Note: Descriptions are shown in the official language in which they were submitted.
wo 93/20818 ,~ 1 1 ;} ~ Pcrtusg3/03s96
SUBSllTU'TE,D INDOLIZINO[ 1 ,2--b]QUINOLINONE,S
Th,is application is a continuation-in-part of U.S. Serial No. 07/870,649,
filed on April 17, 1992, which is a continuation-in-part of U.S. Serial No.
07n83.063. filed on Octo,ber 25, 1991, which is a continuation-in-part of U.S.
Serial No. 07/606,216, filed on, October 31, 1990.
~ Sco~e of the Invention
'This invention relates to methods of treating v*al infections, antiviral
compounds, and pharmaceutical çompositions thereof. More specifically, this
16 invention relates to a method of treating viral infections, certain
indolizino[I,2-b]quinolinyl derivatives which have antiviral activity and 1.
pharmaceutical compositions thereo~.
',~
Back,~round -
Certain lH-pyrano[3',4':6,?~indolizino[1,2-b]quinolinones are known tO have
cytotoxic and antiviral activity. Carnptothecin is an example of such compounds. lt -
is a water-insoluble, cytotoxic alkal,oid produced by Campto~eca acuminata treesindigenous to China ,and Notha,~,od,vtes f~tida trees indigenous to India.
25 Cam~to~he~i~and its~close congeners are known to inhibit eukaryotic topoisomerase
I. In-fact, the cytotoxic and andtumor activity of carnptoth,ecin and its close
congeners results from inhibition of eukaryotic topoisomerase I (Ca,ncer Res. 19,~,
48, 1722, Mo,lec. Phar,macol. 1988, 34, 755). Compounds that are related in
structure to c~m,ptoth,ecin but do not inhibit eukaryotic topoisomerase I are not
30 cy~otoxic to mammalian cells and have no antitumor activity (J. Med. Chem. 1988,
32,:~15;~Cancer Res. 1989, 49, 1465; Cancer Res. 1989, 49, 4358).
A number of investigators have shown that camptothecin possesses antiviral
acivity. However, although camptothecin has demonstr~ted antiviral activity in in
vitro tissue culture systems. camptothecin and its close analogs that have a
3~ hydroxylactone moiety cannot be considered as useful in ~ivo antiviral agents
W O 93/20818 21 1 ~32 1 PC~r/US93/03S96
because they undesirably inhibit mammalian topoisomerase I, as well as host cellDNA replication, and are cytotoxic to mammalian cells. Furthermore, camptothecinis not an attractive candidate for drug development as an antiviral agent because of L
unacceptable dose-limiting toxicity, unpredictable toxicity, and poor aqueous
solubility, andlor unacceptable shelf life stability.
There is a need for new antiviral agents. Substituted
indolizino[1,2-b]quinolinones that lack the a-hydroxylactone moiety oÇ
camptothecin have been shown to be non-cytotoxic to mammalian cells and to lack
antitumor activity (Ann. Rev. Pharmcol. Toxicol. 1977, 17, 117; J. Med. Chem.
1989, 32, 715). This is because these compounds do not contain the essential
structural features re~uired to inhibit eukaryotic topoisomerase I. However, recently
we have found that certain substituted indolizino[1,2-b]quinolinones lacking the a-
hydroxylactone moiety do have antiviral activity but not the undesirable cytotoxicity
of camptothecin. Thus, such substituted indolizino[1,2-b]quinolinones are usefulfor treating viral infectlons.
S~,J~IAR,~I~ INVENTIQN
One aspect of the present invention provides a method for treating viral
infections comprising administering to an infected host in need thereof an effective
amount of a compound of Formula I, or a pharrnaceutically acceptable salt thereoÇ,
alone or in combination with a calTier -
g ,
R R
R ` ~ ~y
I
whcrein:
R7 is -H, -CN, Iower alkyl or -(CH2)nCH2V where n=0-3;
wo 93/20818 ~ 3 ~ Pcr/us93/o3596
R9 IS -H, -OR, -NRRl, -CN, -(CH2)nCH2V where n=0-3; -
R10is-H,-OR,-NRRl,-CN,-COR12,-CH(OH)R12,-0-(CH2)1 sCH2NRR1,
-OC(O)NRRI, 1,4' bipiperidine-1'-carboxy, -(cH2)ncH2v where n~0-3;
Y is -OH, -oCoR14 OP(O)(OH)R15 or -NRR1; -
R11 is -H or -OR;
R12 is -H or lower alkyl;
R13 is loweralkyl; ~:
R and R1 are independently selected from the group consisting of -H, -C
1~ alkyl, and, when R and R1 are substituted on nitrogen, R and R1 can be ¦ ~ ~
taken together to form a 5-7 membered saturated heterocyciic ring - .
containing the nitrogen; : :
R14 iS CR12R16R17;
-(CH2)nCH2Rl7 (where n=1-33; ;~
~J;
2~
3 ( ~H2R
..
- (where n=0 or 1, and CH2R17 can be substituted on the
30 phenyl at the 2, 3, or 4 position);
wo 93/20818 Pcr/us93to3s96
- 4
-o(CH2)nCH2R17 (where n = 1-3);
-NRR1;
6 -NH(CH2)nCH2R17 (where n = 1-3);
R15 is OH, OR18 or CH2NH2;
R16 is H or the side ehain of any naturally occuring a-amino acid;
R17 is NRR1 ~) N~N --N3N~
where X is any pharmaceutically acceptable anion;
i
R18 is lower alkyl;
16 ~O
X is -CH(OH)CH(OH)CH3, ~CHR3R4 or 6
Y is -CH3 or -CH20R2;
_
R2 is -H, -C(O)H, -CoR14~ or -P(O)(OH)R1S;
- ~-~ ~ R3 is -OH, -oCoR14, or -oP(o)(oH)R15;
,
R4 is -H, lower alkyl, or -OR; and
26
R6 is -H or lower alkyl.
- provided that: -
a) if one of R7, R9, R10 or R11 is other than -H, only one of the others
may be other than -H;
b) only one of R7, R9, R10 or R1 I may be -NRR1;
WO93/20818 21 t ~ i! PCl'~US93/03596
c) when X is -CHR3R4 and R4 is -OR, R3 is -OH;
d) when Y is -CH20R2, X is R
This invention also provides compounds having the formula of Formula I as
described hereinabove, except that: ;
a~ when R7, R9, R10, and Rl l are all -H and Y is -CH3, then X is not
-C(O)H, -CH20H, -C(O)CH2CH3. or-CH(OH)CH2CH3; and
b) when R7, R9, R10 and Rl 1 are all -H ar~d Y is -C~20C(O)H, then X
is not -C(O)CH2CH3.
Another aspect of the present invention relates to pharmaceutical
compositions comprising a compound of Formula I in combination with a
pharmaceutically acceptable carrier or excipient. ¦
In yet another aspect, the present invention relates to processes for making a
compound of Forrnula I.
.
DETALED DESCRIPllON OF THE INV~NTION
,
2û The following definitions are used throughout this patent application._ _ !
"Aliphatic" is intended to include saturated and unsaturated radicals. This
includes normal and branched chains, saturated or mono or poly unsaturated chains ¦
where both double and triple bonds may be present in any combina~ion. The phrase"lower alkyl" and "C1 6 alkyi'~ refer to an alkyl group of l to 6 carbon atoms in any
isomeric form, but particularly the normal or linear forrn. "Lower alkoxy" meansthe group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo. "Acyl"
means the radical having a terminal carbonyl carbon.
The phrase "5-7 membered saturated heterocyclic ring containing the
nitrogen" is intended to include saturated rings such as piperidine, pyrrolidine,
molpholine, piperazine, and~N-alkyl piperazine.
wo 93~20818 Pcr/us93/~3596
- 6 -
The ~erm " l ,4'-bipiperidine- l '-carboxy" is used to identify the following
radical:
~ ~N~ N--C--O--
Salts of any sort may be made from these compounds, provided that an
acidic group or a sufficiently basic nitrogen is present in the compound. Particularly
preferred are the phamnaceutically acceptable salts of the instant compounds. These
salts are defined as those which are acceptable in their application to a
10 pharmaceutical use, meaning that the salt will retain the biological activity of the
parent compound and that the salt wi1l not have untoward or deleterious effects in its
application and use in treating diseases.
Pharmaceutically acceptable salts are propared in a standard manner. The
parent compound, in a suitable solvent, is reacted with an excess of an organic or
15 inorganic acid in the case of acid addition salts of a base moiety; or an excess of
organic or inorganic base in the case where the parent contains an acid group.
Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, acetic acid, màleic acid, succinic acid and methanesulfonic acid.
Cadonic salts are readily prepared from alkali metals such as sodium, potassium,- 20 calcium, magnesium, zinc, copper or the like as well as ammonia. Organic bases
include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids,
caffeine, and the like.
- _ - The chemic~l nomenclature used tbroughout this patent application to name
the compounds of the present invention is in accordance with the structural formula
25 rèpresented as Formula II.
y '
~ ~
6 7 II ~
WO93/20818 f l 3 ', ci 2 ~': PCI/US93/03596
In the event that some combination of substituents creates a chiral center or another
form of an isomeric center in a compound of this invention, all fonns of such ;
isomer(s) are considered to be aspects of the present inventions. When a compound
of the present invention contains a chiral center, the present invention includes the ~ -
racemic mixture, the pure enantiomers, and any enantiomerically enriched mixturethcreof.
The present invention provides a method of treating viral infections
comprising administering to an infected host in need thereof an effective amount of
a compound of Formula I as described hereinabove, or a phannaceutically
acceptable salt thereof, alone or in combination with a carrier or excipient.
The present method is useful for treating viral infections in animals,
particularly mammals, most pàrticularly humans, caused by a broad vanety of DNA
replicating animal viruses. The present method is particularly useful in treating
viral infechons caused by herpes simplex virus, particularly herpes simplex virus
typc 1 (HSV1 ) and herpes simplex virus type 2 (HSY2), varicella zoster virus ¦ ~
(VZV), or cytomegalovirus (CMV) when the infected host is a mammal, ~ -
par~icuiarly when the infected host is~human.
A preferred method of treating viral infections according to the present
invention uses compounds of Formula IM1
20 _ "
~ y
~0
X is -CH(OH)CH(O~)(~H3, -CHR3R4, or R; and Y is -CH3 or -CH20R2,
25 Fo~mula IMl co~esponding to Folmula I wherein R7, R9, R10, and R1 } are each -
H and X and Y arc as ~esclibed herein. A more preferred method uses compounds
of Forrnula IMl~wlrere X is CHR3R4 where R3 is -OH, oCOR14 or
~0
oP(o)(oH)R~5 and Y is -CH3, where X is R where R6 is -H or lower alkyl
and Y is -CH3 or -CH20R2, or where X is -CH(OH)CH(OH)CH3 and Y is -CH3.
WO 93/20818 1 8 - P~r/US93~03596
~ "
Ano~her preferred method for ~eating viral infections according to the
present invention uses compounds of Formula IM2
R
IM2
Formula IM2 corresponding~to Formula I wherein R7, R9, and Rl 1 are each H, R10 :~
is as defined hereinabove for Fo~nula I except that R l0 is not -H, and X and Y are ~:
as defined hereinabove in Fonnula I. A more preferred method uses compounds of
Formula IM2 where R10 is -OR, -CN, COR12, or -(CH2)nCH2V; or X is -CHR3R4
where R3 is -OH. oCORl4 or OP(O)(OH)Rl5 and R4 is -H or lower alkyl and Y is
-CH3. or X is R where R6 is -H or lower alkyl and Y is -CH3 or CH20R2.
Yet another preferred method of use according to the present invention uses
compounds of Pormula IM3
R
Y
IM3
.
, .
- - Fonnula IM3 corresponding to Formula I wherein R7 and Rl 1 are each I :
- 20 -H, R9 and R10 are as defined hereinabove for Fo~nula I except that R9 and R10 ~ j :
=- - are each not -H, and X and Y are as defined hereinabove in Formula I. A more
preferr~d method uses compounds of Formula IM3 wherein R9 is -(CH2)nCH2V,
Rl0 is -OR, X is CHR3R4 where R3 is -OH, oCORl4 or OP(O)(OH)Rl5 and R4 is
Wo 93/20818 '~ Pcr/uss3/o3~96
_~0
-H or lower alkyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3 or
CH20R2.
Another prefeIred method of use according to the present invention uses
compounds of Formula IM4
C, '~`
IM4 -~
Fonnula IM4 co~esponding to Formula I wherein R9, R10 and Rl 1 are each -H, R7
10 is as defined hereinabove except that R7 is not -H, and X and Y are as defined
hereinabove in Fo~mula 1. A more prefe~red method uses compounds of Formula
IM4 where R7 is lower alkyl, -CN, or -(CH2)nCH2V; X is CHR3R4 where R3 is -
OH, oCOR14 or OP(O)(OH~R15 and R4 is -H or lower alkyl, or X is R
where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2.
Yet another prefe~ed method of use according to the present invention uses
compounds of Fonnula IM5
- - R9
IM5
~0
Formula IM5 corresponding tO Formula l wherein R7, R10 and Rl 1 are
wo93~2û818 21 ~ /13 PCr/US93/03596
- 10-
-H, R9 is as defined hereinabove for Forrnula I except that R9 is not -H, and X and
Y are as defined hereinabove in Forrnula I. A more preferred method uses
compounds of Fonnula IM~ where R9 is -OR, X is CHR3R4 where R3 is -OH,
~0
oCOR14 or OP(O)(OH)Rl5 and R4 is -H or lower alkyl, or X is R where R6
5 is -H or lower alkyl, and Y is -CH3 or CH20R2
Still another preferred method of use according to the present invention uses
compounds is represented by Fonnula IM6
~" J `~ y
IM6
Fonnula IM6 corresponding to FoImula I wherein R7, R9 and R10 are each H, Rl 1
is -OR, and X and Y are as deflned hereinabove in Fonnul~ I. A more prefeIIed
method uses compounds of Formula IM6 where R11 is OR, X is CHR3R4 where R3 ¦ -
~0
15 is -OH, oCORl4 or OP(O)(OH)R15 and R4 is -H or lower alkyl, or X is R
where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2. - ~ :;
The present invention also provides compounds having antiviral activity, and
pharmaceutically acceptable salts thereof, said compound having the structure -~
- --represented by Forrnula I hereinabove except that:
2~ ~ ~ a) when R7, R9, Rl0, and R l 1 are all -H and Y is -CH3, then X is not
-C(O)H, -cH2oH~ -CH(OH)CH(OH)CH3, -C~O)CH2CH3, or
-CH(OH)CH2CH3; and
b) when R7, R9, R10 and Rl 1 are all -H and Y is -CH20C(O)H, then X
is not -C~O)CH2CH3. ~ . .
