CA1244412A - Mitomycin analogs - Google Patents
Mitomycin analogsInfo
- Publication number
- CA1244412A CA1244412A CA000398102A CA398102A CA1244412A CA 1244412 A CA1244412 A CA 1244412A CA 000398102 A CA000398102 A CA 000398102A CA 398102 A CA398102 A CA 398102A CA 1244412 A CA1244412 A CA 1244412A
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- Prior art keywords
- lower alkyl
- methoxy
- indole
- hexahydro
- azirino
- Prior art date
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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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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula, II, wherein: Y is hydrogen or lower alkyl ; and X
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 selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical, or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydroxy or piperidyl substituted 1-piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino 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 substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives 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, and N-morpholinyl lower alkyl.
Novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, IIa, 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 selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomor-pholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydroxy or piperidyl substituted 1-piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or a radical of the formula,
Compounds of the formula, II, wherein: Y is hydrogen or lower alkyl ; and X
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 selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical, or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydroxy or piperidyl substituted 1-piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino 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 substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives 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, and N-morpholinyl lower alkyl.
Novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, IIa, 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 selected from the group consisting of 1-pyrrolinyl, 1-indolinyl, N-thiazoladinyl, N-morpholinyl, 1-piperazinyl and N-thiomor-pholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical or a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or an hydroxy or piperidyl substituted 1-piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or a radical of the formula,
Description
BP~CKGROUND
The present invention relates generally to anti-biotic mitosane compsunds and to their use in the treatment of neoplastic disease states in animals.
The disclosure of my allowed, co-pending U.S.
patent Application Serial No. 100,331 (issued May 19, 1981 as U.S. Letters Patent 4,268,676) and my ~.S. Patent Ns.
4,460,599 provides both essential and non-essential material relating to the present invention.
Briefly summarized, said patent 4,268,6~6 sets forth a statement of the background of the ongoing search in the art for new and useful compounds which are structur-ally 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, said patent discloses new compounds of the formula, I, o X~ 2 ~ NB2 C ~
wherein: Y is hydrogen or lower alkyl; and X
is a thiazolamino radicalS a furfurylamino radical or a radical of the formula, R Rl - N ~ C - ~3 ~,~j :12~
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, tetrahydrofuryl and benzene sulfonamide.
Said patent also discloses 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, O O
Z ~ ~ ~ CH20~NH2 H3C ~ NY
o wherein: Y is hydrogen or lower alkyl; and Z
is a thiazolamino radical, a furfurylamino radical, a cyclo-propylamino radical, a pryidylamino radicalt or a radical of the formula, - N C R
in which R4, R5, 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, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
~RIE SUMMARY
According to the present invention, there are provided novel compounds of the formula, II~
~LZ~f~
o X ~ CH20CNH2 , ~
ll 11 ~ CH3 II
H3C ~ N ~
o wherein: Y is hydrogen or lower alkyl; and X
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 selected from the group consisting of l~pyrrolinyl, l-indolinyl, N-thiazoladinyl and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted l-aziridinyl radical, or a lower alkyl, formyl or acetylphenyl substituted l-piperazinyl radical, or an hydroxy or piperidyl substituted piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or R
a radical of the formula, -N-R' wherein R is hydrogen or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-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 substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives thereof, cyano 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, and N-morpholinyl lower alkyl.
A150 provided according to the invention are novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effec-tive amount of a compound of the formula/ IIa, O
Z_ CH20CNH2 H3C~'' ~ N ~ NY IIa o wherein: Y is hydroyen 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 selected from the group consisting of l-pyrrolinyl, l-indolinyl, N-thiazoladinyl N-morpholinyl, l-piperazinyl and N-thiomor-pholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted l-aziridinyl radical, or a lower aklyl, formyl or acetylphenyl substituted 0 l-piperazinyl radical, or an hydroxy or piperidyl substituted piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or R
a radical of the formula, -1-R~
wherein R is hydrogen or lower alkyl and R" is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-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, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives thereof, cyano 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 dialkyl-amino lower alkylO
Unless otherwise indicated, the term l'lower"~
as applied to "alkyl" radicals shall designate such straight or branched chain radicals as 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 II are all comprehended by the specifications of formula IIa. Put another wayS all the novel antibiotic mitomycin derivatives of formula II are useful in practice of the novel antineoplastic therapeutic methods which involve admini-stration of compounds of formula IIa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with appropriately selected amine compounds. The N-alkylmitomycin (e.g., N methylmito-mycin) derivatives are similarly prepared by the reactionof a selected amine with N-alkylmitomycin ~ prepared from mitomycin C, e.gO, according to the methods generally disclosed in Cheng, et al., J.Med.Chem., 20, No. ~, 767-770 (1977).
The preparative reactions generally yield the desired product as a crystalline solid which is readily soluble in alcohol.
Therapeutic methods of ~he invention comprehend the administration of effective amounts of one or more of the compounds of formula IIa, 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 iO0 mg per kgO, and preferably from about 0.2 to about 51.2 mg per kg, of body weight of the animal treated. Paren-teral administration, and especially intraperitoneal adminis-tration, 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 THE INVENTION
The following examples 1 though 42, 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 (20C), 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.
1,la,2c8,8a,8b-Hexahydro~8-(hydroxymethyl)-8a- ethoxy-5-methyl-6-(Z-cyano-l-aziridinyl)-azirino[~',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate A solution of mitomycin A (100 mg~ or 0.286 mmol) in 8 ml of anhydrous methanol was treated with 2-cyanoaziridine -(38.9 mg. or 0.572 mmol) and 30 mg. of potassium carbonatel under nitrogen at room temperature. When thin-layer chrom-atography on silica gel (2:8 methanol-chloroform as solvent) showed that starting material was no longer present, the mixture was diluted with 50 ml of methylene chloride, filtered, and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel with a mixture of methanol and chloroform (2:8 by volume) as the solvent. This procedure gave 33 mg. (30% yield) of the desired product having a melting point of 87-89C
(decomposing) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
The disappearance of a singlet at 4.02 (due to the 6-methoxy group in the starting material) on the appearance of new signals at 2.13 (d, 2) and 2.53 (broad s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hYdroxYmethyl)-8a-methoxy-5-methyl-6-~thiomorpholinyl)-azir no[Z',3':3,4~p~rrolo[1,~-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 52 mg. of mitomycin A ~nd ~00 mg. of thiomorpholine was obtained 14 mg. (22% yield) of the desired product having a melting point of 90-91C (decomposition) and providing the following analysis:
NMR (CDC13, TS)~'~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the enhancement of peaks at 2.8 (m, increase by 4) and 3.6 (m, increase by 4) 1,la,2,8,8a,8b-HexahYdro-8-(hYdroxYmethyl)-8a-methoxy-5-methyl-6-(1-indolinyl)-azirinol2',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 potassium carbonate was omitted.
From 100 mg. of mitomycin ~ and 69 mg. of indoline was obtained lZ~
45 mg. (36% yield) of the desired product having a melting point of 127-135C (decomposition) and providing the follow-ing analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6-methoxy peak at 4.Q2, and the appearance of new peaks at 2.85-3.7 (group, 4) and 6.15-7.5 (group, 4).
1,la,2,8!8a!8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(6-methoxy-3-~yridyl)amino]-azirino[2',3':3,4]-pyrrolo[l,2-a] _dole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 2 drops of 3-amino-6-methoxy-pyridine was obtained 96 mg. (76~ yield) of the desired product baving a melting point of 260-262C (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 3.93 (s, 3), 6.77 (s, 1), 7.26 (d, 1), 7.60 (d, 1) and 7.87 (s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hydrox~methyl)-Ba-methox~-5-methyl-6 [(6-methoxy-8-quinolinyl)amino]-azirinoL2',3'-3,4]-pyrrolo[l,2-a]indole carbamate This compound was prepared by the procedure described in Example 1. From 60 mg. of mitomycin A and 54 mgO of 8-amino-6-methoxyquinoline was obtained 26 mg. (32% yield) ~z~ 4~
of the desired product having a melting point of 135-145C
~decomposition) and providing the following analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance oE new peaks at 6.4 ~d, 1~, 6.67 (d, 1), 7.30 (dd, 1), 8.0 (dd, 1) and 8.90 (dd, 1) l a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-quinuclidinylamino)-azirino[2',3'.3,4]py~rolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 3-aminoquinuclidine (prepared by treating an aqueous solution of 73 mg. of 3-aminoquinucli-dine hydrochloride with sodium hydroxide) was obtained 86 mg. (54% yield) of the desired product having a melting point of 138-146 (decomposition) and providing the following analysis:
NMR (CDC13 TS) '~' values in ppm.
~bsence of the 6-methoxy peak at 4.02 enhancement of the peaks at 2.8 and 3.8, and the appearance of new broad peaks at 1.2 and 2.5.
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(y-butyrolactonyl)amlno]-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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 60 mg. of ~ amino-y-butyrolac-tone hydrochloride was obtained 68 mg. (57~ yield) of the desired product having a melting point of 87-89C (decomposi-tion) and providing the following analysis:
NMR (DMSO-d . TS~ '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 t and the appearance of new peaks at 1.90-2.87 (m, 2), 3.80-4.70 (m, 3), and 8.3-9.2 (broad s, 1).
