Note: Descriptions are shown in the official language in which they were submitted.
1~7~3~7
1 The present invention in one aspect thereof provides
anthracycline glycosides of the formula I
O OH O
l,,~f , '/`f CH2
O OH
o
Rr
wherein X is hydrogen or hydroxy, Rl is hydrogen or methyl, one
o~ R2 and R3 is methoxy and the other of R2 and R3 hyclrogen; and
pharmaceutically acceptable acid additions salts thereof.
~hese compounds are named as ~ollows:
4-demethoxy-4'-O-methyl-daunorubicin
~Ia: Rl=R3=X=H, R2=0CH3),
4-demethoxy-4'-epi-4'-O-methyl-daunorubicin
.Ib Rl=R2=X=H, R3=0CH3~,
~-demethoxy-2,3-clim~thyl-~-O-methyl-daunorubicin
(Ic; Rl=CH3, R2=OCH3, R3=X=H),
4-demethoxy-2,3-dimethyl-41-epi-4'-O-methyl-daunorub.icin
(Id: Rl=CH3, R2=X=~, R3=OCH3),
4-demethoxy-4'-O-methyl-doxorubicin
~Ie: R~=R3=H, R2=OCH3, X=OH),
--1--
3~7
1 4-demethoxy-4'-epi-4'-0-meth~l-doxorubici.n
( 1 2 ' 3 3~ )~
4-demethoxy-2,3-dimethyl-4'-0-rnethyl-doxorubicin
(Ig: Rl=CH3~ R2=OCH3~ R3--H~ X=OII)~ and
4-demethoxy-2r3-dimethyl-4l-epi-4l-o-Methyl-doxorubicin
~ Rl CH3~ R2=H~ R3=0CH3, X=OH).
In ano-ther aspect thereof the invention provides a pro-
cess for preparing the anthracycline glycosides Of the formula I.
The process according to the invention comprises con-
10 densing 4-demethoxy-daunomycinone or 2,3-dimethyl-4-demethoxy-
d~aunomycinone (United States Patent No. 4046878) with 2,3,6-
trideoxy-3-trifluoroacetamido-4-0-methyl-L-lyxo-hexopyranosyl
chloride or 2/3,6-trideoxy-3-trifluoroacetamido-4-O~methyl-L-
arabino-hexopyranosyl chloride (United States Patent No. 4183919)
to give one Of the protected ~-glycosides 0~ the formulae IIa to
IIdr
0 0~1 0
~ ~ CH3
0 01
o
IIa: Rl=R3=~i; R2=OCH3
IIb Rl=R2--H; R3=OCH
3 / ~ 1 3; 2 OCE13; R3 H
R3 __~ / I IId Rl=CH3; R2=II; R3=CEJ3
¦ NHCQCF3
3~
~ 7~3~
1 removin~ the N-trifluoroace~l protecting c3roup by mild alkaline
hydrolysis to give the corresponding daunorubiein clerivatives
Ia to Id, and optionally convertinc~ the ~aunorubicin derivative
to the corresponding doxorubicin derivative Ie to Ih by bromin-
ation and treatment of the resulting 14-bromo-derivative with
aqueous sodium formate.
The conversion of the daunorubicin derivative Ia to Id
to the correspondin~ doxorubicin derivatives Ie to Ih follows the
method described in United States Patent No. 3803124.
In still another aspee-t thereof the invention provides
pharmaeeutieal compositions comprising an anthraeyeline glyeoside
of the formula I or a pharmaceutically aeceptable salt thereof in
adrnixture with a pharmaceutically aeeeptable diluent or carrier
thereEor.
The .invention is illustrated by the following examples
and biologieal data.
