Note: Descriptions are shown in the official language in which they were submitted.
- 2 -
This is a divisional application of co~ending application,
serial no. 432,584, filed July 18, 1983.
BACKGROUND OF THE INVENTION
Several 2,5 and 2,7-disubstituted anthra[l,9 cd]pyrazol
6(2H)-ones are disclosed in the prior literature. See for
example J. Chem. Soc., 1630 (1952); J. Chem. ~oc., 189~
(1954). Neither reference discloses any utility for these
compounds.
S~MMARY OF THE INVENTION
The invention in its first generic chemical compound
aspect is a compound having the structural formula
lo w~
X' O ~R~
wherein X, X' and W may be the same or different and are
hydrogen, hydroxy, alkoxy having one to four carbon atoms
and chlorine; R is H or alkyl of from one to six carbon
atoms; Y is H, alkyl of from one to six carbon atoms which
may be substituted with an ORl group wherein Rl is H or
alkyl of from one to six carbon atoms, or ANR2R3 wherein A
is straight or branched alkylene of from two to eight carbon
atoms, R~ and R3 may be the same or different and are H,
alkyl of from one to six carbon atoms which may be substituted
with OH or an NRaRa wherein Ra may be the same or different
and is H or alkyl of from one to three carbon atoms which may
be substituted with OH, or NRbRb wherein Rb is the same
3 ~ 2
or different and is H or alkyl of from one to three carbon
atoms, or R2 ancl R3 when taken together may be ethylene or
may form
-(C~2)
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 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-
~(C~2)n \
) B
-(CH2)m /
wherein n and m and s are defined above, Z is ~, alk-ll
of from one to six carbon atoms ~hich may be substi
tuted with an ~(Rl)2, SRl, or ORl group wherein
Rl is the same or different and is defined above, or
D~IR2R3 wherein D is st~aight or branched al'.Yylene
o from t~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 acc~ptable
salts thereo~; with the following provisos, 1) when
X, ~' and r~7 are R and Z is H, R and Y when taken
together do not complete a piperidine ring, ~) when
J~ ~ X ~ 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 Lormula
X N N-Z
W-~ '
X' O NRY
w'nerein X; X' and ~ may be the same or different
and are H or O~, alkoxy having one to four carbon
atoms or chlorine; R is H or alkyl of from one to si:c
carbon atoms; Y is H, alkyl of from one to six carbon
atoms which may be substituted with an P~l group
wherein Rl is ~ or alkyl of from one to six carbon
atomsr or A~R2R3 wherein A is straight or hranched
aL~ylene of from two to ei~ht carbon atoms, R2 and
~ ~ 5 ~
R3 may be the same or different and are H, al'.~yl of
) Ero~ one to si~ car~on atoms which may ~e substituted
with OH or an ~RaRa ~herein Ra may be the same or
different and is H or alkyl of from one to three
carbon atoms which may be substi~uted with OH, or
NRbRb wherein Rb is the same or different and is H
or al~l of from one to three carbon atoms, or R2 and
R3 when ta~en together may be ethylene or may form
~(C~2)n\
B
- ~ CEI2 ) in/
wherein n and m may be tne same or different and are
one, two, or three provided that the sum of n and m
i5 an integer oE from three to six, and B is a direct
bond, O, S, or N-R~ 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
(CE~2)n\
B
-~CH2)m /
wherein n, mr and 3 are defined above; Z is H, alkyl
oE rom one to six carbon atoms which m~y ~e
substituted with an l~(Rl)2, SRl, or OR1 group
wherein R1 is the same or different and is defined
a~ove, or DNR2R3 wherein D is straight or branched
alkylene of from two to eight carbon atoms which may
be substituted with an OH group and R2 and R3 are as
defined above; and the pharmaceutically accepta~le
salts~ thereof; with the following provisos, 1) when X,
X', and W are H and Z is H, R and Y when taken
together do not co~plete a piperidine ring, 2) when X,
X', and W are H and Z is CH3 R and Y when taken
together do not complete a piperidine ring or a
morpholine ring.
~5~
CL5 1 -5~
The invention sought to be patented in its
! third generic chemical compound aspect is a com~ound
ha-~ing the structural Eormula
N N-Z
xlx~3, ~i
O NRY
wherein X and X' may be the same or different and are
~, OH, alkoxy of one to four carbon atoms or chlorlne;
R is B or alkyl of Lrom one to six carbon atoms; Y is
H, alk~l Oe from one to six carbon atoms which may be
substi~u~e~ with an ORl group wherein Rl is H or
al~yl of from one to six carbon atoms, or ANR2R3
wherein A is al~ylene of from two to 11 carbon atoms,
R2 and R3 may be the same or di,ferent and are H,
alkyl o from one to six carbon atoms which may be
substituted with OH or an NRaRa wherein Ra is H or
alk~yl of from one to three carbon atoms which may be
substituted with OH, or NRbRb wherein Rb is the
same or difrer~nt and is d or alkyl of from one to
~h~ee carbon atoms, or R2 and R3 when t~ken together
may be et~ylene or may form
~(C~2)n
-(C~2)m~
wnerein n, m, and B are defined above; Z is H, alkyl of
from one to six carbon atoms whicn may be substituted
with an N~Rl)2, SPl, or ORl sroup wherein Rl is
defined above, or DNR2R3 wherein D is al~ylene
of from two to 11 carbon atoms which may be substituted
with an ~ group and R2 and R3 are as defined above;
and the phar~aceutically acceptable sal.s thereof; with
the ~ollowing provisos, 1) when X is H and z is H, R
~25~L~L~l2
and Y when ta'~en together ~o not complete a piperidine
ring r 2) ~hen X is H and Z is CH3 R and Y when taken
together do not complete a plperidine ring or a
morpholine ring.
~~C~2)n\B
-(CH2)m /
wherein n, ~, and B are defined abovei 2 is ~, alkyl of
from one t~ six carbon atoms which may be substituted
with an N(Rl)2, SRl, or ORl group wherein Rl is
defined above, or DNR2R3 wherein D is alkylene
of from two to 11 carbon atoms which may be sub~ti~uted
with an OH group and R2 and R3 are as defined above;
and the pharmaceutically acceptable salts.thereof; with
the followiny provisos, .1) when X i.s H and Z i~ H, R
and Y when taken together do not complete a piperidine
ring, 2) when X is H and Z is CH3 R and ~ when ta,cen
together do not complete a piperidine ring or a
morpholine ring.
The invention in its fourth generic chemical
compound aspect is a compound ha~ing the structural
formula I
X N - N-z
' O
I
wherein X, and X' may be the same or different and
are 'd or OH; R is H or alkyl of from one to si~ carbon
atoms; Y is H, alkyl of from one-to 5iX carbon atoms
which may be substituted with an ORl group wherein
Rl is ~ or alkyl of from one ~o six carbon atoms, or
ANR2R3 ~herein A is straight or branched al.~ylene of
from two to eight carbon atoms, R2 and R3 may be t`ne
J
~;~5~2
--8--
same or aifEerent and are ~, alkyl of from one to six
car~on âtOmS which may be su~stituted with OH or an
NRaRa wherein ~a is the same or dirferent and as
H or alkyl o from one to three carbon atoms which may
be substituted with OH, or NRbRb wherein Rb is the
same or different and is H or alXyl of 'rom one to
three carbon atoms, or R2 and R3 when taken together
may be ethylene or may form
-(C~I2!n\
-(C~12)m/
and m is an integer of from three to si~, and B is a
direct ~ond, O, S, or N-R4 wherein R~ is H or alkyl
of from one to six carbon atoms; R and Y when taken
t:ogether ma~ be ethylene or may Eorm
-(CH2)n~
~ B
-(CH2)m~
wherein n, ~, and B are defined above; Z is H, alXyl
of from one to six carbon atoms which may be
substituted with an N(Xl)2, SRl, or ORl group
wherein Rl is the same or different and is as defined
above, or DNR2~3 wherein D is straight or branched
alX~ylene of Erom two to eight carbon atom3 which may
be substituted with an OH group and R2 and R3 are as
deined above; and the pharmaceutically acceptable
salts thereof; with the following provisos, 1~ ~hen X
and X' are H and Z is H, R, and v when taXen together
do not complete a piperidine ring, ~) when X and X'
are H and Z is CH3, ~ and Y when taken together do
not complete a piperidine ring or a morpholine ring.
The invention in a first subgeneric aspect of its
fo~rth chemical co~pound aspec~ is a chemical compound
having structural Lormula I wherein X and Xl are O~;
and the pharmaceutically acceptable salts thereo.
~5~
CLG-l -9-
The inven~ion in a second subseneric aspect of
its fourth chemical compound aspect is a chemical
compound na~Jing structural formula I wherein X and X'
are H; and the pharmaceutically acceptable salts
thereof.
The lnvention in a third subgeneric as~ect of its
fourth chemical compound aspect is a chemical compound
ha~Jing structural formu~a I wherein A and D are the
same or different and are ethylene or propylene; and
the pharmaceutically acce~table salts thereof.
The invention in a fourth subgeneric aspect of
its fourth chemical compound aspect is a compound
having structural formula I'
N N-Z'
O NR'Y'
I'
wherein R' is H or alkyl of from 1 to ~ carbon atoms;
Y' is CH2CH~NHCH2CH20H when Z' is alXyl of from
one to four c~rbon atoms which may be substituted with
an SRi, or o~i group wherein Rl is H or
alkyl of from one to four carbon atoms or
D'~R2~3 wherein D' is strai~ht or branched
alkylene of from t~o to four carbon atoms which may ke
substituted with an OH group and P~2 and R3 may
be the same or diferent and are H, alkvl of from one
to six carbon atoms which may be substituted with an
OH or R2 and R3 when taken together may be
ethyler.e or may form
-(CH~)n'
-(C~2)~'/
4L L~ 2
]~o
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, ~" or N-R4 wherein R4 is ~ or
alkyl of from one to four carbon atoms; or Z' is
CH2CH2NHCH2CH2OH when Y' is H, alkyl of from one to six carbon
atoms which may be substituted with an ORl group wherein R
is as defined above or A'NR2R3 wherein A' is alkylene of
from two to four carbon atoms and R2 and R3 are as defined
above; and the pharmaceutically acceptable salts thereof.
The invention in a fifth subgeneric aspect of its
fourth chemical compound aspect is a compound having
structural formu.a I''
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 ORl' group wherein Rl' 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''
-(C~2)m'' ~
wherein n'' and m'' may be the same or different and are one
or two provided that the sum of n'' and m'' is three or four,
and B'' is a direct bond, O, S, or N-R4lwherein R4' is H *r 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 Nl -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 whlch
may be substituted with an OH or R2 and
R3'' when taken together may be ethylene or may
for~
~(C~2)n' ~ i\
B'''
-(C~2)~n' '
wherein n''' and m''' may be tne same or different and
are one or two provided that the s~m of n''' and m'''
is three or our, 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
SRl , or ORl group wherein Rl
is de~ined above, or ~" 'NR2 R3
wherein D" ' is alkylene of ~rom 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 OL
its fourth chemical compound aspect is a compond
haviny the structural formula I " "
N - I-Z''''
OH o NR''''Y''''
I''''
wherein R'' " is H or alkyl of from one to six carkon
atoms; '~" '' is H, alkyl of from one to si~ carbon
atom~ which may be substituted with an oRi
group wherein Rl is H or alkyl of from one
to four carbon atoms, or A''''NR2 R3
wherein A'''' is alkylene of ~rom two to four carbon
atoms, R2 and R3 may be the same
or diLferent and are H, alkyl of from one to six
~L~5~
CLG-l -13-
carbon atoms which may be substituted with an O~ or an
NRa''''Ra''i' whe~ein Ra'l'' is tne same or different
and is H or alkyl of from one to three carbon atoms
which may be substituted with an OH or 22
and R3 when taken together may be ethylene
or mav .orm
-(cH2)n
B'''
~(CH2)m~
wherein n'''' and m'''' may be the same or different
and are one or two provided that the sum of n' " ' and
m'''' is three or four, and B " '' is a direct bond, O,
S, or N-R~ wherein R4 is ~ or
alkyl of from one to four carbon atoms; Z " '' is al~yl
of from one to four carbon atoms which may be
~ubstituted with an SRi ', or oRi '
group wherein R¦ is defined above, or
D " ''NR~ R3 wherein D" " is
alkylene of from two to four carbon atoms which may be
substituted with an O~ group and R2 and
~3 ' are as defined above; and the
pharmaceutically acceptab1e ~alts thereof.
The invention in an eighth subgeneric aspect of
its fourth chemical compound aspect is a compound
haviny the structural formula I~
N - N_zv
~ ~ '
NRVyv
IV
5 ~ ~ L~
CLG-l -14-
wherein E~v is H or alkyl of from one to six car~on
atoms; yv is Fl, alkyl of from one to four carbon
atoms or AVNR2VR3v wherein Av is alkylene
of from two to four carbon atoms, R2Vand R3v may be
the same or different and are H or alkyl of from one
to six carbon atoms which may be substituted with an
OH or R2V and R3v when taken together may be
ethylene or may form
-(CH2)n
3V
-(C~2)mV/
wherein n~ and mV may be the s2me or different and
are one or two provided that the sum of nV and mV is
three or four, and Bv is a direct bond, 09 S7 or
NR4V wherein R4v is H or alkyl o~ from one to
four carbon atoms; zv i9 alkyl of from one to four
carbon atoms, which may be substituted with an SRlV,
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 R~v 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
GH ~ NRViyvi
Ivi
CLG-l -15-
wherein RVi is ~ or alkyl o~ from one to six car~on
atoms; ~vi is H, alkyl of from one to four carbon
atoms which may ~e substitu~ed with an oRlVi group
wherein Rlvi is ~ or alkyl of from one to four
car~on atoms or Avl~R2vlR3vl wherein
~vi is alXylene of from two to four carbon atoms
R2qi and R3Vi may be the same or different and
are alkyl of from one to six carbon atoms which may be
substituted with an OH, or R2Vi and R3Vi when
taken -together may ~e ethylene or may form
-(CH2)nvi\
3vi
-(CH2)mvi/
wherein n~Jl and mVl may be the same or different
and a-ce one or ~wo provided that the sum of nvi and
i i~ three or four, and BVi is a direct ~ond,
O, St or NR4Vi wherein R~Vi is H or alkyl of
~rom one to four carbon atoms; ~vi is
DVlNR2vlR3vl wherein ~vl is alkylene o~
from two to four carbon atoms r R2Vi and R3Vi
are defined above; and the pharmaceutically acceptable
salts thereof.
The invention as species of the fi~st generic
chemical compound aspect of the invention are the
chemical co~pounds having the following names:
2-[2-(diethylamino)ethyl)]-5-[[2-[(2~hydroxyethyl)-
amino]ethyl3amino]anthra[1,9-cd]pyrazol-6(2El)-one;
2-[2-~(2-hydroxyethyl)amino~ethyl3-5-[[2-[(2-hydroxy-
ethyl)amino]ethyl3amino]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-dihydroxy-5-[[2-
~
hydroxyethyl)amino]ethyl]aminoJanthra[1,9-cd]-
pyrazol-~(2H)-one;
CLG-l -16-
5 [[2-[(2-hydroxyethyl)amino]ethyl]amino~-7,10-
dihyaroxy~2-(2-hydroxyethyl)anthra[l,9-ca]pyrazoi-
6(2H)-onej
2-~2-~[2~(dimethylamino)ethyl]amino]ethyl~-5-[[2 [(2~
hydroxyethyl)amino]ethyl]amino]-7,10-dihydroxyanthra-
~l,9-cd]pyrazol-6(2H)-ane;
Z-[2-(diethylamino)ethyll-[[2-(4-morpholinyl)ethyl)J-
amino]anthra[l,g-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2~)-one;
5-[~2-aminoethyl)amino]-2-[2-(diethylamlno)ethyl]-
7,lQ-dihydroxyan~hra[1,9-cd]pyrazol-6(2~)-one;
2-[2-~diethylamino)ethyl]-7,10-dihydroxy-5-[[2~
~methylamino~ethyl]amino]anthra[1,9-cd]pyrazol-
6~2H)-one;
2-[2-(dimethylamino)ethyl]-7,10-dihydroxy-5-[[2-[(2-
hydroxyethyl)amino]e~hyl]amino]anthra[l,9-cd]pyrazol-
6(2_)-one;
5-~2-aminoethyl)amino]-2-[2-~dime~hylamino)ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
5-[~3-aminopropyl)amino]-2-[2-(dimethylamino)ethyl]-
7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2H)-one;
5-[(2-aminoetnyl)amino]-7,10-dihydroxy-2-(2-hydroxy-
ethyl)anthra[l,9-cd]pyrazol-6(2H)-one;
5-[[2~~dimethylamino)ethyl]amino]-7,10-dihydroxy-2-
(2-hydroxyethyl)anthra[l,9-cd]pyrazol-6(2H)-one;
2-~3-(diethylamino)-2-hydroxypropyl~-7,10-dlhydroxy-
5-[[2-[(2-hydroxyethyl)2mino]ethyl]amino]anthra
[l,9-cd]~pyrazol-6(2H)-one;
5-[(2-aminoethyl)amino]--2-[3-(diethylamino)-2-hydroxy-
propyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-[3-(dimethylamino)propyl]-7,10-dihydroxy-5-[[2-
[(2-hydroxyethyl)amino]ethyl]amino]anthra[l,9-cd]-
pyrazol-6(2H~ one;
CLG-l ~17-
7,10-dihydroxy-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-2-[2-[(2 hydroxyethyl)methylamino]eLhyl]-
anthra[l,9-cd]pyrazol-6(2H)-one;
7,10~dihydroxy-5-[[2-[(2-hydroxyethyl)a~ino]ethyl]-
amino]-2-13-[(2-hydroxyethyl)amino]propyl3anthra-
[l,9-cd]pyrazol-6(2~)-one;
5-[(2-aminoethyl)amino]-7,10-dihydroxy 2-[2-[(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol-
6(2~)-one;
5-[[2-(dimethylamino)ethyl]amino]-7,10-dihydroxy-
2 [2-[(2-hydroxyethyl)amino]ethyl]anth~a[l,9-cd]-
pyrazol-6(2H)-one;
5-[~2-tdiethylamino)ethyl]amino3-7,10-dihydroxy-2-[2-
~(2-hydroxyethyl)amino~ethyl]anthra[l,9-cd]pyrazol-
6(2H~-one;
5-[(3-aminopropyl)amino]-7 r 10-dihydroxy-2-[2-[~2-
hydroxyethyl)amino]ethyl]anthraEl,9-cd]pyrazol-6-
(2H)-one;
7,10-dihydroxy-2-[2-t~2-hydroxyethyl)amino]ethyl]-5-
~[3-[(2-hydroxyethyl)amino]propyl]amino]anthra[l,9-
cd]p~razol-6(2H)-one;
5-[[Z-[[2-(dimethylaminoethyl]amino]ethyl~amino]-7,10-
dihydroxy-2-[2-[(2-hydroxye~hyl)amino]ethyl]anthr2-
[1,9-cd]pyra~ol-6(2H)-one;
5-[[2-1(2-aminoethyl)amino]ethyl]amino]-7,10-di-
hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]anthra-
[l,9-cd]-pyrazol-6(2H) one;
5-[12-[bis~2-hydroxyethyl)amino]ethyl]amino]-7,10-
dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl~anthra-
[l,9-cd~pyrazol-6(2H)-one;
7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
1[2-(methylamino)ethyl]amino]anthra[1,9-cd~pyrazol-
6(~H)-one;
Cr.G-l -18-
2-(2-aminoethyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl)aminoJethyl]amino]anthra[l,9-cd]pyrazol-
6(2H~-one;
2-(2-aminoethyl)-5-[(2-aminoethyl)amino3-7,10-
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-[2-aminoethyl)-5-[[2-[[2-(dimethylamino)ethyl]-
amino]ethyl]amino]-7,10-dihydroxyanthra[l,9-cd]-
pyrazol-6(2H)-one;
2-(2-am.inoethyl)-5-[[3-[(2-hydroxyethyl~amino]propyl]-
amino~-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one;
2-(2,3-dihydroxypropyl)-7,10-dihydroxy-5-[[2-
~(2-hydroxyethyl)amino]ethyl]amino]anthra[l,9-cd]-
pyrazol-6(2H)-one;
7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-
~[2-[(2-hydroxvet.hyl)amino]ethyl]amino]anthra[l,9-cd]
p~frazol-6(2Hl-on~7
7 hydroxy-2-[2-[(2-hydro.Yyethyl)amino]ethyl)-5- E [ 2-
(methylamino)ethyl]amino]anthra[l,9-cd]pyrazol-6(2~)-
one;
10-Hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-
5-[~2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-
cd]pyra~ol-6(2H)-one;
7,8,10-trihydroxy-2-[2-[(2-hydroxethyl)aminO]ethyl]-
S-[t2-[(2-hydroxyethyl)amino~ethyl]amino]anthra-
~l,9-cd]pyrazol-6(2H)-one;
7,8,10-trihydroxy-2-[2-[(2-hydroxyethyl)amino)]ethyl]-
5-1[2-(~ethylamino)eth~l]amino]anthra[l,9-cd)pyrazol-
6(2H)-one;
.5-[[2-[(2-aminoethyl)amino]ethyl]amino]-7,10-
dihydroxy-2-(2-hydroxyethyl)anthra[l,9-cd]pyrazol-
6(2_)-ore;
2-(3~aminopropyl)-7,10-dihydroxy-5-[[2-[(2-hydroxy-
ethyl~aminoIethyl]amino]anthra[l,9~cd3pyrazol6(2H)-
one;
2-(3-aminopropyl)-5-[[2-[[2-(dimethylamino)ethyl
amino]ethyl~amino]-7,10-dihydroxy anthra[l,9-cd]-
pyrazol-6(2H)-one;
/
CLG-l -19-
2-(2-aminoethyl)-7~10-dihydroxy-S-[E2-(methylamino)-
ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-one;
5-[(2-aminoethyl)amino]~2-[3--(dimethyla~ino)propyl]-
7,10~dihydroxyanthra[1,9-cd]pyrazol-6(2H)-one;
7,8-dihydroxy-2-{2-[(2-hydroxyethyl)amino]ethyl]-5-
[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[l,9-cd~
pyrazol-6(2H)-or.e; and
the pharmaceutically acceptable salts thereof.
The ln~-ention in its f~fth generic chemical
compound aspect is a chemical compound having ~he
structural formula
N N-Z
Q" ~
~herein Q, Q', and Q'' may be the same or different
and are hydrogen, OH, alkoxy of one to four carbon
atoms, chlorine, benzyloxy, ~-chlorobenzyloxy and
p-methoxyben~yloxy; and the pharmaceutically
acceptable salts thereof; Z is defined above; and the
pharmaceutica'ly 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 aspect is a chemical compound having tne
structural formula III
[~$
Q~ o Cl
III
CLG-l -20-
wherein Q and Q' may be the same or different and
are H, OH, Cl 4alkoxy, benzyloxy, p-chlorobenzyloxy, or
o-meLhoxybenzylo~y and Z is define~ above; and the
pharmaceutically acceptable salts thereof; provided
that ~hen Q = ~' = H~ Z may not be H or CH3~
The invention in a first subgeneric: aspect of its
sixth chemical compound aspect ls a che~ical compound
ha~ing structural for~ula III wherein Q and Q' are H;
and the pharmaceutically acceptable salts thereof.
The invention in a second subgeneric aspect of
its sixth chemical co.npound aspect is a chemical
compound having the structural formula III wherein Q
and Q' are benzyloxy, ~-chloroben~yloxy, or
~-methoxybenzyloxy; and the pharmaceutically
acceptable salts thereo~O
The invention in a third subqeneric aspect oE its
sixth chemical compound aspect is a chemical compound
having structural ~ormula III wher~in Q and Q' are O~I;
~nd the pharmaceutically acceptable salts thereof.
