Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~2~ gl~
This is a divisional application or copending application,
serial no. 432,584, filed July 18, 1983.
BACKGROUND OF THE INVENTION
.
Several 2,5 and 2,7-disubstituted anthra[l,~-cd]pyrazol
6(2H)-ones are disclosed in the prio~ literature. See for
example J. Chem. Soc., 1630 (1952); J. Chem. Soc., 1894
(1954). Neither reference discloses any utility for these
compounds.
SUl~YARY OF THE INVENTION
The invention in its first generic chemical compound
aspect is a compound having the structural formula
~T ~ Z
~
X' O ~RY
wherein X, X' and W may be the same or different and are
hydrogen, hydroxy, alkoxy having one to four carbon atoms
and chlorine; R is H or alkyl of from one to six carbon
atoms; Y is H, alkyl of from one to six carbon atoms which
may be substituted with an ORl group wherein Rl is H or
alkyl of from one to s~x carbon atoms, or ANR2R3 wherein A
is straight or branched alkylene of from two to eight carbon
atoms, R2 and R3 may be the same or different and are H,
alkyl of from one to six carbon atoms which may be substituted
with OH or an NRaRa wherein Ra may be the same or different
and is H or alkyl of from one to three carbon atoms which may
be substituted with OH, or NRbRb wherein Rb is the same
_ 3 _ ~L~7
or different and is H or alkyl of from one to three carbon
atoms, or R2 and R3 when taken together may be ethylene or
may form
~(CH2)n\
~B
-(CH2)m~
wherein n and m may be the same or different and are one,
two, or three provided that the sum of n and m is an
integer of from three to six, and B is a direct bond, O, S,
or N-R4 wherein R4 is H or alkyl of from one to six carbon
atoms; R and Y wnen taken together may be ethylene or may
form
- 12Æ8-~9'~
CLG-l -4-
-(CH2)n\
) 3
-(CH2)m /
wherein n and m and B are deined above; Z is H, alkyl
oE from one to six carbon atoms which may be substi-
tuted with an ~(Rl)2, SRl, or ORl group wherein
Rl is the same or different and is defined above, or
DNR2R3 wherein D is straight or branched al'.~ylene
of from two to eight carbon atoms which may be sub-
stituted with an OH group and R2 and R3 are as
defined above; and the pharmaceutically acceptable
salts thereof; with the following provisos, 1) when
X, X' and W are ~ and 2 is H, R and Y when taken
together do not complete a piperidine ring, ~ when
X, X1, and r~ are EI and Z is C~3, ~ and Y when taken
together do not complete a piperidine ring or a
morpholine ring.
The invention sought to be patented in its
second generic chemical compound aspect is a compound
haqing the structural formula
X N - N-Z
W~
X' O NRY
wherein X, X' and W may be the same or different
and are H or OH, alkoxy haviny one to four carbon
atoms or chlorine; R is H or alkyl of from one to si~
carbon atoms; Y is H, alkyl of from one to six carbon
atoms which may be substituted with an ORl group
wherein Rl is H or alkyl of from one to six carbon
atoms, or ANR2R3 wherein A i5 straight or branched
aLkylene o~ ~rom two to eight carbon atoms, R2 and
R3 may be the same or different and are H, alkyl of
from one to si~ carbon atoms which may be substituted
with OH or an ~RaRa wherein Ra may be the same or
different and is H or al~yl of from one to three
carbon atoms which may be substi~uted with OH, or
NR~Rb wherein Rb is the same or different and is H
or alkyl of from one to three carbon atoms, or R2 and
R3 when taken together may be ethylene or may for~
-(CH2)n~
~B
-(C~2)~
wherein n and m may be tne same or different and are
one, two, or three provided that the sum of n and m
is an integer of from three to six, and B is a direct
bond, O, S, or N-R4 wherein R4 is H or alkyl of from
one to six carbon atoms; R and Y when taken together
may be ethylene or may form
-(CH2)n\
B
-(CH2)m /
wherein n, m, and B are defined above; Z is H, alkyl
of rom one to si~ carbon atoms which may ~e
substituted with an N(Rl)2, SRl, or ORl group
-~herein Rl is the same or different and is defined
above, or DNR2R3 wherein D is straight or branched
alkylene of from two to eight carbon atoms which may
be substituted with an OH group and R2 and R3 are as
defined above; and the pharmaceutically acceptable
salts thereof; with the following provisos, 1) when X,
X', and W are H and Z is H, R and Y when taken
together do not complete a piperidine ring, 2) when X,
X', and '~1 are H and Z is CH3 R and Y when taken
together do not complete a piperidine ring or a
morpholine ring.
~4~
CL5-1 -5-
The inven.ion sought to be patented in its
! third generic chemical compound as~ect is a compound
having the structural Lormula
N N-Z
X~
O NRY
wherein X and X' may be the same or different and are
~, 0~, alkoxy o one to our carbon atoms or chlorine;
R is H or al'.~yl of from one to si~ carbon atoms; Y is
~, alkyl of from one to six carbon atoms which may be
substituted with an ORl group wherein Rl is ~ or
al~yl oE from one to six carbon atoms, or ANR2R3
wherein A is alkylene of from .wo to 11 carbon atoms,
R2 and R3 may be the same or difEerent and are H,
alXyl of fro~ one to six carbon atoms which may be
substituted with OH or an NRaRa wherein Ra is H or
al'.~l of Erom one to three carbon atoms which may be
substituted with OH, or NRbRb wherein Rb i3 the
same or diErer~nt and is ~ or al~vl oX from one to
th~oe ca.bon atoms, or R2 and R3 when taken together
may be ethylene or may Eorm
~(c~2?n\
_,B
-(C~ )m''
w'nerein n, m, and B are defined above; Z is H, alkyl of
rrom one to six carbon atoms which may be substituted
with an N(Rl)2, S~l, or ORl group wherein Rl is
defi~ed above, or DNR~R3 wherein D is alkylene
oE from two to 11 carbon atoms which may be substituted
with an 0~ grouo and R2 and R3 ar~ as defined above;
and the pharmaceutically acceptable salts thereo; with
the Collowing provisos, 1) when X is H and Z is H, R
J
~L2~
and v when taken together do not com?lete a piperidine
ring, 2) when X is H and Z is CH3 R and Y when taken
together do not complete a piperidine ring or a
morpholine ring.
-(CH2)n
B
- ( C'd2 ) m'~
wherein n, m, and 3 are defined above; Z is H, alkyl of
from one to six carbon atoms which may be substituted
with an ~ )2~ SRl, or ORl group wherein Rl is
defined above, or DNR2R3 wherein D is alkylene
of from two to 11 carbon atoms which may be substituted
wi~h an OH group and R2 and R3 are as defined above;
and the pharmaceutically acceptable salts thereof; with
the following provisos, 1) when X is ~ and Z is H, R
and Y when taken together do not complete a piperidine
ring, 2) when ~ is ~ and 2 is CH3 R and Y when ta'cen
together do not complete a piperidine ring or a
morpholine ring.
The invention in its fourth generic chemical
compound aspect is a compound having the structural
~ormula I
X 1--l Z
~.
X' o ~RY
I
wherein X, and X' may be the same or different a~d
are 'd or OH; R is H or alkyl of from one to six carbon
atoms; Y is H, alkyl of from one-to six carbon atoms
which may be substituted with an ORl group wherein
Rl is ~ or alkyl of from one .o six carbon atoms, or
~NR2R3 ~herein ~ is straight or branched alkylene of
from two to eight carbon atoms, R2 and R3 may be the
12~8~
--8--
same or different and are H, alkyl of from one to slx
carbon atoms which may be substituted with OH or an
NRa~a wherein Ra is the same or different and as
H or al'.~yl af from one to three carbon atoms which may
be substituted with OH, or NRbR~ wherein Rb is the
same or different and is ~ or alkyl of from one to
three carbon atoms, or R2 and R3 when taken together
may be ethylene or may form
-(CH2!n\
,B
~(c~l2)m/
and m is an integer of from three to si~, and B is a
airect 30nd, O, S, or N-R~ wherein R4 is H or alkyl
of from one to six carbon atoms; R and Y when taken
~ogether may ~e e.hylene or may Eorm
-(C~I2)n\
/ B
-~CH~)m
-~erein n, m, and B are deined above; Z is H, alkyl
o from one to six carbon atoms which may be
substituted with an N(~1)2, S~l, or ORl group
wherein ~1 is the same or di~ferent and is as defined
above, or DNR2R3 wherein D is straight or branched
al'.~lene of from two to eight carbon a.oms which may
be substituted with an OH group and ~2 and R3 are as
defined a~ove; and the pharmaceutically acceptable
salts thereof; with the following provisos, 1~ when X
and Xl are d and Z is H, Rr and Y when taken together
do not complete a piperidine ring, 2) when X and X'
are 'd and Z is CH3, R and Y when taken together do
not complete a piperidine ring or a morpholine ring.
The invention in a first subgeneric aspect of its
fourth chemical compound aspect is a chemical compound
`naving structural ormula I wherein X and X' are 0'~;
and the pharmaceutically acceptable salts thereof.
~2~ 7
CLG-l -9-
The inven~ion in a second subgeneric aspect of
i;s fourth chemical compound aspect is a chemical
compound having structural 'ormula I wherein X an~ X'
are H; -~nd the pharmaceutically acceptable salts
thereof .
The invention in a third subgeneric aspect of its
fourth c~emical compound aspect is a chemical compound
ha~Jing structural formula I wherein A and D are the
same or diferen. and are eth~lene or propylene; and
the pharmaceutically acceotable salts thereof.
The invention in 2 fourth subgeneric as~ect of
its fourth chemical compound aspect is a compound
h~ing structural formula I'
~ N-3'
." ¢~, .
O NR'Y'
I'
wherein R' is d or alkyl of from 1 to h carbon atoms;
Y' is C~2CH2NHCH2CH20H when 2' is al~yl of from
one to four carbon atoms which ma~ be substituted with
an S~i, or O~l group wherein Rl is 'd or
alkyl of from one to four carbon atoms or
D'NR2R3 wherein D' is straigh~ or branched
al'cylene of from two to four c~_bon atoms which may be
substituted with an Od group and P~ and R3 may
be the same or different and are 'd, alkyl of fro~, one
to six carbon atoms which may be substituted with an
OH or R2 and R3 when taken together may be
ethylene or may form
-(CH~)n' \
B'
~(C~l2)~n'/
39~7
-- 10 --
wherein n' and m' may be the same or different and are one
or two provided that the sum of n' and m' is three or four,
and B' is a direct bond, O, S, or N-R4 wherein R4 is H or
alkyl of from one to four carbon atoms; or Z' is
CH2CH2NHCH2CH2OH when Y' is H, alkyl of from one to six carbon
atoms which may be substituted with an ORl group wherein R
is as defined above or A'NR2R3 wherein A' is alkylene of
from two to four carbon atoms and R2 and R3 are as defined
above; and the pharmaceutically acceptable salts thereof.
The invention in a fifth subgeneric aspect of its
fourth chemical compound aspect is a compound having
structural formu a I''
HO Nl - N-Z"
~1
~;0 0 NRnY"
I''
wherein R'' is H or alkyl of from one to six carbon atoms;
Y'' is H, alkyl of from one to six carbon atoms which may
be substituted with an ORi' group wherein Ri' is H or alkyl
of from one to four carbon atoms, or A''NR2'R3' wherein A''
is alkylene of from two to four carbon atoms, R2' and R3'
may be the same or different and are H, alkyl of from
one to six carbon atoms which may be substituted with an
OH or an NRa''Ra'' wherein Ra'' is the same or different
and is H or alkyl of from one to three carbon atoms which
may be substituted with an OH or R2' and R3' when taken
together may be ethylene or may form
2~
~(CH2)n' '~B
-(CH2)m'' ~
wherein n'' and m'' may be the same or different and are one
or two provided that the sum of n'' and m'' is three or four,
and B'' is a direct bond, O, S, or N~R4'wherein R4' is H or alkyl of
from one to four carbon atoms; Z'' is alkyl of from one to
four carbon atoms which may be substituted with an SRi', or
ORi' group wherein Ri' is defined above, or D''NR2'R3' wherein
D'' is alkylene of from two to four carbon atoms which may be
substituted with an OH group and R2' and R3' are as defined
above; and the pharmaceutically acceptable salts thereof.
The invention in a sixth subgeneric aspect of its
second chemical compound aspect is a compound having the
structural formula I'''
OH ~ Z' "
HO ~
OH O NR "'Y'''
I "'
wherein R''' is H or alkyl of from one to six carbon atoms;
Y''' is H, alkyl of from one to six carbon atoms which may
be substituted with an ORi'' group wherein Rl'' is H or
alkyl of from one to four carbon atoms, or A'''NR2''R3''
wherein A' " is al}cylene of from two to four carbon atoms,
R2'' and R3'' may be the same or different and are H, alkyl
of from one to six carbon atoms which may be substituted with
an OH or an NRa'''E~a''' wherein Ra''' is the same or
different and
~2~
CLG-l -12-
is H or alkyl of from one to three carbon atoms which
may be substituted with an OH or R2 and
when taken together may be ethylene or may
form
~(c~l2)n~
i3' 1 '
-(C~i2)!n' ' ''
wherein n''' and m' " may be tne same or diferent and
are one or two provlded that the sum of n'1' and m'''
is three or four, and B' " is a direct bondr O, S, or
N-R~ wherein Rg is H or al'.~yl o from
one to four carbon atoms; Z''' is alkyl of from one to
four carbon atoms which may be substituted with an
SRi , or oRi group wherein R
is defined a~ove, or D" 'NR2 ~3
wherein D''' is alkylene of from two to four carbon
atoms which may be substituted with an OH group and
R2 and R3 are as defined above; and
the pharmaceutically acceptable salts thereof.
The invention in a seventh subgeneric aspect of
its fourth chemical compound aspect is a compond
ha~ing the structural formula I''''
N--I_Z''''
OH o NR''''Y''''
I''''
wherein R'''' is H or alkyl of from one to six carbon
atoms; Y'''' is ~, alkyl of from one to six carbon
atoms which may be substituted with an oRi
group wherein Ri is H or alXyl of from one
t~ four carbon atoms, or A "''NR2 R3
wherein A'' " is alkylene of from two to four carbon
atoms, R2 a:nd R3 may be the same
or different and are H, alkyl of from one to six
CLG-l -13- ~ 97
carbon atoms which may be substituted with an O~ or an
NRa''''Ra'''' wherein 2a'''' is the same or different
and is H or alkyl of from one to three carbon atoms
which may be substituted ~ith an OH or R2
and R3 when ta~en together may be ethylene
or mav Eorm
~(CH2)n''~'\
B''''
~(CH2)m'''' /
wherein ~' "' and m'''' may ce the same or different
and are one or two provided that the sum of n'''' and
m'''' is three o. four, and B'''' is a direct bond, O,
S, or N-R4 wnerein R4 is a or
alkyl oE from one to four carbon atoms; Z " '' is alkyl
of fro~ one to four carbon atoms which may be
subs~ituted with an SRl , or oR
group wherein ~1 is defined above, or
D''''~R~ R3 wherein D'l'' is
alkylene of from two to four carbon atoms which may be
substituted with an Od group and R2 and
R3''' are as defined above; and the
pharmaceutically acceptable salts thereof.
The invention in an eighth subgeneric aspect o~
its fourth chemical compound aspect is a compound
having tne structural formula Iv
N - ~_zv
NRVyv
IV
CLG-l -14- -
wh2rein Rv is H or alkyl of from one to six carbon
atoms; yv is ~, alkyl of from one to four carbon
atoms or AVNR2vR3v wherein Av is al~ylene
of from two to four carbon atom~, R2Vand R3v may be
tne same or different and are H or alkyl of rom one
to six carbon atoms which ~ay be substituted with an
O~ or R2V and R3v when taken together may be
ethylene or may form
-(CEI2)nY
~BV
-(CH2)mV~
wherein nV and mV may be the same or different and
are one or two provided that the sum of nV and mV is
three or four, and sV is a direct bond, O, S, or
NR~V wnerein R4v is H or alkyl or from one to
four carbon atoms; zv is alkyl of from one to our
carbon atoms, which may be substituted with an SR1V,
or ORlV group wherein RlV is H or alkyl of rom
one to four carbon atoms, or DVNR2VR3V wherein
Dv is alkylene of from two to four carbon atoms which
may be substitu.ed with an OH group and R~v and
R3v are defined above; and the pharmaceutically
acceptable salts thereof.
The invention in a ninth subgeneric aspect or
its fourth cnemical compound aspect is a com ound
having tne structural formula IVi
HO Nl N-zvi
OEI O NRViyvi
Ivi
CLG-l -15-
wherein RVi is H or alkyl of from one to six carbon
atoms; ~vi is H, alkyl of from one to four carbon
atoms which may be substituted with an oRlVi group
wherein RlVi is H or alkyl of from one to four
car~on atoms or AViNR2viR3vi wnerein
~vi is alXylene of from two to four carbon atoms
R2'~i and R3Vi may be the same or different and
are al.~yl of from one to six carbon atoms which may be
substituted with an OH~ or R2Vi and R3Vi when
taken tosether may be ethylene or may form
~(C~2)nvi\
vi
~ ( C~2 )mvi~
w~erein nvi and mvi may be the same or different
and are one or t-~o provided ~hat the sum of nvi and
m~i is three or four, and BVi is a direct ~ond,
O, S, or NR4Vi wherein R4Vi is H or alkyl of
from one to fou- carbon atoms; zvi is
DViNR2viR3vi wherein DVi is alXylene of
~rom two to four carbon atoms, R2Vi and R3Vi
are defined above; and the pharmaceutically acceptable
salts thereof.
The invention as species of the first generic
chemical compound aspect of the invention are the
chemical compounds having the following names:
2-[2-(diethylamino)ethyl)]-5-[[2-[(2-hydroxyethyl)-
amino]etbyl~amino]anthra[l,9-cd~pyrazol-6(2H)-one;
2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[ E2- [ ( 2-hydroxy-
el:hyl)a;nirlo]ethyl~a;nino]anthra[l,9-cd]pyrazol-6(2~1)-
one;5-[(2-aminoethyl)amino] -2- [ ?- [ ( 2-hydroY.yethyl ) amino]-
ethyl]anthra[1,9-cd]pyrazol-6(2~)-one;
2-[2-(diethylamino)ethyl]-7,10-dihydroxy-S-[~2-[(?-
hydroxyethyl)amino]et~yl]amino3anthra[1,9-cd]-
pyrazol-6(2H)-one;
'g7
Cr.G-l -16-
5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-7,10-
r~ihydroxy-2-(2-hydroxyethyl)anthra[l~9-cd]pyrazol-
6(2H~-one;
2-[2-~[2-~dimethylamino)ethyl]amino]ethyl]-5-[[2-[(2-
hydroxyethyl)amino]ethyl]amino]-7,10-dihydroxyanthra-
t 1, 9 - ca ~ pyrazol-6(2H)-one;
2-[2-(die~hylamino)ethyl]-[[2-(~-morpholinyl)ethyl)~-
aminolznthra[l,S-cd]pyrazo1-6(2H)-one;
2-(2-aminoethyl)-5-[[2-[~2-hydroxyethyl)amino]ethyl]-
amino~anthra[l,9-cd]pyrazol-6(2H)-one;
5-1(2--aminoethyl)amino]-2-r2-(diethylamino)ethyl]-
7 t l~-dihyaroxyanthra[l~9-cd]pyrazol-6(2H)-one;
2-[2-~dietnylamino)ethyl]-7,10-dinydroxy-5-[[2-
(~ethylamino)etnyl]amino]anthra[l,9-cd]pyrazol-
6(2~)-one;
2-12-(dimethylamino)ethyl]-7,10-dihydroxy-5-[[2-[(2-
hydroxyethvl)amino]ethyl]amino]anthra[l,9-cd]2yrazol-
6(2H)-one;
5-t(2-aminoethyl)zmino]-2-[2-~dimethylamino)ethyli-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-[(3-aminopropyl)amino]-2-[2-(dimethylamino)ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-[t2-aminoethyl)amino]-7 t 10-dihydroxy-2-(2-hydroxy-
ethyl)lnthratl,9-cd]Pyrazol-6(2H)-one;
5-[[2-(dimethylamino)ethyl]2mino~-7,10-dihydroxy-2-
(2-hydroxyethyl)anthra[l,9-cd]pyra~ol-6(2~)-one;
2-t3-~diethylamino~-2-hydroxypropyl]-7,10-dihydroxy-
5-tt2-t(2-hydroxyethyl)amino]ethyl]amino]anthra-
[l,9-cd]-pyrazol-6(2H)-one;
5-[(2-a~inoethyl)amino]-~-[3-~diethylamino)-2-hydroxy-
propyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-t3-(dimethylamino)propyl]-7,10-dihydroxy-5-[[2-
t(2-hydroxyethyl)amino]ethyl]zmino]anthra[l,9-cd]-
?Y~a~Ol-6(2H)-one;
7 24~ 30~7
CLG-l -17-
7,13-dihydroxy-5-[[Z- E ( 2-hydroxyethyl)amino]ethyll-
am.no]-2-t2-[(2-hydroxyethyl)methylamino]ethyl]-
anthra[l,9-cd]pyrazvl-6(2H)-one;
7,10-dihydroxy-5-E[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-2 [3-[(2-hydroxyethyl)amino]propyl]anthra-
tl,9-cd]pyrazol-6(2H)-one;
5-[(2-aminoethyl)amino]-7,10-dihydroxy-2-[2-[(2-
hydroxyethyl)am.no]ethyl]anthra[l,9-cd]pyrazol-
6(2H)-one;
5-[[2-(dimethylamino)ethyl]amino]-7,10-dihydroxy-
2-t2-t(2-nydroxyethyl)amino]ethyl]anthra[l,9-cd]-
pyrazol-6(2H)-one;
5-[[2-(diethylamino)ethyl]amino]-7,10-dihydro~y-2-t2-
t(~-hydroxyethyl)amino]ethyl]anthra[1,9-cd]pyrazol-
6(2H)-one;
5-t(3-a~lnopropyl)amino]-7,10-dihydroxy-2-[2-t(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol-6-
(2H)-one;
7,1~-dihydroxy-2-[2-[(2-hydroxyethyi~amino]ethyl]-5-
[[3-[(2-hydroxyethyl)amino]propyl]amino]anthra[l,9-
cd]pyrazol-6(2H)-one;
5-[[2-[[2-(dimethylaminoethyl]amino]ethyl]amino]-7,10-
dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]anthr2-
[l,9-cd]pyrazol-6(2H)-one;
5-~[2-[(2-aminoethyl)amino]ethyl]amino]-7,10-di-
hydroxy-2-t2-[(2-hydroxyethyl)amino]ethyl]anthra-
tl~9-cd]-pyrazol-6(2H)-one;
5-tt2-[bis(2-hydroxyethyl)amino]ethyl]amino]-i,10-
din~ydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]anthra-
tl,9-cd]pyrazol-6(2~)-one;
7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
t[2-(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one;
Cr.G-l -18-
2-(2-aminoethyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl)amino3ethyl]amino]anthra[1,9-cd]pyrazol-
6(2EI)-one;
2-(2-aminoethyl)-5-[(2-aminoethyl)amino~-1,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-[2-aminoethyl)-5-[[2-[[2-(dimethylamino)ethyl]-
amino~ethyl]amino]-7,10-dihydroxyanthra[l,9-cd]-
pyrazol-6(2H)-one;
2-(2-a.~.inoethyl)-5-[[3-[(2-hydroxyethyl)amino]propyl]-
amino]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-(2,3-dihydroxypropyl)-7,10-dihydroxy-5-[[2-
~2-hydroxyethyl)amino]ethyl]amino~nthra[l,9-cd]-
pyrazol-6(2H~-one;
7-hydrox~y-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
[[2-~(2-hydroxyethyl)amino]ethyl]amino]anthra[l,a-cd]
pyrazol-6(2H)-one;
7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl)-5-[[2-
(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-
one;
10-Hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-
5- [ E 2-[(2-hydro~yethyl)amino]ethyl]amino]anthra[
cd]pyrazol-6(2H)-one;
7~8~10-trihydroxy-2-[2-[(7-hydroxethyljamino]ethyl]
5-[[2-[(2-hydroxyethyl)aminolethyl]amino]anthra-
ll,g--cd]pyrazol-6(2H)-one;
7,8,10-~rihydroxy-2-[2-~(2-hydroxyethyl)amino)]ethyl]-
5- [ [2-(metnylamino)ethyl]amino~anthra[l,9-cd]pyrazol-
6(2H)-one;
5-1[2-[(2-aminoethyl)amino]ethyl]amino]-7,10-
di~ydroxy-2-(2-hydroxyethyl)anthra[l,9-cd]pyrazol-
6(2H)-one;
2-(3-a~inopropyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl)amino]ethyl]amino]anthra~l,9-cd]pyrazol6(2H)-
one;
2-(3-aminopropyl)-5-[[2-[[2-(dimethylamino)ethyl]-
amino]ethyl~amino]-7,10-dihydroxy anthra[l,9-cd]-
pyrazol-6(2H)-one;
3~
CLG-l -19-
2-~2-aminoethyl)-7,10-dihydroxy-5-[[2-(methylamino)-
ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-one;
5-[(2-aminGethyl~amino]-2-[3--(dimethylamino)propyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
7,8-dihydroxy-~-[2-[(2-hydroxyethyl)amino]ethyl]~S-
[~2-~(2-hydroxyethyl)amino]ethyl]amino]anthra[l,g-cd]-
pyrazol-6(2H)-or.e; and
the pharmaceutically acceptable sal.s thereof.