1,la,2,8,8a,8b-Hexahydro 8-(hydroxymethyl)-8a-me ho~-5-methyl-6- _-carboxamidoanllino)-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 100 mg. of mitomycin A and 82 mg. of 4-aminobenzamide was obtained 36 mg. (28~ yield) of the desired product having a melting point of 167-169C (decomposi-tion) and providing the following analysis:
NM~ (Acetone-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.67 (d, 3) and 7.73 (d, 2) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-dimethoxybenz~lamino?-azirino[2'!3':3,4]~rrolo-11,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 29 mg. of mitomycin A and 69.4 mg. of 3,4-dimethoxybenzyl--\ ~z~
amine was obtained 29 mg. (72% yield) of the desired product having a melting point of 112C ~decomposition) and providing the following ana]ysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 3~9 (5, 6), 4.65-4.75 (d, 2), 6.55 (broad s, 1) and 6.86 (s, 3) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethy1)-8a-methoxy-5-methyl-6-[(1-ethyl-2-pyrrolidino)methylamino]-azirino[2',3':3,4]-Ey~ L_,2-a]i~dole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 150 mg. of mitomycin A and 2 drops of 2-aminomethyl-l-ethylpyrrolidine was obtained 78 mg. (41% yield) of the desired product decomposing at temperatures above 300C
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 1.07 (t, 3), 1.4-2.33 (m, 5), 2.36-3.03 (m, 4), 3.3-3.83 (m, 2), and 6.77-7~20 (broad S, 1) EX~MPLE 11 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-5-methyl-6-[(1-methoxycarbonyl-3-methylthio)propylamino]-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 potassium carbonate was replaced ~2~
by 0.5 ml. of triethylamine. From 150 mg. of mitomycin A and 110 mg. of L-methionine methyl ester hydrochloride was obtained 64 mg. (30% yield) of the desired product having a melting point of 83-85C (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 1.63-2.40 (m, 3), 2.10 (s, 3), 2.43-3.0 (m, 2), 3.80 (s, 3) and 8.3, g.3 (broad s, 1).
1,la,2,8,8a,8b-Hex~ydro-8-~ydroxymethx1)-8a-methoxy-5-methyl-6-(2-phen~lcyclopropylamino)-azirinoI2',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 potassium carbonate was omitted.
From 125 mg. of mitomycin A and 85 mg. of 2-phenylcyclo-propylamine was obtained 70 mg. (63%) of the desired productdecomposing at temperatures abcve 250C and providlng 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 0.6-1.53 Im, 4), 6.20-6.50 (broad s, 1) and 7.18 (broad s, 5).
3~Z~
1,la,2,8,8a,8b-Hexahydro-8-(hydro ymethyl)-8a-methoxy-5-methyl-6-[(5-chloro-2-benzoxaz~lyl)amino]-azirino[2',3':3,4]-~rrolorll2-a]indole-4~7-dione carbamate .
This compound was prepared by the procedure described in Example 1. From 100 mg. of mitomycin A and 50 mg. of
The present invention relates generally to anti-biotic mitosane compsunds and to their use in the treatment of neoplastic disease states in animals.
The disclosure of my allowed, co-pending U.S.
patent Application Serial No. 100,331 (issued May 19, 1981 as U.S. Letters Patent 4,268,676) and my ~.S. Patent Ns.
4,460,599 provides both essential and non-essential material relating to the present invention.
Briefly summarized, said patent 4,268,6~6 sets forth a statement of the background of the ongoing search in the art for new and useful compounds which are structur-ally 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, said patent discloses new compounds of the formula, I, o X~ 2 ~ NB2 C ~
wherein: Y is hydrogen or lower alkyl; and X
is a thiazolamino radicalS a furfurylamino radical or a radical of the formula, R Rl - N ~ C - ~3 ~,~j :12~
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, tetrahydrofuryl and benzene sulfonamide.
Said patent also discloses 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, O O
Z ~ ~ ~ CH20~NH2 H3C ~ NY
o wherein: Y is hydrogen or lower alkyl; and Z
is a thiazolamino radical, a furfurylamino radical, a cyclo-propylamino radical, a pryidylamino radicalt or a radical of the formula, - N C R
in which R4, R5, 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, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
~RIE SUMMARY
According to the present invention, there are provided novel compounds of the formula, II~
~LZ~f~
o X ~ CH20CNH2 , ~
ll 11 ~ CH3 II
H3C ~ N ~
o wherein: Y is hydrogen or lower alkyl; and X
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 selected from the group consisting of l~pyrrolinyl, l-indolinyl, N-thiazoladinyl and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted l-aziridinyl radical, or a lower alkyl, formyl or acetylphenyl substituted l-piperazinyl radical, or an hydroxy or piperidyl substituted piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or R
a radical of the formula, -N-R' wherein R is hydrogen or lower alkyl and R' is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-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 substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives thereof, cyano 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, and N-morpholinyl lower alkyl.
A150 provided according to the invention are novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effec-tive amount of a compound of the formula/ IIa, O
Z_ CH20CNH2 H3C~'' ~ N ~ NY IIa o wherein: Y is hydroyen 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 selected from the group consisting of l-pyrrolinyl, l-indolinyl, N-thiazoladinyl N-morpholinyl, l-piperazinyl and N-thiomor-pholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted l-aziridinyl radical, or a lower aklyl, formyl or acetylphenyl substituted 0 l-piperazinyl radical, or an hydroxy or piperidyl substituted piperidyl radical, or a lower alkoxy, amino or halo substituted pyridyl-amino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or R
a radical of the formula, -1-R~
wherein R is hydrogen or lower alkyl and R" is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-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, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted deriva-tives thereof, cyano 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 dialkyl-amino lower alkylO
Unless otherwise indicated, the term l'lower"~
as applied to "alkyl" radicals shall designate such straight or branched chain radicals as 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 II are all comprehended by the specifications of formula IIa. Put another wayS all the novel antibiotic mitomycin derivatives of formula II are useful in practice of the novel antineoplastic therapeutic methods which involve admini-stration of compounds of formula IIa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with appropriately selected amine compounds. The N-alkylmitomycin (e.g., N methylmito-mycin) derivatives are similarly prepared by the reactionof a selected amine with N-alkylmitomycin ~ prepared from mitomycin C, e.gO, according to the methods generally disclosed in Cheng, et al., J.Med.Chem., 20, No. ~, 767-770 (1977).
The preparative reactions generally yield the desired product as a crystalline solid which is readily soluble in alcohol.
Therapeutic methods of ~he invention comprehend the administration of effective amounts of one or more of the compounds of formula IIa, 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 iO0 mg per kgO, and preferably from about 0.2 to about 51.2 mg per kg, of body weight of the animal treated. Paren-teral administration, and especially intraperitoneal adminis-tration, 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 THE INVENTION
The following examples 1 though 42, 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 (20C), 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.
1,la,2c8,8a,8b-Hexahydro~8-(hydroxymethyl)-8a- ethoxy-5-methyl-6-(Z-cyano-l-aziridinyl)-azirino[~',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate A solution of mitomycin A (100 mg~ or 0.286 mmol) in 8 ml of anhydrous methanol was treated with 2-cyanoaziridine -(38.9 mg. or 0.572 mmol) and 30 mg. of potassium carbonatel under nitrogen at room temperature. When thin-layer chrom-atography on silica gel (2:8 methanol-chloroform as solvent) showed that starting material was no longer present, the mixture was diluted with 50 ml of methylene chloride, filtered, and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel with a mixture of methanol and chloroform (2:8 by volume) as the solvent. This procedure gave 33 mg. (30% yield) of the desired product having a melting point of 87-89C
(decomposing) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
The disappearance of a singlet at 4.02 (due to the 6-methoxy group in the starting material) on the appearance of new signals at 2.13 (d, 2) and 2.53 (broad s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hYdroxYmethyl)-8a-methoxy-5-methyl-6-~thiomorpholinyl)-azir no[Z',3':3,4~p~rrolo[1,~-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 52 mg. of mitomycin A ~nd ~00 mg. of thiomorpholine was obtained 14 mg. (22% yield) of the desired product having a melting point of 90-91C (decomposition) and providing the following analysis:
NMR (CDC13, TS)~'~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the enhancement of peaks at 2.8 (m, increase by 4) and 3.6 (m, increase by 4) 1,la,2,8,8a,8b-HexahYdro-8-(hYdroxYmethyl)-8a-methoxy-5-methyl-6-(1-indolinyl)-azirinol2',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 potassium carbonate was omitted.
From 100 mg. of mitomycin ~ and 69 mg. of indoline was obtained lZ~
45 mg. (36% yield) of the desired product having a melting point of 127-135C (decomposition) and providing the follow-ing analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6-methoxy peak at 4.Q2, and the appearance of new peaks at 2.85-3.7 (group, 4) and 6.15-7.5 (group, 4).
1,la,2,8!8a!8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(6-methoxy-3-~yridyl)amino]-azirino[2',3':3,4]-pyrrolo[l,2-a] _dole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 2 drops of 3-amino-6-methoxy-pyridine was obtained 96 mg. (76~ yield) of the desired product baving a melting point of 260-262C (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 3.93 (s, 3), 6.77 (s, 1), 7.26 (d, 1), 7.60 (d, 1) and 7.87 (s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hydrox~methyl)-Ba-methox~-5-methyl-6 [(6-methoxy-8-quinolinyl)amino]-azirinoL2',3'-3,4]-pyrrolo[l,2-a]indole carbamate This compound was prepared by the procedure described in Example 1. From 60 mg. of mitomycin A and 54 mgO of 8-amino-6-methoxyquinoline was obtained 26 mg. (32% yield) ~z~ 4~
of the desired product having a melting point of 135-145C
~decomposition) and providing the following analysis:
NMR (CDC13, TS) '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance oE new peaks at 6.4 ~d, 1~, 6.67 (d, 1), 7.30 (dd, 1), 8.0 (dd, 1) and 8.90 (dd, 1) l a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-quinuclidinylamino)-azirino[2',3'.3,4]py~rolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 3-aminoquinuclidine (prepared by treating an aqueous solution of 73 mg. of 3-aminoquinucli-dine hydrochloride with sodium hydroxide) was obtained 86 mg. (54% yield) of the desired product having a melting point of 138-146 (decomposition) and providing the following analysis:
NMR (CDC13 TS) '~' values in ppm.