- ,
wo 93/20818 ~ Pcr/uss3/o3s96
Prefe~Ted compounds of the present invention include those of Formula IN1
I ~ y
6 IN1
Formula IN1 corresponding to Formula I wherein R7, R9, R10 and Rl 1 are each -H, ~0
X is R where R6 is -H or lower alkyl, and Y is CH3 or CH20R2 (provided
R6 is not -CH2CH3 when Y is -CH3) or X is CHR3R4 where R3 is -OH, oCORl4
10 or OP(O)(OH)R lS and R4 is -H or lower alkyl (provided that R4 is not -CH2CH3 when R3 is OH), and Y is -CH3.
Compounds of Formula IN2 are also preferred according to the present
invennon
o
~ "1 ~
- X IN2
- Foiniula IN2 colTesponding to Formuia I wherein R7, R9 and Rl 1 are each -H, R 10
is as desc~ibed hereinabove for Forrnula I except that R10 is not -H, and X and Y
are as defined hereinabove for Formula I. More prefe~Ted compounds of Fonnula
~2 include those-where-R1~ is -OR, -CN, -COR12, or ^(CH2)nCH2V, and X is
CHR3R4 where R3 is -OH, oCOR14 or OP(O)(OH)R15 and R4 is -H or lower
Q,
alkyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2.
Another pFeferred group of compounds of the present invention is
represented by Forrnula IN3
wo 93/20~18 Pcr/us93/03~96
21~ 8 ` ~
R ~ 12-
IN3
Formula I~3 co~responding to Formula I wherein R7 and R l l are each -H, R5~ and5 R10 are as descnbed hereinabove for Formula I except that R9 and R 10 are not -H,
and X and Y are as defined hereinabove for Formula I. More prefe~red compounds
of Fo~mula IN3 include those where R9 is -(CH2)nCH2V, R10 is -OR, X is
CHR3R4 where R3 is -OH, oCOE~l4 or oP(o)(oH)R15 and R4 is -H or lower ;-
~6 1 ~-
yl, or X is R where R6 is -H or lower aL~cyl, and Y is -CH3 or CH;~OR2.
S~ll another prefeTred group of inven~ve compounds is represented by
Fonnula IN4 :
R
IN4 :~
.
Formula IN4 corresponding to Formula I wherein R9, R10 and Rl 1 are each -H, R7 ~;
is as desc~ibed hereinabove for Formula I except that R7 is not -H, and X and Y are
as defined hereinabove for Formula I. More preferred compounds of Formula IN4
include those compounds where R7 is lower aL~cyl, -CN, or -(CH2)nCH2V; X is
CHR3R4 where R3 is -OH, oCOR14 or oP(o~(oH)R15 and R4 is -H or lower
~
20 aLtcyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3.
WO 93/20818 r~ ~ PCI /US93/03596
Another preferred group of compounds according to the present invention is
represented by Formula IN5
_~Y
~ IN5 -
, .
Formula IN5 corresponding to Fonnula 1 wherein R7, R10 alld R11 are each -H, R9
is as described hereinabove for Formula I except that R9 is not -H, and X and Y are :~
as defined hereinabove for Formula I. More prefe~ed compounds of Formula IN5 j :
include those compounds where R9 is -OR, X is CHR3R4 wh`ere R3 is -OH,
oCOR14 or OP(O)(OII)R15 and R4 is -H or lower aLIcyl, or X is R where R6 , ~
is -H or lower alkyl, and Y ls -CH3 or CH20R2 ~ `
Yet a further group of preferred compounds is represented by Formula IN6
R ~ ~ Y
=
- - - - X
IN6
Formula I~6 correspondmg to ~ormula I wherein R7, R9 and Rl0 are each -H, R
is -OR, and X and Y are as defined hereinabove for Formula I. More preferred
compounds of Formula IN6 ar-e compounds where R 1 1 is -OR, X is CHR3R4 where
R3 is -OH, oCOR14 or oP(o)(o~)R15 and R4 is -H or lower aLkyl, or X is
R where R6 is -H or~lower alkyl, and Y is -CH3 or CH20R2
WO 93/20818 PCr/US93/03596
f`~ 3 2 ~;
- - 14 -
The following compounds are particularly preferred:
7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino[172-b]quinolin-9(1 1~)-one;
5 7-[1-[(3-arnino- 1-oxopropyl)oxy]propyl]-8-methylindolizino
[ 1 ,2-b]quinolin-9( 1 lH)-one;
8-methyl-7- [ 1 -[(2-pyITolidinylcarbonyl)oxy]propyl]indolizino -
[1,2-b]quinolin-9(1 lH)-one; ~-
' '''''''
7-[1 -~2-amino-3-( lH-imidazol-4-yl)- 1 -oxopropyl]oxy]propyl]-8-
methylindolizino[ 1 ,2-b]quinolin-9( 1 lhr)-one; ~:
7-[1-[(2-arnino-3-methyl- 1 -oxobutyl)oxy]propyl]-8-methylindolizino
. -: 15 [1 j2-b]quinolin-9(1 1H)-one;
7-[1-[(2-amino-2-methyl-1-oxopropyl)oxy]propyl3-8-me~hylindolizino[1 ,2-
b]quinolin-9(1 lH)-one; j
20 7-[1-~(aminoacetyl)oxy]propyl]-2-cyano-8-methylindolizino-
[1,2-b]quinolin-9(1 l*')-one;
8-methyl-7-[ 1 -[[(2-pyrrolidinylcar~onyl)aminoacetyl]oxy]-
propyl]indolizino[ 1 ,2-b]quinolin-9( 1 1H~-one;
8-methyl-7-[ 1 -~[(dimethylamino)acetyl]oxy]propyl]indolizino[ 1 ,2-b]quinolin-
9(1 lH)-one;
- - 7-[1-[[(1 ,4'-bipiperidin- 1 '-yl)acetyl]oxy]propyl]-8-methylindolizino[ 1 ,2-b]quinolin-
30~ 9(1 lH)-one;
- ~ 8-methyl-7-[1 -[(4-morpholinylace~yl)oxy]propyl]indolizino[1,2-b]quinolin-9(1 lH)-
one;
WO93/20818 `~J ~ '' PCl/US93/035~6
8-methyl-7-[1 -[[(4-methylpiperazin-l-yl)acetyl]oxy]propyl]indolizino[1,2-
b]quinolin-9(1 IH)-one;
7-~l-[[(l-imidazolyl)acetyl]oxy]propyl]-8-methylindolizino~1,2-b]quinolin-9
5 one;
8-methyl-7-[1-1(pyridinioacetyl)oxy]propyl]indolizino~1,2-b]quinolin-9(llH)-one ,
iodide;
7-[1-[[4-~(dimethylamino)methyl]benzoyl]oxy]pro~yl]-8-methylindolizino[1,2-
b]quinolin-9(llH)-one; :
~.
8-Methyl-7-~1-[[4-(pyridiniomethyl)benzoyl]oxy]propyl]indolizino[1,2-b]quinolin- ~ ~-
9(1 lH)-one trifluoroacetate;
- I :~
8-~[(~morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-
9(11H)-one;
i ,
7-~1-[~(aminomethyl)hydroxyphosphinyl]oxy]propyl~-8-methylindolizino
[1,2-b]quinolin-g(l 1H)-one;
12-[~(arninoacetyl)oxy~methyll-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-
9(11H)-one; ~ -
8-methyl-12-[[~4-morpholinoacetyl)~xy]méthylr-7-~1-oxopropyl)indolizino
[1,2-b]quinolin-9(1 lH)-one; - ~ ~
8-methyl-7-[ 1 -[(phosphono)oxy]propyl]inodlizino[ 1 ,2-b]quinolin-9(1 lH)-one; and
8-[t(dimethylaminoacetyl)oxy]methyl]-7-( 1 -ox~propyl)indolizino[ 1 ,2-b~quinolin-
9(11H)-one. -=~
Some compounds used in the method for treating viral infections according
to the present invention are known. The publications listed herein discussing the `
wo 93/20818 PCr/US93/03596
21 ~ 3 ~ ~
- 16-
preparation of such compounds are incorporated herein by reference. The
compounds of the present invention can be prepared by several means from known
starting materials or by adding the appropriate substituent to the starting materials ;
used in published synthetic methods for making camptothecin. The preferred
5 synthetic methods for preparing the inventive compounds are outlined in the
following reaction flow charts.
In general, the inventive compounds are prepared by opening the lactone
ring of carnptothecin or a camptothecin derivative which may have the desired R7 - ' -
R11 substituenttoobtainan8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin- ! :-
9(11H)-one. Alternatively, the lactone ring may be opened and then the R7 R1 1 ¦ -
substituents introduced. In yet another alternative method, an existing R7 R1 1 ` i
group is modified to obtain the desired compound. Once the lactone ring is opened, : :
the resulting X and Y groups may be further modified as needed to make the subject
compounds.
Starting materials are commercially available or can be made by published ¦ -
methods. Carnptothecin, 10-hydroxycamptothecin and 9-hydroxycamptothecin are
natural products. Camptothecin and 10-hydroxycamptothecin are available from
sources in the People's Republic of China. A 9-hydroxycamptothecin compound
which can be used as starting material for making some of the inventive compounds -
is described in Published Japanese Patent Application No. 59-51,289. The syntheses
of 9- and 12-nitrocamptothecins are described by Wall, et al. (J. Med. Chem. 1986,
29, 2358). A total synthesis of camptothecin is described by Wall, et al., J. Med. -
Chem 1980, 23, 554. The 1980 Wall, et al. synthesis can be used as a means to
int~oduce one or more R7 - R 11 substituents into the compounds of Formula I. This
involve~ m~if-9ing the Wall synthesis at the appropriate step in a manner which
puts in place the desired substituent, then continuing with the desc~ibed synthesis.
The ring-opening reaction is illustrated by Scheme 1. For the sake of
convenience7 all reaction schemes shown herein are illustrated with compounds
which are substitutcd with -H at R7 - R 11. However, these methods also apply tocompounds of the present invention having any other combination of R7 - R l 1
subsd~uenrs as dcfined herein above, including compounds in which one or more
subsdtuents may rcquire protection during chemical reactions and deprotection
thercafter, as is well-known to those of ordinary skill in the art.
wog3t~0818 ;~ I 1 8 ~ Pcr/US93~03596
- 17-
Scheme 1
/~ 2 ~o
Compounds of formula 1 are converted to compounds of formula 2 by ~`
heating the compounds in a high boiling, preferably unreactive, solvent such as
N,N-dimethylformamide or triglyme (tIiethylene glycol dimethyl ether).
As shown in Scheme 2 the keto group of compounds of formula 2 can be
reduced to give the corresponding hydroxy compounds 3 from which the halo
compounds 4 can be derived. The keto group also can be converted to an oxime
(compounds 5) which can In turn be reduced to give the primary amino compounds ¦
6. The keto group also can be convened to a ketal group such as a 1,3-dioxolane
- (compounds 7~ which are useful intermediates for further transformations). The
hyd~oxyl group of compounds 3 can also be acylated to produce esters, carbonates,
- and carbamates (8) or phosphorylated to produce phosphates and phosphonates (9) ;~
wherein~R20 and R21 are groups convertible into R14 and R15 respectively, by
either deprotection or further elabora~on by well-known methods.
- -- - -- .
.
, ' . _ .
.
WO 93/20818 PCr/US93/03596
;f 1 1 ~ 3 2 i
- 18 - :
Scheme 2
2 ~' ~ 3~il- .;~
~--OH R = hab ~R
NOH ~--NH2
~7 ~
',,
3 ~ ~N
8 ~ 20
~OOOR
~OP(O)~OH)R
- - _
wo 93/20818 i~ ~ 1. 8 .? '' ~ PcrtlJsg3/03sg6
.
As illustrated in Scheme 3, dehydration of alcohols 3 gives alkenes 10 which
can be hydroxylated ts:) diols 11. Oxidative cleavage of the diols generates
aldehydes 12 which may be covalently solvated by water or an alcoholic solvent tO
produce compounds of formula 13. Hydride reduction of compounds of formula 12
5 and 13 give the primary alcohols 14.
Scheme
.,
3 ~,r~ ~
,;/ ~)H j
H~
1 2
R o
13
0 a~2 OH
Also derived from carnptothecins are the a-hydroxy acids 15 which are
formed by hydrogenolytic cleavage of the lactone ring as shown in Scheme 4.
. . .
WO 93/208l~ P~r/US~3~03~96
-- .
Schemç 4
~ COOH ~
OH .~ .,
Some ring subs~ituents may be labile tO the conditions used in the preferred ~.
