Serial No.
206,529 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,
wherein: Y is hydrogen or lower alkyl; and X is a thiazolamino radical, a furfurylamino radical or a radical of the formula,
in which R, R1 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, halolower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl and benzene sulfonamide.
Said U.S. patent and pending application 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, la,
wherein: Y is hydrogen or lower alkyl; and Z is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula,
in which R4, R6, and R6 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R7 is selected from the group consisting of lower alkenyl, halolower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, th ienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
Co-pending U.S. patent application Serial No. 264,187 also discloses compounds with a substantial degree of antitumor activity in animals of the following formula Blab,
wherein: Y is hydrogen or lower alkyl; and Z is a lower alkoxy substituted quinolinylarnino radical, a cyano substituted pyrazolylamino radical or a mono- or di-lower alkyl substituted thiazolamino radical, or
a nitrogen-containing heterocyclic radical selected from the group consisting of 1-pyrrolinyi, 1indolinyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyi, and N-thiornorpholinyl radicals, or
a cyano, phenyl, carboxamido or lower alkoxy-carbonyl substituted 1-aziridinyl radical, or
a lower alkyl, formyl or acetyiphenyl substituted 1-piperazinyl radical, or
an hydroxy or piperidyl substituted 1 -piperidyl radical, or
a lower alkoxy, amino or halo substituted pyridylamino radical, or
a carboxamido, mercapto or methylenedioxy substituted anilino radical, or
a radical of the formula,
wherein R is hydrogen or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and 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 group 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 lower alkyl, mono-, di- and tri-lower alkoxy phenyl 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.
Also pertinent to the background of the present invention are the following references:
Cosulich, et al., U.S. Patent No. 3,332,944; Matsui, et al., U.S. Patent No. 3,410,867;
Nakano, et al., U.S. Patent No. 4.231,936; Matsui, et al., U.S. Patent No. 3,429,894;
Remers, U.S. Patent No. 4,268,676; Matsui, et al., U.S. Patent No. 3,450,705; Matsui, et al.,
U.S. Patent No. 3,514,452; and Imai, et al., Gann, 71, pp. 560-562 (1980).
BRIEF SUMMARY
According to the present invention, there are provided novel compounds of the formula, Ill,
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 benzothiazolyl, or R' 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, mono- and di-hydroxy phenyl lower alkyl, 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, lila,
wherein: Y is hydrogen or lower alkyl; and Z is
an hydroxy substituted 1-pyrrolidinyl radical, or
a lower alkyl substituted piperidyl radical, or
a 1-piperazinyl radical or an acetamino, actetyl, 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 benzothiazolyl, or R' 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, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, 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 Ill are all comprehended by the specifications of formula Illa. Put another way, all the novel antibiotic mitomycin derivatives of formula Ill are useful in practice of the novel antineoplastic therapeutic methods which involve administration of compounds of formula Illa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with the appropriately selected amine compounds. The N-alkylmitomycin (e.g., N-methylmitomycin) derivatives are similarly prepared by the reaction of a selected amine with N-alkylmitomycin A 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 comprehend the administration of effective amounts of one or more of the compounds of formula Illa, as an active ingredient, together with desired pharmaceutically acceptable diluents, adjuvants and carriers, to an animal suffering from a neoplastic disease state. Unit dosage forms of compounds administered according to the methods of the invention may range from about 0.001 to about 5.0 mg and preferably from about 0.004 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 about 0.2 to about 51.2 mg per kg, of body weight of 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 invention will become apparent upon consideration of the following description.
DESCRIPTION OF INVENTION
The following Examples 1 through 32, describing 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 out at room temperature (20"C), without added heat. Unless otherwise indicated, all thin layer chromatographic (TLC) procedures employed to check the progress of reactions involved the use of a pre-coated silica-gel plate and a mixture of methanol and chloroform (2:8 by volume) as a developing solvent.