The in~ention in its fl.th generic chemical
compound aspect is a chemical compound having the
structural formula
N - N-Z
Q~
O Cl
~herein Q, Q', and Q" may be the same or different
and are hydrogen, OH, alkoxy of one to four carbon
atoms, chlorine, benzyloxy, ~-chlorobenzyloxy and
~-methoxyben~yloxy; and the oharmaceu.ically
~cceptable salts thereof; Z is defined above; and the
pharmaceutically acceptable salts thereof; ~rovided
that when Q = Q' = Q" = ~, Z may not be H or CH3.
The invention in its sixth generic chemical
comoound as?ec~ is a chemical compound having the
structural formula III
Q N ~-Z
,. ~
Q' O Cl
III
9~
CLG-l -20-
wherein Q and Q' may be the same or different and
are H, OH, Cl 4alkoxy, benzyloxy, p-chlorobenzyloxy, or
o-me.hoxybenzylo~y and Z is defined above; and the
pharmaceutically acceptable salts thereof; provided
that when ~ = Q' = H, Z may not be H or CH3.
The invention in a first subgeneric aspect of its
sixth chemical compound aspect-is a che~ical compound
having structural formula III wherein Q and Q' are H;
and the pharmaceutically acceptable salts thereo~.
The invention in a second suogeneric aspect of
its sixth chemical compound aspect is a chemical
compound having the structural formula III wherein Q
and Q' are ben2yloxy, ~-chlorobenzyloxy, or
~-methoxybenzyloxy; and the phar~aceutically
acceptable salts thereoEO
The invention in a third subgeneric aspect of its
sixth chemical compound aspect is a chemical compound
having structural formula III wherein Q and Q' are OH;-
and the pharmaceutically acceptable salts thereof.
The invention as species of the fi~th generic
chemical compound aspect of the invention are the
chemical compounds having the following names:
5-chloro-2-12-(diethylamino~ethyl]anthra~l,9-ca]-
pyrazol-6(2H)-one;
S-chloro-2-t2-[(2-hydroxyethyl)amino]ethyl~anthra~l,g-
cd]pyrazol-~(2H)-one;
5 chloro-2-[2-~diethylamino)ethyl]-7,10-dihydroxy-
an~hra[l,9-cd]pyrazol-o(2H)-one;
5-chloro-1,10-dihydroxy-2-[2-hydroxyethyl)anthra[1,~-
cd~pyrazol-6(2H)-one;
5-chloro-2 [2-(diethylamino)ethyl]-7,10-bis(phenyl-
methoxy)anthra[l,g-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[l(~-methylphenyl)sulfonyl]oxy]ethyl]-
7,10-bis(p'nenylmethoxy)anthra[1,9-cd]pyrazol-6(2U)one;
5-chloro-7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]-
! . ethyl]anthra[1,9-cd]pyrazol-6(2H)-one;
CLG-l -21- ~248~
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,10-bis-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[[2-(dimethylamino)ethyl]amino]ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-(2-aminoeth~l)-5-chloroanthra[l,9-cd]pyrazol-6-
(2H)-one;
5-chloro-2-[2-(dimethylamino)ethyl]-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[3-(diethylamino)-2-hydroxypropyl]-
7,1~-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[3-(dimethylamino)propyl]-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
~ethoxy)anthra El, 9-cd]pyrazol-6(2H~-one;
5-chloro-7,10-dihydroxy-2-[2- E ( 2-hydroxyethyl)-
methylamino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-one;
~-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]
7,10-bis~phenylmetho.xy)anthra[l,9-cd]pyrazol-6(2H)-
one;
5-chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)-
amino]propyl]anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[3-[(2-hydroxyethyl)amino]propyl]7,10-
~is~phenylmethoxy)anthra ~,9-cd~pyrazol-6(2H)-one;
5-chloro-2-~3-[[4-methylphenyl)sulfonyl]oxy]-
propyl]-7,10-bis(phenylmetnoxy)anthra[l,9-cd]pyrazol-
6(2H)-one;
5-chloro-2-(3-hydroxypropyl)-7,10-bis(phenyl-
~ethoxy)anthra~l,9-cd]pyrazol-6(2H)-one;
2-(2-a~inoethyl)-5-chloro-7,10-dihydroxyanthra-
Il,9-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-chloro-7,10-bis(phenylmethoxy)-
anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-L(2 r 2-dimethyl-1,3-dioxolan-4-yl)-
methyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd]-
pyrazol-6(2H)-c)ne;
5-chloro-2-[2-[(2-hydro.Yyethyl)amino]ethyl]-7-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(~H)-one;
CLG-l -22-
5-chloro-2-12-[(2-hydroxyethyl)amino]ethyl]-lU-
(phenylmetlloxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydro.Yyethyl)aminolethyl]-
7,8,10-tris(pnenylmetho~y)anthra[l,9-cd]pyrazol-
6(2H)-one;
2-(3-aminopropyl)-5-chloro-7,10-bis(phenylmethoxy) -
anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,8-
bis(phsnylmethox~y)anthra[l,g-cd]pyra201-6(2H)-one;
5-chloro-2-[2-[~2-(dimethylamino)etllyl]amino3ethyl~-
7,10-~is(phenylmethoxy)anthra[l,9-cd]pyrazol-6(~H)-
one; and the phar~aceutically acceptable sal's
thereof.
The invention in its seventh generic chemical
compound aspect is a compound having the structural
formula IV
N N-Z
NRY
IV
wherein R is H or alkyl of from one to six carbon
aioms; ~ is H, al~yl of from one to six carbon atoms
which ~ay ~e substituted with an ORl sroup wherein R
is ~ or al.cyl of from one to six carbon atoms, or
~R2R3 wherein A is alkylene of from two to eisht
carbon atoms, R2 and R3 may be the same or different
and are H, alkyl of from one to six carbon atoms which
may be substituted with OH or an ~RaRa whsrein Ra may
be the same or different and is H or alkyl of from one
to hree carbon atoms which may be substituted with
OH, or R~ and R3 when taken tosether may be ethylene
or may form
97
Cr.G-l -23-
~(CH2)n\
: B
-(C~2)m/
wherein n and m may be the same or different and are
one, two, or three, provided that the sum o~ n and m
is an integer of from three to six, and B is a direct
bond, O, S, or N-~4 wherein R4 is H or alkyl of from
one to six carbon atoms; R and Y when taken together
may be ethylene or may form
~(c~2)n
B
-(CH2)m /
wherein n, m, and B are defined above; Z is H, alkyl
of from one to six carbon atoms which may be
substitut2d with an N(Rl)2, SRl. or ORl group
wnerein Rl may be the same or different and is
defined above, or DNR2R3 wherein D is alkylene of
Erom two to eight carbon atoms which may be
substituted with an OH group and R2 and R3 are as
defined ahove; and the pharmaceutically acceptable
salts thereof; with ~he following provisos, 1) when Z
is H, R and Y when ta~en together do not complete a
piperidine ring, 2) when Z is CH3, R and Y when taken
together do not complete a piperidine ring or a
morpholine ring.
The invention as species of the seventh generic
cnemical compound aspect of the invention are-the
chemical compounds having the follo~ing names:
2-t2-(diethylamino~ethyl3-7-[[2-[(2-hydroxyethyl)-
a~ino]ethyl]amino]anthra[l,9-cd]pyrazol-6(2~)-one;
2-[2-(diethylamino)ethyl-7-[[2-(diethylamino)ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2~)-one;
2-[2-~(2-hydroxyethyl)amino]ethyl]-7-[[2-~(2-
hydroxyethyl)amino]ethyl]amino]anthra[l,9-cd]pyrazol-
6-(2H)-~ne; and the pharmaceutically acceptable salts
thereof.
~8(~
CLG-l -24-
The invention in its eighth generic chemical
compound aspect is a compound having the structural
formula VII
IN--I - Z
Cl O
~II
wherein Z is defined above, pro~ided it is not H or
CH3-
The inven~ion as a species o~ the eighth seneric
chemical compound aspect of the invention is the
chemical compound having the following names
7-chloro-2-[2-(diethylamino)ethyl]anthra[l,9-cd]-
pyrazol-6(2H)-one;
7-chloro-2-[~-[(2-hydrox~ethyl)amino]ethyl]anthrall,
9-cd]pyrazol-6(2~)-one; and the pharmaceutical~y
acceptable salts thereof.
The invention in its ninth chemical compound
asDect is ~,8-dichloro-1,4,9,10-anthracenetetrone.
The invention in its tenth chemical compound
aspect is the compound 2-[(hydrazinoethyl)amino]
ethanol and the acid addition salts thereof.
The invention in its first generic chemic21
process aspect is a process for preparing a compound
having the structural formula
W-~
which COmQriSeS reacting a compound having the
structural formula
CLG-L -25- ~ 248097
N N-2
Q"
wi,~ an amine having the formula HNRY wherein W, X~
X', Q, Q', Q'', Y, Z, and R are defined above and,
when necessary, removing bv catalytic hydrogenation or
by treat~ent with boron tribromide or trichloride any
benzyl groups.
The invention in its second generic chemical
process aspect is a process for preparing a compound
having structural formula I
X ~ - N-Z
[~1
X' O NRY
I
which comprises reacting a compound having structural
fo~lula II
¢'~5
~' O Cl
II
)g7
CLG-l -26-
with an amine having the formula HNRY wherein X, X',
Q, Q', Y, Z, and R are defined above and, when
- necessary, r2moving ~y catalytic hydrogenation or by
treatment with boron tribromide or boron trichloride
any benzyl groups.
The invention in a first subgeneric aspect of its
second chemical process aspect is the process defined
above wherein X and X' are OH.
The invention in a second subgeneric aspect of its
second chemical process aspect is the process defined
above wherein X and X' are H.
The invention in its third generic chemical
proces~ aspect is a process for preparing a compound
having structural formula III
Q
.' ~
Q' O C1
III
which comprises reacting a compound having formula V
Q o C1
Q' O C1
V
with a hydrazine having the formula H2N-NHZ, wherein
Q, Q' and Z are defined above.
~2~ 7
C~G-l -27-
The invention in a first subgeneric aspect of its
thi.d chemical rocess aspect is the process defined
above wherein Q and Q' are ~en yloxy,
~-chlorobenzyloxy, or ~-metho~ybenzyloxy.
The invention in a second subgeneric aspect of
its third chemical process aspect is the process
~efined above wherein Q and Q' a.e OH~
The invention in a third subgeneric aspect of its
third chemical process aspect is the process defined
above wherein Q and Q' are ~.
The inventlon in its fourth generic chemical
~rocess aspect is a process for preparing a compound
having struc,ural ~ormula IV
N - ~-Z
~ .
NRY O
I-~
which comprises reacting a compound having structural
formula Vl-
~
IN--~-Z
Cl o
VII
with an amine having the Eormula HNRY, wherein Y, Z,
and R are defined above.
8~
CLG-l -28~
The invention in its fifth chemical process
aspect is a process Eor preparing 5,8-dichloro-
1,4,9,10-anthracenetetrone which comprises reactins
1,~-dichloro-5,8-dihydroxy-9,10-anthracenedione with
lead tetracetate.
The invention in its sixth chemical process
aspect is a process for preparing
2-t(hydrazinoethyl)amino]ethanol ~hich comprises
reacting hvdrazine with N-(2-hydroxyethyl)aziridine.
The in~ention in its ~irst pharmaceutical
composition aspect is a pharmaceutical composi'ion
comprising a compound having structural formula I and
the pharmaceutically accept~ble salts thereof in
combination with a pharmaceutically acceptable
carrier.
The invention in its second pharmaceutical
composition aspect is a pharmaceutical composition
comprising a compound having struc~ural formula I' and
the pharmaceutically acceptable salts thereof in
combination with a pharmaceutically acceptable
carrier,
The invention in its third pharmaceutical
composition aspect is a pharmaceutical composition
comprising a compound having structural fo~mula Il'
and the pharmaceutically acceptable sal~s thereo~ in
co~bination with a ~harmaceutically acceptable
carrier.
T~e invention in its fourth pharmaceutical
composition as~ect is a pharmaceutical composition
comprising a compound havina structural
~ormula I " ' and the pharmaceutically acceptable salts
thereof in combination with a pharmaceutically
acceptable carrier.
~1~4~
CLG-l -29-
The invention in its fifth pharmaceutical com-
position aspect is a pharmaceutlcal composition com-
prising a compound having structural formula I' "'
and the pharmaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its sixth pharmaceutical com-
position aspect is a pharmaceutical composition com-
prising a compound ha~ing structural for~ula Iv
and the p~armaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its seventh pharmaceutical com-
position aspect is a pharmaceutical composition com-
prising a compound having structural formula I'~i
and the ~harmaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its eighth pharmaceutical
composition aspect is a pbarmaceutical composition
comprising a compound having structural formula IV
and the pharmaceutically acceotable salts tnereof in
combination wi~h a pharmaceutically acceptable
carrier.
Tne invention in its first pharmaceutical method
aspect is a method for treating microbial infections
in a mammal which comprises administering a
suEficient amount of a compound having structural
formula I and the pharmaceutically acceotable salts
thereof in combination with a pharmaceutically
accep~able carrier to a mammal in need thereof.
The invention in its second pharmaceutical method
aspect is a method for treating leukemia in a mammal
which comprises administering a sufficient amount of a
compound having structural Lormula I' and the
pharmaceutical:ly acceptable salts thereof in
.
- 30 ~ Og7
combination with a pharmaceutically acceptable carrier, to a
mammal in need thereof.
The invention in its third pharmaceutical method aspect
is a method for treating leukemia in a mammal which
comprises administering a sufficient amount of a compound
having structural formula I'' and the pharmaceutically
acceptable salts thereof in combination with a
pharmaceutically acceptable carrier, to a mammal in need
thereof.
The invention in its fourth pharmaceutical method
aspect is a method for treating solid tumors in a mammal
which comprises administering a sufficient amount of a
compound having structural formula I''' and the
pharmaceutically acceptable salts thereof in combination
with a pharm~ceutically acceptable carrier, to a mammal in
need thereof.
The invention in its fifth pharmaceutical method aspect
is a method for treating solid tumors in a mammal which
comprises administering a sufficient amount of a compound
having structural formula I'''' and the pharmaceutically
acceptable salts theraof in combination with a
pharmaceutically acceptable carrier, to a mammal in need
thereof.
The invention in its sixth pharmaceutical method aspect
is a method for treating solid tumors in a mammal which
comprises administering a sufficient amount of a compound
having structural formula Iv and the pharmaceutically
acceptable salts thereof in combination with a pharmaceuti-
cally acceptable carrier, to a mammal in need thereof.
The invention in its seventh pharmaceutical method
aspect is a method for treating solid tumors in a mammal
which comprises administering a sufficient amount of a
compound having structural formula IViand the
pharmaceutically acceptable salts thereof in combination
with a pharmaceutically acceptable carrier, to a mammal in
need thereof.
~L2~ 7
CLG-l -31-
The invention in its eighth pharmaceutical method
aspect is a method for treating solid tumors in a
mammal which comprises administering a sufficient
amount of a compound having structural formula IV
and the pharmaceutically acceptable salt~ thereof in
combination with a pharmaceuiically acceptable
carrier, to a mammal in need thereo~.
CLG-l -32- ~248097
DESCRIÇTION OF THE P~EFERRED E~BODIMENTS
The co~pounds of the invention may be prepared
conveniently by the following reaction se~uence
O Cl N N-Z
Q" ~ ~ - Q"
V ~II
- ~ `
N -- N-Z
- N -~-Z
¢ ~ C - - r~7 ~
O NRY X' O Cl
I II
The reaction step "A," involves the reaction of
compound V and a suitably substitu~ed hydrazine,
N~2-NH~ wherein Q, Q' and Q-l, and Z are defined
hereinabove. This reaction may be accomplished in any
o a variety of reaction inert solvents by mixin~
ap~roximately equimolar amounts of compound V and the
desired hydrazine in the cnosen solvent at elevated
'emperature. Use of a catalyst such as potassium
fluoride or of a slight molar excess of the hydrazine
reactant may improve a particular yield. Examples of
su-table solvents are N,N-dimethyl ormamide,
di~ethylsulfoxide, pyridine, acetonitrile, the
cellosolves, and the li~e. Pyridine is the preferred
solvent, suitab:Le reacbion te~peratures are from aoout
!
~4~3097
CLG-l -33-
30-~5C. In general, the reaction is allowed to
proceed for about six to about 24 hours at which time
tne reaction is substantially complete. The
CQmDleteneSs of a particular reaction may be measured
by ~nown procedures such as thin layer cbromatography
for e~.mple. It is generally observed that increasing
the reaction temperature will decrease the time
necessary for completing the reaction. The proper
choice of the reaction variables is within the skill
of the art. The products of the reaction are isolated
and purified by standard procedures. For example, the
reaction mixture may be concentrated by evaporating
the solvent and the residue may be partitioned between
water and a convenient nonwater-miscible organic
solvent such as chlorofor~.~ ~en~ene, dichloromethaner
and the like. The solvent may then be evaporated and
the residue may be chromato~ra?hed, ~or example, on
silica gel. Cholce o~ the proper chromatography --~
solvent is within the skill of t~.e art. After - -
chromatography, the product may be recrystallized, if
desired. When the Q, Q', and Q" substituents or the
so produced compound III compri~e benzyloxy,
-chloroben~yl.~xy, or ~-methoxybenzyloxy, the benzyl
substituents may be removed, ror example, by treatment
with ~oron trichloride or boron tribromide in a
chlorinated hydrocarbon solvent such as
dichloromethane at about 0C to produce compound II
wherein the corresponding X subs.i~uents represent
hydro.xyl. Acid addition salts may also be prepared by
standard procedures. For example, a hydrochloride
salt ~ay ~e prepared by dissolving the free base in a
convenient solvent such as 2-propanol and treating
this solution with a solution o~ hydrogen chloride in
2-?ropanol. The acid addition salts may be
reconverted to the respec~ive ~ree base by treatment
with a dilute solution of sodiu~ hydroxide or
potassium carbonate ~or example.
CLG-l -34- 1248097
The reaction step "B" involves the reaction of
compound II with a suitably substituted amine HN~Y
wherein R, W, ~, X', Y, and Z are defined hereinabove.
This reaction may be accomplished in any of a variety
of reaction inert solvents by mixing approximately
equimol2r amounts of compound II and the desired amine
in the chosen solvent at elevated temperature. The
use of a slight molar excess of the a~ine reactant, an
inert atmosphere and a catalyst such as anhydrcus
cuprous chloride may improve a particular yieid. The
use of these variations for a particular reaction is
o~tional and is within the s~ill of the art. 2xamples
of suitable solYents are N,N'-dimethylformamide,
dimethylsulfoxide, pyridine, acetonitrile, the
cellosolvesl and the like. Suit~ble reaction
temperatures are from about 85-130C. This reaction
has been observed to proceed particularly e$ficiently
in refiux~ng pyridine.- In ger,eralj-the reaction-is ---
allowed to proceed for about ~ to about 24 hours at
which time i. is substan.ially complete. The
completeness of a particular reaction may be measured
by known procedures such as thin layer chromatography
Eor example. It is generally observed that increasing
the reaction tem?erature will decrease the time
necessar~- for completinq the reaction. The proper
choice of the reaction variaoles is within the skill
of the art. The products of the reaction are isolated
and puri~ied by standard procedures which are
su~stantiall~ identical to those described above ~or
compound II. Likewise, acid addition salts of
co~pound I may be prepared by standard procedures such
as that described hereinabove for compound II.
Alternativel~, the compound of formula III may oe
_reated directly with an amine oE ~ormula H~RY to
produce a compound of the Eormula
~2~9~
CLG-l -35-
N N-Z
Q.. ~ ¢ ~
Q' b NRY
This compound may then be debenzylated 'oy a
standard procedure to produce the corresponding
compound having structural formula I.
In an alternate process the compounds of formula
I wherein X and X' are hydro~ may ~e prepared by
t~e reaction of compound VI (compound V wherein Q and
Q' are dihydroxy
0~ 0 Cl
.~
OH O C1
VI
~ith a suitably substituted hydrazine ~H2-N~Z to
produce a compound Oc structural formula II wherein
is OH; ~ is defined hereinabove~ The reaction of VI
and the hydrazine may be acco~plished by ~ixing
approximately equimolar amounts of the reactants in a
solvent such as ~,N-dimethylformamide,
di~ethylsulfoxide, pyridine, and the li~e at
temperatures a~out 30-90C, preferably 30-60C, in the
presence of a base such as potassium bicarbonate.
Pyridine is the preferred sol~ent and when utilized
does not require an additional base. The use of
catalyst such as potassium fluoride may improve
CLG-l -36- 12~8097
.ne yleld of a particular reaction The subsequent
conversion of the so produced comoound II wherein
and X' are hydroxy to the corresponding compound I
is carried out as already described hereinabove as
reaction steQ "B"
In an alternate method for preparing the
compounds of formula III, a compound of formula V is
reacted with a hvdroxyalkyl`nydrazine oF the formula
~2-N~tC~2)2-ll-OH~ preferably NH2-NH(CH2)2_3-OH
to produce a compound of formula III wherein Z is
-(C~2)2_11-0~ and is preferably -tC~2)2-3-OH
This reaction is carried out substantially as
described hereinabove as reac.ion step "An The 0
group o~ the Z substituent is then derivatized to
produce an easily displaceable substituent Xnown to
those skilled in the art as a "leaving group" Fcr
example, the 0~ group may be converted to a tosyloxy
or mesvloxy group by reaction with respectively --
~-toluenesulphonylchloride--or~methanesulphonylchloride- - -
in pyridine by procedures known to those ~killed in
the art The leaving group, so produced, may be
subsequently displaced with, for exam~le, an amine
such as diethylamine to produce a Z substituent of the
structure -(C~2)2_11-NEt2 In the preferred
procedure the substituent Z so produced is
-(CH2]2_3NEt2 The benzyl aroups or substituted
benzyl grou?s of compound III, if present, arè removed
as described above to produce a compound oF formula
II, which may be converted to a compound of formula I
as already described hereinabove as reac.ion step '!B"
The compounds having structural formula I wherein
X and X' are chloro are prepared starting from
compound VI by first converting VI to the
corresponding di-2-toluenesulfonic acid ester VI'
CLG-l ~37~ ~L248097
o~o~
VI'
~ his conversion is conveniently carried out by
treating VI with ~-toluenesulfQnyl chloride in a
nonreactive solvent such as acetonitrile àt reflux
temperature. The diester VI' is then treated with a
substituted hydrazine N~2NHZ subst2ntially as
desc ibed above for the conversion of compound V to
compound III. The product of this reaction, VI "
Cl ~ -Z
~'
Cl O OTos
VI"
is then treated witn an amine having the formula ~NYR
su~stantially -s described above ror the conversion of
compound II to compound I. The product of this
rea_tion has the followin~ structural formula~
Cl ~1 -N-z
~ '
Cl o NRY
wnerein ~, Y, and Z are as defined hereinabove.
~2~8~3~
- 38 -
The compounds having structural formula IV are prepared
by reacting a compound having structural formula VII with an
amine having the formula HNRY using substantially the same
reaction conditions described above for the conversion of
compound II to compound I, i.e., reaction step "B". A
particular Z substituent, for example, CH2CH2OH may also be
derivatized and converted to another particular Z
substituent, for example CH2CH2NEt2 in a similar manner to
the procedure already described hereinabove.
The compounds of structural formula VII are prepared by
reacting a suitably substituted hydrazine, ~H2-NHZ, wherein
~ is defined hereinabove, with 1,5-dichloro-9,10-
anthracenedione in a manner substantially identical to that
described above for converting compound V to compound III,
i.e., reaction sequence "A".
The present invention also contemplates the novel
hydrazine, 2-~(hydrazinoethyl)amino]ethanol,
NH2NHCH2CH2NHCH2CH20H. This novel hydrazine is a useful
intermediate for the preparation of a variety of final
compounds of the invention. This novel hydrazine may be
prepared by a variety of procedures which are considered
equivalent for purposes of the invention. One such
procedure involves the reaction of hydrazine and
N-t2-hydroxyethyl)aziridine in an aqueous medium at reflux
temperature. The novel 2-[(hydrazinoethyl)amino]ethanol so
produced is isolated by standard procedures as a clear
liquid which has bp 120 C at 0.035 mmHg. The novel
2-~(hydrazinoethyl)amino]ethanol forms acid addition salts
with organic and inorganic acids such as hydrochloric,
hydrobromic, sulfonic, phosphonic, methanesulfonic, acetic,
benzoic, and the like. For purposes of the invention, such
salts are considered equivalent to the free base form of the
novel hydrazine.
_ 39 _ ~ ~ ~80~7
The benzylated ethers V wherein any of -the Q
substituents represent benzyloxy, p-chlorobenzyloxy, or
p-methoxybenzyloxy may be prepared by treating compound V
wherein any of the Q substituents represent OH with the
corresponding benzyl bromide or benzyl chloride in a
convenient nonreactive solvent such as acetone,
dimethylsulfoxide, N,N-dimethylformaMide, and the like. The
use of a hydrogen halide acceptor such as an alkali metal
carbonate (e.g., potassium carbonate~ for this reaction is
preferred.
The novel intermediate, 5,8-dichloro-1,4,9,10-
anthracenetetrone may be prepared by oxidation of
5,8-dichloro-1,4-dihydroxy-9,10-anthracenedione. The
reaction may be carried out with lead tetracetate in glacial
acetic acid at or near room temperature.
The 1,4-dichloro-9,10-anthracenedione, compound V
wherein Q = Q' = Q'' = hydrogen, may be prepared by known
methods, see for example J. Am. Chem. Soc., 48; 3198 (1926).
The 1,4-dichloro-5,8-dihydroxy-9,10-anthracenedione,
compound VI, may be prepared by known methods, see for
example US Patent No. 3,631,074.