The invention as species of the fi~th generic
chemical compound aspect of the invention are the
chemical compounds having the Eollowing names:
5-chloro-2-~2-(diethylamino~ethyl]anthra[l,9-cd]-
pyrazol-6(2H~-one;
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl~anthraEl,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,~-
cd]pyrazol-6(2H)-one;
5-chloro-2--[2-(diethylamino)ethyl]-7,10-bis(phenyl-
methoxy)anthra[l,9-cd~pyrazol-6(2H)-one;
S-chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy]ethy1]-
7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)one;
S-chloro-7,10-dihydroxy-2-[2-[(2-hydroxyethyl~amino]-
ethyl]anthra[l,9-cd]pyrazol 6(2H)-one;
~.~5~ .2
CI.G~l -21-
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyll-7,10-bis-
~phenylmethoxy)anthra[l,9 cdlpyrazol-6(2H)-one;
5-chloro-2-~2-[[2-(dimethylamino~ethyl]amino]ethyl]-
7,10-dihydroxyanthra[l,9-cd~pyrzzol-6(2H)-one;
2-(2-aminoethyl)-5-chloroanthra[l,9-cd]pyrazol-6-
(2H)-one;
5-chloro-2-[2-(dimethylamino)ethyl]-7,10-
dihydroxyanthra[l,9-cdjpyra~ol-6(2H)-one;
5-chloro-7-~3-(diethylamino)-2-hydroXypropyll-
7,10-dihydroxyanthra[1~9-cd]pyrazol-6(2H)-one,
5-chloro-2-[3-(dimethylamino)propyl]-7,10-
dihydroxyanthra[l,9-cd~pyrazol-6(2H)-one;
S-chloro-2-~2-hydroxyethyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6~2H)-one;
5-chloro-7,10-dihydroxy-2-[2-~(2-hydroxyethyl)-
methylamino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro 2-[7.-[(2-hydroxyethyl)methylamino]ethyl]
7,10-bis~phenylmetho.xy)anthra[1,9-cd]pyrazol-6(2H)-
one;
5-chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)-
amino]propyl]anthra[l,9-cd]pyraæol-6(2H)-one;
5-chloro-2-[3-~(2-hydroxyethyl)amino]propyl~7,10-
~is(phenylmethoxy)anthra,l,g-cd]pyrazol-6(2H)-otle;
5-chloro-2-[3-[[4-methylphenyl)sulfonyl]oxy]-
propyl]-7,10-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2H)-one;
5-chloro-2-(3-hydroxypropyl)-7,10-bis(phenyl-
~ethoxy)anthra[1,9-cd~pyrazol-6(2H)~one;
2-~2-a;ninoethyl)-5-chloro-7,10-dihydroxyanthra-
~1,9-cd]pyrazol-6(2H)-one;
2-(2-aminoethyl)-5-chloro-7,10-bis(phenylmethoxy)-
anthra[l,9 cd]pyrazol-6~2H)-one;
5-chloro-2-[(2,2-dimethyl.-1,3-dioxolan-4-yl)-
methyl]-7,10-bis(phenylinethoxy)anthra[l,9-cd]-
pyrazol-6(2~)-one;
5-chloro 2-~2-~(2-hydroxyethyl)amino]ethyl]-7-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(~H)-one;
.)
~s~
CLG-l -22
5-chloro-2-[2-[(2 h-ydroxyethyl)amino]ethyl]-10-
(phenylmetlloxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydro~yethyl)amino]ethyl]-
7,8,10-tris(phenylmethoxy) anthra[1,9-cd~pyrazol-
6(2M)-one;
2-(3-aminopropyl)-5-chloro-7,10-bis(phenylmetho~y)-
anthra[l,9-cd]pyrazol-6(2H)-one;
5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl~-7,8-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one;
5 chloro-2-[2-[[2-(dimethylamino~etllyl]amino]ethyl}-
7,10-bis(phenylmethoxy)anthra[1,9-cd]pyraæol-6(2~)-
one; and the pharmaceutically acceptable salts
thereof.
The invention in its seventh seneric chemical
compound aspect is a compound having the structural
formula IV
N N-Z
$3~
NRY O
IV
wherein R is H or alkyl of from one to six carbon
atoms; '~ is H, alkyl or from one to six carbon atoms
which may be substituted with an P~l group whereir R
is H or alcyl of from one to six carbon atoms, or
A~R2R3 wherein A is alkylene of from two to eisht
carbon atoms, R2 and R3 may be the same or different
and are H, alkyl of rom one to six carbon atoms which
may be substituted with OH or an NRaRa wherein Ra may
be the same or different and is H or alkyl of from one
to ~hree carbon atoms which may be substituted with
OH, cr R2 and R3 when taken tosether may be ethylene
or may form
ChG-l -23-
-(CH2)n \
B
~(C~2)m/
wherein n and m may be the sa~e or di~ferent and are
one, t~o, 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 si~ carbon atoms; R and Y when ~aken together
may be ethylene or may form
-(CH2)n\
B
~(cH2~m/
wherein n, m, and B are defined above; Z is H, alkyl
of rom one to six carbon atoms which may be
su~stituted ~ith an N(Rl)2, SRl, or ORl group
wherein Rl may be the same or difEerent and is
deEined above, or DNR2R3 wherein D i9 alkylene of
Erom two to eight carbon atoms which may be
substituted ~ith an OH group and R2 and ~3 are as
defined above; and the pharmaceutically acceptable
salts thereof; with the following provisos, 1) ~hen 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 20 not complete a piperidine ring or a
morpholine ring.
The invention as species of the seventh generic
chemical compound aspect of the invention are~the
chemical compounds having the following names.
2-[2-(diethylamino)ethyll-7-[~2-[(2-hydroxyethyl)-
a~ino~ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-one;
2-~2-(diethylamino)ethyl-7-1[2-(dlethylamino)ethyl]-
amino]anthra[l,9-cd]pyrazol-6(2~)-one;
2-[2-~(2-hldroxyethyl)amino]ethyl]-7-[[2-[(2-
hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-
6-(2H)-one; and the pharmaceutically acceptable sal.s
thereo f .
J
CLG-1 -24-
The invention in its eighth generic chemical
compound aspect i5 a compound haYing the structural
formula VII
N - I-Z
C1 0
VII
wherein Z is defined above, provided it is not H or
CH3,
The invention as a species of the eighth seneric
ch~mical compound aspect oE the invention is the
chemical compound having th~ fo~lowiny names:
7-chloro-2-~2-(diethylamino)ethyl]anthra[l,9-cd]-
pyrazol-6~2H)-one;
7-chloro-2-[2-[(2-hydrox~ethyl)amino]ethyl~anthra[l,
9-cd]pyra201-6(2H)-one; and the pharmaceutically - - -
accep~able salts thereof.
The invention in its ninth chemical compouna
aspect is 5,8-dichloro-1,4,9,10-anthracenetetrone.
The invention in its tenth chemical compound
aspect is the compound 2-[(hydrazinoethyl)amino]
ethanol and the acid addition salts thereof.
The invention in its first generic chemical
process aspect is a process Eor preparing a compound
having the structural formul~
X ~ Z
W-~
X o NRY
which com~rises reacting a compound haviny the
s tructural formula
f~
CLG~ 25~
N - N-Z
~G C~
with an amine ha~ing the formula HNRY wherein W, X,
X', ~, Q', Q'', Y, Z, and R are deined above and,
when necessary~ removing by catal~tic hydrogenation or
by treatment with boron tribromide or trichloride any
ben~l groups.
The invention in its second generic chemical
process aspect is a process Eor preparing a compcund
ha~ing structural ~ormula I
N - N-Z
X' o NRY
I
which comprises reacting a compound having structural
f ormula II
~$
Q~ o Cl
II
~.5~
CLG-l -26-
with an amine having the 'ormula HNRY ~herein X, X',
Q, Q', Y, Z, and R are defined above and, when
necessary, removing by catalytic hydrogenation or by
treatment with boron tribromide or boron trichloride
any ben~yl groups.
The invention in a first subgeneric aspect of its
second chemical process aspect is the process defined
above wherein X and X' are OH.
The invention in a second subgeneric aspect of its
seco~d chemical process aspect is the process definecl
above wherein X and X' are H~
The invention in its third generic chemical
process aspect is a process for preparing a compound
having structural formula III
Q N - N-Z
11
.' ~1,
Q' Cl
III
which comprises reacting a compound having formula V
Q o Cl
¢~
Q~ o Cl
V
with a hydrazine having the formula H2N-NHZ, wherein
Q, Q' and Z are defined above.
-
~S~f~
C'G-l -27-
The invention in a first su'ogeneric aspect of its
thi~d chemical process as~ect is the process defined
above wherein Q and Q' are benz~loxy,
p-chlorobenzyloxy, or p-methoxybenzylo~y.
The inqention in 2 second subgeneric aspect of
its third chemical process aspect is the process
defined above wherein Q and Q' are OH.
The invention in a third subgeneric aspect of its
third chemical process aspect is .he process definec~
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 ~ormula IV
N ~-Z
~ ''
NRY o
I-~
which comprises reacting a compound having structural
formula VIT
N ~-Z
~1 ` ~
Cl o
VII
with an amine having the formula HNRY, wherein Y, Z,
and R are defined above.
~5~ 2
CLG-l -28-
The invention in its fifth chemical 2rocess
aspec~ is a process for preparing 5,8-dichloro-
1,4,9,10-anthracenete~rone which comprises reacting
1,4-dichloro-5,8-dihydroxy-9,10-anthracenedione with
lead tetracetatet
The invenkion in its sixth chemical process
aspect is a process for preparing
2-[(hydrazinoethyl)amino3ethanol ~hich comprises
reacting hydrazine with N-~2-hydroxyethyl)aziridine.
The in~ention in its ~irst pharmaceutical
composition aspect is a pharmaceutical composition
comprising a compound having structural formula I and
the phar~aceutically acceptable salts thereof in
combination with a pharmaceutically acceptable
carrier.
The invention in its second pharmaceutical
composition aspect is â pharmaceutical composition
comprising a compound having structural formula I' and
the pharmaceutically acceptable salts thereof in
combination with a pharmaceutically acceptable
carrier.
The invention in its third pharmaceutical
composition aspect is a pharmaceutical composition
comprising a compound having structurâl formula Il'
and the pharmaceutically acceptable salts thereo~ in
co~bination with a pharmaceutically acceptable
carrier.
The invention in its ~ourth pharmaceutical
composition aspect i3 a pharmaceu-tical composltion
comprising a compound havina structural
formula I''' and the pharmaceutically acceptable salts
thereo in combination with a pharmaceutically
acceptable carrier.
~,~,5~ 'LL~
CLG-l -29-
The invention in its fifth pharmaceutical com-
position aspect is a pharmaceutical composition com-
prising a compound having structural formula I''''
and the pharmaceutically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its sixth pharmaceutical com-
position aspect is a pharmaceutical composition com-
prising a compound having 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 i9 a pharmaceutical composition ~-om-
pris;ncJ a compound having structural eormula I~i
and the pharmaceu~ically acceptable salts thereof
in combination with a pharmaceutically acceptable
carrier.
The invention in its eighth pharmaceutical
composition aspect is a pharl~aceutical composition
comprising a compound having structural formula IV
and the pharmaceu.ically acceptable salts thereof in
combination wilh a pharmaceutically acceptable
carrier.
The invention in its first pharmaceutical method
aspect is a method for treating microbial infections
in a mammal which comprises administering a
~suEEicient amount of a com~ound having structural
formula I and the pharmaceutically acceptable salts
thereof in combination with a pharmaceutically
acceptable czrrier to a mammal in need thereof.
The invention in its second pharmaceutical method
aspect i~ a method for tr~ating leukemia in a mammal
which comprises administering a sufficient amount of â
compound having structurâl Lormula I' and the
pharmaceutically acceptable sal.s thereof in
5 ~" 1, h ~
- 30 -
combination with a pharmaceutically acceptab:Le 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 thereoE.
The invention in its fifth pharmaceutical method aspect
is a method for treatiny solid tumors in a mamma]. which
comprises administering a suEficient 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 m~thod for treating solid tumors in a mammal which
comprises administering a sufficient amount of a compound
having structural formula IV and the pharmaceutically
acceptable salts thereof in combination with a pharmaceuti-
cally acceptable carrier, to a mammal in need thereof.
The invention in its seventh pharmaceutical method
aspect is a method for treating solid tumors in a mammal
which comprises administering a sufficient amount of a
compound having structural formula IViand the
pharmaceutically acceptable salts thereof in combination
with a pharmaceutically acceptable carrier, to a mammal in
need thereof.
f~-rl~r
CLG-l -31-
The inven~ion in its eighth pharmaceutical method
aspect is a method for treating solid tumors in a
mam.mal which comprises administering a sufficient
amount of a compound having structural formula I'J
and the pharmaceutically acceptable salts thereof in
combination with a pharmaceu~ically acceptable
carrier, to a mammal in need thereof.
~5~
CLG-l -32-
DESCRI3?TION OF THE: P~EFERRED E~;~IBODIMENTS
The co~pounds of the invention may be prepared
conven~ently by the follGwing reaction sequence
Q ~ A
~ III
I
N N-~ N - N-Z
W ~ B
X O NRY X~ O Cl
I II
The reaction step "A," involves the reaction of
compound V and a suitably substituted hy2razine,
NH2-N~I~ wherein Q, Q' and Q " , and Z are defined
hereinabove. This reaction may be accomplished in any
of a variety of reaction inert solvents by mixing
api~roxi-mately equimolar amounts of compound V and the
desired hydrazine in tne chosen solvent at elevated
temperature. Use of a catalyst-such as potassium
fluoride or of a slight molar excess of the hydlazine
reactant may improve a particular yield. Examples of
suitable solvents are `~ -dimethylLormamide,
dimethylsulfoxide, pyridine, acetonitrile, the
cellosolves, and the li`~e. Pyridine is the preferred
solvent, suitable reaction temperatures are from aoout
!
CLG-l -33-
30-8S~C. In general, the reaction is allowed to
proceed for about six to about 24 hours at which time
the reaction is substantially complete. The
completeness o~ a particular reaction may be measured
by ~nown procedures such as thin layer chromatography
for example. It is generally observed that increasing
the reaction temperature will decrease the time
necéssary for completing the reaction. The proper
choice of the ~eaction ~Jariables is within the s~ill
of the art. The products of the reaction are isolated
and purified by standard procedures. For example, the
reaction ~ixture may be concentrated by evaporating
the solvent and the residue may be partitioned between
water and a convenient nonwater-miscible organic
solvent such as chloroform~ ~enzene, dichloromethane,
and the like. The solvent may then be evaporated and
the residue may be chrornato~raphed, ~or example, on
silica gel. Choice of the proper chromatography
solvent is within the skill of the art. After
chromatography, the product may be recrystallized, if
desired. When the Q, Q', and Ql substituents of the
so produced compound III comprise benzyloxy,
p-chlorobenzyloxy, or ~-methoxyben2yloxy, the benzyl
substituents may be removed, for example, by treatment
with boron trichloride or boron tribromide in a
chlorinated hydrocarbon solvent such as
dichloromethane at about 0C to produce compound II
wherein the corresponding X substituents represent
h~droxyl~ Acid addition sal~s may also be prepared by
standard procedures. For example, a hydrochloride
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-propanol. The acid addition salts may be
recon~erted to the respective free base by treatment
with a dilute solution of sodium hydroxide or
potassium carbonate for example.
CLG-l ~34~
The reaction step ~'a~ involves the reaction of
compound II with a suitably substituted amine HNRY
wherein R, W, X, Xl, y, and Z are defined heceinabove.
This reac~ion nay be ~ccomplished in any of a variety
of reaction in~rt solvents by mixing approximately
equimolâr amounts of compound II and the desired amine
in the chosen solvent at elevated temperature. The
use of a slight molar excess of the amine reactant, an
inert atmosphere and a catalyst such as anhydrcus
cuorous chloride may improve a particular yieid. The
use of these variations for a particular reaction is
optional and is within the s~ill of the art. Examples
of suitable solvents are N,N'-dimethylformamide,
dimethylsulEoxide, pyridine, acetonitrile, the
cellosolves, and the like. Suit~ble reaction
temperatures are from about 85-130C. This reaction
has been o~served to proceed particularly efficiently
in refluxing pyri.dine. I~ general; the reaction ls
allowed to proceed ~or about 6 to about 24 hours at
which time it is substantially complete. The
completeness of a particular reaction may be ~easured
by known procedures such as thin layer chromatography
~or example. It is generally observed t~.at increa~ing
the reaction tem?erature will decrease the time
necessary for co~pleting the reaction. The proper
choice of the reaction variables is within the skill
of the art. The products of the reaction are isolated
and puriEied by s-tandard procedures which are
substantially identical to those described above for
compound II. Likewise, acid addition salts of
compound I may be prepared by standard procedures such
as that described hereinabove for compGund II.
Alternatively, the compound of formula IIi ~ay be
~reated directly with an amine of formula HNRY to
produce a compound of the Eor~ula
~.5~
CLG-l -35~
N - N-Z
` Q~ ~ ~ ~
Ql b NRY
This compound may then be debenzylated by a
standard procedure to produce the corresponding
compou~ld 'naving structural formula Io
In an alternate process the compounds of formula
I wherein X and X' are hydro~y may be prepared by
the reaction of compound VI (compound V wherein Q and
Q' are d;hydroxy
OH O Cl
VI
with a suitably substituted hydrazine WH2-NHZ to
produce a compound of structural formula II wherein
is OH; Z is defined hereinabove. The reaction of VI
~nd the hydrazine may be accomplished by mixing
approximately equimolar amounts of the reactants in a
solvent such as ~,N-dimethylformamide,
dimethylsulfoxid2, pyridine, and the like at
temperatures about 30-90C~ preferably 30-60C, in the
presence of a base such as potassium bicarbonate.
Pyridine is the preferred sol~ent and when utilized
does not require an additional base. The use of
catalyst such as potassium fluoride may improve
~'5'~ 2
CLG-l -36- -
~he yield of a particular reaction. The subsequent
conversion of the so produced compound II ~herein
X and X7 are hydro~y to the corresponding compound
is carried out as already described hereinabove 2S
reaction step "8".
In an alternate method for prepari.ng the
compounds of formula III, a compound of formula V is
reacted ~ith a hydroxyalkylnydrazine of tne for~ula
NH2-NH(CH2)2-ll-OH, preferably NH2-NH(CH2~2-3-O~
to produce a compound of formula III wherein ~ is
-(C~2)2-ll-~ and is pre erably -(CH2)2-3-OH-
This reaction is carried out substantially as
described hereinabove as reaction step "An. The OH
group of the Z substituent is then derivatized to
produce an easily displaceable substituent known to
those skilled in the art as a "leaving group". ~or
example, the O~ group may be converted to a tosyloxy
or mesyloxy group by reaction wi.th respectively
p-toluenesulphonylchloride or methanesulphonylchloride
in pyridine by procedures ~nown to those skilled in
the art. The leaving group, so produced, may be
subsequently displaced with, for exam~le, an amine
such as diethylamine to produce a Z substituent of the
structure -~C~2)2~ll-NEt2. In the preferred
procedure the substituent ~ so produced is
-~CH2)2_3NEt2. The benzyl aroups or substituted
benzyl groups of compound III, if present, arè removed
as described above to produce a compound o ~ormula
~I, which may be converted to a compound of formula I
as already described hereinabove as reaction step '!B".
The compounds.having structural formula I wherein
X and X' are chloro are prepared starting from
compound VI by first converting VI to the
corresponding di-~-toluenesulfonic acid ester VI'.
CLG-l -37-
Cl O OTos
Cl o OTos
VI'
~ his conversion is conveniently carried out by
treating VI with ~-toluenesulfonyl chloride in a
nonreactive solvent such as ace~onitrile at reflux
temperature. The diester VI' is then treated with a
substituted hydrazine ~H2N~Z substantially âS
described above for the conversion of compound V to
compound III. The product of this reaction, VI "
Cl N - N-Z
11 1
'' ~3~3 ,,
Cl O OTos
~II"
is then treated with an amine having the for~ula HNYR
substantially as described above Lor the conversion of
compound II to compound I. The product of this
reaction has the follo~ing structural formula.
J~ 1
Cl o NRY
wherein ~, Y, and Z are âS deined hereinabove.
- 38 -
The compounds having structural formula IV are prepared
by reacting a compound having structural formula VII with an
amine having the formula HNP~Y using substantially the same
reaction conditions described above for the conversion oE
compound II to compound I, i.e., reaction step "B". A
particular Z substituent, for example, CH2CH2OH may also be
derivatized and converted to another particular Z
substituent, for example CH2CH2NEt2 in a similar manner to
the procedure already described hereinabove.
The compounds of s-tructural formula VII are prepared by
reacting a suitably substituted hydrazine, NH2-NHZ, wherein
Z is defined hereinabove, with 1,5-dichloro-9,10-
anthracenedione in a manner substantially identical to that
described above for converting compound V to compound III,
i.e., reaction sequence "A".
The present invention also contemplates the novel
hydrazine, 2-[(hydrazinoethyl)amino]ethanol,
~H2NHCH2CH2NHCH2CH2OH. 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
~-(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 120 C at 0.035 mmHg. The novel
2-[(hydrazinoethyl)amino]ethanol forms acid addition salts
with organic and inorganic acids such as hydrochloric,
hydrobromic, sulfonic, phosphonic, methanesulfonic, acetic,
benzoic, and the like. For purposes of the invention, such
salts are considered equivalent to the free base form of the
novel hydrazine.
f~
- 39 -
The benzylated ethers V wherein any of the Q
subs-tituents represent benzyloxy, p-chlorobenzyloxy, or
p-methoxybenzyloxy may be prepared by treating compound V
wherein any of the Q substituents represent OH with the
corresponding benzyl bromide or benzyl chloride in a
convenient nonreactive solvent such as acetone,
dimethylsulfoxide, ~,N-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,~,9,10-
anthracenetetrone may be prepared by oxidation of
5,8-dichloro-1,4-dihydroxy-9,lO-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 ~. Am. Chem. Soc., ~8; 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
.,
CLG-l -40-
equivalent amount of the desired acid in the
conventional manner~ The free base forms may be
regenerated by treating the salt form with a base.
For example, dilute a~ueous base solutions may be
utilized~ Dilute aqueous sodium hydroxide, potassium
carbonate, a~monia, and sodium bicarbonate solutions
are suitable for this purpose. The free base forms
aiffer from their respective salt forms somewhat in
certain physical pr~perties 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 exist in un-
solvated as well as solvated forms, including hydrated
forms~ In general, the solvated forms, with
pharmaceutically acceptable solvents such as water,
et~anol and the like are equivalent to the unsolvated
forms for purposes of the inv~ntion.
The term halogen is intended to include fluorine,
chlorine, bromine, and iodine.
The alkyl and alkoxy groups contemplated by the
invention, unless specified otherwise, comprise both
straight ar.Z branched carbon chairs of from one to
about six carbon atoms. Representative of such groups
are methyl, ethyl, isopropyl, butyl, pentyl, 3-methyl-
pentyl, methoxy, ethoxy, i-propoxy, t-butoxy, n-
hexoxy, 3-methylpentoxy, and the like.
The alkylene groups contemplated by the inven~
tion, unless specified otherwise, comprise both
straight and branched carbon chains of ~rom two to
about 11 carbon atoms. Representa.ive of such groups
are ethylene, npropylene, n-butylene, n-heptalene,
i-propylene, 3-ethyl-1,5-pentalene, 3-propyl~
1,6--hexalene, and the like. The preferred alkylene
groups of the invention have the following structural
formulas:
CLG--1 ~41-
l H3 CH3 CH3 CH3 C2H5
(CH2~-2~ CH-CH2 ; -C~2--c~ ; -CH--CE~-; CH-CH2-
C2H5 l ~I3 CH3 CH3
2 ; C~l CH2 C~2; -CH2-c~-c~2-; -cH2-cx2-cH-
Certain substituents, such as alkyl or alkylene
subs-tituents contemplated by the invention are defined
as possibly being substituted with additional
substituents, e.g., NH2. Those skilled in the art
will recognize that certain combinations of such
substituents are ]nost probably unstable and these are
not intended to be included wi~hin the scope of the
de~lni~ions. For example, an ~-aminoalkyl or
alkylene ~Jroup of the general formula = N-CH-NH2
would not be expected to be stable whereas the
- corresponding dialkylated substituent = N-CH-N~Alk)2
is e~pected to be stable and is intended to be
included within the definitions~ It is within the
s~ill of the art to recognize these and other such
substituents which are possibly unstable~
The compounds of the invention are new chemical
substances of value as pharmacological agents for the
treatment of bacterial and fungal infections in
warm-blooded animals. They may also be utilized as
antiseptic agents such as for use in the sterilization
of labora'cory glasswars etc, The antibacterial and
an~ifungal activity of representative compounds of the
inven~ion ~as established by the screening procedure
described belowO
, . ~1., ;2 ~S ~. ~ L~y 2
CLG-l -42-
1. Pre~aration of inocula
.