~bsence of the 6-methoxy peak at 4.02 enhancement of the peaks at 2.8 and 3.8, and the appearance of new broad peaks at 1.2 and 2.5.
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(y-butyrolactonyl)amlno]-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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 60 mg. of ~ amino-y-butyrolac-tone hydrochloride was obtained 68 mg. (57~ yield) of the desired product having a melting point of 87-89C (decomposi-tion) and providing the following analysis:
NMR (DMSO-d . TS~ '~' values in ppm.
Absence of the 6-methoxy peak at 4.02 t and the appearance of new peaks at 1.90-2.87 (m, 2), 3.80-4.70 (m, 3), and 8.3-9.2 (broad s, 1).
1,la,2,8,8a,8b-Hexahydro 8-(hydroxymethyl)-8a-me ho~-5-methyl-6- _-carboxamidoanllino)-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 100 mg. of mitomycin A and 82 mg. of 4-aminobenzamide was obtained 36 mg. (28~ yield) of the desired product having a melting point of 167-169C (decomposi-tion) and providing the following analysis:
NM~ (Acetone-d6, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.67 (d, 3) and 7.73 (d, 2) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-dimethoxybenz~lamino?-azirino[2'!3':3,4]~rrolo-11,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 29 mg. of mitomycin A and 69.4 mg. of 3,4-dimethoxybenzyl--\ ~z~
amine was obtained 29 mg. (72% yield) of the desired product having a melting point of 112C ~decomposition) and providing the following ana]ysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 3~9 (5, 6), 4.65-4.75 (d, 2), 6.55 (broad s, 1) and 6.86 (s, 3) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethy1)-8a-methoxy-5-methyl-6-[(1-ethyl-2-pyrrolidino)methylamino]-azirino[2',3':3,4]-Ey~ L_,2-a]i~dole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 150 mg. of mitomycin A and 2 drops of 2-aminomethyl-l-ethylpyrrolidine was obtained 78 mg. (41% yield) of the desired product decomposing at temperatures above 300C
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 1.07 (t, 3), 1.4-2.33 (m, 5), 2.36-3.03 (m, 4), 3.3-3.83 (m, 2), and 6.77-7~20 (broad S, 1) EX~MPLE 11 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-5-methyl-6-[(1-methoxycarbonyl-3-methylthio)propylamino]-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 potassium carbonate was replaced ~2~
by 0.5 ml. of triethylamine. From 150 mg. of mitomycin A and 110 mg. of L-methionine methyl ester hydrochloride was obtained 64 mg. (30% yield) of the desired product having a melting point of 83-85C (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 1.63-2.40 (m, 3), 2.10 (s, 3), 2.43-3.0 (m, 2), 3.80 (s, 3) and 8.3, g.3 (broad s, 1).
1,la,2,8,8a,8b-Hex~ydro-8-~ydroxymethx1)-8a-methoxy-5-methyl-6-(2-phen~lcyclopropylamino)-azirinoI2',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 potassium carbonate was omitted.
From 125 mg. of mitomycin A and 85 mg. of 2-phenylcyclo-propylamine was obtained 70 mg. (63%) of the desired productdecomposing at temperatures abcve 250C and providlng 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 0.6-1.53 Im, 4), 6.20-6.50 (broad s, 1) and 7.18 (broad s, 5).
3~Z~
1,la,2,8,8a,8b-Hexahydro-8-(hydro ymethyl)-8a-methoxy-5-methyl-6-[(5-chloro-2-benzoxaz~lyl)amino]-azirino[2',3':3,4]-~rrolorll2-a]indole-4~7-dione carbamate .
This compound was prepared by the procedure described in Example 1. From 100 mg. of mitomycin A and 50 mg. of
2-amino-5-chlorobenzoxazole was obtained 35 mg. (25% yield) of the desired product having a melting point of 118-120C
(decomposition) and providing the following analysis:
MMR (CDC13, TS)~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks in the region 6.70-7.63 (m, 4).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[5-methyl-2-(1,3,4-thiadiazolYl)amino]-azirin [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 100 mg. of mitomycin A and 53 mg. of 2-amino-5-methyl-1,3,4-thiadiazole was obtained 31 mg. (25%
yield) of the desired product having a melting point of 91~-93~C (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 2.68 (s, 3), and 7.47-7.63 (broad s, 1) f~
_la,2,8,8a,8b-~lexahydro-8 (hydroxymethyl)-8a-methox~
meth~l-6-~,2-dimethoxyethylamino~-azirino[2',3':3,41pyrrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure de~cribed in Example 1, except that the potassium carbonate was omitted.
From 60 mg. of mitomycin A and 35 mg. of 2,2-dimethoxyethyl-amine was obtained 60 mg. (83% yield) of the desired product decomposing at temperatures above 220C 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 3.45 (s, 6), 3.33-3.93 (m, 2), 4.33-4.85 (broad s, 1) and 6.15-6.66 (broad s, 1.) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-3a-methoxy-5-methyl-6-(2-mercaptoethylamino)-azirino[2',3':3,4]pyrrolo-l,Z-aJindole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 150 mg. of mitomycin A and 100 mg. of 2-mercaptoethylamine hydrochloride was obtained 50 mg. (44~ yield) of the desired product having a melting point of 152-154C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TMS~ ' values in ppm.
Absence of the 6 methoxy peak at 4.02, and the appearance of new peaks at 2.53-3.10 (m, 4), 7.30~7.50 (broad S, 1) EXAM _E 17 1,la,2,3,8a,8b-Hexahydro-8-thydroxymethyl)-8a-methoxy-5-methyl-6-[t4-methyl-2-thiazolyl)amino]_azirino[2',3':3,4]pyrrolo-[1,2-2]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 150 mg. of mitomycin A and 96 mg. of 2-amino-4-methylthiazole was obtained 85 mg. (59~ yield) of the desired product having a melting point of 116-118C
tdecomPosition) and providing the following analysis:
NMR tCDC13, TS ): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 2.23 ts, 3), 6.30-6.60 tbroad s, 1) and 7.30 ts, 1).
1,la,2,8,8a,8b-Hexahydro-8-thydroxymethyl)-8a~methoxy-5-methyl-6-t4-mercaptoanilino)-azirino[2',3':3t4]pyrrolo[1,2-a]-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 200 mg. of mitomycin A and 143 mgO of 4 mercaptoaniline was obtained 120 mg. t47% yield) of the desired product having a melting point of 97-99C (decomposition) and provid-ing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4O02r and the appearance of new peaks at 6.53 (d, 2) and 7.0-7.7 (m, 3).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy~
methyl-6-(3,4-methylenedioxyanilino)-azirino[2',3':3,41pyrrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 80 mg. of mitomycin A and 0.1 ml. of 3,4-methylenedioxy-aniline was obtained 50 mg. (48% yield) of the desired product having a melting point of 86-83C (decomposition) and provid-ing the Eollowing analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 5.97 (S, 23, 6.0-6.7 (m, 3), 7.27 (S, 1).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(1-pyrrolidino)ethylamino]-azirino[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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.2 ml. of 2-(1-pyrrolidino) ethylamine was obtained 7.5 mg. (61% yield) of the desired product decomposing at temperatures above 200C and providing the following analysis:
NMR (~DC13, TS): '~' values in ppm.
Absence oE the 6-methoxy peak at 4.02, and the kfl~2 appearance of new peaks at 1.57-1.93 (M, 4), 2.33-3.03 (m, 8), and 6.92 (t, 1).
.
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(5-isoquinolinylamino) 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 90 mg. of mitomycin ~ and 810 mg. of 5-aminoisoquinoline was obtained 28 mg. (24% yield) of the desired product having no melting point below 340C 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 6.8-7.65 (m, 3), 7.85 (d, 1) and 8.55 (d, 1).
_ 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(5-indazolylamino)-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 90 mg. of mitomycin A and 666 mg. of 5-aminoindazole was obtained 35 mg. (30~ yield) of the desired product having no melting point below 340C and providing the following analysis:
NMR (CDC13, TS~ ' values in ppm.
Absence oE the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.8-7.65 (m, 3) and 8.0 (S, 1).
- ~L,2~
1,la,2/3,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methQx~-5-meth~l-6-~4-(2,1,3-benzothladiazolyl)amin ]-azirino[2~,3':3,4]-pyrrolo[l,Z-a~indole-4,7-dione car~amate This compound was prepared by the procedure described in Example 1. The reaction did not go to completion in 19 hours, despite the use of excess amine~ From 50 mg.
of mitomycin A and 300 mg. of 4-amino-2,1,3-benzothiadiazole was obtained 32 mg. (48~) of the desired product having a melting point of 139-140C (decomposition) and providing the following analysis:
NMR (CDC13 + CD30D, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.6 (m, 1), 7.6 (m, 2) and 8.25 (broad s, 1).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethy1)-8a-methoxy-5-methyl-6-(N-glycinyl)-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 40 ml. of methanol was used and 10 ml. of triethylamine was used instead of potassium carbonate.
From 100 mg. of mitomycin A and 600 mg. of glycine was obtained 47.4 mg. (42~ yield) of the desired product having no melting point below 350C and providing the following analysis:
NMR (CDC13 + CD30D, T5): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of a new peak at 3.45 (S, 2).