Example 1
~-demethoxy~ 0-methyl-daunorubiein ~Ia)
A solution Oe 3.6~ g of g-deme-thoxy-daunomyeinone in
400 ml o~ anhydrous methylene diehloride eontaininc~ g of 1-
ehloro-~0-methyl~-N--triEluoroaeetyl-daunosamine was vigorously
stirred in the presenee o~ moleeular sieve (30 g, ~A Merek) and
1.3 g of silver triEluorome-thane-sulphonate. AEter 10 minutes at
room temperature, the reaction mixture was neutralized with 0.55
ml oE symcollidine. After ~0 mlnutes the suspension was ~iltered
and the oryanic phase was washed with 0.01 N aqueous solution of
hydroehlorie aeid, with water, with a saturated aqueous solution
of sodium bicarbonate and finally with water to neutrality. The
residue, obtained by evaporating off the solvent under vaeuum,
was dissolved in 150 ml of acetone, treated with 600 ml of 0.2 N
--3--
1 ~L~3'7Z~3'~
1 aqueous sodium hydroxide ancl di.lu-ted with ~50 ml o-E water. ~fter
5 hours at 0C the solution was adjusted to p~I 5.8 and extrac-ted
with chloroform until the chloroform extracts were no longer
colored. The organic extracts were combined and acidified to
pH 5 with 0.1 N methanolic hydrogen chloride. sy evaporation
under vacuum to a small volume (150 ml) pure 4-demethoxy-4' 0-
methyl daunorubicin ~0.6 g) crystallized. The mother liquor was
purified on a column of silica gel ~uffered at pH 7 with phosphate
bufEer M/15, ~sing the solvent system chloroform:meth~.~nol:water
10 (10:2:0.2 by volume). The elute, containing the pure compound,
was diluted with wa-ter and the organic phase was se~arated off/
wclc;hed with water and evaporated to a small volume and thereafter
ao~idified to pH 5 with 0.1 N methanolic hydrogen chloride.
further amount (0.4 g~ of 4-demethoxy-4'-0-methyl-daunorubi.cin
hydrochloride was obtained: m.p. 189-190C (with decomposition~.
TI,C on Kiesel.gel plates (.Merck F 254) solvent system chloroform:
methanol:water (.10:2:0.2 by volume).
Il~'LC. experimental analysis: column microbondapack C18; mobile
phase: w~ter:a~:etonitrile ~69;3:L by volume) at pH 2 with 10~
orthophosphoric acid: flux rate 1.5 ml/min., retention time 22
min,
FD-r~S: m/z 511 (M ~
F.x~mple 2
~~demetlloxy-4'-0-methyl-doxorubicin (Ie)
A solutioIl of 0,5 g of ~-demethoxy ~'-0-methyl~dauno-
rubicin, prepared as described in Example 1, in a mixture of
methanol (.8 ml) and dioxan (20 ml) was treated with bromine to
form the 14-bromo deriva-tive. Treatment of the 14-bromo deriva-
tive with an aqueous solution of sodium formate at room temper-
30 ature ~or .18 hours gave 0.310 g of 4-demethoxy-~'-0-methyl-
doxorubicin which was isolated as its hydrochloride m,p. 16~-165 C
rrc~cle ~c~rk
7~
1 (with decornposition); TLC on Kieselyel plate ~Merck F 254) sol-
ven-t system chloroform:me-thanol:water (10:2:0.2 by volume);
Rf 0.18.
HPLC: experimen-tal conditions: column microbondapack
C18; mobile phase water:acetonitrile (.69:31 by volume) at pH 2
with 10% orthophosphoric acid; flux rate 1.5 ml/min; retention
time; 10 min.
Example 3
4-demethoxy-2,3-dimethyl-4'-0-methyl-daunorubicin (Ic~
The coupling reaction between 4-demethoxy-2,3-dimethyl-
daunomycinone and l-chloro-4-0-methyl-N-trifluoroacetyl-dauno
samine uncler the conditions described in Example 1 afforded the
title compound.
Example 4
4-demethoxy-2,3-dimethyl 4'-0-methyl-doxorubicin (Iy)
'rhe conversion of compound Ic to the title compound was
performed using the procedure described in Example 2.
Example 5
4-demethoxy-4'-epi-4'-0-methyldaunorublc.in (Ib) and ~-demethoxy-
20 2,3-dimethyl-4'-epi-4'-0-methyl-daunorubicin ~Id)
The coupling reactions, as described in Example 1, of
4-demethoxy-daunomyc:inone and 4-demethoxy-2,3-dimethyl-daunomycin-
one with 2,3,6-tr:ideoxy-3-t.rifluoroacetamido-4-0-methyl-L-arablno~
hexopyranosyl chloride af:Eorded, after hvdrolys.is of the N-pro--
tectiny yroup, the title compounds.