IA) Bacteria and yeast-
The bacterial and yeast isolates are
~aintained in agar slants or in li~uid media,
hereby designated as inoculum media~ The
cultures are transferred at regular intervals
in such media. (See Table for the correspon-
ding inoculum media o each culture.~ The
organisms are generally transferred on to
agar slants or liquid inoculum media and
incubated overnight (18-20 hours): 37C for
the bacterial isolates and 28C for the
Eungal cultures.
The microbial cells from the overnight agar
slants are then scraped o~f ancl suspended in
sallne solution (0.85~ NaCl). The microbial
concentratlons are adjusted to a light
transmittancy of 20-35~, Junior Coleman
Spectrophotometer (555 M ). For the
organisms that are maintained in liquid
media, an ali~uot of the culture suspension
is simply diluted with saline to 20-35% light
transmittancy.
The above microbial suspension serve as in-
ocula for tne assay plates. Thus, 0.16-10 ml
(see Table for exact amount) are used to
inoc~late 100 ml of the ~olten-agar assay
medium.
(B) Mycelial fungi:
~he Penicillium avellaneum is grown for six
.
days, at 28C, on an agar medium. This is to
allow sporulation of the culture. The
organism is then harvested by scrapilg of
the cells from the agar surface (mycelia and
spores~ and suspending them in saline
solution containing 0.05% Tween 80.
*trade mark
CLG~l -A3-
The suspension is adjusted to a light trans-
mitancy of 20~. One ml of this suspension is
used to inoculate lOO ml of the molten-agar
assay medium.
20 Preparation of assay 2~ates
Stainless steel frames, 12.3 x 25.3 cm (ID) and
glass plates, 15~3 x 31.7 cm are used to make the
test trays. The frames are attached to the plates
with tape at each end and the inner edges sealed
with 2~ agar. Twenty five ml of inoculated assay
medium is spread evenly on each tray and allowed
to soliaify. The trays are covered, inverted, and
refrigerated until used.
3. Disking of samples
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 i5 <10~ . * The
compounds are tested at different concentrations:
3,000; l,OOO; 500; lOO; and lO mcg/ml. Paper
discs (1207 m~ diameter) are placed on the agar
trays with forceps, then O.OS ml of the dissolved
compound is pipetted onto each disc using a 0.2 ml
pipette. (*If the co~pound does not stay in
solution at <10% alcohol, then the fuli strength
alcohol is used. However r the impregna.ed discs
are air-~dried before they are laid on to the
seeded agar plates.)
4 Inter~retation of results
.
The disXed agar trays are incubated overnight
(18-20 hours) at 37C for the bacterial cultures
and 28C for the yeasts~ The Penicillium
avell2neium tray is incubated for at least 20-24
CLG~ 4~
hours since it is a slower-growing orqanism.
Active compounds show a zone o~ inhibition around
the disc~ The diameter of the zone is measured in
mm. The ~one diameter of active co~.pound~ 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 he compound: the larqer the zone
the greater the activity~
CLG--1 --45--
'c ~, O l O ~
a a ~__ ____ ____ ___._ _ ~_
1~ è _, _, O ~ _,
Ie -
u __ _ o o D ____
~ e ~ ~D O O ~
- I.bT3,'~
~ 3~
CLG-l -46
5. Culture media
The composition of the various culture media,
except for the commercially available media, are
sho~n below. The co~mercial ready-made Yeal
Infusion Medium is obtained from Difco
Laboratories, Detroit, 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~ 0,03
Na2X?0~ 0.07
Salts #la 1 ml
Salts ~2~ 10 ml
H20 (distilled)
asal~s ~ 1 % bSalts # 2 %
MgS04 1.0 MnS0~ 1.0
CaC12 5.0 ZnS04.7H20 1.0
NaCl 5.0 FeS0~.7H20 1.0
CuS04 5~20 0.01 ~2 (distilled)
~2 (distilled)
CLG 1 -47-
A.~-09
.~ ~2HP4 3.9 gm
Dextrose 25 gm
Na-citrate 2 H2O 34O4 gm
Casein hydrolysate 6,2 gm
Asparagine 375
~-tryptophan 125 mg
Cysteine 312,5 my
Gluta-thione 3,1 mg
Thiamine HCl 250 g
Riboflavin 625 g
Ca ~antothenate 500 g
Nicotinic acid 500 g
~-aminobenzoic acid 625
Bio~in 120 5 9
Pyridoxine HCl 2.5 g
Folic Acid 500 g
NaCl . 12.5
MgSO~ 250 g
FeSO4 12.5 g
MnSO4-H2O 125 g
Tween 80 62.5 mg
H20 (dis~illed) 1000 ml
AM 25 %
Na2HPo4 ~ H20 n O35
~H2P4 0.05
Yeast Extract (Difco) 0.5
Dextrose l,0
Distilled Water
Utiliziny the above described procedure, the
following results were obtained for representative
compounds of the invention.
CI.G-l -48-
C_ oo oooooo
_ ____._______________
~o U o o ~ _ o
__ ___________________
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1=~=<~=o " __ __,____,__,_-___~_-'__ 1
~< ~ C C) O O O O O O ~
o _~C ___________________
_ ~ ~ Z ~ O~ U
C C~ J U C~ U I
3 C~ 3 3 S = ~ _ 3 _ I
__ ______--_-- _ _ o
C~ U U U U
~ ~ U U ~ U U _~ O
~ ~ ~ ,,. ~ ~ ~ ~ ~. l
u u ~J ~ u u u u u
__ U U U U U U ~ ~ U_ I
X S _ :~ S 3~
~;~.5~
CL.G-l -49-
_ o ô o o o o o ô - ~ _
I '' ~ O o o o ~ I
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tO~J O _ o O r~l ~ o _ _ r~ I
o ,n .r `n ,n o ~ ., I
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¢ rJ o o -- o o ~1 --I _ O O ~1 I
c--------------------------------------------------¦
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l a ~, a a 3 a a a a a S
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o o o c~
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U o o o o ~ _ ~ I
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¢O ~ o o _ I
h C7 0 0 01 1-- ~' O
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~1 _ - '..1 Z Z Z Z
U U 'J 'J U U Uy I
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CLG--1 --51-
E ~
C o o o o o o o o o o o
tl, _ ~ r~ ~ ~ ~ ~ ~ ~ ~I ~ r~
A~ _______________________
a' ô ô o o o o ô ô ô o ô
U! O _ _ _ _ _ _ _ _ _ _ _
J ~ O O O ~ q O ~ ~ O ~
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_ O O O O O O O O O O O
._ ~ _
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r~ __ _ _ ~ _ _ _
W O _ _ _ _ _
.r c~ o ~ ~o ~ In ~ 1~ ~ o
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O O. O. O. In U O. Ul U O O ~
¢ rt _ O ~ O O _ _ O
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_ ______________________
O
~ r~ U ~ ~ ~ Tr~ .
__ __ ____________________
O O O O - -- r
X I I I I I I I I I __
CLG-l -52-
C o o o ô o ô o o o
_ _ _ _ _ __ _ _ _ _ _-- _ _ __ __ _
0 ô C~ o o C~ ô o ô ô
_ ~
0 _ _ __ _ _ _ _ - __ _ _ __ __ _
~ ~1 _ r~ ~ ~ ~ C l _ _
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U _~ ~ _
~iO~ o' ~ o o
_ _ r r~l r~ r~ r~ r~
r ~ N r rJ
a ~ r~ ~ ~ ~ r~ r~ r~ t~l
__ U U ~ C = U U = U
1 rl r~ ~ rl r~ ~ ~ V
U U U U U U U U U
_ _ r~ r~ r~ r~ 1~1 ~ ~ ~ N
~C _ r S = ~ S O O O g
r~
~51.,4 .,;~,~,.A~
CL~;-L _53-
a
I o O O O O O O a o o
rl ,.~ " ,.~ ,,, ~ ~ . .
I _ _ _ _ _ _ _ _ _
e O O O O O O O O O O
I o o C~ o o o o o o o
U r~
I o O O o O O O O O
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I O O O O O O O
S _ _ ~ _ _ ~ r
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t~l I ~ o u~ O _ In o
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ON ON 3N C
_ ~ _
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~ _ _ _ _ Z Z ~ ~ ~ o~ ~ .
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tJ CJ t~ tJ tJ CJ ~J C,l tJ ~ O
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:~ ~ Z =~
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O O O O o e o o o _
X O O O ' ~' O O ' O ' Ul
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C LG~ 4 -
C _ ~ ~ _ _ ~ _ _ _ _ _
C o o o o o o o o ~ o o o o o ~
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_ _ ~ _ _ _ _ _ ~ --------------_ _ _ _ _ _ _ _
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ol ~_ ~ _ ~ ~ ~ _
c~ ~o o. o, o
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U ~ U U U U ~ -- , U U _ ~ _
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u -- -- -- _ _ _ _ , _
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.r~ z 2 z z Z 2 ~
'Jr~ ~U ~ U a .-3 a a ~ ~ ~ # ~ # # _
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_LC;--1 -56-
a
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C ~ Z Z _
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f~
C~G 1 -57-
In addition to their useralness as antibio~io and
antifur.gal agents, cer~ain o the compounds of ~he in
vention display in vivo zntileukemic ar~.iv:i~y ~hen
tes~ed by th~ following procedure.
The in YiVo lym~hocy~ic leukemia ~3a8 test is
carried out by the United Sta~es .~ational t:~ncer
Institute. Th~ animals used ar~ eith2r m2le or e~ale
C~2Fl miceO There are six to seven animals ~er ~es~
groupO The tumor trar.s~lant i5 ~y l~trap~ri~oneal
injection of dil~t~ ascitic ~luid conta.~ing cell3 oE
lymphocy~ic l~ukemia P38~. ~he :es. compounds.are
ad,~inister-d in~rap~ritone~lly in t~o single dose~
~ith a fouroda~ interval bet~een dos2s ~t various dos~
levels following tumor inoculation. The anim~ls are
wei~hed and survivors are rPcor~ed on a regul2r basis
for 30 day~ A ratio of survival ~ime ~or tre~ted
(T)/control ~C~ animals is calculated. ~he c_iterion
for efficacy is ~/C X 100 ~ 125~. The.positive . .~.
control com~ound in ~hi~ ~e t is 1,4-dihydro~y-5,8-
[bis~[2-~2-hydroxyethyl)amin~l-ethyllamino]-9,10-
anthrac~nedione given at dosages ranging ~ro~ 12~0 to
O.075 mg/Xg. See C2nce~ Chemot~era~Y ~e~orts, Part 3,
3, 1 ~1972) for a compr~hensive di_cussion o~ the
Drotoco 1 .
Utilizing this procedur~, the ro'lowiAq results
were obta.ned or represen~a~ive co~pounds o~ t.~a
invention.
N - -~ Z
10 11
X
7 O NR~
~ 5~ 6'~
CLG-! -58-
X Z NRY Dose ~/C X iO0
_ mg/kq ( P~r~ent ) _
~)2~3 2)2NI-~e)21~H~C~2)2Na~c~2)2oHl 12.5 j242, 182
6 25 1 214, 214
j ~2HC1 ~ 1 3 121192, 171
1.561163
I I I 0 781151
7,iO-(CH~2¦(CH2)2N(~e)2iNH(C~2~2NH2 ¦ 6 ~51216 192
2~1C1 1 1 3 ;21 182 173
1.56 l 194, 149
0.781194, 146
(OH)2¦(CH2)2N(Et)2¦NH(CH2)2N(Et)Z ¦100 llaO, 1~4
168 154 ~46
2HC1 11 25 1140 143 149
12. 5 1 132, 114, 140
¦ tc82)2l~(Et) 2¦NHIC82) 2N [cH2)2] 2oi 400 1 211
I 2HCl IILoO 1145, 126
H¦ (CH2)2NlE:t)2¦NH(CH2)2'~H~c~2)2 ¦ ¦
12 5 161 152 178
21~C1 1 1 6 251145 146 161, 178
3.121123, 142, 164, 151
1~561 142, 142, 146
,781135
. __
t
~ ~5~
~--1 ;9
.
X j 3 I NPY Dose ~/C ~ 100
~ mq/k~ _rcent I
7,10-(OH!2¦ (CH2)2';Ee)2 ¦NH(CH2)2NH(CHZ)2OH¦ 12.5 126~, 212
I ~ 2 H C 1 1 1 3 121164, 164, 165
I I I 1. ;61 14a 149 lSS
0.781140 lSl lS9
~ I 1 0.391152, 126
7,10-(OH)2l(~72)2N(E )2 INH(cH2)2~yd~e ¦ 25 1219 .ures
I I 1 6.251163
3.121154
2HCl ¦ NH ( CH 2) 2NH2 ¦ 12 5 ¦ 280 189 Cures
I 1 3.121154, 160
I i 1 1.561172
2J( Z)2 H( ~2)2~(~e)2l~H(c~2)2NH(cH2)2oHl 53 1226
l l 1 12.5 1179,219
I I 1 6 25118~3,191
7,10-~OH)2¦(CH2)2 H(CH2~2 ¦ 3(C 2)2N(Me)2 ¦ 162 z;l179
7,10 - (cH~7l(cH2)2Na(cH2)2oH ¦~[(CH2)212:~Me I 25 llS0
2HC1 1 12 S 169
~¦ (C'12)zNH~C~2)2OH INH~CH2)2 ~ 2 1 12 5 ¦16j 1674
3.1Z1158
*~
CLG--I
--6~--
G I Dose T/C :: 100
____ I _ _ ma/kq I ( Per_ent )
7,10-(OH)~ cH2)2NalcH2)2oalNH~cd2)2~ ~e)2 ¦ 25 1 a8 Curss
2HC1 1 1 12 5 1220, 250 Cures
3.121165 165
1. 561161 165
I o.7alls2
H¦ (CH2)2:~Hlc'i2)2~HlNB~cH2)2N~Et)2 ¦ 25 1149
2HC1 1 1 12. S 1150, 155, lsa lSO
6.25 l 13a 146 150 ' 142
3.121 143 143 144, ISl
1 1.561138, L33
)21~H2)2~H~C82)20H¦NH~c't2)2N~Ee)2 ¦ so 1241
2HCl I ¦ L2.5 ¦ L77 L90
3 12¦ L4'3, 150
1. ;6 l 131 135
)2l~cH2)2~H~cH2)2oHlNH~cH2)2NHlcH2)2NlMe)2l 50 1200 254 CUres
! 251C1 1 125 1CUra~228,129
. I I l2.5 1157, L79 ~ las
6.25116~ 172
3.121152 163
Hl ~C}l2)2NHlc'l2)2OHlNH~cH2)2NH~csl2)2oH I 50 ¦ 199
C~t3C02H I I L2.5 ¦ 143 La9 L66
6.~51147, 157, 166
3.121138 150 166
.. ' . ~$~
CLG-l -61-
X ¦ ~ ~ NRY 1~ / q I (~oreen~)
21 2 Z ( 2)2'i¦NH(C~2)2`;d(c~l2)2~il o ~139
2HC1 1 1 12.5 1153, 177
6. 251206 Cuces
3.121 107, 187
1. 561158, l~a
al (CH2)2t;il(c~2)2HlNH(cH2)2 1 25 ,139
2 1 12 . S 1 175, 180
1 6.2511~6, 180
2HC1 1 1 3.121162t 173
1 1.561150
7,1D-(o~J)2i(ca2~2Na(c~2)2otllNH(c~2)2~H2 ¦ 1 561173, 187 Cures
1 0, 78 1 1~32
2HCl I 1 0 . 391 17 5
7,10--(OH)2¦(CH2)2Na~CH,)20~;¦NH(CH2)3t~H(CH2)~OH¦ 6 25¦169, 25~ Cures
1 . 56 1 201, 166
28Cl l I
7,10-(Oa)2j(Ca2)2N~(c~2)2O~lNH(cH2)3NH2 1100 1~3L Cures
2HC1 1 1 25 1 207 ZS0 Cures
12. S 1 177, 190
6. 25 1 165 172
3.121 16~ 165
7,10-(OH)2' (Crl2)2NH~CH2)2oHlNH(cH2)~NH2 ¦100 1172 173
t I I so I L39 165
~ICl I 1 25 1 150, 152
1 12.5 1139, 145
I I 1 6.251131
3.121 130
7~l~-(oH)2l(cH2)2Na(cH2)2oHlNH(cH2)5NH2 1100 ILSO
1 25 1 127, 127
2HC1 1 1 12.5 1127
C G-1 62
.
3 ¦ ?IRY I DO5e 1 ~/C ~. 100
`q/lCq I !?~r~dnc)
2HC1 I:~HICH2)2t~H(C~2)2O ¦ 12 5 1173 177
3.121 1~9, 158
1 1.561139
.2HC1 1 1 12 5 1182
3. 121160
1.5S I 153
7,10-(Ot)2~ 2)2O~e ¦NH(CH2)2NH(C:;2)2OHI1OO 1139, 140
.HC1 1 1 25 1127, 131
12.5 1127
¦NH(C~2)ZN(Ye)2 1200 l157, 283 C~lres
.2RC1 100 225 242
1 25 1153, 157 173
1 12.5 1124 135, 139
7 10-(0H)2~(CH2)20H INH(C~2)2N(Et)2 130O 1~77
2RC1 1 120O 1 167
1 150 1 155
1100 1149
1 75 1135
37 5 1135
1 25 1 129
7 1O-~OH)2I(CR2)2OH ¦tlH(CR2)2NH(CH2)20H¦200 l196, 271
. HC1 1 1 50 1163 L65
1 25 1165, 187
1 12 5 1158, 163
1 6.251143, 163
_ _ _ ,1 =_ , , ,,, 1. _,,,, _ , _
X ; 7 ¦ NRY I Dose ¦ ~/C X 100
---- I m~ ( Perc a n t )
7 10- ( OH ) ~ ( -H ) Od I Ya ( cH2) 2N~'2 1 25 j 146, 154
12.5 1145, 1;1
6. 2S ~ 135
?'l0-(OH~2t~-t!2~2S~te ¦ 2 2 ( 2)2OH ¦ 16 25~140
~ 2HCl
7~lo-(cH)2icH2cHoHcH2~y(-t)2 I~H(ca2)2 ( )2 ~ 50 ll3l, l35
1 12.5 1128
7,10-SoH)2lcH2cHoHct2N(Et)2 ¦-IH(ct32)2 ( 2 2 1 6.25¦123 203
I 0,73 l l 32
7,10--(oH)2tcHzcHoHcH2y(-t)2 ¦NH(ca2)2 H2 1 1262 Cur~s
3.12l 166, 182, 202
1 56l157 145
1 0.391135
7~lo-soH)2lMe ¦NH(Ct3z)2NH(CH2)2OH ¦100 ¦1?4
12.5 ll30 149
6,251133 L 55
7,10-(OH)2¦ C112C~12NH2 INIIC~12C'12NH2 1 25 i1;6, 21a
2HCl j 1 12.5 1144, 203, 221
7,10-(oH~2l C32CH2Nr.~e2 ¦ 2 H2CH2NH2 ¦ 12.5 1205, 208
2HC1 1 16.251196 Cures
7,10-(OH)2!~'32CH2CH2N~3e2 ~NHCH2CH2NHCE2CH2OH ¦ 12.5 ¦213, 203
2HC1 1 16.25l185 167
7~lo-(oH)2lc~l2cH(oH)c~l2o~3¦Nr3cH2cH2~yHcx2cH2oH ~400 i281 255
HCl 1. 1200 ; Z18, 213
100 j 20a, 194 Cures
1 25 1184, 166
? ,10-(OH)2 ICH2CH2CY2NMe2 ~ HCH2CH2CH2NH2 ¦ 25 i 194, 212
2HCl i j 12 5 1173 130
7,10-(OH)2~CH2C112cH2~Me2 ¦NaCH2cH2NH2 i 12.; 1224 Cure~
I 2~1C1 1 1 6,251186 200
3.121191' lao
7,10-(OH)2~CH2C~12~1MeCH2CH20H ¦NaCH2CH2NHC'32CH2OH ¦ 12.5 ¦203
1.6HC1 1 1 6 2511a2
3 121184
, a SOH)2¦CH2CH2N13CH2CH2OH ¦NH(C92)3N(CHzCH2OH)2l100 i192
50 1167
1 25 1163
7~10--(OH)2~C-32CH2NHCHzCH2OH INHC9 "H NHCH CH NH I 25 l221 22
6.ZS1194 1~7
-64-~
C~~-l
. _ _ _ _
NRY ¦Dose ¦ T/C ~ 100
I Imajcq I (P~r-enC)
7,~0-(OH)2 ICff2.H2r;HCH2CH2Off INHCH2'H2~CH2 2 )2 ¦!00 ¦223, 254
.2.3HC1 ¦ 1 50 1203, 169
i j 25 1137 194
~'1-(#)2 1~2cH2t~Hc~2~H2oH ¦~H(C:~2)3~(cH2)~H(cH2)3r~l2l 12. 1 ,
I 2.75HC1 1 1 6.251127, 109
7,10_(0H)2 l(cH2)3Naca2cH2oH ¦NHCH2CH2tJHCH2CH2O l100 l259 Cures
l222, ~33
I I I }2.5 I!57 146
' (OH)`2 ¦(cq2)3~;HcH2~H2o~l INacH2c:i2c~2Na2 l100 ¦135, lSS
0.1HC1 1 1 50 l160, 146
( ~3)2 ¦ca2CH2~Hc~2cH2OH ~aCH2CH2NHCH3 1 12.5 l277, 275 Cures
¦ CH3C2#-HB~ ¦ ¦ 6.25¦277, 275 Cures
I I 1 3.121263, 177 Cures
7,10-lOH)2 jCa~cH2~H2 INHCH2CH2tiHCH2CH2NMe2 ¦ 50 !220 Cures
i 3.3HC1 1 1 25 1192, 177
i j 1 12.5 il86, 157
7,10-(OH~2 ¦C~2cH2aH2 ¦ 2 2 2 2C 2 ¦ 6.25l184, 194
2.1~C1 1 1 3.12l177 194
~ 1.56jl81 172
?,10-(CH)2 ¦C.H2CH2CH2NH2 IN~CH2CH2#HCU.2CH20H ¦ ;0 l235 Cures
j 2HCl I I i2.5 l247, 163 Cures
I I 1 6.25l193, 134
7,10-(OH~2 tC!~2CH2CH2~H2 ¦NHCH2CH2NHCH2CH2NMe2 ¦ 25 122a, 130
I 3HC1 1 1 12.5 1219, 123
7,10-(OH~2 ¦CH2CH2NHCH3 ¦NHCH2CH2HCH2CH2OH I 12.5 ¦147
1 2HCl I
7-OH ICH2CH2NqCH2CH20H ¦NHCH2CH2NHCH2CH2OH ¦ 25 l285, la4 Cures
2HC1 1 1 12.5 l22a, 142 Cures
~j Ij j 6.25j133, 134
10-OH ICH2c~2NHcH2cH2H INHCH2cH2NHcH2cH2 ¦100 1221, 184
I 2,1HC1 1 1 50 l172, 162
i j 1 25 j163, lSS
7~a~lo-(oH)3~cH2cH2NHcQzcH2oc ¦NHCH2CH2NHCH2CH2OH I 25 ¦265 Cure3
I 2.lHC1 1 1 12,5 l257 Cure~
7~9~1o-(oH)3icH2cq2`lHcH2cH2oH INHCH2cH2NHcH2cH2H ¦ 3.12¦165
I 2.1HCl i 1 1.561155
. CLG-l -65-
~0~ ol ,., D~r
_~
1.1 Q Lg 5~ 00 OU~ CI O _
C l ~_U C __ _____ _ ___
O ~ 2~j=o , O '' o I I o
o!l x~x o~ - ___________ o
o o _ _
"~ ¦ U _ ~
,. ~ L~2
Ci.G-l -66-
~[Z-lDiethvl-
a:nlno?sChv' 1-7~10-d~h~droxv-5-~ (2-hvdrcxvfJthvl)-
z:n~nole~hvllamlno~anthra[l,9-cdlpvrzzol-6(2!1)-on2
Dlhvdrochlo~ide in Yice
1~0 N--~ (CHz) 2N (Et~ 2
$~ ~ 2HCl
OH O Nff(CH2)2NH~CH2)20H
I Route i --
I'umor Frumor/la9ginenl ~ Do,5e ~ C x 1001 ~ Tumor
__ I Drua ¦ mg/ g) I ~Pe~cent) IRedUction
~DJ-PC6 Plas~acytoma IIP/}P l004DXO3l 16 1 163
I I 1 8 1 235
I I I ~ 1 216
I I 1 2 1 2D7
316 :~slanoma (35Fl)IrP~rP ¦QO1DXO9I 8 1 176
~ 1 151
(36t3~, 1 )anoma I IP/IP I QOlDxO9 1 6 1 189
Colon 18 (aDPl) 15.~IP IQOlOx09¦ 16 1 l 7.l
LJ.210 Lsukzr~la(CDFl)lIP~I2 IQOlDXO9l 16 1 133
I I 1 8 1 240
144
l 1 137
~5076 Ovary IrP~IP IQ040x041 lO I 260
I I I S 1 186
I I 1 1.251 143
167 (1930~ al~d re~erenceC-ajnCitr ~Clhem0th9rlpy Reviews~ 7,
~l~53l~
CL~ 67-
In addi ion ~o ~heir usef~!lness as anti~iotic and
anti~ur.gal aqen~s and as antileukemic agent.s~ cer_ain
of the comDounds of t~e invention display in Yit'o
activi~y agair.st solid tumors when tested by the
~ollo~.~ing proc~dure,
~ CT~ (human colon adenocarcinoma) cells ar~
t.ypsinized using Trypsin-EDTA0 ~ single cell
susDension is ~chieved by DasSinq the cells throuqh a
25 ~ug~ needle with a 20 cc syringe~ ~ cell
suspension is ?r~p~red using RP~I 164~ srow;h ~edi~m
~avail~ble ~roln Gibco Laboratories) + 10~ f~t~l.calf
ser~m ~ 50 ug/ml g~ramyci;~ wi:h a c~ll concentra~ion
of approximately 30,000 cells/mlO The cell sus~ensian
is dispe~ed in Linbro 2~-well plates; 1 ml/we~l. T~e
plates are incubated ~oc apnroxi~ately 48 hrs ~t 37C
in a 5~ C02 at~osohere. ~t t~is time tes~ compcunds
are added in the ap~ropr1ate cancent~ation. Pive ~1
o~ the 2C0 ~g~ml stoc~ solution is added to eac~
well in a primary test~ Ten ~1 of the ap~ropriate
dilution is added to each well or a titration .est.
