Note: Descriptions are shown in the official language in which they were submitted.
~25~3~
~`his is a divisional application of copending application,
serial no. 432,584, filed July 18, 1983.
BACKGROUND OF THE INVENTION
Several 2,5 and 2,7-disubs-tituted anthra[l,9-cd]pyrazol
6(2H)-ones are disclosed in the prior literature. See for
example J. Chem. Soc., 1630 (1952); J. Chem. Soc., 1894
(1954). Neither reference discloses any utility for these
compounds.
SUMMARY OF TH~ INVENTION
The invention in its first generie chemical eompound
aspect is a compound having the structural formula
Nl - ~I-Z
~
X O NR'~
wherein X, X' and W may be the same or difrerent and are
hydrogen, hydroxy, alkoxy having one to four earbon 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 six carbon atoms, or ANR2R3 wherein A
is straight or branehed alkylene of from two to eight earbon
atoms, R2 and R3 may be the same or different and are H,
alkyl of from one to six earbon 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 _ ~5~3~
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~
~(C~2);n/
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 when taken together may be ethylene or may
form
~%~
CLG-l ~4-
~(CH~)n~ \
-(CH2)m /
wherein n and m and B are defined above; Z is H, alkyl
of ~rom 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 tt~o 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, ~' and W are H and Z is H, R and Y when taken
together 20 not complete a piperidine ring, 2) when
X, Xl, and r~ are 'I and 2 is CH3, R 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
having the structural .ormula
N - N-Z
W~
X' O NRY
wnerein X, X' and W may be the same or different
and are H or 0~, alkox~l having-one to four carbon
atoms or chlorine; R is H or alkyl of from one to six
carbon atoms; Y is H, alkyl of Erom one to six carbon
atoms which may be substitutsd with an P~l group
wherein Rl is H or alkyl of from one to six carbon
atomsr or A~R~R3 wherein A i5 Strâight or ~ranched
~ ylene oF from tt~o to eight carbon atoms, R2 and
~33~
--5
R3 may be the same or different and are H, alk~l of
from one to si~ carbon atoms ~hich may be sllbstiLuted
with OH or an ~RaRa wherein Ra may be the same or
different and is ~ or alkyl o from one to three
carbon atoms whic~ may be substituted with OH, or
NRbRb wherein Rb is the same or dirferent and is H
or alk-yl Oe from one to three carbon atoms, or R2 and
R3 when ta~en together may be ethylene or may form
-(CH2)n\
B
~(C~2)rn/
wherein n and m may be the same or different and are
one, two, or three provided that the sum of n and m
i5 an integer of Erom three to six, and B is a direct
bond, O, S, or N-R~ wherein R4 is H or alkyl of ~rom
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 ~, alkyl
o rom one to six carbon atoms which may be
substituted with an II(Rl)2, SRl, or ORl group
wherein Rl is the same or different and is defined
above, or DN~2R3 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~ tnereof; 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.
-
~l2'5~
CL5-1 ~5~
lhe invention sought to be patented in its
! third generic chemical compound as?ect i5 a corn~ollnd
having the st.uctural formula
N ~I-z
X~
I
X ~ NR'~
wherein X and X' may be the same or differen~ and are
~, OH, alkoxy of one to four carbon atoms or chlorine;
is ~ or alktyl of from one to six carbon ato~s; Y is
~, alkyl of from one to six carbon atoms which may ~e
substitu~ed with an ORl group wherein Rl is ~I or
alkyl of from one to six carbon atoms, or ANR2R3
wherein A is alkylene of from two to 11 carbon atoms,
R2 and R3 may be the same or diCferent and are H,
al'~yl o ~rom one to six carbon atoms which may be
substituted with OH or an NRaRa wherein Ra is H or
alXyl of from one to t'nree carbon atoms which may be
substituted with OH, or NRbRb wherein Rb is the
same or difCer~nt and i9 '~ or alkyl o~' from one to
~h-ee ca-~on atoms, or R2 and R3 when taXen together
may be et~ylene or may form
~(C~2)n\
-(CH2)m /
wherein n, m, and B are defined'above; % is H, alkyl of
~rom one ~o six carbon atoms which may be substituted
with an M(R1~2, SRl, or ORl group wherein Rl is
defined above, or DNR2R3 wherein D i5 alk~lene
oE fro~ two to 11 carbon atoms which may be substituted
with an OH group and R2 and R3 are as defined above;
and the p~armaceuticall~ acceptable sal~s thereof; with
the Collowing provisos, 1) when X is H and Z is H, R
J
~$T~;~3~
7-
and Y when taken ~ogether do not complete a piperidine
ring, 2) when X is H znd Z is CH3 R and Y whsn tal~en
together do not complete a piperidine ring or a
morpholine ring.
~(CH2)n\B
-(CH2)m/
wherein n, m, and B are defined aboYe; Z is H, alkyl of
from one to six carbon atoms which rnay be substituted
with an ~(~1)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 b2 substituted
wl'h an OH group and R2 and R3 are as defined above;
and the pharmaceutically acceptable salts thereof; with
the followiny provisos, 1) when X is H and Z is H, R
and Y when taken together do not complete a piperldine
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.
The invention in its fourth generic chemical
compound aspect is a compound having the structural
formula I
X 1 1 Z
1~, ~1
~' O ~'f
I
wherein X, and X' may ke the same or diferent and
are H or OH; 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 ~ or alXyl o~ from one to six carbon atoms, or
~NR2R3 ~herein ~ is straight or branched alkylene of
from two to eight carbon atoms, R2 and R3 may be the
--8--
same or ~ifferent and ar ~, al~yl of frsm one to ~i~
car~on atoms which may be substituted with Ofl or an
NRaRa wherein ~a is tne same or different and as
~ or al~yl of from one to three carbon atoms which may
be substituted with OH, or NRb~ wherein Rb is the
same or different and is H or alkyl of 'rom one to
three carbon atoms, or R2 and R3 when taken together
may be ethylene or may form
-(C~2!n~B
~(C~2)m/
and m is an integer of from three to si~, and B is a
direct ~ond, O, S, or N-R4 ~herein R~ is H or alkyl
of from one to si~ carbon atoms; R and Y when taken
together may be ethylene or may form
~(CEI2)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
substituted with an N(Rl)2, SRl, or ORl group
wherein Rl is the same or different and is as defined
above, or DNR2R3 wherein D is straight or branched
al~lene 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
and Xl are H and Z is H, R, and Y when ta'~en together
do not complete a piperidine ring, 2) when X and X'
are ~ and Z is CH3, R and Y ~hen taken together do
not complete a piperidine ring or a morpholine ring.
The invention in a first s~bgeneric aspect of its
fourth chemical compound aspect is a chemical compound
having structural formula I wherein X and X' are OH;
and the pharmaceutically acce~table salts t~ereof.
CLG-l -9-
The inven~ion in a second subgeneric aspert o~
its fourth chemical compound aspect is a chernical
compound having struc~ural 'ormula I ~herein X an~ X'
are H; and the pharmaceutically acceptable salts
thereof .
The ~nven~ion in a third subgeneric aspect of its
Eourth chemical compound aspect is a chemiczl compound
ha~ing structural formula I wherein A a.nd D are the
same or different and are ethylene or propylene; and
the pharmaceutically acceptable salts thereof.
The invention in a fourth subgeneric as~ect of
its fourth chemical compound aspect is a compound
having structural ~ormula I'
N - N-Z'
O NR'Y'
I'
wherein R' is H or alkyl of from 1 to ~ carbon atoms;
Y' is CH2CH2NHCH2CH20H when Z' is al~yl of from
one to four carbon atoms which ma~ be substituted with
an SRl, or ORl group wherein Ri is H or
alkyl of from one to four carbon atoms or
D'NR2~3 wherein D' is strai~ht or branched
al~lene of from two to four c,a~bon atoms which may be
substitute~ with an OH group and P~2 and R3 may
be the same or diEferent and are H, alkyl of fro~ one
to six carbon atoms whlch may be substituted with an
OH or R2 and R3 when taken together may be
ethylene or may form
(C~2)n' \
B'
i ' -(CH2)~ /
-- 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 havin~
structural formu.a I''
HO Nl - N-z"
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 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
-(CH2)n''
\B''
-(CH2)1n' '/
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-R4lwherein 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 N - N-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 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
CLG-l -12-
is ~ or alkyl of from one to three carbon atoms ~hlch
may 'oe substituted with ~n OH or R2 and
R3'' when taken together may be ethylene or ma~
form
-~c~2)n' ' '
-(CH2)m'''
wherein n''' and m' " may be tne same or dif erent and
are one or two provided that ~he sum of n''' and m'''
is three or four, and 3' " is a direct bond, O, S, or
N-R~ 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 ORL group wherein Rl
is defined a~ove, 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 seventh subgeneric aspect Oc
its fourth chemical compound aspect is a compond
haYing the structural formula I'' "
Nl N-Z''''
OH o NR''''Y " ''
I''''
~herein R'''' is H or alkyl oE from one to six carbon
atoms; '~" " 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 four carbon atoms, or A'" 'NR2 R~
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
CLG-l -13~
carbon atoms ~Ihich may be substituted with an OH or an
~Ra''''Ra''l' wherein Ra " '' is the sa~e or different
and is H or alkyl of f~om one to three car~on atoms
which may be substituted with an OH or ~2
and R3 when taken together may be ethylene
or may form
~(C~2)n-'''\
B' " '
-Ic~2)m~ '
wherein n'' " and ml''' may be the same or different
and are one or two provided that the sum of n" '' and
m'''' is three or four, and s " '' is a direct bond, O,
S, or N-R~ wherein R4 is H or
al~l o from one tc four carbon atoms; Z'''' is ~lkyl
oE from one to four carbon atoms which may be
substituted with an SRl , or oRi
group ~-herein Rl is defined above or
D''''NR~ R3 wherein D" '' is
al~ylene 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 an eigh~h ~ubgeneric aspect of
its fourth chemical compound aspect is a compound
havin~ tne structural formula Iv
N N_zv
NRvyv
IV
~2~
CLG-l -14-
wherein Rv is H or alkyl of from one to six carbon
atoms; yv is H, alkyl of from one to four carbon
atoms or AVNR2vR3v ~herein A'~ is alkylene
of from two to four carbon atoms, ~2Vand R~ may be
the same or different and are ~ or alkyl of from one
to six carbon atoms which may be substituted with an
O~ or R2V and R3v when taken together may be
ethylene or may form
-(C~12)n
3V
-(CH2)mV~
wherein ~ 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
NR4V wherein R4v is H or alkyl of from one to
four carbon atoms; zv is alkyl of from one to four
carbon atoms, which may be substituted with an S
or ORlV group wherein RlV is H or alkyl of from
one to four carbon atoms, or DVNR2VR3V wherein
Dv is alkylene of from two to four carbon atoms which
may be substituted with an OH group and R2V and
R3v are defined above; and the pharmaceutically
acceptable salts thereof.
The invention in a ninth subgeneric aspect of
its fourth chemical compound aspect is a compound
having tne structural formula IVi
N - N-zvi
~,.
~ O NRVlY
Ivi
CLG-l -15-
wherein R~Ji is H or alkyl of from one to six car~on
atoms; ~vi is H, alkyl of from one to four car~on
atoms which may be substituted with an oRlVi group
wherein RlVi is H or alkyl of from one to four
carbon atoms or AViNR2viR3vi wherein
~vi is alkylene of fr~m two to four carbon atoms
R2Vi and R3Vi may be the same or different and
are alkyl of from one to six carbon atoms which may be
substituted with an OHt or R2vi and R3Vi when
taken -together may be ethylene or may form
-(CH2)nVi\
3Vi
-(CH2)mVi
wherein n'~i and mvi may be the same or different
and are one or ~ o provlded that. the sum of nVl and
mvi is three or four, and BVi is a direct bond,
O, S, or NR4Vi wherein R4Vi is H or al~yl o~
from one to four car~on atoms; zvi is
DViMR2viR3vi wherein DVi is all~ylene of
from two to four carbon atoms, R2Vi and R3Vi
are defined above; and the pharmaceutically acce2table
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]ethyl3amino]anthra[1,9-cd]pyrazol-6(2H)-one;
2-[2-~(2-hydroxyethyl)amino]ethyl3-5-[[2-[(2-hydroxy-
ethyl)amino]ethy'l3amino]anthra[1,9-cd]pyrazol-6(2H)-
one;
5-[(2-aminoethyl)amino]-2-[2-[(2-hydroxyethyl)amino]-
ethyl]anthra[l,9-cd]pyrazol-6(2~)-one;
2-[2-(diethylamino~ethyl]-7,10-dihydro~y-5-[[2-[(2-
hydroxyethyl)amino]ethyl]amino]antllra~l,9-cd]-
pyrazol-6(2H)-one;
.3~
CI,G-l -16-
5-[[2-[(2-hydroxyethyl)arnino]ethylja~ino]-7,10-
: dihydroxy-2-(2-hydroxyethyl)anthra[1,9-c~]pyrazoi-
6(2H)-one;
2-[2-[~2-(dimethylamino)ethyl]amino]ethyl]-5-[[2--[(2-
hydroxyethyl)amino]ethyl]amino]-7,10-dihydroxyanthra-
ll,9-cd]pyra2ol-6(2H~-one;
2-[2-(diethylamino)ethyl]-[[2-(4-morpholinyl)ethyl)l-
amino]anthra[l,9-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]anthra[l,9-cd]pyrazol-6~2H~-one;
5-[(2-aminoethyl)amino]-2-[2-(dier.hylamino)ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-[2-(diethylamino)ethyl]-7,10-dihydroxy-5-[[2-
(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one;
2-[2-(dimethylamino)ethyl]-7,10-dihydroxy-S-[~2-[(2-
hydroxyethvl)amino]ethyl]amino]anthra~l,9-cd]pyrazol-
6(2H)-one;
5-[(2-aminoethyl~amino]-2-[2-(dimethylamino)ethyl]-
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-[(2-aminoethyl)amino]-7,10-dihydroxy-2-(2-hydroAy-
ethyl)anthra[l,9-cd]pyrazol-6(2~)-one;
5-[[2-(dimethylal~ino)ethyl]amino]-7,10-dihydroxy-2-
(2-hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)-one;
2-[3-(diethylamino)-2-hydroxypropyl]-7,10-dihydroxy-
5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra-
~1,9-cd]-pyrazol-6(2H)-Gne;
5-l(2-aminoethyl)amino]-~-l3-(diethylamino)-2-hydr
propyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-[3-(dimethylamino)propyl]-7,10-dihydroxy-5-[[2-
1(2-hydroxyethyl)amino]ethyl]amino]anthra[l~9-cd]
?YraZol-6(2H)-one;
~æs~3~
CLG-l -17-
7,10-dihydroxy-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-2-[2-[(2-hydroxyethyl)methylamino]ethyl]-
anthra[l,9-cd]pyrazol-6(2H)-one,
7~l0-dihydroxy-S-~[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-2-f3-l(2-hydroxyethyl)amino]propyl]anthra-
[l,9-cd]pyrazol-6(2_)-one;
5-[(2-aminoethyl)amino]-7,10-dihydroxy-2-[2-[(2-
hydroxyethyl)amino]ethyl]anthraLl,9-cd]pyrazol-
6(2H)-one;
5-[[2-(dimethylamino)ethyl]amino]-7,10-dihydroxy-
2-[2-[(2-hydroxyethyl)amino]ethyl]anthra[l,9-cd]-
pyrazol-6(2H)-one;
5-[12-(diethylamino)ethyl]amino]-7,10-dihydroxy-2-[2-
1(2-hydroxyethyl)amino]ethyl]anthra[1,9-cd]PYrazol-
6(2~)-one;
5-[(3-aminopropyl)amino]-7,10 dihydroxy-2-~2-[(2-
hydroxyethyl)amino]ethyl~anthra[l,9-cd]pyrazol-6-
~2H)-one;
7,10-dihydroxy-2-[2-[(2-hydroxyethyi)amino]ethyl]-5-
~[3-[(2-hydroxyethyl)amino]propyl]amino]anthra[l,9-
cd]pyrazol-6(2~)-one;
5-[[2-[[2-(dimethylaminoethyl]amino]ethyl]amino]-7,10-
dihydroxy-2-[2-[~2-hydroxy~thyl)amino]ethyl]anthr2-
tl,9-cd]pyra~ol-6(2H)-one;
5-[[2-[(2-aminoethyl)amino]ethyl]amino]-7,10-di-
hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyllanthra-
[l,9-cd]-pyrazol-6(2H)-one;
5~[[2-[bis~2-hydroxyethyl)amino]ethyl]amino]-i,10-
.lihydroxy-2-[2-1(2-hydroxvethyl)amino]ethyl]anthra~
[1,9-cd]pyrazol-6(2H)-one7
~,lO-dihydroxy-2-[2-L(2-hydroxyethyl)amino]ethyl]-5-
I~2-(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one;
~æ~ 3~
Cr.G-l -18-
2-(2-aminoethyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl)amino]ethyl]amino]anthra[l,9-cd]pyrazol-
6(2H)-one;
2-(2-aminoethyl)-5-[(2-aminoethyl)amino]-7,10-
dihydroxyantnra~l,9-cd]pyrazol-6(2H)-one;
2-[2-aminoethyl)-5-[12-[[2-(dimethylamino)ethyl]-
amino]ethyl]amino]-7,10-dihydroxyanthra[l,9-cdl-
pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-[[3-[(2-hydroxye~hyl)amino]propyl]-
amino]-7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2H)-one;
2 (2,3-dihydroxypropyl)-7,10-dihydroxy-5-[[2-
[(2-hydroxyethyl)amino]ethyl~amino]anthra[l,9-cd]-
pyrazol-6(2H)-one;
7-hydroxy-7.-[2-[(2-hydroxyethyl)amino~ethyl]-5-
I[2-L(2-hydroxyethyl)amino]e~hyl~amino]anthra[l,9-cd]
pyrazol-6(2H)-one;
7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl)-~-[[2-
(methylamino)ethyl~amino]anthra[l,9-cd]pyrazol-6(2H)-
one;
10-Hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl~-
5-[[2-[(2-hydroxyethyl)amino]ethyl]aminG]anthra[1,9-
cd]pyrazol-6(2H)-one;
7,8,10-trihydroxy-2-[2-[(2-hydroxethyl)amino]ethyl]-
5-[[2-[(2-hydroxyethyl)amino~ethyl]amino]anthra-
~~l,9-cd]pyrazol-6(2H)-one;
7,8,10-trihydroxy-2-[2-[(2-hydroxyethyl)amino)]ethyl]-
5-[[2-(methylamino)ethyl]amino]anthra[l,9-cd]pyra2O1-
6(2H~-one;
5-[[2-~(2-aminoethyl)amino3ethyl]amino]-7,10-
dihydroxy-2-~2-hYdroxyethyl)anthra[l,9-cd]pyrazol-
6(2H)-one;
2-(3-aminopropyl)-7,10-dihydroxy-5-[[Z-[(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-dihydrox~-5-[[2-(methylarnino~-
ethyl]amino]anthra[l,9-cd~pyrazol-6(2H)-one;
5-[(2-aminGe~hyl)amino]-2-[3-(dirnethylamino)prop~l]~
7,10-dihydroxyanthra[l,9-cd~pyrazol-6(2H)-one;
7~S-dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
[[2-~(2-hydroxyethyl)amino]ethyl]amino]anthra[l,9-cd]-
pyrazol-6(2H)-one; and
the pharmaceutically acceptable salts thereof.
The in~entlon in its fifth seneric chemical
compound aspect is a chemical compound having the
structural formula
N ~-Z
Q" ~
wherein Q, Q', and Q" may be the same or different
and are hydrogen, OH, alkoxy of one to four carbon
atoms, chlorine, benzyloxy, p-chlorobenzyloY.y and
2-methoxyben~yloxy; and the pharmaceutically
acceptable salts thereof; Z is defined above; and the
pharmaceutically acceptable salts thereof; provided
that when Q = Q' = Q'' = H, Z may not be H or CH3.
The invention in its sixth generic chemical
compound as?ect is a chemical compound having the
s~ructural formula III
~'
Ql o Cl
III
~;6~3~
CLG-l -20-
wherein Q and Q' may be the same or different and
are H, OH, C]_~alkoxy, benzyloxy, p-chlorobenzylo~y, or
~-methoxybenzyloxy and Z is defi.ned above; and the
pharmaceutically acceptable salts thereof; provided
that ~hen Q = Q' = H9 Z may not be H or CH3~
The invention in a first subgeneric aspect of its
sixth chemical compound aspect is a chemical compound
having structural for~ula III wherein Q and Ql are H;
and the pharmaceutically acceptable sal.s thereof.
The in~ention in a second subgeneric aspect of
its sixth chemical compound aspect is a chemical
compound having the structural formula III wherein Q
and Q' are benzyloxy, p-chlorobenzyloxy, or
~-methoxybenzyloxy; and the pharmaseutically
acceptable ~alts thereo~O
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 fifth generic
chemical compound aspect of the invention are the
~hemical compounds having the following names:
5-chloro-2-[2-~diethylamino~ethyl]anthra[l,9-cd]-
pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]anthra[l,9-
cd]pyrazol-6(2H)-one;
5-chloro-2-[2-(diethylamino)ethyl]-7,10-dihydroxy-
anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-7,10-dihydroxy-2-(2-hydroxyethyl)anthra[l,9-
cd]pyrazol-6(2H)-one;
S-chloro-2--[2-(diethylamino)ethyl]-7,10-~is(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-~[(4-methylphenyl)sulfonyl]oxy]ethyl]-
7~10-bis(pnenylmethoxy)anthra[l~9-cd]pyrazol-6(2U.)one;
5-chloro-7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]-
ethyl]anthra[l,9-cd]pyrazol 6(2H)-one;
CLG-l -21-
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,10-bis-
(phenylmethoxy)ant~hra[l,g-cd]pyrazol-6(2H)-one;
5-chloro-2-[Z-[[2-(dime~hylamino)ethyl]amino]ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-chloroanthra[l,9-cd]pyrazol-6-
(2 )-one,
5-chloro-2-~2-(dimethylamino)ethyl]-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[3-(diethylamino)-2-hydroxypr
7,10-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-
methoxy)anthra~l,9-cd]pyrazol-6(2H)-one;
5-chloro-7,10~dihydroxy-2-[2-L(2--hydroxyet'nyl)-
methylamino]ethyl]anthra[l,9~cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]
7,10-bis~phenylmetho.yy)anthra[l,9-cd]pyrazol-6~2H)-
one;
5-chloro-7,10-dihydroxy-2-[3-[(2-hydrOxyethyli
amino]propyl]anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[3-[(2-hydroxyethyl)amino]propyl]7,10-
~i_,(phenylmethoxy)anthra,;,~-cd]pyraæol-6(2~.)-olle;
S-chloro-2~~3-[[4-methylphenyl)sulfonyl]oxy]-
propyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-
6(2H)-one;
S-chloro-2-(3-hydroxypropyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cdJpyrazol-6(2H)-one;
2-(2-aminoethyl)-5-chloro-7,10-dihydroxyan-thra-
[l,9-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-chloro-7,10-bis(phenylmethoxy)-
anthra[l,9-cd]pyrazol-6(2H)-Gne;
5-chloro-2-~(2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl]-7,10-bis(phenylmethoxy)anthra[1,9-cdl-
2YraZol-6(2~)-one;
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(~H)-one;
CLG-l -22-
5-chloro-2-~2-[(2-hydrox~ethyl)arnino]ethyl]-10-
~phenylmetho%y)anthra[1,9-cd]p~razol 6(2H)-one;
5-chloro-2-[2-[(2-hydro~yethyl)anlino]ethyl]-
7,3,10-tris(phen~flmethoxy)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]-1,8-
bis(phenyl~ethoxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-~2-[[2-(dimethylamino) ethyl]amino]ethyl]-
7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2~)-
one; and the pharmaceutically acceptable salts
thereof.