Example 1
1, 1 a, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-hydroxy- 1 -pyrrolidinyl)- azirinof2', 3': 3, 4]pyrrolo[1, 2-a]indole-4, 7-dione carbamate
A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3pyrrolidinol (13 mg) under nitrogen at room temperature. When thin-layer chromatography on silica gel (2:8 methanolchloroform as solvent) showed that starting material no 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 (4Q% yield) of the desired product having a melting point of 82"-85"C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): 'S' 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,1).
Example 2
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-methylpiperdyl)aziri- no[2', 3': 3, 4)pyrroloF 1, 2-a]indole-4, 7-dione carbamate
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 product having a melting point of 75"-88"C (decomposition) and providing the following analysis:
NMR (CDCL3, TS): 'd' values 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).
Example 3 1, 1 a, 2,8, 8a, 8b-Hexah ydro-8-(hydroxymeth yi)-8a-meth6xy-5-methyi-6-( 1 -piperazinyl)-aziri- no[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 30 mg of anhydrous piperazine was obtained 23 mg (34% yield) of the desired product having a melting point greater than 200"C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.9 (broad s,1) and 2.9 (s,8).
Example 4
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[4-(acetylamino)anilino]- azirino[2/, 3/:3,4]pyrrolo[l. 2-a]indole-4, 7-dione carbamate
This compound was prepared by the procedure described in Example 1. From 100 mg of mitomycin A and excess 4-(acetylamino)aniline was obtained 102 mg (76% yield) of the desired product having a melting point of 143 -145 C (decomposition) and providing the following analysis:
NMR (CDCL3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 7.4 (d,2), 7.6 (s,1) and 8.9-9.3 (s,1).
Example 5
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[3-(acetylamino)anilino] 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 70 mg of mitomycin A and 150 mg of 3-(acetylamino)aniline was obtained 67 mg (72% yield) of the desired product having a melting point of 140"-143"C (decomposition) and providing the following analysis:
NMR (Acetone-d6, TS): 'S' 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,1) and 9.3 (s,1).
Example 6
1, Ia, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-acetylanilino)-aziri- no[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 70 mg of mitomycin A and 510 mg of 4-acetylaniline was obtained 25 mg (28% yield) of the desired product having a melting point of 103"-104"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 6.6(d,2), 7.3 (d,2) and 7.0-7.3 (broad s,1).
Example 7 1,1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[4-( 1 -ureido)anilino]-aziri no[2', 3':3,4]pyrrolo[1, 2-a]indole-4, 7-dione carbamate
This carbamido-substituted compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 227 mg of 4-(1-ureidoìaniline was obtained 49 mg (67% yield) of the desired product having a melting point of 93"-95"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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,1) and 8.4 (s,1).
Example 8
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-cyanoanilino)-aziri- no[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 70 mg of mitomycin A and 472 mg of 4-aminobenzonitrile was obtained 23 mg (24% yield) of the desired product having a melting point of 124 -126 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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,1).
Example 9
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-cyanoanilino)-aziri- no[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 71 mg of mitomycin A and 500 mg of 3-aminobenzonitrile was obtained 30 mg (34% yield) of the desired product having a melting point of 97"-98"C (decomposition) and providing the following analysis:
NMR (CDCI3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.2-7.8 (m,4).
Example 10
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[4-(N-glycyl)anilino]-aziri- no[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 249 mg of 4-(N-glycyl)aniline was obtained 62 mg (90% yield) of the desired product having a melting point of 83"-85"C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and 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).
Example 11
1, 1 a, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3, 4-dimethoxyanilino) azirino[2', 3': 3, 4]pyrrolo[l, 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 the desired product having a melting point of 114 -116 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6), 6.3-6.9 (m,3) and 7.7 (s,1).
Example 12
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methyoxy-5-methyl-6-(3, 5-dimethoxyanilino) azirino[2', 3': 3, 4jpyrrolo 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 3,5-dimethoxyaniline was obtained 60 mg (88% yield) of the desired product having a melting point of 98 -100 C (decomposition) and providing the following analysis:
NMR (CDCI3, TS): 'S' 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,1).