5 method of making compounds 2 as given in Scheme 1. To make compounds which
are unstable under ~hose conditions, ~he sequence set out in ~cheme S can provide ..
access to certain of those compounds or provide intermediates for making other
compounds. :-
' . .:
Scheme.5
~ o ~ o ~ o
16~ 1~ HJ~ ¦ -~
R' 2 R ~ R I ~:
HO~ H~
More specifically~ th~c~rbonyl group of compounds 16 is first protected as a
15 ketal ~17), and then the pyridine-ring is reduced to give compounds 18, for exarnple
with sodium cyanoborohydride in an acidic solvent such as acetic acid. Finally,
oxidation of compounds 18, for example by iodobenzene diacetate, gives the 2-
hydroxy ketals 19 which along with the keto compounds 20 derit~ed from the ketals
by acid hydrolysis can be used to make compounds with other substituents as
20 illustrated in Scheme~-
WO 93/20818 ~ 1 ~ 3 J ; '-~ PCr/US93/03596
- 21 -
Schem~
RO~ o
W~N~
,~0
1 2
12 R
R COQ
20 ..~ ~_
t2~
13 ~ R
R 05 ~(0)0
R' 2~
RR NC(Op~, ~ o
20 ~ ~N~--
~0
R-2
CF,S03
S R
W~ 93/~0818 PCr/US93/03596 ~:
~l83~
- 22
S~heme 6~on'~!
H2 NC~2~ 0 2 2~ o
28~ ~N~
Rt 2 o~ Rt 2
25 ~ X --
25 = ~ r I ~
32 ~
~----~ - O-- - OHC
34
13
R O
, -
25 _`~[;r~_COI~
R
WO93/20818 ;f i ~ ' P~tUS93/035~6
- 23 -
Sç~e~ç 6 (cQn't)
H~N~ ~ o H,N ~ ~ ~
R 0 12
R NH
R S02 N 3
H~ ~ ~ o R S02 NH
qO ~ W~4N4~4
R O
R.2 ¦
3
R CONH~ o R" CON
46----~ 0~
F~ O ~ 2
The compounds in Scheme 6 are prepared either by alkylation (compounds
21) or acylation (compounds 22, 23, and 24) of the 2-hydroxy ketones 20 or by
replacement of the 2-hydroxy group in the ketals (19) via the triflates (25).
Cyanation of the triflates following the method of Kosugi, M, et ai, Chem. Lett.1981, 69 gives compounds 26 which are hydrolyzed to compounds 2T - (~atalytic
hydrogenation of the cyano group of compounds 26 gives aminomethyl ketals 28
which upon hydrolysis gives the ketones 29.
Alte~atively, starting with the ~iflates (25), a carbonyl group can be
introduced onto the ring, for example by the procedure of Cacchi, S, et al,
W O 93/20818 PC~r/US93~03596 ~
,`.~183~-J -
-' ,
Tetrahedron Lett. 1986, 27, 3931. If an amine or alcohol is used, the corresponding
amides (30) or esters (32) are obtained which are then hydrolyzed to the respective
keto compounds 31 and 33. Reduction of the esters 32 with a hydride gives the
primary alcohols 34 which upon hydrolysis produce the keto alcohols 35 which can5 be acylated to give carboxylates, carbonates and ca}bamates or phosphorylated to
give phosphates or phosphonates by methods similar to those used for prepanng
such derivatives from compounds 3. Aldehydes (compounds 36) can be made by
oxidizing the alcohols 34 using a mild oxidant which gives the aldehyde in
preference to the acid (for example, MnO2). Deprotection gives the keto aldehydes
10 37-
Similarly, the triflates are converted to vinyl ethers 38 following the method
of Cabri, W., et al. (J. Org. Chem. 1990, 55, 3654), and then compounds 38 are .
hydrolyzed to diketones 39. Selective hydrolysis of the enol ether function in
compourids 38 produces the 2-keto compounds that can be reduced to secondary
16 alcohols from which the ketal groups can be removed and the alcohol function
acylated or phosphorylated as described for compounds 3.
Introduction of an amino group at the 2-position is accomplished by
hydrolyzing esters 32, conver~ing the resulting acids to acid halides (acid chlorides),
treating the acid halides vith sodium azide and heating those products followed by ! :
20 ~eatment with water to form the amines (40) which upon deblocking gives
compounds 41. These arnines can be alkylated (42), sulfonylated (44), or acylated
(46) by known means and then deprotected to compounds 43, 45, and 47, ~;
respectively. - ~
Compounds with a substituent at the 1-position that cannot be made by the
25 method of Scheme 1 can be made by USilfg the activating effect of the 2-hydroxy
group in compounds 19; the hydroxy group may be retained in the product or
removed. These preparations are illustrated in Scheme 7.
wo 93/20818 ,; ~ ~. " 3 ? ~1 Pcr/us93/o3s96
- 25 -
Scheme 7
~, o HO~
~N
R ~ halo
CN ~
CN
4i(1R~) HO~ ~
2 ~ ~
RR ~ RR N~
~R G~
R _.
Halogenation of compounds 19 is accomplished by stan~ard means to
6 praduce 1-halo ketals 48 which are cleaved to the corresponding ketones 49. Cyano
ketals 50 are prepared using the iodides (48) in the cyanation reaction described for
the synthesis of compounds 26. Cleavage of compounds 50 giw~corn-pounds ~1, or
alternatively, the hydroxy function can be removed from 50 by converting the
compounds to the co-~responding triflates 52 and then reducing them to compounds0 5~ L~, the method of . acchi, S. et al., Te~rahedron L:e~t. 1986, 2-7~5541. Hydrolysis
of ketals ~3 gives ketones 54.
The conversion of compounds 19 to compounds 5~is accomplished using
tetramethyldiaminomethane and an acid. The dioxolane protec~ing group can then
be hydrolyzed to obtain the keto compounds 56.
W O 93~20818 PCT/US93/03596 :~
2 i I i~
- 26 -
Methods for making compounds with different groups at the 7-position are
illustra~ed in Scheme 8. :~
~h~me Ps
~0~ o ~o
S2 a~3
58~ ~O
CN
~OF~ ' U~ C~ ~ ;
63 ~
- OH
Sa ~ r, ~
- NRR
NNR
sa ~ 3~
wo 93~208i8 ~ PCr/USg3/û3596
Scheme 8 (con't)
s~ ~ ~o
NPIR
R '0~ CH20H
~ ~, ~0
R,J,s R~3,s0
The hydroxy compounds 57 are made as described by Sugasawa, T., et al.,
Ch~m. Pharm. Bull. 1974, 22, 771. The ~iflates (58~ are prepared in the usual
manner. Reduction to compounds 59 is ca~Tied out by the same method used for
compounds S2. Cyanation of the triflates tO give compounds 60 uses the method
employed tO prepare compounds 26. Alkoxyvinylation of ~he triflates to give
compounds 61 is carried out as in the preparation of compounds 38; acid hydrolysis
of the vinyl ethers gives the ketones 62 which upon reaction with diazome~hane by
the method of Kametani, T., et al. (Heteroc~cles 1975, 3, 167) give methyl
derivatives 63 which are reduced by hydrides to the alcohols 64. Coupling of the _
triflates with 3-dialkylaminopropyne by the method of Echavarren, A. M.~an~Stil!e,
J. K. (J. Am. Chem. Soc. 1988, llO, 15573 gives compounds 65 which are
catalytically hydrogenated to compounds 66. Vinylation of the triflates by the
procedure of Chen, Q-Y. and Yang, Z-Y. (Tetratledron Lett. 1986, 2~, 1171) givescompounds 67 which are catalytically hydrogenated to ethyl compounds 68~
Carbonylation of the triflates in the prescnee of an amine or an alcohol by t~e
20 pr~ccdure used to make compounds 30 and 32 leads to amides 69 and ester~ 70,
- respectively. As descnbed for compounds 62, compounds 70 are methylated with
dhzomethane to give derivatives 71 which then are reduced to alcohols 72 by
hydrides~ Displacement of the ~iflate function from compounds 58 by thiols givessulfides 73 which are oxidized to sulfoxides 74.
.. . ~ . , , ~ ,, . ! . ' , . , ' ,: . . .. .
W O 93/20B18 P ~ /US93/03596
21 ~
- 28 -
Compounds with substituents in the 12-position are prepared as illustrated in
Scheme 9. '
Scheme 9
R " R
R R ~-
~ O ,~ O
112
R ' 2 o~ 17
NHCHzAr - NHCHzAr
~ ~o ~
R1 2 o~ R1 2 ~ ~
W0 93/208l8 ,~ Pcr/US93~03596
- 29-
Scheme 9 (con't)
_ R
C~2 NH2 C~l~ N~2
fH2 NRR R,
~,NRR ~NRR
R
NRR ~,NRR -
~5 \~
OR 1 3 1 3
WO93/20818 ;. ~ , PCr/US93/03596
- 30 -
Sch~me 9 (con't)
CH2 Os02 R 2 CN . CH2 CN
~ O ~ o ~ o ':
99 ~ 00
~H2 fNH2 ; i
100 > ~_ ~, ~N~
2 O~ ~
R R
CH2oR~3 CH2~13 i
99 ~N~ ~N~ ¦
~Xo~ R
Wo 93/208~8 PC~/US93/03596
12-Hydroxymethyl compounds 76 are prepared by the method of Miyaska,
T. et al. (~eterocycles 1981,16,1713) using ferrous sulfate, hydrogen peroxtde and
methanol with sulfuric acid. These alcohols are acylated or phosphorylated as
described for compounds 3 to produce carboxylates, carbonates and carbamates, orphosphates and phosphonates. Sirnilarly, 12-alkyl compounds 77 are prepared by
the method of Miyasaka, T. et al. (IJ.S. Pat. No. 4,399,282). Oxidation of
compounds 78, for example, with hyd~ogen peroxide in acetic acid, gives the N-
oxides 79 which upon heating with tosyl chloride in N,N-dimethylformamide gives
the 12-chloro compounds 80 that can be converted to many other compounds.
Heating of the chloro compounds with arylols, such as phenol, gives the 12-aryloxy
compounds 81 which upon deprotection give the ketones 82; i~, however, an
aminomethylarene is included in the reaction, the products are compounds 83 which
upon hydrolysis give keto compounds 84. Ille chloro substituent of compounds 80
can be replaced with an iodo group (85) by heating with potassium iodide in acetic
acid containing some acetic anhydride. The iodo derivatives are easily used in
various coupling reactions similar to those carried out with tnflates 25 and 58.Cyanation gives compounds 86 which are deblocked to ketones 87 or are reduced toaminomethyl compounds 88 which give ketones 89 upon hydrolysis. Likewise,
propynylamines 90 can be produced and then deprotected to compounds 91 or
catalytically hydrogenated to compounds 92 and 94 which are hydrolyzed to keto
compounds 93 and 95, respectively. Heating compounds 85 with sodium acetate in
acetic acid giYes the 12-hydroxy compounds 96 which can be aLkylated using ei~her
base and alkyl halides or diazoalkanes to give 12-alkoxy compounds 97 which upondeprotecdon afford ketones 98. The 12-hydroxymethyl compounds 76 can be
protected and then activated for displacement reactions by conversion to a s~lfonate-~
(99), for example, a mesylate. Cyanide displacement on compounds 99 giYes the
ketals 100 which upon hydrolysis give 12-cyanomethyl ketones 101. The cyano
ketals can also be redu~ed to aminoethyl compounds 102 that give ketones 103 after
hydrolysis. Treatment of sulfonates 99 with alcohols in the presence of bases gives
ethers 104 which can be converted to keto ethers 105.
The reactions illustrated in Scheme 9 for the 12-hydroxymethyl c~p-ounds
76 could likewise be applied to hydroxymethyl compounds 34 to produce
denvatives co~csponding to compounds 99 through 105.
As shown in Scheme 10, compounds 107, the open nng form of compounds
106, which are described in co-pending U.S. Ser. No. 071839,823, are acylated or
wo93~20818 ,'. ~ S J ~ PCI/US93/0359~ ~.
phosphorylated as describe~d for compounds 3 to give compounds ~08 and 109,
respectively. ~-
Sçheme 10
~N ~ CH2 OH
0~ ~0 1~ ~
123H 12~=
R R
O
107 ~ W~N~CH20COR 8
1 08 ~z~cO
R
~, O
07 ~ W` ~CH~OP(O)(OH)R
12
R
The compounds of the present invention exhibit antiviral activity and are
generally useful in treating DNA rcplicating animal virus infections, particularly
those caused by viruses in the herpes farnily. More specifically, these compounds
10 are useful in treating infections caused by the following human pathogens:
Herpes Simplex v~rus types 1 and 2;
Cytomegalovirus;
Varicella Zoster virus;
Epstein Ba~r virus; and
Papilloma virus (multiple types)
Infections caused by the following animal pathogens may also be treated w~th thepresent ~ompounds:
wo s3/20818 '~ PCr/US93/û3596
-33-
Equine Herpes virus;
Porcine Herpes ~n~s;
Marek's disease virus;
Feline Rhinotracheitis virus; and
6 Bovine Herpes virus.
Assa~ys
The assay used to test the compounds of the present invention for antiviral
10 activity was taken from the literature and was modified in well-known ways to adapt
it to currentiy available technology. A generalized descliption of the assay follows.
~ssay Procedure
Well plates were seeded with the appropriate cells at a concentration of
15 lxlO5 cells per well suspended in 0.5 mL of Earle's Minimum Essential Medium
(EMEM) containing 10% fetal bovine serum (~BS) and antibiotic and antimycotic
soludon. After- cells were 8~90% confluent (24 hours), old medium was removed
and washed with Hank's buffered saline solution (HBSS). CelIs were then infectedfor 1 hour at 37C with 100-200 plaque fonning units per well of a he~pes simplex
20 virus suspended in 250 mL HBSS. Following adsorption, the following were added:
A) 250 m~Jwell 2 x EMEM containing Human IgG
(ca 0.1 mg/mL; Sigma No. G-67633;
B) Z50 mL/well EMEM containing 10% FBS and antibiotic/antimycotic
solutioh;
C) 250 nL/well HBSS containing appropriately - ~
diluted compound.
i
After 24 48 hours ~optimum time determined by examination of the plaques
under microscope), old medium was aspirated off. Each well was stained with a `~
selected stain solution (0.5% crystal violet in MeOH:H20 7:3) and then rinsed with
water and air dried and plaques counted. Compound effectiveness was evaluated in -` -~
tenns of percent plaque reduction as compared to untreated, infected controls.