The invention in its seventh generic chemical
compound aspect is a compound having the structural
formula IV
N N-Z
[~'
NRY O
IV
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 P~l group wherein ~1
is ~I or al.~yl of from one to six carbon atoms/ or
A~R2R3 wherein ~ is alkvlene of from two to eisht
carbon atoms, R2 and R3 may be the same or diferent
and are H, alkyl of from one to six carbon atoms ~Jhich
may be substituted with OH or an NRaRa wherein Ra may
be the same or dieren~ and is H or alkyl o~ from one
to three carbon atoms which may be substituted with
OH, or R2 and R3 when taken together may be ethylene
or may form
CLG-l -23-
; ~(CH2)n \
-(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 s is a direct
bond, O, S, or ~I-R4 wherein R4 is H or alkyl of from
one to six carbon atoms; R and Y when taXen together
may be e~hylene or may form
~(cH2)n\B
-(CH2)m/
wherein n, m, and B are defined above; Z is H, alkyl
of ~rom one to six carbon atoms which may be
substitut2d with an NtRl)2~ SRl, or ~Rl group
~herein Rl may be the same or different and is
defined above, or DNR2R3 wherein D is alkylene o~
rom two to eight carbon atoms which rnay be
substituted ~ith an OH group and R2 and R3 are a
deined above; and the pharmaceutically acceptable
salts thereofi with the 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
chemical compound aspect of khe invention are-the
chemical cornpound~ having the following names:
2-[2-(diethylamino)ethyl]-7-[[2-[(2-hydroxyethyl)-
amino]ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-one;
2-[2-(diethylamino)ethyl-7-[[2-(dlethylamino)ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2~)-one;
2-~2-~(2-hydro~yethyl)amino]ethyl]-7-[[2-[(2-
hydroxyethyl)amino~ethyl]amino]anthra[l,9-cd]pyrazol~
6-~2~)-one; and the pharmaceutically accepta~le salts
thereof.
~'æ5~
CLG-l -24-
The invention in its eighth generic che~ical
compound aspect is a compound having the structural
formula VII
N -N-Z
~,X~
Cl O
~II
wherein ~ is defined above, provided it is noc H or
CH3.
The invention as a species o. the eighth seneric
chemical compound aspect of .he invention is the
chemical compound having the following names: ~
7-chloro-2-[2-(diethylamino)ethyl]anthra[l,g-cd]-
pyrazol-6(2~)-one;
7-chloro-2-[2-~2-hydrox~ekhyl)amino]ethyl]anthra[l,
9-cd]pyrazol-6(2H)-one; and the pharmaceutically
acceptable salts thereof.
The invention in its ninth chemical compound
acpect is 5,8-dichloro-1,4,9,10-anthracenetetrone.
The inven~ion 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 chemical
process aspect is a process for preparing a compound
ha~ing the structurâl formula
~ - N-Z
W~
Xl O NRY
which coJnprises reacting a compound haviny the
structural formula
3~
CLG-l -25-
N ~ Z
' Q"
with an amine having the formula HMRY wherein W, X
X~ Q~ Q~r Ql~ y~ z~ and R are deFined above and,
when necessary, removing bv catalytic hydrogenation or
by treatment with boron tribromide or trichloride any
b~næ~l groups.
The invention in its second generic chemical
process aspect is a ~rocess for preparing a compound
having struc.ural formula I
N - N-Z
X' o NRY
I
which comprises reacting a compound having structural
ormula II
Q N - N-Z
11 1
Q' O Cl
II
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, removing by catal~tic hydrogenation or by
treatment with boron tribromide or boron trichloride
an~ 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 su~generic aspect o~ its
second chemical process aspect is the process defined
above wherein X and X' are Ho
The invention in its third generic chemical
process aspect is a process for preparing a compound
having structural rormula III
N -- N-Z
Q' Cl
III
which comprises reacting a compound having formula V
Q O Cl
Q~ o Cl
V
with a hydrazine having the form~la H2N-NH~, wherein
Q, Q' and Z are defined above~
~25~3~
C~G-l -27-
The invention in a first subgeneric aspect of i~s
third chemical process as?ect is the process defined
above wherein Q and Q' are benz~loxy,
~-chlorobenzyloxy, or p-metho~c~benzylo~.
The invention in a second subgeneric aspect oE
its third chemical process aspect i5 the process
defined above wherein Q and Q' are OH.
The invention in a third subgeneric aspect of its
third chemical process aspect is the process define~
above wherein Q and Q' are H.
The invention in its fourth generic chemical
process aspect is a process for preparing a compound
having structural formula IV
N - N-Z
NR~ b
IV
which comprises reacting a compound having structural
~ormula VII
N - N-Z
Cl O
VII
with an a.~ine having the formula HNRY, wherein Y, Z,
and R are defined above.
~æs~
CLG-l -28-
The invention in its fifth chemical proces~
aspec~ is a process for preparing 5,8-dichloro-
1,4,9,10-anthracenetetrone which cornprises reacting
~ dichloro-5,8-dihydroxy-9,10-anthracenedione ~Jith
lead tetracetate,
The inqention in its sixth chemical process
aspect is a process for preparing
2-[(hydrazinoethyl)amino]ethanol ~hich comprises
reacting hydrazine with N-(2-hydroxyethyl)aziridine.
The invention in its first pharmaceutical
eomposition aspect is a pharmaceutieal composition
eomprising a eompound having structural formula I and
the pharmaceutically acceptable salts thereof in
combination with a pharmaceutically acceptable
carrier.
The invention in its second pharmaceutieal
eomposition aspect is a pharmaceutical compositlon
eomprising a compound having s4ructural formula I' and
the pharmaceutically acceptable salts thereof in
eombination with a pharmaceutically acceptable
carrier.
The invention in its third pharmaceutical
composition aspect is a pharmaceutical composition
comprising a compound having struetural formula I''
and the pharmaeeutically acceptable salts thereof in
combination with a pharmaceutically acceptable
carrier.
The invention in its ~ourth pharmaceutical
eomposition aspect is a pharmaceutical composition
comprising a compound having structural
~ormula I"' and the pharmaceutically acceptable salts
thereof in combination with a pharmaeeutieally
acceptable carrier.
~S~i~3~
CLG-l -29-
The int~ention in its fifth pharmaceutical com-
position aspect is a pharmaceutical composition com-
prising a compound having structural forMula I''''
and the pharmaceu-tically acceptable salts thereo
in combinatlon with a pharmaceutically aczeptable
carrier.
The invention in its sixth pharmaceutical ^om-
position aspect is a pharmaceutical composition com-
prising a compound ha~Jing structural formula Iv
and the pharmaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its seventh pharmaceutical com-
position aspect is a pharmaceutical composition com-
pri.siny ~ compou,ld having structural formula I'ti
and the pharmaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its eighth pharmaceutical-
composition aspect is 2 pharmaceutical composition
comprising a compound having structural formula IV
and the pharmaceutically acceptable salts thereof in
combination wi~h a pharmaceutically acceptable
carrier.
The invention in its first pharmaceutical rnethod
aspect is â method for treating microbial infections
in a mammal which comprises administering a
suEficient amount of a compound havinq 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 second pharmaceuti.cal method
aspect is a method for treating leukemia in a mammal
which COmQrises administering a sufficient amount of a
compound having structural .ormula I' and the
pharmaceutically acceptable salts thereof in
~5Ei~
- 30 -
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 pharmaceutically 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 thereof 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
~r, compound having structural formula IViand the
pharmaceutically acceptable salts thereof in combination
with a pharmaceutically acceptable carrier, to a mammal in
need thereof.
~ `
, _
~5~3~
CLG-l -31-
The invention in its eighth pharmaceutical ~.ethod
aspect is a method for treating solid tumors in a
mammal which comprises administering a sufficient
amount of a compound havirlg structural formula L'~
and the pharrnaceutically acceptable salts thereo' in
combination with a pharmaceutically acceptable
carrier, to a mammal in need thereof.
CLG-l ~32-
~ESCRIPTION OF THE PRE:FERRED E~IB(~DI~ENTS
The compounds of the invention may be prepared
conveniently by the follo~/irlg reaction sequence
Q" ~ ------3~ Q"
V IXI
I
W N- Z ~ _ z
W~ C B -- r~
X o NRY X ' O Cl
II
The reaction step "A," involves the reaction of
ccmpound V and a suitably substituted hydrazine,
NH2-N~ wherein Q, Q' and Q'', and Z are defined
hereinabove. This reaction may be accomplished in any
of a variety o~ reaction inert solvents by rnixing
aporoxi;nately equimolar amounts of compound V and the
desired hydrazine in the chosen solvent at elevated
t~mperature. Use of a catalyst such as potassiurn
fluoride or of a slight molar excess of the hydrazine
reactant may improve a particular yield. Examples of
sultable solvents are N,~-dimethylformamide,
dimethylsulfoxide, ~yridine, acetonitrile, the
cellosolv~s, and the li~e. Pyridine is the preferred
solvent, suitable reaction te:nperatures are from aoout
CLG-l ~33~
3~-85C. In general, the reaction is allowed to
proceed fo-r about six to about 24 hours at ,lhich time
the reaction i5 substantia].ly complete. The
completeness of a particular reaction may be measured
by ~nown procedures such as thin layer chromatography
for ex2mple. It is generally observed that increasin~
the reaction temperature will decrease the time
necessary for completing the reaction. The proper
choice of the reaction variables is ~ithin the s~ill
of the art. The products of the reaction are isolated
and purified by standard procedures. For exam21e, the
reaction mixture may be concentrated by evaporating
the solvent and the residue may be partitioned bet-~een
water and a convenient nonwater-miscibl2 organic
solvent sucn as chlorororm~ benzene, dichloromethane~
and the like. The solvent may then be evaporated and
the residue may be chromatographed, for example, on
silica gel. Cholce of the proper chromatog~aphy
solvent is within the skill of the art~ After -
chromatography, the product may be recrystallized, if
desired. ~hen ~he Q, Ql, and Ql- substituents of the
so produced co~pound III comprise benzyloxy,
p-chloroben~yloxy, or ~-methoxybenzyloxy, the benzyl
substituents may be removed, for 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 substi~uents represent
h~droxyl. Acid addition salts may also be prepared by
standard procedures. For example, a hydrochlo~ide
salt may be prepared by dissolving the free base in a
convenient solvent such as 2-propanol and treating
this solution with a solution of hydrogen chloride in
2-?ropanol. The acid addition salts may be
reconverted to the respective ~ree base by treatment
with a dilute solution of sodium hydroxide or
potassium carbonate for example.
CLG-l ~34~
The reaction step "B" involves the reaction of
compound II with a suitahl~ subs~ituted amine ~5NR'~
wherein ~, W, X, X', Y~ and Z are deeined hereinabove.
This reaction may be accomplished in any of a variety
oE reaction inert solvents by mixing approximately
equimolar amounts oE compound II and the desired amine
in the chosen solvent at elevated temperature. The
use of a slight molar excess Oe the amine 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
optional and is within the skill of the art. ~xamples
of suitable solvents are ~I,N'-dimethylEormamide,
dimethylsulfoxide, pyridine, acetonitrile, the
cellosolves J and the like. Suitable reaction
te~peratures are erom aoou~ 85-130C. This reaction
has been observed to proceed particularly e~Eiciently
in refiuxlng pyridlne. I~ generalj the reaction is - - ~-
allowed to proceed for about 6 to-about 24 hours at
which time i~ is substantially complete. The
completeness of a particular reaction may be meacured
by known procedures such as thin layer chromatography
or example~ It is general~y 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 ourified by standard procedures which are
substantially identical to those described above Lor
compound II. Likewise, acid addition salts oE
compound I may be prepared by standard procedures such
as that described hereinabove for compound II.
Alternatively, the compound o~ formula III may be
treated directly with an amine oE eormula HNRY to
produce a compound of the Eormula
CLG-l ~35-
a~ N~
Q"~
Q' b ~RY
This compound may then be debenzylated by a
standard procedure to produce the corresponding
compound having structural formula I.
In an alternate process the compounds of formula
I wh2re~rl ~ and X' are hydroxy may be prepared by
the reaction of compound VI (compound V wherein Q and
Q' are dihydroxy
O~ O Cl .
¢~
OH O Cl
VI
with a suitably substituted hydrazine ~IH2-N~ to
proauce a compound of structural formula II wherein
is OH; ~ is defined hereinabove~ The reaction of VI
~nd the hydrazine may be accornplished by ~i~ing
approximately equimolar amounts of the reactants in a
solvent such as ~,N-dimethylormamide,
dimethylsulfoxide, pyridine, and the like at
temperatures about 30-90C~ preferably 30-60~C, in the
presence of a base such as potassium bicarbonate.
Pyridine is the preferred solvent and when utilixed
does not require an additional base. The use of
catalyst such as potassium fluoride may improve
~56~
CLG-l -36-
~he yieId of a particular reaction~ The subsequent
conversion of the so produced comoound II ~1herein
X and X' are hydro~y to the corresponding compound I
is carried out as already described hereinabove 2S
reaction step "B".
In an alternate method for prepa.ing the
compounds of ~ormula III, a compound of formula V is
reacted ~ith a hydroxyalkylhydrazine of tne formula
N~2-NH(Ca2)2_11-OH, preferably NH2-Na(C~2)2_3-O~
to produce a compound of -Eormula III wherein 3 is
-(CH2)2~ ~ and is pre.erably -(CH2)2_3-OH.
This reaction is carried out substantially as
described hereinabove as reaction step "An. The OH
grou~ of the Z su~stituent is then derivatized to
produce an easily displaceable substituent known to
those skilled in the art as a "leaving group". For
example, the O~ group may be converted to a tosyloxy
or mesyloxy group by reaction with respectively -
p-toluenesulphonylchloride or methanesulphonylchloride --
in pyridine by procedures known to those skilled in
the art. The leaving group, so produced, may be
subseauently displaced with, for example, 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 groups or substituted
benzyl grou?s of compound III, if present, arè removed
as described above ~o produce a compound of formula
II, which may be converted to a compound of formula I
as already described hereinabove as reaction step "B".
The compounds having structural formula I ~herein
X and X' are chloro are prepared starting from
compound VI by first converting VI to the
corresponding di-p-toluenesulfonic acid ester VI'.
C~G-l ~37-
Cl O OTos
~3
Cl O OTos
~JI'
~ his conversion is conveniently carried out by
treating VI with p-toluenesulfonyl chloride in a
nonreactive solvent such as acetonitrile at reflux
temperature. The diester VII is then treated with a
substituted hydrazine NH2N~Z su~stantially âS
described above for the conversion of co~pound V to
compound III. The product of this reaction, VI''
N - N-Z
~3 ..
Cl O OTos
VI"
is then treated with an amine having the formula HNYR
subs~antially as described above for the conversion of
compound II to compound I. The product of this
reaction ha~ the following structural formula.
Cl ~ N-z
~3
Cl o NRY
wnerein R, Y, and Z are as defined hereinabove.
- 38 -
The compounds having s-tructural 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 conver~ion of
compound II to compound I, i.e., reaction step "B".
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, NH2-NHZ, wherein
Z is defined hereinabove, with l,5-dichloro-9,10-
anthracenedione in a manner substantially identical to that
described above for converting compound ~T to compound III,
i.e., reaction sequence "~".
The present invention also contemplates the novel
hydrazine, 2-[(hydrazinoethyl)amino]ethanol,
NH2NHCH2CH2NHCH2CH2OH. 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-(2-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 120C 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. ~or purposes of the invention, such
salts are considered equivalent to the free base form of the
novel hydrazine.
~25~;~3~
- 39 -
The benzylated ethers V wherein any oE the Q
substituents represent benzyloxy, p-chlorobenzyloxy, or
p-methoxybenzyloxy may be prepared by treating compound ~l
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,~-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
~:5f6~3~
CLG-l -40-
equivzlent amount of the desired acid in the
conventional manner. The free base forms may be
regenerated by treating the salt form with a hase.
For example, dilute a~ueous base solutions may be
utilized. Dilute aqueous sodium hydroxide, potassium
carbonate, a~monia, and sodlum 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 the invention can exis~ in un-
solvated as well as solvated forms, including hydrated
forms~ ~n general, the solvated forms, with
pharmaceutically acceptable solvents such as water,
ethanol and the like are equivalent to the unsolvated
forms for purposes of the invention~
The term halogen is intended to include fluorine,
chlorine, bromine, and iodine.
The alkyl and al~oxy groups contemplated by the
invention, unless specified otherwise, comprise both
straight an~ branched carbon chairs of from one to
about six carbon atoms. Representative of such groups
are methyl, ethyl, isopropyl, butyl, pen~yl, 3-me~hyl-
pentyl, methoxy, ethoxy~ i-propoxy, t-butoxy, n-
hexoxy, 3-methylpentoxy, and the liXe7
The alkylene groups contemplated by the inven-
tion, unless specified otherwise, comprise both
straight and branched carbon chains of from two to
about 11 carbon atoms. Representative of sucn groups
are ethylene, npropylene, n-butylene, n-heptalene,
~-propylene, 3-ethyl-1,5-pentalene, 3-propyl~
1,6-hexalene, and the like. The preferred alkylene
~roups of the invention have the following structural
formulas:
CLG~l -41-
1 l~3 CH3 C~I3 CH3 C2H5
-(CH2)-2~11; -CH-CH2-; -CH2-CH-; - CH - CH-; ~CH-CH2-,
C2EI5 l~3 C~3 C~3
- ca-; -C~!-CH2-C~2-; -C~2~C~ CH2 ~ 2 2
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 s~illed in the art
will recosnize that certain combinations of such
substituents are Inos~ probably unstable and these are
no~ intended to be included within the scope of the
defini~ions~ For example~ an ~amlnoal~yl or
al'.~ylene group of the general ~or~ula = N-CH~NHz
would not be expected to be stable whereas the
corresponding dialkylated substituent - N~CH-N~Alk)2
is expected to be stable and is intended to be
included within the definitionsO It is within the
s~ill of the art to recognize these and other such
substituents which are possibly unstable.
The compounds of the.invention are new chemlcal
substances of value as pharmacological agents for the
treatment of bacterial and fungal infections in
warm-blooded animals. They ~,ay also be utilized as
antiseptic agents such as for use in the steriliza~ion
of la'oora'cory glassware etc, The antibacterial and
antifungal activity o~ represeptative co~pounds of the
invention was es~ablished by the screening procedure
described belowO
~25;~3~
CLG-l ~42-
1. Pre~aration of inocula
_
~A) Bacteria and yeast-
The bacterial and yeast isolates are
maintained in agar slants or in liquid media,
hereby designated as inoculum media~ The
cultures are transferred at regular intQrvals
in such media. (See Table for the correspon-
ding inoculum media o~ each culture.) The
organisms are generally transferred or. to
agar slants or liquid inoculu~ media and
incubated overnight (18-~0 hours~: 37C for
the bacterial isolates and 28C for the
fungal cultures.
The microbial cells rrom the overnisht 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 M ). 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 the assay plates. Thus, 0.16-10 ml
(see Table for exact amount) are used to
inoculate 100 ml of the ~olten-agar assay
medium.
(B) Mycelial fungi:
The Penicillium avellaneum is grown for six
days, at 28C, on an agar medium. ~his is to
allow sporulation of the culture. The
organism is then harvested by scraping of~
the cells from the agar surface (mycelia and
spores) and suspending them in saline
solution con'aining 0.05% Tween* 80.
*trade mark
~5~3~L
CLG-l -43-
The suspension is adjusted to a light trans-
mitancy of 20~. One ml of this suspension is
used to inoculate 100 ml of the mo]t~n-ayar
assay mediu~.
2. Preparation of assa~_~lates
Stainless steel Crames, 12.3 x 25.3 cm (I~) 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 the inner edges sealed
with 2% agarO Twenky five ml of inoculated assay
medium is spread evenly on each tray and allo~ed
to solidify. The trays are covered, inverted, and
refrigerated until used.
3. Diskinq of sam21es
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 of 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
~rays with forceps, then 0.08 ml o~ the dissolved
compound is pipetted onto each disc using a 0.2 ml
pipette~ (*If the compound does not stay ln
solution at <10% alcohol, then the fuli strength
alcohol is used. However~ the im2regnate~ discs
are air dried before they are iaid on to the
seeded agar plates.)
4 Interpretation of results
.
The disked agar trays are incubated overnight
(18-20 hours) at 37C for the bacterial cultures
and 28C for the y~asts. The Penicil]ium
avelianeium tray is incubated for at least 20-24
~S~i~3~
C1G-1 ~44~
hours since it is a slower growing organism.
Acti~e compounds show a zone of inhibition arounZ
the disc. The diameter of the zone is measured in
mm~ The zone diameter o~ 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 zctivity.
~2S6~3~
CLG-l -45-
~z L ~
1~` ~ ~ o ~ ~
~ ~ J~o~ L~ 1
I Q u~ ~ u7 q~ ~o
E~ _1 co~ 0~ O c~
__ ~ ~___ ____ _ 1-- ____
~ u~ .~ ~u~l ~ ~u~ ~uL ~
~l2~
CLG-l ~46
5. Culture media
The composi~ioll of the various culture media,
except for the commercially available media, are
sho-.~n below. The commercial ready-made Veal
Inusion Medium is obtained from Difco
Laboratories, D~troit, Michigan, USA~ Add 1.5%
agar to these media for use as agar plates.
AM-08 %
. . _
Glucose 0.2
Sodium Glutamate 1.04
K~2P0~ 0003
Na2HP04 0.07
Salts ~la 1 ml
Salts ~2~ 10 ml
H20 (distilled)
aSalts ~ 1 % bSalts ~ 2 %
... .. ..