The compound 1,5-dichloro-9,10-anthracenedione, which
is utilized to prepare the compounds of formula VII is
commercially available or may be prepared by methods known
to those skilled in the art, see for example Beilstein 7,
787.
The compounds of the invention form pharmaceutically
acceptable salts with both organic and inorganic acids.
Examples of suitable acids for salt formation are
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,
malonic, salicylic, malic, fumaric, succinic, ascorbic,
maleic, methanesulfonic, isethionic, lactic, gluconic,
glucuronic, sulfamic, benzoic, tartaric, pamoic, and the
like. The salts are prepared by contacting the free base
form with an
L2~0~7
CLG-l -40-
equiv21ent amount of the desired acid in the
! conventional manner. The free base forms may be
regenerated by treating the salt form with a base.
For example, dilute agueous base solu-ions may be
utilized. Dilute aqueous sodium hydroxide, potassium
carbonate, ammonia, and sodium bicarbonate solutions
are suitable for this purpose. The free base forms
differ from their respective salt forms somewhat in
certain physical properties such as solubility in
polar solvents, but the salts are otherwise equivalent
to their respective free base forms for purposes of
the invention.
The compounds of tne invention can exist in un-
solvated as well as solvated forms, including hydrated
f~rms. In general, the solvated forms, with
pharmaceutically acceptable solvents such as water,
ethanol and tne like are equivalent to the unsolvated
forms for purposes of the invention.
The term halogen is intended to include fluorine,
chlorine, hromine, and iodine.
~ he alkyl and al~oxy groups contemplated by the
inqention, unless specified otherwise, comprise both
straight ar2 branched carhon chains of from one to
about six carbon atoms. Representative of such sroups
are ~ethyl, ethyl, isopropyl, butyl r pentyl, 3-me.hyl-
pentyl, methoxy, ethoxy, i-propoxy, t-butoxy, n-
hexoxy, 3-methylpentoxy, and the li~e.
The al~ylene groups contemplated by the inven-
~ion, unless specified otherwise, comprise both
st aight and branched carbon chains of from two to
about 11 carhon atoms. Representa.ive of such groups
are ethylene, npropylene, n-butylene, n-heptalene,
i-propylene, 3-ethyl-1,5-pentalene, ~-propyl-
1,6-hexalene, and the like. The preferred alkylene
groups of the invention have the following structural
formulas:
CLG-l -41- ~248097
CH3 CH3 CH3 CH3 C2H5
-(CH2)-2-ll; -CH-CH2-; -CH2-C~-, -C~- CH-; -CH-CH2-7
C2}I5 IH3 ~H3 c~3
2 ; CE C~2 C~2 ; -C~2-C~~C~2~; -CH2-CH2-CH-
Certain substituents, such as alkyl or alkylene
substituents contemplated by the invention are defined
as possibly being substituted with additional
substituents, e.g., NH2. Those skilled in the art
will recosnize that certain combinations of such
substituents are most probably unstable and these are
not intended to be included within the scope of the
definitions. For example~ an ~-aminoalXyl or
al.~ylene aroup of the general for~ula = N-CH-NH2
would not be expected to be stable whereas the
corresponding dial~ylated substituent = N-CH-N(Alk)2
is e~pected to be stable and is intended to be
included within the definitions. It is within the
s~ill of the art to recognize these and other suc~
substituents which are possibly unstable.
The compounds of the invention are new chemical
substances of value as phar~acological agents for the
treatment o bacterial and fungal infections in
wa.m-blooded animals. They ~ay also be utilized as
antiseptic agents such as for use in the sterilization
oE laboratory glassware etc, The antibacteriàl and
antifungal activity of representative compounds of the
invention was established by the screening procedure
described below.
1~48(~97
CLG-l -42-
1. Pre~aration of inocula
-
(A) Bacteria and yeast:
The bacterial and yeast isolates are
main.ained in agar slants or in li~uid media,
hereby designated as inoculum media~ The
cultures are transferred at regular intervals
in such media. (See Table for the correspon-
ding inoculum media of each culture.) The
organisms are generally transferred on to
agar slants or liquld inoculum media and
incubated overnight (18-20 hours): 37C for
the bacterial isolates and 28C for the
-fungal cultures.
The microbial cells Erom the overnight agar
slants are then scraped off and suspended in
saline solution (0.85~ NaCl). The microbial
concentrations are adjusted to a light
transmittancy of 20-35%, Junior Coleman
Spectrophotometer-(555 i~, -). -For the
organisms that are maintained in liquid
media, an aliquot of the culture suspension
is simply diluted with saline to 20-35% light
transmittancy.
The above microbial suspension serve as in-
ocula for tne assay plates. Thus, 0.16-10 ml
(see Table for exact amount) are used to
inoculate 100 ml of the molten-agar ~assay
medium.
~B) Mycelial fungi:
The Penicillium avellaneum is grown for six
days, at 28C, on an agar medium. This is to
allow sporulation of the culture. The
organism is then harvested by scraping off
the cells from the agar surface (mycelia and
spores) and suspending them in saline
solution containing 0.05~ Tween* 80.
*trade mark
4t~0~7
CLG-l -43~
The sus~ension is adjusted to a light trans-
mitancy of 20%. One ml of this suspension is
used to inoculate 100 ml of the molten-agar
assay medium.
2. ~reparation of assay ælates
Stainless steel frames, 12.3 x 25.3 cm (ID) and
glass plates, 15.3 x 31.7 cm are used to make the
test trays. The frames are attached to the plates
with tape at each end and .he inner edges sealed
with 2% agar. Twenty five ml of inocuiated assay
medium is spread evenly on each tray and allowed
to solidify. The trays are covered, inverted, and
refrigerated until used.
3. Disking o sa~ples
The compounds or samples to be tested are dis-
solved in suitable solvents, e.g., alcohols,
dimethylsulfoxide, or N,N-dimethylformamide. The
samples are generally dissolved so that the final
concentration o the solvent is ~10~.* The
compounds are tested at different concentrations:
3,000; 1,000; 500; 100; and 10 mcg/ml. Paper
discs tl2.7 m~ diameter) are placed on the agar
trays with forceps, then 0.08 ml of the dissolved
compound is pipetted onto each disc using a 0.2 ml
pipette. (*If the compound does not stay n
solution at <10% alcohol, then the full strength
alcohol is used. ~owever, the impregnate~ discs
are air-dried before the~ are laid on to the
seeded agar plates.)
4. Interpretation of resul_s
The disXed agar trays are incubated overnight
(18-20 hours) at 37C for the bacterial cul.urqs
and 28C for the yeasts. The Penicillium
avellaneium tray is incubated for at }east 20-24
CLG-l ~44~
hours since it is a slower-growing organism.
~ctiqe compounds show a zone o~ inhibition around
the disc. The diameter of the zone is measured in
mm. The zone diameter of active compounds ranges
from a minimum of 13.5 mm to as high as 60 mm.
The size of the zone diameter generally reflects
the activity of the compound: the larger the zone
the sreater the activity~
CLG--1 - 4 5-- ~L248097
3~
1248Q97
CLG-l -46-
5. Culture media
! The composition of the various culture media,
e;Ycept Eor the commercially available media, are
sho-~n below. The co~mercial ready-made Veal
Infusion Medium is obtained from Difco
Laboratories, Detroit, Michigan, USA. Add 1.5
agar to t~ese media for use as agar plates.
AM-08 %
Glucose 0.2
Sodium Glutamate 1.04
K~2PO~ 0.03
Na2~O4 0.07
Salts $la 1 ml
Salts ~2b 10 ml
~2 (distilled)
~Salts ~ 1 % bSalts ~ 2 %
~gSO~ 1.0 MnS0~ 1.0
CaC12 5.0 ZnSO~.7H20 1.0
NaCl 5.0 FeS04.7H20 1.0
CuSo4~5H O 0.01 ~2 (distilled)
~2 (distilled)
CLG-l -47- ~24~9~
A.~-09
i K2HP04 309 gm
Dextrose 25 gm
Na-citrate 2 ~2 3404 gm
Casein hydrolysate 6.2 gm
Asparagine 375 mg
L-tryptophan 125 mg
Cysteine 312.5 mg
Glutathione 3,1 mg
Thiamine HCl 250 g
Riboflavin 625 g
Ca ~antothenate 500 g
Nicotinic acid 500 g
p-aminobenzoic acid 625
Biotin 12,5 g
~yriaoxine ~Cl 2.5 g
Folic Acid 500 9
~aCl 12.5 g
MgS04 25U g
FeS04 12.5 g
~nS04 ~20 125 g
T~een 80 62.5 mg
~2 ~distilled) 1000 ml
A~-25 %
Na2HP04'~20
~2P4 0-05
Yeast Extract (Difco) 0.5
Dextrose 1,0
Distilled Water
Utilizing the above described procedure, the
following results were obtained for representative
compounds of the invention.
C~ 8-
I o o ~ o ô ~ o ^ _
C ~. O ~ o o O ~D O
_ __________________
-- V-------~
CLG--I 1248097
o ~o o o o o o ~ ~ ~ ~r
e
-~ooooo 3 o
o ~1o.r,o oO g
e ~ O O " ~ O O O----_------~
~,24~
CLG-' -53-
~1
o o o o, -_
_ ~ ___ ____ __ ___ ____
_ ,~ ~O
~D _ _______-______-_
i ___ -_--_- -_ I
oooo. ,~o
__________________
CLG--l --51--
1~ O o O O - I
~ _______-_______________
_ - _ ~
_ ______________________
c~ loooooooo~~~
a __ __ __ _ _ __ _ _ _ ~ ______ __ _
_ o o o o U'~
.r o o u~ n o
, n ~ ~~~~~~--~--~ ~ ''
_~ _____~_~ ~ ~ _~ ~ ~ _ _
~ V~ ~ ~
:~ ~ Z Z _ _
. _ ______________________
o ! orl~o ~ o~
__ __ ____________________
~ ~ o ~
97
CLG-l -52-
e
o o o ô o o o o ô
_ _ _ _ _ _ _ _ _ _
~C O O o o o ~ o o o
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _. _ _ _ _ _
u o o o o o o o o o
~ o o o ~ ~ oo o
__ ________ ___________
_ o o o o ~o u~ o o o
Q8 _ _ ~ ~ O ~
:a _ _ _ 'r ~ ~ ~ O O
__ ~ o ô o ~ u~ o o o
~0 o _ _ _ o o
__ _ _ _ _ __ _ ~ _ ~ ~ ~ _ _
2 O ~" ~ o In u o o ~
¢ o - - - - - - - - -
_ _ N N N N N N
N N ~ N ~ ~ N N N
U U U U U -- N ~ N
__ ___________________
ON ON
:~ N N --NZ Z Z _ N N
U ~ U U~ _ _N S~ N
_ _ ~ N N N N N N N N
~ I o I I o~ o
C~ 53- ~L248~
~v ô o ô o o o o o o ô
~ o o o o o o a o o o
~q ô o o ô o o o o ô o 1
~ o o o o o o o o o ~
__ ô ô ô o ô ô o ô ô
_ ~ O
u~ o ~ o o o o o ~ o .r
__ ___~ ____________- _ _
C _~_~_~_~____~_____~ __ ..
_~ _____~ _~ __~ _~ _~ _~ _~ ___ C~.
r~ _ : = Z 2 2 2 2 2 0 O
__ ~ ~ ~ ~ ~ ~ ~ CJ _
:~ T T ~ ~ _ .~ ,
~T I o ~ ~ ~ 7: o T ~,
48~37
C LG~
Cl. ~ ", ~ . . ~ O ô O
l o o w w o w .r ~ U-
_ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
3. ~ o o o o o ~ ~r w o ~ u7 ~ o o
_ o .. .... _ o _ o o o ô
_~n ____ __ __ __ __ _~ _~ _______________
_ u~ O ô
._ ~
a _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
~o w i i,, i E i ~ - o o ~,
__ _ ___ ___.__________________ . ... .. ....
ei~~ N N U U U U O ~ -- -- U U b~ _
ON ~ -- _ Z Z Z N ~ N O O N N ~
_ _U C~ N r~ ~ U ~ U U U U U C
. U--_ ~ ~ N O
__ V -- U S = -- S ~ U 'U ~J CJ U U C.l _
NN ~ N N C
X O O O O- - S = = ~ ~ ~ .
C1,5-1 -5~- ~248~7
.,' ô o o o '~
e O O O O
W ____________
~ r~ rrl rr~
c12, ~ .
n ___________
_ O
?J ___________
e ~ .
C __________ _ ..
~ o~ o~ ?
~ -- N O
__ _--_--_--__-_--_ O
O
-~ ~
__ ____________ C
~ ~ .
- :~ O O O _
X O o O o ~ .
' ' ' ` - . . .
GLG--1 -56- 3124809~7
~ _ ~ _
. -_-___ .
ê Q o ~
o _ __ __ __ _
_ _ o o _
C~ _ _ _ _ _ _ _ _
.1 o~ ,n u- u~
C .C C O O O
o. ~t _______ . ...
e ~ 5~ u
~ .~ N N
_ _ _ _ _ _ _ _
97
CLG-l -57
In addi~ion to their use.~lness as antibio~io and
antitungal agen~s, cer~ain of ehe comoounds Ot the in-
vention disDlay in vivo antileukemic ac;~vity when
tested by the following proced7ure.
The in Yi~o lymohocy~ic leu~eMia P3a8 test i5
car-ied out by the United States ~ational Cancer
InstituteO Th~ ani~als used are eithar male or re~a7e
~D2Fl mice. There are six to seven animals per test
group. The tumor trar.solant is by intraoeriton2al
injection o~ dilute ascitic fluid contai~ing cells of
lym~hocytic t~kemia P3S~. The 2S . compounds are
ad~inistered intrao~riton~ally in t~ si.qgl~ doses
with a fouroday lnterval b~t~e~n do3e~ at vario~s dos~
levels following tumor inoculation. T~e animals are
weisned and survivors are recor~ed on a reguler basis
for 30 day~. ~ ratio of survival time for ~reated
(T)/control (C~ anim~ls is calculated. The c_it~rion
for e~ficacy is T/C X iOO ~ 12S%. The positive
control comoound in ~nis test is l,4-di~ydroxy-5,a-
~bis [12-[(2-hydroxye~hyl)aminol-et~yllaminol-9.lO-
~nthracen~dione given at dos~ges ranging 'rom 12.0 to
O.075 mg/Xq. See Cance_ Che~othe aoY ~eDorts, Part ~,
3, 1 (l9t2~ fo~ a compr~her.sive discussion o~ the
protocol.
Utilizing tr.is procedure, t~e ~ollowinq results
were obtained for representa~ive compounds o,~ t~e .
inv~ntion.
~ - N-Z
;0 11
X-~ ~
O NR"
Cl.G-l -58- 3L2~L~7
:llq/'Cq ( Psrcent )
7~10 IC~)2I[CH2)2 ~ 2 2 2 2 ! s'25i2l4' 214
~ . 56 1 163
O . 78 1 lSl
7,iO (C8)z~ 2)7 IMe)~iNHlCH2~2NH2 1 6~5i215~ 192
1 . 56 t 194, 149
I 0. 78 1 194, 146
;OH~2itCH2~2N(Et~2~ CH2)2N~Et)2 jlOO ¦130~ 174
~2HC1 1 l 25 1140' 1454' 146
15................ 1132, 114 lSO
Ca2 ) 2N ~ _ ) 2 1 ~H ~ CH~ ) 2 ~ ['g2 ) 2 ] 2 ¦ 4 00 ! 211
2 22¦ ~ ~2)2NH~Cg2)~oHl 25 ¦197
~2~C11 1 1 55ll~2, 1i2. 146 15
J 1 0.781135
- ~ CLG-l -;9- ~24~
I N ~ Y ~ ~ 100
7,1~-(O:~2¦(CH~)2';E')2 l~;H(cH2)2~H(ca2)2oHl 12 S 2~, 212
I 2 HC l ~ ~ 35.25 ¦ 130, 180, 164
7,10 - (OH)21tc72)~ - )2 1 ( 2)2~H~e 0 391152 126' 1~9
2H3r 1 1 12.5 1 lgl
1 6.251163
7,10-~OH)2jl_H~)2NlEt), ¦ (Ca2~2NH2 ¦ 25 1179 Cures
2acl 1 12 5 230, 139 Cures
3.12 ~ 154, 160
)2l~c8~)2NHlc92)2~l~e)2lNH(c~2)2~H~cH2)2oHl 50 ¦226
1 12.5 1179,219
1 6.251198,191
7.10 - 1OH)2llc82)2~lca2)2oH ¦NCH3(CH2)2Nl~e!~ ¦ 12 5 199
1 28Cl I ~ 5.~51179
7~lo - (oH~ 2)2~8(cH2)2oH ¦N~C~2)212:~Me I 25 ~50
I -2C1 1 1 12 5 il69
H! ICH2)2N8~c~2)2o3 ¦NHlCH2)2U(~e)2 j 25 162
2~Cl I . 1 12 5 1166, '63
1 3,12l158
`- c~- :~2~8~97
-Sd-
~ ,~ _
m~ I Percent )
H) ~ i ~c~2)zNatcH2 )2oalNH~c~2 ) ~ e)2 ¦ 25 ¦ 88 Cure3
~29Cl ¦ 1 6 251165, 132
3.121 165,165
1 0 781152' 5
N¦~CH2)2NY;c~2)20HlNH(cH2)2~(E~)2 ¦25 ¦119
~ 2NC1 1 1 16 5 l lS0lS~, 158, 160
o--(aH~2 1 ~H2 )2~;H~c}l2 )2oHl ~iH ~cy2 ) 2 ( ) 2 ¦ 52 ¦ 2~1
-2HC1 1 ¦ 122 5 1l9O~ 209 Cures
6. 25 1 1;4168
3 . 12 1 148 lS0
1 1.56~131 135
21~ Y2)2NH(c32)2oHlNH(ca2)2NH(cy2)2~(He)2l so 1200~ 254 Cures
-2HC1 1 1 25 1 207, 228, 129
12 . S I lS~, 179, 188
6.251 lo9, 172
1 3.121152, 163
al(c~2)2NH(cy2)'~oHlNH(cH2)2:~H(c:~2)2o ¦ 5o ¦199
'CH3CO2H , ~3 ~ 1211 4 7 ~ lS 7, 16 3
C .G--1 -61- :~L24~30~37
_ , _ ., . _ ., _ . . _ . ~
X ¦ ~ ¦ NRY I Dose ¦ ~/C X 100
I Porcen ~ ) _
' O--~ O H ) 2 ~ i 2 ) 2 ~a ( c 3 2 ) 2 o ~ l NH ( c l 2 ) 2 ~ ( 2 2 ¦ 2 5 ¦ l S o l o 8
1 5.251206 Cures
3.121 la7, 137
1. 5~1 lSô, l~a
11 1CH2~2~;a(c~{2)20~lNHtcH2)2iH2 ¦ 25 1l39
2HC1 1 1 6 251146 180
1, 56 1 lS0
7,13--(oH)2 j (CB2 )2Na(C32 )~~1 ~H(c~2 )2NH2 i 1 56il73 197 Cure9
2HCl I 1 0 781182
2~ 2 2 ' 2 ¦ (CH2)3~1H(Ci2)20H¦36 15¦169 254 Cures
.2HC1 1 1 1.561201, 166
7~'U--(oH)2l(cH2~2`~(c~2)2o3l ~H(C82)3NH2 ¦100 ¦131 Cures
50 254, 272 Cures
2HC1 1 1 25 1207, 250 Cures
12. S 1 17~, 190
I 6.251165, 172
3.121 L65, 165
?,10--(OB)2~ 2)2NH(ca2)2;~H¦NH(CH2)1 2 1 25 jlS0, LS2
1 12.5 1139, l~S
1 6.251131
3.121 130
~lo - (o~)2~(c82)2:~a(c~2)2oHl 1H~cH2)s~H2 ¦100 1l50
2HCl I I L2. 5 1127
CLG-1 ~L~4~3~)97
X
NRY I Dose ¦ r/c 5! 100
cq I !?erc~nc~
~1 (Ca2)2~a2 ¦~(CH2)2~tC~2I2O~I 25 ¦1a7 187
I 2HC1 12; 173, 177
I 1 5 251153, 173
I 1 3 1211~9, 158
1 1 ;61139
7 10 - ~OH~ ¦t-82)2X~2 jj 1 2)2 ~(C~ 1 ONj 125 5 l257 Cures
1 6 251~63
I j 1 3 121160
1 1 S5~ 153
7~10-(~ -9 ) OH ¦ 2 2 2)20HI1500 l139 140
1 25 1127, 131
1 12 5 1127
~1a-(OH)2I(CH2I2Ot j~H(Ca2)2X(~e)2 l200 ¦157~ 233 Cures
I 2HC1 1 100 225, 242
I ! 1 25 ll153 1572 132
7 10 - 10H)2j(CH2)20~ ¦N~(C~2)~N(~t~2 1 12 5 1124, 135, 139
I 2~C1 1 300 177
~ j j 150 j 155
1l00 11~9
Ij 1 75 1135
1 37 5 1135
1 25 1123
' 1O - ~OH)2ItC~2)2Oa ¦N~tC:~2)2NHtC~2)2O~j2OO ¦196, 271
I ~C1 1 100 172, 134
I 50 1163, 155
1 25 1165, 37
1 12 5 1158 163
1 6.251143, 163
.
~ o~ -
o~
X ~ ose I ~/C X 100
ma~clIPerc~nt)
1(C32)2Oa ~Y~IC~I2~YH2 11OO ¦172, 196
.2HC1 ; 162, 172
25 l 146, 154
1 12.5 l145, 151
6. 25 l 135
7 1 - (0H ) 2 ~ H2 I 2S:te l ~;H ~ CH2) 2NH ( C~2 ) 2OH ¦ 12.5 132
2HC1 6 25¦140
7~1O - (~H~23CH2CHOHC82~q(rt)2 IYH~Ca2)2N(Ee~2 ~100 157
2!iCl I I S0 l 131, 135
S l 131, 135
I2. S ! 128
2il 2 !1 HC92Y(Et)2 I IH~C82~2N8(C~2~2O8 ¦ 12.5 j182, 223 Cures
-2HC1 1 6.25 128, 203
! 3.12l129, 188, las
1 1.56l139
1 0.7ail32
7 10--(O8~21CR2CHOHCR2q(-~2 ~Na(CR2~2N82 ¦ 12.5 142, 210
.2HC1 j 6.25I166, 189,
1262 Cures
3.12l 166, 182, 202
l.Sol 157, 1~6
1 0.78l132, 173
1 0.3sll3s
7~10--(CH)23~e ¦NH(C~2)2nH(CH2I2ON 1100 174
50 1162~ 154
1 25 1 150, 16C
1 12,5 l140, lS9
6.25 l 133, 155
3.12 l 133
I C32C92NH2 jNHC82C92~H2 j 25 ¦ 156, 218
1 12.5 l144 203, 221
7,10 (OR)2! C~2C82~Y~e2 1 2 2CH2nH2 - I 12.5 1205, 208
6.251196 Cures
2 jC32CH2C82~~e2 INHCH2CH2NHCH2CR2OH j 12.5 ~1218, 203
1 6.25l185 167
7~10--(O~9)2!CH2CH(OH~CR2OH ¦N8C:~2CH2~YHC82CR2OH 14 j281 255
I 200 ; 218 213
~l 150 l 208 194 CUreS
1 25 1184, 166
.28C1 ¦ 2C82CH2YH2 ¦ 25 ¦194~ 212
1 12.5 l173 180
1 6.251l67 l73, 190
.28C1 ¦NHCH2CH2NH2 ¦ 12.5 ¦224 CU
1 6.25 l 186 200
¦C32CH2NMeC82CH20H ¦NHCR2CH2YHCH2C32O8 ; 12 5 l203
1 6.251l82
3.12 l 184
,1 (o~)2ilcH2cH2NHc82cH2oH ¦nH(c~2~3~ 82c820H~2lloo ¦192
1 50 l 167
1 25 l 163
1 (OH)2~C32C92nHCH2CH2OH jNHCH2 H2YHCH2CH2nH2 ¦ 25 j221, 227 CUr9S
12. S 1233 231 Cures
6.25; 194 157
-64-
C ~ -! ~L24~30~7
X ; 7 I NRY
IDOSe I T/C ~ loo
. ~OH)2 ¦~2 ~2NHCH2 H2 Y INnC~2 H2 ~(CH2CH2OH)~ mq;cq ~ ~ ro~lr.)
1 50 1203, 169
I 1 25 ~187, 194
1 12 5 115a 166
2 1 2 2 CH2-~20H I~H~CH2)3~H(CH2)~H(C~2)3Na2I 12 5 l145 117
~OH)2 I(C~2;3~HCa2-H2OH ¦NHCH2CH2NHCH2CH2OH I 6 251127 L09
I 1 50 1222 183
I I 1 25 1183 174
1 tOH)2 i( H2~3;HC~2 ~20~ INHCH2Ca2C~2Na2 1100 1l85 155
1 50 1160, 146
7 10 (OH)2 ICa2^H2 HCH2CH2CH j~nCH2~2~HCH ¦ 6 25¦277 275 CUr S
10 tGH)2 ICa~C~2 H2 ¦NHCH2CH2NHCH2CH2~Me2 1 3 121263 177 CUreS
1 25 1192 17?