This procedure can be used to test compound efficacy against many viruses
3~ besides he~pcs simplex by simply modifying the cell type used in the first step to --
wo 93~20818 PCr/US93/03596
h :1 '. 8 3 ~ ~
match the virus being tested and following the procedure outlined above. Other cell
types which could be used in this assay include mouse mammary tumor cells,
human lung fibroblasts, sheep chorioplexus cells, and green monkey kidney cells.Other assays which are useful for determining the antiviral activity of the
5 present compounds include the following types: cell count, clonogenic, cytopathic
effect, dish-colony formation, microtiter-growth inhibition, thymidine incorporation
and yield reduction. Each of these well-known assays is in the literature and
selected assays are available cornmercially.
10 Pharmaceutical Com~ositions and Method of Treatment
The present invention provides a broad variety of compositions prepared
from compounds of the present invention. Such composieions have u~ility for
human and veterinary antiviral use, and for treating viral infections in plants, e.g.,
agricultural or ornamental seeds and plants. Such compositions comprise a caITier
15 which is acceptable for the intended end use together with at least one inventive
compound. Por example, in veterinary use, the carrier may be a liquid, or spray, or
may be formulated in a solid, non-degradeable or degradeable form for inser~ion in
the rumen. Por agricultural use, the compound can be mixed with a fertilizer, other
microbiocides such as fungicides, or insecticides and the like. The present
20 compounds may also be forrnulated in powders or sprays for application to plant
surfaces.
The pharmaceutical compositions of this invention comprise one or more
compounds of the present invention in admixture with an inert pharmaceutically
acceptable camer or diluent. Compositions may contain an effective amount of the25 inventive compound in one unit, such as in a single pill, capsule, or pre-measlLred
intravenous dose or pre-filled syringe for injection, or, as is frequently the case, the
composition may be prepared in individual dose forms where one unit, such as a
pill, contains a sub-optimal dose with the user being instructed to take two or more
unit doses per treatment. When the composition is presented as a cream, it contains
30 a discrete amount of drug and the user applies an effective amount of the cream one
or more ~mes until the disease is in remission or hasbeen~ffectively treated.
Concentrates for latcr dilution by the end user may also be prepared, for instance for
IV formuladons and muld-dose injectable formulations.
CarTiers or dilucnts contemplated for use in these compositions are generally
35 hlown in the pharmaceutical formulary arts. Reference to useful materials can be
.
.;
W0 93~2~818 ~ PCl /US93/~3~96
-35-
found in well known compilations such as Re~n~ PhaIm,aceutical Sciences,
Maclc Publishing Co., Easton, PA, 18042, USA.
The nature of the composition and the pharmaceutically acceptable camer or
diluent will, of course, depend upon the intended route of administration, for
exampls, by intravenous and intramuscular injection, parenterally, topically, orally,
or by inhalation.
For parenteral administration the phannaceutical composition may be in the
form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous
liquid suspension.
For topical administration the pharmaceutical composition may be in the
form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for
administration to the skin, eye, ear, nose or genitalia.
For oral administration the pharmaceutical composition may be in the form
of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
1~ The pharmaceutically acceptable carrier employed may be either a solid or
liquid. Exemplary of solid carriers are lactose, kaolin, terra alba, sucrose, talc,
gelatin, agar, pectin, acacia, magnesium stearate, mannitol, steasic acid and the like.
Ex~mples of appropriate pharmaceutically acceptable liquid carriers or
diluents include: for aqueous systems, water, for non-aqueous systems, ethanol,
glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid
paraffins and mixtures thereof with water. For aerosol systems, phannaceuticallyacceptable car~iers include dichlorodifluoromethane, chlorotrifluoroethane and
compressed carbon dioxide. Also, in addition to the pharmaceutical carTier or
diluent, the instant compositions may include other ingredients such as stabilizers,
andoxidants, preservatives, lubricants, suspending agents, viscosity modifiers and -
the li~e, provided that the additional ingredients do not have a detnmental effect on
the therapeutic action of the instant compositions. Similarly, the carrier or diluent
may include time delay materials well known to the art, such as glyceryl -
m~nostearate or glyceryl distearate alone or with a wax, ethylcellulose,
hydroxypropylmethylcellulose, methylmethacrylate and the like.
To obtain a stable water soluble dose form, a pharmaceutically acceptable ~
salt of a compound of the present invention is dissolved in an aqueous solution of an ~
organic or inorganic acid or base. If a soluble salt form is not available, the
inwntive compound may be dissolved in a suitable co-solvent or combinations
thercof. Examples of such suitable cosolvents include, but are not limited to,
wo 93/20818 PCr/US93/03596
~ 1 1 8 3 ~ ~
-36-
alcohol, pr~pylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the
like in concentrations ranging from 0-60% of the total volume.
It will be appreciated that the actual preferred dosages of the compounds of
the present invention used in the pharrnaceutical and other compositions of thisinvention will vary according to the par~icular complex being used, the particular ~-
composition formulated, the mode of adrninistration and the particular site, host and
disease being treated. These compounds are active in the concentration ranges oftwo commercial antiviral drugs, Cytovene (ganciclovir) and Zovirax (acyclovir).
For example, thc latter is manufactured in 200 mg capsules with instructions fortreating herpes simplex viruses by taking one capsule every 4 hours, but not to I ~ -
exceed 5 capsules per day.
In the following Examples, temperature is in degrees Centigrade (C).
Unless othe~wise indicated, all of the starting materials were obtained from
commercial sources. Without further elaboration, it is believed that one skilled in ¦ -
the art can, using the preceding description, utilize the present invention to its fullest
- extcnt. These Examples are given to illustrate the inYention, not to limit its scope.
Rcferencc is made to the claims for what is reserved to the inventors hereunder. ¦
~xam~
fi)-1-Methoxv-7~ hydroxy~rQ~y~:~nethylindolizinorl.2-blquinolin-9(1 lH)-one
- A solution of 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-
b~quinolin-9(1 1H)-one (5.0 mg, 15 11mol) in a mixture of MeOH (0.2 mL), CH2C12
(0.6 mL) and THF (0.2 mL) was treated with a single portion of sodium
b~rohydride (4.0 mg, liO ~mol). After sti~Ting at room temperature-for ~3 h, therçaction mixture was concentrated under reduced pressurç. The residue was treated
with 10% aqueous NH4Cl (350 pL) and allowed to stand at 4C overnight. The
solid which formed was collected by filtration, washed sparingly with H20 and
dried to afford the ~tle compound. lH NMR (CDC13/MeOH-d4) d 8.77 (s, lH),
7.69 (m, 2H), 7.59 (s, lH), 6.92 (dd, J = 6.8, 1.7 Hz, lH), 5.23 (br s, 2H), 4.89 (m,
lH), 4.05 (s, 3H), 2.24 (s,3H), 1.79 (m, 2H), 1.03 (t, J = 7.4~~, 3EI).- ~
.
WO 93~208]8 ~ J~ Pcr/us93/o3s96
Exam,?le,.~
f~ 2-Cvano-7-f1-hydroxv~ro~"vl)-8-~hy~ Qlizino~1~2-b~q~l~-9(1lH~-one
The title compound was prepared according to the procedure in Example 1
except using 2-cyan~8-methyl-7-(1-oxopropyl)indolizino~1,2-b]quinolin-9(11~)-
onc. lH NMR (CDC13/MeOH-d4~ d 8.29 (s, 1H), 8.32 (d, J=1.7 Hz, lH), 8.20 (d, J
= 8.9 Hz, lH),7.92 (dd, J = 8.8, 1.8 Hz, lH), 7.67 (s, lH), 5.30 (br s, 2H), 4.91 (m,
lH), 2.26 (s, 3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for
C20H17N32 H2O: C, 68-75; H, 5.48; N, 12.03, Found: C, 68.97; H, 5.26; N,
11.72.
Exam~le 3
~m~11-8-methvlindolizino~ 1.2-b]quino~i~n-9( l lH~-one
Hydrot~i~Qaçetate
3A. (+)-8-Methyl-7-rl-~[(1.1-dimethylethoxv)carbonyllamino3-
acetvlloxvlvro~yllindolizinoLl,2-b~quinolin-9!1:1H)-one
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]glycine (1.15 g, 6.6
rnmol) in CH2C12 (50 rnL) under an argon atmosphere was added 1,3-
dicyclohexylcarbodiim~ide (1.35 g, 6.5 mmol). After stirring at room temperaturefor 0.5 h, (i~-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(l lH)-one(1.0 g, 3.3 rnmol) was added followed by a few mg of 4-dimethylaminopyridine.
The resulting mixture was allowed to stir at r~om temperature overnight and tbenwas filtered. The filtrate was washed successively with 2.5% aqueous NaHCO3
2~ (100 mL), 0.1 N HCl (100 mL) and H20 (100 rnL), dried over sodium sulfate and
concentrated in vacuo. The solid residue was p~ified by column chromatography
on silica gel clu~ng with a solvent gradient of 0-2% MeOH/CH2C12 tO provide the
title compound. lH NMR (CDCl3) d 8.34 (s, lH), 8.21 (d, J = 8.8 Hz, lH),7.91, I
(d, J = 8.3 Hz, lH), 7.81, (m, lH), 7.63, (m lH), 7.32 (s, lH), 5.96 (apparent br t, J
= 7.0 Hz, lH), 5.25 (s, 2H), 5.03 (br s, lH), 4.15-3.94 (m, 2H), 2.36 (s, 3H), 2.04- `
1.84 (m, 2H), 1.44 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). Anal. Calcd for
C26H29N3O5-1/8 H20: C, 67.04; H, 6.33; N, 9.02. Found: C, 66.95; H, 6.54; N,
8.83.
wo 93~20818 Pcr/us93/03596
r~ l L ~ ?) ", .
-38-
3B. fi)-7-r 1-~(Ar~unoacetvl)oxyl~ vll-8-methvlindolizinor L2-b~quinolin-
9(1 l~)-one Hvdro~ifluoroaçetate To a stiIring suspension of (i)-8-methyl-7-[1-
[[[[(1,1- ,
dimethylethoxy)carbonyl]amino]acetyl~oxy~propyl]indolizino~ 1 ,2-b]quinolin-
9(11~)-one (1.15 g, 2.5 mmol) in 1,3-dimethoxybenzene (12 mL) under an argon
atmosphere was added trifluoroacetic acid (13 mL). After stirring for 1.5 h at room
temperature, the mixture was concentrated under reduced pressure. The residue was
dissolved in H20, extracted with Et20, filtered and lyophilized to afford the title
compound as a pale yellow solid. lH NMR (DMSO-d6) d 8.68 (s, lH~, 8.24 (m,
lH~, 8.13 (m, lH), 7.86 (apparent br t, lH), 7.70 (apparent br t, lH), 7.19 (s, lH),
S.91 ~apparent br t, lH), 5.26 (s, 2H), 4.02 (br s, 2H), 2.25 (s, 3H), 2.06-1.81 (m,
2H), 0.96 (t, J = 7.2 Hz, 3H). ~ Anal. Calcd for C2lH2lN3o3- CF3C02H 9/4 H20: ;
C, 53.33; H, 5.16; N, 8.11. Found: C, 53.09; H, 4.91; N, 7.74.
Exam~lç 4
(i)-7-rl-r(3-Amino-l-oxoprogvl~oxYlgrogYl!-8-methvlindolizino~l .2-b~quinolin-
9(1 lH)-one Hvdroacetate
4A. (~ethvl-7-rl-rr3-rr(l.l-~ethylethoxY)çarbonvllaminol-L
oxogro~ylloxvl~ro~vllin~olizinor 1 .2-bl~uinolir~-9( 1 1 H)-one
A mixture containing (:t)-7-(1-hydroxypropyl)-8-methylindolizino[ 1,2-
b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg,
0.06 rnmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate
(248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-
dichloroethane (S mL) under an argon atmosphere was heated~at reflux-for S d.
Thin layer chromatographic analysis at this time indicated that the reaction wasincomplete, so the mixture was transferred to a pressure bottle and heated at 90-
95C for 1 d. Afterwards, additional 4-nitropbenyl 3-~[(1,1-
dimethylethoxy)carbonyl]amino]propionate (248 mgt 0.80 rn~nol) and dry
triethylamine (222 rnL, 1.60 mmol) were added, and heating was continued for 13
d. Thc mixture was then purified by flash chromatogEaphy-ehl~ng with a solvent
gradient of 0-3% MeOH/CH2C12. The material tnat was i-soIated was recrystallizedfrom Et20 and dried in vacuo to afford the title compound, mp 15S-8~C. lH NMR
(CDCl3) d 8.35 (sl lH), 8.22 (d, J = 8.6 Hz, lH), 7.91 (d, J = 7.2 Hz, lH), 7.81 ~m,
lH), 7.63 (m, lH~, 7.32 (s, lH), S.90 (dd, J = 7.7, 6.1 Hz, lH), 5.26 (s, 2H), 5.02
WO93~20818 ff ,~ ,i, ;?` ~ PCr/US93/03596
-39-
(br s, lH), 3.44 (m, 2H~, 2.66 (q, J = 5.8 Hz, 2H), 2.02- 1.80 tm, 2H), 1.38 (s, 9H),
0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C27H31N3Os- 1/5 H20: C, ~7.40; H,
6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35.
4B. fi)-7-rl-r(3-Amino-l-oxopropvl)oxy~propyll-8-
methvlindolizino~1.2-bl~uinolin-9(l lhn-one Hvdroacetate
The title compound was prepared according to the procedure in Example 3B
except using ~+)-8-methyl-7-[1-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-
oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(l lH)-one with the product being
purified by reversed phase chromatography on Partisil 40 ODS-3 elu~ing with a
gradient of ~100% MeOH in H20 containing 1% ace~c acid. lH NMR
(CDC13/MeOH-d4) d 8.42 (s, IH), 8.20 (d, J = 8.4 Hz, lH), 7.96 (d, J - 8.3 Hz,
lH), 7.84 (m, lH), 7.67 (m, lH),7.43 (s, lH), 5.92 (dd, J= 7.7, 6.0 Hz, lH), 5.28
(s, 2H), 3.02 (br s,2H),2.69 (apparent br t, J = 5.9 Hz, 2H), 2.36 (s, 3H)~ 2.02 (s,
3H), 2.02-1.82 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). CIMS f~NH3, m/e, rel. int.) 378
(100) [(M+H)+]. AnaL Calcd for C22H23N3O3-C2H4O2-13/4 H2O: C, 58.11; H,
6.81; N, 8.47. Found: C, 58.22; H, 6.13; N, 8.10.