MgS0~ 1.0 MnS0~ 1 0
CaC12 5.0 znSO4-7H20 1.0
NaCl 5.0 FeS04.7H20 1.0
CuS04-5~20 0.01 ~2 Idistilled)
H20 (distilled)
~2S~
CLG-l -47-
A.~-09
R2HPO4 3~9 gm
Dextrose 25 y~
Wa-citrate ~2 H2O 34,4 gm
Casein hydrolysate 6~2 gm
Asparagine 375 mg
L-tryptophan 125 mg
Cysteine 312~5 mg
Glutathione 3,1 mg
Thiamine HCl 25G g
Ribo1avin 625 g
Ca antothenate 500 g
Nicotinic acid 500 g
~-aminobenzoic acid 625 g
Bio~in 12~5 g
Pyridoxine HCl 2.5 g
Folic Acid 500 9
NaCl .12.5 g
MgSO4 250 g
FeSO4 12.5 g
MnSO4 H2O 125 g
Tween 80 62.5 mg
~2 (distilled) lO00 ml
AM-25 %
Na2HPO4'~2O
~2PO4 0-05
Yeast Extract ~Difco) 0.5
Dextro~e l.0
Distilled Water
Utiliziny the above described procedure, the
following results were obtained for representative
compounds of the invention.
S~D~3~
CLG-l -4a-
a
_ o O ," O O O - - _
a ~ ~ ~ ~
~nV o o _~ o r~
__ _ ~ _ ~' _ _ ~ _ ~ _ ~ _ .~ _ ~ ___
._ ~ _ _ ~
a ~v o o o o o o o o o
__ __~
8 ~_ ~ o
o ~ a _~_~_~_~_~___~_~_~_
~ c C~ o o o o o o o O _~
c ~ ~ 2 ___________________
X O
~: ~ N ~J V
_ ~ Z Z ~ O Z Z
U t~ V (J U V i
. _ _ V V V ~ O
N N ~ = 2 2
V J 'J V V U t~ ~J V
_ _ N N N N N C`~ t`l N I J
~ ~ S
3~
CL~ C9-
E ~ ~ ~ ~
o o o o o o o o o o o I
a.- ~
o ~
1 0 _ _ -- -- "~ ô ô ~,~ o ô o I
I ~ rl o -~ o o ~ ~ o -~ - ~ I
~ o ~ O .
l __ ____________ __________----l
o o o o o ~ ~ I
Oq ~ ~ ~D O ~ I
l ----------------------~---- -- -- --. 1
1~i0 _~ ~ o _~ o ~
~ __ ~ tl O ~ _ Q O O _ _ O I
C O O - O O '1 _ _ O O
¢ ~ _ V O ~O O
__ _________________________~
I a u a a . I
~1 ~ ~ ~ :`d I
. C2 U 'J U ~J V ~ _ '.2 t.~ '' ~ .
J U CJ ~ -J ~J I
l __ __ __________ ------,----------------l
-~ 2 ~E ~Z~ z ~ z
- - - - - ~ 2 ~ 2 2
U 2 ~
l __ _________________________l
l ~ = -- = _ = = = 2 = = 2 1
''LG-l -;0-
. c~l o ~ ô o o -o o
~L~ r~ I .
__ ________________l
~ o o o C:~ o o ~ I
_ ~ ," ,." ,_, _ o I
___ ___I
__ o ~ ~ _ I
_ ô ô o o o
~ r _ _ _ _ ~ _ o I
__ ________________
~ C ^ ~ ~ ~
hi O ~ I
__ o o ~ o _ _ _~ I
~ ô ô ô _ ~ o ô I
_ r~ O O _ ~ I
~C C _ _ _ _ _ _ I
~: O o o ~ ,_ .r o I
_ I--------------------------_ ----I
~ Z Z Z l
~ u u '~ 3~ u u u I
__ U U t~ 'J ~J O ~J I
~ ~ z~ I
Z
~ a u ~. l
U ~ U U U I
__ _ __ __ __ __ _ __ __ __ I
~ - ~ = = S O O I
- - I
. . ~
CLG-I _51_
E I ~ _ _
C o o o o o o o o o o
_ O o o ~r o o o o o o o
_ _______________________ . ~
_ ôôooooooooo
U ~
Ul ~ _ _ _ _ ._ _ _ _ _ _ _
~ ~ O o o ~ o ., ~o C~
__ _______________________
ô ô a o o o o o o o o
. _ r~
¢~ _ ._ _ _ _ _ _ _ _ _
__ O r~ ~ ~o 1~ 'n ~ ~ ~ o
O o o o U~ o 4~ o
.,~ r~ o o o o -- o r~
~ ~J ~ o o
__ _~_____________________
~ o o O ~ O O~' ^ - _
__ _ _____________________
O ~
~Y
h~ 2
~J 'J
w ~ ~ Z~ Z~ Oa ~-, Z~ z~ z~
a a a a ~ a ~
_ u ~ u-- -- -- --
_ O O ~ O
. u ~ .
u tJ ~ 3 a ~
Ja J U tJ ~ J
__ ___________ ____________
O O O O O O O O O O
~C I I I O I I I ~ ~ - _
CLG-l - 52 ~
c o o o O O O -- -- _
c.~ ___________^_______
r- ~ r~ r.~ ~ r-7
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ ~ O ~ r~
_ _ ~ _
~ a _________________~' _
C o' ", ", ~ O ~ O
I ¢ ~ _ _ _ _ _ _ _ _ _
_______~'___________
rl U U ~ U U U 'J
~ ~ zC z O ,=, z ~ z z
_ r~ r ~ r~ ~ ~ r~
_ U U U U ~ r'~ =~ r~
. O~a~
_. ~ --~ -- C z z z z
UUUUUUUUU
l __ ____________________
l O O O O O ~ O O O
~S O ~
-j3~
_ _ ~ ___ _. _ _ _
J O O O OOO O O O O
_ r~r r~r r~ r~ r~ r~ r~ r~ _ _
D O O O O O O O O O
_ O o o o-- _ _ _ ------__
_. r . r~r~ r~ r.~ r l rrr r~ r~r r~
Cr _ _ ___ _ _ _ _ _
~ OOOOOOOOO
_ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ r~ _ r~7rr~r~ r~ rr~ r~ O
r~ O 1~1 0 0 0 0 0 <~ O ~
. o a ô o o o o o o o
._~ ~ r~ r~ _ ~ _
b~ ,0 ~ ~ O U~ O ~r~n O
rJ ______________________
¢ O' ~
r O O ~ In O
- ~ S ~ C
r~l r~r~lr~ _
'J U 'J U r' r~~ r.~ U
r.~ _ _ ~ _ _ j~ ro~ ~ _ rr
r~ r- r~ r~- r~ r~ =`l, _ r~l r
__ J U U U U U U _ _ U O,
= ~r
. ~ r~ r~JI
7~ [~~ r~`~ C-' r~ _ J
w ~ 5 ::~ z z z z ZZ~ ~D
_ _ ~ r~ C
~ a~J_,D a a a a a 3 ~
__ __ _ _ _ Z Z -- -- _-- _ _ _ C
r~l r~rr~ r~ r~ r~ w rJ
I _ _ _ =~ _ ~ _ ~_ L~
O O O Oo e, C' ~ o . _.
~c o o oI ' o o o I o I ~I
r~ ` ` ` Ul
C L~ 4 -
C _. ,_ ~ _ _ _ _ _ _ ~ _ _ _ ~ _
V o o o o o o o o U~ o o o o o Ul
;1. _ _ _ _ _ _ ~ ~ o ~ ~ ~ o
¢ o o o o o o o o ~ .o o
__~___________ ___________________
_ ôoooooôooôooooô
~ _______________
~ Y~ O O O O O C _ ~O O U U7 ~r o o
__ ____________________________.___
~ _ o l- o o ~ o o ~ _ _ ~ ~ ~ _
_ _ o ~ ,_, o ~ ", ~ -' O o o C
. _ ~ o r~ o _ rt ~ .~~
_ O ~O ~r ~ ~ .r ~ ~1~ ~o .r '.D ~ ~r ~r o
__ ________________________________
_ "., _ _ ~ 4~ o ô
_ o I , , , I I I , ~ _
;~ ~ 0 0 ,7 ,,
__ _______________________________
U ~ _ _ _ _ _
. ¢C ~
__ __ __ __ ____.__ __ ____ __ _________. _ . _. _ . . . _. .
~ O C~
Y ~ ~ z z u a u -~ ~ ~ _
~J ~ u u r '~ o
a ~ U ~ U U U a a U U ~
__ _ _ _ _ _ U U U _ ~
~ Z~ . U O ~ O o _ .
~ = a u ~, ,. cJ h
. U U ~ U C.~ U C ~ .
U U ~'- U U U _ U 11 ~ 4 ~ _ _, _
~ u 'J a U U~ a U U ~ ~U U u u u ~
__ ____________________________.~_ c
^ I ^ = = = = - S -
o o o _ _ 3 o o3 _
X o o ~ o ~, o ~ o ' o U~
r r 1~ ~
. ~2~
~:L~ S~-
v oôo ô
n :~ ___________
V~-~-~-~~-~- '
__ __ _ __ __ _ __ _
rJ r~ Z ~ Z"~ E
-U~-U~--u~ 9~ -
~ ~uvu u I
x ~ ' â ~, O O ~u~
C L~ 5 6 -
O ~ _______
C ~ ~ U
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C~G-l ~57~
~ n addltion to their use4alness as an~ibio~ic znd
antifungal agents, cer~ain o.' the comsounds o the in-
ven~ion displav in ViYo antileukemic activity when
tested by the followinq proced~re.
The in ~ivo lymohocy~ic leukemia P398 test is
carried out by the ~nited States Mational Cancer
TnstituteO Th~ ani~.als used ar~ eitA2r m2le or ~emale
Fl mics~ There are six to seven animals ,?er te~s~
groupO The tumor trar.splan~ i5 ~y Lntraperi~oneal
injection o~ dilu~ ascitic fluid contalning cells of
lym~hocyti~ ~eukemia P388. The ~es compounds.are
~d~iniste~d intrap~ritoneally in ~wo single doses
wit~ a ~our~da~ int~rval be~een dos2s at vario~s dos~
levels following tumor inocula~lo~. The animals are
weighed and survivors are recorded on a regulzr basis
for 30 day~. A ratio o~ survival ~ime 'or treated
(T)/control ~C) animals ~s calculated. ~he c~i~erion
for efficacy is T/C X 100 > 125%. T~.e.positive . .~.
control com~ound in ~his test is l,4-dihydroxy-5,8-
[bis~[2-C~2-hydroxye~hyl)amino]~ethyl]amino]-9,10-
anthracer.edione given a~ dosages ranging 'rom 12.0 to
0.075 mg/~g. See Czncef Che~otheraDY ~eports, Part 3,
3, 1 (1972) for a co~prehen~ive discussion of the
protocol~
Utilizing tnis procedure, the ~olLowi nq res~l ts
were ob~ained for representa~ive compounds oO~ th~ ,
invention.
N - M-Z
10 11
X~
7 0 NR
13~L
CLG-! -58-
X ¦ ~ ¦ N~
... __ I . _ Im~/k~ I (7O~cent)
7~10 (~32 (CH2)2N(-~e)2!~H(c~2)2Nd(cd2)2oHl 12.5 1242, 162
I ~ I 0.781161
7,10 ( CH ) 2 ! ( C H2) 2N ( ~e ) 2 ¦ ~H ( C d 2) 2 NH 2 6 25 ¦ 216, 192
0 781194 146
( H)2¦(CH2)2N(Et)2¦~H(CH2)2~(Et)2 11 118 174
.2Hcl I i 25 1140, 143, 149
12.5 1132, 114, 140
(CH2)2r (t)2lNH(cH2)2NicH2)2]2ol2ooo 1l2~o l4a
I l lO0 l 145, 126
Hl(cH2)2N(Et)2l~H(cH2)2N~l(cH2)2 ¦ 12 5 ¦161, 152 178
6,25l145, 146 161, 17a
3.121128, 142, 164, 151
1.561142, 142 146
~2~J~
CLG-l -;9-
X ¦ 3 ! tlR'~ I Dos ~ r/C X 100
7~lo-(oH!2l (CH2 )2~;Et)2 ¦'iH(C~12)2 JH(Cr~2 )2OH¦ 12.5 ¦Z64, 212
6.251 180,180, 164
2HC1 1 13.121164,154, 166
1.56114a,L49, lS;
10,781140,151, lC9
.391 152 126
7,10-(OH)2 11~H2)2N(Et)2 1~H(C~2~2.1H~e ¦ 2S I L72
2HBr I 112.S 1191
6.251 163
3.121154
7,10-(OH)2~(C.'1~)2N(Et)~, H(CH2)2NH2 25 L79 Cures
12.5 280, 189 Cures
2i~C1 1 16.251189,191
3.121154, 160
1.561 172
21 2)2 (C2)2N(.`~e)21NH(C~2)2N8(CH2)2OHI S0 1226
12. S 1179,219
6.251 198,191
3.121207
7,10-~OH)2¦(CN2)2 ~s(cH2)20H It1CH3(C~'12)2N~?4e)2 ¦ 6:2sll7s
2HCl I l l
7,10-(OH)7¦(-H2)2NH(CH2)2OH ¦N~(CHz)212:1Me I L2.5 ¦L69
1 21!C1 ~ 16.251163
H ¦ ~Cg2 ) 2NH ~C~2) zOHI NH ( CH2 ) 2N (Me ) 2 ¦ 25 I L62
2HC1 1 ¦6.251163, 174
- I I I3.121 158
_
~.~S6~
CLG--'
--50-
_~ ____
X ¦ 2 ¦ NRYI ~ose 1 ~/C X 100
m~/Xq I I ?er-ent
7,10-~OH),i(CHz~2r~;~(CH2)2OHlNH(c~2)2~ e)2 ¦ 25 1 8a Cures
12.5 1220, 250 Cures
1 2EIC1 1 1 6.251165 la2
3.121165 165
1. 561161, 165
0.7811;2
Hl ~c82)2NH(cH2)2oHlN8(cH2)2`l(Et)2 ¦ 25 11~9
I L2.5 llS0 lS; 15a, lS0
2HC1 1 1 6.251138 146 lS0 142
3.121 143, 143, 14~ lSl
1.56 l 138, 133
7,10--~0~)2 j~CH2~2NH~C~2)20H¦NH~C~2)2~Et)2 ¦ Sû 1241
125 1190 209 Curss
2HC1 1 112.5 1177; 190
6.251 154 16a
3.121 148 lS0
11.561131, 135
7~1~ (0H~2l~tu2)2NH~cil2)2oHlNH~cH2)2N8(cH2)%N(l~e)2i 50 1200, 254 Cures
125 120~, 228, 12
2~1Cl l lI Cur2q
12.5 1157, 179, la8
16.251169, 172
3.121 152, 163
~¦ ~CH2)2NH(C~2 ),~¦ ~i8 ICH2)2NH(CH2)2O~} ¦ So ¦ 199
125 1171 185, 185
CR3CO2R I 1 12.5 1148 189, 166
6.251147, 157, 166
3.121138 lS0, 166
I _ 1 1. 561132 142
3~
CLG-l ~o l -
X 1 2
r ~ S/~ I (?~rcent)
7,10-(OH)2~ }2)2;i~i(c~z~2otilNH(ci2)z' i1(c~2)2o ¦ l
~2HC1 1 1 12.5 1153, 177
6.251206 Cur~s
3.121107, 187
I I I l . Sfj I lSa, 16a
H¦ (cH2)2tia(c~z)2o~iNH(cH2)2~;fl2 ¦ 12.5 jl75, 1S30
I ZHCl ll I 1 561150
7,l3-tOH~2l(CB2)2N~(c~2)10Hl~H(c~2)2~lH2 1 3 12¦15i3, 196 Cures
! 2HC1 1 1 0 7S3l1a2
7~lo - ~oH)2l(cH2)2N~(cH7)2odl~H(cH2)3tlH(~-Rt)2oHl 6 251169 254 Cure~
1 ~2RC1 ¦ 1 1.561201, 167
7~lo-(oH)2t(cH2)2NH(c~2)2oHl~H(cH2)3NH2 1100 jl31 Cures
1 ~2HCl I 1 25 1207 250 Cures
12.5 1177 190
' I 6.25 l 165, 172
l l 1 3.121165, 165
7~10 - (O~)2l(CR2)2NH(CH2)20H¦NH(C~2)4N 2 1 25 llS0 152
1~.5 1139 14;
6.251131
I I I ~.1211~0
7,10--(0H~2¦(CH2)2Nfl(CH2)20H¦NH(CH2)5NH2 ¦100 ¦1SO
S0 127, 139
2HC1 1 1 12,5 ¦127
C.G-I -62 -
X ¦ ~ ¦ NllY I DOf~Q ¦ -/C X 100
~ q/kq I ~ r c~ r t ) _
gl (Cq2)2;~H2 1:`lH(cH2)2~H(c~2)2oHl 12 5 ¦173~ 177
3.121 1~9, 158
1 1.561139
7,10-(Qa) j(-H ) ::H ¦ ¦ 12.5 ¦182
3 12 1 160
1. 561 153
7 lo-~C~ "H ) Ole ¦ ~ 50 ¦135
12. 5 1 127
7~10--(9H~2¦~c~2)2oH ¦~H(Ca2)2N~He)2 ¦100 ¦225 242
~ I I S0 1 180, 182, 182
1 29 ! L53, 157, 173
1 12.5 1124, 135, li9
7 ~ 10--( O H ) 21 ~ C H 2 ) zOH I 1 2 0 0 1 16 7
00 1143
1 135
37.5 1135
1 25 112a
7,10--(0g)2¦(C12)2Oa ¦NH(CH2)2NH(CH2)20H¦200 1196, 271
gCl I î 50 1163 155
1 165, 187
12.5 1158, 163
6.251143, 163
7 _ rl R Y
I rr;~kq I ~ P g r e ~ n ~ )
7 10-(OH~2~ 2~ZOr! I (CH2)Z~B2 11OO l172, Lg6
I .2HC1 I S~ 1162 L72
1 12 5 l145 l51
I I 1 6 25l135
7 10~(OH12I(~H2)2~e 1 ( 2)2 (C 2)20H I 126 25l1L4302
7,10-I~H)ZtC92CHOHCB2N(Et)2 INH(CH2)2N(Et)2 l100 ¦157
I .2HC1 1 1 50 131 135
1 12.5 l128
21 2 0 C~2~(Et)2 ¦!la(CH2)2NH(CH2)20a 1 12 ~ ¦132 223 Cures
I ! 3.12l129, 188, la9
I I 1 1.56l139
1 0.781132
7 1O-IOH)2ICH2CHOHCH2~(Et)2 ¦NH(CE2)2NH2 1 12.5 t142, 213
I .2HC1 6.ZS 16O, 189,
I 1 1262 CUre5
1 1.5ollS7~ 1~;6
( 0 . 7a ( 132, 179
I 1 0 39l135
7,10-(OH)2lMe ¦NH(CB2)2NH(CB2)20H 11OO ¦174
j I 1 25 ILSO~ 164
1 12.5 l140, 149
I 1 6.25l133, 1;5
i I 1 3 12l138
7 10-(0H)2l CB2CH2NH2 ¦NHCB2CB2NH2 1 25 l156, 218
1 12.5 l144 203, 221
7,10-(OH)2¦ C92CB2NMe2 1 2 2CH2Na2 1 12.5 l205, 208
1 6 25l196 Cures
7~1O-(OH)2ICB2CB2CH2 2 INHCH2CH2NHCa2CH20H I 12 5 ~218 203
1 6.25l185,167
7 1O-(OB)2IC~2CH(O~)CB2OB¦NaCH2CH2NHCH2CH2OH l400 l281, 255
I200 ;218, 213
II 1 50 1177
1 25 11B4 166
¦ .2aC1 ¦~HCB2CH2CH2Na2 1 12.5 1173 180
j ~ 6.25l167,173, 190
7~1O-(O8~2ICH2CII2CH2~Me2 ¦NHCH2CH2NH2 i 12 5 1224 Cure~
I I 1 3 12l191, lao,~0-(OH)2¦CB2CH~NMeCH2CH20H ¦NHCH2CH2NHCB2CH20H 1 12.5 l203
.1 6HC1 1 1 6.25I182
I 1 3 12l184
( ~2!CH2CH2NHCH2CB2OH ¦NH(C92~3 (CH2CH2OH)2I1OO l192
I I 1 25 l163 (OH)2 CB2CH2NHCH2CH20H INHCH2CH2~HCH2CH2NH2 1 25 l221, 227 Cure9
~ j 12 5 1233 231 CUre9
-S4- 3~ 5~i~3:~
C~
~t ~ 7 ¦ ~RY I Gose ¦ ' iC X 100
I r;w/ ~ s I ~ 7g r ~C e n 1: )
( H)2 IC:{2cH2NHcH2~H2(7H jNHCH2~H2!J(CH2CH20H)2 1100 ¦223, 254
2.3HC1 1 1 50 1203, 169
25 ,1a7, L94
12.5 I1;a, 156
)2 ~ 2cH2~yHcH2cH2oH ¦NH(cH2)3~yd(cH2)4NH(cH2)3Nii2l 12-5 I145, 117
2. 75HCl I I 6.25 ! 127, 109
7~10-~OH)7 ¦(C~2)3~HCH,_H20H ¦NHCH2CH2NHCH2CH20H I100 ¦2sg Cur?s
1222, 183
I1a3, 174
I 12.5 ILS7, 146
'(OH)2 j (CH2)3t;HcH2cH2oH jNdcH2c:{2c'!2Nii2 I100 I185, 155
O.lHC7 I I SO I160, 146
(OH)2 ¦C'12CH2NHCH2CH20H jNacH2cH2NHcH3 1 12.5 I277, 275 Cures
CH3C02H-H3r ~ I6.25¦277, 275 Curcs
3.121268, 177 CJres
7,10--(OH)2 ¦ca7CH2~H2 ¦NHcH2cH2~yHcH2cH2NMe2 ¦ SO ¦ 220 Cùres
3.3HC1 1 1 25 1192 177
12. 5 I1B6 157
7,10--(OH)2 ¦CazCH2NH7 1 2 2 2 CH2cH2oH I 6.25I1a4, L94
2.1HCl I 1 3.121 L77, 134
I ~L.561131, 172
7,lO-(OH~2 ¦ca2c~d2cH2NH2 ¦NHCH2CH2YHC-Y2CH20H ¦ SO ¦285 Cures
2HC1 1 1 25 I285 Cur?s
1 12.5 I247, 163 Cures
_ __~ _ I I 6.25I193, 134
7,1O_~OH)2 ¦Ca2cH2c 2 2 ¦NHCH2CH2NHCH2CH2YMe2 ¦ 25 I223 L30
7,10--(Oil)2 ¦Ca2CH2 3 ¦NEiCH2C92RHCa2CH2oH I 12.5 I147
7-OH ¦Cd2Ca2NHCH2CH20H ¦NHCH2CH2NHCH2CH2GH I 25 I285, 184 Cures
2aU I 1 12.5 I228, 142 ures
6.ZSI 133, 134
10-oti ICH2cn2NHcH2cH2H INHCH2cH2NHcH2cH2H lloo ¦221, 184
2.1HCl I 1 50 I172, 16i
I 25 I163, lSS
7~8~10-(OH)3tCH2CH2~IHCH2CH2Gl; IYHCH2C'd2!iHCH2CH20H ¦ 25 I265 Cuces
2.1HC1 I 1 12.5 1257 Cures
7~9~i--~:~H~3IcH2cH2NHcH2cH20H INHcH2cH2NticH2cH2oH I 3.121165
2.1HCl I I 1.561155
Cl,G-l -55-
,, ~_
O Z ~ O ___ _ __ _ ______
~ X _ ~- ~ o C~ o
.~__ _.__________ ~o.