1,la,2,8,8a,8b-Hexahydro--8-~hydroxymethyl)-8a-methoxy-5-methyl-6-(2-cyanoethylamino)-azirino[2'r3':3,4]pyrrolo[1,2-a~-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 210 mg. of mitomycin A and 90 mg. of 3-aminopropionitrile Eumarate was obtained 151 mg. (65% yield) of the desired product having a melting point of 68-70C (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 2.1-2.77 (m, 4) and 6.57 (t, 1).
1,la,2,8,8a,8b-Hexahydro-8-[hydrox meth~l)-8a-methoxy-5-methyl-6-(2-fluo oethylamino)-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 2-fluoroethylamine hydrochloride (220 mg.) was neutralized with sodium methoxide (119 mg.) in 2 ml. of methanol at 5C before the mitomycin A (77 mg~) was added, and potassium carbonate was not used. A 62 mg.
(74%) yield of the desired product was obtained, having no melting point below 340C and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm~
Absence of the 6-methoxy peak at 4.02, and the ~2,~
appearance of new peaks at 3.3-3.9 (m, 2), 4.2 (t, 2) and 6.5 (broad sr 1).
EX~MPLE 27 1,la,2,8,8a,8b-Hexahydro-8-thydroxymethyl)-8a-methoxy-5-methyl-6-[1-(3-pyrrolinyl)]-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 potassium carbonate was omitted and a change was made necessary by the presence of pyrrolidine impurity in the commercial sample of 3-pyrroline. The pyrroli-dine formed a crystalline derivative with mitomycin A that was removed from the mixtur~ by filtration. The filtrate was then worked up as described in Example 1. From 100 mg. of mitomycin A and 1 g. of commercial 3-pyrroline was obtained 30 mg. ~27% yield) of the desired product having a partial decomposition temperature of 85-90C, but not melting below 250C, and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of a new peak at 5.9 (s, 2). It was not possible to distinguish the 2-proton peak in the 3.4 region from other absorption.
lsla,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8-methoxy-5-methyl-6-(3-thiazolidino)-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 potassium carbonate was omitted.
From 250 mg. of mitomycin A and 0~5 ml. of thiazolidine 4~
was obtained 125 mg. (43~ yield) of the desired product having a melting poin~ of 105-107C (decomposition) and providing the following analysis:
NMR CDCl , TMS~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 2.62 tbroad S, 2), 2.68-3.02 (broad S, 2), and 3.32-4.02 (broad S, 2).
1,la,2,8,8a,8b-~exahydro-8-(hydr~y~ y~)-8a-methoxy-5_ methyl-6~[1-(4-methylpiperazino)]-azirino[2',3':3,4]p~rrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.2 ml. of N--methylpiperazine was obtained 50 mg. (42% yield) of the desired product having a melting point of 84-87C (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 2.27 (s, 3), 2.47 (t, 4) and 2.92 (t, 4).
1,la,2,8,8a,8b-~exahydro-8-(hydroxymethy1)-8a-methox -5-methyl-6-[3-(pyrazol~l)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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 48 mg. of 3-aminopyrazole was obtained 50 mg. (44% yield) of the desired product having a melting point of 142-145C (decomposition) and providing the following analysis:
NMR (CDC13, TMS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.50 (d, 2), 6.67-6.83 (broad S, 1) and 8.07 (S, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-~ethyl-6 [2-(N-morpholino)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 potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.5 ml. of N-(2-aminoethyl)-morpholine was obtained 70 mgO (55% yield) of the desired product having a melting point of 74-76C (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 2.27-2.73 (broad, 8),
(decomposition) and providing the following analysis:
MMR (CDC13, TS)~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks in the region 6.70-7.63 (m, 4).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[5-methyl-2-(1,3,4-thiadiazolYl)amino]-azirin [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 100 mg. of mitomycin A and 53 mg. of 2-amino-5-methyl-1,3,4-thiadiazole was obtained 31 mg. (25%
yield) of the desired product having a melting point of 91~-93~C (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 2.68 (s, 3), and 7.47-7.63 (broad s, 1) f~
_la,2,8,8a,8b-~lexahydro-8 (hydroxymethyl)-8a-methox~
meth~l-6-~,2-dimethoxyethylamino~-azirino[2',3':3,41pyrrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure de~cribed in Example 1, except that the potassium carbonate was omitted.
From 60 mg. of mitomycin A and 35 mg. of 2,2-dimethoxyethyl-amine was obtained 60 mg. (83% yield) of the desired product decomposing at temperatures above 220C 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 3.45 (s, 6), 3.33-3.93 (m, 2), 4.33-4.85 (broad s, 1) and 6.15-6.66 (broad s, 1.) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-3a-methoxy-5-methyl-6-(2-mercaptoethylamino)-azirino[2',3':3,4]pyrrolo-l,Z-aJindole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 150 mg. of mitomycin A and 100 mg. of 2-mercaptoethylamine hydrochloride was obtained 50 mg. (44~ yield) of the desired product having a melting point of 152-154C (decomposition) and providing the following analysis:
NMR (DMSO-d6, TMS~ ' values in ppm.
Absence of the 6 methoxy peak at 4.02, and the appearance of new peaks at 2.53-3.10 (m, 4), 7.30~7.50 (broad S, 1) EXAM _E 17 1,la,2,3,8a,8b-Hexahydro-8-thydroxymethyl)-8a-methoxy-5-methyl-6-[t4-methyl-2-thiazolyl)amino]_azirino[2',3':3,4]pyrrolo-[1,2-2]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 150 mg. of mitomycin A and 96 mg. of 2-amino-4-methylthiazole was obtained 85 mg. (59~ yield) of the desired product having a melting point of 116-118C
tdecomPosition) and providing the following analysis:
NMR tCDC13, TS ): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 2.23 ts, 3), 6.30-6.60 tbroad s, 1) and 7.30 ts, 1).
1,la,2,8,8a,8b-Hexahydro-8-thydroxymethyl)-8a~methoxy-5-methyl-6-t4-mercaptoanilino)-azirino[2',3':3t4]pyrrolo[1,2-a]-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 200 mg. of mitomycin A and 143 mgO of 4 mercaptoaniline was obtained 120 mg. t47% yield) of the desired product having a melting point of 97-99C (decomposition) and provid-ing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4O02r and the appearance of new peaks at 6.53 (d, 2) and 7.0-7.7 (m, 3).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy~
methyl-6-(3,4-methylenedioxyanilino)-azirino[2',3':3,41pyrrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 80 mg. of mitomycin A and 0.1 ml. of 3,4-methylenedioxy-aniline was obtained 50 mg. (48% yield) of the desired product having a melting point of 86-83C (decomposition) and provid-ing the Eollowing analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 5.97 (S, 23, 6.0-6.7 (m, 3), 7.27 (S, 1).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(1-pyrrolidino)ethylamino]-azirino[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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.2 ml. of 2-(1-pyrrolidino) ethylamine was obtained 7.5 mg. (61% yield) of the desired product decomposing at temperatures above 200C and providing the following analysis:
NMR (~DC13, TS): '~' values in ppm.
Absence oE the 6-methoxy peak at 4.02, and the kfl~2 appearance of new peaks at 1.57-1.93 (M, 4), 2.33-3.03 (m, 8), and 6.92 (t, 1).
.
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(5-isoquinolinylamino) 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 90 mg. of mitomycin ~ and 810 mg. of 5-aminoisoquinoline was obtained 28 mg. (24% yield) of the desired product having no melting point below 340C 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 6.8-7.65 (m, 3), 7.85 (d, 1) and 8.55 (d, 1).
_ 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(5-indazolylamino)-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 90 mg. of mitomycin A and 666 mg. of 5-aminoindazole was obtained 35 mg. (30~ yield) of the desired product having no melting point below 340C and providing the following analysis:
NMR (CDC13, TS~ ' values in ppm.
Absence oE the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.8-7.65 (m, 3) and 8.0 (S, 1).
- ~L,2~
1,la,2/3,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methQx~-5-meth~l-6-~4-(2,1,3-benzothladiazolyl)amin ]-azirino[2~,3':3,4]-pyrrolo[l,Z-a~indole-4,7-dione car~amate This compound was prepared by the procedure described in Example 1. The reaction did not go to completion in 19 hours, despite the use of excess amine~ From 50 mg.
of mitomycin A and 300 mg. of 4-amino-2,1,3-benzothiadiazole was obtained 32 mg. (48~) of the desired product having a melting point of 139-140C (decomposition) and providing the following analysis:
NMR (CDC13 + CD30D, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.6 (m, 1), 7.6 (m, 2) and 8.25 (broad s, 1).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethy1)-8a-methoxy-5-methyl-6-(N-glycinyl)-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 40 ml. of methanol was used and 10 ml. of triethylamine was used instead of potassium carbonate.
From 100 mg. of mitomycin A and 600 mg. of glycine was obtained 47.4 mg. (42~ yield) of the desired product having no melting point below 350C and providing the following analysis:
NMR (CDC13 + CD30D, T5): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of a new peak at 3.45 (S, 2).
1,la,2,8,8a,8b-Hexahydro--8-~hydroxymethyl)-8a-methoxy-5-methyl-6-(2-cyanoethylamino)-azirino[2'r3':3,4]pyrrolo[1,2-a~-indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 210 mg. of mitomycin A and 90 mg. of 3-aminopropionitrile Eumarate was obtained 151 mg. (65% yield) of the desired product having a melting point of 68-70C (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 2.1-2.77 (m, 4) and 6.57 (t, 1).