Example 13
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-nitroanilino)-aziri- no[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 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 following analysis:
NMR (Acetone-d6, TS): 'S' 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), 7.4-7.9 (d,2) and 7.9-8.4 (broad s,1).
Example 14
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-sulfamylanilino)-aziri- no[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 70 mg of mitomycin A and 688 mg of sulfanilamide was obtained 25 mg (26% yield) of the desired product having a melting point of 113 -115 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.0 (d,2), 7.5 (s,1) and 7.9 (d,2).
Example 15
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-methylanilino)-aziri- no[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 -115 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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,1).
Example 16
1, Ia, 2, 8, 8a, 8b-Hexah ydro-8-(hydroxymeth yl)-8a-methoxy-5-methyl-6-(3-methylan ilino)-aziri- no[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 70 mg of mitomycin A and 276 mg of 3-methylaniline was obtained 66 mg (78% yield) of the desired product having a melting point of 89 -91 C (decomposition) and providing the following analysis:
NMR (CDC13, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.4 (s,3), 6.7-7.5 (m,4) and 7.8 (s,1).
Example 17
1, 1 a, 2, 8, 8a, 8b-Hexahydrn-8-(hydrnxymethyll-8a-meth oxy-5-meth yI-6-U5-amino- 1,2, 4-triazol-3 yl)amino]-azirino[2', 3/: 3, 4]pyrrolo[l. aa]indole-, 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 50 mg of mitomycin A and 30 mg of 3,5-diamino-1,2,4-triazole was obtained 13 mg (5.5% yield) of the desired product having a melting point of 117 -120 C (decomposition) and providing the following analysis:
NMR (DMSO-d,, TS): 'S' 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, Ia, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6[(3-methylisothiazol-5-yl)- amino]-azirino[2', 3': 3, 4jpyrrolo 1, 2-afindole-4, 7-dione carbamate
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 was obtained 4.5 mg (8.5% yield) of the desired product having a melting point of 87"-90"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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,1) and 6.4 (s,1).
Example 19
1, 1 a, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(2-benzothiazolyl)amino]- azirino[2', 3':3, 4]pyrrolo[1, 2-a]indole-4, 7-dione carbamate
This compound was prepared by the 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 2aminobenzothiazole was obtained 12 mg (1 8% yield) of the desired product having a melting point of 82"-85"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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, 1 a, 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
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 2amino-6-nitrobenzothiazole was obtained 20 mg (27% yield) of the desired product having a melting point of 86"-89"C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): 'S' 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, 1 a, 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 having a melting point of 89 -91 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.1-8.0 (broad s,4).
Example 22
1, 1 a, 2, 8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(2-aminoethyl)amino]-azir- ino[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 the solvent was dichloromethane. From 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane was obtained 35 mg (65% yield) of the desired product having a melting point of 202"-205"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'A' values in ppm.
Absence 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).
Example 23
1, 1 a, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[methyl(2-methylaminoe- thyl)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 50 mg of mitomycin A and 25 mg of sym-dimethylethylenediamine was obtained 28 mg (50% yield) of the desired product having a melting point of 99-101 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): '#' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.3 (s,1), 2.5 (s,6), and 2.7 (s,4).
Example 24
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methyoxy-5-methyl-6-[2-(2-hydroxyethylamino) ethylamino]-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 the solvent was dichloromethane. From 50 mg of mitomycin A and 18 mg of 2-(2-aminoethylamino)ethanol was obtained 35 mg (58% yield) of the desired product having a melting point of 115 -118 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): '#' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.7 (broad s,7) and 3.7 (t,3).
Example 25
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methyoxy-5-methyl-6-[2-(2-hydroxyethoxy)ethylamino]-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 the solvent was dichloromethane. From 60 mg of mitomycin A and 20 mg of 2-(2-aminoethoxy)ethanol was obtained 30 mg (42% yield) of the desired product having a melting point of 99'-1 02'C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
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,1).