The plates are reincubated ~n additional 60-6~ hrs a~
37~C in a 5~ C02 a~osphereO The test is read by
Iysinq the cells usin~ a mix o~ cationic surfactan~,
~lacial ac~tic ~cid and sodium c~.loride. Two ml of
the lysed cell sus~ension from each ~ell is added ~o
8 ml o~ diluen~. Each sample is re2d with~a Coulter
counte~ ~Z8~ ~od~l). The ac'ivity o~ each sample is
me~sured as a pe.cent~ge of the con~rols and the dat~
is repo~ted as I3so, ~hat i5 ~he molar quantity o~
drug required to kill 50~ of tne t~mor cells.
Utilizing ~his proc~dure, ~h~ follawing results
~ere obt~in~d .ar ~Ppresent~ e compour.ds o~ the
inven~ion~
~5~
C~ 6a-
In Vitro Activity o~ Amil~oanthra~yrazoles
Against Hu~an Colon Aclenocarc;no~a
U --N-Z
X~'
O NRY
Xl Z9 I N~Ys ¦ IDso ~olar
Hl~cH2)2NEt2 ¦ ~ 2)2NEt2 ~ x 10-7
1 ~2HCl l I
B¦ Ctl3 INH~cq2)2N~t2 1 4.1 X 10-7
( 2)20H ¦ ( 2)2NEt2 ¦ 1.3 x 10-6
1 ~2HCl
Y¦ H ¦N~(CH2)2Nff(CH2)20H¦ 1.5 x 10-6
j HCl
H¦ CH3 ¦NH(CY2)2NH(CH2)20H¦ ~.0 X lo-7
I ffCl I I
a¦(CB2)2NEt2 1 ~ 2)2NH2 ~ 5.2 x 10-3
I 2qCl
H¦ ~Cil2)2:~H~CH2)2oH ¦N!~cH~)2NH~c~q2)oH I 9.6 x 1o-7
'CH3C02H l l
rs~
CLC-l -69--
Xl 8 I NRY ¦ ILlB0 !Yolar
H ¦ ( C QZ ) 2 YH ( CH 2 ) 2 OH ¦ NH ( CH Z ) 2 NH2 I ~ . 2 X 10 - 8
HI (CH2)2 H(ca2)2GH¦NH(CH2J2 2 I 1.2 X 10--7
8 ¦ ( C q z ) 2NH ( CH2 ) 2 0H ¦ N~ ( C~ 2 ) 2 ;M 2 1 2 . 3 ~ l Q -7
H¦ (CH2)2NH(Gl2)20HlNQcH3 ¦ 2.B X 10--7
~ICl I I
2HCL ¦~lQ(cH213NEtz ¦ 4. a x L0-7
¦ ~ Hi2 ) 2NEt2 ¦ 1 2 ) 2N ~ ¦ 1, 2 X 10-7
~211Cl ¦ H(Ca2)3NEt2 1 1.8 X 10-7
HI ~C~2)2NE t2 ¦NHIcH2)~NEt2 I 2.2 x 10-7
2.qcl
H¦(C~I2)2NEe2 1 ~ 2~7NEt2 I 2.2 X 10--6
2~iCl I I
1 2 ) 2 t2 ¦ ( 2 ) 2N~ NH I 3. 8 x 10-7
2HCl ¦NH(CH2)ZN~CH2~20Hl 6.a x 1o-8
t~
C~ 70-
. .
:C I 2 I N~Y I IDs~ Mol~r
7 1-(Y)2i(-H2)2NEt2 ¦NH(CH2)2Na(C82)20KI 2.7 ~ 10-7
7 iO-(OH)ZI(CiI2)2NEt2 INH(C;2)2~Et2 1 6.~ X 10-7
~ )2; ~a3 ¦N~(CHZ)2NH(CH2)20a¦ 7 9 X 10 7
7 lo - !oH)2t~cH2)2NEt2 ¦ ( 2)~ X2 1 3.8 X 10-7
I .2HC1
7 L0-(08)2~(CH2)2NEt2 INH'C~2'2NH~e I 1 2 ~ 10-7
7~1O-!OH) (CB ) NMe ¦NH(CH2)ZNHtCH2)20HI 1.a X !0-7
7 10-~OH)2¦ Ca2CH08CH2~E~2 INH(CH2)2 2 1 ~.6 X 10-7
7 10-~0~)2¦ CX2CHOHCX2NEt2 INH~CH2)2WH(CH2)20 1
I .2~1C1
7~10-~OH)2~(CH2)20H INH~C8Z)2NMe2 1 1.7 X 10-7
I .~C1
I ZHC1 1 ( 2)2NH2 1 1.~ X 10-7
7 1a t~l)21~CI2)2 12 ¦NH(CH2)2NHtCH2~20HI 1.7 ~ 10-6
CLG-L -71-
-r
NRY I IDso Molat-
7,10-(OH)2t (C~2)2NH(Ci2 )2q j ~NJi C-~3 j ;,4 x 10-7
~ 2HCl
7~1o-(oH!2i(c.!2)2~H2 ¦ ! zl2N;i2 j 3.1 x 10-7
~ 2HCl
7,10-(OH)2; (-H2)2iiMe2 ¦ NH(CH2)3NH2 ¦ i.l .Y 10-6
~211Cl
7,10-(OH)2~ i2)3~Me2 j NH(Ci2)3NH2 j 3.5 x 10-7
- 2HCl
7~lo-(o!i)2lcH2cH2cH2NM~2 iN~C~q2cH2`~iHcH2cH2o~i 1 9.2 x 1o-8
~ 2HCl
7~lo-(oq)2ilc1l2cH2NMecH2cH2o~qiNHc~q2cH2NEcH2cH2o
1 . 8HCl
7~10--(oH12lc~q2cH2qHcH2cH2oH INHCH2C 2 3 ¦ '~' x 10-7
-3.3HCl ¦NHCH2CH2-qHCH2CH2NMe2¦ 1.2 x 10-6
.10--(OH~2~ 2cS12~jjl2 ~ l(CH2~3NHCH2C~q7H ¦ 2-8 ~ 10-7
2 lilCl l I
~ 2 9iiCi I 12CH2CH~NH2 ~ X 10~7
7~10-1os~2lcH2cs~cs~2~`~H2 ¦NHC112CS12NHCR2Cil20H I 7.7 x 10-7
7,1~i-(OH~2!CH2cH2NHcH3 ¦NHcH2cH2NHcH2cH2oH I 2.3 x 10-7
¦CH2cH2NHcH2cH20H INHcH2cH2NHcH2cH2oH I 6-1 x 10-8
i ICS~2CH2r~HCH2CH20H INHc~q2cH2NHcH2cH2oH I 1.1 X lo-6
7-oH!cH2cH2NHcH2cH2oH jNHcH2cH2NHM0 1 2.7 x 10--8
~l~8Hcl l I
.,
CLG--1 -72--
N--N-Z
NRY O
Z I NRY ¦ :tDso Molar
_ _
,
(CH2)2NEt2¦ N~(CH2)2~Et2 j 2~,2- x 10--7
~ 2HC1 ¦ i
( CH2 ) 2NEt2 ¦ ~H ( C~2 ) 2NH ( C~2 ) 2OH I ~ . 3 x 1o--8
CTJG-l -73~
When being utilized as antibiotic and antifungal
agents, the compounds of the invention can be prepared
and ad.ministered in a wide variety o~ topical~ oral,
and parenteral dosage forms. It will be clear to
those skilled in the art that the 'ollowin~ dosage
forms may comprise as the actlve component, either a
compound of formula I, certain of the compounds of
ormula II or a corresponding pharmaceutically
acceptable salt of one o. said compounds or a mixture
oE such compounds and/or salts.
For preparing phar.~aceutical compositions from
the compounds described by this invention, inert,
phar~aceutically 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,
flavor1ng agents, solubilizers, lubricants, suspending
agents, binders, or tablet disintegrating agents; it
can also be an encapsulating material. In powders,
the carrier is a finely divided solid which is in
admixture with the finely divided active compound. In
the tablet the active compound is mixed with carrier
having the necessary binding properties in suitable
proportions and compacted in the shape and size
desired. The powders and tablets preferably contain
fro~ 5 or 10 to about 70 percent of the activ.e
ingredient. Suitable solid carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dex'rin, starch, gelatin, tragacanth, methyl
cellulose, sodium carboxy~ethyl cellulose, a low
melting wax, cocoa butter, and the like. The ter~
"preparation" is inten2ed to include the formulation
of the active compound with encapsulating material as
carrier providing a caQsule in which the active
co~.ponent ~with or witAout other carriers) is
CLG-l -74
surrounded by carrier 9 which is thus in association
with it. Simllarly, cachets are incl~ded. 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 ~ay be
mentioned water or water-propylene glycol solutions
for parenteral injection~ Liquid preparations can
also be formulated in solution in aqueous polyethylene
glycol solution. Aqueous solutions suitable for ora:L
use can be prepared by dissolving the acti-~e component
in water and adding suitable colorants, Llavors,
stabili2ing~ and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made
by dispersing the finely divided active component in
water with viscous material, i.e., natural or
synthetic gurns, resins, meth~l cellulose, sodium
carbox~methyl cellulose, and other 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, Chapter 43, 14th ed. 1~70, Mack
Publishing Co., Easton PennsylYania 18042, USA.
Pre~erably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparat~ion is
subdivided into unit doses con~aining appropriate
quantities of the active component. The unit dosage
form can be a packaged preparation, the package con-
taining discrete quantities of p-eparation, for
example, pac~eted tablets, capsules, and powders in
vials or ampoules. The unit dosage form can also be a
capsule, cachet, or tablet itsel~ or it can be the
appropriate number of any o these packaged form.
CLG-l -75-
The quantity of active compound in a unit dose of
preparation may be varied or adjusted from 50 mg to
500 mg according to the particular application and tne
potenc~ of the active ingredient.
In tnerapeutic use as antibiotic and antifungal
agen~s the compounds utilized in the pharmaceutical
~ethod 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 005 mg to about 10 mg
per ~ilogram is preferred, The dosages, however, may
~e varied depending upon the requirements o~ the
patient, the severity of the condition being
treated, and the compound being e~ployed. Determi-
nation of the proper dosage for a particular situation
is sJithin the sklll o~ the ar~g Generally, treat~len~
is initia-ted with smaller dosages which are less than
the optimum dose o~ the compound. Thereafter, the
dos~ye is increased by small-increments until the !~
optimum ef~ect 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
p~renterally or intraperitoneally. Solutions of the
active compound as a free base or pharmaceutically
~cceptable salt can be prepared in water sui~ably
mixed with a surfactant such as hydrox~propyl-
cellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene ~lycols, and mixture~
thereof and in oils. Under ordinary conditions of
storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable
use include sterile aqueous solutions or dispersions
and sterile powders for the extemporaneous preparation
oE sterile injectable solutions or dispersions. In
all cases the form must be ste.ile and mus. be fluid
~2~
CLG--1 -76--
to the extent tnat easy syrinsability existsO ~t
must be stable under the conditions of manufacture
and storage and must be preserved agai.nst the
contaminating action of miCrOQrganiSmS such as
bacteria and fungi~ The carrier can be a solvent
or dispersion medium containing, for example, water,
ethanol, polyol ~for exa~ple, glycerol, propylene
glycolf 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 coating such as lecithin 9 by the maintenance
o~ the required particle size in the case of disper~
s ion and by the use of surfactants~ The prevention of
the action of microorganisms can be brought: abou~ by
arious antibacterial and antieungal agents, for
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
gela~in.
Sterile in~ectable solutions are prepared ky
incorporating the active compound in the required
amount in the appropriate solvent with vario~s of ,he
other ingredients enumeratecl above, as required,
ollowed by filtered sterilizationO Generally~
dispersions are prepared by incorporating the various
sterillzed active ingredient into a sterile vehicle
which contains the basic dispersion medium and the
required other ingredients from those enumerated
above~ In the case of the sterile powders for the
preparation of sterile injectable solutions/ the
preferred methods of preparation are vacuu~ drying and
the free~e-drying technique which yield a powder of
the active ingredient plus any additional desired
CLG-l -77~
ingredient from a previously sterile-filtered solution
.hereof.
As used herein, "phar~aceutically acceptable
carrier" includes any and all solvents, dispersion
media, coatings, antibacterial and antlfungal agent~,
isotonic and absorption delaying agents and the like.
The use of such media and agents for pharmaceutlcally
active subs~ances is wel1 known in the art. Except
insofar as any conventional media or agen, 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 formulata
parenteral composi-tions in dosage unit ~orm ~or ease
of administration and unlformity o~ dosage. Dosage
unit form as used herein refers to physically
discrete units suitable as unitary dosages or the
mammalian subjects to be treated; each unit
containing a predetermined quantity of active
material calculated to produce the desired ther~peutic
effect in association with the required
pharmac2utical carrier. The specification for the
novel dosage unit forms of the inventio~ are dictated
by and directly dependent on (a) the unique
characteristics of the active material and the
particular therapeutic eEfect to be achieved, and (b)
the limitation inheren~ in ~he art of compounding such
an active material for the treatment of disease in
livin~ subjects having a diseased condition in which
bodily health is impaired as herein disclosed in
detail.
The principal ac~ive in~redient is compounded
for convenient and ef~ective administration in
effective amounts with a suitable pharmaceutically-
acceptable carrier in dosage unit form as hereirbGEore
disclosed. A unit dosage form can, for example,
CLG-l -78-
contain the pri}lcipal active compound in amounts
ranging from about 0.1 to 2bout 500 mg, with from
about a.s to about 250 mg being preferred. ExDressed
in proportions, the a~tive compound is generally
present in from aboùt 0.1 to about 500 mg/ml of
carrier~ In the case of compositions cGntalning
supplementary active ingredients, the dosages are
dete~mined by reference to the usual dose and the
manner o administration of the said ingredients. T~.e
daily parenteral doses for mammalian subjects to be
treated ranges from 0.1 mg/kg to 100 mg/kg. The
preferred daily dosage range is 0O3 mg/kg to 10 mg/kc;~
The following nonlimiting examples illustrate the
inventors' preferred methods for preparing the
compounds of the inven~ion~
CLG-l -79-
EXAMPLE 1
2-[2-(Diet_ylamino)ethYl)]-5-[[2-(diethyl
amino]a _ hra~l,9~cd]pyrazol-6(2H)-on2
A mixture of 1.2 g (3.4 mmol) of 5-chloro-2-[Z-
(diethylamino)e-thyl]anthra[l,9 cd]pyrazol-6(2~)-one
1.0 g (8 mmol) of N,N-diethylethylenediamine~ about
1 mg of anhydrous cuprous chloride and 30 ml of
anhydrous 2-ethoxyethanol is heated at reflux under
argon. After seven hours, an additional 0.5 g
(4 mmol) of the diamine and about 1 mg of catalys~ is
added and the mixture is refluxed for 23 hours~
cooled, and concentratedO The residue is dissolved in
dichlorome~hane, washed successively with wa.er,
di.lute ammonium hYdroxide, and brineO Chromatography
of the dried dichloromethane layer over silica gel
with 10:1:89 methanol:triethylamine:dichloromethane
provides the puri.~ied product Dissolution in hot
2-propanol followed by treatment with excess hydrogen
chloride in 2-propanol a~fords 1.2 g of the dried
product as a salt with 2.1 equivalents of hydrogen
chloride solvated with 1.2 equivalents of water; mp
262-276C (decompo3ition)~
5-Chloro-2-~2-~diethylamino)ethyl]anthra[l,9-cd]-
pyrazol-~(2~)-one is prepared as follows:
A mixture of 4.15 g (15 ~mol) of 1,4-dichloro-
9,10-anthracenedione [J. Amer. Chem. Soc. 48; 3198
(1926)] 2.~ g (20 mmol) of (~-diethylaminoethyl)
~drazine ~J. Med.. Chem , l, 493, (1964)~ and 35 ml
o~ pyridine is hea~:ed at reflux 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
with ethyl acetate and then 95:5 ethyl
acetate:methanol affords 3.8 g of a solid whose
crystal'ization from 2-propanol gives 2.9 g of pure
material; mp 90-92C.
~5~
CLG--1 - 8 0 ~
Dissolution o~ 0, 89 g of the product in hot 2-
propanol followed by treatment with excess hydrogen
chloride in 2-propanol affords 0.9 g of the
hydrochloride salt; mp 263-256C (decomposition).
EXAMPL2 2
2-[2-(Diethvlamino)ethyl)]-5-[[2-[(2-hydroxyethv~
--- _
amino]ethyl]amino]anthra[l,9-cd]pYra o]-6(2H)-
. . . ~ _ _
one
A mixture of 2.5 g (7.1 ~mol) of 5-chloro-2-[2-
(diethylamino)ethyl]anthra[l,9-cd~pyrazol-6~2H)-one,
1 g (9 mmol) of 2-(2-aminoethylamino)ethanol and
catalytic amounts of anhydrous cuprous chloride and
potassium iodide in 25 ml of anhydrous 2-ethoxyethanol
is heated at reflux under argon, Additional 0.5-1.0 g
po~tions oE the amine and catalytic amounts of -the
halide sa}ts are added after six and 12 hours~
respectively. After a total reflux time of 30 hours,
the mixture is worked up as described for Example l,
with purification on silica gel utilizing first
10:1:8~ and then 15:1:84 methanol:triethylamine:ethyl
acetate. Following treatment with hydrogen chloride,
~here is obtained 1.1 g of the dried pro2uct as a salt
with 2.0 equivalents of hydrogen chloride solvated
with 2.4 equivalents of water; mp Z39-241C
(decomposition).
EXAMPL2 3
5-[(2-Aminoethyl)amino~-2-[2-(diethvlamino)ethyl]
anthra~l,9-cd]pvrazol-6(2H) one
A mixture o~ 1.6 g (~.5 mmol) of 5-chloro-2-[2-
(diethylamino)ethyl]anthra[l,9-cd]pyrazol-6(2H)-one,
2.5 ml of anhydrous ethylenediamine, and 25 ml of
anhydrous pyridine is heated at reflux under argon for
seven hours, cooled, diluted with toluene, and
concentrated. The solid residue is dissolved in
dichloromethane, washed with water, and then brine.
Chro~atography o~ the dried dichloromethane layer over
silica gel with 1:9 ~ethanol:dichloromethane pro~ides
.
~5~L~J~2
CLG l -81-
0.8 g of 'he product. Dissolution in hot 2-propanol
followed by treatment with excess hydro~en chloride in
2-propanol affords 1.0 ~ of dried procluc~ as a sait
with 2.0 equivalents of hydrogen chloride solvated
with 1.8 equivalents of water; mp 276-279C
(decomposition).
The following compounds are prepared as described
in Example 3 from 5-chloro-2-[2-(diethylami.no)ethyl]-
anthra[l,9-cdlpyrazol-6(2H)-one and the corresponding
amine:
EXAMPLE 4
2-[2-(Diethyl2mir.o?ethyl]-[[2-(4-morpholi~ l?ethYl)]-
amino]anthra[l,9-cd]pyrazol-6~2H)-one
Reaction with 4-(2-aminoethyl)morpholine gives
the product as a sal~ with 2.0 equivalents of hydrogen
chloride solvated with 1.2 equivalents of water; mp
288-290C (decomposition).
~X~PLE 5 `
2-~2-(Diethylamino)~thyl]-5-[E3 (diethylamino~ro~oyl]-~ - --
amino]znthra[1,9-cd]pyra201-6(2H)-one
Reaction with N,N-diethyl-1,3-propanediamine
~ives the product as a salt with 2.0 equivalents of
hydrogen chl~ride solvated with 0.2 e~u.ivalent of
water; mp 270-272C (decomposition)
EX~MPL~ 6
2-~2 (Dlethylamino)et yl]-5-[[7-(diethvlamino~hep-Yl]-
amino]anthra[l,9-cd]~vrazol-6(2H)-one
. . . _ ~ .
Reaction wlth ~,N-diethyl-1,7-heptanediamine
gives the product as a salt with 2.0 equi.valents of
hydrogen chloride solvated with 0.3 equivalent of
water; mp 190-192C (decor~position)D
EXAMPL~ 7
5-~[4-(Die~.hylamlno)butyl]amino]-2-[2~ Av ~ o
ethyl]anth~a[1,9-cd]~yrazol-6(2H)-one
Reaction wlth N,N-diethyl 1,4-butanediamine gives
the product as a salt with 2.0 equiv~lents o~ hyd;o~er.
CLG-l -82-
chloride solvated with 0.7 equivalent or water;
mp 2~3-246C (decomposition).
EXAMPL~ 8
2-~2-(Diethyl2mino)ethyl]-5-(hexrrlamino)anthra~
cd]-pyrazo1-6(2H~-one
Reaction with n-hexylamlne gives the product as a
salt with 1.0 equivalent of hydrogen chloride solvated
with 0.1 equivalent of water; mp 176-179C
(decomposition)
~ X~PLE 9
2-~2-~ kylam~no)ethyl~-5-[~2-(1-pi~razinvl)eth~rl]-
a.~ino]anthra[l ! 9-cd3pyrazol-6(2H)-one
Reaction with 4-(2-aminoethyl)-1-piperazin~
carbo~ylic acid, benzyl ester, then hydrolysis o~ the
isolated intermediate with hot 48% hydrobromic acid in
acetic acid gives the product as a salt with 3.3
equivalents oE hydroyen bromide solvated with 1.4
eauivalents of water and 0.1 equiv21ent o~-~cetic -~ -- -
acid; mp 284-287C (decomposition).