1,la,2,8,8a,8b-Hexahydro-8-[hydrox meth~l)-8a-methoxy-5-methyl-6-(2-fluo oethylamino)-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 2-fluoroethylamine hydrochloride (220 mg.) was neutralized with sodium methoxide (119 mg.) in 2 ml. of methanol at 5C before the mitomycin A (77 mg~) was added, and potassium carbonate was not used. A 62 mg.
(74%) yield of the desired product was obtained, having no melting point below 340C and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm~
Absence of the 6-methoxy peak at 4.02, and the ~2,~
appearance of new peaks at 3.3-3.9 (m, 2), 4.2 (t, 2) and 6.5 (broad sr 1).
EX~MPLE 27 1,la,2,8,8a,8b-Hexahydro-8-thydroxymethyl)-8a-methoxy-5-methyl-6-[1-(3-pyrrolinyl)]-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 potassium carbonate was omitted and a change was made necessary by the presence of pyrrolidine impurity in the commercial sample of 3-pyrroline. The pyrroli-dine formed a crystalline derivative with mitomycin A that was removed from the mixtur~ by filtration. The filtrate was then worked up as described in Example 1. From 100 mg. of mitomycin A and 1 g. of commercial 3-pyrroline was obtained 30 mg. ~27% yield) of the desired product having a partial decomposition temperature of 85-90C, but not melting below 250C, and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of a new peak at 5.9 (s, 2). It was not possible to distinguish the 2-proton peak in the 3.4 region from other absorption.
lsla,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8-methoxy-5-methyl-6-(3-thiazolidino)-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 potassium carbonate was omitted.
From 250 mg. of mitomycin A and 0~5 ml. of thiazolidine 4~
was obtained 125 mg. (43~ yield) of the desired product having a melting poin~ of 105-107C (decomposition) and providing the following analysis:
NMR CDCl , TMS~ ' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 2.62 tbroad S, 2), 2.68-3.02 (broad S, 2), and 3.32-4.02 (broad S, 2).
1,la,2,8,8a,8b-~exahydro-8-(hydr~y~ y~)-8a-methoxy-5_ methyl-6~[1-(4-methylpiperazino)]-azirino[2',3':3,4]p~rrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.2 ml. of N--methylpiperazine was obtained 50 mg. (42% yield) of the desired product having a melting point of 84-87C (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 2.27 (s, 3), 2.47 (t, 4) and 2.92 (t, 4).
1,la,2,8,8a,8b-~exahydro-8-(hydroxymethy1)-8a-methox -5-methyl-6-[3-(pyrazol~l)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 the potassium carbonate was omitted.
From 100 mg. of mitomycin A and 48 mg. of 3-aminopyrazole was obtained 50 mg. (44% yield) of the desired product having a melting point of 142-145C (decomposition) and providing the following analysis:
NMR (CDC13, TMS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 6.50 (d, 2), 6.67-6.83 (broad S, 1) and 8.07 (S, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-~ethyl-6 [2-(N-morpholino)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 potassium carbonate was omitted.
From 100 mg. of mitomycin A and 0.5 ml. of N-(2-aminoethyl)-morpholine was obtained 70 mgO (55% yield) of the desired product having a melting point of 74-76C (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 2.27-2.73 (broad, 8),
3.47-4.03 (broad, 4) and 7.27 (t, 1).
1,la,2,8,8a,8b-~1exahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(ethylthio)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 0.5 ml. of ~riethylamine was used instead of the potassium carbonate. From 250 mg. of mitomycin ~ 23 -- :~.%4~
A and 101.5 mg. of 2-(ethylthio)ethylamine hydrochloride was obtained 220 mg. (73% yield) of the desired product having a melting point of 103-106C (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 1.27 (t, 3), 2.40-2~90 (m, 4), 3.40-3.93 (m, 2~ and 6.56 (t, 1).
1,la,2,8,8a,8b-Hexahydro 8-(hydroxymethyl)-8a-methoxy-1,5-dimethyl-6-(2-mercaptoethylamino)-azirino[2',3':3,4~p~rrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 250 mg. o N-methyl-mitomycin A and 78 mg. of 2-mercaptoethylamine hydrochloride was obtained 150 mg. (54% yield) of the desired product having a melting point of 85-87C (decomposition) and provid-ing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy group at 4.05, and the appearance of new peaks at 2.57-3.10 (broad s, 4) and 6.20-6.93 (broad s, 1) 30 1,la,2l8,8a r 8b-Hexahydro-8-(hydrox~methyl) 8a-methoxy-5-methyl-6-(2-methoxyethy~amino)azirino[2',3':3,4]pyrrolo[1,2 a]-indole-4,7-dione carbamate This compound was prepared by the procedure described - 2~ -~Z~
in Example 1, except that the potassium carbonate was omitted.
From 120 mg. of mitomycin A and 0.2 ml. of 2-methoxyethylamine was obtained 99 mg. (73% yield) of the desired product having a melting point of 106-109C (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 3.42 (S, 3), 3.5-3O9 (broad S, 4)l 6.27-6.77 (broad S, 1).
1,la,2,8,8a,8b-Hexah~dro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-~4-methoxyanilino)-azirino[2l,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 potassium carbonate was omitted.
From 77 mg. of mitomycin A and 27 mg. of 4-methoxyaniline was obtained 70 mg. (74% yield) of the desired product having a melting point of 103-108C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy group at 4.02, and the appearance of new peaks at 3.8 (s, 3), 6.8 (s, 4) and 7.7 (s, 1).
~z~
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(1-adamantylamino)-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. The reaction did not yo to completion in 48 hours, despite the use of excess amine. From 147 mg.
of mitomycin A and 666 mg. of 1-aminoadamantane was obtained 60 mg. (30~ yield) of the desired product having a melting point of 149-150C (decomposition), with partial decomposition at 85-90C, and providing the following analysis:
NMR (CDC13 + CD30D, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 1.55-2.3 (m, 15).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)8a-methoxy-5-methyl-6-[1-(1,3,4-triazolyl)amino]-azirino[2',3':3,4]pyrrolo[1,2-a]- 0 indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 100 mg. of mitomycin A and 80 mg. of l-amino-1,3,4-triazole was obtained 35 mg. (30% yield) of the desired product having a melting point of >250C (decomposi-tion) and providing the following analysis:
NMR (CDC13, TMS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 8.00 (s, 2).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4,5-trimethoxybenzylamino)-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 potassium carbonate was omitted~
From 65 mg. of mitomycin A and 437 mg. of 3,4,5-trimethoxy-benzylamine was obtained 55 mg. (57% yield) of the desired product having a melting point of 94~95C ~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 3.85 (s, 9), 4.46-4.76 (d, 2) and 6.45 (s, 2).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-1,5-dimethyl-6-[2-(ethylthio)ethylamino]-azirlno[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 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 120 mg. of N-methyl-mitomycin A and 70 mg. of 2-(ethylthio)ethylamine hydrochloride was obtained 100 mg. (69% yield) of the desired product having a melting point of 114-116C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the
1,la,2,8,8a,8b-~1exahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(ethylthio)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 0.5 ml. of ~riethylamine was used instead of the potassium carbonate. From 250 mg. of mitomycin ~ 23 -- :~.%4~
A and 101.5 mg. of 2-(ethylthio)ethylamine hydrochloride was obtained 220 mg. (73% yield) of the desired product having a melting point of 103-106C (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 1.27 (t, 3), 2.40-2~90 (m, 4), 3.40-3.93 (m, 2~ and 6.56 (t, 1).
1,la,2,8,8a,8b-Hexahydro 8-(hydroxymethyl)-8a-methoxy-1,5-dimethyl-6-(2-mercaptoethylamino)-azirino[2',3':3,4~p~rrolo-[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 250 mg. o N-methyl-mitomycin A and 78 mg. of 2-mercaptoethylamine hydrochloride was obtained 150 mg. (54% yield) of the desired product having a melting point of 85-87C (decomposition) and provid-ing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy group at 4.05, and the appearance of new peaks at 2.57-3.10 (broad s, 4) and 6.20-6.93 (broad s, 1) 30 1,la,2l8,8a r 8b-Hexahydro-8-(hydrox~methyl) 8a-methoxy-5-methyl-6-(2-methoxyethy~amino)azirino[2',3':3,4]pyrrolo[1,2 a]-indole-4,7-dione carbamate This compound was prepared by the procedure described - 2~ -~Z~
in Example 1, except that the potassium carbonate was omitted.
From 120 mg. of mitomycin A and 0.2 ml. of 2-methoxyethylamine was obtained 99 mg. (73% yield) of the desired product having a melting point of 106-109C (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 3.42 (S, 3), 3.5-3O9 (broad S, 4)l 6.27-6.77 (broad S, 1).
1,la,2,8,8a,8b-Hexah~dro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-~4-methoxyanilino)-azirino[2l,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 potassium carbonate was omitted.
From 77 mg. of mitomycin A and 27 mg. of 4-methoxyaniline was obtained 70 mg. (74% yield) of the desired product having a melting point of 103-108C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy group at 4.02, and the appearance of new peaks at 3.8 (s, 3), 6.8 (s, 4) and 7.7 (s, 1).
~z~
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(1-adamantylamino)-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. The reaction did not yo to completion in 48 hours, despite the use of excess amine. From 147 mg.
of mitomycin A and 666 mg. of 1-aminoadamantane was obtained 60 mg. (30~ yield) of the desired product having a melting point of 149-150C (decomposition), with partial decomposition at 85-90C, and providing the following analysis:
NMR (CDC13 + CD30D, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 1.55-2.3 (m, 15).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)8a-methoxy-5-methyl-6-[1-(1,3,4-triazolyl)amino]-azirino[2',3':3,4]pyrrolo[1,2-a]- 0 indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 100 mg. of mitomycin A and 80 mg. of l-amino-1,3,4-triazole was obtained 35 mg. (30% yield) of the desired product having a melting point of >250C (decomposi-tion) and providing the following analysis:
NMR (CDC13, TMS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the appearance of new peaks at 8.00 (s, 2).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4,5-trimethoxybenzylamino)-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 potassium carbonate was omitted~
From 65 mg. of mitomycin A and 437 mg. of 3,4,5-trimethoxy-benzylamine was obtained 55 mg. (57% yield) of the desired product having a melting point of 94~95C ~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 3.85 (s, 9), 4.46-4.76 (d, 2) and 6.45 (s, 2).