E _ _
CLG-1 -66-
Broad ~ectrum Ant1~mor Activit~ oF 2-¦2-(D1eth~L-
a:~lno)erhv' 1-7,10-dihYdrox~ 12-1(2-h~drox~ t'~
a~L~0¦2 ~lla ! - ~ -[ L~
HO N ~-N (Ca2) 2N (Et) 2
2i~C1
OH d NH(ca2)zNEi(ca2)2oH
Tumor ITumor/l~egi~enl Dose I~C x 100) ~ Tumor
.. .. - . !Dru~ g/kg)i~2e~cent)l~eduction
ADJ-PC5 P'as~7acytoma IIP/IPIQO4DXO3l 16 1 163
I l 1 8 1235
~ Z16
I I 1 2 1207
al6 :~elanoma ~3DF1) IIP/IP lOO1DXO9I 3 ¦ 176
151
ai6 ~leLanoma IIP/IP ¦Q01Dx091 6 1 189
(36C~'l) I I 1 3 11~1a
Co1Orl 3a taDpl) ¦SC/IP IQO1DXO9¦ 16 l l 71
L1210 Leulcemia(C3F1)lIP/IP IQOIDXO9l 16 1 133
1 8 1 240
I 1 4 1178
2 1-144
l l 1 1 1137
M5075 Ovary IIP/IP IQO4DXO4¦ 10 1 260
I I 5 1186
1 2.5 1 233
1.251 143
~Proc~ure described in Cancer Chemotherapy Reviews, 7
167 (1930) and reference.~ cited therein.
~ZS6~
CLG-l -67-
In addi~i~n ~o ~eir usefulness as anti~iotic and
anti.ur.gal agen~s and as antileukemic agents, cer~ain
of the comoounds o~ ~e invention display in vitro
activity aqair.s soli tumors when tested by ~he
ollowing procedure,
~ C~8 (human colon adenocarcinoma) cellc ar~
trypsini2ed using Trypsin-E~T.~, ~ sinql~ c~ll
sus~ension is ac~iev2d by ~assing the cells throuqh a
2S ~ausc needle ~ih a 20 cc syringe. ~ cell
suspension is prepared using RP~I 1640 grow;A medlum
(availabl~ ero1~ Gibco ~abora~ori~s) + 10~ f~tal calf
~er-um ~ 50 ~g/ml garamycin wi h a cell concentra~,io~
of appro~ima~ely 30,000 cells/~l~ Th~ cell sus~ensicn
is dispe~sed in ~inbro 23-well plates; 1 ml/w~lL. T~e
~lates are incub~ted 'or apDroxi~ately 48 hrs at 37C
in a S~ C02 at~osohere, A~ this ~ime tes. compcunds
are added in the ap?ropr~ate concent.ation. Five ~1
of the 2C0 ~g~ml stock solution is added t~ .eac~
well in a primary testl Ten ~1 of the zpprooriate
dilution is added ~o e~ch well for a titratlon tes~.
The pl2tes are reincubated an additional 60-6~ hrs at
37~C in a 5~ C02 a~osphereO The test is read by
lysing the ceLls usin~ a mix of cationic surfactan~c,
glacial acetic acid 2nd sodium chloride~ Two ~.1 of
the lysed cell su~oension ~rom eac~ well is added ~o
8 ml o~ dlluent. Each sample is read with~a Coulter
counte_ ~Z3I ~od21). ~he ac~ivity of e~ch sample i5
measured as a pe.centage of ~he con~rol~ and the da a
is reported as IDso, ~hat i5 the molar quanti~y of
drug requir2d to kill 50~ of the tumor cells/
U'cilizing ~hi~ procedur2, ~h~ Eollowing re~ults
wer~ obcained ~or represen'cative compounds o~ 'cn~
in~en~on~ '
C-~G-l -68-
r.. Vitro Activity o~ Aminoanthra?yrazoles
Aqainse Ruman Colon Adenocarcino~a
N N-Z
10 11
X~
X¦ Zs ¦ ~Ys ¦ IDso Molar
N¦~CH2)2NEt2 ¦ (CY2)2~Et2 1 1.4 x 10-7 ..
2HCl
H¦ CH3 ¦ I ~)2 t2 ¦ 4.1 x 10-7
2HCl l l
¦(C 2)20H INH(CY ) I 1.8 x 10-5
I ,2HCl l l
B¦ H ¦Nd(CH2)2NH(CH2)20H¦ 1.5 x 10-6
j ~HCl
H¦ CH3 ¦N~(CH2)2NH(CH2)20H¦ S.O % 10-7
I ~YCl l l
a¦(CH2)2NEt2 1 ( Y2)2 2 1 5.2 x 10-'3
~2HCl I I ~
¦( 2)2~H(CH2)20H ¦NY(_R2)2N~(CH2)0H ¦ 9.6 x 10-7
CH3Co2H
CIG-l -69--
T~
Xl Z I NRY I ID90 Molar
I
HIICH2)~H(CH2)2OHINH(CH2)2NH2 1 ~.2 X 10-8
I .2HC1
HI(CH2)2NH(C~2)2OEINH(CH2)2NEt2 1 1.2 ~ 10-7
I .2HC1
~¦(C~2)2~H(C~2~20HINH(C~2)2 ~e2 1 2 3 K 10-7
I .2HC1
H¦(CH2)2NH(ca2)20HlNHcH3 ¦ 2.8 K 10-7
I ~IC1
~I(CH2'2H I (C 2)3NEt2 1 ~.8 X 10-7
I .2HC1
H¦(CH2)2NEt2 ¦NH(CH2)2N~_~O I 1.2 X 10-7
. 2Hcl ~ l
H¦ (CH2)2NEt2 ¦ (Ca2)3NEt2 ¦ 1.3 K 10~7
I .2~C1
H¦(CH2)2NEt2 1 ~C 2)~ Et2 1 2 2 X 10-7
I .2HC1
H¦(CH2)2NEt2 1 ( 2)7 t2 ¦ 2 2 X 10-6
I 2HCL
H¦(CH2)2NEt2 1 ( 2)2 ~ ~ H ¦ 3.8 x 10-7
3H~r
I~C 2)2NH2 ¦NH(CH2)2N~CH2)2OH¦ 6 . 8 x !0 -8
I .2HC1
C~G-l -70-
X I ~ I NRY I ID50 ~t~l~r
., I .
,l0-(OH)2~ 2)2rlEe2 ¦NH(C~2)2`~(CH2)20H¦ 2.7 x 10-7
~2HCl I l
7,10~(OH)2¦(C~12)2NEe2 1 ( 2)2 Et2 ¦ 5.~ x 10-7
1 ~2HCl l l
7,10-~OH)2l CH3 ¦~8(CH2)2r~H(CH2)20H¦ 7.9 x 10-7
.~ICl
7~}0-!oH)2l(cH2)2qEt2 1 ( 2)2 'i2 ¦ 3.3 x ;0-7
28C
2i 2)2 2 ¦NH(cH2)2NH~2 1 1.2 X 10-7
1 ~2HBr
7~lo-!oH)2l ~CH2)2N~e2 ¦NH~CH2)2NH(CH2)20'i¦ l.a x !o-7
1 ~2HCl
7,1d-(OH)2¦ Ca2c~oHc~2~Et2 ¦NH(CH2)2 2 1 4.6 x 10 - 7
I 2HCl
7~10--(OH)2~ C~l2cHoHcsi2~qEt2 INH(CH2)2NH(cH2)2o
J 2~1Cl
7~lo-~oH)2l(cH2)2oH ¦NH(CH2)2NMe2 1 1.7 x 10-7
I .I~t:l l I
7-10-(oH)2i(ca2)2N~e2 ¦NH(CH2)2N~i2 ¦ 1.4 X 10-7
I 2HCl
7.10-~oH)2l~c~i2)2NH2 ¦NH(CH2)2NH(CH2)20H¦ 1.7 x 10-6
2HCl
I
~s~
C~G-l -71-
. _ I
X I Z I N~Y I 1350 ~ola~
7,10-(OH)21(cH2)2NH(c 2)2 ¦ ~ 3 ¦ ;.4 x 10-7
?,lO-(OH!2¦(CH2)2~H2 ¦ ! 2)2 t2 ¦ 3.1 x 10-7
7HCl
7,10-(OH)2¦(C~2)2~Me2 1 ( 2)3 2 1 i.l x 10-6
I 2tlCl l l
7,10-(OH)2t~CH2)3'~Me2 1 ( 2)3 2 ¦ 3.5 x 10-7
1 ~2HCl I I
7~lo-(ott)2lcH2cH2cH2NM~2 INfiCH2c~2~`~HcH2cH2H I 9-2 x 10-8
I 2HCl
7~lo-(oa)2lcll2cH2~MecH2ra2oHlNHcH2cH2NilcH2cH2oH I ~.5 ~ 10-7
7,10-(OH)2¦CH2CH2lqiiCH2CH2oH jNHCH2CH2NHCH3 ¦ ~.0 x 10-7
I .1.8HCl l I
7'1-(H)2lCU2CII2NH2 ¦NHCH2CH2NHCH2CH2~Me2¦ 1.2 x 10-6
1 ~3.3HC1
( )2~ 2 2NH2 ¦~H(CH2)3NHCH2CH~H I z.a ~ 10~7
I 2.1HCl
7~lo-(oH)2lcH2cH2Ntt2 ¦~HCt~2CH2CH2Na2 1 3.5 x 10-7
I 2.9HCl
7~lo-(otl)2~cH2cH2cH2~qH2 ¦NtiCH2CH2qHCH2cH2oH ¦ 7.7 x 10-7
I 2HC1
7,10-(OH)2¦CH2CH2NttCH3 ¦NHCHzCH2NHCH2C!t2OH j 2.3 x 10-7
1 ~2HC1 1 1
7-OH¦CH2CH2NHCH2cH2oa ¦NHCH~CH2NilCH2CH2oH I 6.1 x 1O-8
1 2NCl
O-OH¦CH2CH2NHCH2CR2OH ¦NHCH2CH2NHCH2CH2OH I 1.1 x 1o-6
~2.1HCl
I 2 2 2 2 ¦NHCH2CH2NHM~ I 2.7 x 10-8
1 ~1.8HC1
CLG--1 -72-
N--N-Z
'. ~
NRY O
- I
æ INRY ¦ IDso Molar
(CH2 ) 2NEt2 ¦NH (CH2 ) 2~Et2 1 2. 2 x 10-7
2HCl ¦ I
2)2NEt2~ NH(C~2)2NH(C~2)2OH ¦ 9.3 x 1o-8
2HC 1 1 1
CTJG-l -73-
When being utilized as antibiotic and antifung~l
agents, the compounds of the invention can be prepared
and administered in a wide variety of topical, oral,
and parenteral dosage forms. It will be clear to
those s~illed in the art that the Lollowing dosage
forms m2y comprise as -the actlve component, either a
compound of formula I, certain o~ the compounds of
formula 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 by this invention, inert,
pharmaceutically acceptable carriers can be either
solid or liquid Solid form preparations include
powders, tablets, dispersible granules, capsules,
cachets, and suppositories. A 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 carri~r is a finely divided solid which is in
admixture with the finely divided ac~ive 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
rom 5 or 10 to about 70 percent of the activ.e
ingredient. Suitable solid carriers are ma~nesium
carbonate, magnesium s~earate, talc, sugar, lactosef
pectin, dex.rin, starch, gelatin, tragacanth, methyl
cellulose, sodium carboxymethyl cellulose, a low
~elting wax, cocoa butter, and the like. The term
"preparation" is intended to include the formulation
of the active compound wi~h encapsulating material as
carrier providing a capsule in which the active
co~.ponent (with or without other carriers) is
C~G-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 for oral administration.
Liquid form preparations include solutions,
suspensions, and emulsions. As an example may be
mentioned water or water-propylene glycol solutions
or parenteral injectionO Liquid preparations can
also be formulated in solution in aqueous pol~ethylene
ylycol solution. Aqueous solutions suitable for oral
use can be prepared by dissolving the active component
in water and adding suitable colorants, 1avors,
stabilizing, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made
by dispersing the finely di~ided active component in
water with viscous material, i.e., natural or
synthetic gums, resins, methyl cellulose, sodium
carboxymeth~l cellulose, and o~her well-known
suspending agents.
Topical preparations include dusting powders,
creams, lotions, gels, and sprays. These various
topical preparations may be formulated by well known
procedures. See for example Remington's Pharmaceu-
tical Sciences r Chapter 43, 14th ed. 1970, ~ack
Publishing Co., Easton Pennsylvania 18042, USA.
Preferably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is
subdivlded into unit doses containing appropriate
quantities of the active component. The unit dosage
form can be a packaged preparation, the package con-
taining discrete quantities of preparation, or
example, packeted 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
appropriate number of any of these packaged form.
~'25~
CLG-l ~75~
The quantity o~ active compound in a unit dose of
preparation may be varied or adjusted from 50 rng to
500 mg according to the particular application and the
potenc~ of the active ingredient.
In t'nerapeutic use as antibiotic and antifungal
agents the 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 Xilogram is preerred, The dosages, however, may
be varied depending upon the requirements o the
patient, the severity o the condition being
treated, and the compound being employed. Determi
nation of the proper dosage ~or a particular situation
~ hin the skill of the artq 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 if
desired.
The active compounds may also be administered
parenterally or intraperitoneally. Solutions of the
active compound as a free base or pharmaceutically
acceptable salt can be prepared in water suitably
mixed with a surfactant such as hydroxypropyl-
cellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene ~lycols, 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
an~ sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersions. In
all cases the form must be ste~ile and must be fluid
CLG-l -7h-
to the extent that easy syringability exists~ It
3 must be stable under the onditions 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~ glycerol, propylene
glycol, and liquid polyethylene glycol, and the like),
suitable mixtures thereof and vegetable oilsO The
proper fluidity can be maintained, for example, by the
use of a coatinq such as lecithin, by the maintenance
of the required particle size in the case of disper-
sion and by the use of surfactantsO The prevention of
the action of microorganisms can be brought abOut by
arious antlbacterial and antifungal agents, ~or
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 absorption of
the injectable compositions can be brought about by
the use in the compositions of agents delaying
absorption, for example, aluminum monostearate and
gelatin~
Sterile injectable solutions are prepared ky
încorporating the active compound in the required
amount in the appropriate solvent wi~h various of the
other ing~edients enumerated above~ as requirad,
~ollowed by filtered sterilizationO Generally7
dispersions are prepared by incorporating the various
sterilized active ingredient into a sterile vehicle
which contains the basic dispersion medium and the
required other ingredients .rom those enumerated
above~ In the case of the sterile powders fo~ the
preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and
the freeze-dryin~ technique which yield a powder of
) the active ingredient plus any additional desired
~5~
CLG-l -77-
ingredient from a previously sterile-filtered solution
thereof.
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 of such media and agents for pharmaceutlcally
active substances is well known in the art. ~xcept
insofar as any conventional media or agent is
incompatible with the active ingredient, its use in
the therapeutic compositions is contemplated.
Supplementary active ingredients can also be
incorporated into the compositions.
It is especially advantageous to ~ormul~te
parenteral compositions in dosage unit form or ease
of administration and uniformity of dosage. Dosage
unit form 2S used herein refers to physically
discrete units suitable as unitary dosages for the
mammalian subjects to be treated; each unit
containing a predetermined quantity of active
material calculated to produce the desired therapeutic
e~fect in association with the required
pharmaceutical carrier. The specification for the
novel dosage unit forms of the in~entio~ are dictated
by and directly dependent on (a) the uni~ua
characteristics of the active material and the
particular therapeutic ef ect to be achieved,`and (b)
the limitation inherent in the 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 ef~ective administration in
effective amounts with a suitable pharmaceutically-
acceptable carrier in dosage unit fcrm as hereirbefore
disclosed. A unit dosage form can, for example,
-
,39L
CLG-l -78-
contain the principal active compound in amounts
ranging from about 0.1 -to about 500 my, with rom
about 0.5 to about 250 mg beiny preEerred. ExprPssed
in proportions, the active compound is generally
present in from about 0.1 to about 500 mg/ml of
carrier. Xn the case of compositions containing
supplementary active ingredients, the dosages are
determined by reference to the usual dose and the
manner Or administration of the said ingredients. The
daily parenteral doses for ma~alian subjects to be
treated ranges from 0~1 mg/kg to 100 mg/Xg. The
preferred daily dosage range is 0.3 mg/kg to 10 mg/Xg.
The following nonlimiting examples illustrate the
inventors' 2referred methods for preparing ~he
compound~ of the inven~,ion.
~L~S~ 3~
CLG-l ~79~
~XAMPL~ 1
`~ 2-~2-(Diethylamino)eth~_]-5-[_[?-( _ t~ ino)ethyll-
amino]anthra[l,9-cd]pyrazol~6(2H)~on~
A mixture of 1.2 g (3 4 mmol) of 5-chloro-2-[2-
~die-thylamino)ethyl~allthra[l,9-cd]pyrazol-5(2a3-one~
1.0 g (8 mmol) of N,N-diethylethylenediamiAe, 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 U 5 g
(4 mmol~ of the diamine and about l mg of catalyst is
added and the mix~ure is refluxed for 23 hours7
cooled, and concentratedD The residue is dissolved in
dichloromethane, washed successively with wa'er~
dilute ammonium hydroxide, and brine. Chromatography
O F the dried dichloromethane layer over siliGa g21
with 10:1:89 methanol:triethylamine:dichloromethane
provides the purified product. Dissolution in hot
2-propanol followed by treatment with excess hydrogen
chloride in 2-propanol a'~ords 1.2 g of the dried
product as a salt with 2.1 equivalents o~ hydrogen
chloride solvated with 1~2 equivalents of water; mp
262-276C (decomposition)
5-Chloro-2-~2-~diethylamino~ethyl]anthra[l,9-cd]-
pyrazol-6(2~)-one is prepared as follows:
A mixture of 4.15 g (15 mmol~ of 1,4-dichloro-
9,10-anthracenedione ~J. Amer. Chem. Soc~ 48; 3198
(1926)] 2.6 g (20 mmol) of (2-diethylaminoeth~yl~-
hydrazine ~J. Med~ Chem~ 493, (1964)~, and 35 ml
of pyridine is heated at reflu~ for ten hours, cooled,
and concentrated~ The residue is dissolved in
dichloromethane and washed with water. Chromatography
of the dried dichloromethane layer over silica gel
wi~h ethyl acetate and then 95:5 ethyl
acetate:methanol affords 3.8 g o~ a solid whose
crystallization from 2-propanol gives 2.9 g of pure
material; mp 90-92C.
CLG-l -80-
Dissolution of 0.89 g of the product in hot 2-
propanol followed by treatment with excess hydrogen
chloride in 2-~ropanol affords O.9 g of the
hydrochloride salt; mp 263-266C (decomposition).
EXAMPLE 2
2-[2-(Diethylamino)ethyl)]-5-[~2-[(2-hydroxyethyl)
amino]e~hyl]amino]anthra[l,9-cd]~yrazol-6(2H)-
one
A mixture of 2.5 g (7.1 mmol) of 5-chloro-2-[2-
(diethylamino)ethyl]anthra[l,9-cd]pyrazol-6(2H)-one,
1 g t9 mmol) of 2-(2-aminoethylamino)ethanol and
catalytic amounts of anhydrous cuprous chloride and
potassium iodide in 25 ml of anhydrous 2-ethoxyethanol
is heated at re~lux under argon. Addi~ional 0.5-1~0 g
portions o~ the amine and catalytic amounts oE the
halide salts are added after six and 12 hoursl
respectively. After a total reflux time of 30 hours,
- the mixture is worked up as descri~ed for Example- 1, - -
with purification on silica gel utilizing first
10:1:89 and then 15:1:84 methanol:triethylamine:ethyl
acetate. Following treatment with hydrogen chloride,
~here is obtained 1.1 g of the dried proZuct as a salt
with 2.0 equivalents of hydrogen chloride solvated
with 2.4 equivalents of water; mp 239-241C
(decomposition).
EX~MPLE 3
5-~(2-Amino~th~l)aminoJ-2-[2-(diethyl2mino)ethyl]-
anthra~l,9-cd~pvrazol-6(2H)-one
A mixture of 1.6 g (4,5 ~mol) of 5~chloro-2-[2-
(die~hylamino)ethyl]ar.thra[l,9-cd]pyrazol-6(2Hj-one,
2.5 ml of anhydrous ethylenediarnine, and 25 ml of
anhydrous pyridine is heated at reflux under argon for
seven hours, cooled, diluted with toluene, and
concentrated. The solid residue i5 dissolved in
dichloro.~ethane, washed with water, ~nd then brine.
Chromatography of the dried dichloromethane layer over
silica gel with 1:9 ~ethanol:dichloromethane provides
,
~l25~
CLG-l -81-
0.8 g of the product. Dissolution in hot 2-propanol
follo~ed by treatment with excess hydrogen chloride in
2-propanol affords 1.0 g of ~ried product as a salt
with 2.0 equivalent.s o~ 'nydrogsn chloride sol~ated
with 1.8 equivalents of water; mp 276~279C
(decomposition).
The following compounds are prepared as described
in Exzmple 3 from 5-chloro-2-[2-(diethylamino)ethyl]-
anthra[l,9-cd]pyrazol-6(2~)-one and the corresponding
amine:
EX~!PLE 4
2-[2-(Diethyla~ino)e'Lh~1]-[[2-(4-morpholinvl?eth
amino]anthra[l,9-cd]Pvrazol-6~2~)-one
Reaction with ~-(2-aminoethyl)morpholine gives
the product as a salt with 2.0 equivaients of hydrogen
chloride solvated with 1.2 equivalents of water; mp
288-290C (decomposition).