Exan~
8-Methvl-7-rl-r(-2-py~ dinylca~b-oDy~ o~ylpropyl]i~idolizino[l~-blquinolin- ! ,'`.
9(11~)-one Hvdrotrifluoroacetate and Separation of Isome~
: .
~
~A.~ (R.S~8-Methyl-7-[l-~rrS)l-~ unç~ethoxy~carbonyll-2- ~
. ~
~vrrolidinvlcarbonvl~oxv~ropyl~indo~i~L2-bl~iuinolin-9f l lH)-gnç
The title compound was prepared according to the procedure in Example 3A ~ ~ ~-
exceptusing N-[(l,1-dimethylethoxy)carbonyl~-L-proline,N,N'- - -
diisopropylcarbodiimide and (~)-7-(1-hydroxypropyl)-8-
methylindolizino[1,2-b]quinolin-9(11H)-one.
. ~,
58. (R~.s~-8-Methyl-7-rl-r(fs)-2-pvrrolidinvlcalbonvl)oxylpropvllindolizino ,i;
.2,-bl~uinolin-9(11~-one Hvdrotrifluoroacetate ~ - - ;
To a mixture rontaining (R,S)-8-methyl-7-[1-[[(S)l-[(l,1- ~ -
dimethylcthoxy)carbonyl~-2-pyrrolidinylcarbonyl]oxy~propyl]indolizino
[1,2-b]quinolin-9(1 lH)~ne (1.66 g, 3.3 mmol) in CH2C12 (50 mL) was added
t~ifluoroacetic acid (10 mL). The resulting mixture was allowed to stir at room
WO 93/2081 8 PCl /US93/03596
-40-
temperature for 1.5 h and then was concentrated under reduced pressure. The
residue was dissolved in H20 (150 rnL) and lyophilized to afford th~ title
compound as a mixture of diastereomers. lH NMR (D2O) d 7.68 and 7.64 (2 s,
lH), 7.45 and 7.36 (two d, lH), 7.33-6.95 (m, 3H), 6.94 and 6.91 (two s, lH), 5.93
(m, lH), 4.9-4.6 (m obscured by HOD peak), 4.2-3.9 (m, 2H), 3.S2 and 3.43
(overlapping m and t, 2H), 2.73-2.55 (m, lH), 2.45-1.95 (m, SH),2.12 and 2.06
(two s, 3H), 1.08 (m, 3H). Anal. Catcd for C24H2sN3O3- 11/4 CF3CO2H: C,
49.41; H, 3.90; N, 5.86. Found: C, 49.84; H, 4.16; N, 6.00. ~-
SC. (S)-8-Methyl-7-rl-rf(S~-2-~Yrrolidinvlcarbonvl)oxyl~ro~YIlindQlizino
rl.2-blQuinolin-9(11H~-one Hvdrotrifluoroacetate
The diastereomeric n~ixture of (R,S)-8-methyl-7-[1-~((S)-2-
pynolidinylcarbonyl)oxy]propyl]indolizino[ l ,2-b]quinolin-9(1 lH)-one was purified
by preparative chromatography (JY column packed with 2 kg 15-20 mm Vydac C 18
RP silica), eluting with 0.1/25n5 TFA/CH3CN/H20. The title compound was the
first to elute and was obtained after solvent removal under reduced pressure andlyophiliza~ion. lH NMR (D2O) d 7.99 (s, lH), 7.75 (d, J = 8.5 Hz, lH), 7.57 (m,
lH), 7.51 (d, J = 8.2 Hz, lH), 7.33 (m, lH), 7.20 (s, lH), 6.09 (dd, J - 7.9,5.6 Hz,
lH), 4.9-4.7 (m obscured by HOI) peak), 4.52 (d, J = 18.9 Hz, lH), 4.40 (d, J -
18.8 Hz, lH), 3.53 (t, J = 7.3 Hz, 2H)~ 2.75 (m, lH~, 2.45-2.08 (m, 5H), 2.30 (s,
--- 3H), 1.19 (t, J = 7.4 Hz,3H). Anal. Calcd for C24H25N3O3-2 CF3C02H 1/4 H2O:
C, 52.88; H, 4.36; N, 6.61. Found: C, 52.76; H, 4.50; N, 6.64.
SD. (R-)-8-Methyl-7-rl-r((S~-2-~vrrolidinYlcarbonvl)ox~l~ro~vllindolizino
[1.2-blquinotin-9(11~)-one Hvdrotrifluoroace~ate
The remaining fracdons from the separation process in Exampl~5C- were
combined and concentrated under reduced pressure. The title compound was
obtained after an additional pre~arative chromatographic separation using the
condinons in Example 5C. lH NMR (D2O) d 8.00 (s, lH), 7.68 (d, J = 8.5 Hz,
lH), 7.5~7.49 (m, 2H),7.32 (m, lH), 7.19 (s, lH), 6.09 (dd, J - 8.0, 5.2 Hz, lH),
4.93-4.67 9m obscured by HOD peak), 4.49 (d, J = 18.9 Hz, lH), 4.40 (d, J = 19.0Hz, lH),3.66-3.57 (m, 2H), 2.78 (m, lH), 2.47 (m, lH), 2~9 (~ 2H), 2.24 (s, 3H),2.15 (m, 2H), 1.17 (t,3H). Anal. Calcd for C24H2sN3o3- 7 CF3C02H-4 H20: C,
35.83; H, 3.17; N, 3.30. Found: C, 35.86; H,3.24; N, 3.64.
wo s3J2o8 1 8 ~ 1 ~ pcr/ Us93/o3~g6
--41--
5E. (R.S)-8-Methvl-7-rl-rrfR)-I-r(1.1-dimethvlethoxv)carbonyll-2-
~lidinylcarborly~ yl~ro~~ zino~l.2-blquinolin-9~1 lH)-one
To a mixture of N-l(1,1-dimethylethoxy)carbonyl]-D-proline (6.74 g, 31.3
mmol) in CH2Cl2 (47 mL) under an argon atmosphere was added
dicyclohexylcarbodiimide (3.22 g, 15.6 mmol). After stirring at room temperaturefor 2 h, the mixture was filtered and concentrated under reduced pressure to afford
N-[(l,l-dimethylethoxy)carbonyl]-D-proline anhydride. This was added to a
suspension of (i)-7~ hydroxypropyl)-8-methylindolizino[ 1 ,2-b]quinolin-9( 1 lH)-
one (1.S0 g, 4.9 mmol) and 4-dimethylaminopyridine (609 mg, 5.0 mmol) in
CH2Cl2 (450 mL), and tbe mixture was allowed to stir at room temperature under
an argon atmosphcre overnight. The reacdon mixture was washed with H20 (2x),
dried ovcr potassium carbonatc and concentrated under reduced pressure. The
rcsidue was purified by flash chromatography eluting with a solvent gradient of 0-
2% McOH/CHCl3 to afford tbc titlc compound.
:15 ! -
,
~E. (R.s3-8-Methyl-7-rl-!((0-2-~vrrolidinyl~bonyl3oxvl~ropvllindolizino . ~'
~1.2-b~qi~in-9(11H)-one Hydrotnfluo~s~
Thc titlc compound was prepared according to the procedurc in Example SB
except using (R,S)-8-methyl-7-~1-[[~R)-l-[(l,l-dimethylethoxy)carbonyl~-2-
20 pslr~lidinylcarbonyl]oxy~propyl]indolizino[l,2-blquinolin-9(11H)-one. lH NMR
was cssentially identical to that of the compound of Exarnple SB. Anal. Calcd for
C241{25N303 2 CF3co2H:- C, 53.25; H, 4.31: N, 6.65. Found: C, 53.07; H, 4.68;
N, 7.02.
..
25 SG. fR3-8-Mctl~yl-7-rl-r((R)-2-~ oxvl~ro~vllindolizl~o
rl~2-bl~uinolin-9f~ -onc Hvdrotrifluoroacetate - ~ ~
The title compound was obtaincd by separation of the diastereomers of
(R,S3-8-methyl-7-[1-[((R)-2-
pynolidinylcarbonyl30xy~propyl]indolizino~1,2-b]quinolin-9(1 lH)-one according tO - ~ , .;.
thc p ocedu~ in Example SC. Anal. Calcd for C24H25~303-3 CF3C02H H20: _ ¦
C, 47.19; H, 3.96; N, 5.50. Found: C, 47.24; H, 4.30; N, 5.83.
(S~-8-Methyl-7-r1-~ -2-~y~rolidinvlcarbonvl)~xy~o~vllindolizino
no~ un-one Hvdrotrifluoroacetate
'..:
W O 93/20818 PC~r/~S93/03S96
~ 1 1 3 3 ~?'~
-42-
The title compound was obtained by separa~on of the diastereomers of ~;
(R,S)-8-methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino
[1,2-b]quinolin-9(l lH)-one according to the procedure in Example SC. Anal. Calcd
for C24H25N3O3-8/3 CF3CO2H-H2O: C, 48.56; H, 4.12; N, 5.79. Found: C,
48.61;H,4.53;N,6.10.
Exam~le 6
(R.S)-7-rl-rr(S)-2-Amino-3-(lH-imidazol-4-vl)-1-oxopro~vl]oxylpro~vll-8-
methvlindolizjnQ~ ~lin-9(1 lH)-one Hv~o~ifluoro~te
6A. (R.S)-8-Methvl-7-rl-rr(S)-2-r~(1.1-dimethvlethoxv)carbonvlla~inol-3-(lH-
imidazol~-vl)- 1 -oxopropylloxvlpropvl~i7r~dolizinor l .2-b]quinQlin-9r l l hr)-one
The title compound was prepared according to the procedure in Example 3A
except using N,1-bisl(l,l-dimethylethoxy)carbonyl]-L-histidine, N,N'-
diisopropylcarbodiimide and (+)-7-(1-hydroxypropyl)-8-
methylindolizino[1,2-b]quinolin-9(l lH)-one. 7
f~ ~R.S)-7-~1-rr(S~-2-Amino-~-(lH-imidazQI-4-yl~-l-oxo~ro~vlloxvlpro~vll-8-
~thvlindolizino[1.2-blquinolin-9(11H)-one Hvdrotrifluoroacetate ~-~
The title compound was prepared according to the procedure in Example 5B
except using (R,S)-8-methyl-7-[1-[~(S)-2-[[(1,1-dimethylethoxy)carbonyl~amino]-3-
(lH-imidazol-4-yl)-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(1 lH)-one
and was purif1ed by preparadve MPI,C eluting first with 0.1 % TFA/H2O followed
by a solvent gradient of 20-50% MeOH in H20 containing 0.1% TFA. lH NMR
(D2O) d 8.64 and 8.35 (two s, lH), 8.22 (d, lH), 7.90 (d, lH), 7.70 (m, 2H), 7.45
(m, 2H), 7.20 (s, lH), 6.04 (m, lH), 4.9-4.6 (m obscured by HOD peak), 3.68-3.47(m, 2H), 2.23 and 2.19 (two s, 3H), 2.15-1.96 (m, 2H), 1.04 and 0.96 (two t, 3H).
An'al. Calcd for C~5H25N503-2.8 CP3CO~H: C, 48.18; H, 3.67; N, 9.18. Found:
C, 48.29; H, 3.93; N, 9.15.
3û
_
W~93/20818 ~.i $ ~ i PCr/US93/03596
- -43 -
Exam~le 7
(:t)-7-rl-~(2-Amino-3-methvl-1-oxobutvl)oxvlDropvll-8-
methvlindolizinor1.2-~lquinolin-9(11H)-one Hvdrotrifluoroa~etate
7A. (~ 8-Methvl-7-rl-rr2^rr(1.1-dimethylethoxv)carbonvll~ninol-~-methvl-1-
oxobut~lloxy]~ro~yllipdolizinorl.2-b~quinolin-9(11H)-one
The title compound was prepared according to the procedure in Example 3A
except using N-[(l,1-dimethylethoxy)carbonyl~-L-valine and (i)-7-(1- ~ -
hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. lH NMR (CDCl3)
d 8.34 (s, lH), 8.22 (m, lH),7.91 (d, J = 8.2 Hz, lH),7.80 (m~ lH), 7.62 (m, lH)9
7.34 (two s, lH), 5.94 (m, lH), 5.26 (s, 2H), S.04 ~two br d, J - 9.3 Hz, lH), 4.36
(two d, J = 4.5 Hz, lH), 2.36 (s, 3H), 2.4-2.2 (m, lH), 2.1-1.8 (m, 2H), 1.44 and
1.38 (two s, 9H), 1.00 (overlapping t and d, 9H).
7B. ~i)-7-rl-r(2-Amino-3-methvl-1-oxobutvl)oxvlpropvll-8-
methvlindolizinorl.2-bl~uinolin-9(11H)-one HYdro~ifluoroacetate
The ~itle compound was prepared according to the procedure in Example 3B
except using (t)-8-methyl-7-~1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-
methyl-1-oxobutyl]oxy]propyl]indolizino[1,2-b]quinolin-9(llH)-one. lH NMR
(CDCl3, MeOH-d4) d 8.3g and 8.35 (two s, lH3, 8.20-8.13 (m, lH), 7.94-7.81 (m,
2H), 7.66 (apparent br t, lH),7.41 (two s, lH), 6.0~ (m, lH), 5.25 (s, 2H), 3.98(two d, J = 4 4 Hz, lH), 2.55-2.36 (m, lH), 2.33 (s? 3H), 2.14-1.90 ~m, 2H), 1.15- -;
1.01 (m, 9H). Anal. Cald for C24H27N303-CF3C02H-7/4 H20: C, 56.67; H,
5.76; N, 7.63. Found: C, 56.65; H, 5.62; N, 7.29.