2 1 2CH2 H2 1 2 2 2 HCH2CH2OH I 12 5 1196 LS7
1 3 1-21177 194
?~1O-tCH)2 ¦C~2CH2CH2~H2 ¦~HCH2CH2NHC~2CH2OH I 50 ¦235 cùres
- I 25 1235 cures
1 12 5 1247 163 cures
7,1 --toH)2 ¦cH2cH2cH2~H2 ~ lNacH2c~l2NHcH2cH2 ~Me2 `- I
7 10 t0~2 C~2CH2NHCH3 ¦N~CH2C~2NHC~2CH2ON I L2 5 IL47
7-OH jC~2CH2 HCH2CH2OH I~HC~2CH2NHCH2CH2GH
¦ 25 ¦285 184 CUreS
I I 1 12 5 1223 142 C1reS
1O-qH ¦CH2C~2NHCH2~2O~ INHC:~2C~2NHCH2CH ~H
11OO l221 184
1 50 1172, 162
7 8 1O-tOH)3ICt2CH2NHC~2CN2O~ INHCH2CH2NHCH CH OH
I 25 ILS3 155
-O-~Oa)3ICH2CH2~HCH2CH2OH INHCH2 H2NHCH2CH2OH
I 3 12lL65
1 1 5611;~
~L2413~7
CLG~ 5--
e I 5 ~' z z' v '
X = O O ~ ,
CLC-I -66- ~ g7
9road SD~cerum ~ntLtumor ~cti~itv~ of 2-[2-(Diethvl-
a:nino)eth~¦-~,10-dLh.ydroxv-~ 2-[~2-hvd-3~v~t'lvl)-
a::lLnole~~vll2~Lnol2nthra[1,9-cdl~ovrazol-612H;-on2
DLhvdr~c~loride :n ~ice
HO N - N(CH212~Et~ 2
2HC1
~W
OH o NH(C~)2NH(C~2)2oH
IOrua I l(~9r~cq)i(~ercenc)l~eduction
.~ W -P~S Plas~acytoma IIP/IP IQO4Dx03l 16 1 163
I I 1 8 1 235
I I I ~ 1 216
I I 1 2 1 20~ 1
3!6 .~elanoma (BDF1) II?~IP 1001DXOgl 3 1 176
151
3L6 elanoma ¦~P~IP IQO1DXO9! 6 1 39
Colon 33 (aDF1~ ¦SC~IP ¦QOlDxO90 16 ¦ 1 71
L1210 ~euke~ia (CDFl)lIP~IP IQOlDxQ9l 16 ¦ 133
I I 1 8 1 2~0
-I I 1 4 1 178
I I 1 2 1 1~4
I I 1 1 1 13~ 1
~5076 Ovary ¦IP/IP IQ04DxOSI 10 1 260
I I I 5 1 186
I I 1 2.5 1 233
I I 1 1,251 143
~Procedur2 desc:it!2d in Cancer Che~otheraoy F2views, 7
167 (1980) and re~e:ences ciee~ therein.
~24~
C~G-l -67-
In addi'ion to their userulness as anti~iotic and
a.~ei~ur.gal agents and as antileukemic agents, cer_a~n
o~ the com30unds o'. the invention display in vitro
activity agair.st solid tumors when eested by the
follo~inq procedure7
~ CT~ ~human colon adenocarcinoma) cells are
t_v~sinized using T~ypsin-EDTA. ~ single cell
suspension is ac~ieved by ~assing t~le cells th-ough a
26 gause needle wi~h a 20 cc syringe, ~ cell
susp~nsion is ~r~pared usinq RP~I 16~0 srow;A m~dium
tavailable ~ro~ Gibco Laboratories) + 10~ fetal calf
s2rum ' 50 ~q/ml garamycin wi~h a c~ll concentratlon
o approxima~ely 30,000 cells/~l. The cell suscensicn
is dis?ensed in ~inbro 2~-well plates; 1 ml/well. The
Dl ates are incub2ted 'or ~pDrOximately ~a hrs at 37C
in a 5~ C02 at~osohere, ~t t~is time tes~ compounds
are added in the ap?ropr~ate concent.at.on~ Five ~1
o the 2C0 ~g/ml s~ock solution is added t~ ~each
~ell in a primary tese. Ten ~1 of the ap~ropriate
dilution is added to each well 'or a titration test,
The plates are reincubated an additional 60-65 hrs at
3/C in a 5~ C02 at~osphere~ The test is read by
lysing ~he c211s usin~ a mix of cationic surfactant,
glacial acetic acid aQd sodium chloride. Two ~.1 0c
the lysed cell sus~ension from eac:~ ~ell is addPd eO
8 ml of diluent, Facn sample is read with~a Coult~r
counte- ~23I ~odel~. ~he ac_ivity of each sample is
measured as a percentage of the con'rols and the da~a
is -eported as IDso, that is ehe molar quantiey Or
drug re~uired to kill 50% of the tumor cells,
U~ilizing ~his procedure, th~ follo~ing resuLts
dere obtain~d or r~resenta~ e com~ounds of e'~e
in~Jen~ion~ '
~24~ 97
C;l~--1 --68--
In Vitro ~ctiviey o~ Aminoanthraoyrazoles
Agalnst Human Colon ~denocarc~no~a
N- Z
10 11
Yl tC!}2~2~1Et2 ! ~ 2)2~iEt2 1 1.4 x 10--7
3 IN~C~2~2NEe2 ¦ ~.1 x 10--7
-H ¦ tC~2 ~ OH I NEI(C~2 )2NEt2 1 1. 8 x 10-6
IICI ¦Na~CH2~2NH~C82~20~¦ 1.5 X 10-6
3 ¦ NH t C~ 2 ) 2 N H t Ca 2 ~ 2OH ¦ ~ . 0 z 10 - 7
tCH2~2~Et2 1 ( 2~2N~2 1 5.2 x 10-a
I ( 2 )2~B(C~2)2H IN~ 2 )2NH(C~}2)OH ¦ 9~6 x 10--7
CH3C0211 1, ,~ _
~L2~ 7
C~G--1 --59--
X! ~ i NRY I ~Ds~ ~oL~r
Ht tcd2) H(CH2)20H¦NH(Cd2)2~d2 1 ~.2 x lo--B
Ht (C~2 )2~Htc:~2 )2oHlNll(c82 !2 ~Et2 ¦ 1. 2 x 10--7
2aCl l I
t ~ 2)2 H(C~2)20dl ~HtcH2)2.NMe2 ¦ 2.3 x 10--7
1}¦ (Cd2)2~1a(cd2)2odlN8cd3 ¦ 2.3 x lQ--7
~2HCl INH(Cd2)3~t2 1 4.8 x L~--7
¦ ( 2)2 -e2 ¦ (C 2)2N~_~o 1 1.2 x lD--7
(C~2 )2NEt2 ¦~a(Ca2)3:1Et2 ¦ 1.8 x 10--7
~ 2~Cl
H¦ (CH2)2NEt2 ¦N-d(cd2)~NEt2 1 2.2 x 10--7
. 2~Cl l I
H¦ (CH2)2YE~2 IYH~c~l2)~NEt2 ¦ 2.2 x 10-6
¦ (Cd2 )2NEt2 ¦ ( 2 ) 2N~NH ¦ 3. B x 10-7
2~ C 1 ¦ NH ( C~ 2 ) 2 Nd ( C d 2 ) 20H ¦ 6 . 8 x 10 -8
. _
C~ 70- ~2~ 9~
I
X I ~ ¦ NRY I ;D5~ ~olar
7,10-~CH~2j(-12)2~E~2 1 ~ 2)2 ~CH2)2H¦ 2-7 x 10
I 2~Cl l I
?~Lo-loH12l(c~l2~2~E~2 ¦NH~C:~2)2,~Ee2 ¦ 5.4 x 10-7
1 2HCl l I
7~lo-loH)2l CH3 ¦NH~CH2~2NHIC~20Hl 7.9 x 10-7
~HCl ~ ~
-lH)~!(c~2)2~Et2 ¦ ( 2)2 H2 ¦ 8.8 x 10-7
1 28Cl
7~1D-loN)2l(cH2)2NEt2 INH(CH2)2NH~e ¦ 1.2 x 10-7
~2H3r
~)2~ H2)2NMe2 ¦NH(CH2)2~H(C~2)20~¦ l.a x 10-7
-2~Cl
-(OH)2¦ C~2c~oHcH2~Et2 INH(cH2)2NH2 ¦ ~.5 x 10~7
1 ~2HCl
7-1--~03)2; C~2cHoHc~2:iEt2 INN(CH2)2NH(
~ 2Ncl ~ ~
2,( 2~2~ ¦NH(CH2)2N~Ye2 ¦ 1.7 x 10-7
- :~1 1 1 .
(oH~2l~ca2~2~xe2 1 ( 2)2NH2 ~ X 10--7
~2~Cl
~,lD ~Oa~2¦(CH2)2~g2 ¦~H(CH2)2~H(CH2~2OH¦ 1.7 x 10-6
~ 8~
CLG-l -71-
NRY I ID50 .~lold~
7,10-[OH)2~(~H2)2~tC 2~2 I N__~ 3 j ;.~ X 10-7
7~10-~oH!2ltcd2~2NH2 ¦ !c82)2Na2 ¦ 9~1 x 10-7
1 ~2HC' I
7~l-(oH)2l(-H2)2~Me2 1 ~ 2)3 H2 ¦ 1.1 X 10-6
1 ~2HCl
¦ ~1HCl ! NH(CH2)3NH2 ¦ 3.5 x 10-7
7~lo-(oH)2~c~q2cH2cH2N~2 ¦N~c~2cH2NHcH2c~q2oH I 9.2 X 10-3
1 ~2HCl
~lo - (o~ll)2lcx2cd2`Mec~q2 - ti2oHlNHcH2cH2NHcH2cH2o
1 1.6HCl
7~1o-(oH)2lc~2cH2NRcd2~q20H INHCH2CN2~NCH3 ¦ 4.0 x 10-7
I 1.8BCl
7~'-(H~21CH2a~2~H2 ¦NHcH2cH2~c~q2cH2~e2l 1.2 X lo-6
1 ~3.3HCl
~2.1HCl ¦NH(CH2)3NHCH2CH2oH ¦ 2.8 X 10-7
2~ 2 2NB2 ¦ 2C 2Cq2Nd2 1 8.5 x 10-7
I 2.9HCl l I
-7,~o_~oH)~lc~d2cH2cN2~H2 ¦ 2 2 2Cq2OH I 7.7 X 10
~2HCl
(od)2lcH2cH2NHcd3 ¦NHcH2cH2NHcH2~q2oH I 2.3 X 10-7
~2HCl
¦ 2CH2N~CH2CH20H ¦NHcH2cH2NHcH2cH2oH I 6.1 X lo-8
1 2CH2NHCa2CX20H ¦NBcH2cH2~HcH2~H2oH ~ 1.1 X 10-6
7-oH!s~d2cd2NHc`q2c~q2oH ¦NHcH2c~q2NHY I 2.7 X 10-8
1 ~1.8HCl l I
~2~ 37
CLG--1 -72--
N - N-Z
NRY O
Z ¦ NRY ¦ IDso Molar
I
(CH2)2N~t2¦ NEl(CHz)2NEt2 ¦ 2.2 x 10--7
2HCl I ¦
2 ) 2~Et2 ¦ NEI (C~2 ) 2Nd (C~2 ) 20H ¦ 9 . 3 x 10--8
2HC
I
CTIG-l -73-
When being utilized as antibiotic and antifungal
agents, the compounds of the invention can be prepared
and administered in a wide variety of topical, oral,
and parenteral dosage ~orms. It will be clear to
those s~illed in the art that the .ollowing dosage
forms n~y comprise as the active component, either a
compound of formula I, certain of the compounds of
lormula II or a corresponding pharmaceutically
acceptable salt of one of said compounds or a mixture
of such compounds and/or salts.
For preparing pharmaceutical compositions from
the compounds described bv this invention, inert,
phar~aceutically acceptable carriers can be either
solid or li~uid Solid form preparations include
powders, tablets, dispersible granules, ca?sules,
cachets, and suppositories. ~ solid carrier can be
one or more substances which may also act as diluents,
flavoring agents, solubilizers, lubricants, suspending
agents, binders, or tablet disintegrating agents; it
can also be an encapsulating material. In powders,
the carrier is a finely divided solid which is in
admixture with the finely divided active compound. In
the tablet the active compound is mixed with carrier
having the necessary binding properties in suitable
proportions and compacted in the shape and size
desired. The powders and tablets preferably contain
fro~ 5 or 10 to about 70 percent of the active
ingredient. Suitable solid carriers are magnesium
car~onate, magnesium stearate; talc, sugar, lactose,
pectin, dex,rin, starch, gelatin, tragacanth, methyl
cellulose, sodium carboxy~ethyl cellulose, a low
~elting wax, cocoa butter, and the like. The term
"preparation" is intended to include the formulation
of the active compound with encapsulating material as
carrier providlng a c~psule in which the active
component (with or withou~ other carriers) is `
8~)97
CLG-l -74-
surrounded by carrier, which is thus in association
with it. Similarly, cachets are included. Tablets,
powders, cachets, and capsules can be used as solid
dosage forms suitable Eor oral administration.
Liquid form reparations include solutions,
suspensions, and emulsions. As an example ~2y be
mentioned water or water-propylene glycol solutions
for parenteral injection~ Liquid preparations can
also be formulated in solution in aqueous polyetbylene
glycol solution. Aqueous solutions suitable for oral
use can be prepared by dissolving the active component
in water and zdding suitable colorants, flavors,
stabili~ing, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made
by dispersin~ the finely divided active component in
water with viscous material, i.e., natural or
synthetic gums, resins, methyl cellulose, sodium
carboxy~ethyl cellulose, and o~her well-known
suspending asents.
Topical preparations include dusting powders,
creams, lotions, gels, and sprays. These various
topical preparations may be formulated by well k~own
procedures. See for example Remington's Pharmaceu-
tical Sciences, Chapter 43, 14th ed. 1970, Mack
Publishing Co., Easton Pennsylvania 18042, USA.
Preferably, the pharmaceutical preparation is in
unit dosage ~orm. In such form, the preparation is
subdivided into unit doses containing appropriate
quantities of the active component. The unit dosage
orm can be a ~acXaged preparation, the package con-
taining discrete quantities of preparation, or
example, pac~eted tablets, capsules, and powders in
vials or ampoules. The unit dosage form can also be a
capsule, cachet, or tablet itself or it can be the
a propriate number of any of these packaged form.
~24~3~97
CLG-l ~75~
The quantity of active compound in a unit dose of
preparation may be varied or adjusted from 50 mg to
500 mg according to the particular application and tne
potenc~ of the active ingredient.
In therapeutic use as antibiotic and antifungal
agents tne compounds utilized in the pharmaceutical
method of this invention are administered at the
initial dosage of about 0.1 mg to about 50 mg per
kilogram. A dose range of about 0.5 mg to about 10 mg
per kilogram is preferred The dosages however may
~e varied depending upon the requirements of the
patient the severity of the condition being
treated and the compound being employed. Determi-
nation of the proper dosage for a particular situation
is ~ hin che s~ill of the ar-tl Generally, treatment
is initiated with smaller dosages which are less than
the optimum dose of the compound. Thereafter, the
dosage is increased by small- increments until the-
~optimum effect under the circumstances is reached.
For convenience, the total daily dosage may be divided
and administered in portions during the day i
~esired .
The active compounds may also be administered
p~renterally or intraperitoneally. Solutions of the
active compound as a free base or pharmaceutically
acceptable salt can be prepared in water suitably
mixed with a surf3ctant such as hydroxypropyl-
cellulose. Dispersions can also be prepared in
gl~cerol, liquid polyet~ylene glycols, and mixtures
thereof and in oils. Under ordinary conditions of
storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable
use include sterile aqueous solutions or dispersions
and sterile powders f~r the extemooraneous preparation
of sterile injectable solutions or dispersions. In
all cases the form must be ste.ile and must be fluid
~8~g7
CLG-l -76-
to the extent tnat easy syringability exists. It
must be stable under the conditions of manufacture
and storage and must be preserved against the
contaminating action of microorganisms such as
bacteria and fungi. The carrier can be a solvent
or dispersion medium containing, for example, water,
ethanol, polyol ~for example, qlycerol, propylene
glycol, and liquid polyethylene glycol, and the like),
suitable ~ixtures thereo~ and vegetable oils The
proper fluidity can be maintained, ~or example, by the
use of a coating such as lecithin, by the maintenance
of the required particle size in the case of disper-
sion and by the use of surfactants The prevention of
the action of microorganisms can be brought bout by
~arious antibacterial and antifungal agents, îor
example, parabens, chlorobutanol, phenol, sorbic acid,
thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example,
sugars or sodium chloride. Prolonged absor2tion of --
tbe injectable compositions can be brought about by
the use in the compositions of agents delaying
absorption, for example, aluminum monostearate and
gelatin.
Sterile injPctable solutions are prepared by
incorporating the active compound in the required
amount in the appropriate solvent with various of the
other ingredients enumerated above, as required,
followed by filtered sterilization Generally~
dispersions are prepared by incorporating the various
sterilized active ingredient into a sterile vehicle
~hich contains the basic dispersion medium and the
required other ingredients from those enumerated
above. In the case of the sterile powders for the
preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and
tbe freeze-drying technique which yield a powder of
`; the active ingredient plus any additional desired
CLG-l -77- ~248097
ingredient ~rom a previously sterile-filtered solution
'hereof.
As used herein, "pharmaceutically acceptable
carrier~ includes any and all solvents, dispersion
media, coatings, antibacterial and antifungal agents,
isotonic and absorption delaying agents and the like.
The use OL SUC.A. media and agents for pharmàceut-cally
active subs.ances is well known in the art. Except
insofar as any conventional media or agent is
incompatible with the active ingredient, its use in
the therapeuiic compositions is contemplated.
Supplementary active ingredients can also be
incorporated into the compositions.
It is es~ecially advantageous to formulate
~arenteral composi.ions in dosage unit form for ease
of administra.ion and uniformi.y of dosage. Dosage
unit form 2S used herein refers to physically
~iscrete units suitable as unitary dosages for the
mammalian subjects to be treated; each unit
containing a predetermined ~uantity of active
material calculated to produce 'he desired therapeutic
eFfect in association with the required
pharmaceutical carrier. The specification for the
novel dosage unit forms of the inventio~ are dictated
by and directly dependent on (a) the unique
characteristics of the active material and the
particular therapeutic effec- to be achieved,'and (b~
the limitation inherent in ~he art of compounding such
an active material for the .reatment of disease in
living subjects having a diseased condition in which
bodily health is impaired as herein disclosed in
detail.
The principal active ingredient is compounded
~or convenient and eEfective administration in
effective amounts with a suitable pharmaceutically-
acce~table carrier in dosage unit fcrm as hereir.before
disclosed. A unit dosage form can, for example,
CLG-l -78- ~2~9~
contain the principal active compound in amounts
ranging from about 0.1 to about ~00 mg, with from
about 0.5 to about 250 mg being preferred. Expressed
in proportions, the active compound is generally
present in from about 0.1 to about S00 mg~ml of
carrier. In the case of compositions containing
supolementary active ingredients r the dosases are
dete.mined by re.erence to the usual dose and the
.~anner of administration of the said ingredients. The
daily parenteral doses for ma~malian sub~ects to be
treated ranges from 0.1 mg/kg to 100 mg/kg. The
?referred aaily dosage range is 0.3 mg/kg to 10 mg/kg~
The following nonlimiting examples illustrate the
inventors' preferred methods for preparing the
com~ounds of the invention.
0~7
C~G-l -79-
EXAMPLE 1
2-[2-(Diethylamino)ethyl)]-5-[[2-(diethvlamlno)ethyl]-
amino]anthra[l,9-cd]pvrazol-6(2H)-one
A ~ixture oE 1.2 g ~3.4 mmol) of 5 chloro-2-[2-
(diethylamino)ethyl~anthra[l,9-cd]pyrazol-6(2X)-one~
1.0 g (8 mmol) of N,N-diethylethylenediamine, about
1 mg of anhydrous cuprous chloride and 30 ml of
anhydrous 2-ethoxyethanol is heated at reflux under
argon. After seven hours, an additional 0.5 g
(4 mmol) of the diamine and about 1 mg oE catalyst is
added and the mixture is reEluxed for 23 hours,
cooled, and concentrated~ The residue is dissolved in
dichloromethane, washed successively with water,
dilute ammonium hydroxide, and brine. Chromatography
of the dried dichloromethane layer over silica g~l
with 10:1:89 methanol:triethylamine:dichloromethane
provides the purified product. Dissolution in hot
2-propanol rollowed by t-eatment with excess hydrogen
chloride in 2-propanol a~fords 1.2 g o the dried
product as a salt with 2.1 equivalents of hydrogen
chloride solvated with 1.2 equivalents o~ water; mp
262~276C (decomposition).
;-Chloro-2-~2-(diethylamino)ethyl]anthra[l,9-cd]-
p~razol-6(2~)-one is prepared as follows:
~ mixture of 4.15 g (15 mmol) of 1,4-dichloro-
9,10-antAracenedione [J. Amer. Cnem. Soc. 48, 3198
(192~)] 2.6 g (20 mmol) of (2-diethylaminoethyl)-
~drazine 1_. Med~ Chem., 1; 493, (1964)1, and 35 ml
oE pyridine is hea~ed at reflux for ten hours, cooled,
and concentrated~ The residue is dissolved in
dichloromethane and washed with water. Chromatography
oE the dried dichloromethane layer over silica gel
wi~h ethyl acetate and then 95:5 ethyl
acetate:methanol affords 3.8 g oE a solid whose
crystallization from 2-propanol gives 2.9 g of pure
material; mp 90-92C,
12~8()~
CLG~ ~
Dissolution of 0 89 g of the product in hot 2-
propanol ollowed by treatment with excess hydrogen
chloride in -propanol affords 0.9 g of the
hydrochloride salt; mp 263-266C (decomposition).
E~XP,MPLE 2
2-[2-(Diethylamino)ethyl)]-5-[[2-[(2-hydrox~ethyl)-
amino]ethyl~amino]anthra[l,9-cd]pvrazol-6(2H)-
one
A mi~ture of 2.5 g (7.1 mmol) of 5-chloro-2-[2-
(diethylamino)ethyl]anthra[1,9-cd]pyrazol-6(2~)-one,
1 g (9 mmol) of 2-(2-aminoethylamino)ethanol and
catalytic amounts of anhydrous cuprous chloride and
potassium iodide in 25 ml of anhydrous 2-ethoxyethanol
is neated at reflux under argon. Additional 0.5-1.0 g
portions of ~he amine and catalytic amounts or the
nalide salts are added after six and 12 hours,
res?ectively. A.ter a total reflux time of 30 hours,
the ~ixture is worked up as descri~ed for Example lr
with purification on silica gel utilizinq first
10:1:89 and then 15:1:84 methanol:triethylamine:ethyl
acetate. ~ollowing treatment with hydrogen chloride,
~here is obtained 1.1 g of the dried pro2uct as a salt
~ith ~.0 equivalents of hydrogen chlori-de solvated
with 2.4 equivalents of water; mp 239-241C
tdecomposi.ion).
EX~LE 3
5-~(2-Aminoeth~l)amino~-2-[2-(diethvl2mino)ethvl]-
anthra~l,9-cd3~vrazol-6(2H)-one
A mixture of l.S g (~.5 ~mol~ of 5-chloro-2-[2-
(diethylamino)ethyl]ar.thra[l,9-cd]pyrazol-6(2H)-one,
2.5 ml of anhydrous ethylenediamine, and 25 ml of
anh~drous pyridine is heated at reflux under argon for
seven hcurs, cooled, diluted with toluene, and
concentrated. The solid residue is dissolved in
dichloro~ethane, washed with water, znd then brine.
Chromatography of the dried dichloromethane layer over
silica gel with 1:9 methanol:dichloromethane ~rovides
~248097
CLG-l -81-
0.8 g of the product. Dissolution in hot 2-propanol
followed oy treatment with excess hydrogen chloride in
2-prooanol a~ords l.G ~ o~ dried product as a sait
with 2.0 equivalents of hvdrogen chloride solvated
with 1.8 equivalents of water; mp 276-279C
(decomposition).
The following compounds are prepared as described
in Example 3 from 5-chloro-2-[2-(diethylamino)ethyl~-
anthra~l,9-cd~pyrazol-6(2~)-one and the correspondin~
amine:
EX~!PLE 4
2-[2-(Diethylamino)ethyl]-[[2-( -mor?holinyl)ethyl)]-
2mino]anthra[1,9-cd]Pyrazol-6(2~)-one
Reaction with ~-(2-aminoetnyl)morpholine gives
the product as a salt ~ith 2.0 equivaients of hydrogen
chloride solvated with 1.2 equivalents of water; mp
2B8-290C (deco~position).
- EX~PLE 5 - ~
2-[2-(Diethylamino)ethyl]-5-[[3-(diethylamino~orooyl]-~ -
amino]anthra~l,9-cd]pyrazol-6(2H)-one
Reaction with N,N-diethyl-1,3-propanediamine
gives the product as a salt with 2.0 equivalents o~
hyarogen chl~ride solvated with ~.2 e~uivalent of
water; mp 270-272C (decomposition).
EX~`lPLE 6
2-~2-(Diethylamino)ethyl]-5-[[7-(diethYlamino)heP.vl]-
amino]anthra[l,9-cd]pyrazol-6(2H)-one
Reaction wi-th N,N-diethyl-1,7-heptanediamine
gives the produc-t as a salt with 2.0 equivalents of
hydrogen chloride solvated wi.h 0.3 equivalent of
water; mp 190-192C (decomposition).
EX~MPLE 7
5-[[4-(Diethylamino)butyl]amino]-2-[2-(diethylamino-
ethyl]anth.a[l,9-cd]pvrazol-6(28)-one
-
Reaction wi~n N,N-die~hyl-1,4-butanediamine gives
the product as a salt with 2.0 equivalents oE hydrogen
-82-
chloride solvated with 0.7 equivalent of water;
mp 243-246°C (decomposition).