EX~PLE 5 --- -
2-~2-(Diethylamino)ethyl-]-5-[[3-(diethylami-no~oropyl-]- - -
amino]antnra[l,9-cd]pyrazol-6(2~)-one
Reaction with N,N-diethyl-1,3-propanediamine
~ives the p~oduct as a salt with 2.0 equivalents of
hydrogen chloride solvated with 0.2 e~u.ivalent of
water; mp 270-272C (decomposition)O
EX~MPLE 6
2-[2-(Diethylamino)ethyll-5-[[7-(dieth~lamino)hep~Yl]
amino]anthra[l,9-cd~pyrazol-6(2H)-one
Reaction wi-th N,N-diethyl-1,7-heptanediamine
gives the product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 0.3 equivalent of
water; mp 190-192C (decomposition).
EXAMPLE 7
5-~[4-(Die~hylamino)butyllamino]-2-[2-(diethylamin
ethyl~ thra~l,9-cd]pyrazol~6(2H)-one
Reaction with N,N-die.hyl-1,4-butanediamine gives
the product as a salt with 2.0 equivalents oE hydro~e~
CLG-l -82-
.
c~loride solvated with 0.7 equivalent of water;
m? 2~3-246C (decomposition).
EXAMPL2 8
2-[2-(Diethylamino)ethyl!-5-(hex~ltlamino)anthra[l~9-
cd]-py~azol-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 176-179C
(decomposition).
2X~PLE 9
2-[2-(Diethylamlno)eth~1]-5-[[2-(1-~iperazin;vl)ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2H)-one
. . . _
Reaction wi~h 4-(2-aminoethyl)-1-piperazine
carboxylic acid, benzyl ester, then hydrolysis of the
isolated intermediate with hot 48% hydrobromic acid in
acetic acid giv~s the product as a salt with 3.3
equivalents oE hydrogen bromide solvated ~tith 1~4
equivalents of water and 0.1 equiv~lent o -~cetic--- - ---- --~ -
acid; mp 284-287C (decomposi-tion). - - -- -
4-(2-Aminoethyl)-l-piperazine carboxylic acid,
benzyl ester, is prepared from 4-(2-aminoethyl)-1-
pipera~ine by a procedure analosous to that described
Eor the preparation of (2-aminoethyl)-methylcarbamic
acid, benzyl ester, in US Pa~ent 3,931,268; lH NMR
(deuteriochloroform): ~ 2.78 (triplet), 5.08
(singlet), 7.30 ~singlet).
EXAMPLE 10
5-[~2-(Diethyl3nino)ethyl]amino]-2-me~hylanthra[l,9-
cd~pyrazol-6(2H)-one
A mixture o~ 1.88 g (7 mmol) of 5-chloro-2-
methylanthra[l,9-cd]pyrazol-6(2H)-one [J. Chem. Soc.,
1630 (1952)~, 1.2 g (10 mmol) of N,N-diethylethylene-
diamine, 0.14 9 of anhydrous ootassium fluoride, and
10 ml of dimethylsul~oxide is heated at re~lux under
argon for four hours, cooled, diluted with water, and
e~racted with dichloromethane. The dichloromethane
extract is washed twice ~ith brine and then with 53
3~L
CLG-l -83-
aqueous hydrochloric acid. The acid solution is
washed with dichlorornethane, 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 productS after thorough washing
with ether, as a salt with 1.8 equivalents of hydrogen
chloride solvated with 0.7 equlvalent of ~ater;
mp 260-264C (decomposition)
EXAMPLE 11
5-[~2-[(2-Hydroxyethyl)amino]etnyl]amlno]-2-methy
_
anthrall,g-cd]~yrazol-6~2H)-one
A mixture of 1.75 g (6.5 mmol) of 5-chloro-2-
methylanthra[l,9-cd]pyrazol-6(2H)-one 7 6 ml (59 ~mol)
O L 2-(2-aminoethylamino)ethanol, catalytic amounts of
anhydrous cuprous chloride and potassium iodlde, and
25 ml of 2-~ethoxyethanol-is-heated:a~-.refl~x under ..~
argon for four.hours, cooled,..and~.concentrated. ~he . ..
residue is dissolved in dichloromethane, washed with
water, and then with 5~ aqueous hydrochloric acid.
The acid solution is washed with dichloromethane, made
basic~ and extracted into dichloromethane
Chromatography of the dried dichloromethane extract
over silica gel with gradient elution 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 ~ith
1.0 equivalent of hy~rogen chloride solvated with 0.1
equivalent of water; mp 270-272C (decomposition).
EXAMPLE 12
2-(2-Hydroxyethyl)-5-[[2-[(2-hydroxvethvl)amino]-
e-thyl]amino]anthra[l,9-cd]Pyrazol-6(2H?-one
A mixture of 896 mg (3 mmol) of 5-ch~oro-2-(2-
hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)-one, 3.1 ml
(30 mmol) of 2-(2-aminoethylamino)ethanol, and 6 ml o
anhydrous pyridine is heated at reflux under argon for
~2~
- 84 -
8.5 hours, cooled, and concentrated to leave a residue~
Trituration from ether:2-propanol leaves a gummy solid
which upon further trituration from rnethanol-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 60 C 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
5-[[2-(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 N,N-diethylethylenediamine, and 6 ml of 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:
CLG-l ~85-
EX~PLE 14
2-(2-~ydroxyethyl~-5-[[2-(4-mor2holinyl)ethyl]a-mino]
[l,9-cd~pyrazol-6(2H)-one
Reaction with 4-(2-aminoethyl)morpholine gives
t~e 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-(Diethyla~ino)~ropvl]amino]-2-(2-h~rdroxyethvl)-
anthra[l,9-cd3pvrazol-6(2H)-one
~ eaction with N,N-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)0
EXAMPLE 16
5-[[4-(Diethylamino~butvl~amino3-2-(2-hydroxyeth~
anthra[l,9-cd]Pyrazol-6(2ff)-one
Reaction with ~,N-dieth~1-1;4-proparediamin~
- gives the product as a salt with 1.9 equivalent3
o hydrogen chlo~ide solvated with 1.0 equivalent
of water; mp 155-185C (decomposition)0
EXAMPLE 17
5-~7-~Diethy~amino)hept~rl~a.~ino]-2-~2-llydrcxyethyl)-
anthra~l~9-cd~pYrazol-6t2H)-one
~ eaction with N,N-die~hyl-1,7-heptanediamine
g ves the product as a salt with 1.0 e~uivalent of
hydrcgen chloride; mp 206-208C (decomposition)~
EXAMPLE 18
2-12-E~ydroxyethyl)-5-[[2-(1-,~iperazinyl)ethyl~aml -
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
prod~ct as a salt with 2.0 e~uivalents OL hydrogen
chloride solvated with 0.5 equivalent of water;
mp 292-297C (decompositior.).
CLG-l -86-
EXAMPLE 19
~, 5-[[2-[(2-Hydroxvethy~amino]ethyl]amino]anthra[l,9_
cd]p~rrazol-6(2H)-one
A mixture of 2.54 g ~10 mmol) of 5-chloroanthra-
l1,9-cd~pyrazol-6(2H)-one [J_ Chem. Soc., 1630
(1952)], 10 ml (100 mmol) of 2-~2-aminoethylamino)-
ethanol, and 25 ml of anhydrous pyridine is heated at
re~lux under argon for 24 hours/ cooled, and
concentrated. The residue is triturated with
2-propanol ~o 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 equivalen-ts of hydrogen
chloride solvated with 0.6 equivalent of water;
m~ 251-~54~C ~decomposition)~
EX~PLE 20
5-[[2-(Diethylamino)ethyl]amino]anthra~l,9-cd]-
pyrazol-6(2H)-one
A mixture of 1.6 g (6.3 mmol) of ~-chloroanthra-
ll,9-cd]pyrazol-6(2~]-one, 3.5 g (30 m~ol) of N,N-
diethylethylenediamine, and 20 ml of anhydrous
pyridine is heated at reflux for 20 hours, cooled, and
concen~-ated. The residue is dissolved in
dichloromethane, washed with water, and then ex~racted
with 1% aqueous hydrochloric acid. The acid solution
is wasned with dichloromethane, then made basic with
aqueous sodium hydroxide. The aqueous solution is
e~ract2d 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 of the dried product as a salt
with 1.4 equivalents Oc hydrogen chloride solvated
with 0.1 equivalent of water; mp 120-130C.
CLG-l -87-
EXAMPLE 21
2-~2-[(2~H~dro:~yetnyl)amino]ethyl3-5-[[2-~(2-~ydroXy-
ethyl~amino]ethyl]amino]anthra[lr9-cd]pyrazol-6(2H)
one
A mixture of 1.91 g (5 mmol) of 5-chloro-2-[2-
~(2-hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol-
6(2~)-one, hydrochloride, 2.6 ml of 2-(2-aminoethyl-
amino)ethanol, and 5 ml o~ 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 salt with 1~0 equivalent o~ acetic acid
solvated with 0.5 equivalent of water; mp 145-148C.
S-Chloro-2-[2-~(2-hydroxyethyl)amino]ethyl]
anthra[l,9-cd]pyrazol 6~2~)-one is prepared GS
follows:
To a refluxing mix~ure 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-E(hydra~inoethyl)amino]ethanol in 3 ml
o acetonitrile. The mi~ture is refluxed for one
hour, cooled, and triturated with cold 2-propanol to
give 602 mg of product; mp 140-14ZC~ Processing of
the mother li~uor affords 71 mg of ad2itional product;
mp 1~4-12-6C. Crystalliza~ion OL the free base from
glacial acetic acid gi~es the diacetate salt; mp
125-130C. The hydrochloride salt is prepared ~s
described in Example 3; mp 260-263C (decomposition).
CLG-l -8~-
2-l~Hydrazinoethyl)amino]ethanol is preQared as
! ~ ollows:
A solution o~ a6 . 3 g (l . O mol) o~ N-(~-h~droxy-
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 ~ure material; bp 120C/0.035 mm.
EXAMPLE 22
5-~(2-Aminoethyl?amino~-2-[2-1(2-hydroxyethyl~amino]
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,g-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 filt-ate is dissolved in water and
purified over a column of ~P-20 resin eluting first
with water and then with methanol. Corlcentration of
the methanol eluate followed by sal-t formation as
described in Example 3 affords 1.0 5 of the dried
product as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.9 equivalent of water;
m? 263-267C (decomposition).
CLG-l -89-
EXAMPLE 23
5-[L2-(Dieth~lamino)ethyl]aminc~]-2-[2-[(2-hydro~y-
ethyl amino~eth ~ ,9-cd]~ ol-6(2 )~
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 3O5 ml (25 mmol) of N,N-diethyl-
ethylenediamine as described in Example 21 affords
1.4 g o 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
~ gives 1.6 g of the dried product as a salt with 2.0
equi~7alen~s of hydrogen chloride solvated with 1.0
equivalen~ of water; rnp 272-274C (decomposition~.
EX~PLE 24
5-l(2-Hydroxyethyl)amino~-2-[2-[(2-hydroxyethyl)
amino]ethyl]anthra~l,9-cd]pyrazol-6(2H)-one
A mixture of 2.5 g (6.6 mmol) of 5-chloro-2-[2-
I(2-hydroxyethyl)amino~ethyl~anthra[l,9-cd]Pyrazol-
6(2H)oner hydrochloride~ 2 ml (33 mmol) of 2-amino-
ethanol and 13 ml of anhydrous pyridine is reacted and
worXed up as described in Example 21 to afford a solid
precipitate whose salt formation as described in
Example 3 affords 1.4 g of the d~ied product as a salt
with 1.1 equivalents of hydrogen chloride solvated
with 0.6 equivalen~ of water; mp 260-261C
(decomposition)~
EXAMPLE 2S
2-l2-l(2-Hydroxyethyl)amino]e~hyl]-5-[~2 (dim~thyl_
amino)ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-
one
~ eaction 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 followed by ~orkup as described in Exa~nple 21
gives a solid residue whose dissclution in not
methanol followed by salt formation as described in
Example 3 gives 1.0 g of the dried product as a salt
with ~.1 equivalen~s of hydrogen chloride solJated
with 0.9 equivalent of water; mp 286-288C
(decomposi~ion).
EXAMPLE 26
2-[2-[(2-~ydroxyethvl)amino]eth~1]-5 (methylamino)-
anthra[l,9-cd]~Yrazol-6(2~)-one
-- _ _
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
amino]ethyl]anthra[l,9-cd]pyrazol~6-(2H)-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).
EXAMPLE 27
2-(2-Aminoethyl)-5-[[2-[(2-hydroxyethyl)amino]ethYl]-
,
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 15 ~nl of
anhydrous pyridine is heated at reflux for 30 hours,
cooled, and filtered. The filtrate is concentrated
and chromatographed over silica gel with 99:2:1
dichloromethane: methanol:triethylamine, then gradient
elution ~o 99:20O1 to provide the purified product.
Sal-t forma~ion as describ~d in ExamplP 3 g-ves 0.8 y
of 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-~minoethyl)-5-chloroanthra[l,9-cd3pyrazol-
6-~2H)-one is prepared as follows:
To a solution of 1.0 g (3.6 T~nole) of l,~-di-
chloro-9,10-anthracenedione in 10 ml of pyridine at
35 is added dropwise 1 9 ml of (2-aminoethyl)-
hydra2ine [8ritish Patent 880,332]~ Th~ mixture is
stirred for four hours, concentrated, and purified on
silica gel utilizing 94:5:1 dichloromethane:
methanol:triethylamine. Salt formation as described
in ~xample 3 giYes 0~45 g of the product as a salt
with 1.0 equivalen~ of hydrogen chloride solvated with
1.2 e~uivalents of water and 0.1 equivalent of
2-propanol; mp 284-285C (decomposition).
EXAMPLE 28
2-~2-(Diethylamirlo)ethyll-7,10-dihydroxy-5~[2-[~2
hydroxyethyl)amino]ethyl]amino]anthra[l ! 9-cd]-
pyrazol-6(2H)-one
__
Reaction of a mixture of 2.9 g (7.5 mmol~ of
5-chloro-2-[2-(diethylamino)e.hyl]-~,10-dihydroxy -----
~anthraEl,9-cd~pyrazol-6(2H)-one, 7.5 ml (75 mmol) of
2-(2-aminoethylamino)ethanol, and 35 ml of pyridine
for four hours at reflux followed by workup a~
described in ~xample 21 and salt formation as
described in Example 3 glves 2~8 g of the dried
product as a salt with 2.0 equivalents of nydrogen
chloride solvated with 0.7 equivalent of water;
mp 198-202C (decomposition)
5-Chloro-2-[2-~diethylamino)ethyl]-7~10-di-
hydroxyanthra~l,9~cd3pyrazol-6~2H)~one i5 prepared as
follows:
Reaction of a mix~ure of 12.7 g (41 mmol) of 1,4-
dichloro-5,8-dihydroxy-9,10~anthracenedione, 12 g
(90 mmol) o (2-diethylaminoethyl)hydrazine, and 65 ml
o pyridine at 50C for four hours follo~ed by workup
s~,~
CLG-l -92-
as described in Example 22 ~ives a residue that is
dissolved in dichloromethane Chromatography over
silica gel with dichloromethane and then with ~%
methanol in dichloromethane affords crude material
whose crystallization from 2-propanol gives ~.5 g of
a purified solid; mp 136-140C. Salt formation as
described in Example 3 on lo 5 g of ~his material gives
1.3 g of a dried solid as a salt with 1.0 equivalent
o~ hydrogen chloride solvated with 0.3 equivalent of
water; mp 280-282C (decomposition)~
EX~MPLE 29
2-~2-(Diethylamino)ethyl]-5-[~2-(diethylamino)ethyl]-
amino]-7,10-dihydrox~an~hra[1,9-cd]pyrazol-6(2H~-
o
Reaction of a mixture o~ 1093 g (5 mmol) of 5-
chloro-2-[2-(diethylamino)ethyl]-7~lo-dihydroxyanthra
Il,9-cd]pyrazol-6(2~)-one, 2.g g (24 mmol) of N,N-
diethylethylenediamine, and 25 ml of pyridine-for fi-ve - '~ --'- ~
hours at reflux ~ollowed-by workup ~s-described in
Example 21 gives a crude solid which is dissolved in
dichlorome~hane. Chromatography over silica gel with
3~, 6~, and 10% solutions of methanol in
dichloromethan~ affords 1.6 g o~ pure material. Salt
ormation as described in Example 3 gives 1 4 g of the
dried product as a salt with 2.0 equivalents of
hydrogen ~hloride solvated with 0.3 equivalent of
water; mp 290-292C (decomposition)
EX~MPLE 3
5-~(2-Aminoet'nyl)amlno]-2-[2-('di'ethylamino)_th
7,10-dihydroxyanthra~l~9-cd]p~raz-ol--6(2H~-one
~ eaction of 5-chloro-2-~2-(diethylamino~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
chlorid* solvated with 1.7 equivalents oE water and
0~1 equivalent of 2-propanol; mp 277 281C
~decomposition).
CLG-l -93-
EX~MPLE 31
2-[2-(Diethylamino)ethvl]-7,10-dihydr x~-5-[[2~
-
(met_yla~ino)ethyl]amino~ant~hra[lt9-cd]pyra
6(2H)-one
Reaction of 5-chloro-2-[2-(diethylamino)ethyl]-
7,10~dihydroxyanthra[1,9-cd]pyrazol--6(2H)-one with
~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
aciA gives the product as a salt with 2.3 equivalents
of hydrogen bromide solvated ~ith 2.7 equivalents o,
water; mp 217-220C (decomposition).
EXAMPLE 3Z
2-~2-(Dimethylamino)ethyl]-7,10-dihydroxy-5-~[2-~[(2-
hvdroxy~hy_~mino]ethyl]amino]anthra[1,9-cd_pyrazol-
6(2~)-one
Reaction of 2.0 g (5.6 mmol) o~ 5-chloro-2-[2-
tdimethylamino)ethyl]-7,lo-dihydroxyanthra-l~9-cd]- -
pyrazol-6(2H3-one, 5.6 ml of 2-~2-aminoethylamino)-
ethanol, and 20 ml of pyridine at 70C for 24 hours
followed by workup as described in Example 21 and salt
formation as described in Example 3 yives 2.4 ~ of
the dried product as a salt with 2~4 equivalents of
hydrogen chloride solvated wi~h 2.0 eauivalents of
water, mp 310-313C (decomposition).
5-Chloro-2-[2-(dimethylamino)ethyl]-7,10-
dihydroxyanthra[l~9-cdlpyrazol-6(2~)-one is
~repared as follows:
Reaction of a mixture of 15.5 g (50 mmol) of
1,4-dichloro-5,8-dihydroxy-9,10-anthracenedione,
10.3 g (100 mmol) of (2-dimethylaminoethyl)-
hydrazine ~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 g7 ves ~he product as a salt with
1.1 equivalents of hydrogen chloride solvated with
1.2 equivalents of water; mp 295-300C
(decomposition).
The following 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:
EX~MPLE 33
5-~(2-Ami~e~ in~l-2~ (dimethylamino)ethyl]-
7,10-dihydroxyanthra[l~9-cd] pyr2ZOl- 6 (2H)-one
Reaction with ethylenediamine gives the product
a3 a salt with 1.9 equivalents of hydrogen chloride
solvated wi~h 2.4 equivalents oE water; mp 300-302C
~decomposition).
EXAMPL~ 34
5-[t3-Aminopropvl)amino]-2-[2-(dimethylamino)ethx~]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2~)-one
Reaction with 1,3-propanediamine 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)ethyl]amino]-?~lo-dihydroxy 2-
(2-hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)
one
Reaction of a mixture of 3.3 g (10 mmol) of
S-chloro-7 t 10-dihydroxy-2-(2~hydroxyethyl)anthra~
¦1,9-cd]p~razol-6(2H)-one, 14;5 ml (100 mmol~ of N,N
diethylethylenediamine, and 20 ml of pyridine Eor
~hree hours at reflux followed by workup 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 of hydrogen chloride solvated with 0.6
equlvalen~ of water; mp 215-219C (decomposition).
f
~:~S1~3~
CLG-l -95-
5-Chloro-7,10-dihydroxy-2-(2-hydro~yethyl)anthra-
`~ {l,9-cd]pyrazol-6(2H)-one is prepared as follows:
~ mix~ure of 12 g (40 ~nol) of 1,4-dichloro-5,8-
dihydroxy-9,10-anthracenedione7 4~5 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 chlorofor~
and hot ~ethanol to give 1.1 g of the dried product;
mp 231-234C.
EXLMPLE 36
5-[[2-[(2-Hydroxyethyl)amino]ethyl]amino]-7,10-
dihydroxy-2-(2-hy~roxyethvl)anthra[l~9-cd]pyra
6(2H)-one
A mixture of 303 g (10 mmol~ of 5-chloro-7~10-
dinydro~ 2 (2-hydroxye~hyl)an~hra[1~9-cd~pyrazol-
6(2H)-one~ 1004 g (100 ~mol) of 2-(2-aminoethylamino)-
ethanol, and 20 ml of pyridine i5 heated at rerlux for
four hours, cooled, and concentrated. Successive
tritura~ion of the residue with acetonitrile,
~-propanol, and methanol gives 1.35 g of a powder.
Salt ~ormation as described in Example 12 affords
1.06 y oE the dried product as a salt with 1.0
equivalent ~f hydrogen chloride sclvated wi~h 0.5
equivalen~ of water; mp 196-203C (decomposition)
The following co~pounds are prepared as described
in Example 35 from 5-chloro-7,10-dihydrox~y-2 (2-
hydroxyethyl)anthra~l,9-cd]p~razol-6( 2HA ) -one and the
corresponding amine:
EX~MPLE 37
5-[(2-Aminoeth~,~l)aJnino]-7,10~dihydroxy-2-(2-hs~droxy
ethvl)anthra[l,9-cd]pyrazol-6(2H)-one
Reaction with ethylenedia.~ ne gives the product
as a salt with 1.8 equ valents of hydrogen chloride
solvated with 0.5 equivalent of water; mp ~195~C
tdecomposition).