Example 26 1,1 a, 2,8, 8a, 8b-Hexahydro-8-(hydroxymethyll-8a-methoxy-5-methyl-6j2-(44mid & ly)ethylami- no]-azirino[2 3/:3,4]pyrrolo[l, 2-a]indole-4, 7-dione carbamate
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 was obtained 61 mg (71% yield) of the desired product having a melting point of 72 -73 C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TS): 'S' 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,1), 8.0-8.7 (broad s,2) and 8.1 (s,1).
Example 27
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(2-nitjro-1-imidazolyl)ethyllamino]-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 72 mg of mitomycin A and excess 1-(2-aminoethyl)-2-nitroimidazole was obtained 60 mg (70% yield) of the desired product having a melting point of 83 -85 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.4 (t,2), 4.6 (t,2), 7.3 (broad s,2) and 7.6 (s,1).
Example 28
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-melthyl-6-[2-(4-hydroxyphenyl)ethyllamino]-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 130 mg of mitomycin A and 510 mg of tyramine was obtained 138 mg (81% yield) of the desired product having a melting point of 120 -125 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): '#' values in ppm.
Absence 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,1).
Example 29
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(3,4-dihydroxyphenyl) ethylamino]-azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate
This compound eas 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 desired product decomposing without melting above 125"C and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 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).
Example 30
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-[(5-nitro-2-pyridyl)ami no]ethylamino) -azirino[23':3, 43pyrrolo[l. 2-a]indole-4, 7-dione carbamate
This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 30 mg of 2-(2-aminoethylamino)-5-nitropyridine was obtained 40 mg (56% yield) of the desired product having a melting point of 76"-79"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'd' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-4.0 (m,4), 6.2-6.7 (broad s,2), 8.1 (d,1), 8.2 (d,1) and 9.0 (s,1).
Example 31
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(1-piperazinyl)ethylami no]-azirino[2 3':3, 47pyrrolo[l, 2-a]indole-4, 7-dione carbamate
This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 20 mg of N-(2-aminoethyl) piperazine was obtained 23 mg (36% yield) of the desired product having a melting point of 138 -141 C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.6-2.1 (broad s,1), 2.2-2.6 (broad s,8), 2.6-2.8 (broad s,4) and 6.9 (t,1).
Example 32
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(2-pyridyl)ethylamino] azirino[2/, 33,47pyrrolo[l. 2-a]indole-4, 7-dione carbamate
This compound was prepared 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) of the desired product having a melting point of 64"-77"C (decomposition) and providing the following analysis:
NMR (CDCl3, TS): 'S' 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 (m,3) and 8.5 (d,1).
With specific reference to the compounds comprehended by formula Illa, the above examples illustrate the following structural variations.
1. Compounds wherein Z is a hydroxy substituted 1-pyrroiidinyl 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 radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower 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 wherein Z is a radical of the formula
and wherein R' 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 benzothiazolyl are represented, respectively, by Examples 17, 18, 19, 20 and 21.
5. Compounds wherein Z is a radical of the formula
R and wherein R' 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, mono- and dihydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, 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 co-pending patent application Serial Nos. 206,529 and 264,187.
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 Illa 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 "Lymphocytic Leukemia P388-Protocol 1.200", published in Cancer Chemotherapy Reports, Part 3, Vol. 3, No. 2, page 9 (September,
1972). Briefly put, the screening procedures involved administration of the test compound to
CDF1 female mice previously 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 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") expressed as the MST of the test animals compared to the MST of controls X 100 ("% T/C"). Within the context of the in vivo P388 procedure noted above, a % T/C value of 125 or greater indicates significant antineoplastic therapeutic activity. The lowest dose in 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 MST values obtained in the P388 screenings reported in Table I are also indicative of the absence of substantial toxicity of the compounds at the dosages indicated.