4-(2-Aminoeihyl)-l-piperazine carboxylic acid,
benzyl ester, is ~repared from 4-(2-aminoethyl~
pipera2ine by a procedure analosous to that described
for the preparation of (2-aminoethyl)-methylcarbamic
acid, benzyl ester, in US Patent 3,~31,268; lH NM~
(deuteriochloroform): ~ 2.78 (triplet), 5.08
(singlet), 7.30 (singlet)~
EXAMPLE 10
5~2-~iethyla~ino)ethvl~amino]-2-methvlanthra[l,9-
~ , .. .. _ .
cd]pyra~ol-6(2H)-one
A mixture of 1~88 g (7 mmol) of 5-chloro-2~
~ethylanthra[l,9-cd]pyra~ol-6(2H)-one [J. Chem. Soc.,
1630 ~1952)], 1.2 g (10 mmol) of N,N-diethylethylene-
diam ner 0.14 g of anhydrous ootassium fluoride, and
10 ml o dimethylsulfoxide is heated at reflux under
arqon for four hours, cooledr diluted with water, and
extracted with dichloromethane. The dichlo~omethane
extract is washed twice with brine and then ~ith 5~
J
CLG-l -83-
aqueous hydrochloric acid. The acid solution is
washed with dichloromethane, made basic with sod um
carbonate, and extracted with dichloromethane. The
dried dichloromethane layer is clarified with
charcoal, filtered, and concentrated to a residue.
The salt ~as ~ade as descri~ed in Example 3 to aford
1.1 g of the dried product, after thorough washing
with ether, as a salt with 1.8 equivalents of hydrogen
chloride solvated with 0.7 equivalent of ~ater;
mp 260-264C ~decomposition).
EXAMPLE 11
5-[~2-[(2-Hydroxyeth~)amino]ethyl]amino]-2-meth
anthra[l,9-cd~pyrazol-6(2H)-one
A mix-ture of 1.75 g ~6.5 mmol) of 5-chloro-2-
methylanthra[l~9--cd~pyrazol-6(2~)-one, 6 ml ~59 ~mol)
of 2-~2-aminoethylamino)ethanol, catalytic amounts o~
anhydro~s cuprous chloride and potassium iodide, and
25 ml of 2-methoxyethanol is heated at reflux under '!~, ','''__
argon for four-hours, cooled, a~d~concentrated. ~he
residue is dissolved in dichloromethane, washed with
water, and then with 5~ aqueous hydrochloric acld.
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-t5%
methanol in dichloromethane provides the purified
product~ The salt was made as described in Example 3
to afford 0.69 g o~ the dried product as a salt with
1.0 equivalent o hydrogen chloride solvated with 0.1
equivalent of water; mp 270-272C ~decompcsition).
EXAMPLE 12
2-(2-Hydrox~et_y~)-5-[-[2-[(2-hxdroxyethvl)amino]
e-thyl}amlno]anthra[l,9-cd]pyrazol-6~2H)-one
A mixture or 896 mg (3 mmol) of 5-chloro-2-(2-
hydroxyethyl)anthra[l,9-cd]pyrazol-6~2H)-one, 3.1 ml
(30 mmol) of 2-(2-aminoethylamino)ethanol, and 6 ml ol
~nhydrous pyridine is heated at r~flux under argon for
~5~
- 84 -
8.5 hours, cooled, and concentrated to leave a residue.
Trituration Erom ether:2-propanol leaves a gummy solid
which upon furt'ner trituration from methanol-ether provides
851 mg of the product. Dissolution in chloroform followed
by treatment with excess hydrogen chloride in 2-propanol
affords 923 mg of the dried product as a salt with 1.6
equivalents of hydrogen chloride solvated with 0.5
equivalent of water; mp 267-272 C (decomposition).
5-Chloro-2-(2-hydroxyethyl~anthra~1,9-cd]pyrazol-6(2H)-
one is prepared as follows:
A mixture of 5.54 g (20 mmol) of 1,4-dichloro-9,10-
anthracenedione, 2.2 ml (33.3 mmol) of (2-hydroxyethyl)-
hydrazine and 20 ml of dry pyridine is stirred at 60C for
32 hours and concentrated. A solid residue is triturated
with ether and then crystallized from chloroform to give
3.58 g of product; mp 209-211 C. Processing of the mother
liquor affords 0.21 g oE additional product; mp 208-210 C.
EXAMPLE 13
5-[~2-(Diethylamino)ethyl]amino~-2-(2 ~ yethyl)-
anthra[l,9-cd]pyrazol-6(2H3-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,~-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[1,9-cd]-
pyrazol-6(2H)-one and the corresponding amine:
CLG-l -85-
EX~PLÆ 14
_-(2-Hv~ xye~hyl)-5-[[2 (4-morphol _vl)eth~yl]amino]-
,9 cd~Dyrazol-6(2~)-one
Reaction with 4-~2-aminoethyl)mol~pholine gives
the product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 0.5 equivalent of water;
mp 260C (decomposition).
EXAMPLE 15
5-[~3-(DiethYlamino~Dro~vl]amino]-2-(2-hYdroxYethvl)
anthra~l,9-cd~p~razol-6(?H)~one
~ eaction with N,N-diethyl-1-1,3-prop2nediamine
gives the product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 0.5 equivalent of
water; mp 201-21nC (decomposition)O
EXAMPLE 15
5-t[4-(Diethvlamino _uty~amino]-2-(2_hydroxyethyl)
anthrat ~ cdl~y~zol-6(2H)-one
Reaction with N/N-die~hyl-1,4--propa~ediamln~
gives the product as a salt with 1.9 equivalents
of hydrogen chloride solvated with 1.0 equivalent
of water; mp 155-185C (decomposition)O
EXAMPL~ 17
5-[~7-(Die~ la ino)he tyl]amino~-Z-~2~'v~rc~ve hv'~-
a thra~l, ~
Reaction with N,N-diethyl-1,7-heptanediamine
gives the product as a salt with 1.0 equivalent of
~drogen chloride; mp 206-208C (decomposition)~ -
EXAMPLE 18
2-~2-f~ydroxvethyl)-5-[[2-(1-piperazinyl)ethvl~amino]-
anthra[l,9-cd]pyrazol-6(2H)-one
Reaction with 4-(2-ami~oethyl)-1-piperazine
carboxylic acid, benzyl ester, then hydrolysis of the
isolated intermediate with refluxing 48~ hydrobromic
acid in acetic acia and salt formation gives the
product as a salt with 2.0 e~uivalents o~ hydro~en
chloride solvated with 0.5 equivalent of water;
mp 292-297~C (decomposition)~
~ 5~ .2
C~G-l 86-
~XAMPLE 19
5~[[2-~(2-Hvdroxvethyl)amino]eth l]amino]anthra[l,9-
~3~
A mlxture of 2.54 g ~10 ~mol) of 5-chloroanthra-
~l,9-cd]pyrazol-~(2~)-one [J. Chem. Soc., 1630
(1952)], 10 ml (100 mmol) of 2-(2-aminoethylamino)-
ethanol, and 25 ml o~ znhydrous pyridine is heated at
reflux under argon for 24 hours~ cooled, and
concentrated. The residue is triturated with
2~propanol to give a solid whose dissolution in
methanol:dichloromethane followed by salt formation as
described in Example 3 affords 1.5 g of the dried
product as a salt with l.S equivalents of hydrogen
chloride solvated with 0.6 equivalent o~ water;
mp 251-~54~C (decomposi~ion)O
EX~'IPLE 20
5-[[2-(Diethylamino)ethyl]amino]anthra[1,9-cd]-
pYrazol-6(2H)-one
A mixture of 1.6 g (6.3 ~mol) of 5-chloroanthra-
~l,9-c_]pyrazol-6(2~1]-one, 3.5 g (30 mmol) of N,N-
diethylethylenediamine, and 20 ml of anhydrous
pyridine is heated at reflux for 20 hours, cooled, and
concent-ated. The residue is dissolved in
dichloromethane, washed with water, and then extracted
with 1% aqueous hydrochloric acid. The acid solution
is ~ashed with dichloromethane, then made basic with
aqueous sodium hydroxide. The aqueous solution is
ex~ract2d with dichlorometharIe and ~he dried
dichloromethane layer is concentrated to a residue
w~Iich is converted into a salt as described for
Example 3 to give 0.7 g of the dried product as a salt
with 1.4 equivalents OL hydrogen chloride solvated
with 0.1 equivalent of water; mp 120-130C.
CLG-l -87~
EXAMPLE 21
2-[2-~(2-Hvdro.Y ethYl)aminoleth 1]-5-[_[2-[~2-nydroxy-
.Y ~
ethy~)amlno]ethyl~amino~anthra[l~9-cd]p~razol-6(2H)
o
A mixture of 1.91 g (5 mmol~ of 5-chloro-2~[2-
~(2-hydroxyethyl)amino]ethyl]anthrall,9-cd]pyrazol-
6(2H~-one, hydrochloride, 2.6 ml of 2-(2-aminoethyl-
amino)etnanol, and 5 ml of anhydrous pyridine is
heated at reflux under argon for 6.5 hours, cooled,
and concentrated. Trituration of the solid residue
with cold 2-propanol gives 1.43 g of the dried
product; mp 154-156C. Crystallization ~rom slacial
acetic acid: 2-propanol gives 1.35 g of the dried
product as a salt wi-th :l.0 equivalent o~ acetic acid
solva~ed with 0.5 equi~ralent o water; mp 146-148C.
5-chloro-2-~2-~(2-hydroxyethyl)amino]ethyl]
anthra[l,9-cd]pyrazol-6(2H)-one is prepared aS
Eollows:
To a refluxin~ mixture of 832 mg (3 mmol) of 1,4-
dichloro-9,10-anthracenedione in 8 ml of dry
acetoni-trile is added dropwise over 40 minutes, 4;0 my
(3.8 mmol) of 2- r (hydrazinoethyl)2mino]ethanol in 3 ml
of ace~oni~rlle, The mixture i5 refluxed for one
~our, cooled, and triturated with cold 2-propanol to
give 602 mg of product; mp 140-142~C. Processing of
the mother liquor affords 71 mg of additional product;
mp 124-126C. Cry~tallizatioll of the free base from
glacial acetic acid gives the.diacetate sal-t; mp
125-130C~ The hydrochloride salt is prepared as
descri~ed in Example 3; mp 260-263C ~decomposition).
3l~5~
, .
CLG-l -88-
2-~ydrazinoethyl)amino]ethanol is prepared as
,ollows:
A solution of 86.8 g (1.0 mol) of N-(2-hydro~y-
ethyl)ethyleneimine and 400 ml (about 6 mol) of 54
aqueous hydrazine is heated at reflux for two davs.
Excess water and hydrazine is distilled at 40-50C/13
mm, then the pot residue is distilled at 142C/0.10 mm
to yield 80.9 g of product with an 88% purity. Care
ful redistillation of a small sample gives
analytically pure material; bp 120C~0.035 ~m.
EXAMPLE 22
5-~(2-Aminoet-h-yl)amin-o]-2-l2-[~2-hydroxyethyl?amin
ethyl~anthra~l,9-cd]py-razol-6(~H)-o-ne
Reaction of 1.91 g of 5-chloro-2-[2-~(2-hydroxy-
etnyl)amino~ethyl]an~hra[l,9-cd3pyra~ol-6(2H)-one
hydrochloride with 1.6 ml ~25 mmol) of 1,2-ethylene-
di.amine, as described in Example 21, followed by
concentration aEfords 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
purlfied over a column of HP-20 resin eluting first
with water and then ~7ith methanol. Coricentration of
the methanol eluate followed by salt formation as
described in Example 3 affords 1.0 g of the dried
product as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.9 equivalent of water;
mo 263-2G7C (decomposition) 7
C~G-l 89-
EXAMPLE 23
ethyl)amino]ethy~anthra [l,9-cd~pyrazo1-6(2H)-
o
Reac-tion oE 1.91 g of 5-chloro-2-~2-t(2-hydroxy-
ethyl)amino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-one,
hydrochloride, with 3.5 ml (25 mmol) of. N,N-diethyl-
ethYlenediamine as described in Example 21 affords
1.~ g of product; mp 132-133O Processing of the
mo~her liquor affords 0.3 g of additional product;
mp 130-131C. Salt formation as described for Example
3 gives 1.6 g of the dried product as a sal~ wi.h 2.0
equivalents of hydrogen chloride solvated wi~h 1.0
equivalent of water; mp 272-274C (decomposition)O
EX~PLE 2~
5-[~2-Hydroxyethyl)amino~-2- E 2- [ ( 2-hy~droxvethYl ) -
amino~ethvl]anthra[l,9-cd~pyrazol-6(2H)-one
A mixt~re of 2.5 g (6.6 mmol) of 5-chloro-2-[2--
1(2-hydroxyethyl)amino]ethyl]anthra~1,9-cd]pyrazol-
6(2H)one, hydrochloride~ 2 ml (33 mmol) of 2-amino-
ethanol and 13 ml of anhydrous pyridine is reacted and
worl~ced up as described in Example 21 to afford a solid
precipitate whose sal~ formation as described in
~xample 3 affords 1.4 g of the dried product as a salt
with 1.1 equivalents o~ hydrogen chloride solvated
with 0.6 equivalent of water, mp 260-261C
(decomposition)O
EX~MPL~ 25
2~2-l(2-~ydroxye~hyl)amino]ethyl]-5
~ -- .
amino)ethvl]amino]anthra[l,9-cd]pxrazol-6(2H)-
one
Reaction of 2.72 g (7 mmol) o. 5-chloro-2-[2-[(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol 6(2H)
one, hydrochloride, 1.2 g (14 mmol) of N,N-dimethyl-
ethylenediamine, and 20 ml of pyridine for 42 hours at
~s~
CLG-l -90-
reflux followed by workup as described in Example 21
gives a solid residue whose dissolution in hot
methanol follo~ed by salt formation as described ln
Example 3 gives 1.0 g of the dried product as a salt
with 2~1 equivalents of hydrogen chloride solvated
with 0~9 equivalent of water; mp 286-Z88C
(decomposition).
EXAMPLE 26
2-[2-[(2-Hydroxy-ethyl)amino~ethyl]-s-(methylamino)
anthra[l,9-cdJ~yrazol-6(2H)-one
Reaction of 5-chloro-2-f2-r(2-hydroxyethyl)--
amino]ethyl]anthra[l,9-cd]pyrazol-6-(2~)-one~ hydro-
chloride, with excess methylamine as described in
Example 21 gives the p.oduct as a salt with 1.0
equivalent of hydrogen chloride, mp 285-288C
(decomposition).
EXA.~PLE 27
2-(2-Aminoethyl)-5-[[2-[(2-hydroxyethyl)amino]ethyl]
amino]anthra[l,9-cd]~yrazol-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 .~1 of
anhydrous pyridine is heated at reflux ~or 30 hours,
cooled, and filtered. The filtrate is concentrated
and chromatographed over silica gel with 9~:2-1
dichloromethane: methanol:triethylamine7 then gradient
elution ~o 99:2001 to provide the purified pr~du~t~
~al~ ~orma~ion as described in ~xa~ple 3 ~ives 0.8 g
oE the dried product as a salt ~ith 1.7 equivalents of
hydrogen chloride solvated with 1.0 equivalent of
water and 0.2 equivalent of 2-propanol; mp 270-272C
~decom~osition).
CLG-l -91~
2-(2-Aminoethyl)-5-chloroanthra[l,9-Cd]pyrazol-
6-~2H)-one is prepared as Eollowso
To a solution of ~.0 g (3~6 ~mole) of lt4-di-
chloro-9,10-anthracenedione in 10 ml of pyridine at
35 is addecl dropwise 1,9 ml of S2-aminoethyl)-
hydraæine [~ritish Patent 880,332~. The mixture is
stirred for four hours, concentrated, and purified on
silica gel utilizing 94:5:1 dichloromethane~
methanol:triethylamineO Salt formaki Otl as described
in Example 3 gives 0~45 g of the produc:t as a salt
with 1.0 equivalent of hydrog~n cbloride solvated with
1.2 equivalenks of water and 0.1 equivalent of
2-propanol; T~ 28~1-285C ~decomposition).
EXAMPLE 28
2-~2-(Diethylamino)eth~1~-7,10-dihydroxy-5 [[2~(2
nydroxyethyl)amino]ethYl]amino]anthra~ 9-cd]
Pyrazol-6~2H)-one
-
Reaction of a mixture of 2.9 g (7.S mmol) o
5-chloro-2-[2-(diethylamino)ethyll-7,10-dihydroxy~
anthra[l,9-cd]pyrazol-6(2H)-one, 7.5 ml (75 mmol) of
2-~2-aminoethylamino)ethanol, and 35 ml of pyridine
Eor four hours at reflux followed by workup as
described in Example 21 and salt forma~ion as
described in ~xample 3 gives 2.8 g of the dried
product as a salk with 2.0 equivalents of hydrogen
chloride solvated with 0.7 equivalent of water;
mp 198-202aC ~decomposi~ion).
5-Chloro-2-~2-(d.iethylamino)ethyl~-7~10-di-
hydrox~anthra~1,9-cd]pyrazol-6(2H)-one is prepared as
~ollows:
Reaction of a mix~ure of 12.7 g (41 mmol) of 1,4-
dichloro-5,8-dihydroxy-9,10-anthracenedione, 1~ 9
590 m~ol) of (~-diekhylamino~thyl)hydrazine, and 65 ml
o pyridine at 50C for four hours followed by workup
~l~5~ 2
CLG-l -92-
as described in Example 22 gives a residue that is
dissolved in dichloromethane~ Chromatography over
silica gel wi~h dichloromethane and then with 3~
methanol in dichloromethane affords crude material
whose crystallization from 2-propanol gives ~.5 g of
a purified solid; mp 136-140C. Salt formation as
descri~ed in Example 3 on lo 5 g of this material gives
1.3 g of a dried solid as a saLt with 1.0 equivalent
of hydrogen chloride solva~ed with 0.3 equivalent of
water; mp 280-282C (decomposition)O
EX~PLE 29
2-[2-(Diethylamino)ethvl]-5~[[2-(diethylamino)ethyl]-
amino~-7,10-dlhydroxy~nthra[l~9-cd]~yrazol-6~2~)
on2
Reactivn of a mlxture oE lo 93 g (5 mmol) 0~ 5~
chloro-2-[2-tdiethylamino)ethyl]-7,10-dihydroxyanthra-
[1,9-cd]pyrazol-6(2~ one, 2.9 g (24 mmol) of N,N-
diethylethylenediamine; and 25 ml oE pyridine ~or five ~~ ~
hours at reflux followed by workup as described-i~
Example ?l gives a crude solid which is dissolved in
dichlorome~hane. Chromatography over silica gel with
3~, 6%, and 10~ solutions of methanol in
dichloromethane affords 1.6 g of pure material. Salt
formation as described in Example 3 gives 1.4 g of the
dried product as a salt wi~h 2.0 equivalents of
hydrogen chloride solvated wi~h 0.3 equivalent of
water; mp 290-~92C (decomposition)O
E~MPL~ 30
5-~[2~Aminoeth~l)amino]-2-[2-(diet~x~lamino)ethyl]-
7~10-dihydroxyanthra[l,9-cd]p~razo1-6(2~)-one
Reaction of 5-chloro-2-[2-(diethyla~ino)ethyl]-
7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one with
ethylenediamine as described in Example 28 gives the
product as a salt with 2.0 equivalents of hydrogen
chloride solvated ~ith 1.7 equivalents of water and
0.1 equivalent of 2-propanol; mp 277-281C
(decomposition).
CLG~ 93-
EXAMPL2 31
2-[2-(Die~h~lamino)ethyl]-7,10-dihy~_ Y~r-5-[[2-
(methylamino)ethyl~amino]anthra~l,g-cd3pyr~201-
6(2H)-one
~ _ .
Reaction of 5~chloro-2-[2-(diethylamino)ethyl~-
7,10-dihydroxyan~hra[l,9-cd]pyrazol-6(2H)-one with
~2-aminoethyl)-methylcarbamic acid, benzyl ester
[US Patent 3,931,268] followed bv isolation of the
intermediate as described in Example 29 then
hydrolysis with hot 48~ hydrobromic acid in acetic
~cid glves the product as a salt with 2.3 equivalents
of hydrogen bromide solvated ~ith 2.7 equivalents of
water, mp 217-220C (decomposition).
EXAMPLE 32
2-~2-tDimeth~lamino)ethyl]-7,10-dihydroxy-5-~[2 [(2-
hydroxyethyl)amino]ethyllamino]anthra[l,9-cd]pyraæol-
6(2H)-one
Reaction o 2~0 g ~5.6 mmol) oE 5-chloro-2-[2-
(dimethylamino)ethyl]-7,10-dihydroxyanthra-1,9-cd]- -
pyrazol-~(2~)-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
f~rmation as described ill ~xample 3 gives 2~4 ~ of
tha dried product as a salt with 2.4 equivalents of
hydrogen chloride solvated with 2.0 equivalents of
water; mp 310-313C (decomposition).
5-Chloro-2-~2-(dimethylamino)ethyl3-7,10-
dinydroxyanthra[l,9-cdlpyrazol-6~2H)-one is
prepared as ~ollows:
Reaction of a mixture of 15.5 g ~S0 mmol) of
1,4-dichloro-5,8-dihydroxy-9,10-anthracenedione,
10.3 9 (100 mmol) of (2-dimethylaminoethyl)-
hydrazine ~J. Med. Chem., 1j493 (1964)] and 60 ml
of pyridine at 35C overnight followed by ~orkup as
described in Example 28 gi~es 3.8 g of product;
mp 1~3-146C. Salt formation as described in
~2~X~'~f~
CLG-l -94-
Example 3 glves the product as a salt with
1.1 equivalents of hydrogen chlori2e solvated ~ith
1~2 equivalents of water; mp 295-300C
decomposition).
The following compounds are prepared as described
in Exa~ple 32 from S-chloro-2-[2-(dimethylamino)-
ethyl~-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one
and the corresponding amine:
EX~MPLE 33
5-[(2-Arninoethyl)amino]-2-[2-dimeth~1am no)ethyl]-
7,10-dihydroxyantnra[1,3-cd]pyra~ol-6(2H)-one
~ eaction with ethylenediamine gives the product
as a salt with 1.3 equivalents of hydrogen chloride
solvated with 2.4 equivalents of water; mp 300-302C
(decompo~lkiorl).
EXAMPLE 3
5-[(3-Aminoerop~Ll)amino]-2-~2-(dimethylamino)~thyl]
7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2R)-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
281-28SC Idecomposition).
EXAMPLE 35
$-~[2-(Diethylamino)ethvl~2mino]-7,10-dihydroxv~-2-
~2-hvdroxyethvl)anthra[l,9-cd]pyrazol-6(2H)
one
Reaction o a mixture o 3 3 g (10 mmol ) of
S-chloro-7,1~-dihydroxy-2~(2~hydroxyethyl)anthra-
[1,9-cd]pyrazol-6(2H)-one, 14;5 ml (100 ~nol) o N,N-
diethylethylenediamine, and 2~ ml of pyridine for
. '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 o~ the dried product as a salt with 1.6
equivalents of hydrogen chloride solvated with 0.6
equivalent of water; mp 215-219C (decomposition).
f
CLG-l -95-
5-Chloro-7,10-dihydroxy-2-(2-hydroxyethyl)anthra-
Il,9-cd]pyrazol-6(2H)-one is prepared as follows:
~ mix~ure of 12 g (40 ~mol) of 1,~-dichloro-5,8-
dihydroxy-9,10-anthracenedione7 4~5 g (60 mmol) of (2-
hydroxyethyl)hydrazine~ and 40 ml of pyridine i~
stirred at 50~ overnight, cooled, and oncentrated.
The residue is triturated successively with chloroform
and hot ~e~hanol to give 1~1 g of the dried product;
~,p ~31-234C.
EX~MPLE 36
5- E [2-[(2-Hydroxyethyl)amino]ethylJa~ino]-7
dihydroxv-2-~2-hydroxyethyl)anthra[i~9-cd~pYra
6~2H)-one
A mixture of 3.3 ~ (10 mmol) of 5-chloro-7~10~
dill~droxy-2~(2-hydroxyethyl)anthraLl,9-cd]pyrazol-
6~2H)-one, 10.4 g (100 mmol) of 2-(2-aminoethylamino~-
ethanol, and 20 ml oE pyridine is heated at reflux for
fo~r hours, cooled, and concentrated. Successive
tritura~ion of the residue with acetonitrile~
2-propanol, and methanol gives 1.35 g of a powder.
Salt ~ormation as described in Example 12 afords
1.06 g of the drled product as a salt with ].0
equi~7alent of hydrogen chloride sGlvated with 0.5
equivale~t of water; mp 195-203C (decompositlon).
The following compounds are prepared as described
in Example 35 from 5-chloro-7,10-dih~droxy-2-(2-
hydroxyethyl)anthra[l,~-cd]pyrazol-6~2H)-one and the
correspondiny amlne.