Example ~
4-demethoxy-4'-epi-4'-0-methyldoxorubicin ~If~ and 4-methoxy-2,3-
dimethyl-4'-epi-4'-0-methyl-doxorubicin (Ih~
The compounds Ib and Id were converted, via their 14-
bromo derivatives under the conditions described in Example 2 to
compound If and Ih respectively.
~L9~3~
1 BIOLOGIC~L ACTIVITY OF Ia and Ie
The compounds Ia and Ie were tested against the parent
compounds, respectively daunorubicin (DN~) and doxorubicin (DX),
in several experi.~ental systems, in order to ascertain their
cytotoxicity, antiturnor activity and cardiac toxicity in exper-
imental animals.
Data reported in Table 1 show that Ia is about 5 times
more cytotoxic than DNR, and Ie is about 9 times more cytotoxic
than DX,
The primary screening in vivo was carried out in CDF-l
mice bearing P388 ascitic leukemia (106 cells/mouse). Results
are reported in Table 2. Both Ia and Ie were found to be more
to~ic and more potent than the parent compounds. Comparison at
the Maximal Tolerated Dose (~IxTD) shows that Ia is as e~Eective
as DNR ~giving similar increase of the mice life span) and Ie has
a good antiturnor activity, ~Ihich is of the same order o.~ magnitude
as that o~ DX.
Several studies were carried out in C3~1 mice bearing
the Gross leukemia injected i.v. (.2x106 cells/mouse). Data on
Ia are repoxted in Table 3. Adm.inistered i.v. on day 1 aEter
the tumor inoculation, Ia was markedly more toxic and more potent
than DNR. At the MxTD o:E 1.25-1~3 mg/K~, Ia was more e~fective
than D~ at the MxTD o:E L0 mg/Kg/, It .i9 well known that DNR is
not active when aclministered by ora:L route, unless very high does
are gi~en ~> 50 mg/Kg~. Data reported in Table 3 show that Ia
ha~ good antitumor activity against Gross leukemia also when given
orally. ~dminis-tered orally on day 1 only, Ia is active at the
dose o~ 5-1.3 mg~Kg, which is also the optimal dose in the case
o:E the i.v. treatment.. This result suggests that absorption of
3~ Ia through the gastrointestinal tract is very efficient.
--6--
t723~7
1 Administered on days 1, 2 and 3 by oral rou-te, Ia is more active
than when administered on day 1 only; at the op-timal dose oE
0.66 mg/Kg/day it has an antitumor activity oE the same order of
magnitude as tha-t of 4-demethoxy-daunorubicin, which was invest-
iyated in parallel at the optirnal dose of 1.9 mg/Kg/day. The
observation that the opkimal dose of Ia is lower than that of
4-demethoxy-daunorubicin suggests a more efficient absorption
through the gastrointestinal tract also in comparison to this
compound.
Data on the antitumor activity of Ie in comparison wlth
DX against Gross leukemia are repor-ted in Table ~. The compounds
were administered on day 1 after the tumor cells inoculum; DX
was given i.v.; Ie was given i.v. and orally. When administered
i.v., at the MxTD of 1 mg/Kc;, Ie showed a good antitumor activi-ty,
similar to that observed after DX treatment. In addition~ Ie was
active also when administered orally at doses from 1.3 mg/Kg on.
Ie was tested against L 1210 leukemia, which w`as in-
oculated in CDF-l mice i.p. ~ascitic form) or i.v. ~105 cells/
mouse~. Treatment was perEormed on day 1 after the tumor cell
inoculation~ i.p. or i.v., respectively. Data repor-ted in Table
5 show that, in the .i.p.-i.p. experiment/ Ie at the MxTD oE 0.83
mg~Kg was as act.ive DX at the ~xTD of ~.~ mg/Kg. In the i.v.-i.v.
experiment, Ie at the tolerated doses o~ 1 and l.3 mg~Kg showed
ant~tumor aativity ~uperior to that o~ DX.
In order to assess the antitumor activity against a
solid tumor, Ie was tested in comparison with DX, against the
m~m~ry carcinoma of C3H female. A third generation tumor trans-
plant was utilized. Treatment started 15 days after the tumor
transplan-t, and was performed i~v., once a week for ~ weeks.