EXAMPLE 8
2-[2-(Diethylamino)ethyl]-5-(hexylamino)anthra[1,9-
cd]-pyrazol-6(2H)-one
Reaction with n-hexylamine gives the product as a
salt with 1.0 equivalent of hydrogen chloride solvated
with 0.1 equivalent of water; mp 176-179°C
(decomposition).
EXAMPLE 9
2-[2-(Diethylamino)ethyl]-5-[(2-(1-piperazinyl)ethyl)-
amino]anthra[1,9-cd]pyrazol-6(2H)-one
Reaction with 4-(2-aminoethyl)-1-piperazine
carboxylic acid, benzyl ester, the hydrolysis of the
isolated intermediate with hot 48% hydrobromic acid in
acetic acid gives the product as a salt with 3.3
equivalents of hydrogen bromide solvated with 1.4
equivalents of water and 0.1 equivalent of acetic
acid; mp 284-287°C (decomposition).
4-(2-Aminoethyl)-1-piperazine carboxylic acid,
benzyl ester, is prepared from 4-(2-aminoethyl)-1-
piperazine by a procedure analogous to that described
for the preparation of (2-aminoethyl)-methylcarbamic
acid, benzyl ester, in US Patent 3,931,268; 1H NMR
(deuteriochloroform); .delta. 2.78 (triplet), 5.08
(singlet), 7.30 (singlet).
EXAMPLE 10
5-[[2-(Diethylamino)ethyl]amino]-2-nethylanthra(1,9-
cd]pyrazol-6(2H)-one
A mixture of 1.88 g (7 mmol) of 5-chloro-2-
methylanthra[1,9-cd]pyrazol-6(2H)-one [J. Chem. Soc.,
1630 (1952)], 1.2 g (10 mmol) of N,N-diethylethylene-
diamine, 0.14 g of anhydrous potassium fluoride, and
10 ml of dimethylsulfoxide is heated at reflux under
argon for four hours, cooled, diluted with water, and
extracted with dichloromethane. The dichloromethan
extract is washed twice with brine and then with 5%
~ ~4~
CLG-l -83-
aqueous hydrochloric acid. The acid solution is
washed with dichloromethane, made basic with sodium
carbonate, and extracted with dichloromethane. The
dried dichloromethane layer is clarified with
charcoal, filtered, and concentrated to a residue.
The salt was made as described :in Example 3 to afford
1.1 g of the dried product, after thorough washing
with ether, as a salt with 1.8 e~uivalents of hydro~en
chloride solvated with 0.7 equlvalent of ~ater;
mp 260-264C (decomposition).
EXAMPLE 11
5-[~2-[(2-H~droxyethyl)amino]ethyl]amino]-2-meth~l-
anthra[l,9-cd]pyra~ol-6~2H)-one
A mixture of 1.75 g (6O5 mmol) of 5-chloro-2-
methylar.thra~l~9--cd]pyrazol-6(2H)-one, 6 ml (59 ~mol)
o~ 2-(2-aminoethylamino)ethanol, catalytic amounts of
anhydrous cuprous chloride and potassi~m iodide, and
25 ml of 2-~ethoxyethanol.i~.heated ai.reflu~ .under ,~
argon for four hours, cooled,.and~.concentrated. ~he... ~. --.
residue is dissolved in dichloromet~ane, washed with
water, and then with 5~ aqueous hydrochloric acid.
The acid solution is washed with dichloromethane, made
basict and extracted in.o dichloromethane
Chromatography of the dried dichloromethane extract
0~7er silica gel with gradient elutior. employing 5-15%
methanol in dichloromethane provides the purified
product. The salt was made as described in Example 3
to afford 0.69 g of the dried product as a salt with
1.0 equivalent of hydrogen chloride solvated with G.l
e~uivalent of water; mp 270-272C (decompcsition)
EXA~PLE 12
2-(2-Hydroxyethyl)-5-[[2-[t2-hydroxy~thyl)amino]-
.
ethvl)amino]anthra[l,9-cd]PYrazol-6~2H)-one
A mixture of 896 mg ~3 mmol) o 5-chloro-2-(2-
hydroxyethyl)anthra[l,9-cd]pyrazol-o(2H)-one, 3.1 ml
(30 mmol) of 2-(2-aminoethylamino)ethanolr and 6 ml o~
an`nydrous pyridine is heated a~ reflux under argon for
- 84 ~ 0~7
8.5 hours, cooled, and concentrated to leave a residue.
Trituration from ether:2-propanol leaves a gummy solid
which upon further trituration from methanol-ether provides
851 mg of the product. Dissolution in chloroform followed
by treatment with excess hydrogen chloride in 2-propanol
affords 923 mg of the dried product as a salt with 1.6
equivalents of hydrogen chloride solvated with 0.5
equivalent of water; mp 267-272 C (decomposition).
5-Chloro-2-(2-hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)-
one is prepared as follows: -
A mixture of 5.54 g (20 mmol) of 1,4-dichloro-9,10-
anthracenedione, 2.2 ml (33.3 mmol) of (2-hydroxyethyl)-
hydrazine and 20 ml of dry pyridine is stirred at 60C for
32 hours and concentrated. A solid residue is triturated
with ether and then crystallized from chloroform to give
3.58 g of product; mp 209-211 C. Processing of the mother
liquor affords 0.21 g of additional product; mp 208-210 C.
EXAMPLE 13
C2-(Diethylamino)ethyl]amino]-2-(2-hydroxyethyl)-
anthra[l,9-cd]pyrazol-6(2H)-one
Reaction of 896 mg (3 mmol) of 5-chloro-2-(2-
hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)-one, 4.2 ml (30
mmol) of ~ diethylethylenediamine, and 6 ml o~ anhydrous
pyridine as described in Example 12 gives 1.02 g of the
dried product as a salt with 1.75 equivalents of hydrogen
chloride solvated with 0.5 equivalent of water; mp 199-205 C
~decomposition).
The following compounds are prepared as described in
Example 12 from 5-chloro-2-(2-hydroxyethyl)anthra[l,9-cd]-
pyrazol-6(2H)-one and the corresponding amine:
~2~39~
CLG-l -85-
E~PLE 14
~-(2-Hydroxyethyl)-5-[[2-(4-morpholinyl)ethyl~amino]-
[ 1, 9-cd ] ~vra zo 1- 6 ( 2EI ) -one
~ . . .
~ eaction with 4-(2-aminoethyl)morpholine gives
the product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 0.5 equivalent of water;
mp 260C (decomposition).
EXAMPLE 15
5-~[3-(Diethylamino)pro~vl]amino]-2-(2-hvdroX-~eth~
anthra[l,9-cd]pyrazol-6(2H)-one
Reaction with N,M-diethyl-1-1,3-propanediamine
gives the pro2uct as a salt with 2.0 equivalents of
hydrogen chloride solvated with 0.5 equivalent of
water; mp 201-210C (decomposition)O
EXAMPLE 16
5-[[4-(Diethylamino)butyl]amino]-2-(2-hydroxyethyl)-
anthrarl,9-cdlpyrazol-6(2H)-one
-- - - Reaction with ~,N-diethyl-1;4-propanedi-amine
- gives the product as a salt with l.9 equivalents
oE hydrogen chloride solYated with 1.0 equivalent
oE water; mp 155-185C (decomposition)~
EXAMPLE 17
5-[~7-(Diethylamino)heptyl7amino]-2-(2-1lydrc~yethyl)-
anthra~l,9-cd]pyrazol-6(2H)-one
Reaction with N,N-diethyl-1,7-heptanediamine
gives the product as a salt with 1.0 equivalent of
h~drogen chloride; mp 206-208C (decompositio~n)~
EXAMPLÆ 1~
2-(2-E~.ydroxyethyl)-5-[~2-(1-Piperazinyl)ethyl]amino]-
anthra[l,9-cd]pyrazol-6(2~)-one
Reaction with 4-(2-aminoethyl)-1-piperazine
carboxylic acid, benzyl ester, then hydrolysis of the
isolated intermediate with refluxing 48~ hydrobromic
acid in acetic acid and salt formation gives the
produci as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.5 equivalent of water;
mp 292-297C ~decompositior.).
~2~309~
CLG-l -86-
EXAMPLE 19
5-~[2-[(2-Hvdroxvethyl)amino]ethyl]amino]anthra[l!9-
..
cd]p~razol~6(2H)-one
A mix-ture of 2.54 g ~10 mmol) of 5 chloroantr.ra-
11,9-cdlpyrazol-6(2H) one [ Chem. Soc., 1630
(1952)], 10 ml (100 mmol) of 2-(2-aminoethylamino)-
ethanol, and 25 ml of anhydrous pyridine is heated at
reflux under argon for 2~ hours, cooled, and
concentrated. The residue is triturated with
2-propanol to give a solid whose dissolution in
methanol:dichloromethane followed by salt formation as
described in Example 3 affords 1 5 g of the dried
product as a salt with 1.5 equivalents of hydrogen
chloride solvated with 0.6 equivalent of water;
mp 251-~4~C (decomposi~ion~0
EX~MPLE ~0
5-~[2-(Diethylamino)ethyl]amino]anthra[l,9-cd]-
. .
pYrazol-6(2H)-one
_
A mixture of 1.6 g (6.3 ~mol) of 5~chloroanthra-
~l,9-cd~pyrazol-6(2~-one, 3.5 g (30 rmmol) of N,N-
diethylethylenediamine, and 20 ml of anhydrous
pyridine is heated at reflux for 20 hours, cooled, and
concent-ated, The residue is dissolved in
dichloromethane, wash~d with water, and then extracted
with 1% aqueous hydrochloric acid. The acid solution
is wasned with dichloromethane, then made basic with
aqueous sodiu~ hydroxide. The aqueous solution i9
e~tract2d with dichloromethane and the dried
dichloromethane layer is concentrated to a residue
which is converted into a salt as described Eor
Example 3 to give 0.7 g o~ the dried product as a salt
with 1.4 equivalents o~ hydrogen chloride solvated
with 0.1 equivalent of water; mp 120-130C.
C~G-l -87- 7
EXAMPLE 21
2-[2-l~2-Hvdro~yethyl)amlno]ethyl]-5-[~2-~(2-hydroxy-
ethyl)amino]ethyl]amino]anthraEl,9-cd]pyrazol-6~ZH?-
one
A mixture of 1.91 g (5 mmol~ of 5-chloro-2-[2-
1(2-hydroxyethyl)amino]ethyl]an.hra~1,9 cd]pyrazol-
6(2H)-one, hydrochloride, 2.6 .nl of 2-(2-aminoethyl-
amino)ethanol, and 5 ml of anhydrous pyridine is
heated at reflux under argon for 6.5 hours, cooled,
and concentrated. Trituration of the solid residue
with cold 2-propanol gives 1.43 g of the dried
product; mp 154-156C. Crystallization from glacial
acetic acid: 2-propanol gives 1.35 g of the dried
product as a sal~ ~ith 1.0 equivalent o~ acetic acld
solvated with 0.5 equivalent of water; mp 146-148C.
5-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl~
anthra[l,9-cd]pyra~ol-6(2E)-one is prepared âS
follo~s:
To a refluxing mixture of 832 mg (3 mmol) of 1,4-
dichloro-9,10-anthracenedione in 8 ml of dry
acetonitrile is added dropwise over 40 minutes, 450 mg
(3.8 mmol~ of 2-[(hydra~inoethyl)amino]ethanol in 3 ml
oE acetonitrile The mixture is refluxed for one
hour, cooled, and triturated with cold 2-propanol to
give 602 mg of product; mp 140-142~C Processing of
the mother liquor affords 71 mg of additional product;
mp 124-126C. Crystalliza~ion of the free hase rom
glacial acetic acid gi~es the diacetate salt; mp
125-130C. The hydrochloride salt is prepared as
described in Example 3; ~,p 260-263C ~decomposition).
~L241~7
CLG-1 -88-
2-t(~ydrazinoethyl)amino]ethanol is prepared as
! follows:
A solution of 86.8 g (1.0 mol) of N-(2-hydroxy-
ethyl)ethyleneimine and 400 ml (about 6 mol) of 54
aqueous hydrazine is heated at reflux for two days.
Excess water and hydrazine is distilled at 40-50C/13
mm, then the pot residue is distilled at 142C/0.10 mm
to yield 80.9 g of product with an 88% purity. Care-
ful redistillation of a small sample gives
analytically pure material; bp 120C/0.035 mm.
E~MPLE 22
5-1(2-Aminoethyl)amino3-2- E 2-[(2-hydrox~ethyl)amlno]-
ethyl]anthra[l,9-cd]pyrazol-6(2H~-one
Reaction of 1.91 g of 5-chloro-2-~2-[(2-hydroxy
etnyl)amino]ethyl]anthra~l,9-cd~pyrazol-6(2H)-one
hydrochloride with 1.6 ml (25 mmol) of 1,2-ethylene-
diamine, as described in Example 21, followed by
concentration affords a solid which is washed with
ether, 2-propanol, and a little dichloromethane-, then
triturated with methanol to remove a solid impurity.
The concentrated filtrate is dissolved in water and
purified over a column of HP-20 resin eluting first
with water and then ~7ith methanol. Corlcentration of
the methanol eluate ~ollowed by salt formation as
described in Example 3 affords 1.0 g of the dried
product as a salt with 2.0 equivalents or hydrogen
chloride solvated with 0.9 equivalent of water;
mD 263-267C (decomposition)7
. .
-
~3L2~L~09
CLG-l -89-
EX~MP~E 23
5-[l2-(Diethylamino)ethyliamino]-2-[2-~(2-hYdroxy-
ethyl)amino]ethyl]anthra[l,9-cd]pYrazol-6(2H)~
one
Reaction of 1.91 g of 5-chloro-2-[2-~(2-hydroxy
ethyl)amino]ethyl~anthra[l,9-cd]pyrazol-6(2H)-one,
hydrochloride, with 3.5 ml (25 mmol) of N,N-diethyl-
ethylenediamine as described in Example 21 affords
1.~ g of product; mp 132-133. Processing of the
mother liquor affords 0.3 g of additional product;
mp 130-131C~ Salt formation as described for Example
3 gives 1.6 g of the dried product as a sal~ with 2.0
~ui~7alents of hydrogen chloride solvated with 1.0
equivalent of water; mp 272-274C (decomposition).
EX~PLE 24
5-t(2-Hydroxyethyl)amino~-2-[2-[(2-hydroxvethyl)-
amino]ethyl]anthra~l!9-cd]pyrazol-6(2H)-one
A mixture of 2.5 g ~606 mmol) of 5-chloro-2-~2
E ( 2-hydroxyethyl)amino~ethyl]anthra[l,9-cdlpyrazol-
6(2H)one, hydrochloride~ 2 ml (33 mmol) of 2-amino-
ethanol and 13 ml of anhydrous pyridine is reacted and
wor'.~ed up as described in Example 21 to afford a solid
precipitat~ whose salt formation as aescribed in
Example 3 affords 1.4 g oE the dried product as a salt
with 1.1 equivalents o~ hydrogen chloride solvated
with 0.6 equivalent of water, mp 260-261C
(decomposition).
EX.~MPLE 25
2 l2-~(2-H~_oxYethYl)zmino]ethyl] 5-_[~2-(dimethyl-
amino?ethyl]amino]anthra[1,9-cd]pyrazol-6~_2H)-
one
Reaction of 2.72 g (7 mmol) o' 5-chloro-2-[2-[(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol-6(2H~-
one, hydrochloride, 1.2 g (14 mmol) of N,N-dimethyl-
ethylenediamine, and 20 ml of pyridine for 42 hours at
CLG-l ~90- .
reflux ollowed by workup as described in Example 21
gives a solid residue whose dissolution in hot
methanol followed by salt formation as described in
Example 3 gives 1.0 g of the dried product as a salt
with 2.1 equivalents o~ hydrogen chloride solvated
with 0.9 equivalent of water; mp 286-288C
decomposition).
EXAMPLE 26
2-[2-[t2-Hydroxyethyl)amino~ethl1]-5-(methx~amino)-
anthra~l,9-cd]pyrazol-6(2H)-one
Reaction o~ 5-chloro-2-[2-[(2-hydroxyethyl)-
amino]e~hyl]anthra[l,9-cd]pyrazol-6-t2H)-one, hydro-
chloride, with excess methylamine as described in
Example 21 gives the product as a salt with 1.0
equivalent of hydrogen chloride, mp 285-288C .-
(decomposition).
EX~MPLE 27
2-~2-Aminoethyl)-5-[[2-~(2-hydroxyethyl)amino]ethvl~-
amino]anthra[l,9-cd]pyrazol-6(2H)-one
A mixture of 3.0 g (8.9 mmol) of 2-(2-amino-
ethyl)-5-chloroanthra[l,9-cd]pyrazol-6(2H)-one, 2.0 ml
of 2-~2-aminoethylamino)ethanol, and lS ml of
anhydrous pyridine is heated at reflux or 30 hours,
cooled, and filtered. The filtrate is concentrated
and chromatographed over silica gel with 9g:2:1
dichloromethane: methanol:triethylamine~ then gradient
elution to 99:20:1 to provide the purified pr~duct.
Sal-~ formation as described in Example 3 ~ives 0.8 g
o the dried product as a salt with 1.7 equivalents of
hydrogen chloride solvated with 1.0 equivalent of
water and 0.2 equivalent of 2-propanol; mp 270-272C
(decom~osition~. .
CLG-l -91-
2-(2-Aminoethyl)-5-chloroanthra[l,9-cd]pyrazol-
6-(2H)-one is prepared as follows~
To a solution of 1.0 g (3.6 mmo7e~ of 1,4-di-
chloro-9,10-anthracenedione in 10 ml of pyridine at
35 is added dropwise 1.9 ml of (2-aminoethyl)-
hydrazine [British Patent 880,332~. The mixture is
stirred for four hours, concentrated, and purified on
silica gel utilizing 94:5:1 dichloromethane:
methanol:triethylamine~ Salt formation as described
in Example 3 gives 0.45 g of the product as a salt
with 1.0 equivalent of hydrogen chloride solvated with
1.2 equivalents of wa~er and 0.1 equivalent of
2-propanol; mp 284-285C (decomposition).
EXAMPLE 28
2-12-(Diethylamino)ethyl~-7_10-dihydroxy-5 ~[2-[~2-
hydroxyethyl)amino]ethyl]amino]anthra[l,9-cdl- ~
pyrazol-6(2H)-one
Reaction of a mixture of 2.-9 g ~7.5 mmol) o
5-chloro-2-[2-~diethylamino)ethyl]-~,-10-dihydroxy~
anthra~l,9-cd]pyrazol-6~2H)-one, 7 D 5 ml S75 mmol) of
2-(2-aminoethylamino~ethanol, and 35 ml of pyridine
for four hours at reflux followed by workup as
described in ~xample 21 and salt formation as
described in Example 3 gives 2.8 g of the dried
product as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.7 equivalent of water,
mp 198-202C (decomposition).
5-Chloro-2-[2-~diethylamino)ethyl]-7 f 10-di-
hydroxyanthra[l,g~cd]pyrazol-6~2H)-one is prepared as
~ollows:
Reaction of a mixture of 12.7 g (41 mmol? of 1,4-
dichloro-5,8-dihydroxy-9,10-anthracenedione, 12 g
S90 mmol) of ~2-die~hylaminoethyl)hydrazine, and 65 ml
of pyridine at 50C for four hours follo~ed by workup
CLG-l -92~
as described in Example 22 gives a residue that is
dissolved in dichloromethane. Chromatography oJer
silica gel with dichloromethane and then with 3~
methanol in dichloromethane affords crude material
whose crystalli~ation from 2-propanol gives ~.5 g of
a purified solid; mp 136-140C. Salt formation as
described in Example 3 on lo 5 y Of this material gives
1.3 g o a dried solid as a sal.t with 1.0 equivalent
of hydrogen chloride solvated with 0.3 equivalent of
water; mp 280-282C (decomposition)O
EX~MPLE 29
2-~2-~Dieth~amino)ethyl]-5-[[2-(diethylaminO)ethyl]
amino]-7,10-dihydroxyanthra[l,9-cd]pyra~ol-6(2H)-
one
Reaction of a m.ixture of 1O93 g (5 mmol) of S-
chloro-2-[2-(diethylamino)ethyl]-7,10-dihyaroxyanthra-
~l,9-cd]pyrazol-6(2H)-one, 2.9 g (2~ mmol) of N,N-
diethylethylenediaminej and 25 ml of pyridine-for f-ive--- -~---~- ---
hours at-reflux ollowed-by workup as-des~ribed-in
Example 21 gives a crude solid which is dissolved in
dichloromethane. Chromatography over silica gel with
3%, 6%, and 10% solutions of methanol in
dichloromethane affords 1.6 g of pure material. Salt
formation as described in Example 3 gives 1.4 g of the
dried product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 0.3 equivalent of
~at6r; mp 290-292C (decomposition)
~-Y~P~ 30
5-~(2-A;ninoethyl)amino]-2-[2-(diethylamino~ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazo_-6(2H)-one
Reaction of 5-chloro-2-~2-(diethyla~ino)ethyl]-
7,10-dihydroxyanthra[l,9-cd~pyrazol-6(2H)-one with
ethylenediamine as described in Example 28 gives the
product as a salt with 2.0 equivalents of hydrogen
chloride solva~ed ~ith 1.7 equivalents of water and
0.1 equivalent of 2-propanol; mp 277-281C
~decomposition).
~2
CLG-l ~93~
EXAMPLE 31
2-[2-~Diethylamino~eth~1~-7,10-dihydrox~-5-[[2-
(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of 5-chlGro-2-[2-~(diethylamino)ethyl]-
7,10-dihydroxyanthra El, 9-cd]pyrazol-6(2~)-one ~ith
(2-aminoethyl)-methylcarbamic acid, benzyl ester
[US Patent 3,931,268] followed by isolation of the
intermediate as described in Example 29 then
hydrolysis with hot 48~ hydrobromic acid in acetic
aci~ gives the product as a salt with 2.3 equivalents
~f hydrogen bromide solvated ~ith 2.7 equivalents of
water; mp 217-220C (decomposition).
EXAMPLE 32
2-~2-(Dimethylamino~ethyl]-7,10-dihydroxy~5-E[2-[(2-
hvdroxyethyl)amino]ethyl]amino]anthraEl,9-cd~pYrazol-
6(2H)-one
Reaction of 2.0 g (5.6 mmol) of 5-chloro-2-[2-
tdimethylamino)ethyl]-7,10-dihydroxyanthra-1,9-cd]-
pyrazol-6(2R)-one, 5.6 ml of 2-(2-aminoethylamino)-
ethanol r and 20 ml of pyridine at 70C for 24 hours
followed by workup as described in Example 21 and salt
f~rmation as described in Example 3 gives Z.4 ~3 of
the dr~ed product as a salt with 2.4 equivalents of
hydrogen chloride solvated with 2.0 equivalents of
water; ~p 310-313C (decomposition).
5-Chloro-2-[2-(dimethylamino)ethyl]-7,10-
dillydroxyanthra~l,9-cd]pyrazol-6(2H)-one is
~repar2d as follows: -
Reaction of a mixture of 15.5 g (50 mmol) o~1,4-dichloro-5,8-dihydroxy-9,10-anthracenedione,
10.3 g (100 mmol) of (2-dimethylaminoethyl)-
hydr~zine [J. Med. Chem., 1;493 (1964)~ and 60 ml
of pyridine at 35C overnight followed by ~orkup as
described in ~xample 28 gives 3.8 g of product;
mp 143-146C. Salt formation as described in
CLG-l -94-
Example 3 gives the product as a salt with
1.1 equivalents of hydrogen chloride solvated with
1.2 equivalents of water; mp 295-300C
(decomposition).
The ollo~ing compounds are prepared as described
in Example 32 from 5-chloro-2-[2-(dimethylamino)-
ethyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6~2H)-one
and the corresponding amine:
EXAMPLE 33
5-[(2-Arninoethyl)amino]-2-[2-(climethylamino)ethYl]-
7,10-dihydroxyanthra[1,3-cd]~Yrazol-6(2~)-one
~ eaction with ethylenediamine gives the product
as a salt with 1.9 equivalents of hydrogen chloride
solvated with 2.4 equivalents of water; mp 300-302C
(decomposition).
EXAMPLE 34
S-r(3-Aminopro~yl)amino]-2-[2-(dilltethylamino)ethyl]-
7,10-dihydroxyanthra~1,9-cd]pyrazol-6(2H)-one
Reaction with 1,3-pro?anedi~mine gives the
product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 1.4 equivalents of water; mp
281-285C [decomposition)~
EXAMPLE 35
5-[~2-(Diethylamino)ethvl]aminol-7,10-dihydroxv-2
(2-hydroxyethyl)anthra[l,9-cd]pyrazol-6(2~)
one
-
Reaction of a mixture of 3O3 g (10 mmol) of
5-chloro-7~10-dihydroxy-2-(2-hyclroxyethyl)anthra-
11,9 cd]p~razol-6(2H)-one, 14;5 ml (100 mmol) of N,N
diethylethylenediamine, and 20 ml of pyridine Eor
three hours at reflux followed by work~p as described
in Example 21 gives 2.47 g of a solid, mp 197-200C.
Salt formation as described in Example 12 affords
2 21 g of the dried product as a salt with 1.6
equivalents o~ hydrogen chloride solvated with 0.6
equivalent of water; mp 215-219C (decomposltion).
.
C1G-1 ~95~
5-Chloro-7,10-dihydroxy-2-(2-hydro~yethyl)anthra-
`~ ll,9-cd]pyrazol-6(2H)-one is prepared as follows:
~ mixture of 12 g ~40 mmol) of 1j4-dichloro-5,8-
dihydroxy-9,10-anthracenedione, ~5 g (60 mmol) of (2-
hydroxyethyl~hydrazine, and 40 ml of pyridine is
stirred at 50C overnight, cooled, and concentrated.