1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl~-8a-methoxy-1,5-dimethyl-6-[2-(ethylthio)ethylamino]-azirlno[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 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 120 mg. of N-methyl-mitomycin A and 70 mg. of 2-(ethylthio)ethylamine hydrochloride was obtained 100 mg. (69% yield) of the desired product having a melting point of 114-116C (decomposition) and providing the following analysis:
NMR (CDC13, TS): '~' values in ppm.
Absence of the 6-methoxy peak at 4.02, and the
4~L~
appearance of new peaks at 1.27 (t, 3), 2.40-2.93 (m, 4), 3.40-3.93 (m, 2) and 6.50-6.80 (broad s, 1).
1,la,2,8,8a,8b~Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(dimeth~l~mino)ethylamino]-azirino[2',3':3,4~pyrrolo-[1,2-a]indole-4,7-dione _arbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 150 mg. of mi~omycin A and 0.2 ml. of 2-(dimethylamino)-ethylamine was obtained 130 mg. (75% yield) of the desired product having a melting point of 72~75C (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 2017 (s, 6), 2.37-2.63 (broad s, 2)~ 3.3-4.0 (broad s, 2) and 6.7-7.1 (broad s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hyro~ymethyl)-8a-methoxy-5-methyl-6-[1-(3-hydroxypiperidyl)]-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 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 130 mg. of mitomycin A and 70 mg. of 3-hydroxypiperidine hydrochloride was obtained 80 mg. (58~ yield) of the desired product having a melting point of 98-101C (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 0.97-2.13 (broad m, 4), 2.17-3.13 (broad m, 4), 3.3-4.33 (broad m, 1) and 4.67-5.73 (broad s, 1).
Through use of mitomycin A and the appropriate amine starting materials, the procedures of the prior examples are susceptible to use in preparation of the following com-pound~:
(a) 1,la,2l8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(2-phenyl-1-aziridinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(b) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(2-methoxycarbonyl-1-aziridinyl)-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(c) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)~
8a-methoxy-6-(2-carboxamido-1-aziridinyl)-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(d) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(N-morpholinyl)-azirino[2',3':3~4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
(e) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(1-piperazinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
(f) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(4-formyl-1-piperazinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(g) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(4-acetylphenyl-1-piperazinyl)-azirino~2',3':3,4~-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(h) 1,la,2,8,8a,8b-hexahydro-B-(hydroxymethyl)-8a-methoxy-6-[4-(1-piperidyl)-1-piperidyl]-azirino[2',3':3,4]-pyrrolo-[1,2-a3indole-4,7-dione carbamate;
(i) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(6-chloro-3-pyridyl~amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(j) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(6-amino-3-pyridyl)amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(k) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(4,5-dimethyl-2-thiazolyl)amino]-azirino-[2',3':3,4~pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(1) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(4-cyano-3-pyrazolyl)amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole 4,7-dione carbamate.
With specific reference to the compounds compre-hended by formula IIa, the above examples illustrate thefollowing structural variations.
1. In the compounds o~ Examples 33 and 39, Y
is lower alkyl and, more specifically, methyl. In all other examples, Y is hydrogen. The identity of ~ is independent of the identity of Z. Compare Examples 16 and 33 wherein Z is the same and Y is hydrogen and lower alkyl respectively.
See also, Examples 32 and 39 which differ in the same way.
2. Compounds wherein Z is lower alkoxy substituted quinolinylamino radical, a ~yano substituted pyrazolamino radical or a mono- or di- lower alkyl substituted thiazolamino radical are represented, respectively, by Examples 5, ~2(1~, 17, and 42 (k).
~ 30 -4~Z
3. Compounds wherein Z is a nitrogen-containing heterocyclic radical selected from the group consisting of l-pyrrolinyl, l-indolinyl, N-thiazoladinyl, N-morpholinyl, l-piperazinyl and N~thiomorpholinyl radicals are represented, respectively, by Examples 27, 3, 28, 42(d), 42(e), and 2.
4. Compounds wherein Z is a cyano, phenyl, carbox-amido or lower alkoxy carbonyl substituted l-aziridinyl radical are represented, respectively, by Examples 1, 42(a), 42~c) and 42(b).
appearance of new peaks at 1.27 (t, 3), 2.40-2.93 (m, 4), 3.40-3.93 (m, 2) and 6.50-6.80 (broad s, 1).
1,la,2,8,8a,8b~Hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(dimeth~l~mino)ethylamino]-azirino[2',3':3,4~pyrrolo-[1,2-a]indole-4,7-dione _arbamate This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted.
From 150 mg. of mi~omycin A and 0.2 ml. of 2-(dimethylamino)-ethylamine was obtained 130 mg. (75% yield) of the desired product having a melting point of 72~75C (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 2017 (s, 6), 2.37-2.63 (broad s, 2)~ 3.3-4.0 (broad s, 2) and 6.7-7.1 (broad s, 1) 1,la,2,8,8a,8b-Hexahydro-8-(hyro~ymethyl)-8a-methoxy-5-methyl-6-[1-(3-hydroxypiperidyl)]-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 0.5 ml. of triethylamine was used instead of the potassium carbonate. From 130 mg. of mitomycin A and 70 mg. of 3-hydroxypiperidine hydrochloride was obtained 80 mg. (58~ yield) of the desired product having a melting point of 98-101C (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 0.97-2.13 (broad m, 4), 2.17-3.13 (broad m, 4), 3.3-4.33 (broad m, 1) and 4.67-5.73 (broad s, 1).
Through use of mitomycin A and the appropriate amine starting materials, the procedures of the prior examples are susceptible to use in preparation of the following com-pound~:
(a) 1,la,2l8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(2-phenyl-1-aziridinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(b) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(2-methoxycarbonyl-1-aziridinyl)-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(c) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)~
8a-methoxy-6-(2-carboxamido-1-aziridinyl)-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(d) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(N-morpholinyl)-azirino[2',3':3~4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
(e) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(1-piperazinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
(f) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(4-formyl-1-piperazinyl)-azirino[2',3':3,4]pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(g) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-(4-acetylphenyl-1-piperazinyl)-azirino~2',3':3,4~-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(h) 1,la,2,8,8a,8b-hexahydro-B-(hydroxymethyl)-8a-methoxy-6-[4-(1-piperidyl)-1-piperidyl]-azirino[2',3':3,4]-pyrrolo-[1,2-a3indole-4,7-dione carbamate;
(i) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(6-chloro-3-pyridyl~amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(j) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(6-amino-3-pyridyl)amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(k) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(4,5-dimethyl-2-thiazolyl)amino]-azirino-[2',3':3,4~pyrrolo-[1,2-a]indole-4,7-dione carbamate;
(1) 1,la,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-6-[(4-cyano-3-pyrazolyl)amino]-azirino[2',3':3,4]-pyrrolo-[1,2-a]indole 4,7-dione carbamate.
With specific reference to the compounds compre-hended by formula IIa, the above examples illustrate thefollowing structural variations.
1. In the compounds o~ Examples 33 and 39, Y
is lower alkyl and, more specifically, methyl. In all other examples, Y is hydrogen. The identity of ~ is independent of the identity of Z. Compare Examples 16 and 33 wherein Z is the same and Y is hydrogen and lower alkyl respectively.
See also, Examples 32 and 39 which differ in the same way.
2. Compounds wherein Z is lower alkoxy substituted quinolinylamino radical, a ~yano substituted pyrazolamino radical or a mono- or di- lower alkyl substituted thiazolamino radical are represented, respectively, by Examples 5, ~2(1~, 17, and 42 (k).
~ 30 -4~Z
3. Compounds wherein Z is a nitrogen-containing heterocyclic radical selected from the group consisting of l-pyrrolinyl, l-indolinyl, N-thiazoladinyl, N-morpholinyl, l-piperazinyl and N~thiomorpholinyl radicals are represented, respectively, by Examples 27, 3, 28, 42(d), 42(e), and 2.
4. Compounds wherein Z is a cyano, phenyl, carbox-amido or lower alkoxy carbonyl substituted l-aziridinyl radical are represented, respectively, by Examples 1, 42(a), 42~c) and 42(b).
5. Compounds wherein Z is a lower alkyl, formyl or acetylphenyl substituted l-piperazinyl radical are rep-resented, respectively, by Examples 29, 42(f) and 42(9).
6. Compounds wherein Z is an hydroxy or piperidyl substituted piperidyl radical are represented, respectively, by Examples 41 and 42(h).
7. Compounds wherein Z is a lower alkoxy, amino or halo substituted pyridylamino radical are represented, respectively, by Examples 4, 42(j) and 42(i).
8. Compounds wherein Z is a carboxamido, mercapto or methylenedioxy substituted anilino radical are represented, respectively, by Examples 8, 18 and 19.
9. Compounds wherein Z is a radial of the ~ormula R
-N-R" and wherein R" is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and halo substituted derivatives thereof are represented, by Examples 6, 30, 37, 21, 22, 13, 14 and 23.
R 10. Compounds wherein Z is a radical of the formula -N-R" and wherein R" is a butyrolactonyl radical, an adamantyl radical or a mono-lower alkoxy substituted phenyl radical are represented, respectively, by Examples 7, 35 and 35.
