Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
12
~,~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,
R4 R5
- N C R
16
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 substituted0 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.
EXAMPLE 1
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)
-- 7 --
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)
EXAMPLE 2
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)
EXAMPLE 3
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).
EXAMPLE 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)
EXAMPLE 5
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)
EXAMPLE 6
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.
EXAMPLE 7
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.
-- 10 --
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).
EXAMPLE 8
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)
EXAMPLE 9
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)
EXAMPIE 10
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
- 12 -
~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).
EXAMPLE 12
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).
- 13 -
3~Z~
EXAMPLE 13
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).
EXAMPLE 14
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)
- 14 -
f~
EXAMPLE 15
_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.)
EXAMPLE 16
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).
EXAMPLE 18
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
-- 16 --
appearance of new peaks at 6.53 (d, 2) and 7.0-7.7
(m, 3).
EXAMPLE 19
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).
EXAMPLE 20
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).
EXAMPLE 21
.
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).
EXAMPLE 22
_
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).
- 18 -
- ~L,2~
EXAMPLE 23
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).
EXAMPLE 24
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).
-- 19 --
EXAMPLE 25
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).
EXAMPLE 26
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
- 20 -
~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.
EXAMPLE 28
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
- 21
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).
EXAMPLE 29
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).
EXAMPLE 30
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
- 22 -
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)
EXAMPLE 31
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).
EXAMPLE 32
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).
EXAMPLE 33
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)
EXAMPLE 34
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).
EXAMPLE 35
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).
- 25 -
~z~
EXAMPLE 36
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).
EXAMPLE 37
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).
- 26 -
EXAMPLE 38
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).
EXAMPLE 39
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).
EXAMPLE 40
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)
EXAMPLE 41
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:
- 28 -
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).
EXAMPLE 42
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;
- 29 -
(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.
- 31 -
~,.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 ...........................................
- 32 -
, ....
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.
TABLE 1
-
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
- 33
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. %
- 34 -
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.
36 -