CLG-l -96-
EX~PLE 38
7,10-Dihydrox~-2-t2-hydroxyethyl)-5-[[2-(4-
mor~holinyl)ethvl]amino] anthra [1,9-cd]
p~razol-6(2~)-one
Reaction wi-th 4-(2-aminoethyl)morpholine gives
the product as a salt with 0.4 equivalent o hydrogen
chloride and 0.3 equivalent of water; mp 240-251C
(decomposition)~
EXAMPLE 39
5-[l2-(Dimethylamino)ethyl3amino]-7,10-dihydroxy-2-
(2-hydroxyethyl)anthra[l~9-cd~pyrazol-6~26)
one
Reaction with N,N-dimethylethylenediamine gives
the produc~ as a salt ~ith 1.5 equivalents of hydrogen
chlo-ride solva~ed with 2.0 e~ui~7alents o water,
mp 250C ~decomposition~
EX~MPLE 40
5-[(2-~minoethyl)amino]-7,10-dihydro~r-2-methvl-- -~
anthra[l,9-cd]Pvrazo1-6(2~)-one
Reaction of a mixture of 3 2 g (10.6 mmol) of
S-chloro-7 r 10-dihydroxy-2-methylanthra~l,9-cd]pyrazol-
6(2H)-one, 5 ml (7~ mmol) of ethylenediamine, and
55 ~1 of pyridine for sevell hours at r~flux fol].owed
by workup as described in Example 21 gives a solid
residue. Dissolution of the solid in hot methanol and
N,N-di~ethylformamide followed by salt formation as
described in Example 3 affords 1.5 g of ~he dried
prodl~ct as a salt ~lth l~0 equivalent of hydrogen
chloride solvated with 0.2 equivalent of water and 0.1
equivalent of N,N~dimethylEormamide; mp 323-326C
[decomposition).
5-Chloro-7~10-dihydroxy-2-methylanthra[l,~-cd]-
pyrazol-6t2~)-one is prepared as follows:
A mixture of 12.4 g (40 mmol) of 1,4-dichloro-
5,8-dihyd~oxy-9,10-anthracenedione~ 2.7 ml (50 mmol~
of methylhydrazine, and 250 ml of pyridine is heated
at 35C for seven hours, treated with an additional
~,2~ 3~
~LG-l -97-
1 ml of methylhydrazine, heated for seven hours at
35C, and cooled. The solids are filte~ad 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-~ihydroxy-5-[[2-[(2-hydroxyethvl)amino]ethvl~-
amino]-2-methylanthra[1,9-cd]py-azol-6(2H)-one
Reaction of a mixture of 3.25 g (10.8 mmol) of
5-chloro-7,10-dihydroxy-2-methylanthra[l,9-cd]pyrazol-
6(2H)-one r 3 ~1 (30 mmol) of 2-(2-aminoethylamino)-
ethanol, and 50 ml of pyridine for seven hours at
reflux fo'lowed by wor~up as described in Example 21
and salt formation as described in Example 3 gives
1.8 g of the dried product as a salt ~ith 1,0
equivalent of hydrogen chloride solvated with 0.6
equivalen.t of ~ater;-~.p-280-284C-(decomposition)~
EX~MPLE 42
5-[[2-(Diethylamino)ethyl]amino]-7,10-dihydroxy-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 followed by workup as described in Example 21
and salt formation as described in Example 3~gives
1.7 g o ~he dried product as a salt with 1.5
equivalents of hydrogen chlor~de solvated with 0.8
equivalent of water; mp 298C (decomposition).
EXAMPLE 43
2-[3-(Diethylamino)-2-hydroxypropyl]-7,10-dihydroxy-
5-[[2-[(2-hydroxvethyl)amino]et-~yl]amino]anthra
tl,9-cd]pyrazol-6(2H)-one
Reaction of a mixture of 1.3 g (3 mmol) of
S-chloro-2-[3-(diethylamino)-2-hydroxypropyl]-7,10-
dihydroxyanthra~l,9-cd]pyra~ol-6(2H)-one, 2.1 ml
.
3~
CLG-l -98-
(21 mmol) of 2-(2-aminoethylamino)e~hanol, and 10 ml
o pyridine at reflux for six hours follo~ed by wor3cup
as described for Example 21 and salt forrnation as
described in Example 3 gives the prod~ct 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-2-13-(diethylamino)-2-hydroxypropyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-5(2~)-one is
prepared as follows:
A mixture of 6.2 g (20 mmol) of 1,4-dichloro~
S,8-dihydroxy-9,10-anthracenedione, 9~7 g (60 Ir~,ol) of
l-(diethylamino)-3-hydrazino-2-propanol (German Patent
1,126,877) and 3S ml of pyridine is stirred at 40C
for one nour then at room temperature overnight The
mixture is concentrated and purified on silica gel
utilizing 97:2:1 dichloromethane methanol:
triethylamine to give 1.7 g of product. Salt
formation as described in Example 3 gives 1.4 g of the
product as a sall with 1.0 equivalent of hydrogen
chloride solvated with 0.7 equivalent of wa.er; mp
264-267C (decomposition).
EXAMPLE 44
5-~[2-(Diethylamino ? ethyl]amino]-2-[3-(diethYlamino)-
2-hydroxypropyl]-7,10-dlhydroxyanthra[1,9-cd]pyrazol-
6(2H)-one
Reaction o 5-~hloro-2~13-~diethylamino)-2-
hydroxypropyl]-7,10-dihydroxyanthra~l,9-cd]pyrazol-
6(2H)-one with N,N-diethylethylenediamine as de~cribed
in Example 43 gives the product as a salt with 2.0
equivalents of hydrogen chloride solvated with 1.9
equivalents of water; mp 253-255C (decomposition).
EXA,~qPLE 45
5-~(2-Aminoethyl)amino]-2-[3-(diethylamino)-2~hYdroxy-
propyl]-7,10-dihvdro~yanthra[l,9-cd]pyrazol-6(2~1)-one
Reaction of 5-chloro-2-[3-(diethylamino)-2-
hydroxypropyl]-7,10-dihydroxyanthra[1,9-cd]pyrazol-
~ z~ 3~
CLG-l -99~
6(2H)-one wi~h ethylenediamine as described in Example
43 gives the product as a salt r~ith 2.0 equivalents of
hydrogen chloride solvated with 2.8 equivalents of
water; mp 148-152~.
EXAMPLE 46
2-[3-(Dimethylamino)pro~yl]-7rlu-dihydroxt~-5-[[2
[(2-hydroxyethyl)amino]eth~]amino]anthra~l,9-cd]
pyrazol-6(2H) one
~ eaction of a mixtura of 2.5 g (6 mmol) of
5-chloro-2-l3 (dime~hyLamino)propyl]-7,10-dihydroxy-
anthratl,9-cd]pyrazol-6(2H)-one~ hydrochloride,
2.8 ml (28 mmol) of 2-(2-aminoethylamino)e~hanol, and
20 ml of pyridine a~ reflux for 24 hours follo~ed by
workup as described for Example 21 and salt formation
as described in Example 3 gives the produc~ as a salt
with ~.0 equivalents of hydrogen chloride solvated
with 1.0 e~uivalent o water; mp 311C
(decomposition).
5-Chloro-2-~3-(dimethyla~ino)prop~1]-7,10-
dihydroxyanthra[l,9-cd~pyrazol-6(2H)-one is prepared
as follows:
To a suspension of 30.9 g (100 mmol~ o~ 4
dichloro-5,8-dihydroxy-9~10-anthracenedione in 200 ml
of pyridine at 37C is added dropwise 14 g (120 mmol)
of (3-dimethylaminopropyl~hydrazine lJ. Med. Chem.,
1;493 (1964)]. The mixture is dilu-ted with 50 ml of
N,N-dimethyl~ormam;de, stirred for ten hours7 and
concentrated. The residue is dis~ribu~ed betT~een
dichloroT~ethane and 5% aqueous sodium bicarbonate.
Puriication of the dried organic layer on silica gel
- utilizing 95.5:4:0.5 dichloromethane:methanol:
triethylamine gives 8 9 of product. Salt formation as
described in Example 3 gives 7.6 g of the product as a
salt with 0.8 equivalent of hydrogen chloride solvated
with 0.1 equivalent of 2-propanol; mp 267-271_
(decomposition).
~5~
CLG-l -100-
EXAMPLE 47
5-[(3-Amino~ropyl)amino]-2-[3-(dimethylamino)propyl]-
7,10-dlhydrox~anthra[1,9-cd]pyrazol~6(2H~-one
Reaction of 5-chloro~2-[3-(dimethylamino)propyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one, hydro-
chloride, with 1,3 propanediamine as desc-cibed in
Example 46 gives the product as a salt with
~.0 equi~alents of hydrogen chloride solvated with
0.5 equivalent of water; mp ~300Co
EXAMPLE 48
7,10-Dihydroxy-5-[[2~[(2-hydroxyethyl)am~no]ethyl~-
amino-2-~2-~methylthio) ethyl ) anthra~l,9-cd]-
pyrazol-6(2H)-one
Reaction of a mixture of 0.66 g (3.6 mol) of
5-chloro-2~~2 t-hiome~hylethyJ)-7~lo-dihydroxyanthra~
Il,9-cd]pyra~ol-6(2H) one, 1.8 ml ~18 mmoli of
2-~2-aminoethylamino)ethanol, and 16 ml of pyridine
at reflux overnight followed by workup as described in
Example 21 and salt formation as described in -
Example 3 gives 0.7 g of the dried product as a salt
with 1.6 equivalents of hydrogen chloride solvated
with 0.5 equivalent of water; mp >133C
(decompqsition).
5-Chloro-2-t2-thiomethylethyl)-7,10-dihydroxy-
anthra-~,9-cd]pyrazol-6(2H)-one is prepared
as follows:
An ice-cold mixture of 2.64 g (5 mmol) of
5-chloro-2-(2 thiomethyleth~L)-7,10-bis(phen~
methox~) anthra[l,9-cd]pyrazol~6~2H)-one in 15 ml
dichloromethane is treated dropwise during 30 minutes
wi~h 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 methanol. The
mixture is warmed to room temperature overnigh~ then
concentrated to a residue which is triturated with
2-propanol to give a red solid. Fur~her trituration
!
C~G-l -101-
with 75 ml of boiliny methanol gives 0.9 g of pure
product; mp 186-190C.
5-Chloro-2-(2-thiomethylethyl)-7,10-bis(pnenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2~)-one is prepared ~s
ollows:
A mixture of 5.1 g (10 mmol) of 5-chloro-2-
(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra-
~1,9-cd3pyrazol-6(2H)-one, 9.4 g (100 mmol) of methyl-
disulfide, 20.2 g (100 mmol) of tri-n-butylphosphine,
and S0 ml of N,N-dimethylformamide 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,
2-propanol, and diethyl ether to give 5.1 g of the
dried product; mp 155-160Co
S-Chloro-2-(2-hydroxye~hyl)-1,10-bis(phenyl-
methoxy)anthra[l,9-cdjpyrazol-6(2H)-one is prepared as
follows:
Reaction of a mixture of 35.~ g (72 mmol) of 1,4-
dichloro-5,8-bis(phenylmethoxy)-9,10-anthracenedione,
11.2 g (147 mmol) of (2-hydroxyethyl)hydrazine, 2.1 g
(37 ~mol) of anhydrous potassium fluoride, 7.4 g
(74 mmol) of 2nhydrous potassium bic~rbonate, and
220 ml o~ dry dimethylsulfoxide as described in
Example S4 gives 33.1 g of the dried product;
mp 118-184C. Crystallization from chloroform raises
the melting point to 201-~04Co
1,4-Dichloro-5,8-bis(phenylme~hox-y)-9,10-anthra-
cenedione is prepared as follows.
A mixture of 51.3 g (160 mmol) of 1,4-dichloro-
~8-dihydroxy-9,10-anthracenedione (US Paten~ Number
3,631,0~4), 46 g (330 mmol) OL powdered anhydrous
potassium carbona~e, 44 ml (380 mmol) of benzyl
bromide, and 670 ml of dry acetone are heated at re-
flux for five days. The mixture is cooled, the solids
are filtered, then washed se~uentially with water,
!
~25~3~
CLG-l -102
methanol, and diethyl ether to give 63.~ g of the
dried product; mp 190-194C. Processing of the
acetone filtrate gives 9.4 g of a second crop' mp
142-155C.
EXAMPLE 49
5-Chloro-2-[2-(diethylamino)ethyl]-7,10-dihydroxY-
anthra[l,9-cd~pyrazol-6(2H)-one
An ice-cold mixture of 9.1 g (16 mmol) of
S-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~
Follo-~ing 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 nydrogen ~-
chloride, and solvated with 0.2 equivalent of water;
mp 280-282C (decomposition~.
5-Chloro-2-[2-(diethylamino)ethyl]-7,10-bis-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follo~s:
A mixture of 4.2 g (6.3 mmol) of 5-chloro-2-
~2-~1(4-methylphenyl)sulfonyl]oxy]ethyl~-7,10-
~is(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-
sulfoxide 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.
S-Chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy]-
ethyl]-7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2~)one is prepared as follows:
~25~
CLG-l -103-
An ice-cold mixture of 22 g (43 mmol) of
5-chloro-2~(2-hydroxyethyl)-7,10-bis~phenyl-
methoxy)anthrall,9-cd]pyrazol-6(2H)-one, 12.3 y
(65 mmol~ o ~-toluenesulfonyl chloride and 170 ml of
pyridine is stirred for .~0 hours. The solid is
Eiltered, washed with methanol and diethyl ether, and
dried to give 10.5 g of the product; m~ 203-206C
~decomposition). Processing of the filtrate gives
9.3 g of additional product; mp 182-188~C
(decomposition).
EXAMPLE 50
2-[2-l~2-(Dimethylamino)ethyl]amino]ethyl]-5-[l2-[(2-
hydrox~ethyl~amino]ethyl]amino]-7,10-dihvdroxyanthra-
fl,9-cd~pyrazol-6(2H)~one
~ eaction of a mixture o~ 3 6 y (7 4 mmol~ 5~
chloro-2-[2-~[2-(dimethylamino)eth~yl]arnino]ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6~2H)-one,
dihydrochloride, 4.5 ml ~45 ~mol) of 2-(2-aminoethyl- f --
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
w~te~; ~p 110-117Co
5-Chloro-2-[2-[~2-(dimethylamino~ethyl]amino~-
ethyl] ~7 ~10-dihydroxyanthra~l,g-cd]pyrazol-6(2H)-one
is prepared as followsO
An ice-cold mixture o 9.-3 g tl6 mmol) of 5-
chl~ro-~-[2~l2-(dime~hylami~no)e~hyllamino]e~hyl~-
7tl0-bis-~Phenylmerhoxy)an' h~a[l,9~cdJpyrazol-
~(2H)-one in 30 ml of dichloromethane is treated
dro~wise during t~70 hours ~ith 96 ml of a 1 M solutlon
of boron trichloride~ Following addition, the mixture
is treated carefully with 30 ml of methanol The
mixture is warmed to room tempera.ure overnight and
the solid resiaue is collected, washed sequentially
with 2-propanol, methanol, and diethyl ether to give
3.68 g of the dried product as a salt with 1.8
~2~
CLG-l -104-
equivalents of hydrogen chloride and solvated "ith 0.2
equivalent of 2-propanol and 0.8 equivalent of water;
mp ~60-268C (decomposition).
~Chloro-2--[2-[~2-(dimethylamino)ethyl]amino]~
e'cshyl]-7,10-~is(phenylmethoxy)anthra[l,9-cdlpyrazol-
6(2H)-one is prepared as follows:
A mixture of 4.2 g (6.3 mmol) of 5-chloro-2-[2-
t[(4-methylphenyl)sulfonyl~oxy]ethyl'J-7,10-bis~phenyl-
methoxy)anthra[l,9-cd]pyraol-6(2H)-one, 5~3 9
(60 mmol~ of N,N-dimethylethylenediamine, 17 g
(12.6 mmol~ of powdered potassium carbonate, and 35 ml
of dimethylsulfoxide is stirred overnight at 50C.
The mixture is cooled and diluted with 50 ml of water.
The solid is collected and washed with water~ The
solid is heated in dichloromethane~ the solution
iltered, then concentrated Trituration of the
residue with hot ethyl acetate gives 1.7 g of the
dried product; mp 148-153C~ . - -
EXAMPLE 51
7,10-Dihydroxy 5-[~2-[(2-hydrox~ethyl)amino~ethyl]-
amino]-2-[2-[(2-hydroxyethyl~methylamino]ethyl]-
anthra[l~9-cd]p~azol-6(2H)-one
Reac~ion of a mixture of 3.3 g (1.3 mmol) of
5-chloro-7~10-dihydroxy-2 ~2~[(2-hydroxyethyl)-
methylamino]ethyl~anthra[l,9-cd]pyrazol-6(2H)-one,
hydrochloride, 3.6 ml (36 mmol) of 2-(2-aminoethyl-
amino)ethanol, and 30 ml of pyridine oYernight at 80C
followea by wor'~up as described :in Fxample 21 and sal~
forma~ion as described in Example 3 gives 1..~ g of the
dried product as a salt wiLh 1~6 equivalents of
h~drogen chloride solvated w~th 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 i5
prepared as follows:
,
~5~3
~LG-l -105-
Reaction of a mixture of 8.3 g (15 mmol) of
5-chloro-2~[~-[(2-hydroxyethyl)methylamino~ethyl]-
7,10-bis(phenylme~hoxy)an~hra[l,9-cd3pyrazol-6(2~)-
one, 87 ml o a 1 M solution o boron trichloride in
dichloromethane, and 60 ml of dichloromethane as
described for Fxample 49 gives 3.5 g o the dried
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 1.75 equivalents o water;
mp 279-282C (decomposition~,
5-Chloro-2-[2-[(2-hydroxyethyl)methylamino]
ethyl]-7,10-bis(pherlylme~hoxy)anthrall,9-cd]pyrazol-
~(2H)-one is prepared as ollows:
Reaction o a mixture of lOo0 9 (15 mmol) of
5-chloro-2-[2-[[4-methylphenyl)sulfonyl]oxy]ethyll-
7,10-bis(phenyl)methoxy)anthra[l,9-cd]pyrazol-6(2H)-
one, 12.1 ml (150 mmol) of 2-m~thylaminoethanol,
4.1 9 (30 mmol) of potassium carbonate, and 90 ml of
dimethylsuifoxide-as described in Example -49 gives -- -
8.5 g of the product; mp 191-194C.
EXAMPLE 52
7,10-Dihydroxy-5-[[2-[(2-hydroxyethyl)amino]etnyl~-
amino ! -2-[3-[(2-hydroxyethvl)amino]propyl]anthra-
[l,g-cd]pyra~ol-6(2H)-one
Reaction of a mixture of 1.4 g (3.6 mmol~ of
5-chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)a~ino]-
propyl]anthra[l,9-cd]pyrazol-6(2H)-one, hydrochloride,
3.7 ml (37 mmol) of 2-(2-aminoethylamino)e!ha~ol and
15 ml oE ~yridine overnigh~ at 80C follow?d by worXup
as described in Example 21 gives 0.9 g of ~he dried
produc~. solvated with 0.6 equivalent of water; mp
10~-105C.
5-Cbloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)-
amino]propyl]anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follo-~s:
;6D~
CLG-l -106-
Reaction of a mixture o 9.0 g (16 mmol) of
! 5-chloro-2-[3-~(2-hydroxyethyl)amino]propyl]-7,10-
bis(phenylme~hoxy)anthra~l,9-cd]pyrazol-6(2H)-one,
63 ml of a 1 M solution of boron trichloride in
dicAloromethane, and 30 ml of dichloromethane as
described for Example 49 gives 6.0 g of the dried
product as a salt with 0.8 aquivalent of hydrogen
chloride solvated with 0.7 equivalent of water;
mp 255-265C (decomposition).
5-Chloro-2-[3-l(2-hydroxyethyl)amino]propyl]7,10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepar2d as follows:
Reaction of a mixture of 13 4 g (19.7 TT~ol) of
5-chloro-2-~3-[[4-methylphenyl)sulfonyl]oxylpropyl]-
7,10-bis(phenylmethoxy)anthra~l,9-cd]pyrazol~6(2H)-
one, 12 ml (197 n~ol) of 2-aminoethanol, 5.5 g
(39.4 mmol) of potassium carbonate, and 120 ml of
dimethylsulfoxide as de.scribed in.~xample 49~gives~
~.85 ~ of the product, mp 174-176C. Crystallization
Erom chloroorm gives material o mp 180-18SCo
5-Chloro-2-[3-[[4-me~hylphenyl)sulonyl]oxy~
prop~ 7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2H)-one is prepared as follows:
Reaction of a mixture of 130 1 9 (25 TT~01) of
5-chloro-2-(3-hydroxypropyl)-7,10-bis(phenylmethoxy)-
anthra[l,9-cd]pyrazol-6~2H)-one~ 9~5 g (S0 TT~ol~ of
~-toluenesul~onyl chloride, 9 ml (65 mmol) of
triethylamine r lS0 mg of 4-dimethylaminopyridine, and
125 ml of dichlorome~ha?la at 5C for one day ~hen at
room temperature for ive hours followed by wor'~up as
described for Example 49 gives 14.3 g of the product;
mp 137-139C.
-S-Chloro-2-(3 hydroxypropyl)-7,10-bis(phenyl-
methoxy)anthra~l,9-cd]pyrazol-6(2H)-one is prepared
as ollows:
~,2~
CLG-l -107-
A mixture of 48.9 g (100 mmol) of 1,4-dichloro-
5,8-bis(phenylmethoxy)-9,10~-an~hracenedione, 18 0 g
(200 mmol) of ~3-hydroxypropyl)hydrazine [J. ~ner.
Chem. Soc. _ , 1283 (1954)1, 2.9 g (50 mmol) af
anhydrous potassium fluoride, 10.0 g (100 mmol) of
anhydrous potassium bicarbonate, and 300 ml of dry
dimethylsulfoxide is stirred at 80C overnight. The
warm mixture is diluted with 1.5 ml of water, then
allowed to cOOla The solids are collected by filtra-
tion, washed sequentially wi~h 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 9
of additional product, mp 150-154C~
EXAMPL~ 53
5-~(3-Aminoeropvl)amino]-7,10-dih~droxy-2-[3~[(2-
hydroxyethyl)amino]propyl]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 1.3 g (3.3 mmol) of
5-chloro-7,10-dihydroxy-2-l3-[(2-hydroxyethyl)amino~-
propyl]anthra[l,9-cd]pyrazol-6(2H)-one, 2.9 ml
(35 mmol) of 1,3-propanediamine~ and 15 ml of pyridine
at 80C overnight followed by workup as described in
Example 21 gives 1.0 g of the dried product as a salt
~-th 0.1 equivalent of hydrogen chloride solvated ~ith
0.3 equivalent of water and 0.1 equivalent oE
2 propanol; mp 120-130C (decomposition).
E~AMPLE 54
7,10-Dih~droxy-2-[2-[(2-hydrox~ethYl~amino~thyl]~5
t [ 2- [(2-hydroxyeth~l?amino]ethyl]amino]a_hra[l,9-cd]-
pyrazol-6(2H)-one
Reaction of mlxture of 1.28 g (3 mmol) 5-chloro-
~,10-dihydroxy-2[2-[(2-hydroxyethyl)amino]ethyl]-
an~hra[l,9-cd]pyrazol-6(2H)-one; hydrochloride, 1.5 ml
(15 mmol) of 2-(2-aminoethylamino)ethanol and 6 ml of
pyridine at 80C overnight followed by workup as
described in ~xample 21 and salt formation as
described in ~xample 3 giVQs 675 mg of the product as
~2~
CLG-l -108~
a salt with 2~0 equivalents of hydrogen chloride
! solqated ~ith 0.9 equivalent of water; mp 215-225~C
(decomposition).