Tumor measurement was performed by caliper every week. Non-tumor
~7~23~
~earing mice were treated inparalle~ in order to evaluate the
general toxici-ty and the cardiac toxicity, which was investiga-ted
in 5 m:ice, treated with the highes-t doses oE the two compounds,
and kil:Led 5 weeks a~ter the last treatment. The results oE
-this expeximent are reported in Table 6. DX was very e~fective,
and it inhibited tumor growth by 93-94% (in comparison with the
untrea-ted controls) at both the doses tested (6 and 7.5 mg/Kg).
In the non-tumored mice treated with DX at ~.5 mg/Kg, toxic
deaths were observed ~2/3) and all the mice examined showed
1~ histologically detectable heart lesions. Ie at the dose o~ 0.4
mg/Kg was slightly active; at the doses of 0.6 and 0,75 mg/K~ it
markedly inhibited the tumor growth. In non-tumored mice treated
with Ie at 0.7S mg/ICg no a-trium lesions were observed, and only
2 out o:E 5 mice showed detectable ven-tricle lesions, which were
less severe than those observed a~ter DX treatment.
Tile data here presented show that Ia and Ie are new
anthracycline analogues endowed with very interesting biological
properties . In comparison with DNR, Ia is about 3 times more
potent when administered i.p~, and about 8 times more potent when
administered i.v. ~t the ~xTD it has an antitumor activ.ity
a~ainst ascitic P3~ and sys-temic Gross leukemia equal to that oE
DNR. In addit:lon, it is active also when administered by oral
route, particular:Ly when treatment is perEormed for 3 consecutive
days, at doses lower than those oE ~-demethoxy-daunorub.icin.
Ie is about 10 times more potent than D~' in vivo.
Comparison at the MxTD shows that it is,in respect to DX~ equally
active a~ainst ascitic P 388 and L 1210 leukemia~ systemic Gross
leukemia and solid m~mmary carcinoma, and it is more e~ective
than DX against systemic ci.v. injected) L 1210 leukemia. In
addition, is active against Gross leukemia also when administered
7;~3~
1 orally, and in a preliminary cardiotoxicity tes-t in C3H rnice
tr~a-ted chronically i.v. it caused only minimal cardiac lesions.
Compound Ia has been studied on P388 leukemia cells resis-tant to
doxorubicin (P388/DX) in vitro and vivo. P38~ leukemia cells
resistant to doxorubicin ~DX) (received by dr. Schabel) are main~
tained by serial trans~er in mice treated with DX i.p.. For
experimental purpose, sDF-l mice were inJected with 10~ leukemia
cells i.p., and treated i.p. on day 1 a~ter the tumor inoculation.
Results, reported in ~able 7, show that daunorubicin (DNRI was
not active against this tumor, while compound Ia, at the optimal
dose o~ O.B mg/kg increased the life span of the treated mice.
P388 and P388/DX leukemia cells were harvested from mice ascitic
fluid and adapted to grow in suspension in vitro. Cytotoxicit~
tests were carried out exposing the cells to various dru~ con-
centrations Eor ~8 hr~; at the end o~ the exposure period, cells
were counted with a Coulter Cell Counter, and the ID50 (dose
~hich gives S0% reduction of the cell number in comparison with
untreated controls~ was calculated. Results, reported in Table
~, show that Ia was about twice as cytotoxlc as DNR on P388 leu-
kemia cells, and was very active also on P388/DX leukemia cells,while DNR was 163-152 -times less ac-tive on the resistant tha~ on
the sensitive line.
Compound Ie was Eurther investi~ated on mnmm~ry carcinoma
oE C3H mice. Mice bearin~ measurable tumor ~3rd ~en~ration trans-
plant) were treated once~week for ~ weeks i.v. with Ie or with
DX. Normal mice were treated in p~rallel, ~or evaluation of
tox~c:ity. Results, reported in Table 9, confirm that Ie was
about 10 times more potent than DX, and had a remarkable antitumor
activit~ in this experimental system at non toxic doses, while
DX was toxic.