TABLE 1
Example Optimal Dose MST MED
No. mg/kg as % T/C
1 25.6 163 0.8
2 25.6 238 < 0.2
3 12.8 200 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
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 > 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 3.2 178 0.4 23 25.6 133 12.8 24 12.8 133 12.8 25 25.6 181 0.4 26 25.6 163 1.6 27 25.6 150 3.2 28 25.6 218 1.6 29 12.8 139 12.8 30 12.8 144 6.4 31 25.6 138 12.8 32 25.6 > 375 0.2
Clearly among the most preferred compounds employed as antineoplastic agents according to the invention are those exhibiting more than twice the relative life-extending capacity generally characterized as evidencing significant therapeutic potential, i.e., those having an MST % T/C value greater than 2 x 1 25. The class of such compounds is seen to include the compounds of
Examples 4, 10, 11 and 32.
As may be noted from Table I, initial single dosages of as little as 0.2 mg/kg showed substantial long term antineoplastic activity. Accordingly, the methods of the invention may involve therapeutic administration 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 compounds as the active ingredient in a suitable pharmaceutical 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 suffering from neoplastic disease. It is preferred that the compounds be administered parenterally. Pharmaceutical compositions suitable for use in practice of methods of the invention may comprise simple water solutions of one or more of the compounds of formula Illa, but may also include well known pharmaceutically acceptable diluents, adjuvants and/or carriers such as saline suitable for medicinal use.
Further aspects and advantages of the present invention are expected to occur to those skilled in the art upon consideration of the foregoing description and consequently only such limitations as appear in the appended claims should be placed thereon.
Claims (7)
1. Compounds of the formula,
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 benzothiazolyl, 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, mono- and di-hydroxy phenyl 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-pyrrolidi nyl)-azirino2',3':3,4]pyrrolo(l ,2-alindole-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-[3-(acetylamino)anilino]no[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)-aziriino[2',3':3,4]yrrolo(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]-azirno[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)-aziriino[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]-azirazirino[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-(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-(4-nitroanilino)azirino[2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate; 1 , 1 a, 2,8, Ba, B b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-sulfamylanilino)-aziri- no[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-triazol3-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-5yl)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-2yl)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-2yl)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(l ,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 carbamte;
1,1 a,2,8,8a,8b-Hexahydro-8-(hyd roxymethyl)-8a-methoxy-5-methyl-6-[2-hyd roxyethyla mi no)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)e thylamino]-azirino[2', 3': 3,4jpyrrolo( 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)ethylam ino]-azirino(2', 3': 3,4]pyrrolo( I ,2-a]indole-4, 7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-[(2-nitro-1-imidazolyl)ethylamino]-azirino[2',3':3,4]pyrrolo(1,2a]indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(4-hydroxyphenyl)e thylamino]-azirino[2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(3,4-dihydroxyphe nyl)ethylaminoj-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-pyridy l)amino]ethylaminoj -azirino[2', 3': 3,4]pyrrolo( 1 , 2-a]indole-4, 7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(1-piperazinyl)ethy lamino]-azirino[2',3': 3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate.
3. A method for treatment of a neoplastic disease state in an animal, said method comprising administering to an animal having such a disease a therapeutically effective amount 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
a 1-piperazinyl 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 benzothiazolyl, or R' 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, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
4. The methods of Claim 3 wherein the compound is selected from the group consisting of:
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-hydroxy-1-pyrrolidi nyl)-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-(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-(1-piperazinyl)aziri no[2', 3':3.41pyrrolo(l ,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': 3,4jpyrrolo( 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 ,1 a, 2,8, Ba, B b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-acetylamimi no)-aziri no[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 , 1 a, 2,8, roxymethyl)-8a-methoxy-5-methyl-6-(4-cyanoanil ino)-aziri- no[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)-azrirno[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-8-[4-(N-glycyl)anilino]-azir ino[2', 3':3,41pyrrolo(l ,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 cartamate;
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)-aziri no(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-sulfemylanilino)azri no[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-methylanilino)-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-methylanilino)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-triazol3-yl)amino]-azirino[2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione caramate;
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)amini no]-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 yI)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-2yl)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] azirinoC2', 3':3,41pyrrolo(l ,2-alindole-4, 7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[methyl(2-methylamino ethyl)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-hydroxyethylam no)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)e thylamino]-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;
1,1 a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(2-n itro- 1 -imidazolyl)ethylamino]-azirino[2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(4-hydroxyphenyl)e thylamino]-azirino(2',3': 3,4]pyrrolo( 1 , 2-a]indole-4, 7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(3,4-dihydroxyphe nyl)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-pyridy I)amino]ethylamino) -azirino[2',3': 3,3]pyrrolo(1,2-a]indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(1-piperazinyl)ethylamino]-azirino[2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate;
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 carbamte.