5-Chloro-7,10-dihydroxy-2-[2-[(2-hydroxyeth~l)
amino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
To an ice-cold mixture of 2608 g (48 mmol) of
5-chloro-2-[2-[hydroxyethyl)amino]ethyl]-7,10-bis-
(phenylmethoxy)an~hra[l,9-cd]pyrazol-6(2H)-one and 60
ml of dry dichlorornethane is added dropwise during
2 1/~ hours 794 ml o' a 1 M solution of boron
trichloride The mixture is stirred for an additional
0.5 hours~ then 200 ml OL methanol is a2ded dropwis~
during lo 5 hoursO The mixture is allowed to ~7arm to
room temperature overnigllt and the solids are fil-
tered, washed sequentially with methanol~
dichloromethane, 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 lZ5-135C (decomposition)O
Crystallization of the solid from m~thanol gives a
salt with 1.~ equivalent of hydrogen chloride solvated
with 0.7 equivalent of water; mp 180-200C
(decompcsition~.
5-Chloro-2-~2-[(2-hydroxyethyl)amino]ethyll-7~10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2~)-one is
prepared as ~ollows~
.~ mi~ture o~ 58/8 g (120 ~mol) ~f 1,4~dichloro--
~,8-bis(phenylmethoxy)-9,10~anthracenedione~ 28.6 y
~240 mmol) of 2-[(hydrazinoethyl)amino]ethanol~ 3.S g
~60 mmol) of anhydrous potassium fluoride, 12 9 (120
mmol) of anhydrous potassium bicarbonate, and 360 ml
of dry dimethylsu]oxide is stirred at 80C overnight.
The mixture is diluted with 400 ml of water and the
orange solids are filtered, washed sequentially with
water, 2-propanol, and diethyl ether to give 51.2 g of
the dried product; mp 164-1O8C
5~
CLG-l -109-
The following compounds are prepared as described
in E~ample 54 from 5-chloro-7,10-dihydroxy-2-[2-[~2-
hydroxyethyl)arnino~éthyl]anthra[l,9-cd]pyrazol-6(2H)-
one hydrochloride and the corresponding amine:
EXAMPLE 55
5-[(2-~minoethyl)amino]-7,10-dihydroxv-2-~2-[(2-
hydroxyethyl)amino]e~ l]anthra[l,9-cdlpyrazol-
6(2H)-one
Reaction with ethylenediamine gives the product
as a salt with 2.0 equivalents o~ hydrogen chloride
sol~7ated with 0.9 equivalent of water; mp 272-278C
(decomposition~
~ X~MPL~ 56
5-[[2-(Di~ethyla~ino)ethYl]amino]-7,10-dihydroxy-
2-[2-[(2-hydrox~ethyl ? amino]ethYl]anthra[1,9-cd3-
pyra~ol-6(2H)-one
Reaction with N,N-dimethylethylenediamine gives
the product as a salt with l.9 equivalents of hydrogen
chloride solvated with 1.7 equi~alents OL water;
mp 278-280C (decomposition).
EXAMPLE 57
5-[[2-(Diethylamino?e~hyl]amino]-7,10-dihydroxy-2-[2-
[(2-hydroxyethvl)amino]ethyl]anthra[l,9-cd]pvrazol-
~(2H~-one
Reaction with N,N-die~hylethy~enediamine gives
the product as a salt with l.9 equivalents of hyd~ogen
chloride solvated with 1.5 equivalents of water;
mp 228-231~C.
EXAMPLE 58
5~[(3-Aminopropyl~amino]-7,10-dihydroxy-2-[2-t(2-
hydroxyethyl)amino~ethyl]an~hra[l,9-cd]pyrazol-6-
~2 ~-one
Reaction with l,3-propanediamine gives the
product as a salt with 1.7 equivalents of hydrogen
chloride solvat2d with l.0 ~quivalent o~ water;
mp 222C (decomposition).
~,~s~
CLG-l -110-
EX~ PLE 59
5-~(4-Aminobut~l)amino]-7,10-dihydroxy-2-[2-[(2-hydro~
ethyl)amino]e~h, ~ ~nthra[l,g-cd]Dyra~ol~5(2H)-Gne
Reaction with 1,4-butanedia~ine gives the product
as a salt with l.0 equivalent of hydrogen chloride
solvated wi~h 0.5 equivalent of water; mp 240-245C
(decomposition)~
EXAMPLE 60
5-~(5-Amir.opentyl)amino]-7,10-dihydroxv-2-[2-~(2-
hydroxvethyl?amino]ethyl]anthra[l,9-cd]2yra
6t2H)-one
Reaction with 1,5-pentanediamine gives the
product as a salt with l.9 equivalents of nydrogen
chloride solvated with 0.7 equivalent of water;
mp 270-275C (decomposition),
EXAMPLE 61
7,10-Dihydroxy-2-[2-[(2-hxdroxvethyl)amino]ethyl]
5-[[2-t4-morphoiln~l)ethyl3aminc]ant,~nr~[1,9-cdl~
pyrazol-6(2H)-one
Reaction with 4-(2-aminoethyl)morpholine sives
the product as a salt with 2.4 equivalen~s of hy~rogen
chloride solvated with 0.8 equivalent of water;
m~ 280C (decomposi~ion)~
EXAMPL~ 62
?, lO-Dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyll-5
[[3-1(2-h~rdroxyethyl)amino]propyl]aminolanthra[l~9-cd3
pyra~ol-6(2H)-one
Reaction with 2-(3-a~inooropyla~ino)ethAanol gives
the product as a salt with 2.1 e~uiJalents of hydrogen
chloride solvated with 0.8 equivalent o~ water and
0.1 e~uivalent of 2-propanol; mp 170-180C
(decomposition).
~5~q~3~
CLG~
E~AMPLE 63
5-1l2-[[2-(DimethYlaminoethyl_amin _~th~amlno]-7 ! 10-
dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]anthra-
[l,9-cd]pyrazol-6(2H)-one
Reaction with N,~l-dime~hyldiethylenetriamine
gives the prod~ct as a salt with 2.4 equivalents of
hydrogen chloride solvated with 1.4 equivalents of
water and 0.2 eciuivalent of 2-propanol; mp 80~90C
(decomposition~O
EXAMPLE 64
7,10-Dihydroxy-2-[2-[(2-h~roxyethyl)amino]ethyl]-5
(4-methyl-1-plperazinyl)anthra[l,9-cd]p~razol-
6~2~)-one
Reaction with N-methylpiperazine gives the
product as a sal~ ~ith 2.2 equivalents o hydrogen
chloride solvated with 0O4 equivalent of water and 0.2
equivalent of 2-propanol; mp >123C (decomposition)O
E~AMPLE 65
5-[l2-(Di~ethylamino)ethyl]methylamino]-7,10-di-
hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]anthra-
[l,9-cd]-~yrazol-~(2~)-one
Reaction with N,N,N-trimethylethylenediamine
gives the product as a salt with 2.1 equivalents of
hydrogen chloride solvated wi~h l 9 equivalents of
water and 0.2 equivalenis of 2-propanol; mp >91C
(decomposition)O
EX~.MPLE 66
5-[12-[(2-~minoetl~vl)amino]etht~]amino]~7,10-di-
hydroxy-2-12-[(2-h~droxyethyl)amlno]etht~l]anthra-
l,9~cd]-pYrazol-6(2~)-one
Reaction wit.h diethylenetriamine gives the
product as a salt with l.0 equivalent of 'nydrogen
chloride solvated with l.0 equivalent of water,
mp 210-215C (decomposition).
3~
CLG-l -112~
EX~PLE 67
5 _ z-[sis(2-hydroxyethyl)amino]ethyl] amino] -7,10-
dihydroxy-2-[-2-[(2-hydrox~e~ amlno]ethyl]anthra-
[1,9-cd]p~razol-6(2H)-one
Reaction with N,N-bi~(2-hydroxyethyl)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~MPLE 68
5-1~3-[Bis(2-hydroxyethyl)amino]propyl]amino]-7,10-
dihydroxy-2-[2-hydroxyethyl)amino]ethyl]anthra-
~l,9-cd]pyrazol-6(2~)-one
Reaction with N,N-bis (2-hydroxyethyl) 1,3-
propanediamine gives the product as a salt with
2.1 equivalents o~ hydrogen chloride solvaked with
l).4 equivalent of water; mp 198-215C (decomposition).
EXAMPLE 69
5-~[3-[[4-[(3-Aminoprop~l)amino]butyl]amino3propyl~- -
amino]-7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]-
eth~l]anthra[l,9-cd]~yrazol-6(2H)-one
Reaction with spermine gives the product as a
~alt with 2.75 equivalents of hydrogen chloride
solvated with 0.6 equivalent of w~ter and 0.1 equiva-
lent of 2-propanol; mp 185-Z00C (decomposltion)~
EX~MPLE 70
7,10-Dihydroxv-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
I[2-(methylamino)ethyl]amino]anthra[1!9-cd]- ,
pyrazol-6(2~)-one
Reaction with (2--aminoethyl~-methylcarbamic
a~id, benzyl ester followed by isolation o~ the
intermediate then hydrolysis with refluxing ~8~
hydrobromic acid in acetic acid gives the product as a
salt with 201 equivalents of hydrogen bromide solvated
with 2.3 equivalents of water and 0.5 equivalent of
acetic acid; mp 222~228C (decomposition).
~2~ 3~
CLG-l -113-
EXAMPLE 71
2-(2-Aminoethyl)-7~lo~dihydrox~-5-[[z-[(2-hydr
ethyl)amino]ethyl~amino]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 2.0 g (6 mmol~ of
2-(2-aminoethyl)-5-chloro-7,10-dihydroxyanthra
~l,9-cd]pyrazol-6(2H)-one, 3 ml (30 mmol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine zt
reflux overnight follo~ed 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 -~7ith
2.0 equival~nts of hydrogen chloride solvated with
0.5 equivalent of water; mp 275~28ûC (decomposition).
2-(2-Aminoe~hyl)-5-chloro-1,10-dihydroxyanthra-
Il,9-cd3pyrazol~Z(2E~)~one is prepared rom 2-(2-ami-no-
ethyl)-5~chloro-7,10-bis(phenylmethoxy)anthr2~1,9-cd]-
pyrazol-6(2H)-one and boron trichloride as described
in Example 54 to give the product as a-salt with- - -
1.0 equivalen~ of hydrogen chloride solvated w-th
0.7 equivalent of water; mp 265-268C tdecomposition).
2-(2-Aminoethyl) -S-chloro-7,10-bis(phenyl-
methox~7)anthra[1,9-cd]pyrazol-6(2H)-one is prepared
from 1,4-dichloro-5~8-bi~(phenylmethoxy)-9,10-
an~hracenedione and (2-aminoethyl)hydrazine as
described in Example 54 to give the product; mp
176-178C.
EXAMPLE 72
2-(2-1~minoethvl)-5-[(2-aminoethyl)amino~ 7,10-
-
dihydroxyanthra[l~9-cd]pyrazol-6(2H)-one
~ eaction of 2-(2-aminoethyl)-5-chloro-7,10-
dihydroxyanthra~l,9-ca]pyrazol-6(2H)-one with
ethylenediamine as described in Example 71 gives
the product as a salc ~ith 1.9 equivalents of
h~rdrogen chloride solvated with 1.0 equivalent of
"ater; mp >230C (decomposition).
~:2 5~3~
CLG-l -114-
E'~A~PLE 73
2-(2-Aminoethvl)~5-[~3-aminopro~y]~)a~nino]-7
-
dihvdroxvanthra[l,9cd]p-~razol-6(2H)-one
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-
dihydroxyanthrall,9-cd]pyrazol-6(2H~-one w~th
1,3-propanediamine as described in Example 71 gives
the product as a salt with 2.9 equivalents of hydrogen
chloride solvated with 3.5 equivalents of water;
mp > 310C (decomposition)O
~ XAMPLE 74
2-~2-Aminoethyl)-5-[[2-[[2-(dimethylamino)ethYl]-
amino]ethyl]amino]-7,10-dihvdroxyanthra[l,9-cd]-
pyrazol-6t2H)-one
Reaction of 2-(2-aminoethyl~-5-chloro-7,10-
dihydroxyanthra~l,9-cd]pyrazol 6(2H)-one with
N,N-dimethyldiethylenetriamine as described in Example
71 gives the product as a salt with 3.3 equivalents
o hydrogen chloride solvated wit~ 1.0 equiJalent
of water and 0.2 e~uivalent of 2-propanol;
mp 245-260C (decomposition)O
EXA.~PLE 75
2-(2-Aminoethyl)-5-[[3-[(2-hvdroxyethyl)amino]propyl~-
amino]-7~lo-dihydroxyanthratl~9-cd]~yrazol-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 th~ product as a ~alt with 2.1 equiv~lents o
hydrogen chloride solvated with 1.0 equi~alent o
water and 0.2 equivalent o 2-propanol; mp 175C
(decomposition).
EXAMPLE 76
7,10-Dihydroxy-5-[[2-[(2 hydroxyethyl)amino]ethyl~-
amino]-2-12-methoxyethyl)anthra[1,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 2~0 9 (5.8 mmol) of
5-chloro-7,10-dihydroxy~2-(2-methoxyethyl)anthra-
4~
CLG-l -115-
[1,9-cd]pyrazol-6(2H)-one, 5.8 ml (58 mmol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine
at 85OC overnight ~ollowed by wor~up as described in
Example 21 gives 1.75 g of product. Salt formation
as described in 2xample 3 gives 1.91 g o~ product
as a salt with 1.1 equivalents of hydrogen chloride
solvated with 0.3 equivalent o~ water and
0.~ equivalent of 2-propanol; mp 68-72C.
~ -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]pyrezol-6(2H)-one, 91 ml of a 1 M solution of
boron trichloride~ and 46 ml of dry dichloromethane zs
described in Example 24 gives 6.25 g of the dried
product; mp 137 145C ~decomposition1O
5-Chloro-2-(2-methoxyethyl)-7,10-bis(phenyl-
methoxy)anthrall,9-cd~pyrazol-6(2H)-one-is--prepared-~-~s
follows:
An ice-cold mixture of 3.2 g (6 mmol) of
5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
methoxy)anthra~l,9-cd]pyrazol-6(2H)-one, 1.23 ml
(20 mmol~ of iodomethane, and 20 ml o~ N,N-dimethyl-
formamide 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 ace~ic acid, then diluted with water.
The solids are filtered, washed sequentially ;~ith
2-propanol and die~hyl ether to give 2.8 g o~ ~he
dried product; mp 174-178C~
EXAMPLE 77
5-[(2-Aminoethvl)amino] 7,10-dihvdroxy-2-(2-methoxy-
__ _
ethyl)anthra[l,9-cd]pyrazol-6(2H)-one
~ eaction of 5-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
)
~s~
CLG~
as a salt with 1 0 equivalen~ o~ hydrogen chloride
solvated ~ith 0.3 e~uivalent of ~ater, mp 263-268~C
(decomposition)~
EX~MPLE 7~
2-(Z,3-Dih~dro~ypropyl)-7,10-dih~ldrox~L-5-~2-
1(2-hydroxvethyl)amino]ethYl]amino~anthra~l,9~cd]-
pyrazol-6(2Hl one
A mixture of 1.3 g (2 mmol) of 2-~(2,2-dimethyl-
1,3-dioxolan-4-yl~methyl]-5-[[2-~(2-hydroxyethyl)-
amino]ethyl]amino-7,10-bis(phenylmethoxy)anthra
[l,9-cd]pyra~ol-~(2~)-one, 260 mg o Z0~ palladium
hydroxide on carbon, and 25 ml of glacial a^etic acid
is stirred under an a~mosph~re of hydrogen or two
hoursO The mixture is filterzd and concentrat2d
~o a residue which is dissolv~d in methanolic
hydrogen chloride~ The mixture i5 stirred at room
temperature for two hours and concentrated to a
solid which is crystallized from 1:1 methanol:
ethanol to give 0.7 g o~ the product zs a salt
with 1.1 equivalents o 'nydrogen chloride solvated
with 1.0 equivalent of water; mp >110C1
2-l(2,2-3imethyl-1~3-dioxolan-4-yl)methyl]-5-[[2-
~(2-hydroxye~chyl)amino]ethyl]amino-7110-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2~)-one is prepared as
follo~s
A mixture o 1.2 g ~2 mmol) of 5-chloro-2-
-dlr~lethyl-1,3~dioxoian~4-yl)methyl]-7,1~-bis-
(phenylrcetho~y)anthra~179~cd]pyrazol-6~2~)~0ne~
~.~ m~ (2~ mmol) of 2-~2~aminoethylamino)ethanol,
17 ml of pyridinef and 0 3 g of anhydrou.s potassium
carbonate is stirred at reflux for 42 hours. The
mixture is diluted with w~ter and filtered to yive
a solid that is purified by silica gel chromatography
utilizing 94:5:1 dichloromethane:methanol:triethyl-
amine. Concentration o the product ractions
ollowed by trituration with 2-propanol gives 730 mg
of pure peoduct; mp 206C.
CLG-l -117-
5-Chloro-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl]-7,10-bis(phenylme~hoxy)anthra[1,9-cd]-
pyrazol-6(2H)-o~e is prepared as follo-~s:
A mixture of 19.6 g (4C ~nol) of 1,4-dichloro-
5~8-bis(phenylmethoxy)-9,10-anthracenedione, 10 g
(68 mmol) of 4-(~ydrazinomethyl)-2,2-dimethyl-1,3-
dioxolan IA , 448; 121 (1926)], 4 g (69 mmol) of
anhydrous potassium fluoride, 5.5 g (40 mmol) of
anhydrous ~otassium carbonate, and 150 ml of dry
dim~thylsulfoxide is stirred at 80C for six hours.
The mix~ure is diluted with water and the solids
are filtered, then dissolved in dichloromethane~
Chromatography of the dried dichloromethane layer
over silica gel with gradient elution utilizing
0~ co 1% methanol in dichloromethane giveC Z g
of a solid that is triturated from 2-propanol,
then crystallized from toluene to afford 1.8 9
of pure product; mp 184-188C. - -
EXAMPLE 79
2-[2-(Diethylamino)ethyl]-7-[[2-~(2-hydroxyeth~l)-
amino]ethyl]amino~anthra~l,9-cd]py~ol-6~2H)-
one
Reaction of 2.5 g (i mmol) o~ 7-chloro-2-~2-(di-
ethylaminojethyl~anthra[l,9~cd]pyra~ol-6(2H)-one, 7 ml
(70 mmol) of 2-(2-aminoethylamino)ethanol, and 20 ml
oE p~ridine or 20 hours at reflux followed by workup
as described in Example 9 gives 1.6 g of a solid/ mp -`
ln4-107C, af-~er recrystalliza,ion from toluene~ Salt
~orma~ion as described in Example 3 gives 1.6 g oE ~he
dried product as a salt with 2.0 equivalents of
hydrogen chloride solvated with l.l equivalents of
water; mp 212-216C (decomposition).
7-Chloro-2-[2-(diethylamino)e~hyl]anthra[1,9-cd]-
pyrazol6(2H)-one is prepared as follows:
CLG-l -118-
A mixture of 13.85 g (50 ~nol) of 1,5-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 of 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).
EX~PLE 80
2-[2-(Diethylamino)ethyl]-7-[[2-(diethylamino)ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2H1-one
Reaction of a mixture of 2.1 g (6 mmol) of 7-
chloro-2-[2 (diethylamino)ethyl]anthra[l,9-cd]pyrazol-
6(2H)-one, S ml (36 mmol) of N,~-diethylethylenedi-
aminet and 20 ml of pyridine for 28 hours at reflux
followed by workup as describ~d for Example 21 gives
1.9 g of the dried product as a salt with 2.0
equivalents of hydrogen chloride solvated with 0.2
e~uivalent of wateri mp 292-294C (decomposition)O
EXAMPLE 81
2-~2-[(2-Hydroxvethyl)amino~ethyl]-7-[[2-[(2-hydroxy-
ethyl)amino]ethvl]amino]anthra[l,9-cdJpvrazol-6-
(2~)-one
A mixture of 1~9 g (5 mmol) of 7-chloro-2-~2-[~2-
hydroxyethyl)amino]e~.hyl]anthra[l9g-cd3pyrazol~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 mixture is cooled, concentrated, and
chromatographed over silica gel with O.S~
triethylamine in dichloromethane, utilizing a gradient
elution of 2-10~ methanol, to give the product. Salt
formation as described in Example 3 gives S00 mg ef
CLG-l -119-
the product as a salt ~ith 2.0 equivalents of hydrogen
chloride sol~ated wlth 0.4 equi~alent of water;
mp 285-287C (decornposition)
7-Chloro-2-[2-[(2-hydroxyethyl~amino3ethyl]-
anthra[l,9-cd]pyrazol-6(2H)-one is preoared as
follows:
A mixture of ll.l g (40 mmol) of 1,5-dichloro-
9,10-anthracenedione, 13.1 g (llO mmol) of 2-
t(hydrazinoethyl)amino]ethanol, 4 g of anhydrous
potassium bicarbonate, l g of anhydrous potassium
~luoride, and llO ml of dimethyl sulfoxide is stirred
at 70C overnight. The mixture is chilled and the
solids are collected by filtration, washed with water,
th~n thoroughly with acetoni-~rile to give a residue
that is crystalliz~d from 2-propanol to leave 2.6 g
o~ product. The hydrochloride salt is prepared as
described in Example 3; mp 272-273C (decomposition).
E~MPLE 82
7,10-Dichloro-2-~2-[t2-hydroxyethyl~amino]ethvl]
5-[[2-[(2-hydroxyethyl)amino~ethyl~amino]anthra-
[l,9-cd~pYrazol-6(2H)-one
Reaction of 7,10-dichloro-2-[2-[(2-hydroxy-
ethyl)aminolQthyl]-5-[[(4-methylphenyl)sulfonyl]-
oxy~anthra[l,9-cd]pyrazol-6(2H)-one, hydrochloride,
wlth 2-(2-aminoethylamino)ethanol gives the product.
7,10-Dichloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-
5-¦[(~-methylPhenyl)sulfonyl]oxy]anthra[l,9-cd]-
pyrazol-6(2~)-one is prepared as follo~s^
To a suspension of 30.9 9 (50 mmol) of 19~-
dichloro-5,8-~is[[(4-methylphenyl)sulfonyl]oxy]-
9,10-anthracenedione, 13 ml (75 mmol) of
N,N-diisopropylethylamine, and 130 ml o
~,N-dimethylformamide at 5C is added dropwise 14.9 g
(125 mmol) of 2-[(hydrazlnoethyl)a~ino]ethanol in 70
ml of ~,N-dimethylformamide. The mixture is allowed
CLG-l -120~
to reach 10C duriny five hours, then is diluted ~ith
20 ml of acetone. Af~er warming to room temperature,
the solution i5 concentrated to an oil that i~
distributed bet-~een water and dichloromethane.