~,.Z~
R 11. Compounds wherein Z is a radical of the formula -N-R" and R" is 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 sub-stituted 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 are represented by Examples 16, 33, 24, 34, 15, 32, 39, 11, 25, 9, 38, 12, 20, 10, 31 and 40.
Finally, it is noteworthy that-use of the compound of Example 26 is comprehended by the disclosure of the use of compounds of the formula Ia in U.S. Patent No. 4,268,676.
It is not encompassed by formula IIa herein.
Compounds according to the present invention, like those of U.S. Patent No. 4,268,676, 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 IIa in the anti-neoplastic therapeutic methods of the invention is demon-strated by the results of in vivo screening procedures wherein the compounds are administered in varying dosage amounts to mice in which a P338 leukemic condition is induced. The procedures were carried out according to "Lymphocytic Leukemia P338 - 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 CDF 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 41 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 ln vivo P388 procedure noted above, a % T/C value of 125 or greater indicates significant anti-neoplastic 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 ("M~D"). 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.
-Exam leOptimal Dose MST MED
P m~/kg as % T/C
1 12.8 339 0.2 2 3.2 211 0.4 3 12.8 150 0.8 4 6.4 211 0.2 6.4 178 0.4 6 25.6 144 12.
7 6.4 175 0.8 TABL~ 1 (cont 'd. ) Optimal Dose MST ME:D
Example mg/k~ as ~ T/C
8 25.6 255 1.6 9 25.6 239 1.6 12. ~ 217 0.8 11 6.4 131 3.2 12 12.8 217 1.6 13 25.6 178 1.6 1~ 12.8 222 0 O 8 6.4 200 0.8 16 12.8 313 <0.2 17 6.4 172 0O4 18 6.4 134 1.6 19 3.2 167 ~0 O 2 12.8 194 0.4 21 12.8 183 0.2 22 25.6 206 0.2 23 12.8 161 0.8 24 6.4 261 0.4 6.4 232 0.4 ~6 6.4 >31~ 0.4 27 12.8 216 0.2 28 25.6 222 0.2 29 3.2 261 <0.2 25.6 > 333 0.8 31 25.6 150 6.4 3~ 12.8 205 1.6 33 25. ~ 170 1.6 34 12.8 205 0. %
TABLE 1 (cont'd.) Example Optimal Dose MST MED
mg~kg_ as % T/C
12.8 >3~6 0.8 36 25.~ 132 6.4 37 12.~ 172 3.2 38 25.6 188 1.~
39 25.6 200 6~4 12.8 >211 0.4 41 12.8 >211 <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 125. The class of such compounds is seen to include the compounds of Examples 1, 8, 16, 24, 26, 29, 2030 and 35.
As may be noted from Table I, initial single dosages of as little as 0.2 mg/kg showed substantial long term anti-neoplastic 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 rom 0O004 mg to 1.0 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 0O2 to about 51.2 mg per kg, of the body weight of the animal suffering from neoplastic disease. It is preferred that ~he compounds be administered parenterally. Pharmaceutical compositions 4~Z
suitable for use in practice of methods of the invention may comprise simple water solutions of one or more of the compounds of formula IIa, 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.
-N-R" and wherein R" is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, l-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and halo substituted derivatives thereof are represented, by Examples 6, 30, 37, 21, 22, 13, 14 and 23.
R 10. Compounds wherein Z is a radical of the formula -N-R" and wherein R" is a butyrolactonyl radical, an adamantyl radical or a mono-lower alkoxy substituted phenyl radical are represented, respectively, by Examples 7, 35 and 35.
~,.Z~
R 11. Compounds wherein Z is a radical of the formula -N-R" and R" is 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 sub-stituted 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 are represented by Examples 16, 33, 24, 34, 15, 32, 39, 11, 25, 9, 38, 12, 20, 10, 31 and 40.
Finally, it is noteworthy that-use of the compound of Example 26 is comprehended by the disclosure of the use of compounds of the formula Ia in U.S. Patent No. 4,268,676.
It is not encompassed by formula IIa herein.
Compounds according to the present invention, like those of U.S. Patent No. 4,268,676, 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 IIa in the anti-neoplastic therapeutic methods of the invention is demon-strated by the results of in vivo screening procedures wherein the compounds are administered in varying dosage amounts to mice in which a P338 leukemic condition is induced. The procedures were carried out according to "Lymphocytic Leukemia P338 - 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 CDF 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 41 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 ln vivo P388 procedure noted above, a % T/C value of 125 or greater indicates significant anti-neoplastic 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 ("M~D"). 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.
-Exam leOptimal Dose MST MED
P m~/kg as % T/C
1 12.8 339 0.2 2 3.2 211 0.4 3 12.8 150 0.8 4 6.4 211 0.2 6.4 178 0.4 6 25.6 144 12.
7 6.4 175 0.8 TABL~ 1 (cont 'd. ) Optimal Dose MST ME:D
Example mg/k~ as ~ T/C
8 25.6 255 1.6 9 25.6 239 1.6 12. ~ 217 0.8 11 6.4 131 3.2 12 12.8 217 1.6 13 25.6 178 1.6 1~ 12.8 222 0 O 8 6.4 200 0.8 16 12.8 313 <0.2 17 6.4 172 0O4 18 6.4 134 1.6 19 3.2 167 ~0 O 2 12.8 194 0.4 21 12.8 183 0.2 22 25.6 206 0.2 23 12.8 161 0.8 24 6.4 261 0.4 6.4 232 0.4 ~6 6.4 >31~ 0.4 27 12.8 216 0.2 28 25.6 222 0.2 29 3.2 261 <0.2 25.6 > 333 0.8 31 25.6 150 6.4 3~ 12.8 205 1.6 33 25. ~ 170 1.6 34 12.8 205 0. %
TABLE 1 (cont'd.) Example Optimal Dose MST MED
mg~kg_ as % T/C
12.8 >3~6 0.8 36 25.~ 132 6.4 37 12.~ 172 3.2 38 25.6 188 1.~
39 25.6 200 6~4 12.8 >211 0.4 41 12.8 >211 <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 125. The class of such compounds is seen to include the compounds of Examples 1, 8, 16, 24, 26, 29, 2030 and 35.
As may be noted from Table I, initial single dosages of as little as 0.2 mg/kg showed substantial long term anti-neoplastic 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 rom 0O004 mg to 1.0 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 0O2 to about 51.2 mg per kg, of the body weight of the animal suffering from neoplastic disease. It is preferred that ~he compounds be administered parenterally. Pharmaceutical compositions 4~Z
suitable for use in practice of methods of the invention may comprise simple water solutions of one or more of the compounds of formula IIa, 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 (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula, wherein Y is hydrogen or lower alkyl and X is a carboxamido or mercapto or methylenedioxy substituted anilino.
2. A compound according to claim 1 named:
1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-carboxyamidoanilino)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-mercaptoanilino)azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-methylenedioxyanilino)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-carboxyamidoanilino)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-mercaptoanilino)azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-methylenedioxyanilino)azirino[2',3':3,4]-pyrrolo[1,2-a]-indole-4,7-dione carbamate.
3. A compound of the formula wherein Y is hydrogen or lower alkyl and X is a radical of the formula, wherein R is hydrogen or lower alkyl and R' is a substituted lower alkyl radical selected from the group consisting of mercapto 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, pyrrolidinyl lower alkyl, or lower alkyl substituted derivatives thereof, and morpholinyl lower alkyl.
4. A compound according to claim 3 named:
1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(2-mercaptoethylamino)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-1-5-dimethyl-6-(2-mercaptoethylamino)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-dimethoxyethylamino)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-(methoxyethylamino)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-(ethylthio)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-1,5-dimethyl-6-[2-(ethylthio)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-[(1-methoxycarbonyl-3-methylthio)propylamino]-azirino[1,2-a]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-hexahydro-8 (hydroxymethyl)-8a-methoxy-5-methyl-6-(2-cyanoethylamino)azirino[2',3':3,4]pyrrolo-[1,2]-indole-4,7-dione carbamate;
1,1a,2,8,8a-8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-dimethoxybenzylamino)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-(3,4,5-trimethoxybenzylamino)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-pyrrolidino)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-[(1-ethyl-2-pyrrolidino)methylamino]azirino-[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(N-morpholino)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-mercaptoethylamino)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-1-5-dimethyl-6-(2-mercaptoethylamino)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-dimethoxyethylamino)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-(methoxyethylamino)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-(ethylthio)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-1,5-dimethyl-6-[2-(ethylthio)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-[(1-methoxycarbonyl-3-methylthio)propylamino]-azirino[1,2-a]pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
1,1a,2,8,8a,8b-hexahydro-8 (hydroxymethyl)-8a-methoxy-5-methyl-6-(2-cyanoethylamino)azirino[2',3':3,4]pyrrolo-[1,2]-indole-4,7-dione carbamate;
1,1a,2,8,8a-8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3,4-dimethoxybenzylamino)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-(3,4,5-trimethoxybenzylamino)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-pyrrolidino)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-[(1-ethyl-2-pyrrolidino)methylamino]azirino-[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[2-(N-morpholino)ethylamino]azirino[2',3':3,4]-pyrrolo-[1,2a]-indole-4,7-dione carbamate.
5. A compound of the formula wherein Y is hydrogen or lower alkyl and X is a nitrogen containing heterocyclic radical selected from the group consisting of formyl or acetylphenyl substituted 1-piperazinyl and lower alkoxy or amino substituted pyridyl amino.