EX~Pr.~ 37
5-~(2-Aminoethyl)amino]-7,10-dihydroxy-2-(2-hydroxy-
ethyl)anthra[l,9-cd]pyrazol-6( H)-one
Reaction WL th ethylenediamlne gives the product
as a salt with 1.8 equivalents of hydrogen chloride
solvated with 0.5 equivalent of water; mp '195~C
(decomposition).
C~ 96-
EX~PLE 38
7,10-Dihydrox~-2-(2-hydroxvethyl)-5-[[2-(4-
morpholinyl)ethyl]amino~anthra[l~9-cd]~
pyrazol-o(2~)-one
-
Reaction wi~h 4-12-aminoethyl)morpholine gives
the product as a salt with 0.4 equivalent of hydrogen
chloride and 0.3 equivalent of ~2ter; mp 240-251~C
(decomposition)~
EXAMPLE 39
5-[t2-~Dimethylamino)ethyl]2mino]-7,10-dih~droxy-2-
(2-hydroxyethyl)anthra[l~9-cd]pyrazol-6(zH)
o
Reaction with N,N-dimethylethylenediamir.e gives
the product as a salt wit~ 1.5 equivalents of hydrogen
chloride ~olvated wi.~h 2.0 e~uivalents of water;
mp 250~C ~decornposition)~
EXAMPLE 40
5-[~2-AminoethYl)amino]-7,10-dihydroxy-2-methyl~
anthra[l,9 cd]~vrazol-6~2H)-one
-
Reaction of a mixture of 3.2 g (10.6 mmol~ of
5-chloro-7,10 dihydroxy-2-methylanthra[1,9-cd]pyrazol-
6(2H~-one, 5 ml (74 ~mol) of ethylenediamine, and
5S ~1 of pyridine for sevell hours at reflux followed
by worXup as described in Example 21 gives a solid
residue. Dissolution of -the solid in hot methanol and
N,N-dimethylforman~ide followed by salt formation as
described in Example 3 affords 1.5 g of the ~ried
product as a salt ~.ith 1~0 equivalent of hydrogen
~hloride solvated ~ h 0.2 equivalent of water and Ool
equivalent of ~,N~dimethylformamide; mp 323-326C
~decomposition).
5-Chloro-7,10-dihydroxy-2-methylanthra[l,g-cd]-
pyrazol-~2~)-one is prepared as followso
A mixture of 12.4 g (~0 mmol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione, 2.7 ml (50 m~ol)
of methylhydrazine, and Z50 ml of pyridine is heated
at 3SC for seven hours, treated with an additional
CLG-l -97-
1 ml of methylhydrazine, heated for se~-en hours at
35C, and cooled. The solids are filtered and
recrys~allized from N,N-dimethylformamide to give
8.85 g of the dried product as a salt with 0.1
equivalent of hydrogen chloride, mp 2a8-305C
(decomposition).
EXA~PLE 41
7,10-Dihy2roxv-5-[[2-[(2-hy~d oxyethyl)amino]ethv~l]-
amino]-2-methylanthra[l,9-cd]pyrazol-6(2H)-one
Reaction of a mixture of 3.25 g ~10.8 mmol) of
5-chloro-7,10-dihydroxy-2-methylanthra[1,9-cd]pyrazol~
6~2H)-one, 3 ml (30 mmol3 of 2-(2-aminoethylamino~-
ethanol, and 50 ml oL pyridine for seven hours at
reflux followed by wor~up as described in Example.21
and salt ormation as described in ~xample 3 gives
1.8 g o the dried product as a salt with 1..0
equivalent o~ hydrogen chloride solvated with 0.6
equivalen~ o~ water; mp-2ao-2340c (decomposition).~ :
EX~MPLE 42
5-[[2-(Diethylamino)ethyl]amino]-7,10-dihydroxy-2
methvlanthra[l,9-cd]pYrazol-6(2~)-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)-one7 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 desc~ibed in Example 3~gives
1.7 g of ~he dried pro~uct as a salt with 1.5
equi~7alents of hyclrogen chlor.~de solvated with 0.8
equivalent of water; mp 298C (decomposition).
~XAMPLE 43
2-[3-5Diethyl2mino)-2-hydroxypropyl]-7,10-dihydroxy_
5-[[2-~(2-hydroxyethyl)amino]ethyl]amino]_nthra-
[l,9-cd]pyrazol-6(2H)-one
Reaction o, a mixture of 1.3 g (3 mmol) of
5-chloro-2-[3-(diethylamino~-2-hydroxypropyl]-7,10-
dihydroxyanthra[l~9-cd]pyrazol-6(2H)-one, 2.1 ml
~;~5~
CLG-l -98-
(21 mmol) of 2-(2-aminoelhylamino)ethanol, and 10 ml
oE pyridine a. reflux for six hours follo~ed by workup
as described ~or Example 21 and salt formation as
described in Example 3 gives the product as a salt
with 2.2 equivalents of hydrogen chloride solvated
with 2.8 equivalents of water and 0.2 equivalent of
2-propanol; mp 105-120C.
5-Chloro-2-[3-(diethylamino)-2-hydroxypropyl~-
7,10-dihydroxyanthra[1,9-cd]pyrazol-6(2~)-one is
prepared as follows:
A mixture of 6.2 9 (20 mmol) of 1,4-dichloro-
5,8-dlhydroxy-9,10-anthracenedione, 9.7 g ~60 m~ol) of
l-(diethylamino~-3-hydra~ino-2-propanol tGerman Patent
1,126,877) and 35 ml of pyridine is stirred at 40C
for one hour then at room temperature overnight~ The
mixture i9 concentrated and purified on silica gel
utilizing 97:2:1 dichloromethane methanol:
triethylamine to give 1.7 g o~ product. Salt
formation as described in Example 3 gives 1.4 g of the
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 0.7 equivalent of water; mp
264-267C (decomposition)O
EXAMPLE 44
5-~2-(Diethylamino3ethyl3amino]-2-[3-(diethylamino)-
2-hydroxyprooyl]-7,10-dlhydroxyanthra~ cd]?yrazol-
6(2H)-one
Reaction oE 5-chloro-2-[3-(diethylamino~-2-
hydro:~ypropyl]-7~10-dihydro;~yant!lra~l,9-cd]pyrazolo
6(2H)-one with N,N-die~hylethylenediamine as deQcribed
in Example 43 sives the product as a salt with 2.0
equivalents of hydrogen chloride solvated wi~h 1.9
equivalents of water; mp 253-255C (decomposition).
EXA~PLE 45
5-~2-A~inoethyl)amino]-2-~3-(diet~lamino)-2-h~droxy-
prooyl]-7,10-dihYdr?~lanthr_[l,9-cd]pyrazol-6(2EI)-on2
Reaction of 5-chloro-2-[3-(diethylamino)-2-
i hydroxypropyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-
~5
CI,G-l -99~
6(2H)-one with ethylenediamine as described in Example
43 gives the product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 2.8 equivalents of
water; mp 148-15~C.
EXAMPLE 46
2-[3-(D~e~hylamlnw~propyl]-7_,10-dihydroxv-5-[ E2-
[(2-hydroxyethyl-)amino]ethyl]amino1anthra[lr9-cd]
pyrazol-6(2H)-one
Reaction of a mixture of 2.5 g (6 mmol) of
5-chloro-~-[3-~dimethylamino)propyl~-7,10-d-hydroxy-
anthra~l,9-cd]pyrazol-6(2H~-onel hydrochloride,
2.8 ml (28 mmol) of 2-(2-aminoethylamino)ethanol, and
20 ml of pyridine at reflux for 24 hours followed by
workup as described for-Example 21 and salt formation
as described in Example 3 gives the product as a salt
with 2,0 equivalents of hydragen chloride solvated
with 1 0 equivalent o~ water; mp 311C
decompositiorl ) O
5-Chloro-2-[3-(dimethylamino)propyl]-7,10-
dihydroxyanthraLl,g-cd]pyrazol-6(2H) one is prepared
as follows~
To a suspension of 30.9 g (100 mmol~ of 1,4
dichloro-5~8-dihydroxy-9,10-anthracenedione in 200 ml
of pyridine at 37C is added dropwise 14 g (120 mmol)
of (3-dimethylaminopropyl)hydrazine ~J. Med_. Chem.,
1;493 (1964)]. The mixture is diluted with 50 ml
N,N-dime~hylformamide9 stirred for ten hours, and
concentrated. The r~sidue is distribute.3 bet~ean
dichloromethane an~ 5% aqueous sodium bicarbonate.
Purification of the dried organic layer on silica gel
utilizing 95.5:4:0.5 dichloromethane:methanol:
triethylamine giv~s 8 g of product. Salt formation as
described in Example 3 gives 7.S g of tAe 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-AmLno~ropyl)amino]-2-[3-(dimethylamino)~r~yl]-
7,10-dih~droxyanthra[l,9-cd]~xrazol-6(2H)-one
Reac~ion of 5~chloro-2-[3~(dimethylamino)propyl]-
7,10-dih~droxyanthra~l,9-cd~pyrazol-6(2H)-one, hydro-
chloride~ ~ith 1~3-propanediamine as described in
Example 4Ç girJes the product as a salt with
2.0 equivalents of hydrogen chloride solvated with
0 5 equivalent of water; mp >300Co
EXA.~PLE 48
7,l0-Dihydroxy-5-[[2-~(2-hydroxyethyl~amlno]ethyl]
amino-2-~2-(methylthio~ethyl)anthra~l,9 cd]-
pyrazol-6(2H~-one
Reaction of a mixtuLe of 0.66 g (3.6 mol) of
5-chloro-~-(2~thlomethylethyl)-7,10-dihydroxyanthra~
1,9 cd]pyrazol~6(2EI)-one~ 108 ml (1~ mmol) of
~-t2~aminoethylamino)ethanol, and 16 ml of pyridine
at reflux overnight followed by ~orkup as described ln
Example 21 and salt ~ormation 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
(decomposition).
5-Chloro-2-(2-thiomethylethyl)-7,10-dihydroxy-
ankhra-[l,9-cd]pyrazol-6(2H)-one is prepared
~s follows:
~ n ice-cold mixture of 2,64 g (5 mmol) of
5~chloro-2-(2-thiome~hyleth~ 7,10-bis(phenyl~
methoxy)anthra[l,9-cd]pyrazol-6~2H)~one in 15 ml
dichloromethane is treated drop~ise during 30 minutes
with 30 ml of a 1 M solution of boron trichloride in
dichloromethane. The mixture is stirred for one hour
then treated carefully with 30 ml of methanol. The
mi~ture is wa med to roo~ temperature overn-ght then
concentrated to a residue which is triturated with
2-proDanol to give a red solid. Fur~her trituration
'~ ,
~s~
CLG-l -101-
with 75 ml of boiling methanol gives 0.9 g of pure
product; rnp 186-190C~
S-Chloro-2-(2-thiomethylethyl)-?,10-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2~)-one is prepared as
~ollo~s:
A mixture of 5.1 g (10 mmol) of 5-chloro-2-
~2-hydroxyethyl)-7,10-~is(phenylmethoxy)anthra-
Il,9-cd]pyrazol-6(2~)-one, 9.4 g (100 mmol) of methyl-
disulfide, 20.2 g (100 mmol) of tri-n-butylphosphine,
and 50 ml of N,N-dimethylformamide is stirred over-
night at roo~ temperature. The mixture is cooled and
treated carefully with 7~ 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 155-160C~
5-Chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2H)-one is pre~ared as
follows: -
Reaction of a mixture of 35.4 g (72 mmol) of lr4~dichloro-5,8-bis(phenylmethoxy)-9,10-anthracenedione,
11.2 g (147 mmol) of (2-hydroxyethyl)hydrazine, 2.1
(37 ~ol) of anhydrous potassium fluoride, 7.4 9
(74 mmol) of ~nhydrous potassium bic~rbonate, and
220 ml of dry dimethylsulfoxide as described in
Example 54 gives 33.1 g of the dried product;
mp 1?8-184C. Crystallization from chloroform raises
the melting point to 201-204C~
1,4-~ichloro-5,8-bis(phenylmethoxy)-9,10-anthra-
cenedione is prepared as ollows:
mixture of 51.3 g (160 mmol) of 1,4-dichloro-
~,8-dihydroxy-9,10-anthracenedione (US Patent Numher
3,631,Q74), 46 g (330 mmol) of powdered anhydrous
potassium carbonate, 44 ml (380 mmol) of benzyl
bromide, and 670 ml of dry acetone are heated at re-
flux for five days. The mixture is cooled, the solids
are filtered, then ~ashed se~uentially with water,
)
~ ~ 5 ~ L~I~ 2
CLG-l -132-
methanol, and diethyl ether to give 63.5 g of the
dried pro2uct; mp 190-194C. Processing of the
acetone filtrate gives 9.4 9 of a second crop; ~p
1~2-155C.
EXA~PLE 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 rnmol) of
5-chloro-2-~2-(diethylamino)ethyl]-7,10-bis(phenyl-
methoxy)anthrall,9-cd]pyrazol-6(2H)-one in 30 ml of
dichloromethane is treated dropwise during two hours
with 96 ml of a 1 M solution of boron trichloride~
Following addition, the mixture is treated carefully
with 30 ml of methanol. The mixture is warmed to room
temperatuee overnight and the solid residue is
collected, washed se~uentially with 2-propanol,
methanol, and die~hyl ether to give S.5 g of the dried
product as a salt with 1.0 equlvalent of hydrogen
chloride, and solvated with 0.2 equivalent o~ water;
mp 280-282C (decomposition).
5-Chloro-2-~2-~diethylamino)ethyl]-7,10-bis-
(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2~)-one is
prepared a~ follo~s:
A mixture of 4.2 G ( 6.3 mmol) of ~-chloro-2-
[2-~[(4-methylphenyl)sulfonyl]oxy]ethyl]-7,10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6(2H)-one,
4.~ y (60 ~mol) of diethylamine, 17 9 (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 ~ of product; mp 209-211C.
5-Chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy~-
e~hyl~-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-
6(2H)one is prepared as follows:
z
CLG-l -103-
An ice-cold mixture of 22 g (43 mmol~ of
5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
- methoxy~anthra[l~9-cd]pyrazol-6(2H~-one, 1~ 3 g
(65 mmol) of P-toluenesulfonyl chloride and 170 ml of
pyridine is stirred Eor 50 hoursO The sclid i5
filtered, T~ashed with methanol and diethyl ether, and
dried to give 10.5 y of the product; mp 203-206C
~decomposition). Processing of the fil'.rate gives
9.3 g of additional product; mp 182-188C
Idecomposition).
EX~MPLE 50
~-~2-~2-~Dimethvlamino)e.h~l]amino~ethyl]-5-[~2-~(2-
h~droxye~hyl)amino~ethyl~amino]-7,10-dihydroxyanthra-
~1,9-cd]pvrazol~6(2H)-one
Reaction o~ a mixture oE 3,6 ~ C7Og mmol~ 5-
chloro-2-[2-~[2-(dime~hylamino)ethyl~amino]ethyl}-
7,10-dihydroxyan~hra[l,9-cd]pyrazol-6(2H)-one,
dihydrochloride, 4.5 ml (45 ~mol) of 2-(2-aminoethyl- ~- -
amino)ethanol, and 35 ml o~ pyridine at 80C overnight
ollowed 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~ter; mp 110 - 117Co
~ -Chloro-2-[2-[[2-(dimethylamino)ethyl]aminol-
ethyl]-7,10-dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one
is prepared as followsO
An i;ce-cold mixture of 9.3 g (16 mmol) of 5-
chloro-~-12-[l2-(dimethylamino)ethyl]amino]ethyl]-
7,10~bis-~phenylmethoxy)anthra~l,9~cdlpyrazol-
6(2H)-one in 30 ml of dichloro~ethane is treated
dropwise during tWQ 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 tempera.ure overnight and
the solid residue i5 collected, washed sequentially
with 2-propanol, methanol, and dietnyl ether to give
3.68 g of the dried product as a salt with 1.8
~5~
.
CLG-l -104-
equivalents of hydrogen chloride and solvated with 0O2
equivalent of 2 propanol and 0~8 equivalent of water;
mp 260-268C (decomposition),
S-Chloro-2-[2-[[2-~dimethylamino)ethyl]amino]~
ethyl]-7,10-bis(phenylmethoxy)anthra~l,9-cd]pyrazol-
6(2H)-one is prepared as follows~
A mixture of 4.2 g (6.3 mmol) of 5-chloro-2-[2-
[[(4-rnethylphenyl)sulfonyl]o:cy]ethyl]-7,'0-bistphenyl-
methoxy)anthrall,9-cd]pyraol-6(2~)-one, 5.3 g
~0 m~ol) of N~N-dimethylethylenediaminef 17 g
(12.6 mmol) of powdered potassium carbonate, and 35 ml
of dimethylsulfoxide is stirred overnight at 50C.
q'he mixture is cooled and diluted with 50 ml of waterO
The solid is collected and washed with wat~r, The
solid is heated in dichloromethane, the solution
filtered, then concentrated~ Trituration of the
residue with,hot ethyl acetate gives 1.7 g of the
' dried produc-t; t~ .1~8-153QC. . .
EXAMPLE 51
7,10-Dihydroxy-5-~-[2-[(2-hydro~yethyl-)amino]ethyl]
amino~-2-[2-[(2-h~droxyethyl)methylamino]ethyl]-
an~hra~l,9-cd]pyrazol 6(2H)-one
Reaction of a mixture of 3.3 g (7.3 mmol) of
5-chloro-7~10-dihydroxy-2 [2-[(2-hydroxyethyl)-
methylamino~ethyl~anthra[l,9-cd]pyrazo1-6(2~)-one,
hydrochloride, 3.6 ml (36 n~ol) of 2-(2-aminoethyl-
amino)ethanol, and 30 ml of pyridine ovarnigh,t at 30C
~ollowed by wor~up as described ln Example 21 and salt
forma~ion as described in Exa~ple 3 gives 1,~ g of ~he
dried product as a salt wi.h 1.6 equivalents of
hydrogen chloride solvated with 0.4 equivalent of
water; mp 240C (decomposition)~
S-Chloro-7,10-dihydroxy-2-~2-[(2-hydroxyethyl)-
methylamino]ethyl]anthra[l,9-cd3pyrazol-6(2H)-one is
prepared as follows:
~S~ 2
CLG-l -105-
~eaction of a mixture of 8.3 g (15 mmol) of
`~ 5-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]~
7,10-bis(phenylmethoxy)anthra[l,9-cdjpyrazol-6(2El)-
one, 87 ml of a 1 M solution of boron trichloride in
dichlorome~hane, and 60 ml of dichloromethane as
described for Example 49 gives 3.5 g of the dried
product as a salt with 1.0 equivalent of hydrogen
chloride solvated with 1.75 equlvalents of water;
mp 279-282C ld~composition)
5-Chloro-2-[2-~(2-hydroxyethyl)methylamino]
ethyl]-7,10-bis(phenylmethoxy~anthra[l,9-cd]pyra~ol-
6(2H~-one is prepared as follows:
Reaction o~ a mixture of 1ODO g ~15 mmol) of
S-chloro-2-[2-[[4-methylphenyl)sulfonyl]oxy]ethyll-
/,10-bis(phenyl)methoxy)anthra[l t 9-cd]pyrazol-6(2H)
one, 12.1 ml (150 mmol) of 2-methylaminoethanol,
4.1 g (30 mmol) of potassium carbonate, and ~0 ml of
dimethylsulfoxide as described in Example 49 gives ~`
8.5 g of the product; mp 191-194~C.
EXAMPLE 52
7~10-Dihydroxy-5-[~2-[(2-hydroxyethyl)amino]ethyl]
amino]-2-[3-[(2-hydroxvethyl)amino]~ropyl]anthra-
.
[l,~-cd]pvrazol-6(2H)~one
Reaction of a mixture of 1.4 g (3.6 mmol) of
5-chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)zmino]-
propyl]anthra[l,9-cd]pyraæol-6(2H)-one, hydrochloride,
3.7 ml (37 mmol) of 2-(2-aminoethylamino)e'ha~ol and
15 ml of pyridine overnight at 80C fol'ow?d by workup
as described in Example 21 gives 0.9 g of the dried
product solva'ed with 0.6 equivalent of water; mp
100-105C.
5-Chloro-7,10-dihydroxy-2-[3-[(2-hydroxyethyl)-
amino]propyl]anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
CL~ 106-
Reaction of a mixture of 9.0 g (16 mmol~ of
5-chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-7,10-
bis(phenylmethoxy)anthra[l,9-cd]pyrazol-6~2H~-one,
63 ml of a 1 M solution of boron trichloride in
dichloromethane~ and 30 ml of dichloromethane as
described for Example 49 gives 6.0 g of the dried
produc~ as a salt with 0.8 equivalent of hydrogen
chloride solvated with 0.7 equivalent of water;
mp 255-265C ~decomposition~0
5-Chloro-2-~3-[~2-hydroxyethyl)amino]propyl]7,10
bis(pnenylmethoxy)anthra~l,9-cd]pyrazol-6(2~-one is
prepared as follows:
Reaction of a mixture of 13 4 g (13.7 mmol~ of
5-chloro~2-l3-[[4-methylphenyl~sulfonyl]oxy]propyl]-
7,10-bis~phen~lmethoxy)anthra~1,9-cd]pyrazol~6(2H)-
one, 12 ml (197 mmol) of 2 aminoethanol, 5.5 g
~39.4 ~nol) of potassium carbonate, and 120 ml of
dimethylsulfoxlde as described in Example ~9^gi~-es ~ ~ -
9~85 g of the product, mp 174-176C. Crystallization -
from chlorofor~ gives material of mp 180-185Co
5-Chloro-2-~3 ~4-methylphenyl)sulfonyl]oxy]-
propyl]-7,10-bis~phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2~)-one is prepared as follows:
Reaction of a mixture o 1301 g (25 mmol) of
5-chloro-2-~3-hydroxypropyl)-7,10-bis~phenylmethoxy)-
an~hra[l,9-cd]pyrazol-6(2~)-one, 9 5 g (50 mmol3 of
~-toluenesul.onyl chloride, 9 ml ~5 mmol) of
triet`nylamine r 150 mg 0~ ~-dimethylaminopyridine, and
125 ml of dichloromekhane at 5C for one day ~hen at
room temperature for fi~e hours ~llowed by workup as
described for Example 49 gives 14.3 g o ~he product;
mp 131-139C.
5-Chloro-2-(3-hydroxypropyl) 7,10-bis(phenyl-
methoxy)anthra~l,9-cd]pyrazo1-6~2H)-one is prepared
as follows:
CLG~ 107-
A mixture of 48.9 g (100 mmol3 of 1,4-dichloro
5,8-bis(2henylmethoxy)-9,10 an~hracenedione, 18O0 g
(200 mmol~ of (3-hydroxypropyl)hydrazine [J. Amer.
Chem~ Soc. 7~; 1283 (1954)~, 2.~ g (50 mmol) of
_
atlhydrous potassium 1uoride~ 10~0 g (100 mmol) of
anhydrous potassium bicarbonate, and 300 ml of dry
dimethylsulfo~ide is stirred at 80C overnight. The
warm mixture is diluted with 1.5 ml of water, then
allowed to cool. The solids are collected by filtra-
tion, washed sequentially with water, 2-propanol, and
diethyl ether to a~ford 31.0 g of the dried product;
mp 159-163C. Processing of the filtrate gives 4.7 g
of additional product; mp 150-154C~
EX~M.PLE 53
5-[(3-Aminopropvl~amino]-7,10-dih~droxy-2 [3-[(2-
h~droxyethvl)amino]prop~l]anthra[l,9-cd]pyrazol-
6t2H)-one
Reaction of a mixture of 1.3 g (3.3 mmol) of
5-chloro-7,10-dihydroxy-2-l3-[(2-hydroxyethyl)aminoj-
propyl]anthra[1,9-cd]pyrazo1-6(2H)-onel 2.9 ml
(35 mmol) of 1,3 propanediamine, and 15 ml of pyridine
at 80C o~ernigh~ followed by workup as described in
Example 21 gives lo O g of the dried product as a salt
with 0 1 equivalent of hydrogen chloride solvated with
0.3 equivalent of water and 0.1 equivalent of
2-propanol; mp 120-130C (decomposition).