The residue is triturated successively with chloroform
and hot methanol to give 1.1 9 o the dried product;
mp 231-234C.
EX~PLE 36
5-[[2-[(2-Hydroxyethyl)amino]ethyl]amino]-7,10-
dihydroxv-2-(2-hydroxyethyl)anthra~i~9-cd]pyra
6~2H~-one
A mixture of 3~3 ~ (10 mmol) of 5-chloro-7,10-
dill~drox~-2-(2-hydroxye~hyl)anthra[l,9-cd]pyrazol-
6(2H)-one, 10~4 g (100 ~mol) of 2-(2-aminoethylamino)-
ethanol, and 20 ml of pyridine is heated at reflux for
four hours~ cooled, and concen~ra~ed. Successive
triLuration of the residue with acetonitrile~
2-propanol, and methanol gives 1.35 g of a powder~
Salt formation as described in Example 12 affords
1.06 g oE the dr.ed product as a salt with 1.0
equi~ralent of hydrogen chloride sGlvated with O.S
eaui~alen~ of water; mp 196-203C (decomposition)
The following ~ompounds are prepared as described
in E.Yarnple 35 from 5-chloro-7,10-dihydroxy-~-(2-
hydroxyethyl)anthratl,9-cd]pyrazol-6(2YA)-one and the
corresponding amine:
EX~MP~E-37
5-~2-Aminoethvl)amino!-7,10-dihydrOY.y-2-(2-hydrOXy-
ethyl)anthra[l ! 9-cd]px~azol-6t2H)-one
Reac~ion wi.h ethylenediam ne gives the product
as a salt with 1.8 equ~valents of hydrogen chloride
solvated with 5~5 equivalent of water; m~ ~195aC
tdecomposition).
~L80~37
C~G-l -96-
EX~PLE 38
7,10-Dihydrox~-2-(2-hydroxyethyl)-5-[[2-(4-
morpholinyl?ethyl]amino]anthra[l,9-cd]
p~rrazol-~(2~)-one
Reac~ion with 4-(2-aminoetllyl)morpholine gives
the product as a salt with 0.4 equivalent of hydrogen
chloride and 0.3 equivalent of ~ater; mp 240-251~C
(decomposition)O
EXAMPLE 39
5-[~2-(Dimethylamino)ethyl]amino]-7,10-dihvdrOXy-Z-
(2-hydroxyethyl)anthra[l!9_cd]pyrazol-6(2~)-
one
-
Reaction with N,N-dimethylethylenediamine gives
the product as a salt with 1.5 equivalents of hydrogen
chloride solva~ed ~ h 2 0 equivalents of water,
mp 250C (decomposition)O
EXAMPLE 40
5-[(2-AminoethYl)amino]-7,10-dihydro~ -2-meth~
anthra~l,9-cd]Pvrazol-6(2H)-one
-- _ = . _
Reaction of a mixture of 3.2 g (10.6 mmol) of
S-chloro-7J10-dihydroxy-2-methylanthral1,9-cd]pyrazol-
6(~)-one, 5 ml (7~ mmol) of ethylenediamine, and
55 ~1 of pyridine ~or seven hours at reflux followed
by ~or~up as described in Example 21 gives a solid
residue. Dissolution of the solid in hot methanol and
N,~l-dimethylformamide followed by salt formation as
described in Example 3 affords 1.5 g of the dried
product as a salt ~lth 1.0 equivalent of hydrogen
chloride solvated with 0.2 equivalent of water and 0Ol
equivalent of N,N-dimethylformamide; mp 323-326C
~decomposition).
5-Chloro-7,10-dihydroxy-2-methylanthra~l,9-cd~
pyrazol-~(2~-one is prepared as follows:
A ~ixture of 12.4 g (~0 m~ol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione, 2.7 ml (50 m~ol~
of methylhydrazine, and 250 ml of pyridine is heated
at 35C for seven hours, treated with an additional
~ 8~
CLG-l -97-
1 ml of methylhydrazine, heated for seven hours at
35C, and cooled. The solids are filtered and
recrystallized from N,N-dimethylformamide to give
8.85 g of the dried product as a salt with 0.1
equivalent of hydrogen chloride, mp 298-305C
(decomposition).
EXAMPLE 41
7~10-Dihydroxy-5-[~2-[~2-hydroxyethyl)amino]ethvl]
. . .
amino]-2-methylanthraEl,9-cd]pyrazol-6(2H)-on
Reaction of a mixture of 3.25 g (10.8 mmol) of
5-chloro-7,10-dihydroxy-2-methylanthra[l,9-cd]pyrazol-
5(2H)-one, 3 ml (30 mmol) of 2-(2-aminoethylamino)-
ethanol, and 50 ml of pyridine for seven hours at
reflux followed by workup as described in Example.21
and salt formation as describ~d in Example 3 gives
1.8 g of the dried produc-t as a salt wi~h 1.0
equivalent of hydrogen chloride solvated with 0.6
equivalen.t of water;-mp-280-284~C (decomposition-)-.
EX~PLE 42
5-~[2-(Diethvlamino)ethyl]amino]-7,10-dlh~roxy-2-
methylanthra[l~9-cd]pyrazol-6(2H)-one
Reaction of a mixture of 2.0 g (6.7 mmol ) of
5-chloro-7,10-dihydroxy-2-methylanthra[l,9-cd]pyrazol-
6(2H~-one, 3.5 ml (20 mmol) of N,N-diethylethylene-
diamine, and 45 ml of pyridine for seven hours at
reflux follo~ed by workup as described in Example 21
and salt formation as described in Example 3~gives
1.7 g of t7ne dried product as a salt with 1.5
equivalents of hydrogen chlor~de solvated with 0.8
equivalent of water; mp 298C (decomposition).
E XAMPLE 4 3
2-[3-(Diethylamino)=2-hydroxypropyl]-7,10-dihydroxy-
5-[[2-[(2 hydroxyethyl-)amino]ethyl]amino]anthra-
[l!9-cd~yrazol-6(2H)-one
Reaction of a mixtu.e of 1.3 g (3 mmol) o~
5-chloro-2-~3-(diethylamino)-2-hydroxypropyll-7,10
dihydroxyanthra[l,9-cd]pyrazol-6~2H)-one, 2 . 1 ml
f~ 0~7
.
CLG-l -98-
(21 mmol) o~ 2-(2-aminoethylamino)ethanol, and 10 ml
o pyridine a. reflux for six hours follo~ed by workup
as described for Example 21 and salt formation as
described in Example 3 gives the product as a salt
with 2.2 equivalents of hydrogen chloride solvated
with 2.8 equivalents of water and 0.2 equivalent of
2-propanol; mp 105-120C,
5-Chloro-2-[3-(diethylamino)-2-hydroxypropyl~-
7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2H)-one is
prepared as follows:
A mixture of 6.2 g (20 mmol) of 1,4-dichloro-
5,8-dihydroxy-9,10-ant~lracenedione, 9.7 g (60 mmol) of
l-(diethylamino)-3-hydrazino-2-propanol (German Patent
1,125,877) and 35 ml of pyridine is stirred ~t 40C
for one hour then at .oom temperature overnight. The
mixture is concentrated and purified on silica gel
utilizing 97:2:1 dichloro~ethane methanol:
triethylamine to give 1.7 g o product. Salt
formation a~ described in Example 3 gives 1.4 g of the
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 0.7 equivalent of wa.er; mp
264-267C (decomposition)~
EXAMPLE 44
5-t[2-(Diethylamino~ethYl]amino]-2-~3-(diethYlamino)-
2-hydroxyprooyl]-7,10-dlhydroxyanthra[1,~-cd]pyrazol-
~(2H)-one
Reaction of 5-chloro-2-[3-~diethylamino)-2-
hydroxypropyl]-7 910-dihydroxyanthra[l,9-cdJpyrazol-
6~2H)-one with N,N-diethylethylenediamine as described
in Example 43 gives the product as a salt with 2.0
equivalents of hydrogen chloride solvated with 1.9
equivalents o water; mp 253-255C ~decomposition).
EXAMP~E 45
5-[(2-Aminoethyl)amino]-2-[3-(diethylamino)-2-hvdrox~-
propyl]-7,10-dihvdroxyanthra[l,9-cd]pyrazol-6~2~?-one
Reaction of 5-chloro-2-[3-(diethylamino)-2-
j hydroxypropyl]-7,10-dih~droxyanthra[1,9-cd~pyrazol-
CLG-l -99~
6(2H)-one with ethylenediamine as described in Example
~ 43 gives the product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 2.8 equival~nts of
water; mp 1~8-152C.
EXAMPLE 46
2-[3-(Dimethylamino)propyll-7,10-dihydroxy-5-[[2-
[(2-hydroxyethyl ? amino]ethyl]amino1anthra_[1,9-cd]
pyrazol-6(2H)-one
Reaction of a mixture of 2 D 5 g ~6 mmol) of
5-chloro-~-[3-(dimethylamino)propyl]-7,10-dih~droxy-
anthra[1,9-cd]pyrazol-6(2~-one, hydrochloride,
2.8 ml (28 mmol) of 2-(2-aminoethylamino)ethanol, and
20 ml of pyridine at reflux for 24 hours followed by
workup as described or Example 21 and salt formation
as described in Ex.ample 3 yives the product as a salt
with ~.0 equivalents of hydrogen chloride solvated
wi.th 1.0 equivalent of water; mp 311C
(decomposition) r
5-Chloro-2-[3-(dimethylamino)propyll-7,10-
dihydroxyanthra~l,9-cd]pyrazol-6(2H)-one is prepared
as follows~
To a suspension of 30.9 g (100 mmol~ o~ 1,4-
dichloro-5,8-dihydroxy-9~10-anthracenedione in 200 ml
of pyridine at 37C is added dropwise 14 g (120 mmol)
of ~3-dimethylaminooropyl)hydrazine ~J. Med. Chem.,
1;493 (1364)]. Th~ mixture is diluted with 50 ml of
N,N-dime~hylEormamide, stirred for ten nours,~and
concentrated. The residue is 2istributad bet~een
dichloroTnet~ane and 5~ aqueous sodium bicarbonate.
Purificakion of the dried organic layer on silica.~el
utilizing 95.5:4:0.5 dichloromethane:methanol:
triethylamine gives 8 g o product. Salt ormation as
described in ~xample 3 gives 7 6 g of the product as a
salt with 0.8 equivalent of hydrogen chloride solvated
with 0.1 equivalent OL 2-propanol; mp 267-271~
~decomposition~.
~24~$0~3~
CLG-l -100-
EXAMPLE 47
5-[(3-Aminopropyl)amino]-2-[3-(dimethylamino)~ropyl]-
7,10-dih~rdroxvanthra[l,9-cd]pYrazol-6(2H)-one
Reaction of 5-chloro-2-[3-(dimethylamino)propyl]-
7,10-dihydroxyanthraEl,9-cd]pyrazol-6(2H)-one, hydro-
chloride, with 1,3-propanediamine as described in
Example 46 gi-~es the product as a salt with
2.0 equivalents of hydrogen chloride solvated with
0~5 equivalent of water; mp >300Co
EXAMPLE 48
7,10-Dihydroxy-5-[[Z-[(2-hydroxyethyl)ami
amino-2-[2-(methylthio)ethyl)anthra[lr9-cd]-
razo1-6~2H)-one
Reaction of a mixture of 0 66 g (3.6 mol) of
5-chloro-2-(2-~hiomethylethyl)-7,10-dihydroxyanthra~
¦l,9-cd]pyra~ol-6(2H~-one~ 1 8 ml (18 mmol) of
2-(2-aminoethylamino)e~hanol, and 16 ml of pyridine
at re~lux overnight followed by workup as described in
Example 21 and salt formation as described in -
Example 3 gives 0.7 g of th~ dried product as a salt
with 1.6 equivalents of hydrogen chloride solvated
with 0.5 equivalent o~ water; mp >133C
(decomp~sition~.
5-Chloro-2-(~-thiomethylethyl)-7,10-dihydroxy-
anthra-~l,9-cd]pyrazol-6(2~)-one is prepared
as follosJs:
An ice-cold mixture of 2.64 g (5 mmol~ of
5-chloro-2-~2-thiomethylethyl)-7,10-bis(phe-nyl-
methoxy3anthra[1,9--cd]pyrazol-6~2H)-one in 15 ml
dichloromethane is ~reated dropwise during 30 minutes
with 30 ml of a 1 M solution of boron trichloride in
dichloromethane. The mixture is stirred for one hour
then treated carefully with 30 ml of ~ethanolO The
mixture is warmed to room temperature overnight then
concentrated to a residue which is triturated with
2-propanol to give a red solid. Fur~her tritUratiQn
.
CLG-l -101~ 9 7
with 75 ml of boiling methanol gives 0.9 g of pure
? product; mp 186-190C.
5-Chloro-2-(2-thiomethylethyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2H)-one is prepared as
follows:
A mixture of 5.1 g (10 mmol) of 5-chloro-2-
(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra-
~1,9-cd]pyrazol-6(2H)-one7 9.4 g (100 mmol) of methyl-
disulfide, 20.2 g (100 mmol) of tri-n-butylphosphine,
and S0 ml of N,N-di~ethylformamide is stirred over-
night at room temperature. The mixture is cooled and
treated carefully with 75 ml of water. The orange
solid is collected and washed successively with water,
~-propanol, and diethyl ether to give 5.1 g of the
dried product; mp 155-160Co
5-Chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cdjpyrazol-6t2H)-one is prepared as
follows: -
Reaction of a mixture of 35.4 g ~72 mmol) of 1,4-
dichloro-5,8-bis(phenylmethoxy)-9,10-anthracenedione,
11.~ g (147 mmol) of (2-hydroxyethyl)hydrazine, 2.1 g
(37 mmol) of anhydrous potassium fluoride, 7.4 g
(74 mmol) of cnhydrous potassium bicarbonate7 and
220 ml of dry dimethylsulfoxide as described in
Example 54 gives 33.1 g of the dried product;
mp 178-184C. Crystallization from chlorofor~ raises
the melting point to 201-204Co
1,4-Dichloro-5,8-bls(phenylmethoxy)-,'Q-anthra-
cenedion2 is prepared as followso
~ mixture of 51.3 g (160 mmol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione (US Patent Number
3,631,074), 46 g (330 mmol) of powdered anhydrous
potassium carbonate, 44 ml (380 mmol) of benzyl
bromide, and 670 ml of dry acetone are heated at re-
f~ux for five days. The mixture is cooled, the solids
are filtered, then washed sequentially with water,
3~
CLG-l -102-
methanol, and diethyl ether to give 63.5 9 of the
dried product; mp 190-194C. Processin~ of the
acetone filtrate ~ives 9.4 g of a second crop; mp
142-155C.
EXAMPLE 49
5-Chloro-2-E2-(diethylamino)ethyl]-7,10-dihydroxy-
anthra[l,9-cd]pyrazol~6(2H)-one
An ice-cold mixture of 9.1 g (16 mmol) of
5-chloro-2-[2-(diethylamino)ethyl]-7,10~bis(phenyl-
methoxy)anthra[l,9~cd]pyrazol-6(2H)-one in 30 ml of
dichloromethane is treated dropwise during two hours
with 96 ml of a 1 M solution of boron trichloride.
Following addition, the mixture is treated carefully
with 30 ml of methanol. The mixture is warmed to room
temperature overnight and the solid residue is
collected, washed sequentially with 2-propanol~
methanol, and diethyl ether to give 5.5 g of the dried
product as a salt with 1.0 -equivalent of hydrogen ~-
chloride, and solvated with 0.2 equivalent of water;
mp 280-282C (decomposition).
S-Chloro-2-[2-(diethylamino)ethyl~-7,10-bis-
~phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
A mixture of 4.2 G (6.3 mmol) of 5-chloro-2-
t2-~t(4-methylphenyl)sulfonyl]oxy]ethyl]-7,10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6~2H)-one,
4.~ g (60 mmol) of diethylamine, 17 g ~12.6 mmol) of
powdered potassium carbonate~ and 35 ml of dimethyl-
suloxide is stirred overnighc at 50C. The mixture
is cooled and diluted with 50 ml of water. The solid
is collected and washed with water. The solid is
crystallized from chloroform:2-propanol (3:1) to give
2.1 ~ o product; mp 209-211C.
~ -Chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy]-
ethyl]-7,10-bis~phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2H)one is prepared as follows:
CLG-l -103- 12~8097
An ice-cold mixture of 2~ g (43 mmol) of
5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
metho~l)anthra[l,9-cd.]pyrazol-6(2H)-one, 12.3 g
(6S mmo].) of ~-toluenesulfonyl chloride and 170 ml of
pyridine is stirred for S0 hours. The solid is
filtered, washed with methanol and diethyl ether, and
dried to give 10.5 g of the product; mp 203-206C
tdecomposltion). Processing of the filtrate gives
9.3 9 of additional product; mp 182-18~C
(decomposition).
EX~MPLE 50
2-[2-[[2-(Dimethvlamino)e~hyl]amino]ethyl]-5-[[2-[(2-
hydroxyethyl)amino]ethyl]amino]-7,10-dihvdroxyanthra-
[l,9-cd3pvrazol-6(2H)~one
Reaction of a mixture of 3.6 y (7~4 mmol~ 5-
chloro-2-[2-[[2-(dimethylamino)eth~l]amino]ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one,
dihydrochloride, 4.5 ml (45 mmol) of 2-(2-aminoethyl- t - ~.,- '-''
amino)ethanol, and 35 ml of-pyridine at 80C overnight
followed by workup as described in Example 21 gives
0.5 g of product as a salt with 0.25 equivalent of
hydrogen chloride and solvated with 0.75 equivalent of
~7~ter; mp 110-117C~
~-Chloro-2-[2-[[2-(dimethylamino)ethyl]aminol-
ethyl]-7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2H)-one
is prepared as follo~sO
An ice-cold mixture of 9.3 g (1~ mmol~ of ~- c
chl~ro-2-l2-[[2-(dimethylamino)e-thyl]amino]ethylJ~
7,10-bis-(phenylmethoxy)anthra[l,9-cdlpyrazol-
~2_)-one in 30 ml OL dichloromethane is treated
dropwise during t~70 hours ~ith 96 ml of a 1 M solution
oE boron trichlorideO Follo~ing addition, the mixture
is treated carefully with 30 ml of me~hanol. The
mixture is warmed to room temperature overnight and
the solid residue is collected, washed sequentially
with 2-propanol, methanol, and dietnyl ether to gLve
3.68 g of the dried product as a salt with 1.8
t
~4~4)97
CLG-l ~104-
equivalents of hydrogen chloride and solvated with 0 2
equivalent o~ 2-propanol and 0.8 equivalent of water;
mp 260-268C (decomposition).
5-Chloro-2-[2-[~2-(dimethylamino)ethyl]amino]-
ethyl~-7,10-bis(phenylmethoxy)anthra[l,9-cdlpyrazol-
6(2H)-one is prepared as follows:
A mixture of 4 2 g ~6.3 mmol) of S-chloro-2-[2-
[[(~-methylphenyl)sulfonylloxylethyl]-7~'0-bis(phenyl-
methoxy)anthra[l,9-cd]pyraol-6(2H)-one, 5.3 g
(60 mmol) of N,N-dimethylethylenediamine, 17 g
(12.6 mmol) of pow2ered potassium carbonate, and 35 ml
of dime~hylsulfoxide is stirred overnight at 50C~
The mixture is cooled and diluted wi~h 50 ml of water.
The solid is collected and washed with water ~he
solid is heated in dichloromethane, the solution
filtered, then concentrat~d Trituration of the
residue with.hot ethyl acetate gives 1.7 g of the
dried product~ p..1~8-153C. .-..
. EXAMPLE 51
7,10-Dihydroxy-5-[[2-[(2-hydroxvethyl)amino]ethyl]-
amino]-2-[2-[(2-hydroxyethyl)methylamino]-e-thyl]
anth~a[l,9-cd]Pvrazol-6(2H)-one
Reaction of a mixture of 3.3 g (703 mmol) of
5-chloro-7 t 10-dihydroxy-2 12 t~2-hydroxyethyl)-
methylamino]ethyl~an~hra~l,9-cd]pyrazol-6(2H)-one,
hydrochloride, 3.6 ml (36 mmol) of 2-(2-aminoethyl-
amino)ethanol, and 30 ml of pyridine o~ernight at 80C
followed by workup as described in Example 21 and salt
~ormation as described in Exampl~ 3 gives 1.~ g of .he
dried product as a salt wi-h lo 6 equivalents of
hydrogen chloride solvated with 0.4 equivalent of
water, mp 240C (decomposition)~
5-Chloro-7,10-dihydroxy-2-[2-[(2-hydroxyethyl)-
methylamino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
- C1G-1 -105~ ~ 2480~
Reaction of a mixture of 8.3 g (15 mmol) of
5-chloro-2-[2~[(2-hydroxyethyl)methylamino~ethyl]-
7,10-bis~phenylmethoxy~anthra[l,9-cdlpyrazol-6(2~i)- -
one, 87 ml of a 1 M solution of boron trichloride in
dichloromethane, and 60 ml of dichloromethane as
described for Example 49 gives 3.5 g of the dried
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 1.75 equivalents of water;
mp 279-282C (decomposition)
5-Chloro-2-[2-[(2-hydroxyethyl)methylamino]
ethyl]-7,10-bis~phenylmethoxy)anthrall,9-cd]pyrazol-
~(2H)-one is prepared as follows:
Reaction of a mixture of lOoO g (15 mmol~ of
5-chloro-2-[2-[[4-methylphenyl)sulfonyl]o~ylethylI-
7,10-bis(phenyl)methoxy)anthra~l,9-cd]pyrazol-6(2~)-
one, 12.1 ml (150 mmol) of 2-methylaminoethanol,
4.1 g ~30 mmol~ of potassium carbonate, and ~0 ml o~
dimethylsulfoxide- as descri~ed in Example 49 gives
8.5 g of the product; ~p 191-194C.
EXAMPLE 52
7,10-Dihydroxy-~-l[2-[(2-hydroxyethyl1aminoletnyl]-
amino!-2-L3-[(2-hydroxyethyl)amino]~ropyl]anthra-
[l,9-cd]pyr~zol-6(2H)-one
Reaction of a mixture of 1.4 g (3.6 ~mol) of
5-chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)amino]-
propyllanthra[l,9-cd]pyrazol-6(2~)-one, hydrochloride~
3.7 ml (37 mmol) of 2-(2-aminoethylamino)e'ha~ol and
15 ml of pyridine overnight at 80C followed by worl~up
as described in Example 21 gives 0. 9 g O~ the dried
product solvated with 04 6 equivalent of water; mp
10~-105C.
5-Chloro-7,10-dihydroxy-2-[3-l(2-hydroxyethyl)-
amino]propyl]anthra[l,9-cdIpyrazol-6(2 )-one is
prepared as follows:
97
CLG-l 106-
Reaction of a mixture of 9.0 g (16 mmol) of
~ 5-chloro-2~[3-[(2-hydroxyethyl)amino]propyl]-7,10-
bis(phenylmethoxy)anthra[l,9-cdlpyrazol-6(2H)-one,
~3 ml of a 1 M solution of boron trichloride in
dichloromethane, and 30 ml o dichloromethane as
described for Example 49 gives 6.0 g of the dried
product as a salt with 0.8 equivalent of hydrogen
chloride solvated with 0~7 e~uivalent of water;
mp 25S-265C ~decomposition)~
5-Chloro-2-[3-[(2-hydroxyethyl~amino]propyl]7,10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6~2H)-one is
prepared as follows:
Reaction of a mixture of 13 4 g (19.7 mmol) of
5-chloro-2-~3~[[4-methylphenyl)sulfonyl]oxy]propyl3-
7,10-bis(phenylmethox~janthra~l,9-cd~pyrazol-6t2H)-
one, 12 ml (197 mmol) of 2-aminoethanol, 5.5 g
(39.4 mmol) of potassium carbonate, and 120 ml of
dimethylsulfoxide as-de.scribe~.in Example.49-gives
9.85 g of the product, mp 174-176C. Crystallization -
from chloroform gives material of mp 180-185C~
5-Chloro-2-~3-[[4-methylphenyl)sulfonyl]oxy]-
propyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-
6(2H)-one is prepared as follows:
Reaction of a mixture OL 13,1 Y ~25 mmol) of
5-chloro-2-(3-hydroxypropyl)-7,10-bis(phenylmethoxy)-
an~hra[l,9-cd]pyrazol-6(2H)-one, 9O5 g (S0 mmol) of
~-toluenesulLonyl chloride, 9 ml (~5 mmol) of
triethylam.iner lS0 mg of 4-dimethylaminopyridine, and
125 ml of dichloromethane at 5~ for one day then at
room temperature for five hours followed by wor'~up as
described for Example 49 gives 14.3 g of the product;
~p 137-139C.
5-Chloro-2-(3-hydroxypropyl)-7,10-bis(phenyl-
methoxy)anthra~l,9-cd]pyrazol-6(2H)-one is prepared
as follows:
~4~97
CLG~ 107-
A mixture of 48.9 g (100 mmol) of 1,4-dichloro-
5,8-bis(phenylmethoxy~-9,10-anthracenedione, 18O0 g
(200 mmol) of (3-hydroxypropyl)hydrazine ~J. Amer.