6. A compound according to claim 5 named:
1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(4-formyl-1-piperazinyl)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-acetylphenyl-1-piperazinyl)azirino[2',3':3,4]-pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
1,1a,2,8,8a,3b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(6-methoxy-3-pyridyl)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-amino-3-pyridyl)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-formyl-1-piperazinyl)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-acetylphenyl-1-piperazinyl)azirino[2',3':3,4]-pyrrolo-[1,2-a]-indole-4,7-dione carbamate;
1,1a,2,8,8a,3b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[(6-methoxy-3-pyridyl)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-amino-3-pyridyl)amino]azirino[2',3':3,4]-pyrrolo[1,2-a]-indole-4, 7-dione carbamate.
7. A compound of the formula, wherein Y is hydrogen or lower alkyl and X is a nitrogen-containing heterocyclic radical selected from the group consisting of cyano or phenyl or lower alkoxy carbonyl or carboxamido substituted 1-aziridinyl, N-triazolodinyl, 1-indolinyl, 1-pyrrolinyl, and hydroxy or piperidyl substituted piperidyl.
8. A compound according to claim 7 named:
1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(2-cyano-1-aziridinyl)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-phenyl-1-aziridinyl)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-methoxycarbonyl-1-aziridinyl)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-carboxamido-1-aziridinyl)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-indolinyl)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(3-pyrrolinyl)]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-thiazolidino)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-piperidyl)-1-piperidyl]azirino[2',3':3,4]-pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[1-(3-hydroxypiperidyl)]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-cyano-1-aziridinyl)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-phenyl-1-aziridinyl)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-methoxycarbonyl-1-aziridinyl)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-carboxamido-1-aziridinyl)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-indolinyl)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(3-pyrrolinyl)]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-thiazolidino)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-piperidyl)-1-piperidyl]azirino[2',3':3,4]-pyrrolo-[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-[1-(3-hydroxypiperidyl)]azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate.
9. A compound of the formula, wherein Y is hydrogen or lower alkyl and X is a radical of the formula, wherein R is hydrogen or lower alkyl and R' is a heterocyclic radical selected from the group consist-ing of quinuclidinyl, benzoxazolyl or a halo substituted derivative thereof, thiadiazolyl or a lower alkyl substituted derivative thereof, thiazolyl or a mono- or di-lower alkyl substituted derivative thereof, indazolyl, benzothiadiazolyl, pyrazolyl or a cyano substituted derivative thereof, 1-triazolyl and butyrolactonyl or an adamantyl radical.
10. A compound according to claim 9 named:
1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(3-quinuclidinylamino)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-[(5-chloro-2-benzoxazolyl)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-[5-methyl-2-(1,3,4-thiadiazolyl)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-methyl-2-thiazolyl)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-[(4,5-dimethyl-2-thiazolyl)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-(5-indazolylamino)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-(2,1,3-benzothiadiazolyl)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-(pyrazolyl)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-cyano-3-pyrazolyl)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-[1-(1,3,4-triazolyl)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-(butyrolactonyl)amino]azirino[2',3':3,4]-pyrrolo[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(1-adamantylamino)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-quinuclidinylamino)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-[(5-chloro-2-benzoxazolyl)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-[5-methyl-2-(1,3,4-thiadiazolyl)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-methyl-2-thiazolyl)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-[(4,5-dimethyl-2-thiazolyl)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-(5-indazolylamino)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-(2,1,3-benzothiadiazolyl)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-(pyrazolyl)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-cyano-3-pyrazolyl)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-[1-(1,3,4-triazolyl)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-(butyrolactonyl)amino]azirino[2',3':3,4]-pyrrolo[1,2-a]-indole-4,7-dione carbamate; or 1,1a,2,8,8a,8b-hexahydro-8-(hydroxymethyl)-8a-methoxy-5-methyl-6-(1-adamantylamino)azirino[2',3':3,4]pyrrolo-[1,2-a]-indole-4,7-dione carbamate.
11. 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 a nitrogen-containing heterocyclic radical selected from the group consisting of N-morpholinyl and 1-piperazinyl radicals, or a radical of the formula, wherein R is hydrogen or lower alkyl and R" is a mono- lower alkoxy substituted phenyl radical, or a lower dialkylamino lower alkyl radical.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26418781A | 1981-05-15 | 1981-05-15 | |
| US264,187 | 1981-05-15 |
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| CA1244412A true CA1244412A (en) | 1988-11-08 |
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| CA000398102A Expired CA1244412A (en) | 1981-05-15 | 1982-03-11 | Mitomycin analogs |
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| KR (1) | KR890000935B1 (en) |
| AT (1) | AT375943B (en) |
| AU (1) | AU559686B2 (en) |
| BE (1) | BE893162A (en) |
| CA (1) | CA1244412A (en) |
| CH (1) | CH655116A5 (en) |
| DE (1) | DE3217769A1 (en) |
| DK (1) | DK161078C (en) |
| ES (1) | ES511874A0 (en) |
| FI (1) | FI78100C (en) |
| FR (1) | FR2505839B1 (en) |
| GB (1) | GB2106096B (en) |
| GR (1) | GR76033B (en) |
| HU (1) | HU186510B (en) |
| IE (1) | IE52956B1 (en) |
| IL (1) | IL64998A0 (en) |
| IT (1) | IT1156453B (en) |
| LU (1) | LU84144A1 (en) |
| NL (1) | NL8200839A (en) |
| NO (1) | NO158743C (en) |
| NZ (1) | NZ199617A (en) |
| PH (1) | PH20358A (en) |
| PT (1) | PT74895B (en) |
| SE (1) | SE450895B (en) |
| YU (1) | YU44819B (en) |
| ZA (1) | ZA82923B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA833967B (en) * | 1982-06-04 | 1984-02-29 | Bristol Myers Co | Amidines |
| DE116208T1 (en) * | 1982-12-07 | 1985-02-28 | Kyowa Hakko Kogyo Co., Ltd., Tokio/Tokyo | MITOMYCIN ANALOGS. |
| NZ206932A (en) * | 1983-02-07 | 1987-08-31 | University Patents Inc | Certain 6-(heterocyclyl or amino) mitosanes and pharmaceutical compositions |
| US4803212A (en) * | 1983-04-11 | 1989-02-07 | Bristol-Myers Company | Amino disulfides |
| US4642352A (en) * | 1983-12-23 | 1987-02-10 | Bristol-Myers Company | Acylamino mitosanes |
| JPS60255789A (en) * | 1984-06-01 | 1985-12-17 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative, its preparation, and antitumor agent |
| FR2571373A1 (en) * | 1984-10-09 | 1986-04-11 | Bristol Myers Co | PROCESS FOR PREPARING N7-SUBSTITUTED MITOMYCIN C DERIVATIVES |
| DE3674043D1 (en) * | 1985-04-10 | 1990-10-18 | Kyowa Hakko Kogyo Kk | PHARMACOLOGICALLY ACTIVE MITOMYCINE DERIVATIVES. |
| US5023253A (en) * | 1987-12-21 | 1991-06-11 | University Patents, Inc. | 6-substituted mitomycin analogs |
| AU2012324803B9 (en) * | 2011-10-20 | 2017-08-24 | Oryzon Genomics, S.A. | (hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL129868C (en) * | 1963-06-07 | |||
| US3420846A (en) * | 1964-08-25 | 1969-01-07 | Kyowa Hakko Kogyo Kk | 7-substituted mitomycin a |
| 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 |
-
1982
- 1982-02-01 NZ NZ199617A patent/NZ199617A/en unknown
- 1982-02-12 ZA ZA82923A patent/ZA82923B/en unknown
- 1982-02-12 IL IL64998A patent/IL64998A0/en not_active IP Right Cessation
- 1982-02-26 GR GR67435A patent/GR76033B/el unknown
- 1982-02-26 IE IE431/82A patent/IE52956B1/en not_active IP Right Cessation
- 1982-03-02 NL NL8200839A patent/NL8200839A/en not_active Application Discontinuation
- 1982-03-11 CA CA000398102A patent/CA1244412A/en not_active Expired
- 1982-03-15 IT IT67321/82A patent/IT1156453B/en active
- 1982-03-30 KR KR8201365A patent/KR890000935B1/en active
- 1982-04-07 FI FI821241A patent/FI78100C/en not_active IP Right Cessation
- 1982-04-16 AU AU82682/82A patent/AU559686B2/en not_active Ceased
- 1982-04-19 JP JP57065598A patent/JPS57188590A/en active Pending
- 1982-04-27 CH CH2580/82A patent/CH655116A5/en not_active IP Right Cessation
- 1982-05-03 ES ES511874A patent/ES511874A0/en active Granted
- 1982-05-07 GB GB08213332A patent/GB2106096B/en not_active Expired
- 1982-05-07 YU YU972/82A patent/YU44819B/en unknown
- 1982-05-11 AT AT0184482A patent/AT375943B/en not_active IP Right Cessation
- 1982-05-11 LU LU84144A patent/LU84144A1/en unknown
- 1982-05-11 FR FR8208163A patent/FR2505839B1/en not_active Expired
- 1982-05-12 DE DE19823217769 patent/DE3217769A1/en not_active Withdrawn
- 1982-05-12 PH PH27285A patent/PH20358A/en unknown
- 1982-05-12 PT PT74895A patent/PT74895B/en not_active IP Right Cessation
- 1982-05-12 BE BE0/208074A patent/BE893162A/en not_active IP Right Cessation
- 1982-05-13 NO NO821598A patent/NO158743C/en unknown
- 1982-05-14 DK DK219182A patent/DK161078C/en active
- 1982-05-14 HU HU821520A patent/HU186510B/en not_active IP Right Cessation
- 1982-05-14 SE SE8203035A patent/SE450895B/en not_active IP Right Cessation
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