5. The method of claim 3 wherein the amount of the compound administered comprises a daily dose of from about 0.2 mg to about 51.2 mg per kg of the body weight of the animal.
6. 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
a 1-piperazinyl 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 R' 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 benzothiazolyl, or R' 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, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
7. Any novel feature or combination of features described herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46461283A | 1983-02-07 | 1983-02-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8402233D0 GB8402233D0 (en) | 1984-02-29 |
| GB2134514A true GB2134514A (en) | 1984-08-15 |
| GB2134514B GB2134514B (en) | 1987-04-01 |
Family
ID=23844605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08402233A Expired GB2134514B (en) | 1983-02-07 | 1984-01-27 | Mitomycin analogs |
Country Status (29)
| Country | Link |
|---|---|
| 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) |
| ZA (1) | ZA84788B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0272063A1 (en) * | 1986-12-13 | 1988-06-22 | Kyowa Hakko Kogyo Kabushiki Kaisha | Mitomycin derivatives |
| US4853385A (en) * | 1987-03-31 | 1989-08-01 | Kyowa Hakko Kogyo Co., Ltd. | 7-N,8-N-Ethylenemitomycin 8-imines |
| EP0485904A1 (en) * | 1990-11-13 | 1992-05-20 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin derivatives |
Families Citing this family (2)
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4268676A (en) * | 1979-12-05 | 1981-05-19 | University Patents, Inc. | Mitomycin analogs |
| GB1603937A (en) * | 1977-08-31 | 1981-12-02 | Kyowa Hakko Kogyo Kk | Mitomycin c derivatives |
| GB2106096A (en) * | 1981-05-15 | 1983-04-07 | University Patents Inc | Mitomycin derivatives their preparation and use |
Family Cites Families (4)
| 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 |
| JPS5686184A (en) * | 1979-12-17 | 1981-07-13 | Kyowa Hakko Kogyo Co Ltd | Novel mitomycin c derivative |
| 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
- 1984-02-06 AT AT0037684A patent/AT385509B/en not_active IP Right Cessation
- 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
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1603937A (en) * | 1977-08-31 | 1981-12-02 | Kyowa Hakko Kogyo Kk | Mitomycin c derivatives |
| US4268676A (en) * | 1979-12-05 | 1981-05-19 | University Patents, Inc. | Mitomycin analogs |
| GB2106096A (en) * | 1981-05-15 | 1983-04-07 | University Patents Inc | Mitomycin derivatives their preparation and use |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0272063A1 (en) * | 1986-12-13 | 1988-06-22 | Kyowa Hakko Kogyo Kabushiki Kaisha | Mitomycin derivatives |
| US4863935A (en) * | 1986-12-13 | 1989-09-05 | Kyowa Hakko Kogyo K.K. | Mitomycin compounds having useful anti-tumor activity |
| US4853385A (en) * | 1987-03-31 | 1989-08-01 | Kyowa Hakko Kogyo Co., Ltd. | 7-N,8-N-Ethylenemitomycin 8-imines |
| EP0485904A1 (en) * | 1990-11-13 | 1992-05-20 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin derivatives |
| US5180825A (en) * | 1990-11-13 | 1993-01-19 | Kyowa Hakko Kogyo Co., Ltd. | Mitomycin derivatives |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940127 |