Chem. Soc. 76; 1283 (1954)], 2.9 g (50 mmol) of
anhydrous potassium fluoride; 10.0 g (100 mmol) of
anhydrous potassium bicarbonate, and 300 ml o~ dry
dimethylsulfoxide i5 stirred at 80C overnight~ The
warm mixture is diluted with 1.5 ml of water, then
allowed to cool. The solids are collected by filtra~
tion, washed sequentially with water, 2-propanol, and
diethyl ether to afford 31.0 g of the dried product;
mp 159-163C. Processing of the filtrate gives 4.7 g
o~ additional product; mp 150-154C~
EXAMPLE 53
5-~(3-Aminoprop~ amino]-7,10-dihydroxy-2-E3-[(2-
hydroxyethyl)amino]propyl]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 1.3 g t3.3 mmol) of
5-chloro-7,10-dihydroxy-2-~3-[(2-hydroxyethyl)amino~-
propyl]anthra[1,9-cd]pyrazol-6(2H~-one, 2.9 ml
(35 mmol) of 1,3-propanediamine, and 15 ml of pyridine
at 80C overnisht followed by workup as described in
Example 21 gives 1.0 g of the dried product as a salt
with 0.1 equivalent of hydrogen chloride solvated with
0.3 equivalent of water and 0.1 equivalent of
2-propanol; mp 120-130C (decomposition)O
EXAMPLE 54
7,10-Dihydrox~-2-r2-[(2-hydrox~ethyl)amino3Gthyl] 5
[E2 [(2-hYdroxYethYl)amino~ethYl]amino]anthra~l~9-cd]
pyrazol 6(2H)-one
Reaction of mixture of 1.28 g (3 mmol) 5-chloro-
7,10-dihydroxy-2~2-~(2-hydroxyethyl)am~no]ethyl]-
anthra[l,9-cd]pyrazol-6(2H)-o~e, hydrochloride, 1.5 ml
(15 mmol) o~ 2-(2-aminoethylamino~ethanol and 6 ml of
~yridine at 80C overnight follo~ed by workup as
described in Example 21 and salt ~ormation as
described in Example 3 givQs 675 mg o' the product as
CLG-l -108-
a salt with 2.0 equivalents of hydroge~ chloride
sol~ated with 0.9 equivalent of water; mp 215-225C
(decomposition).
5-Chloro-7,10-dihydroxy-2-[2-~(2-hydroxyethyl)
amino]ethyl]anthra~1,9-cd]pyrazol~6(2H)-one i5
prepared as follows:
To an ice-cold mixture of 26.8 g (48 mmol) of
5-chloro-2-[2-[h~droxyethyl)amino]ethyl]-7,10-bis-
(phenylmethoxy)an~hra[1,9-cd]pyrazol-6(2H)-one and 60
ml of dry dichloromethane is added dropwise during
2 1/4 hours 794 ml of a 1 M solution of boron
trichloride. The ~ixture is stirred for an additional
0~5 hours, then 20~ ml of methanol is a2ded dropwis~
during 1~5 hours~ The mix~ure is allowed to warm to
room temperatura overnigllt ~nd the solids are fil~
tered, washed sequentially with methanolf
aichloromethane, diethyl ether, and 2-propanol to give
14.7 g of the dried product; mp 175C (decomposition)~.~ -~
Processing of the filtrate affords 5.4 g of additional
product; mp 125-135C (decomposition)~
Crystallization of the solid from ~ethanol yives a
salt with 1.0 equivalent of hydrogen chloride solvated
with 0.? equivalent of water; mp 180-200C
(decomposition).
5-Chloro-2-[2-~(2-hydroxyethyl)amino]ethyl~-7~10-
bis~phenylmethoxy)anthra~l~9-cd]pyrazol-6(2H)-one is
prepared as ~ollo~.s
A mi3ture of 58O8 ~ (120 ~nol) of 1,4~dichloro--
~,8-bis(phenylmethoxy)~,10-anthracenedione, 28.6 y
(240 mmol) of 2- E (hydrazinoethyl)amino]ethanol, 3.5 g
(60 mmol) of anhydrous potassium fluoride, 12 g (120
mmol~ of anhydrous potassium bicarbonate, and 360 ml
of dry dimethylsulEo~i~e is stirred at 80C overnight.
The mixture is diluted with 400 ml of water and the
oranse solids are filtered, washed sequentially with
water, 2-propanol, and diethyl ether to give 51.2 g of
the dried procluct; mp 164-168C.
~l2~97
CLG-l -109-
The following compounds are prepared as described
in Example 54 from 5-chloro-7,10-dihydroxy-2-[2-[(2-
hydroxyethyl)arnino3ethyl]anthra[1,9-cd]pyrazol-6(2H)-
one nydrochloride and the corresponding a~ine:
EXAMPLE 55
5-[(2-A_minoethyl)amino]-7,10-dihydrox,v-2-[2-[(2-
hvdroxvethyl)amino]ethyl]anthra[l ! 9-cdlpyrazol-
6(2H)-one
Reaction with ethylenediamine gives the product
as a salt with 2.0 equivalents of hydrogen chloride
solvated with 0.9 equivalent of water; mp 272-278C
(decomposition).
EXAMPLE 56
5-[[2-(Dimethylamino)ethyl]amino]-7,10-dihvdroxy
2-[2-[~2-hydrox~ethyl)amino]ethyl]anthrz[l,9-cd]~
pyrazol-6(2H)-one
Reaction with N,N-dimethylethylenediamine gives
the product as a salt with--l.9 equivalents of-hydroge-n
chloride solvated with 1.7 equivalents OL water;
mp 78-280C (decomposition).
EXAMPLE 57
5-[~2-(Diethylamino)ethyl]amino]-7,10-dihydroxy-2-[2-
[(2-hydroxyethyl)amino]eth~ll]anthra~l,9-cd~pYra
6(2H)-one
Reaction with N,N-diethylethylenediamine gives
the product as a salt with 1.9 equivzlents of hyd~ogen
chloride solvated with 1.5 equivalents of water;
mp 2 8-231Co
EXAMPLE 58
5-[(3-Aminopropyl)amino]-7,10-dihydroxy-2-[2-[(2-
hYdroxyethyl)amino]ethyl]anthra~l,9-cd]pyrazol-6-
( 2H?-one
Reaction with 1,3-propanediamine gives the
product as a salt with 1.7 equivalents of hy2rogen
chloride solvated wi~h 1.0 equivalent of water;
mp 222C ~decomposition).
`,
12~80~7
CLG-l -110-
EXA~PLE 59
5-[(4-Aminobutyl)amino]-7,10-dihydroxy-2-~2-[~2-hydroxv-
ethyl)amino]ethyl]anthra[l,9-cd]pyra3O1-5(2H)-one
Reaction with 1,4-butanediamine gives the product
as a salt with 1.0 equivalent of hydrogen chloride
solvated wi~h 0.5 equivalent of water; mp 240-245C
(deco~position).
EXAMPLE 60
5-r(5-Aminopentyl)amino]-7~lo-dihydroxy-2-[2-[(2
hydroxvethyl)amino]ethyl]anthra~l,9-cdl~yrazol-
6t2H)-one
Reaction with l,S-pentanedlamine gives the
product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 0.7 equivalent of water;
mp 270-275C (decomposition)~
EX~MPLE 61
7~10-Dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]
5-~[2-(4-morpholiny~)ethyl]aminc]anthra[1,9-cdJ~
pyrazol-6(2H)-one
Reaction with 1-(2-aminoethyl)morpholine gives
the product as a salt with 2.4 equivalen~s of hyZrogen
chloride solvated with 0.8 equivalent of water;
m~ 28~C (decomposi~ion).
EXAMPL~ 62
7,10-Dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyll-5-
~[3-[(2-hydroxyethyl)amino]propyl]amino]anthra[l,9-cd3-
pyr zol-6(2H)-one
Reaction with 2-(3-amino~ropyla~ino)e~hanol gi~es
the product as a salt wi~h 2.1 equivalents of hydroyen
chloride solvated with 0.8 equivalent of water and
0.1 equivalent of 2-propanol; mp 170-180C
(decomposition~.
97
CLG-l 111-
EXAMPLE 63
5-~[2-[[2-(Dimethylaminoethyl~aminolethyl]amino~-7,1Q-
dihydroxy-2-[2-[~2-hydroxyethyl)amino]ethvl]anthra-
[1,9-cd]pyrazol-6(2H)-one
Reaction with N,~-dimethyldiethylenetriamine
gives the prod~ct as a salt Wit}l 2.4 equivalents of
hydrogen chloride solvated with 1.4 equivalents of
water and 0.2 equivalent of 2-propanol; mp 80-90C
(decomposition)~
EXAMPLE 64
7,10-Dihydroxy-2-t2-~2-hydroxyethyl)amino]ethyl] 5-
(4-methyl-1-piperazinyl)anthra[l,9-cd]Pyrazol-
6(2H)-one
Reaction wi~h N-methylpiperazine gives the
product as a sal~: ~ith 2.2 equivalents of hydrogen
chloride solvated with 0 4 equivalent of water and 0.2
equivalent of 2-propanol; mp >123C (decomposition)~
E~AMPLE 65
5-[[2-(Dimethylamino)ethyl]methylamino~-7,10-di-
hYdroxY-2-[2-[(2-hydroxvethyl)amino]ethyllanthra-
~l!9-cd]-pyrazol-6(2H)~one
Reaction with N,N,N-~ri~ethylethylenediamine
gives the product as a salt with 2.1 equivalents of
hydrogen chloride solvated ~ith 1 9 equivalents of
water and 0.2 equivalents o~ 2-propanol; mp >91C
(decomposition)O
. EXAMPLE 66
5-~12-[(2-~minoetnvl)amino]ethYl]aminol-7,10-di_
hydroxy-2-~2-[(2-hydroxye~hyl)aminolethyl]anthra-
,9-cd]-pyrazol-6(2H)-one
Reaction with diethylenetriamine gives the
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 1.0 equivalent of water;
mp 210-215C (decomposition~.
~2~30~3~
CLG~l -112~
EXAMPLE 67
5-[[2-[Bls(2-hydrox~ethyl)amino]ethYl]amino]-7,10-
dihydroxy-2-[2-[(2-hydroxyethyl)amino~ethyl]anthra-
~l,9-cdl~vrazol-6(2H)-one
Reaction with N,N bis(2-hydro,xyethy,l)ethylene-
diamine gives the product as a salt with 2.3 equiva-
lents of hydrogen chloride solvated with 0,8
equivalent of water; mp 230C (decomposition).
EX~PLE 68
5-1[3-[Bis(2-hYdroxyethyl)amino]propyl]amino]-7,10-
dihydroxy-2-[2-hydroxyethyl)amino~ethyl~anthra
[l,9-cdlpyrazol-6(2H)-one
Reaction with N,N-bis (2-hydroxyetbyl)-1,3-
propanediamine gives the product as a salt with
~.1 equi.valents o- hydrogen ch:Loride solva~ed ~ith
0.4 equivalent of water; mp 198-215C (decon~position).
EXAMPLE 69
5-~ ~3-~ [4-[(3-AminoproPyl)amino]butyl]amino]
amino]-7~10-dihydroxy-2-[2-[(2-hydroxyethyl-)amino]
eth~l]anthra~l,9-cd]pvrazol-6(2H)-one
Reaction with spermine gives the product as a
3~1t with 2.75 equivalents of hydrogen chloride
solvated ~ith 0.6 equivalent of water and 0.1 equiva-
lent o~ 2 propanol; mp 185~200C (decomposition)~
EXAMPLE 70
7,10-Dihydroxv-2 ~2-[(2-hydroxyethyl3amino]ethyl]-5-
I[2-(methylamino)ethyl]amino]anthra[l,g-cd]-
-
pyrazol-6(2H)-one
Reaction wi~h (2-aminoethyl~-methylcarbamic
a~id t benzyl ester followed by isolation of the
intermediate then hydrolysis with refluxing 48%
hydrobromic acid in acetic acid gives the product as a
salt with 2.1 equivalents of hydrogen bromide solvated
with 2.3 equivalents of water and 0.5 eq~ivalent of
acetic acid; mp 222-228C (decomposition).
CLG-1 -113-- 1248~)97
EX~MPLE 71
2-(2-Aminoethyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl)amino]ethyl]am1no]anthra[1,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 2.0 g (6 mmol) of
2-(2-aminoethyl)-S-chloro-7,10- dihydroxyanthra
~l,9-cd]pyrazol-6(2H)-one, 3 ml (30 ~nmol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine at
reflux overnight followed by workup as described in
Example 21 and salt formation as described in
Example 3 gives 1.3 g of the product as a salt ~ith
2.0 equivalents of hydrogen chloride solvated with
0.5 equivalent of water; mp 275-280~C (decomposition).
2-(2-Aminoethyl)-5-chloro-7,10-dihydroxyanthra-
[l,9-cd]pyrazol-~(.2EI~ one is 2repared from 2~(2-ami~o-
ethyl)-5-chloro-7,10-bis(phenylmethoxy)anthra[l,9-cd]-
pyrazol-6~2H)-one and boron trichloride as described
in E:xample. 54 to give the product as a-salt with
1.0 equivalent. of hydrogen chloride solvated with
0.7 equivalent of ~iater; mp 265-268C (decomposition).
2-(~-Aminoethyl)-5-chloro-7,10-bis(phenyl-
methox~anthra~l,9-cd]pyrazol-6(2H~-one is prepared
from l,4-dichloro-5~8-bi~(E)henylmethoxy)-9,10-
anthracenedione and (2-aminoethyl)hydrazine as
described in Example 54 to give the product; mp
176-178~C.
EXAMPLE 72
2-~2-;~minoethyl) 5 [(2-aminoethyl)amillo~7,10_
. __
dihydroxyan~hra[l,9-cd]pYrazol-6(2H)-one
Reaction of 2-(2-aminoethyl)-5-chlorG-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one with
ethylenediamine as described n Example 71 gives
the product as a salt ~ith 1.9 equivalents of
hydrogen chloride solvated with 1.0 equi.valent of
.~ater; mp >230C (decomposition).
. .
CLG~l -114-
EXAI~PLE 73
2-(2-Aminoethvl)-5-[(3-aminopropyl)amino]-7,10-
dihydroxyanthra[l~9cd]pyrazol-6(2H)-one
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one with
1,3-propanediamine as described in Example 71 gives
the product as a salt with 2.9 equivalents of hydroqen
chloride solvated with 3.5 equivalents of water;
mp > 310C (decomposition)O
EXAMPLE 74
2-[2-Aminoethyl)-5-[[2 [[2-(dimethYlamino)ethyl]-
amino]ethyl]amino]-7,10-dihydroxyanthra[l~9-cd]
pyrazol-6(2H)-one
Reaction of 2-(2-aminoethyl~-5-chloro-7,10- .
dihydroxyan~hra[l,9-cd Ipyra~ol-6 ( 2H~-one with
N,N-dimethyldiethylene~riamine as described in Example
71 gives the product as a salt with 3.3 equivalents
of hydrogen chloride solvated wit~ 1.0 equivalen~
oE water and 0.2 equivalent of 2-propanol;
mp 245-260C ~decomposition)~
EXAMPLE 75
2-(2-Aminoethyl)-5-[[3-~(2-hvdroxyethyl)amino]~r-opyl]
amino]-7,10-dihydroxyanthra[l,9-cd~pyrazol-6(2H)
one
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one with 2-(3-
aminopropylamino)ethanol as described in Example 71
gives the product as a salt with 2~1 equivalents o~
~ydrogen chloride solvated with 1.0 equivalen~ of
water and 0~2 equivalent of 2-propanol; mp 175C
(decomposition).
EXAMPLE 76
7,10-Dihy~roxy-5-~[2-[(2-hydroxyethyl)amino~ethyl]-
aminol-2-~2-methoxyethyl)anthra[l,~-cd]pYrazol-
6(2E)-one
Reaction o~ a mixture o~ 2.0 g (5.8 mmol) of
5-chloro~7,10-dihydroxy-2-(2-methoxyethyl)anthra-
~4~
ChG-l -115-
[l,9-cd]pyrazol-6(2H)-one, 5.8 ml (58 mmol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine
at 85C overnigh~ Eollowed by workup as described in
Example 21 yives 1.75 g of product. Salt formation
as described in Example 3 gives 1.91 g of product
as a salt with 1.1 e~uivalents of hydrogen chloride
solvated with 0.3 equivalent of water and
0.2 equivalent of 2-propanol; mp 68-72C.
5-Chloro-7,10-dihydroxy-2-(2-methoxyethyl)anthra-
[l,9-cd]pyrazol-6(2H)-one is prepared as follows:
Reaction of 11.9 g (23 mmol) of 5-chloro-2-
(2-methoxyethyl)-7,10-bis~phenylmethoxy)anthra-
[l,9-cd]pyrzzol-6(2H)-one, 9L ml of a 1 M solution of
boron trichloride~ and 46 ml of dry dichloromethane as
describ~d in Example 24 gives 6~25 g of the dried
product; mp 137-1~5C ~decomposition)~
5-Chloro-2-(2-methoxyethyl)-7,10-bis(phenyl-
- methoxy)anthra~l,9-cd]pyrazol-6(2H)-one~is-prepa-red~s~ Y
follows:
An ice-cold mixture of 3.2 g (6 mmol) of
5-chloro-2-(2-hydroxyethyl)-7,10-bis~phenyl-
methoxy)anthra[1,9-cd]pyrazol-6(2H)-one, 1~23 ml
(20 mmoll of lodomethane, and 20 ml ~ N,N-dimethyl-
~ormamide is treated gradually with 0.18 g (8 mmol) of
sodium hydride. The ice bath is removed and the
mixture is stirred for two hours, treated with five
drops of glacial acetic acid, then diluted with water.
Tne solids are filtered, washed sequentially ;~ith
2-propanol and diethyl ether -to give 2 8 g of the
dried product; mp 174-178C.
EXAMPLE 77
5-~(2-AminoeLhyl)amino]-7,10-dih-vdroxy-2-~2-methoxy-
ethyl)anthra[l,9-cd]pyrazol-6(2H)-one
Reaction of S-chloro-7,10-dihydroxy-2-(2-methoxy-
ethyl)anthra[l,9-cd]pyrazol-6(2H) one with ethylene-
diamine as described in Example 76 gives the product
)
97
CLG-l -116
as a salt with 1.0 equivalent of hydrogen chloride
solvated with 0.3 equivalent of water; mp 263-268C
(decomposition)O
EXAMPLE 78
2-~2,3-Dihydroxypropyl~-7~lo-dihydroxy-5-[[2-
[(2-hydroxvethy~)amino]ethYl]amino]anthra[l,9-cd]-
pyrazol-6(2H)-one
A mixture of 103 g (2 m~ol) of 2-t(2~2--dimeth
1,3-dioxolan-4-yl)methyl]-5-[[2-[(2 hydroxyethyl)-
amino]ethyl]amino-7,10-bis(phenylmethoxy)anthra-
[l,9-cd~pyrazol-6(2H)-one, 260 mg of 20% palladium
hydroxide on carbon, and 2S ml of glacial acetic acid
is stirred under an atmosphere of hydrogen Eor two
hours~ The ~ixture is filter2d and concentrated
~o a residue which is dissolved in methanolic
hydrogen chlorideO The mixture is stirred at room
temperature for two hours and concentrated to a
solid ~hich is crystallized from 1:1 ~ethanol:
ethanol to give D.7 g o the product as a salt
~ith 1.1 equivalents of hydrogen chloride solvated
with 1.0 equivalent of water; mp >110Co
2-[(2,2-~ime~hyl-1,3-dioxolan-4 yl)methyl]-5-[[2-
1(2-hydroxyethyl~amino~ethyl]amino-7,10-bis(phenyl-
me tho xy ~ anthra[l,9-cd~pyrazol~6(2~)-one is prepared as
follo~s:
A mix~ure of 1O2 g (2 mmol) of 5-chloro-2-
[(2,2-dimethyl-1,3~dioxolan-4-yl)methyl]-7~1~-bis-
(phenylm~ethox5~ thra[1,9-cd]pyrazol-6t2~ one~
2.~ ~ (2~ mmol) of 2-~2~aminoethylamino)ethanol,
17 ml of pyridine, and 0.3 g of anhydrous potassium
carbonate is stirred at reflux for 42 hours. The
mixture is diluted with w~ter and iltered to give
a solid ~hat is purified by silica gel chromatography
utilizing 94:5:1 dichloromethane:methanol:triethyl-
amine. Concentration of the product fractions
followed by trituration with 2-propanol gives 730 mg
of pure product; mp 206C.
9~
CLG-l -117-
5-Chloro-2-[~2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl]-7,10-bis(phenylmethoxy)anthra[l,9-cd]-
pyrazol-6~2~)-one is prepared as follows.
A mixture of 19.6 g ~4C ~nol) or 1,4-dichloro-
5,8-bis(phe~ylmethoxy)-9~10-anthracenedione, 10 g
(68 mmol) of 4-~hydrazinomethyl)-2,2-dimethyl-1,3-
dioxolan [Ann. 448; 121 (1926)], 4 g (69 mmol) of
anhydrous potassium fluoride, 5.5 g ~40 mmol) of
anhydrous potassium carbonate, and 150 ml of dry
dimethylsulfoxide is stirred at 80C for six hours.
The mi~ture is diluted with water and the solids
are filtered, then dissolved in dichloromethane~
Chromatography o~ the dri~d dichloromethane layer
over silica gel with gradient elution utilizing
0~5 ~o 1~ nethanol in dichlorom~thane yives Z g
of a solid that is triturated from 2-propanol,
then crystalli~ed from toluene to afford 1.8 g
of pure product; mp 184-18SCo - -
EXAMPLE 79
2-[2-tDieth~ ino~ethyl]-7-[l2-~ roxyethyl)-
amino]ethyl]amino]anthra[l,9-cd]pyrazol-6~2H)-
one
~ eaction of 2.5 9 (, mmol) of 7-chloro-2-~2-(di-
ethylamino)ethyl~anthra[l~9-cdlpyra2Ol-6t2H)-one, 7 ml
(70 mmol) of 2-(2-aminoethyl2mino)ethanol, and 20 ml
oE p~ridine for 20 hours at reflux followed by workup
as described in Example 9 gives 1.6 g of ~ solid, mp
104-107C, af-ter recrystallization fro~ toluene. Salt
for~nation as described in Example 3 gives 1.6 g of the
dried product as a salt with 20 0 equivalents of
hydrogen chloride solvated with 1.1 equivalents of
water; mp ~12-216C (decomposition)
7-Chloro-2-[2-(diethylamino~ethyl]anthra[1,9~cd]-
pyrazol6(2~)-one is prepared as follows:
~ 4~ 37
CLG-l -118-
A mixture of 13.85 g (50 mmol) of l,S-dichloro-
9,10-anthracenedione, 13.1 g (100 mmol) of (2-diethyl-
aminoethyl)hydrazine~ and 100 ml of pyridine is stir-
red at 50C for five hours, treated with an additional
10 ml of the substrate hydrazine, stirred at 35C for
48 hours, cooled, filtered, and concentrated.
Trituration of the residue with 2-propanol:ethanol
gives 8 g o~ a solid powder; mp 129-132C.
Dissolution of a 0.9 g sample in hot methanol followed
by salt formation as described in Example 3 gives 0.8
g of the dried product as a salt with 1.0 equivalent
of hydrogen chloride; mp 272-275C (decomposition).
EXAMPLE 80
2-[2-tDiethylamino)ethyll-7-~[2-(diethylamino)ethyl]
amino]anthra[l,9-cd]pyrazol-6(2H~-one
Reaction of a mixture oE 2.1 g (6 mmol) o~ 7-
chloro 2-t2-(diethylamino)ethyl]anthra[l,9-cd]pyrazol-
6~2~)-one, 5 ml (36 ~mol~ o-N,N-diethylethylenedi~
amine, and 20 ml of pyridine for 28 hours at reflux
followed by wor~up as described for Example 21 gives
1~9 g of the dried product as a salt with 2.0
eauivalents of hydrogen chloride solvated with 0 2
equivalent o water; mp 292-294C (de~omposition).
EXAMPLE 81
2-~2-~(2-Hvdroxvethyl?amino~ethyl]-7-[[2-[(2-hydroxy-
eth~l~amino]ethyl]amino]anthra[l,9-cd]pyrazol-6-
2~)-one
A mixture o~ 1.9 g ~5 mmol) of 7-chloro-2-~2-~(2-
hydroxye~hyl)amino~ethyl~anthra~l,9-cd~pyrazol-6(2H)-
one, 2.0 ml (20 mmol) of 2-(2-aminoethylamino~ethanol,
and 20 ml of pyridine is heated at reflux for
72 hours. The mix~ure is cooled, concentrzted, and
chro~atographed over silica gel with 0.5~
triethylamine in dichloromethane, utilizing a gradient
elution of 2-10% methanol, to give the product. Salt
formation as described in Example 3 gives 500 mg o~
!
C~G-l -119- 1248097
the product as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.4 equivalent of water;
mp 285- 87C (decomposition~
7-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-
anthra[l,9-cd]pyrazol-6(2H)-one is prepared as
ollows:
A mixture of 11.1 g ~40 mmol) of 1,5-dichloro-
9,10-anthracenedione, 13.1 g (110 mmol) of 2-
~(hydrazinoethyl)amino]ethanol, 4 g of anhydrous
potassium bicarbonate, 1 g of anhydrous potassium
~luoride, and 110 ml of dimethyl sulfoxide is stirred
at 70~C overnight. The mixture is chilled and the
solids are collected by filtration, washed with water,
then thoroughly with acetonitrile to give a residue
that is cr~s~allized from 2-propanol to leave 2.6 g
of product. The hydrochloride salt is prepared as
described in Example 3; mp 272-273C (decomposition).