_g_
7~
1 secause o~ the yood anti-tumor activity against m~mm~ry
carcinoma, compound Ie was -tested against two solid tumors: the
colon 26 and the colon 38 adenocarcinomas, transplanted s.c. in
BALB/c mice and in BDF-1 mice, respec-tively. Treatmen-t started
on day 1 after the tumor inoeulation (early) or when tumor was
already palpable (advanced), and was performed i.v. once/week or
every 6 days, for 3 or 4 times. Tumor growth was assessed by
caliper measurement.
Non-tumor bearing mice were treated inparallel, for
toxicity evaluation, and were observed for 90 days. Results of
three experiments are reported in Table 10. Against early colon
2G, Ie at the m~xlm~. tolerated dose oE 0.9 mg/kg/day was more
active than DX at the m~;m~l tolerated dose of 7.5 mg/kg/day.
Against advanced colon 26, Ie at the m~x;mal dose tested of 0.7
mg/kg~day was not toxie, and gave a higher tumor growth inhibition
than DX at the maximal tolerated dose of 6 mg~g/day. Against
advanced colon 38, Ie at the maximal dose tested of 0.9 mg/kg/day
was as aetive as DX 9 mg/kg/day in inhibiting tumor growth, but
produeed a higher inerease of survival time.
In eonelusion, all data here xeportecd eonf;rm that eom-
pounds Ia and Ie are e~tremely interesting new anthraeylines,
endowed with h.igh potency, activity by oral route, activity
acJainst anthracycl:ine resistant tumors (Ia), aetivity against
so:ild tumors superior to that o~ DX and not eardiotoxie (.Ie~.
~ a'72~3~
1 Table 1 - Colony .inh:ibi-tion test agains-t Hela cells in vitxo .
(Trea-tment for 24 hrs)
Compound Dose a ID50
(ng/ml) % (.ny/ml)
DNR 12.5 42
6.2 66 ~ 12
3.1 121
Ia 25 0
6.2 0 ~ 2.5
1.~ 7~
~y 12.5 20
6.2 79 ~ g
3.1 17~.
Ie 10 0
2.5. 9-9
0.62 82 ~ 1
0.15 8
No. of colonies; % of untrea-ted controls.
Table 2 - Antitumor activity against P388 leukemia
Treatment i.p. on Da~ 1
Compound Dose T/Ca LTsb Toxic c
~mg/Kg) % deaths
DN.R~ 2.9 15~ OjlO 0/10
4.~ 140,15~ 0/20 ~/20
6.6 109,163 0/20 13/20
Ia 0.5 127 0/10 0/10
0.6~ 127 0/10 0/10
0.8 172,1.27 0/20 1/20
1.0 145 0/10 0/10
1.3 ~5 0/10 10/10
DX 4.~ 180 0/10 0/10
6.6 200 2/10 . 0/10
1O.Oe 315 4/10 0/10
Ie 0.44 180 0/10 0/10
0.66 215 0/10 ~/10
1.0 250 0/7 1/7
1.5 2~5 2/10 ~/10
-11~
~'37~
aMedian survi.val time; ~ over untreated controls
Long term survivors ~>60 days)
CEvaluated on the basis of autop-tic findings on dead mice
Data of two experiments
This is the Ma~imal Tolerated Dose of DX in this experimental
system
Table 3 - Activity of Ia against Gross leukemia
Trea-tment T/C Toxic c
Rouke Schedulea Compound mg/kg/day % de~ths
.i.v. 1 DNR 10 133,150 0~20
175,175,166 3/30
22.5 20~,191,216 6~30
i,v. 1 Ia 0.5~ 116 0/10
0.76 133 0/10
1.0 158,166 0/20
1.25-1.3 183/208 0/'20
- 1.56 100 9/10
1.95 116 6/10
oral 1 1.1 133 0/10
1.25-1.3 133,166 1/20
1.56-1.6 16~,166 3/20
1.95-~.0 175,183 2/20
oral 1,2,3 4-de- 1.31 125 0/10
methoxy
DNR 1.58-1.46 133,150 1/20
1.9 133,190 1/20
2.5 210 2/10
3.3 140 6/10
oral 1,2,3 Ia 0.44 133 0/9
0.66 183 0/10
1.0 200,220 9/20
1.25 1~0 8/10
a Daysafter tumor inoculation
b,c see Table 2.