~5 --- -
.
Exam~le 8
(i~-7-r 1 -~(2-Amino-2-methvl- 1-oxo~ro~vl)oxvl~r~vll-8-methvlindolizinor 1 2-
b]quinolin-9(11~f)-one Hvdrotnfluoroa~etate `~
,
30 ~A. (i~-8-Methvl-7-rl-rr2-rr(1.1-dimethvlethoxY)carbonYlLaminol-2-m~hvl-1-
oxoDropvlloxvlpro~Yllindolizi~lor 1.2-bl~uinoli~-9f 11 H)-one
To a mix~ure containing 2-methyl-2-[N-
~dimetbylethoxy)carbonyl~aLmino]propionic acid (406 mg, 2.0 mmol) and
dicyclohexylca~bodiimide (432 mg, 2.0 mmol) in CH2C12 (3 mL) under an argon
35 atrnosphere were added (i)-7-(1-hydroxypropyl)-8-methylindolizino
wo 93/20818 Pcr/us93/03596
t J 1 .L 8 3
-44-
[1,2-b]quinolin-9(llH)-one (153 mg, 0.5 mmol) and 4-dimethylaminopyridine (25
mg). The resulting mixture was allowed to stir at room temperaturc for 4 d and then
was poured into CH2Cl2, washed successively with 5% aqueous NaHCO3, 0.5 N
HCl and H20, and dried over sodium sulfate. Removal of the solvent in vacuo and
5purification of the residue by column chromatography (silica gel) eluting with a ~;
solvent gradicnt of 1.5-5% MeOHlCH2C12 afforded the ti~le compound as an off-
white solid. lH NMR (CDC13) d 8.33 (s, lH), 8.20 (d, J = 8.9 Hz, lH), 7.90 (d, J = ;
8.3 Hz, lH), 7.80 (m, lH), 7.62 (m, lH), 7.33 (s, lH), 5.92 (dd, J = 7.5, 6.3 Hz,
lH), 5.25 (s, 2H), 5.10 (br s, lH), 2.38 (s, 3H), 2.08-1.82 (m, 2H), 1.56 (s, 3H),
101.55 (s, 3H), 1.41 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). ;
(~-7-rl-r(2-Amino-2-mothvl-1-oxoprovvl)oxvl~ro~vll-8-
~ethylindolizinorl.2-blquinolin-9(1 lH)-one Hvdrotrifluoroacetate
Thc title compound was prepared according to the procedure in Example 3B
15cxccpt using (+)-8-methyl-7-[1-~[2-[[(l,l~imethylethoxy)carbonyl~aminol-2-
methyl-1-oxopropyl~oxy~propyl]indolizinoll,2-b]quinolin-9(1 lH)-one. lH NMR
(DMSOLd6) d 8.67 (s, lH), 8.11 (m, 2H), 7.84 (m, lH), 7.70 (m, lH), 7.21 (s, lH),
5.85 (dd, J = 7.9, 5.8 Hz, lH), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s,
3H), 1.49 (s, 3H), 0.97 (t, J = 7.3 Hz, 3H). Anal. Calcd for
20C~sN303-CF3CO2H-2 H20: C, 55.45; H, 5.58; N, 7.76. Found: C, 55.85; H,
.19;N,7.83.
-
~ :
fi)-7~r 1 -r(Aminoacctvl)oxyl~ro~yll-2-cvano-8-meth~vlindolizinor 1 .2-blquinolin-
9(1 lH~-one H~drotrifluoroaçetate
9A. (~:)-2-Cvan~8-methvl-7-r 1 -rrrr( 1.1-
dim~thvlcthoxvkarbonvllaminolacetylloxvl~ vllindolizinor 1 .2-blquinolin-
9(1 lH)-onc
The title compound was prepared according to the procedure in Example 3A
cxcept using (:~2-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]~uinolin-
9(1 lH)-one.
9B. (i)-7-r1-r(Aminoacetvl)oxvl~ro~Y11-2-cvano-8-
35 m~~ zinorl~2-bl~uinolin-9(~ -one
W093~208l8 ~ 1 ~ 3 ` ~. 1 Pcr/uss3/o3s96
-45-
The title compound was prepared according to the procedure in Exarnple 3B
except using (~ 2-cyano-8-methyl-7-[1-~[~[(1,1-
dimethylethoxy)carbonyl~amino]acetyl]oxy3propyl]indolizino[ 1 ,2-b]quinolin-
9(1 lH)-one. lH NMR (DMSO-d6) d 8.81 (d, J = 1.5 Hz, lH), 8.77 (s, lH), 8.27 f~d,
J = 8.9 ~Iz, lH), 8.13 (dd, J = 8.9, 1.8 Hz, lH), 7.24 ~s, lH), 5.91 (apparent br t, J =
6.7 Hz, lH), 5.29 (s, 2H), 3.98 (br s, 2H), 2.26 (s, 3H), 2.05-1.81 (m, 2H), 0.96 (t, J
= 7.4 Hz, 3H). Anal. Calcd for C22H20N4O3-3/2 CF3C02H-H20: C, 52.00; H,
4.10; N, 9.70. Pound: C, 52.04; H, 4.32; N, 9.73.
~xample 10
f:t~-7-rl-r(Aminoacetvl)oxvl~ro~vll-12-cvano-8-methylindolizino~1.2-~lquinolin- -:
- 9(11~)-one Hydrotrif~uoroacetate
10A. (:~:)-12-Cvano-8-methvl-7-rl-rrrr(1.1- , ~-
~im~l~hQ~carbonYllaminolacetylloxylpropyllindolizino~ 1 .2-b]quinolin- 1 -
9fll~)-ol~.e
The title compound was prepared according to the procedure in Example 3A
exceptusing (i~12-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin- , ~-
9(1 lH)-one. lH NMR (GDC13) d 8.31 (d J = 8.5 Hz, lH), 8.27 (d, J = 8.3 Hz, lH), -
7.95 (m, lH), 7.84 (m, lH), 7.32 (s, lH), 5.95 (apparent br t, J = 7.0 Hz, lH), 5.43
(s, 2H), 5.0 ~br s, lH), 4.03 (m, 2H), 2.38 (s, 3H), 0.99 (t, J = 7.4 Hz, 3H).
10B. (+)-7-rl-r(Aminoacetvl)oxvl~ropvll-12-cvano-8-
methylindolizirlD~1.2-bl~inolin-9(1 lH)-one Hyd~otrifluoroacetate
25 - ~ - - ~ --:T~-e tIde compound was prepared according to the procedure in Example 3B
- except using (i)-12-cyano-8-methyl-7-[1-l[[[(1,1-
dimethylethoxy)carbonyl]amino3acetyl~oxy]pr~pyl]indolizino[1,2-b]quinolin-
9(1 IH~-one. lH NMR (CDCl3/MeOH-d4) d 8.28 (d, J = 8.5 Hz, lH), 8.22 (d, J =
- 8-.4 Hz, lH), 7.95 (m, lH), 7.82 (m, lH), 7.36 (s, lH), 6.00 (apparent t, J = 6.6 Hz,
1H), 5.41 (s, 2H), 3.92 (br s, 2H), 2.33 (s, 3H), 2.08-1.82 (m, 2H), 1.00 (t, J = 7.2
3~1). Anal. Calcd for C22H2oN4(:)3 3/2 CF3co2H 5/2 H20: C, 49.67; H,
4.42; N, 9.27. Found: C, 49.41; H, 4.23; N, 9.29.
..
wo 93/20818PCr/US93/03~96
f 1 18.-, ?, 1
-4~
Exam~le 1 1
(R.S)-8-Methvl-7-rl -rr(S~-(2-~vrrolidinvlcarbonvl)aIninQacetvlloxvl- -
,Dro,Dyllindolizinorl.2-b]quinolin-9(1 lH~-one Hv~ro~rifluorQacetate
1 lA.fR.S~8-Methvl-7-r1-rrrr(S~1-rt1.1-dimethvle~oxv~carbQnyll-2-
,Dyrrolidinvlcarbonvllarninolacetv!loxvl~yllindolizinor 1 .~-bl-quinolin-9f 1 1~- ~ ~
one ~:
The title compound was prepared according to tne procedure in Example SE
except using (i)-7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino
~1,2-b]quinolin-9(1 lH)-one.
1 lB. fR.S)-8-Methvl-7-rl-rr(S)-(2- :~
~vrrolidinvlcarbonyl~ami~oacetvlloxvlDro~vllindolizinor 1 .2-blquinolin-9( 1 1~)-Qne
The dtle compound was prepared according to the procedure in Example 5B
except using (R,g)-8-methyl-7-11-[[[[(S)l-[(1,1-dimethyle~hoxy)carbonyl]-2-
pyrrolidinykarbonyl]amino]acctyl]oxy]propyl]indolizino[l,2-~uinolin-9(1 lH)-
one. Anal. Calcd for Ci6H2gN4o4 3/2 CF3C02~I-H20: C, 53.62; H, 4.89; N,
8.63. Found: C, 53.64; H, 5.29; N, 8.50. i
E~LLe l2
(+)-8-Methvl-7-rl-rrfdimethvlamin~a~etvllox~o~vllindolizinorl.2-blquinolin-
9(11H) one Hvdrochloride
~- 25 12A. (:0-7-r1-rrChloroacetyl)ox~opvll-8-methylindolizinQrl.2-blquinolin-
- - - 9(1 lH)~n~
To a suspension of (t)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-
b]quinolin-9(1 lH)-one (306 mg, 1.0 mmol) in freshly distilled CHCl3 (45 mL) were
added chloroacetic anhydride (205 mg, 1.2 mrnol), pyridine (80 mL, 1.0 mmol) and4 dime~hylaminopyridine (12.2 mg, 0.1 mmol). The resulting mixture, which
became homogeneous aftcr 20 min, was allowed to stir at room temperature
ov~night. The mixture was concentrated under reduced pressure, and the residue
was dissolved in CH2C12, washed successively with H20 (2x), 0.1 N NaOH and
H20 and dried over sodium sulfate. The solvent was removed in 1~acuo to afford
35 the title compound. lH NMR (CDCl3) d 8.35 (s, lH), 8.24 (d, lH), 7.93 (d, lH),
WO 93/20818 ~f ~ 2 ~ PCI`/US93/03~96
47 :
7.85 (m, lH),7.65 (m, lH),7.33 ~s, lH), 5.99 (dd, lH), 5.28 (s, 2H), 4.19 (s, 2H),
2.40 (s, 3H), 2.12-1.95 (m, 2H), l.OO (t, 3H). Anal. Calcd for C21HlgClN2O3-1/2
H2O: C, 64.37; H, 5.14; N, 7.15. Found: C, 64.29; H, 4.86; N, 6.82. , `
.
5 12B. f+)-7-rl-r(lodoacetvl)oxyl~ yll-8-methYlindolizinorl.2-blquinolin-
,9(1~ ,o"n,e -'
To a mixture of (_)-7-[1-[(chloroacetyl)oxy]propyl]-8-methylindolizino[1,2-
b3quinolin-9(l lH)-one (100 mg, 0.26 mmol) in acetone (10 mL) was added sodium
iodide (150 mg, 1.0 mrnol), and the resulting solution was heated at reflux for 1 h.
10 Upon cooling, a solid precipitate appeared. The solvent was removed in vacuo, and
thc residue was partitioned between CH2Cl2 and H2O. The organic extract was
washed with H20 (3x), dried over sodium sulfate and concentrated under reduced
pressure to afford the title compound. lH NMR (CDCl3) d 8.35 (s, lH), 8.22 (d, J= 8.2 Hz, lH),7.92 (d, J = 8.0 Hz, lH), 7.81 (rn, lH), 7.66 (m, lH),7.38 (s, lH),
5.91 (dd, J = 7.9, 6.0 Hz, lH), 5.26 (two s, 2H), 3.84 (d, J = 10.1 Hz, lH), 3.75 (d, I ~`
J = 10.1 Hz, lH), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C21H19IN203-1/2 H20: C, 52.19; H, 4.17; N, 5.80. Found: C,52.16;
H, 4.05; N, 5.39. ;~
12C. (i)-8-Methvl-7-rl-rr(dimethvlamino)ace~ylloxvl~ro~vllindolizinorl.2- `
b~uinolin-9(11H~-one Hvdrochloride
A stream of dimethylamine was introduced into a solution containing (+)-7
[1-[(iodoacetyljoxy3propyl]-8-methylindolizino[1,2-b]quinolin-9( l lH)-one (50 mg, !