Concentration of ~he dried dichlorome~hane layer
follo-~ed by salt formation as described in E%ample 3
gives 18.1 g of the dried product as the hydrochloride
sa~t; mp 158-160Co
1,4-Dichloro-5, 8-bis [ ~ ( 4-methylphenyl)sulfonyl]-
oxy~-9,10-anthracenedione is prepared as follows:
A mixture of 9.3 g (30 ~mol) of 1,4-dichloro-
5,8-dihydroxy 9,10-anthracenedione, 12.6 g (66 mmol)
of ~-toluenesulfonyl chloride, 12.2 ml ~70 mmol) o~
N,N-diisopropylethylamine~ and 120 ml of acetonltrile
i~ hea~ed at 70C for one hour~ then cooled The
crystals are collect~d by filtration to leave 14~4 g
of dried product; mp 195.5-196O5C. Processing of
the filtrates.gives 2~2.g.of..additional product~
mp 19~-192C~ .
EX~MPLE 83
7-~ydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
~2-~(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]
pyrazol-6(2~)-one
Reaction of a mixture of 2-[2-1(2-hydroxyethyl)
amino]ethyl]-5-[[2-[(2-hydroxyethyl~amino]ethyl]-
amino]-7-(phenylmethoxy)anthra~l,9-cd]pyrazol 6(2H)-
one with hydrogen and 20~ palladlum hydroxide on
~arbon as ~escribed in Example 78 giv~s the product as
~ 5al~ with 2.0 equivalent~ oE hydrogen chloride
solYated with 2.3 equivalents of water, mp 265-270C
~decomposition).
2-12~[(2-hydroxyethyl)amino~ethyl]-5-[[2-[(2-
hydroxye~hyl)amino]e~hyl]amino-7-(phenylmethyoxy)
anthra[l,9-cd]pyrazol-6(2H)-one is prepared as
f ollows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
an~.ino3ethyl]-7~(phenylmethoxy)anthra[1,~-cd~pyrazol-
CLG-l -121-
6(2H)-one with 2~(2-aminoethylamino)etha~ol as
described in E~ample 78 yives the product;
- mp 157-159C.
5-Chloro-2-[2-1(2-hydroxyethyl)amino~ethyl]-7-
(phenylmethoxy~anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
A mixture of 4.2 g (11.0 m~ol) of 1,4-dichloro-
5-(phenylmethoxy)-9,10-anthrace~edione, 2.6 g (22.0 mmol)
of 2-~(hyrazinoethyl)amino~ethanol, 320 mg (5.5 mmol)
of anhydrous potassium fluoride, 1.1 g (11.0 mmol) of
anhydrou5 potassium bicarbonate, and 33 ml of dimethyl-
sulfoxide is stirred overnight at 80C~ The mixture is
cooled and poured into water. The aqueous mixture is
centriuged 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
~ollowed by tritura-tion from-methanol gives 84~-~g ~~~
o 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 g (18 mmol) of 1,4-dichloro-
S-hydroxy-9,10-anthracenedione (British
Pat~nt 1,029~448), 2~6 g (19 mmol) of powdered
anhydrous potassium carbonate, 2~5 ml (21 mmol)
of ben~yl bromide, ~nd 75 ml of dry acetone is
heated at re~lux overnight The mixture is cooled
and the solids are washed well with acet~ne.
Concentra~ion of -~he ~iltrates gires a solid which
is triturated with ether to afford 5.8 g of the
dried product; mp 118-1~2~C
Prepared in a fashion s~milar to Example 83 is
the following~
3~S~;~39
CLG-l -122~
2X~MPLE 84
7-Hydroxy~2-[2-[(2-hvdrox~et~y~-aminoJethyl)-5-[[2-
(methylamino)ethyl~amino]anthra[l,9-cd]pyrazol-6(2H)-
one as a salt with 1,8 equivalents of hydro~en
chloride sol~ated with 1.2 equivalents o ~ater,
- mp 280-282C (decomposition) is prepared from 2-[2-
[(2-hydroxyethyl)amino]ethyl]-5-[[2 [methyl(phenyl-
methyl)amino]ethyl]amino]-7-(phenylmethoxy)anthra
[1~9-cd]pyrazol 6(2~)-one; mp 110-113~C, which is
prepared ~rom the reaction of N-methyl-N-(phenyl-
methyl)-1,2-ethanediamine (US Patent 3,201,459) with
5-chloro-2-[2-[(2-bydroxyethyl)amino]ethyl]-7-(phenyl
methoxy)anthra~l,9-cd]pyrazol-6(2H)-one,
EX~MPLE 85
10-Hydroxy-2~[2-[~2-hydroxyethyl)amino]ethyl]-
5-[[2-~(2-hydroxyethyl)amino]ethyl]amino]a-nthra
[l,9-cd]-pyrazol-6(2H)-one
Reaction of a mixture. .o~..2-.E2-~(2-hyaro~y~thyl)-.
amino]ethyl]-5-~[2- E ( 2-hydroxyethyl)amino~ethyl] .
amino]-lO~(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 ~ater; mp 260-267C
(decomposition)O
2-[2-[(2-hydroxyethyl)amino3ethyl]-5-[[2~[(2-
hydroxye~hyl)amino3e~.hyl~amino 10 (phenylmetXoxy)-
anthra~l,9-cdlpyrazol-6(2EI~-one is p~epared a~
follaws~
Reaction of 5-chloro 2-[2-L(2-hydroxyethyl)
amino]-ethyl]-10-(phenylmethoxy)anthra~1,9 cd]pyrazol-
6(2H)-one with 2 (~-aminoethylamino)ethanol as
described in 2xample 78 gives the product;
mp 178-180C.
5-Chloro-2-~2-[(2-hydro~yethyl)amino]ethyl]-10-
(phenylmethoxy)2nthra[1,9-cd]pyrazol-6(2H)-one is
prepared as follows:
~lZ~ 3~
CLG-l -123-
Reaction of 1,4-dichloro-5-(phenylmethox~)-9,10-
anthracenedione wi~h 2-[(hydrazinoethyl)amino]ethanol
as described in Example 83 gi~es the product as the
minor isomer; mp 165-167C.
EXAMPLE 86
?, 9, 10-Trihydroxy-2-[2-[(2-hyd~ox~ethyl_am no]ethyl]-
5-[[2-[(2-hydroxyetnyl)amino~ethyllamino]anthra~
[l,9-cd¦-p~razol-6(2H)-one
Reaction of a solution of 2-[2-[(2-hydroxyethyl)-
amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
aminol-7,9,10-tris(phenylmethoxy)anthra[1,9-cd]-
pyrazol-6(2H)-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
equivalents of hydrogen chloride solvated with 0.8
eyuivalent of water; mp > 235C (decomposi~ion)~
2-[2-[(2-Hydroxyethyl)amino]ethyl]-5-[[2-[(2-
~_ hydroxyethyl)amino~ethyl]amino]-7,9,10-tris(phenyl-
methoxy)anthra[l,9-cd]pyra~ol-6(2~)-one is p.eparea
as follows:
A mixture of 660 mg (1 mmol) of 5-chloro-2-[2-
t(2-hydroxyethyl)amino]ethyl]-7,9,10-tris (phenyl-
methoxy~anthra[l,9-cd]pyrazol-6(2H)-one, 1 ml
(10 mmol) of 2-(2-aminoethylamino)ethanol~ and 2 ml
o pyridine is heated at reflux for 28 hours. Workup
as described in Example 21 gives a solid whose
crystallization from acetonitrile chloro-orm affords
30~ mg of product; mp 158-159C.
5-Chloro-2-[2-[(2-hydroxyethyl)amino~ethyl]-
7,9,10-t-ris(pnenylmethoxy)anthra[l,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)-9,10-anthracenedione, 209 g
(24 mmol) of 2-1(hydrazinoethyl)amino]ethanol,
350 mg (6 mmol) of anhydrous potassium flouride, 1.2 g
(12 mmol) of anhydrous potassium bicarbonate, and
25 ml of dimethylsulfoxide is stirred overnight at
!
~25;~i~3~
CLC~ 124-
75C. The mixture is cooled7 then triturated wi'ch
~-propanol. The solids are filtered, ~ashed ~ell ~ith
water, 2-propanol, ~hen crystallized from chloro-form
to give 2.3 g of orange solid; mp 172-173C.
2rocesslng of ~he nonaqueous filtrates yi~7es
640 mg of additional product corresponding to caO 1:1
mlxture of isomers by 1~ ~IR; ~p 135-140~C,
5,8-Dichloro-1~2,4-tris(phenylmethoxy)-9,10-
anthracenedione is ~repared is as follows~
A suspension of 7.5 g (23 mmol) of 5,8-dichloro-
1,~,4-trihydroxy-9,10-anthracenedione, 9.6 ml
~81 mmol~ of benzyl bromide~ 9O9 g (72 mmol) of
powdered anhydrous potassium carbonate, 0,4 ~1 of
methanol/ 92 ml of acetone, and 46 ml of
~,N-dimethylfo-rmamide is heated at. reflux under argon
for two days. An additional 2.7 ml of benzyl ~romide
is added and the mixture is heated for three daysO
The suspension is filtered and--the filtrate is~
concentrat2d to an oil which i5 distributed betwee~
dichloromethane and 10% aqueous acetic acid. The
dried dichloromethane layer is concentrated to a solid
whose crystallization from ethyl acetate affords 7~2 g
o~ product; mp 174-175Co
~ ,8-Dichlorc-1,2~-trihydroxy-9,10-
anthracenedione is prepared as Eollows
A ~uspension of 451 mg (1 ~mol) of 1,29 4-tris
(ace~ylox~)-5,8-dichloro-9710-anthracenedioneJ S ml
o glacial acetic acid; and 5 ~nl of 6 N aqlleous hydro-
chloric acid is heated at 70~ for one hollr~ Ths
suspension is cooled and the solids are filtered off.
Af~er washing with water and drying, there remains
2~7 mg oE the dried product; mp 290-295C
(decomposition)u
1,2,4-Tris(acetyloxy)-5,8-dichloro-9,10-
anthracenedione is prepared as follows:
A suspension of 307 mg (1 mmol) of 5,8-dichloro-
1~4,9,10-anthracenetetrone, 0.05 ml of 72~ perc~loric
i .
~s~
CLG-l -125-
acid, and 10 ml of acetic anhydride is s~irred 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.
Trituration of the solid from ethyl acetate lea~es
235 mg of product; mp 205-206C.
5,8-~ichloro-1,4,9,10-anthr2cenetetrone is
prepared as follows;
A suspension o 618 mg (2 mmol~ of 1,4-dichloro-
5~8-dihydroxy-9~10-~nthracenedione, 1.06 g (2.4 mmol)
of lead tetraacetate, and 25 ml of glacial acetic acid
is stirred at room temperature for 45 minutes~ The
mixture is treated with 0.5 ml ethylene glycol, and
a~ter 15 minutes is diluted with dichloromethane.
The mixture is washed wi~h water and ths dried organLc
layer is evaporated to a solid. Trituration of the
solid from diethyl ether ~ives 569 mg of product;
mp 255-257~ (decompGsition)-.-
~
EX~MPLE 877,8,1G-Trihydroxy-2-[2-~(2-hydroxethyl)Gmino~ethyl]-
5-l[2-[(2-hydroxyethYl)amino]ethyl]amlno]anthra-
~l,9-cd]pyra7O1-6(2H)-one
Reaction of a solution of 2-[2-[(2-hydrox~ethyl)-
amino~e-thyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]
amino]-7,8,10-tris(phenylmethoxy)anthra[l,9-cd~-
pyrazol-5(2 )-one in glacial acetic acid with hydrogen
and 20% palladium hydroxide on carbon as described in
Example 78 gi~es the product as a salt with 2~1
equi~7alents oE hydrogen chlorlde solvatecl with 0.
equivalent of ~ater; mp >210C (decomposition)~
2-[2-[(2-Hydroxyethyl)a~ino]ethyl]-5-[[2-[(2-
hydroxyethyl)amino]ethyl]amino]-7,8,10-tris(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2~)-one is prepzred
as follows:
Reaction of 5-chloro-2-[2~[(2-hydroxyethyl)-
amino]ethyl]-7,8,10-triq(phenylmethoxy)anthra[1,9-cd]-
.. ,
B3~
CLG-l -126-
pyrazol-6(2H)-one with 2-(2-aminoethylamino)ethanol as
described in Exa~ple 86 gives the pro2uct;
mp 186-188C.
5-Chloro-2-~Z-[(2-hydroxyethyl)amino]ethyl~-
7,8,10-tris(phenyl~ethoxyjanthra[l,9-cd]pyrazol-
6(2H)~one is prepared as follo~5:
Reaction of 5,8-dichloro-1,2,~-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 164-167~C~
Prepared in a fashion similar ~o Exam21e 87 is
the following:
E~AMPLE 88
7,8~10-Trihydro~y-2-[2-[(2-hydroxyethyl)amino)]ethyl]
5-C[2-(methylamino)ethyl]amino]anthra~1,9-cd]~
pyra2O1-6(2H)-one as a salt with ~.0 equivalents
of hydrogen chloride solvated with 0.7 equivalent of
water; mp >220C (decomposition~, which is prepared
from 2-[2-[(2-hydroxyethyl)amino]ethyl~-5-
t[2-[methyl(phenylme~hyl)amino]ethyl]amino]-7,8,10-
tris (phenylmethoxy)anthra[1,9~cd]pyrazol-6(2H)-one;
mp 104-~108C which is prepared from the reaction of
N-methyl-N(pn~nylmethyl)-1,2-ethanediam~ne with
5~chloro-2-[2-l(2~hydroxyethyl)amino]ethyl~
7,8,10-tris(phenylmethoxy)anthra~l/9-cd]pyrazol-
G(2~)-one~
EXA~2LE 89
5-[~2-[(2-Aminoe-~hyl)amino~etnyl~amino]-7,10
dihydroxt~-2-(2-nydroxyethyl)a~hra[1,9-cd]-
pyrazol-6(2H)-one
Reaction of a 5olution o 5-[[2-[(2-aminoethyl)-
amino]e~hyl]amino-2-(2-hydroxyethyl)-7,10-bis(phenyl-
metho:sy)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 equivalents of hydrogen chloride
solvated with 0.8 equlvalent of water; mp 170-1~5~C
(decomposition).
CLG-l -127~
5-[[2-[(2-Aminoethyl)amino]ethyl]amino-2-(2-
hydroxyethyl)-7 10-bis(phenylmethoxy)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~lo-bis(phenylmethoxy)anthra[l~9-cd
pyrazol-6(2H)-one 10 g (100 mmol) of diethylene-
triamine~ 1.4 g (10 mmol) of anhydrous potassium
carbonate and 60 ml of pyridine is heated a~ reflux
for 28 hours. The mixture is cooled 7 the solids are
collected by filtration then washed seque~tially with
water and 2-propanol to give 3.1 9 of the product;
mp 185-190C.
EXAMPLE 90
2-~3-Aminopropyl)-7~10-dihydroxy-5-[[2-[(2-hydroxy
ethyl)ami}lo]e~hvl~aTnino]anthra[l,9-cd]~Yrazol-
~(2H)-one
Reaction of a solution of 1~2 g (2 mmol) of
- -2-t3-aminopropyl)-5 ~2- E-( 2-hydroxyeth~l)amino3ethyl~~
amino]-7 10-~is(phenylmethoxy)anthra[l 9-cd~pyrazol-
6(2H)-one in glacial acetic acid with hydrogen and 20
palladium hydroxide on carbon as described in Example
7~ ollowed by salt formatlon as described in Example
3 gives 8~0 mg of ~he product a salt with 2.0 equi-
valents o hydrogen chloride solvated wi~h 1.1 ~qui-
valents of water; mp 292-294C (decomposition)0
2-(3-Aminopropyl)-5-[[2-[(2-hyroxyethyl)amino]-
ethyl]amino-7,10-bis(phenylmethoxy)anthra[1~9-cdJ-
pyrazol-6(2a)~one is prepared as follows.
A mixture of 530 mg (1 mmol~ oE 2-(3-amino-
propyl)-5-chloro-7 10-bistphenylmethoxy)anthra-1 9-
cd3pyrazol-6(2H)-one 1 ml (10 mmol) of 2-(2-
aminoethylamino)ethanol 140 mg (1 mmol) of anhydrous
potassium car~onate and 8 ml oE pyridine is heated at
reflux or 22 hours. Workup as described in Example
89 gi-~es 400 mg of the product; mp 191-195C.
2-(3-Aminopropyl)-5-chloro-7 10-bis-
(phenylmethoxy)anthra[l 9-cd]pyrazol-6(2~)-one is
) prepared as follows:
25~3~L
CLG-l -128-
Reaction oE a mixture o~ 1,4-dichloro-5,8-bis~
(phenylmethoxy)~9,10-anthracenedione and (3-amino-
propyl)hydrazine [Helvetica _ himica Acta 4Z; 533
(1959)] as described in Example 54 gives the product;
mp 180-18~C.
Prepared in a fashion similar to Example 90 i5
the ollowing:
EXAMPLE 91
2-53-Aminopropyl)-5-[[2-[[2-(dimethylamino)ethyl]-
amino ~ amino]-7,10-dihydroxy---thra[l;9~cd]
pyrazol-6(2H)-one as a salt with 3.0 equivalents
of hydrogen chloLide solvated with 2.0 equivalents of
water; mp 294C (decomposition), which is prepared
froln 2 (3-aminopropyl)-5-[[~-[[2 (dimeth.ylamino)-
ethyl]a~ino]ethyl]amino]-7,10-bis(phenylmethoxy)
anthra[l,9-cd]pyrazol-6(2H)-one; mp 143-160C, which
- is prepared from the reaction OL N,N-dimethyldi-
e.hylene~riamine with 2-(3-aminopropyl)-5-chloro-
7,10-bis(phenylmethoxy)anthra[l,~-cd3pyrazol-
~(2H)-one.
EXAMPLE 92
2-(2-Aminoethyl)-7,10-dihydroxy- _ [[2-(methylamino)-
ethyl]amino]anthra[l,9-cd]pxrazol-6(2 ?-one
Reaction of a mixture of 2-(2-a~inoethyl)-5-
1[2-methyl(phenylmethyl)amino]ethyl]amino]-7rlo-bi
(phenylmethoxy)anthra~l,9-cd]pyrazol-6~2H)-one with
hydrogen and 20~ palladium hydroxide on carbon as
- described in Example 78 giYeS the ~roduct 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)-
amino3ethyl3amino]-7,10-bis(phenylmethoxy)anthra[l,9-
cd~pyrazol-6(2~)-one i5 prepared as follows:
Reaction of 2-(2-aminoetnyl)-5-chloro-7,10-bis-
(phenylmethoxy)anthra[l,9-cd]pyra~ol-6(2H)-one ~ith
?
331
CLG-l -129-
N-methyl-~-(phenylmethyl)-1,2-ethanediarnine as de-
scribed in Example 7a gives the product; mp 169-172~C.
EXA.~PLE 93
7~10-Dihydroxy-5-[[2-[(2-h~!droxyethyl)amino]ethyl]-
amino]-2-[2-(methyiamino)ethyl]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction of a mixture of 5-~[2-~(2-hydroxyethyl)-
a~ino]ethyl]amino]-2-[2-(methylamino)ethyl]-7,10-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 as a salt
with 2.0 equivalents of hydroyen chloride solvated
with 1.8 equivalents of wa~er; mp 180-185C
(decomposition)O
5-112-~(2-hydroxyethyl~amino]ethyl]amino3-2-
[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)ethyl]- - ~
7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-
one with 2-(2-aminoethylamino)ethanol as described in
Example 78 gives thP product; mp 185-189C~
5-Chloro-2-[2-(methylamino)ethyl]-7,10-bis-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follo-~s:
Reaction of 5-chloro-2-[3-[[4-methylphenyl)-
sulfonyl]oxy]ethyl]-7,10-bis(phenylmethcxy)anthra-
[l,9-~d~pyrazol-6(2H)-one with methylamine as de-
scribed in Example 51 gives the product; mp 171-176C.
EX~MPLE 94
5-~(2-A~inoethvl)amino]-2-~3-(dimethYlamino)propyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H~-one
-
~ eaction of S-chloro-2-[3-(dimethylamino)propyl]-
7,10-dih~ydroxyanthra[l,9-cd]pyrazol-6(2H) one, hydro-
chloride, with ethylenediamine as described in
Example 46 glves the product as a salt with 2.0
equivalents of hydrogen chloride solvated with 0.5
equivalent
~2~ 3~
CLG-l -130-
of water and 0.1 equivalent of 2-propanol; mp 316C
(decomposition).
EXAMPLE 95
7,8-Dihydroxy-2-[2-[(2-hydroxvethyl)amino]ethy1]-5-
[~2-[(2-hydroxyethyl)amino]e~y~amino]anthra[l!9-cd]
pYrazol-6(2H)-one
Reaction of a mixture of 2-[2-[(2-hydroxyethyl)-
amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino~ethyl]-
aminoj-7,8-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2~)-one with hydrogen and 20~ palladium hydroxide
on carbon as described in Example 78 gives the
product.
2-[2-~t2-hydroxyethyl)amino]ethyl]-5-[[2-[~2-
hydroxyethyl)amino]ethyl~amino]-7,8-bis-
(phenylmethoxy)clnthra[l,9-cd]~yrazol-6(2H)-one is
prepared as follows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
amino]ethyl]-7,8-bis(phenylmethoxy)anthra[l,9-cd]-
pyrazol-6(2H)-one with 2-(2-aminoethylamino)ethanol
as described in Example 78 gives the product.
5-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,8-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
Reaction of 1,4-dichloro-5,6-bis(phenylmethoxy)-
9,10-anthrâcenedione with 2-[(hydra~inoethyl)amino3-
ethanol as described in ~xample 54 gives the product.
1,4-~ichloro-5,6-bis(ph~nylmethoxy)-9,10-
anthracenedione is prepared as follows:
Reaction of 1,4 dichloro-5,6-dihydroxy-9,10-
anthracenedione with benz~l bromide as described in
Example 48 gives the product.
1,4-Dichloro-5,6-dihydroxy-9,10-anthracenedione
is prepared as follows:
Reaction of nitrosyl sulfuric acid and 5,6-
diamino-1,4-dichloro-9,10-anthracenedione [~him.
Geterotsikl~ Soedln. 808 (1968)] gives the product.