E~AMPLE 54
7,10-Dih~droxy-2-~2-[(2-hydroxyeth~l)amino'ethyl]_ 5
[[2-[(2-hydroxyet~l)amino]ethyl]amino]anthr_[l,9-cd]-_
pyrazol-6(2H)-one
Reaction of mixture of 1~28 g (3 mmol) 5-chloro-
7,10-dihydroxy-2[2-[(2-hydroxyethyl~am~no~ethyl]-
anthra~l,9-cd]pyrazol-6(2H)-o~e, hydrochloride, 1.5 ml
(15 mmol) of 2-(2-aminoethylamino)ethanol and 6 ml of
oyridine at 80C overnight followed by workup as
described in Example 21 and salt formation as
described in 2xample 3 gives 675 mg o the product as
CLG-l -108-
a salt with 2.0 equivalents of hydrogen chloride
solvated wi~h 0.9 equivalent of water; mp 215-225C
~decomposition).
5-Cnloro-7,10-dihydroxy-2-[Z-~(2-hydroxyethyl~
a.~ino]ethyl]anthra{l,9-cd]pyrazol-6(2H~-one is
prepared as follows:
To an ice-cold mixture of 26.8 y (48 mmol~ of
5-chloro-2-[2-[hydroxyethyl)amino]ethyl]-7,10-bis-
(phenylmethoxy)an~hrall,9-cd]pyrazol-6~2~)-one and 60
ml of dry dichloromethane i~ added dropwise during
2 1/4 hours 794 ml o' a 1 M solution of boron
trichloride. The mixture is stirred for an additional
0~5 hours t then 200 ml o' methanol is added dropwise
during 1~5 hoursO The mixture is allowed to warm to
rooln temperature oYernight and the solids are fil-
tered, washed sequentially with methanol~
dichloromethane, dieth~l ether, and 2-propanol to give
14 7 g of the dried product; mp 175C (de~omposition);
Processing of the filtrate affords 5.'1 g of additional
product; mp 125-135C (decomposition)O
Crystalli2ation of the solid from methanol gives a
salt with 1.0 equivalent of hydrogen chloride solvated
with 0.7 equivalent of water; mp 180-200C
(decompcsition).
5-Chloro-2-~2-[(2-hydroxyethyl)amino]e~hyl]-7~10-
bistphenylmethoxy)anthra~l,9-cd]pyrazol-6(2H)-one is
prepared a~ ~ollows
A mi:cture of 58.~ g ~120 ~moL) of l~a-dichloro--
5,8-bistphenylmethoxy)-9,10-anthracenedione~ 28.6 9
1240 n~ol) of 2-[(hydrazinoethyl)amino]ethanol, 3.5 g
S60 m~ol) of anhydrous potassium fluoride, 12 g ~120
mmol~ oE anhydrous potassium bicarbonate~ and 360 ~1
of dry dimethylsulfoxide is stirred at 80C overnight.
The mixture is diluted with 400 ml of water and the
oranse solids are filteredl washed sequentially wlth
water, 2-propanol, and diethyl ether to give 51.2 g of
the dried product; mp 164-1O8C.
CLG-l -109-
The following compounds are prepared as described
in Example 54 from 5-chloro-7,10-dihydroxy-2-[2-~(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]pyrazol-6(2H)-
one nydrochloride and the corresponding amine:
EXAMPLE 55
5-~(2-Aminoethyl)amino]-7,10-dihydrox~-2-[2-[(2-
hydroxyethyl)amino]ethvl]anthra[l,9-cd]pyrazol-
6(2H)-one
Reaction with ethylenediamine gives the prcduct
as a salt with 2.0 equivalents o hydrogen chloride
sol~7ated with 0.9 equivalent of water; mp 272-278C
(decomposition).
EX~MPL~ 56
5-[[2-(Dimethylamino)ethyl]amino]-7,10~dihvdrox~Y-
~=[2-[(2-hydroxyethyl)amino]ethvl]anthr_
p~razol-6~2~)-one
Reaction with N,N-dimethylethylenediamine gives
the product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 1.7 equivalents o~ water;
mp 278-280C (decomposition~.
EXAMPLE 57
5-[[2-(Diethylamino)ethyl]amino]-7,10-dihydroxy-2-~2-
~(2-hydroxyethyl)amino]eth~l]anthra[l~9-cd]pyra
6(2H ? -one
React.ion with N,N-diethylethylenediamine gives
the product as a salt with 1.9 equivalents o~ hydrogen
chloride solvated with 1.5 equivalents of water;
m~ 228-231UC.
EX~M3?LF. 58
5-[~3-~minopropyl)amino]-7,10-dihydroxy-2-[2-[(2-
hydroxyethyl)amino]ethyl3anthra[1,9-cd3pyrazol-6-
(2~)-one
Reaction with 1,3-propanediamine gives the
product as a salt with 1.7 equivalents of hy2rogen
chloride sclvated with 1.0 equivalent of water;
mp 222C ~decomposition).
~,
~l~5~ 2
CLG-l -110-
E~A~PLE 59
5-[(4-Aminobutyl)amino]-7~lo-dihydroxy-2-[2-l(2~hydr
_thyl)amino]ethyl]anthra[ll9-cd]pyra~ol-5(2H)-one
Reaction with 1,4-butanediamine gives the product
as a salt with 1.0 equivalent of hydrogen chloride
solvated wi~h 0.5 equi~Jalent of water; mp 2~0-245C
(decomposition).
EXAMPLE 60
5 r ( 5-A~inopentvl)amin?]-7,10-dihydroxy-2-l2-[(2-
hydroxyethyl)amino]ethyl]anthra[l,9-cd]~yrazol-
6(2H)-one
Reaction with 1,5-pentanediamine gives the
product as a salt with 1.9 equivalents of hydrogen
chloride solvated with 0.7 equivalent of water;
mp 270-275C (decomposition),
EXAMPLE 61
7,10-Dihydroxy-2-f2-l(2-hydroxyethyl)aml_no]ethyl]-
5-[[2-(4-mor~holinvl)ethyl]aminolant.'nra[1,9-cd]-
pyrazol-6(2H)-one
Reaction with 4-(2-aminoethyl)~.norpholine sives
the product as a salt with 2.4 equivalen~s of hycrogen
chloride solvated with O.B equivalent of water;
~,~ 2gOC (decomposi~ion).
EXAMPL~ 62
7,10-Dihydroxy-2-[2-f(2-hydroxyethyl)amino]ethyll-5-
f_1~2-hYdroxyethyl)amino]oropyl]amlno]an~chra[l~9-cd]
pyra~ol-6(2H)-one
Reaction with 2-(3-aminopropylamino)eth.anol gi~es
the product as a salt wi.~h 2.1 equivalents of hydrogen
chloride solvated with 0.8 equivalent of water and
0~1 e~uivalent of 2-propanol; mp 170-180C
(decomposition~.
~5~ 2
CLG~
EXAMPLE 63
5-[[2-[[2-(3imethylaminoet~xl]àminolethyl]amino]-7,1Q-
dihydrox~L-2-[2-[~2-hydroxyethvl)amino]ethyl]anthra-
[1,9-cd]pyrazol-~(2~)-one
_. _
Reaction with N,M-dimethyldiethylelletriamine
yives the prod~ct as a salt with 2.4 equivalents of
hydrogen chloride solvated with 1.4 equivalents oE
water and 0.2 equivalent of 2-propanol; mp 80-90C
(decomposition)O
- EXAMPLE ~4
7,10-Dihydroxy-2-[2-[(2-hydroxyethyl)amino3ethyl]-5-
(4-methyl~ iperazinyl)anthrall,9-cd3pyrazol-
6~2~)-one
Reaction with N methylpipera2ine gives the
product a~ a saLt ~itll 202 e~ulvalsnts o~ hydroyen
chloride solvatecl with 0.~ equivalent o~ water and 0.2
equivalen-t o~ 2-propanol; mp >123C (decon~position).
E'~AMPLE 65
5-[l2-(Dimethylamino)ethyl]methylamino]-7~lo-di-
hydroxy-2-[2-[~2-hydroxyethyl) _ino3ethyl3anthra-
[l,9-cd]-~yraæo1-6(2H)-one
Reaction with N,N,N-trimethylethylenediamine
gives the product as a salt with 2.1 equivalents of
hydrogen chloride solvated with 1.9 equivalents of
water and 0.2 equivalents oE 2-propanol; mp >91C
!decomQosition) ..
EX~MPI,E 66
5-~12-[(2-P~minoetllvl)amino]ethvl]amino]-7,10-di-
hydro~y-2=~2-[(2-~droxyethyl)amino]ethYl]anthra-
[1,9-cd]-pyrazol-6(2H)-one
Reaction with diethylenetriamine gives the
product as a salt with 1~0 equivalent of hydrogen
chloride solvated with l.0 equivalent of water;
mp 210-215C (decomposition).
~ ~5~
CLG-l -112~
EXAMPLE 67
5-[[2-~3is(2-hydro~yethy~amino]ethyl]amino]-7
dihydroxy-2-[2-[(2-hydroxyethYl)amino]ethyl]anthra
Reaction with N,M-bis(2~hydroxyeth~,1)ethylen~-
diamine gives the product as a salt with 2.3 equiYa
lents of hydrogen chloride solvated with 0.8
equivalent of ~ater; mp 230C (decompos:ition~,
EX~PLE 6Q
5-~[3-[Bis(2-hydroxyethyl~amino]propyl]amino]-7,10-
dihydroxy-2-~2-hydroxyethyl)ami~o]ethyl~anthra-
[l,9-cd]pyrazol-6(2~-one
R2action with N,N-bis (2-hydroxyethyl)-1,3-
propanediamine gives the product as a salt with
~1 equi.valents o hydrogen chloride solvated with
t).4 equivalent of water; mp lg8-215C (decomposition).
EXAMPLE 69
5-[[3-[[4-[(3-~minoprop~l)amino]butyl]amino]propy:l]- -
amino]-7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]-
ethyl]anthra[l,9-cd]pyrazol-6(2H)-one
Reaction with spermine gives the product as a
s~l~ with 2.75 equivalents of hydrogen chloride
solvated with 0.6 equivalent of w~er and 0.1 equiva-
lent o~ 2~propanol; mp 185~200C (decomposition)O
EX~MPLE 70
7,10-Dihydroxv-2-[2-[(2-hydroxyethyl)amino]eth~ 5-
1[2-tmethylamin_)ethyl]amino3anthra[1, -cd]-
pyra~ol-6(2E)-one
Reaction wi~h (2~aminoethyl)-methylcarbamic
a~id, benzyl ester followed by isolation o~ the
intermediate then hydrolysis ~ith refluxing 48%
hydrobromic acid in acetic acid gives the product as a
salt with 2.1 equivalents of hydrogen bromide solvated
with 2.3 equivalents of water and 0.5 equivalent of
acetic acid; mp 222~228C (decomposition).
~l~5~
CLG--l -113-
EXAI~IPLE 71
2-(2-~minoeth~1)-7,10-dihydroxy-5-[[2-~(2-hydroxy-
ethvl)amino]ethvl]amino]anthra[l,9-cd] Pyra
6~2H)-one
Reaction of a mixture of 2.0 g (6 nunol~ of
2-~2-aminoethyl)-5-chloro-7,10-dihydroxyanthra
[l,9-cd]pyrazol-6~2H)-one, 3 ml (30 T[rnol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine at
reflux overnight follo~led 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 with
2.0 equivalents of hydrogen chloride solvated with
O.5 equlvalent of water; IE~? 275-280C (decomposition~.
2-(2-Aminoe~hyl)-5-chloro-7,10-dihydroxyanthra-
~l,9-cd]pyrazol -~(2~)-one is prepared Erom 2-(2-amino-
ethyl)-S-chloro--7,10-bis(phenylmethoxy)anthra~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 equivalent of hydrogen chloride solvated with
0.7 equivalent of ~iater; mp 265-268C (decomposition).
2-(~-Aminoethyl)-5-chloro-7,10 bis(phenyl-
~nethox~)anthra[l,9-cd]pyrazol-6(2H)-one is prepared
from 1,4-dichloro-5v8-bi;,(E~henylmethoxy)-9,lO-
anthracenedione and (2-aminoethyl)hydrazine as
described in ~xample 54 to give the product; mp
176-178C.
EXAI"lPLE 72
_inoeth~1)-5-[(2-aminoethyl)amino]- 7,10-
dihydroxvanthra[1,9-cd]pvrazol-6(2H)-one
Reaction of 2-~2-aminoethyl~-5-chloro-7,10--
dihydroxyanthra[l,9-cd]pyrazol-6(2H)-one with
thylenediamine as described in Example 71 gives
the product as a salt ~ith 1.9 equivalents of
h~drogen chloride solvated with 1.0 equivalent of
.~ater; mp >230C (decolnposition).
CLG-l -114-
EX~.~PLE 73
2-(2-Aminoethvl)-5-[(3-aminopropyl)a~ino]-7,10-
dlh~droxyanthra[l,9cd]pyr~zol-6(2H)-one
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-
dihydroxyanthrall/9-cd]pyrazol-6(2H)-one with
1,3-propanediamine as described in Example 71 gives
the product as a salt with 2.9 equivalents of hydrogen
chloride solvated with 3.5 equivalents of water;
mp > 310C (decomposition~.
EXAMPLE 74
2-[2-Aminoethyl)-5-[~2-[[2-(dimethylamino)ethyl]-
amino]ethyl]amino]-7,10-dihvdrox~anthra[l,9-cd]_-
pyrazol-6(2~)-one
Reaction of 2-(2 aminoe-thyl)--5-chloro-7,10-
dihydroxyant'nra[l,9-cdlpyrazol-6~2H)-one with
N,N-dimethyldiethylenetriamine as described in Example
71 gives th~ product as a salt with 3.3 e~uivalents
o hydrogen chloride solvated with 1.0 equivalent
of water and 0.2 equivalent of 2-propanol;
mp 245-260C (decomposition)O
EX~PLE 75
2--(2-Aminoethyl)-5-[[3-[(2-hYdroxyethyl)amino]oropyl}-
aminol-7~10-dihydroxyanthra[l~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 ~he product as a ~alt with 2~ equival~nts o~
hydrogen chloride solvated with 1.0 equivalent of
water and 0.2 eq~ivalent of 2-propanol; mp 175C
(decomposition).
EXAMPLE 76
7,10-Dihydrox~5-[[2-[(2-hydroxyethYl)amino]ethyl]-
amino]-2-t2-methoxyethyl)anthra[lr9-cd]pyrazol-
__
6(2H)-one
Reaction of a mixture o~ 2.0 9 (5.8 mmol) of
5-chloro-7,10-dihydroxy-2-(2-methoxyethyl)anthra-
CLG 1 -115-
[l,9-cd]pyrazol-6(2H)-one, 5.8 ml (58 mmol) of
2-(2-aminoethylamino)ethanol, and 25 ml of pyridine
at 85C overnight followed by wor~up as described in
Example 21 gives 1.75 g of productO Salt formatîon
as described in Example 3 gives 1.91 g of product
as a salt with 1.1 e~uivalents of hydrogen chloride
solvated with 0.3 equivalent of water and
0.2 equivalent o~ 2-propanol; mp 68-72C.
5-Chloro-7,10-dihydroxy-2-(2-methoxyethyl)anthra-
~l,9-cd]pyrazol-6(2H)-one is prepared as follows:
Reaction of 11.9 g (23 mmol) of 5-chl`oro-2-
~2-methoxyethyl)-7,10-bis(phenylmethoxy)anthra-
[1,9-cd]pyrazol-6(2H)-one, 91 ml of a 1 M solltion of
boron trichloride, and 46 ml of dry dichloromethane as
descr.ibed in Example 24 givcs 6.25 g of the dried
product; mp 137~145C (decomposition).
5-Chloro-2-(2-methoxyethyl)-7,10-bis(phenyl~
methoxy)~nthra[l,9-cd]pyrazol-6(2H)-one-is-prepared~a~
~ollo~s:
~ n ice-cold mixture of 3.2 g (6 mmol) of
S-chloro-2-(2-hydroxyethyl)-7,10-bis(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6~2H)-one, 1.23 ml
(20 mmol) of j.odomethane, and 20 ml ~ N,N-dimethyl-
formamide is treated gradually with 0.18 g (8 mmol) of
sodium hydride. The ice bath is removed and the
mix~ure is stirred for two hours, treated with five
drop~ of glacial acetic acid, then diluted with water.
The solids are filtered, washed sequentially with
2-propanol and die~.h~Il ether to give 20 8 g oE the
dried product; mp 174-178Co
EXAMPLE 77
5~t(2-Ami.noe~hyl)amino~-7,10-dihydroxy-2-(2-methox~
ethyl)anthra[l,9-cd]pyrazol-6(2H~)-one
Reaction of 5-chloro-7,10-dihydroxy-2-(2-methoxy-
ethyl)anthra~l,9-cd]pyrazol-6(~H!-one with ethylel~e-
diamine as described in Example 76 gives the produc'
~.5~
CLG-l -116
as a salt with 1.0 equivalent of hydrogen chloride
solva~ed with 0.3 equivalent of water, mp 263-268C
(decomposition~
EX~MPLE 78
2-(2,3-Dih~droxypropyl~-7~10-dihyaroxy-~-[[2
[(2-hydroxyethyl)amino]ethYl]amino]anthra[l,9-cd]-
pyrazol-6(2H)-~ne
A mixture of 1.3 g (2 m~ol) 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]pyrazol-S~2~)-one~ 260 mg of 20% palladium
hydroxide on carbon, and 25 ml of glacial acetic acicl
is stirred under an atmosphere of hydrog~n for two
hoursO The mix~ure i5 filtered and concen~rated
to a residue which is dissolve-l in me~h~nolic
hydrogen chloride. The mixture is stirred at room
temperature Eor two hours and concentrated to a
solid which i~ crystallized from 1:1 methanol:
e~hanol to give 0.7 g of the product 2s a salt
with 1.1 equivalents o~ hydrogen chloride solvated
with 1.0 equivalent of water; mp jllOC.
2-l(2,2-Dimethyl-1,3-dioxolan-4-yl~methylj-5-[[2
I(2-hydroxyethyl)amino]ethyl]amino-7,10-bis(phenyl-
mebhoxy~anthra[l~9-cd]pyrazol-6(2H~-one is prepared as
follo-~s:
A mixture of 1.2 g 52 mmol) of 5-chloro~2-
[(2,2-dimethyl-1,3 dioxolan-4-yl)methyl]~7 7 l~-bis-
~phenylrr~etno~)an~hra[l,9-cd]pyrazol-~(2H)-one,
2.~ m~ t22 mmol) o~ 2-(2-aminoethylamino)ethanol,
17 ml of pyridine, and 0~3 g of anhydrous potassium
carbonate is stirred at reElux for 42 hours. The
mixture is diluted with water and fil~ered to give
a solid that is purified by silica gel chromatography
utilizing 94:5:1 dichloromethane:methanol triethyl-
amine. Concentration of the product fractions
followed by trituration with 2-propanol gives 730 mg
of pure product; mp 206C.
~2~5~
CLG-l -117~
5-Chloro-2-~(2 r 2-dimethyl-1,3-dioxolan-~-yl)-
methyl]-7,10-bis(phenylmethoxy)ankhrall,9-cd]-
pyrazol-6~2~)-one is prepared as follows:
A mixture of 19 6 g (4C ~nol) of 1,4-dichloro-
5,8-bis~phenylmethoxy)~9,10-anthracenedione, 10 g
(68 n~ol) of 4-(hydrazinomethyl)-2,2-dimethyl-1,3-
dioxolan lAnn 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
dimethylsulfoxide is stirred a-~ 80C for six hours.
The mixture 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 utili~ing
0O5 ~o 1% net~lanol in dichloromethane gives 6 g
of a solid that is triturated from 2-propanol,
then crystallized from toluene to aEford 1.8 g
of pure product; mp 184-188C.
EXAMPLE 79
2-[2-~Diethylamino)ethyl]-7-[[2-~(2-hydroxyeth
amino~ethyl]amino]anthra[l,9-cd]pyrazol-6(2H)-
o
Reaction of 2.5 g (i mmol) of 7 chloro-2-~2~di-
ethylamino)ethyl]anthra[l,9~cd]pyrazol-6(2~)-one, 7 ml
~70 ~mol) of 2-(2-aminoethylamino)e~hanol, and 20 ml
oE p~ridine or 20 hours a~ reflux followed by workup
as described in Example 9 gives 1.6 g of a solid, mp
104-107C, after recrystalliza~ion from toluene. Salt
forlnation as described in Ex~mple 3 gives 1~ g of the
dried product as a salt with 2.0 equivalents of
hydrogen chloride solvated with 1.1 equivalents of
water; mp 212-216C (decomposition).
7-Chloro-2-[2-(diethylamino)ethyl]anthra[l,9-ca]-
pyrazol6(2~)-one is prepared 25 follows:
t
~.~.5~
CLG-l -118-
A mixture of 13.85 g (50 mmol) of 1,5-dichloro-
9,10-anthracenedione, 13.1 g (100 mmol3 of (2-diethyl-
aminoethyl)hydrazineJ and 100 ml of pyridine is stir-
red at 50C for five hours, treated with an additional
10 ml of the substrate hydrazine, stirred at 35C for
48 hours, cooled, filtered, and concentrated.
Trituration of the residue with 2-propanol~ethanol
gives 8 g o a solid powder; mp 129-132C.
Dissolution of a 0.9 g sample in hot methanol followed
by salt formation as described in Example 3 ~ives 0.8
g of the dried product as a salt with 1.0 equivalent
of hydrogen chloride; mp 272-275C (decomposition3.
EX~PLE 80
2-[2-(Diethylamino)ethyl]-7-[[2-(diethylamino)ethyl]-
amlno]anthra[l,9-cd]pyrazol-6(2H)-ona
Reaction of a mixture of ~.1 g (6 mmol) o~ 7-
chloro-2-t2-~diethylamino)ethyl]anthra[1,9-cd]pyrazol-
6(2H)-one, 5 ml (36 ~mol) o~ N,N-diethy~ethylenedi- -
~amine, and 20 ml of pyridine for 28 hours at reflux
followed by workup as des-cribed 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
equivalent of water; mp 292-294C (decomposition).
EXAMPLE 31
2-~2-~(2-Hydroxvethyl)amino]ethyl]-7-[[2-[(2-hydr
ethyl)amino]ethyl]amino]anthra[l,9-cd3pyrazol-6-
(2H)-one
A mixture o~ 1 9 g (5 mmol) of 7-chloro-2-~2-[(2-
hydroxye~hyl)amino3e~hyl~a-nthra~1,3-cd]pyrazol-6(2H3-
one, 2.0 ml (20 mmol) o~ 2-(2-aminoethylamino~ethanol,
~ and 20 ml of pyridine is heated at reflux for
72 hours. The mixture is cooled, conce-ntr2ted, and
chromatographed over silica gel with 0.5%
triethylamine in dichloromethane, utilizing a gradient
elution of 2-10~ methanol, to give the product. Salt
fcrmation as described in Example 3 gives 500 ma of
- ~5~ 2
CL~ 119-
the product as a salt with 2.0 equivalents of hydrogen
chloride solvated with 0.4 equivalent of water;
mp 285-287C (decomposition~
7-Chlo~o-2-[2-~ hydroxyethyl)amino]ethyl]-
anthra[l,9-cd]pyrazol-~(2H)-one is prepared as
~ollows:
A mix~ure of 11.1 g (40 mmol) of 1,5 dichloro-
9,10-anthracenedione, 13.1 g (110 mmol) of 2
~(hydrazinoethyl)amino]ethanol~ 4 9 of anhydrous
potassium bicarbonate, 1 g of anhydrous potassium
fluoride, and 110 ml of dimethyl sulfoxide is stirred
- at 70C overnight. The mixture is chilled and the
solids are collected by filtration~ washed with water,
then thoroughly with acetonitrile to give a residue
that is cr~stalli22d from 2-propanol to leave 2~6 g
of product. The hydrochloride salt is prepared as
described in Example 3; mp 272-273C (decomposition)~
2~MPLE 82 -
7,10-Dichloro-2-[2 E ( 2-hydroxyethyl)amino]ethyl]-
5-[[2-[~2-hydroxyethyl)amino]ethyl]amino]anthra-
[1,9-cd3~yrazol-6(2H)-one
Reac~ion OL 7,10-dichloro-2-[2-[(2-hydroxy-
ethyl)aminolethyl]-5-[~(4-methylphenyl)sulfonyl]-
oxy3anthratl,9-cd]pyrazol-6(2H)-one/ hydrochloridev
with 2-(2-aminoethyla~ino)ethanol gives the product.