0.11 mmol) in anhydrous CH2C12 (15 mL). The resulting solution was allowed to
stir for 2 h an~- then was-concentrated under reduced pressure. The residue was
partidoned bctween CH2Cl2 and H20, and the organic layer was washed several i --
times with H2O and dIied over sodium sulfate. Into this solution was bubbled a
stream of HCl gas, and the resulting cloudy mixture was stirred for 15 min and then
was concentrated in vacuo. The rcsidue was dissolved in H20 and Iyophilized to
afford thc dtle compound as an orange solid. lH NMR (DMSO-d6) d 8.68 (s, lH),
8.15 and 8.1~ ro overlapping d, 2H), 7.86 (m, lH), 7.71 (m, lH),7.17 (s, lH),
5.96 (apparcnt br t, lH), 5.26 (s, 2H), 4.41 (s, 2H), 2.84 (br s, 6H), 2.26 (s, 3H),
2.20~1.86 (m, 2H),0.96 (t, J = 7.3 Hz, 3H). CIMS (NH3, m/e, rel. int.) 392 (100)~(M+H)+]. Anal. Calcd for C23H25N303-2HCI-13/8H20: C, 55.96; H, 6.18; N,
8.51. Found: C, 56.27; H, 6.03; N, 8.04.
wo 93/20818 PCr/VS93/03596
~11 3~,?ii
-48-
E~camPl~ 13
(*)-7-~l-rrtl~4~-Bi~i~endin-l~-vl!acetyl~Qxy~ yl]-8-methylindolizinQcl~2
blquinolin-9(1 1~)-nne Hvdroiodidç
To a suspension of (+)-7^[1-[(iodoacetyl)oxy]propyl]-8-
methylindolizino[1,2-b]quinolin-9(1 1hl)-one (50 mg, 0.11 mmol) in CH2Cl2 (4
mL) was added 4-pipendinopiperidine (17.6 mg, 0.11 mmol3. A~ter sti~ring at roomtemperature for 3.5 h, thin layer chromatographic analysis indicated that the reaction
was incomplete,. Addi~ional 4-piperidinopiperidine (2.7 mg, 0.Q16 mmol) was
added, and sti~ring was continued for 2 d. The mixture was concentrated under
reduced pressure, and the residue was purified by eolumn chromatography eluting
wi~ a solvent ~ient of 0-100% MeOH in H20 containing 1% HOAc. The title
compound was obtained after lyophilization. lH NMR (CDC13~ d 8.35 (s, lH),
1~ 8.21 (d, J = 8.4 Hz, lH), 7.92 (d, J = 8.3 Hz, lH), 7.83 (m, lH~, 7.63 (m, lH), 7.34
(s, lH), 5.94 (apparent t, lH), 5.26 (s, 2H), 3.32 (s, 2H), 3.00- (br m, 2H), 2.37 (s,
3H), 2.~1.4 (m, 13H~, 0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C3 1H3gN4O3- 1/4HI-3/8 H2O: C, 67.28; H, 7.10; N, 10.12. Found: C, 67.67; H, 6.79; N, 9.69.
2~ Exam~le 14
$-Methvl-?-r1-r(4-mor~bolinylaççtyl)oxv~r~y~dolizino~1 .2-blquinolin-
9(11H)-one Hyd~ochloride -
The ~tle compound was prepared according to the proceduue in Example 13
- - 2~ except using (:t)-7-[1-[(iodoacctyl)oxy~propyl~-8-methylindolizino[1,2-b~quinolin-
- - 9(1 lH)-one and morpholine. lH NMR (CDC13/MeOH-d4) d 8.51 (s, lH), 8.26 (d,
J = 8.5 Hz, lH), 7.99 (d, J - 8.3 Hz, lH), 7.88 (m, lH), 7.70 (m, lH), 7.53 (s, lH),
5.98 (dd, J= 7.4, S.9 Hz, lH), S.30 (s, 2H), 4.29 (s, 2H), 4.02 (br s, 4H), 3.45 (br s
partially obscured by HOD peak), 2.33 (s, 3H), 2.10-1.87 (m, 2H), 1.03 (t, J = 7.4
30 Hz, 3H). Anal. Calcd for C2sH27N3O4 2HCl H20: C, 57.25; H, 5.96; N, 8.01.
- - Found: C, 57.37; H, 6.28; N, 7.65.
W0 93/208]8 .~ PCr/US93/03596
Exam~l 1 5
(*)-8-Methvl-7- r 1 -r ~¢4-methvl~iper~in- 1 -yl2acetvll~ro~yllindolizinor 1.2-
bJq~i~olin-9(1 1H)-on~Hydr~chl~ridç
The titlccompound was prepared according to the procedure in Example 13 `;
except using (i:)-7-~1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin- : `
9(11H) one and N-methylpiperazine. 1H NMR f~DMSO-d6) d 8.67 ~s, lH), 8.15
(m7 2H), 7.87 (m, lH), 7.72 (m, lH), 7.11 (s, lH), 5.84 (m, lH), 5.25 (s, 2H), 3.5-
2.6 (m, 13H), 2.23 f~s, 3H), 2.04 1.82 (m, 2H), 0.95 (t, J - 7.5 Hz, 3H). Anal. Calcd
for C26H30N403-2 HCl 9/2 H20: C, 52.00; H, 6.88; N, 9.33. Found: C, 52.12;
H, 9.1 1; N, 9.30. --
16
(i)-7-rl-rrf l-Imida2;01vl)acetylloxv~ vl~-8-metbylindolizin~ -bl~luinolin-
~(1 lH)^Q~ HvdrQ~hl~Lde
The ~ide compound was prepared according to the procedure in Example 13 i :
except using [~ 7-[1-[~iodoacetyl)oxy]propyl]-8-methylindoliz:ino~1,2-bJquinolin-
9(1 lH)-one and imidazole. lH NMR (CDC13/MeOH-d4) d 9.17 (s, lH), 8.60 (s,
lH), 8.34 (d, lH), 8.04 (d, lH), 7.95 (m, lH), 7.75 (m, lH), 7.61 (s, lH), 7.51 (br s,
lH), 7.41 (~r s, lH), 5.95 (m, lH), 5.65 (d, lH), 5.42 (d, lH), 5.33 (s, 2H), 2.36 (s,
3H~, 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C24H22N403-2 HCl- 11/4 H20: i -
C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29.
2~ - : ~cam~le 17
8-MethYI-7-r 1 -rrpyridinioacet~)oxyl~r~vllindolizinor 1 .2-blquinolin-9( 1 1 H~ one iodide
The title compound was prepared according to the procedur~ in Example 13
except using (+)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinoiin-
9(11*')~ne and py~idine~ (CDCl3/hIeOH-d4) d 9.09 (d, J = S.S Hz, 2H),
8.65 (t~ J = 7.9 Hz, lH~, 8.Si (s, lH), 8.17 (m~ 3H), 7.99 (d, J = 8.1 Hz, lH), 7.89
(m, lH), 7.70 (m, lH), 7.50 (s, lH), 6.ûS (d, J = 17.2 Hz, lH), 6.02 (m, lH).5.87
(d, J = 17.2 Hz, lH), 5.30 (s, 2H), 2.31 ~s, 3H), 2.18-1.94 (m, 2H), 1.09 (t, J = 7.4
wo 93/20818 PCr/uSs3/03s96
2~ 1 3,,, ,~
-50-
Hz, 3H). Anal. Calcd for C26H24IN303- 1/4 H20: C~ 55.97; H, 4.43; N, 7.53.
Found: C, S5.72; H, 4.30; N, 7.26.
~xam~le 18
5 (i~-7-r 1-rr~r(Dimethvlamino)methvllbenzQyl!oxvl~ro~vll-8-methvlindolizinor 1.2-
bl~uinolin-9(1 1H~-one Hvdrochlonde
18A. (t)-7-r1-rr4-(Chloromethvl)benzoylloxvl~ro~vll-8-methylindQlizinorl.2-
bl~uinolin-9f11H)-one
The title compound was prcpared according to the procedure in Example 3A
except using (i)-7-tl-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(1 1H)-
one and 4-(chloromethyl)benzoic acid. lH NMR (CDCl3) d 8.33 (s, lH), 8.16 (m,
3H), 7.91 (br d, J = 7.3 Hz, lH), 7.78 tm, lH), 7.61 tm, lH), 7.51 (d, J = 8.3 Hz, '
2H), 7.40 (s, lH), 6.11 (dd,J= 8.1, 6.1 Hz, lH), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s,
16 3H), 2.21-1.93 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Anal. Calcd for
C27H23ClN2O3-1/2 H2O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16;
N, 6.02.
I
18B. (+~-7-rl-rr4-r(Dimethvlamino)methvllbenzovlloxvl~ro~yll-8-
20 methvlindolizinorl.2-bl~uinolin-9fllH)-one Hvdrochloride
A suspension containing (:~)-7-[1-[[4-(chloromethyl)benzoylloxy3propyl]-8-
methylindolizino[l~2-b]quinolin-9(llH)-one (35 mg, 0.08 mmol) and sodium iodide
(57 mg, 0.38 mmol) in dry acetone (50 mL) was heated at reflux for 1 h and then
allowed to cool and s~r at room temperature overnight. Into this mixture
25 - dinlediyla-~nine was bubbled for several min, and the mixture was allowed to stir at
- rooni temperature for 1 h. The mixture was concentrated under reduced pressure,
and the residue was partitioned between H20 and CH2C12. The organic layer was
washed with H20 and dricd over sodium sulfate. The solvent was removed in
~-Yacuo, and the residue was purified by column chromatography eluting with a
solvent gradicnt of 0-5% MeoHlcH2cl2! The isolated material was treated with 3
H20 and 0.3 mL 0.1 N HCl and lyophilized to afford the title compound as a
beige solid. lH NMR (CDCl3JMeOH-d4) d 8.44 (s, lH), 8.26 (d, J = 8.3 Hz, 2H),
8.17 (d, J = 8.6 Hz, lH), 7.96 (d, J - 8.~ Hz, lH), 7.82 ~m, lH), 7.74 (d, J = 8.4 Hz,
2H), 7.66 (m, lH), 7.55 (s, lH), 6.14 (dd, J = 7.9, 5.8 Hz, lH), 5.28 (s, 2H), 4.31 (s,
3~ 2H), 2.80 (s, 6H), 2.44 (s, 3H), 2.20-1.95 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H). Anal.
w0 93/20818 ~ ;q PC~/US93/03596
':
-- : ~
Calcd for C2gH2gN303-3/2 HCl-712 H20: C, 59.51; H, 6.46; N, 7.18. Found: C,
59.91; H, 6.85; N, 6.85.
- ':.
Exam~le 19
(*~-8-Methvl-7-r l-rr4-~vndiniomethvl~benzovlloxylpro~vllindolizino~ 1.2-
bl~ginolin-9(11H~-one t~ifluoroacetate
.
To a suspension of (~)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-
b]~uinolin-9(1 lH)-one and (77 mg, 0.25 mmol) in py2idine (8 mL) under an argon
atmosphere was added 4-(chloromethyl)~enzoic acid (250 mg, 1.3 mmol). The
resulting mixture was iallowed to stir at room temperature for 2.5 d and then was
concentrated under reduced pressure. The residue was par~tioned between H20 and -
CH2C12. and the phases were separated. The aqueous phase was adjusted to pH 7.5
by the addition of 5% iaqueous NaHC03 iand re-extracted with CH2C12. The
16 aqueous layer was concentrated under reduced pressur~, iand the residue was applied
to a RP1g column and eluted with a solvent gradient of H20 to MeOH. The
material that was isolated was chromatographed two additional times on a RP1g
column, eluting with a solvent gradient of 0.1% TFA/H20 to 0.1% TFA/MeOH to
afford, ~ter lyophiliza~on, the ti~e compound. IH NMR (CDCl3/MeOH-d4) d
9.07 (d, J = 5.7 Hz, 2H), 8.46 (m, lH), 8.39 (s, lH), 8.23 (d, J = 8.2 Hz, 2H), 8.16
(d, J = 8.6 Hz, lH), 8.05 (m, 2H), 7.93 (d, J - 8.5 Hz, lH), 7.81 (m, lH~, 7.65 (m,
lH), 7.59 ~d, J = 8.2 Hz, 2H), 7.49 (s, lH), 6.13 (dd, J = 7.8, 5.9 Hz, lH), 6.00 (s,
2H), 5.27 (s, 2H), 2.42 (s, 3H), 2.2-2.0 (m~-2H), 1;08 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C34H2gF3N30s-5/2 CF3C02H 5/2 H20: C, 49.53; H, 3.78; N, 4.44.
Found: C, 49.53; H, 3.31; N, 4.27. - ~
(i:)-7-rl-rr((~hLoromethYl)hydrox~hos~hinvlloxYlpro~yll-8-methYlindolizinQ~l~2
b~uino!in-9~1 l~)-one 'r~ie~vlamine Salt
_
~o a suspension of (+)-7-(1-}~ydroxypropyl)-8-methylindolizino[1,2-
b]quinolin-9(1 1H)-onc (92 mg, 0.3 mmol) in CH2C12 (5 mL) under an argon
atmosphere was added Et3N (42 mL, 0.3 mmol) followed by
chloromethylphosphonic dichloride (31 mL, 0.3 mmol). The resulting mixture was
allowed to stir at room temperature for 2.5 d, and ~en Et3N (42 mL) and MeOH
WO 93/20818 PCI'/US93/03596
2 ~ , ? ,~
-52-
(200 mL) were added and stiITing was continued overnight. The mixture was
concentrated under reduced pressure, and the residue was par~tior.. d between H20
and CH2C12. The organic layer was washed with H20 (2x), and the combined
aqueous extracts were Iyophilized. The material that was obtained was applied to a
RP1g column, eluted with a solvent gradient of H20 to MeOH and lyophilized to
afford the title compound. lH NMR (CDCl3) d 8.27 (br s, lHj, 8.13 (m, lH), 7.9-
7.5 (m, 4H), 5.60 (m, lH), 5.19 (br s, 2H), 3.49 (br d, J = 10.2 Hz,2Hj, 3.05 (m,
~3H), 2.0-1.8 (m, 2H), 1.28 (t, J --7.3 Hz, ~5-6H)1.00 (t, J = 7.2 Hz~ 3H). Anal.
Calcd for C29H20ClN2O4P-1/2 C6H1sN-7/4 H20: C, 55.15; H, 6.24; N, 6.99.
Found: C, 54.94; H,5.81; N, 6.92.
Exam~le 21
f+)-7-r 1 -r(2-Cyanoethoxv)hvdroxy~hos~hinvl)oxvlyro~vll-8-methvlindolizinor1.2- b~ Qlin-9(l lH)-one Sodium Salt
(+)-7-(1-Hydroxyp~opyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one
(153 mg, 0.50 mmol),2-cyanoethyl phosphate (derived from 322 mg, 1.0 mmol of
the barium salt by the procedurc of Moffatt, J.G., J. Am. Chem. Soc. 1963, 85,
1118), and N,N'-dicyclohexylcarbodiimde (462 mg, 2.24 mmol) in dry pyridine (4.0- 29 mL) were heated at 45C for 24 h with exclusion of moisture. Water and MeOH
were added to the reaction, and the solvents were all stripped off in vacuo.