EX~MPLE 82
7,10-Dichloro-2-[2-[(2-hydroxyethyl~amino]ethLvl]-
_-[[2-[~2-hydroxyethyl?amino]ethyl]amino]anthra
[l,9-cd]pyrazol-6(2H)-one
Reaction of 7,10-dichloro-2-[2-~(2-hydroxy-
e~hyl)aminol~thyl]-5-[[(4-methylph~nyl)sulfonyl]-
oxylanthra[l,9-cd]pyrazol-6(2H)-one, hydrochloride,
with 2-(2-aminoethylamino)ethanol gives the product.
7,10-Dichloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-
5-[~t~-methylphenyl)sulfonyl]oxy]anthra~l,9-cd]-
pyrazol-6(2~)-one is prepared as follows~
~ o a suspension of 30.9 ~ (50 mmol) of 1~4-
dichloro-5,8-bis[[(4-methylphenyl)sulfonyl]oxy~-
9,10-anthracenedione, 13 ml (75 mmol) of
N,N-diisopropylethylamine, and 130 ml of
N,N-dimethylformamide at 5C is added dropwise 14.9 g
t125 mmol) of 2-[(hydrazinoethyl)amino]ethanol in 70
ml o _,N-dimethylformamide. The mixture is allowed
C~G-l -120-
to reach 10C during five hours, then is diluted with
! 20 ml of acetone After ~arming to room temperature,
the solution is concentrated to ~n oil that is
distributed between water and dichloromethane.
Concentra~ion of the dried dichloromethane layer
follo-~ed by salt formation as described in Example 3
gives 18.1 g of the dried product as the hydrochloride
salt; mp l5a-l600c.
1,4-Dichloro-5, 8-bis ~ [ t 4-methylphenyl)sulfonyl]-
oxy~-9,10-anthracenedione is prepared as follows:
A mixture of 9.3 g (30 ~nol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione, 12~6 g (66 mmol)
o~ p-toluenesulfonyl chloride, 12.2 ml (70 mmol) of
N,N-diisopropylethylamine~ and 120 ml of acetonitrile
is heated at 70C ~or one hourt then cooled, The
crystals are collected by filtration to lea~e 14 d g
of dried product; mp 195.5-196.5C. Processing of
the filtrates.gives.. 2.2 .g of-.additional product~ 3-: - -
mp 190-192C.
EX~MPLE 83
7-Hydroxy-2-[2-[(2-hydroxyethyl)amino]ethYl]-5-
1[2-[(2-hydroxy-ethyl?amino]e-thyl]amino]anthra[l~9-cd~
p~razol-6(2~)-one
Reaction of a mixture of 2-~2-~(2-hydroxyethyl)-
amino]ethyl~-5-~E2-E(2-hydroxyethyl)amino]ethyl]-
amino]-7-(phenylmethoxy)anthraEl/9-cd]pyrazol-6~2H)-
one with hydrogen and 20~ palladium hydroxide on
carbon as described in Example 78 gives the product as
a salt with 2.0 e~uivalents oE hydrogen chloride
solvated with 2.3 equivalents of water; mp 26;-270C
(decomposition).
2-[2-[(2-hydroxyethyl)amino]ethyl]-5-E[2-E(2-
h~droxyethyl)amino]ethyl]amino-7-(phenylmethyoxy)
anthra[l,9-cd]pyrazol-6(2H)-one is prepared as
follows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
amino~ethyl]-7-(phenylmethoxy)anthra[l,9-cd]pyrazol-
CLG-l -121- ~248097
6(2H)-one with 2-(2-aminoethylamino)ethanol as
described in ~xample 78 gives the product;
mp 157-159C.
S-Chloro~ 2-~(2-hydroxyethyl)amino]ethyl]-7-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2~)-one is
prepared as follows:
A mixture of 4.2 g (11.0 mmol) of 1,4-dichloro-
5-~phenylmethoxy)-9,10-anthracenedione, 2.6 g (22~0 mmol)
of 2-[(hyrazinoethyl)amino]ethanol, 320 mg (5.5 ~mol)
of anhydrous potassium fluoride, 1.1 g (11.0 mmol) of
anhydrous potassium bicarbonate, and 33 ml of dimetkyl-
sulfoxide is stirred overnight at 80C. The mixture is
cooled and poured into water. The aqueous mix~ure is
centrifuged and the aqueous phase is decanted to leave
an oil that is dried and purified on silica gel
utilizing 4:1 dichloromethane:methanol as eluting
solvent. Concentration of the product fractions
followe~ by trituration from--me~hano~1- gives 8~0-~g
of the dried product; mp 141-145C.
1,4-Dichloro-5-(phenylmethoxy)-9,10-anthra-
cenedione is prepared as follows:
A mi~ture of 5.33 9 (18 mmol) of 1,4-dichloro-
~-hydroxy-9,10-anthracenedione (British
Patent 1,029,448), 2~6 g (19 ~mol~ of powdered
anhydrous potassium carbonate, 2.5 ml (21 mmol)
of benzyl bromide~ and 75 ml of dry acetone is
he~ted at reflux overnighk The mixture is cool~d
and the solids are washed well with acetorle.
Concentration of the Eil~rates gives a solid which
is triturated wi-th ether to afford 5.8 g of the
dried product; mp 118-122~C
Prepared in a fashion similar to ~xample 83 is
the following: ~~
CLG~l -122~ ~L248097
EXAMPLE 84
7-Hvdroxy-2-[2-[(2~hydroxyethyl)amino~ethyl)-5-[[2-
(methylamino)ethyl]ami_o]anthra[l,9-cd]pyrazol-6(2H)
one as a salt with 1.8 equivalents of hydrogen
chloride sol~ated with 1.2 equivalents of water7
mp 280-282C (decomposition) is prepared from 2-[2-
[(2-hydroxyethyl)amino]ethyl]-5-[[2-[methyl(phenyl-
methyl)amino]ethyl~amino]-7-(phenylmethoxy)anthra
[l,9-cd]pyrazol-6(2H)-one; mp :110-113C, which is
prepared from the reaction of N-methyl-N-(phenyl-
methyl)-1,2-ethanediamine (US Patent 3,201,459~ with
5-chloro-2-[2-[(2-hydroxyethyl~amino]ethyl]-7-(phenyl
methoxy)anthra~l,9-cd]pyrazol-6(2H)~one,
EXAMPLE 85
1O-Hydroxy-2-[2-[~2-hydroxyet~ aminolethyl]
5-~[2-[(2-hvdroxYethyl)amino]ethyl]amino]anthra-
. . _
[l,9-cd]-pYrazol-6(2H)-one
. Reaction of.a ~ixture of.. 2-12-[(2-hydro~yP.thyl~
amino]ethyl]-5-[[2-Et2-h~droxyethyl)amino]ethyl.] .
amino]-10-(phenylmethoxy)anthra[1~9-cd]pyrazol-6~2H)-
one with hydrogen and 20~ palladium hydroxide on car-
bon as described in Example 78 gives the product as a
salt with 2,1 equivalents of hydrogen chloride sol-
vated with 0.8 equivalent of water; mp 260-267C
(decomposition) J
2-l2-[(2-hydroxyethyl)amino]ethyl3-5-~[2-[~2-
hydroxyeth~l)aminolethyl]amino-lO~tphenylmet~ioxy)-
anthra~l,9-cd]pyrazol-6(2 )-one is prepared as
~ollows:
Reaction of ~-chloro-2-[2-[(2-hydroxyethyl~ '
amino]-ethyl]-10-(phenylmethoxy)anthra~l,9-cd]pyrazol-
6(2H)-one with 2-~2-aminoethylamino)ethanol as
described in ~xample 78 gives the product;
mp 178-180C.
5-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-10-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one, is
prepared as follows:
~LG-l -123- ~ ~ 4 ~ ~ ~7
Reaction of 1,4-dichloro-5-(phenylmethoxy)-9,10-
anthracenedione with 2-[(hydrazinoethyl)amino]ethanol
as described in Example 83 gives the product as the
minor isomer; mp 165-167C.
EXAMPLE 86
7,9,10-Trihydroxy-2-12-~(2-hydroxyethyl)amino]ethYll-
5-[~2-[~2-hydroxyethyl)amino]ethyl]amino]anthra-
[l,9-cd]-pyrazol-6(2H)-one
Reaction of a solution of 2--[2-[(2-hydroxyethyl)-
amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-7,9,10-tris(phenylmethoxy~anthra[l,9-cd]-
pyrazol-6(2~)-one in glacial acetic acid with hydrogen
and 20% palladium hydroxide on carbon as described in
Example 78 gives the product as a salt with 2 1
e~uivalents o~ hydrogen chloride solvated with 0.8
equivalent of water; mp > 235C (decomposition).
2-[2-[(2-Hydroxyethyl)amino]ethyl]-5-[[2 [(2-
hydroxyethyl)amino~ethyl]amino]-7,9,10-tris(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2H)-one is prepared
as follows:
A mixture of 660 mg (1 mmol) of 5-chloro-2-[2-
~(2-hydroxyethyl)amino]ethyl]-7,9,10-tris (phenyl-
me~hoxy)anthra[l,9-cd]pyrazo1-6(2H)-one, 1 ml
(10 mmol) of 2-(2-aminoethylamino)ethanol, and 2 ml
- of pyridine is heated at reflux for 28 hours. Workup
as described in Example 21 gives a solid whose
crystallization from acetonitrile chloroform affords
308 mg of product; mp 158-159C
S-Chloro-2-[2-[(2-hyd-roxyethyl~amino]ethyl]-
7,9,10-tris(phenvlmethoxy3anthraLl,9-cd]pyrazol-6(2H)-
one is prepared as follows:
A suspension of 7.2 g (12 mmol) of 5,8-dichloro-
1,2,4-tris(phenylmethoxy)-3,10-anthracenedione, 2.9 g
(2~ mmol~ of 2-[(hydrazinoethyl)amino]ethanol,
350 mg (6 mmol) of ~nhydrous potassium flouride, 1.2 g
~12 mmol) of anhydrous potassium bicarbonate, and
25 ~1 of dimethylsulfo~ide is stirred overnight a~
~2~ 7
CLG-l -124-
75C. The mixture is cooled, then triturated with
~-propanol. The solids are filtered, washed well with
water, 2-propanol, the~ crystallized from chloroform
to give 2.3 g of orange solid; mp 172-173C
Processing of the nonaqueous filtrates giqes
640 mg of additional product corresponding to ca. 1:1
mlxture of isomers by lH ~SR; ~p 135-140C~
5,8-Dichloro-1,2,4-tris(phenylme~hoxy)-9,10-
anthracenediona is prepared is as followso
A suspension of 7.5 9 (23 mmol) of 5,8-dichloro-
1,2,4-trihydroxy-9,10-anthracenedione, 9 6 ml
(81 mmol) o~ benzyl bromide~ 9.9 g t72 mmol) o
powdered anhydrous potassium carbonate~ 0 4 ml o~ -
methanol, 92 ml of acetone, and 46 ml of
~,~-di~nethylformamide ~s heated at reflux under argon
for t~o days. ~n additional 2.7 ml of benzyl bromide
is added and the mixture is heated for three days.
The suspension is filtered and- the ~iltrate IS'-'''''~
concentrated to an oil wr.ich is distributed between-- ----
dichloromethane and 10% aqueous acetic acid. The
dried dichloromethane layer is concentrated to a solid
whose crystallization from ethyl acetate affords 7D 2 9
o~ product; mp 174-175C~
~ ,8-Dichloro-1,2,~trihydroxy-9,10-
anthracenedione is prepared as follows:
A suspension of 451 mg (1 mmol) of 1,2,4-tris
(acetyloxy)-5,8-dichloro-9~10-anthracenedione, 5 ml
o glacial acetic acid~ and 5 ml of 6 N aqueous hydro-
chloric acid is heated at 70~ for ona hour~ The
suspension is cooled and the solids are filtered off.
After washing with water and drying, there remains
287 mg oE ~he dried product; mp 290-295C
(~ecolnposition)~
1,2,4-Tris(acetyloxy)-5,8-dichloro-9,10-
anthracenedione is prepared as follows:
A suspension of 307 mg (1 ~nol) o 5,8-dichloro-
1,4,9,10-anthracenetetrone, 0.05 ml of 72% perchloric
\
C1G-1 -125-
acid, and 10 ml of acetic anhydride is stirred at
room temperature for 30 minutes. The solution is
diluted with water, the organic layer is separated,
and dried, then concentrated to a solid residue.
~rituration of the solid from ethyl acetate leaves
235 mg of product; mp 205-206C.
~ ,8-Dichloro-1,4,9,10-anthracenetetrone is
prepared as follows:
~ suspension of 618 mg ~2 rnmol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione, 1.06 g (2.4 mmol)
of lead tetraacetate, and 25 ml of glasial acetic acid
is stirred at room temperature for 45 minutes. The
mixture is treated wi~h 0.5 ml ethylene glycol~ and
after 15 minutes is diluted with dichloromethane.
The mixture is washed wi~h water and the dried organic
layer is evaporated to a solid. Trituration of the
solid from diethyl ether ~ives 569 mg of product;
~p 255-257~-(decompGsitio~
EXAMPLE 87
7,8,10-Trihydroxy-2-~2-[(2-hydroxethyl)amino]ethyl]-
5-~2-~(2-hydroxyethyl)amino]eth~l]zmlno]anthra
¦l,9-cd]pyrazol-6(2H)-one
Reaction of a solution of 2-l2-~(2-hydroxyethyl)-
amino~ethyl]-5-[~2-E(2-hydroxye~hyl)amino]e.hyl]-
arninol-7,8,10~tris(phenylmethoxy~anthra~1,9-cd]-
pyrazol-5(2~-one in glacial acetic acid with hydrogen
and 20~ palladium hydroxide on carbon as described in
Example la sives the product as a salt with 2.1
equivalents o hydr3gen c'nloride solvated with 0.6
equivalent of wa.er; mp >210C (decomposition).
2-[2-[(2-Hydroxyethyl)ainino]ethyl]-5-[12-~(2-
hydroxyethyl)amino]ethyl]aminol-7,8,10-tris(phenyl-
~ethoxy)anthra[l,9-cd]pyraæol-6(2H)-one is prepared
as follows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
amino]ethyll-7,8,10-tris(phenylmethoxy~anthra[1,9-cd]-
37
CLG-l -126-
pyrazol-6(2H)-one with 2-(2-aminoethylamino)ethanol as
~; described in Example 86 gives the product;
mp 186-188~.
5-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-
7,3,10-tris(phenylmethoxy)anthra[l,9-cdIpyrazol-
6(2H)-one is prepared as follows:
Reaction of 5,8-dichloro-1,2,4-tris(phenyl-
methoxy)-9,10-anthracenedione with 2-[(hydrazino-
ethyl)amino]ethanol as described in Example.86 gives
the product as the minor isomer; mp 164-167C.
Prepared in a fashion simi:Lar to Ex~mple 87 is
the following:
EXAMPL~ 88
?,8,10-Trihydroxy-2-[2-~(2-hydroxyethyl)amino)]ethyl]-
5-[[2-(metlIylamino)ethyl]amino]anthra~l,9 cd]-
pyrazol-6(2H)-one as a salt with 2.0 e~uivalents
of hydrogen chloride solvated with 0.7 equivalent of
water; mp >220C (decomposition), which is prepared
from ~-[2-[(2-hydroxyethyl)amino]ethylI-5-
t[2-[methyl(phenylmethyl)amino]ethyi~amino]-7,8,10-
tris (phenylmethoxy)anthra~l,9-cdIpyra~ol-6(2H)-one;
mp lO~ 108C which is prepared from the reaction of
N-methyl-N(pnenylmethyl)-1,2-ethanediam~ne with
5-chloro-2-l2~ hydroxyetllyl)amino~ethyl]-
7,8,10-tris(phenylmethoxy)anthra~l/9-cd]pyrazol-
6(2H)-one~
EX~P~E 89
5-[[2-[(~-Aminoeth~l)amino]ethyl]amino]-7,10-
.
dihvdroxy 2-(2-hydroxye~hYl)a~thra[lr9-cd]
pyrazol-6(2H)-one
_
Reaction of a solution of 5-~[2-[(2-aminoethyl)-
amino~ethyl]amino-2-(2-hydroxysthyl)-7,10-bis(phenyl-
methoxy)anthra~l,9--cd]pyrazol-6(2H)-one in glacial
acetic acid with hydrogen and 20~ palladium hydroxide
on car~on as described in Example 78 gives the product
as a salt with 2.4 e~uivalents of hydrogen chloride
solvated with 0.8 equivalent of water; mp 170-185C
(decomposition).
~L2a~8C~9i7
CLG-l -127-
5-[[2-[(2-Aminoethyl~amino]ethyl~amino-2-(2-
hydroxyethyl)-7,10-bis(phenylmethoxy)anthr~[l,9-cd]-
pyra~ol-6(2H)-one is prepared as follows.
A mixture of 5O1 g (10 mmol) of 5-chloro 2-(2-
hydroxye~hyl~-7,10-bis(2henylmethoxy)anthra~1,9-cd]-
pyrazol-6(2H)-one, 10 ~ (100 mmol~ of diethylene-
triamine, 1.4 g (10 mmol) of anhydrous potassium
carbonate, and 60 ml of pyridine is heated at reflux
for 28 hours. The mixture is cooled, the solids are
collected by filtration then washed sequentially with
water and 2-propanol to give 3.1 g of the product;
mp 185-190C.
~ XAMPLE 90
2-~3-Aminoprop~vl )-?,10-dihydroxy-5-1_[2-[(2-hydro_Y-
ethyl)amino]e~hyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of a solution of 1~2 g (2 mmol) of
- - ---2-(3-aminopropyl)-5~2--[-(2-hydroxye-thyl)am`ino]ethy~
a~ino]-7,10-bis(phenylmethoxy)anthr~[l,9-cd3pyrazol-
6(2H)-one in glacial acetic acid with hydrogen and 20
palladium hydroxide on carbon as described in Example
7~ followed by salt formation as describe~ in Example
3 gives 850 mg of the product a salt with 2.0 equi-
alents of hydrogen chloride solvated with 1.1 ~qui-
valents of water; mp 292-294C (decomposition)~
2-(3-Aminopropyl)-5-[[2-r(2-hyroxyethyl)amino~-
ethyl]amino-7,10-bis(phenylmethoxy)anthra[l,9~cd~-
pyrazol-6(~ one is prepared as followss
A mi~ture of 530 ~g (1 mmol~ of 2-(3-amino-
propyl)-5-chloro-7,10-bis(phenylmethoxy)anthra-1,9-
cd]pyrazol-6~2H)-one, 1 ml (10 mmol) of 2-(2-
aminoethylamino)ethanol, 140 mg (1 mmol) of anhydrous
potassium carbonate, and 8 ml of pyridine is heated at
reflu~ for 22 hours. Workup as described in Exam21e
89 gi~es 400 mg of the product; mp 191-195C.
2-(3-Aminopropyl)-5-chloro-7,10-bis-
(pnenylmQthoxy)anthra[l,9-cd]pyrazol-6(2EI)-one is
prepared as follows:
~L2480~7
CLG-l -128-
Reaction of a mixture of 1,4-dichloro-5,8-bis-
(phenylmethoxy)-9,10-anthracenedione and (3-amino-
propyl~hydrazine ~Helvetica Chimica Acta 42; 533
(1959)] as described in Example 54 gives the product;
mp lB0-184C.
Prepared in a fashion similar to Example 90 i5
the following:
EX~MPLE '31
2-(3-~minopropyl)-5-[~2-~[2-(dimethylamino)ethyl]
amino~ethyl]amino]-7,10-dihydroxyanthra E 1, 9-cd]
pyrazol-6(2H)-one as a salt with 3.0 equivalents
of hydrogen chloride solvated with 2.0 equivalents of
water; mp 294C (decomposition), which is prepared
from 2-(3-aininopropyl)-5-~[~-[[2-(dime-thylamino)-
ethyl]a~ino]ethyl]amino]-7,10-bis(phenylmethoxy~
anthra[l,9-cd]pyra~ol-6(2H)-one; mp 143-160C, which
is prepared from the reaction of N,N-dimethyldi-
ethylenetriamine with 2-(3-am'inopropyl)'-5-chloro-' `' '' '
7,10-bis(phenylmethoxy)anthra~ cd]pyrazol-
6(2H)-one.
EXAMPLE 92
2-~2-Aminoethyl)-7,10-dihydroxv-5-[[2-(methylamino)-
_ _ .
ethyl]amino]anthra[l,9-cd]pyrazol-6(2Yl)-one
Reaction of a mixture of 2-t2-aminoethyl)-5-
[[2-methyl(phenylmethyl)amino~ethyl~amino]-7,10-bis-
(phenylmethoxy)anthra El, 9-cd ] pyrazol~6t2H)-one ~ith
hydrogen and 20~ palladium hydroxide on carbon as
described in Example 78 sives the product as a salt
with 2.2 equivalents of hydrogen chloride solvated
with 0.5 equivalent of water; mp 259-264C
(decomposition).
2-(2-Aminoe~hyl)-5-[[2-[methyl(phenylmethyl)-
a~ino~ethyl]amino~-7,10-bis(phenylmethoxy)anthra[1,9-
cd]pyrazol-6(2H)-one is prepared as ~ollows:
Reaction o~ 2-(2-aminoetnyl)-5-chloro-7,10-bis-
tphenylmethoxy)anthra~l~9-cd~pyra~ol-6(2H)-one with
~L~4L8~ !37
CLG-l -129-
N-methyl-N-[phen~lmethyl)-1,2-ethanediamine as de-
scribed in Example 78 gives the product; mp 169-172~C.
EX~MPLE 93
7,10-Dih~drox~v-5-[[2-[(2-hydroxyethyl)amino]eth
aminol-2-[2-(methylamino)ethyllanthra[l,9-cd]pyra
6(2HJ-one
Reaction of a mixture of 5--[[2-[(2-hydroxyethyl)-
amino]ethylIamino] 2-[2-(methylamino)ethyl]-7,10-bis-
(phenylmethox~)anthra[l,9-cd]pyrazol-6(2~) one with
hydrogen and 20~ palladium hydroxide on carbon as
described in Exa~ple 78 gives the product as a salt
with 2.0 equivalents of hydrogen chloride solvated
with 1.8 equivalents of wa~er; mp 180-185C
(decomposition)~
5-[[2-[(2-hyd-coxyethyl~amino]ethyl~aminoI-2-
~2-~methylamino)ethyl]-7,10-bis(phenylmethoxy)anthra-
[l,9-cd]pyrazol-6(2H)-one is prepared as follows:
Reaction of 5-chloro-2-r2-(methylamino)ethylI- ~
7,10-bis(phenylmethoxy)anthra~l,9-cd]pyra~ol-6(2H)-
one with 2-~2-aminoethylamino)ethanol as described in
Example 78 gives the product, mp 185-189~Co
5-Chloro 2-~2-(methylamino)ethyl]-7,10-bis-
(phenylmethoxy)anthra[l,9-cdIpyrazol-6(2~)-one is
prepared as follo-~s
Reaction of 5-chloro-2-[3-[~4-methylphenyl)-
sulfonyl]oxy]ethyl]-7,10-bis(phenylmethoxv)antbra-
[l,9-cdlpyrazol-6(2H)-one .~ith methylamir.e as de~
scribed in ~xample Sl give~ the product; mp 171~176C.
- EX~PLE ~4
5-t~2-Aminoethvl)amino~-2-~3-(dimethylamino)propyll-
7,10-dihydroxyanthra[l,9-cdIpyrazol-6(2H)-one
Reaction of 5-chloro-2-[3-(dimethylamino)propylI-
7,10-dihydroxyanthra[l,9-cdIpyrazol-6(2~)-one, hydro-
chloride, with ethylenedia~.ine as described in
Exa~ple ~G gives the product as a salt ~ith 2.0
equivalents of hydrogen chloride solvated with 0.5
~quivalent
8(~9~
CLG-l -130-
of water and 0.1 equivalent of 2-propanol; mp 316~C
~decomposition).
~ XAMPL~ 95
7,8-Dihydroxv-2-[2-[(2-hydroxyethyl)aminolethyl]-5
[[2-[~2-hydroxyethyl)amino]ethyl]amino]anthra~l~9-cd]
pyrazol-6(2H)-one
Reaction of a ~ixture of 2-[2-[(2-hydroxyet~yl)-
amino]ethyl]-5-~[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-7,8-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2H)-one with hydrogen and 20% palladium hydroxide
on carbon as described in Example 78 gives the
product.
2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-
hydroxyethyl)aminolethyl]amino]-7,3-bis-
(phenylmethoxy)anthra[1,9-cd]pyra~ol-6(2H)-one is
prepared as follows:
Reaction of 5-chloro-2-[2-[(~-hydroxyethyl)-
amino]ethyl]-7,8-bis(phenylmethoxy)anthra[l,9-cd]-
pyrazo1-6(2H)-one with 2-(2-aminoethylamino)ethanol
as described in ~xample 78 gives the product.
5-Chloro-2-~2-[(2-hydroxyethvl)amino]ethyl]-7,8-
bis(phenylmethoxy)anthra~1,9-cd]pyrazol-6(2H)-one is
prepared as follows:
Reaction of 1,4-dichloro-5,6-bis(phenylmethoxy)-
9,10-anthracenedione with 2-[(hydrazinoethyl)aminoj-
ethanol as described i~ Example 54 gives the product~
1,4-Dichloro-5 r 6-bis(pheQylmethoxy) 9,10-
anthracenedione is prepared as fO11GW5:
Reaction of 1,4-dichloro-5,6-dihydroxy-9,10-
an-hracenedione with benzyl bromide as described in
~xample 48 gives the product.
1,4-Dichloro-5,6-dihydroxy-9,10-anthracenedione
is prepared as follows:
Reaction of nitrosyl sulfuric acld and 5,6-
diamino-1~4-dichloro-9,10-anthracenedione ~Xhim.
Ge~erotsikl. ~ 808 (1968)1 gives the pro2uct.