-12-
7~
1 Table 4. Activity of Ie against Gross ].eu]cemia
~reatmenta b Toxic
T/C deathsC
Rou te Compou~ld mg/kg %
i.v. DX 10 200 2/8
13 200,216 2/18
16.9 250,266 3/lg
Ie 1.0 183,233 0/18
1.3 192,208 ~/18
1.7 217,200 7/18
2.2 142 7/10
Oral Ie 1.0 125 0/8
1.3 150 0/8
166, 0/8
166 0/8
On Day 1 after tumor inoculation
b,c See 1'able 2.
Table 5. Act.~vity of Ie ayainst L1210 leukemla
.
L1210 Treatment Compound m~/k~ T/ca LTsb TQxic c
inoculum % deaths
i~p. i.p. DX ~ .4 150 0/9 0~9
6.6 150 0/10 1/10
~ ~Ø0162 0/10 1/10
Ie 0. 83:L62 2/10 0/10
0 187 1/10 1/10
1.2 393 ~/10 3/10
i.v. .i ~v. DX 10.0 120 0/10 0/10
13.0 120 0/10 0/10
L6.9 133 0/10 0/10
Ie 1.0 200 0~10 0/10
1.3 173 0/10 0/10
1.7 >580 5/10 0/10
a,b,c
See I`able 2.
- 13 -
~72~7
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-14-
~9 ~1 ~)r3"`~
1 Table 7. Effec-t on doxorubicin-resistant P388 leuks~mia in vivo.
CompoundDose ~/ca ~TsbToxic c
~mg/kg~ ~ deaths
DNR 2.9 93 0/100/10
4.~ 87 0/101/10
6.6 8~ 0/103/10
Ia 0/53 133 0/100/10
0.8 1~2 1/100/10
1.2 106 0/104/10
a Median Survival time; % over untreated controls.
Long-ter~;l survivors ~> 60 days~
c Evaluated on the basis o:E autoptic findings on dead mice
Table 8. Effect on sensitive and sloxorubicin-resistant P388
leukemia in vitro.
Compound ID50 (n~/ml~ Re
P388 P388/DXd
DNR 5~8,2,3 950,350 163,152
Ia 0.35,1.3 1.~,5 ~,3.8
a Data of two experiments~
Do9e ~ivin~ 50% reduction of cell number in comparison with
untreated controls.
c P388 leukemia cells sensitive to DX
d P388 leukemia cells resistant to DX
Ratio between ID50 on P388/DX and ID50 on P388
-15-
Table 9. Activiiy of Ie againsi mamary carcinoma of C3-I mice -
Tumored mice Non tumored mice
Compound mg/kg~day ~umor a T/C~ MsTc T/cd deaihse
weigni % g6
~mg)
651 115.5 0/10
DX 6.0 238 37 149 129 1/10
7.5 209 32 100 87 7/10
Te o~ 6 422 65 118 103 0/10
0.75 263 40 126.5 110 0/10 ~
g3
Evaluated 1- wee~ arie~ ihe last irea~ment, ~y caliper measurement.
~ Tumor weight of ireaied mice/t~mor weight of controls, x 100.
c Median survival t-~me ~days~.
d MST or treated mice/~,ST of conirols ~xlO0).
e Mice were observed for 90 days.
3~
Table 10. Effect of Ie and D~ against two transplanted colon
adenocarcinomas in mice
I'umor Stagea Scheduleb Compd. Dose %c T/cd Toxic e
(mg/kg) inhib. ~ deaths
Colon early q7dx4 DX 6 56217 0/10
26 7.5 82224 0/10
g.3 81161 9/10
Ie 0.6 81258 0/10
0.75 85227 0/10
0.9 93246 1/10
advanced q6dx3 DX 6 34 237 0/9
9 62237 4/9
Ie 0.6 48232 0/9
0.7 521~5 0/9
Colon advanced q7dx4 DX 6 65 92 0/10
38 83144 1/1~
Ie 0.6 55133 0/10
0.75 60129 0/10
0.9 8118~ 0/10
a Tlme o~ start oE treatment in respect to tumor development.
Days oE i.v. aclministration.
c % inhibition o tumor growth, as comparecl with untreated controls.
d Median survival time of treated mice/median survival time of
controls, x 100.
e Evaluation in non-tumored mice -treated in parallel and observed
for 90 days.
-17-