7/10-Dichloro-2-[2-[(2-hydroxyethyl)amino]ethyl~-
5-l[~4-methylphenyl)sulfonyl]oxy]anthra[l,9-cd]-
pyr~zol-6(2~.~)-one is prepared as follows
To a suspension of 30~9 g (S0 mmol) of 1~-
dichloro-5,8-bis[[(4-methylphenyl)sulfonyl]oxy3-
~,10-anthracenedione, 13 ml (75 mmol) of
N,N-diisopropylethylamine, and 130 ml of
N,N-dimethylformamide at 5C is added dropwise 14.9 g
(l~S mmol) of 2-[(hydra~inoethyl)amino]et~anol in 70
ml of .~,N-dimethylformamide. The mixture is allowed
~5~
CLG-l -120~
to reach 10C during five hours, then is diluted with
t 20 ml of acetone. After warming to room temperature,
~he solution is concen~rated to an oil that is
dis~ributed bet~een water and dichloromethane~
Concentration of the dried dichloromethane layer
followed by salt formation as described in ~xa~ple 3
gives 18O1 g of the dried product as the hydrochloride
salt; mp 158-160C.
1,4-Dichloro-5,8-bis[[~-methyl2henyl)sulfonyl]-
oxy]-9,10-anthracenedione is prepared as follows:
A mixture of 9.3 g (30 mmol) of 1,4-dichloro-
5,8-dihydroxy-9,10-anthracenedione, 12.6 g (66 mmol~
of p-toluenesulfonyl chloride, 12.2 ml (7Q mmol) of
N,N-diisopropylethylamine~ and 120 ml of acetonitrile
is heated at 70C ~or one hour, then cooled. The
crystals are collected by filtration to leave 14.4 g
of dried product; mp 195.~196.5C. Processing oE
the Eiltrates glves 2.2 g of additional product~
mp 19~-192C.
EX~MPLE 83
7-Hydroxy-2-12-[(2-hydroxyethyl)amino]ethyl~-5-
[[2-1(2-hydroxye~hyl)amino3e~hyl~amino]anthra[1,9-cd3
. .
~yrazol-6(2~)-one
Reaction of a mixture o 2-[2 [(2-hydroxyethyl)~
amino]ethyl]-5-[[2-[(2-hydroxyethyllamino]ethyl]-
amino]-7-(phenylmethoxy~anthra~1,9-cd]pyrazol-6(2H)
one with hydrogen and 20~ palladium hydroxide on
carbon as described ln Example 78 ~ives the product as
a salt with 2.0 equivalen~s oE hydrogen chloride
solvated with 2.3 equivalents of water; mp 265-270C
(decomposition).
2-12-[(2-hydroxyethyl)amino~ethyl]-5-[[2-[t2-
hydrox~f 2 thyl)amino]ethyl]amino-7-(phenylmethyoxy)
anthra[l,9-cd]pyrazol-6(2H)-one is prepared as
follows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl)-
amino]ethyl]-7-(phenylmethoxy)anthra[l,9-cd]pyrazol-
~-5~ 2
CLG-l -121-
6(2H)-one with 2-(2-aminoethylamino)ethanol as
described in Example 78 gives the product;
mp 157-159C.
S-Chloro-2-~2-[(2-hydroxyethyl)ami~o~ethyl]-7-
(phenylmethoxy~anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
A mixture of 4.2 g (11.0 mmol) oE 1,4-dichloro-
5-(phenylmethoxy)-9,10-anthracenedione, 2.6 g ~22.0 mmol)
of 2-L(hyra2inoethyl)amino]ethanol, 320 mg (5.5 ~mol)
of anhydrous potassium fluoride, 1.1 g (11.0 mmol~ of
anhydrous potassium bicarbonate, and 33 ml of dimethyl-
sulfoxide is stirred overnight at 80~C, The mixture is
cooled and poured into water. The a~ueous mixture is
centrifuged and ~he aque~ous phase is decanted to leave
an oil that ls dried and purified on sillca gel
utilizing 4:1 dichloromethane:methanol as eluting
solvent. Concentration o~ the product fractions
~ollowed by trituration ~rom methanol gives 840-~g
of the drie~ product; mp 1~1-145C.
1,4-Dichloro-5-~phenylmethoxy)-9,10-anthra-
cenedione is prepared as follows:
A mixture of 5.33 g ~18 mmol) of 1,4-dichloro-
5-hydroxy-9,10-anthracenedione ~British
- Patent 1,029~448), 2.6 g (19 mmol) of powdered
anhydrous potassium carbonate, 2.5 ml (21 mmol)
of benz~l bromide, ~nd 75 ml of dry acetone is
he~ted at reflux overnight. The mixture is cooled
~nd t.he solids are washed well with acetone,
Concentration oE ~he Eiltrates gives a solid which
is triturated with ether to afford 5,8 g of the
dried product; mp 118-122C
Prepared in a fashion similar to 2xample 83 i5
the Eollowing:
~5
CL~ 122--
EX~MPLE 8
! 7-Hydrox~ 2~[(2-hx~_oxyethyl)amino]ethyl1-5-[[
(methylamino)ethyl~amino]anthra[l~9-ca]pyrazol-6(2H)
o as a salt with 1.8 equivalents of hydrogen
chloride sol~Jated with 1.2 equivalents of water;
mp 280-282C (decomposition) is prepared from 2-[2-
[(2-hydroxvethyl~amino~ethyl]-5-[[2-~methyl(phenyl-
methyl)amino]ethyl]amino]-7-~phenylm~thoxy)anthra
~l,9-cd]pyrazol~6(2H)-one; mp llO-1139C, which is
prepared rom the reaction of N-methyl-N-(phenyl
methyl)-1,2-ethanediamine (US Patent 3,201,459~ with
5-chloro-2-12-~2-hydroxyethyl)amino]ethyl]-7-(phenyl-
methoxy)anthra[l,9-cd]pyrazol~6~2~)-oneO
EXAMPLE as
10-Hydrox~-2-[~-[~2-~ydroxyethyl)amino]ethyl]--
5-~[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra-
d ~ razol-6(2~)-one
Reaction of.a ~ixture..of..2-E2-[(2-hydro.Yyethyl)-~..r...~ - .~.
amino]ethyl]-5-~2- E ( 2-hydroxyethyl)ami~o]ethy.l.] .-. -
amino]~10-(phenylm thoxy)anthra~l,9-cd~pyrazol-6(2~)-
one with hydrogen and 20~ palladium hydroxide on car-
bon as described in Example 78 gives the product as a
salt with 2.1 equivalents of hydrogen chloride sol-
vated with 0.8 equivalent of water, mp 260-267C
(decomposition) D
2-[2-[(2-hydroxyethyl)amino~ethyl]-5-~[2 [(2-
hydroxyethyl)amino]ethyl]amino-lO~(phenylmethox~
anthrarlJ9-cdlpyrazol-5~2E~~one is pr~par2d ~s
follows:
Reaction of 5-chloro-2-[2-[(2-hydroxyethyl~
amino~-ethyl]-10-(phenylmethoxy)anthra[l,9-cd]pyrazol-
6~2H)-one with 2--~2-aminoe-thylamino)ethanol as
described in ~xample 78 gives the product;
mp 178-180C,
5-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-10-
(phenylmethoxy~anthra[1,9-cd]pyrazol-6(2H)-one is
prepared as follows:
CLG-l -123-
Reaction of 1,~-dichloro-5-~phenylmethoxy)-9,10-
anthracenedione wi'h 2-[thydrazinoethyl)a~ino]ethanol
as described in ~xample 83 gives the product as the
minor isomer; mp 165-167C~
EXAMPLE 86
7,9,10-Trihydroxy-2-~2---[(2-hydro~rethxl)amino]ethyl]
5-[~2-[(2=h~droxyethyl)aminolethyl]amino]anthra-
[l,9-cd]-pxra~ol-6(2H)-one
Reaction of a solution of 2-[2-[(2-hydroxyethyl)-
amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino~ethyl~-
amino]-7,9,10-tris(phenylmethoxy)anthra[l,9-cd]~
pyrazol-6(2H)-one in glacial acetic acld with hydrog~n
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
equivalen~ of water; mp ~ 235C (decomposition)~
2-[2-[(2-Hydroxyethyl)amino]ethyl]-5-~[2-[(2-
. _. hydroxyethyl)amino]ethyl]amino]-7.,9,10-tris(phenyl-
methoxy)anthra[l,9-cd]pyrazol-6(2H)-one is prepared
as follows:
A mixture o 660 mg (1 mmol~ of 5-chloro-2-[2-
~(2-hydroxyethyl)amino~ethyl]-7,9,10-tris (phenyl-
methoxy~anthra[l,9-cd]pyrazo1-6(2H)-one, 1 ml
(10 mmol) of 2-(2-aminoethylamino)ethanol, and 2 ml
of pyridine is heated at reflux for 28 hours, Workup
as described in Example 21 gives a solid whose
crystallization from acetonitrile chloroform afEords
308 mg of product; mp 158-159C,
5-Chloro-2-[2-[(2-hydroxyethyl)amino]e~hyl]-
7,9,10-tris(p'nenyl~etho~y)anthra~l,9-cd]pyrazol-6(2H)-
one is prepared as fo1lowsO
A suspension of 7.2 g (12 ~mol) of 5,8-dichloro-
1,2,4-tris(phenylmethoxy)-9,10-anthracenedione, 2 g g
(2~ mmol) of 2-[(hydra~inoethyl)amino]ethanol,
350 mg ~6 mmol) of ~nhydrous potassium flouride, 1.2 g
(12 mmol) of anhydrous potassium bicarbonate, and
25 ml of dimethylsulfo~ide is stirred overnight a~
CLG~ 124-
75C. The mixture is cooled7 then triturated with
2-~ropanol. The solids are filtered, ~ashed well with
water, 2-propanolJ then crys~alli2ed from chlorororm
to give 2~3 g of orange solid; mp 172-:L73C,
Processing of the nonaqueous filtrates gi~es
640 mg of additional product corresponding to ca. 1:1
mixture of isomers by 1H ~IR, ~P 135-140C,
5,8-Dichloro-19 2,4-tris(phenylmethoxy) 9,10-
anthracenedio~a is ~repared is as ollowsO
A suspension of 7.5 g (23 mmol~ of 5,8~dichloro
1,2,4-trihydroxy-9,10-anthracenedione, 9,6 ml
(81 m~ol) or benzyl bromide7 9.9 g (72 mmol) of
powdered anhydrous potassium carbonate, 00~ ml of
methanol r 92 ml of acetone, and 46 ml of
dimethylformamide is heated a~. reflux under argon
for two days. An additional ~.7 ml of benzyl bromide
is added and ~he mixture is heated for ~hree days.
The suspension is filtered and-the filtrate is~
concentrated to an oil w~ich i5 distributed between~
dichloromethane and 10~ aqueous acetic acid~ The
dried dichloromethane layer is concentrated to a solid
whose crys~allization from ethyl acetate affords 7.2 g
of product; mp 174-175Co
5,8-Dichloro 1,2~-trihydroxy-3,10-
anthracenedione is prepared as follows:
A suspension of 451 mg (1 mmoll of 1,2,4-tris
~acetylox~)-5,8-dichloro 9,10-anthracenedione~ 5 ml
of g].acial ac2tic acid~ and 5 ml o~ 6 N ~queous hydro-
chloric acid is hea~ed a~ 70~ or ona hour. The
suspension is cooled and the solids are filtered off.
After washing with water and drying, there remains
287 mg oE the dried product; mp 790-295C
decompos ition ~ ~ -
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
~5
CLG-l -125-
acid, and 10 ml of acetic anhydride is stirred at
room temperature for 30 minutes The soluti.on is
. diluted with water, the organic layer is separated,
and dried, ~hen concentrated to a solid residue.
Trituration of the solid from ethyl acetate leaves
235 mg of product; mp 205-206Co
5,8-Dichloro-1,4,9,10-anthra~enetetrone is
prepared as followsO
A suspension of 618 mg 12 ~mol) of 1,4-dichloro-
5,8-dihydrsxy-9,10-anthracenedione, 1.06 g (2.4 mmol~
of lead tetraacetate, and 25 ~1 of glacial acetic acid
is stirred at room temperature for 45 minutes~ The
mixture is treated with 0.5 ml ethylene glycol, and
ater 15 minutes is diluted with dichloromethane.
The mixture is ~ashed with water and the dried organic
layer is evâporated ~o a solid~ Trituration of the
solid from diethyl ether gives 569 mg of product;
~p 255-257C (decompGsition)i ~
EX~MP~E 87
7~8~10-Trihydroxy-2-[2-[(2-hydroxethyl)amino]ethyl]
5-l[2-[(2-hydroxyethyl)amino]ethyl]am no]anthra-
[1,9-cd]pyrazol-6(2~)-one
Reaction of a solution of 2-[2-~(2-hydroxyethyl)-
amino]ethyl]-5-[[2-~(2-hydroxyethyl)amino]ethyl~
amino]-7,8,10-tris(phenylmethoxy)anthra~l,9-cd]-
pyrazol-5(2H)-one in glacial acetic acid with hydrogen
and 20% palladium hydroxide on carbon as described in
Example 78 gives the produc~ as a sal~ with 2.1
equi~7alents of h~drogen chloride solvated with 0,~
equivalent of water; mp >210C (decomposition).
2-~2-[(2-~ydroxyethyl)a~ino]ethyl]-5-[~2-[(2-
hydroxyethyl)amino]ethyl]amino~-7,8,10-tris(phenyl-
~ethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is prepared
as follows:
Reaction o~ 5-chloro-2-[2-~(2-hydroxyethyl)-
amino]ethyl]-7,8,10-tri~phenylmethoxy)anthra[1,~-cd]-
~5~2
CLG~l -126~
pyrazol-6(2H)-one with 2-~2 aminoethylamino)ethanol as
described in Example 86 gives the product;
mp 186-188~C~
5-Chloro-2 [2-1(2-hydroxyethyl)amino]ethyl]-
7,~,10-tris(phenylmethoxy~arlthra[1,9rcc!]pyra~ol-
6(2H)~one is prepared as follows:
Reaction of 5,8-dichloro-1,2,4-tris(phenyl-
methox~)-9,10-anthracenedione with 2-[(hydrazino-
ethyl)amino]ethanol as described in Example 86 gives
the product as the minor isomer; mp 164-167~Co
Prepared in a fashion similar to Exam~le 87 is
the following:
EXAMPLE 88
7,8~10-rrihydroxy-2-[2-[(2-hydroxyet-hyl)amino)-~ethy].]~
5-[[2-(methylamino)ethylIamino]anthrall,9-cd]
~yrazol 6(2H)-one as a salt with 2.0 equivalents
oE hydrogen chloride solvated with 0.7 equivalent of
water; mp ~220C (decomposition), which is prepared
from 2 [2-[(2-hydroxyethyl)amino]ethyl]-5-
~L2-[methyl(phenylmethyl)amino]ethyl~amino]-7,8,10-
tris (phenylmethoxy)anthra[l,9-cd~pyrazol-6(2H)-one;
mp 104-108aC which i5 prepared from the reaction of
N-methyl-N(pn~nylmethyl)-1,2-ethanediamine with
5-chloro-2-[~-1(2~hydroxyetIlyl)amino]ethyl]
7,8,10-tris(phenylmethoxy)anthra~l,9-cdIpyrazol-
6(2~)-one.
EXA~P~E 89
_-[l2-[(2-Aminoethyl)amlno~e~hyl]amino]-7,10-
dihvdroxv 2-(2-hYdroxvethvl)an~hra[l,9-cd~-
_
pyrazol-6(2B)-one
Reaction of a solution of 5-[12-[(2-aminoethyl)-
amino]ethyl]amino-2-(2-hydroxysthyl)-7~10-bis(phenyl-
me~hoxy)anthrall,9--cd3pyrazol-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 sal~ with 2.4 equivalents of hydrogen chloride
solvated with 008 e~u.valent of water; mp 170-185C
(decomposition).
~S~ 2
CLG-l -127-
5-~[2-[(2-Aminoethyl)amino]ethyl]amino-2-(2-
hydroxyethyl)-7,10-bis(phenylmethoxy)anthra[l,9-cdl-
pyrazol-6(2H)-one is prepared as follows
A mixture of 501 g (10 mmol3 of 5--chloro-2-12-
hydrox~yethyl)-7,10-bis(phenylm.ethoxy)anthra~l,9-cd3-
pyrazol~6(2H)-one, 10 g (100 mmol] of cliethylene-
triami.neJ 1.4 g (10 mmol) of anhydrous potassium
carbonate, and 60 ml of pyridine is heated at reflux
for 28 hours. The mixture is cooled, the solids are
collected by filtration then washed sequentially with
water and 2-propanol to give 3.1 g of the product;
mp 185-190C.
EXAMPLE gO
2-~3-Amino~ro~yl)-7,10-dihy_~oxy-5-~2-[(2-hydroxy-
ethyl~aminole~hyl]amino~anthra[l,9-cd]l~yrazol-
~2H)-one
Reaction of a solution of 1.2 g (2 mmol) o~
-2~(3-aminopropyl)-5-[~2-[(2-hydroxyethyl)amino]ethyl]
amino]-7,10-bis(phenylmethoxy)anthra~1,9-cdlpyrazol-
6~2H)-one in glacial acetic acicl with hydrogen and 20
palladium hydroxide on carbon as described in Example
78 ~ollowed by salt formation as described in Example
3 gives 850 mg of the product a salt with 2.0 equi-
~ralents of hydrogen chloride solvated with 1.1 equi-
valents of water; mp 292-294C (decomposition)~
2-(3-Aminopropyl)-5-[ L 2-[(2-hyroxyethyl)amino]
ethyl]amino-7,10-bis(phenylmethoxy)anthra[l,9~cd~-
pyrazol~ M)-one ls prepared as follows~
A mi~ture of ~30 mg (1 mmol~ of 2-(3-amino-
propyl)-5-chloro-7,10-bis(phenylmethoxy)anthra-1,9-
cd3pyrazol-~(2H)-one, 1 ml (10 mmol) of 2-(2
aminoethylamino)ethanol, 140 mg (1 m~ol) of anhydrous
potassiu~ carbonate, and 8 ml of pyridine is heated at
refluY~ for 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[1,9-cd]pyrazol-o(2~)-one is
prepared as follows:
s~
CLG-l -128-
Reac~ion of a mixture of 1,4-dichloro-5,8-bis-
tphenylmethoxy)-9,10-anthracenedione and (3-amino-
propyl)hydr~zine ~Helvetica Chimica Acta 42; 533
(1959)~ as described in Example 54 sives the product;
mp 180-184~C.
Prepared in a fashion similar to :Example 90 is
the following:
EX~MPLE 91
2-(3-~minopro~yl)-5-[[2-~2-(dimethylaJnino)ethy1]-
amino~ethyl]amino]-7,10-dihydroxyanthra[l;9-cd~
pyrazol-6(2H)-one as a salt with 3~0 equivalents
of hydrogen chlo-;ide solvated with 2.0 equivalents of
water; mp 294C (decomposition), which is prepared
fro~n 2-(3-aminopropyl~-5-[[2-[[2 (dimethylamino)-
ethyl]amino]ethyl]amino]-7,10-bis(phenylmethoxy)
anthra[l,9-cd]pyrazol-6(2H)-one; mp 143-160C, which
is prepared from the reaction of N,N-dimethyldi-
ethylenetriamine with 2-(3-aminopropyl)-5-chloro-
7,10-bis(phenylmethoxy)anthra[l,~-cd]pyrazol-
6(2~)-one.
EXAMPLE 92
2-~2-Aminoethyl)-7,10-dihydroxy-5-~[2-(methylamino ? -
ethyl]amino]anthra[l,9-cd]Pyrazol-6(2~)-one
Reaction of a mixture of 2-(2-aminoethyl)-5-
l[2-methyl(phenylmethyl~amlno]ethyl]amino]-7 r 10-bis-
tphenylmethoxy)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 2~7 equivalents of hydrogen chloride solvated
with O.S equivalent of water; mp 259-264C
tdecomposition).
2-~2-Aminoethyl)-5-[[2~[methyl(phenylmethyl)-
a~ino]ethyl]amino]-7,10-bis(phenylmethoxy)anthra[1,9-
cd]pyrazol-6(2H)-one is prepared as follows:
Reaction of 2-(2-aminoethyl)-5-chloro-7,10-bis-
(phenylmethoxy)anthra[1,9-cd~pyrazol-6t2H)-one with
CLG-l -129-
_-methyl-~-(phenylmethyl)-1~2-ethanediamine as de-
scribed in Example 7~ gives the product; mp 169-172C.
EX~,~PLE 93
7,10-Dihydroxy~5-[[2-[t2-hydroxyet~ )alr.ino]ethyl]-
amino~-2-[2-(methylamino)ethyl]anthra[l,9-cd]pyra
6(2H)-one
Reaction of a mixture of 5-[[2-[(2-hydroxyethyl~-
amino]ethyl]amino]-2-[2-(methylamino)ethyl]-7,10-bis-
(phenylmethox~)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 equiYalents of hydroyen chloride solvated
with 1.8 equivalents of water; mp 180-185C
(decomposition)O
5-[~2-l(2-hyc~-coxye~hyl)amino]e~hyl]amino~-2-
[2-(methylamino)ethyl]-7,10-bis(phenylmethoxy)anthra-
[1,9-cd]pyrazol-6(2H)-one is prepared as Eollows:
Reaction of 5-chloro-2-[2--(methylamino)ethyl]- ~~
7,10-bis(phenylmethoxy)an.thra[l,9-cd]pyrazol-6(2H)-
one with 2-~2-aminoethylamino)ethanol as described in
Example 78 gives the 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:
~ eaction of 5~chloro-2-[3-[~4-methylphenyl)-
sulfonyl]oxy]ethyl]-7910-bis(phenylmethoxy)anthra-
[l,9-~d]pyrazol-6(~H)-one ~ith methylamine as-de-
scribed in ~xample 51 give~ the product; mp 171-176C.
EXAMPLE ~4
2-Aminoethvl)amino]-2-[3-(dimethylaminO)~rOpYl]-
7,10-dihydroxyanthxa[l~9-cd]pyra2ol=6~2H)-one
_
Reac~ion of 5-chloro-2-[3-(dimethylâmino)propyl]-
7,10-dihydroxyanthra[l,g-cd~pyrazol-6(2~)~one, hydro-
chloride, with ethylenediamine as described in
Example 46 gives the product as a salt with 2.0
equivalents of hydrogen chloride solvated with 0.5
equivalent
5~
~LG-l -130- -
of water and 0.1 equivalent of 2-propanol; mp 316C
; (decomposition).
EXAMPLE 95
7,8-DihydroxY- _ (2-hy~roxyethyl)amLno]ethyl]-5
[[2-[(2-hydroxyethyl?amino]ethyl]aminolanthra[l~9-cd]
pyrazol-6(2H~-one
Reaction of a mixture of 2-[2-[(2-hydroxyethyl)-
amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]-
amino]-7,8-bis(phenylmethoxy)anthra[l,9-cd]pyrazol-
6(2H)-one with hydrogen and 20% palladium`hydroxide
on carbon as described in Example 78 gives the
product.
2-~2-~t2-hydroxyethyl)amino]ethyl]-5~[[2-[(2-
hydroxyethyl)amino]ethyllamino]-7,8-bis-
(phenylmethoxy)anthra[1,9-cd]pyrazol-6(~H)-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-aminQethylamino)ethanol
as descrlbed in Example 78 gives the product.
S-Chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,8-
bis(phenyl~ethoxy)anthra[l,9-cd]pyrazol-6(2H)-one is
prepared as follows:
Reaction of 1,4-dichloro~5,6-bis(phenylmethoxy)~
9,10-anthracenedione with 2-[(hydrazinoethyl)amino]-
ethanol as described in ~xample S4 gives the product~
1~4-Dichloro-5,6-bis(ph~nylmethoxy) 9,10-
an-thracenedione is prepared as fGllows:
Reaction of 1,4-dichloro-5,6-dihydroxy-9,10-
anthracenedione with benzyl bromide as described in
Example 48 gives the product.
1,4-Dichlcro-5,6-dihydroxy-9,10-anthracenedione
is prepared as follows:
Reaction of nitrosyl sulfuric acld and 5,6-
~iamino-1,4-dichlsro-9,10-anthracenedione fxhim .
Geterotsikl. Soedin. 808 (1968)] gives the prcduct.
. _