Additional H20 and MeOH were added along with NaOAc (1.02 g), an insoluble
soli~was removed by fil~a~on, and the solvents were stripped off again. The
residue was applied as an aqueous soludon to a reversed phase column of Partisil 40
ODS-3~and eluted with a gradient of 0-100% MeOH/H20 to give the ~itle
compound. lH NMR (MeOH-d4) d 8.58 (s, lH), 8.19 (d, J = 8.1 Hz, lH), 8.05 (dd,
J = 8.1, 1.0 Hz, lH),7.86 (m, lH), 7.71 (s, lH), 7.68 (m, lH), 5.54 (m, lH), 5.29
(s, 2H), 3.98 (m, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H), 2.07-1.88 (m, 2H), 1.10
(t, J = 7.4 ~z, 3H). Anal. Calcd for C22H21N3NaOsP- 15/4 H20: C, 49.96; H,
5.43, N,-7.94. Found: C, 49.95; H, 5.22; N, 7.63.
.
WO 93/20818 ~ PCr/US~3/03596
-53- ~-
Examl~le 22
-8-Me~hvl-7-r1-r(phos~hono~o~vlpro~Yllindolizin~[l~ir.olin-9(11H)-one
TnmethYlamine Salt
To (~ 7-~1-[(2-cyanoethoxy)hydroxyphosphinyl)oxy]propyl~-8- ~:
methylindolizino[1,2-b]quinolin-9(11H)-one sodium salt (89.4 mg, 0.19 mmol) in
MeOH (1.0 mL) was added lN NaOH (1.65 mL), and the reaction mixture was
stirred under argon for 7 h at room temperature. The reaction was acidified with lN
Ht 1 (1.75 rnL), stripped and redissolved in H20. This solution was applied of areversed phase column of Par~sil 40 ODS-3 and eluted with a gradient of 0-100%
MeOHlH20. After some of the dtle compound eluted as a sodium salt, another
~rac~on came off as mostly the free acid. The acid fraction was dissolved in MeOH,
and ~CH3)3N in MeOH was added to raise the pH to app~oximately 10. The MeOH
was stripped off, H2O was added and the solution was lyophilized to give the title j ~-
1~ compound as a partial sodium salt. lH NMR (MeOH-d4D20) d 8.58 (s, lH), 8.16(d, J = 8.5 Hz, lH), 8.04 (d, J = 8.3 Hz, lH), 7.85 (m, lH), 7.74 (s, lH), 7.68 (m,
lH), 5.50 (br dd, lH), 5.26 (s, 2H), 2.92 (s, ~6.5H), 2.33 (s, 3H), 1.gS (m, 2H), 1.08
(t, J = 7.4 Hz, 3H). Anal. Calcd for C19H1 gN20sP-3/4 C3HloN- 1/4 Na 9/2 H20: ,
C, 49.35; H, 6.72; N, 7.45. Found: C, 49.41, H, 6.43; N, 7.02.
., _
am~le ~3 :`~
(i)-7-rl-rr(Aminomethvl)hvdrox,vphQ~binylloxvlpropvll-8-m~thvlindolizinorlæ-
b~uinolin-9(1lh~)-one
23A. (+)-7-~1-rrrrr(9-
nuorenvlmethoxv~carbonvll~uninolmethyllhvdroxy~hosphinvlloxY~ro~vll-~-
m~do~izinorl.2-bl~uinolin-9fl 1~)-one
T~e title compound was prepared according to the procedure in Example 21
exceptusing (+)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b~quinolin-9(11H)-
oneand[[[(9-~uorenylmethoxy)carbonyl]amino]methyl]phosphonicacid. Anal. !
Calcd for C35H32N306P-9/8 H20 C, 65-~49;-H, -5.38; N, 6.55. Found: C~ 65.83;
H,5.28;N,6.14.
~B. (il-7-r1-rr(Aminomethyl)hydrox~hosphinvlloxvlpro~11-8^
methvlindoli~inQfl~-bl~uinolin-9(1 lH)-one
r~s~
wo 93/20818 P~r/US93/03596
h 1 1 3 ~ 2 `1
- -54-
A mixture of Et2NH (10 mL) and (~ 7-[1-[[[[[(9-
fluorenylmethoxy)carbonyl]arnino]methyl]hydroxyphosphinyl]oxy]propyl]-8-
methylindolizino[1,2-b]quinolin-9(llH)-one (328 mg, 0.51 m~nol) was stirred at
room temperature in a capped vial for 3h. The reaction m~xture was str~pped to
5 dryness, and H20 was added. The this partial solution was extracted with EtOAc,
filtered and lyophilized to give a viscous oil which was triturated with CH3CN to
produce a golden solid. The solid was dissolved in H20 and lyophilized to give the
title compound as a par~al Et2NH salt. lH NMR (FDCl3/MeOH-d4) d 8.49 (s,
lH), 8.12 (d, J = 8.7 Hz, lH), 8.00 (d, J = 8.3 Hz, lH), 7.84 (m, lH), 7.69
10 (overlapping s and m, 2H), S.S9 (dd, J = 14.9, 6.5 H z, l H), 5.27 (s,2H), 2.98 (q,J
= 7.2 Hz, ~1.lH), 2.85 (dd, J = 12.7, 2.6 H z, 2H), 2.31 (s, 3H), 2.02-1.83 (m, 2H),
1.31 (t, I - 7.3 Hz, -1.8H), 1.05 (t, J = 7.4 Hz, 3H). Anal. Calcd for
C20 H 22 N 3 O 4P-1/4 C4 H ll N-S H 2 O: C, 49.68; H, 6.90; N, 8.97. Found: C,50.08;
H, 6.49; N, 8.46.
~IP.le...24
12-rr(AminoacetYl~oxYlmethvll-8-methyl-7-(1-oxo,~ro~vl)indolizinorl .2-
bl~uinolin-9f 11H)-one HvdrofluorQacetate
24A. 8-Methvl-12-rrrrr(1.1-dimethvlethoxv)carbonvllaminolacetylloxvlmethvll-
l-(l-oxo~ vl)indolizinorl.2-blquinolin-9(l lH)-one
The title compound was prepared according to the procedure in Example SE
.. .
exceptusing 12-(hydroxymethyl)-8-methyl-7-(1-oxopropyl)indolizino[1,2-
b~quinolin-9(11H)-one and N-[(l,1-dimethylethoxy)carbonyl]glycine.
.4B. 12-rr(ArninoacetvnoxYlmeth~rll-8-methY1-7-(1-oxo~ro~vl~indolizinorl~2-
blquinolin-9(l lH)-one Hvdrotnfluoroacetate
The title compound was prepared according to the procedure in Example 5B
except using 8-methyl-12-[[[[[(1,1-
30 dimetnylethoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(1-oxopropyl)indolizino~1,2-
bJquinol~n-9~1H)-one. lHNMR (D2olDss) d 7.6-7.3 (m, 4H), 6.64 (s, lH), 5.58
(s, 2H), 4.58 (s,2H), 4.20 (s,2H), 2.92 (q, J = 7.2 Hz, 2H~, 1.94 (s, 3H),1.22 (t, J =
7.2 Hz, 3H). Anal. Calcd for C22H21N304-CF3C02H-H20: C, 55.07; H, 4.62; N,
8.03. Found: C, 55.32; H, 4.69; N, 7.98.
W O 93/2081~ f~ PC~r/US93~b3596
.
Exam~le ~5
8-Methyl-12-rr(4-morpholinoa~e~l)oxvlmethvll-7-(1-oxQDro~vl)indolizino~1.2- .
hl~uinolin-9(1 lH)-on~Hv~rochlolide
To a suspension of 12-hydroxymethyl-8-methyl-7-(1-
oxopropyl)indolizino[l,2-b]quinolin-9(1 lH)-one (523 mg, 1.56 mmol) in anhydrousCH2C12 (58 mL) at room temperature under an argon ahnosphere was added
snhydrous pyIidine (130 yL, 1.61 mmol) and 4-dimethylaminopyridine (19 mg,
û.16 mmol). The reaction was stirred for 10 min and then was treated with
iodoacetic anhydride (554 mg, 1.57 mmol) in one portion. After 1 h the turbid
orange soludon was treated with morpholine (815 yL, 9.4 mmol) and stirred for 1 h.
The reaction rnixture was filtered to remove morpholine hydroiodide, and the
filtrate was concentrated in vacuo at 15C and punfied by flash chromatography
eluting with 2% MeOH in CHCl3 to give, after removal of solvent, a yellow powderwhich was suspended in H20 (10 mL~ and ~eated with 0.1N HCl (16 mL) to give a
pH of 1.7. The resulting slu~ry was ~lltered and washed with MeCN followed by
Et20 to give the ti~le compound as yellow f~akes(, mp. 148-150C ~dec.). lH NMR
(CDC13) d 8.22 (d, J = 8.6 Hz, lH), 8.11 (d, J = 8.6 Hz, lH), 7.84 (m, lH), 7.70 (m,
lH), 7.25 (s, lH), 5.77 (s, 2H), 5.50 (s, 2H), 3.73 (m, 4H), 3.33 (s, 2H), 2.92 (q, J = -
7.6 Hz, 2H), 2.58 (m, ~H), 2.31 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H). Anal. Calcd for
C26H27N305 HCl l/2 H20: C, 61.60; H, 5.77; N, 8.29. Found: C, 61.62; H,
5.~4; N, 8.25.
~,
~m~le 26
8-rr(IXmethYlaminoacetvl)QxYlmethYll-?-(l-~2xoDro~yl)indolizinor~ bl~inQlin
9(1 IH~-one HvdrochloFide ~
26A. 8-rr(Iodoa~etvl)oxvlmethvll-7-(1-oxopropvliindolizinorl.2-blquinQlin-
9(1 1H)-one
To a suspension of (t)-3-ethyl-1,1 1-dihydr~3-hydroxy-3H,13H-
3a furo[3',4':6,7]indolizino[1,2-b]quinolin-13-one (320 mg, 1.00 mmol) in dIy CH2C12
(20 ~) under argon was added over 4 min diIsobu~ylaluminum hydride (1.10 rnL
of 1.0M in CH2C12). After 15 min iodoace~ic anhydride (530 mg, 1.~0 mmol) was
added in one portion. After 2 h, MeOH (10 mL) was added to the reac~ion, and
after sti~ing 20 min, the solvent was removed in vacuo. The residue was dissolved
in CH2Cl2 and chromatographed on silica gel eluting with a gradient of 0-5%
O 93/20818 PCr/US93/03596
r~
= -56-
MeOEVCH2C12 to give the title compound and some unreacted star~ng material.
lH NMR (CDC13) d 8.42 (s, lH), 8.24 (d, J = 8.4 Hz, lH), 7.96 (d~ J = 8.3 Hz, lH),
7.85 (m, lH), 7.69 (m, lH), 7.29 (s, lH), 5.33 (s, 4H~, 3.70 (s, 2H~, 2.99 (q, J = 7.2
Hz, 2H), 1.28 ~t, J = 7.2 Hz, 3H). CIMS (NH3, mJe, rel. int.~ 489 (100) [(M+H)+~.
5 Anal. Calcd for C21H17IN2O4-1/2 H2O: C, 50.72; H, 3.65; N, 5.63. Found: C,
50.53; H, 3.35; N, 5.45.
26B. 8-rr(Dimethvlaminoacetvl)o1~v!methYll-7-(1-oxo~ro~v~olizino~1.2-
bl~uinolin-9(1 lH)-one Hvdr~chloride
A suspension of 8-[[(iodoacetyl)oxy]methyl~-7-(1-oxopropyl)indolizino[1,2-
b]quinolin-9(1 lH)-onc (48.8 mg, 0.098 mmol) in dry CH2C12 (5.0 n~) was
covered by an atrnosphere of (CH3)2NH (balloon). Within a few min the solid had
dissolved and after 5 min the reaction was strippcd to dryness. The residue was
dissolvcd in CH2C12, washed first with 5% aqueous NaHCO3 and then with H20,
and dried over Na2S04. The sohent was removed in vacuo, and the residue was
suspended in H20 (20 rnL) to which was added lN HCl (100 ~1L) to dissohle most
of the solid. After fil~a~ion, lyophilizauon gave the ~tle compound. lH NMR
(CDC131MeOH-d4) d 8.47 (s, lH), 8.23 (d, J = 8.3 Hz, lH), 7.98 (d, J = 7.5 Hz,
lH), 7.87 (m, lH), 7.71 (m, lH), 7.44 (s, lH), 5.38 (s, 2H), 5.35 (s, 2H), 3.95 (s,
2H), 3.05 (s, 6H), 3.02 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). Anal. Calcd
for C23H23N3O4 HCl 7/4 H2O: C, 58.35; H, 5.86; N, 8.88. Found: C, 58.26; H,
5.51;N,8.68. -
!
Exam~le 27
8-rr(4-Mor~holiwace~vI~oxvlmethYll-7-fl-oxo~rogvl)indolizinorl.2-blquinolin-
- - 9f 1 l~-one Hvdrochloride
A suspension of 8-[~(iodoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino~1,2-
b]quinolin-9(11~)-onc (138.2 mg, 0.278 2r~nol) in dry CH2C12 (18 mL) containing
morpholine (75 ~, 0.86 mmol) was sti~red with moisture exclusion for 1.5 h, and
thcn H2O was~cd and the layers separatcd. The organic layer was washed
successively with H2O, 5% aqucous NaHCO3, and ~1nally H2O. After drying over
Na2S04~ the o~ganic layer was stripped to dryness, and H20 (50 mL) and lN HCI
(284 ~) were added to dissolve all the residue. Lyophilization gave the title
35 compound. lH NMR (CDC13/MeOH-d4) d 8.50 (s, lH), 8.23 (d, J = 8.6 Hz, lH),
WO 93/20818 ~ PCT/US93/03596
-57-
8.00 (d, J = 8.1 Hz, lH),7.88 (m, lH),7.72 (m, lH),7.47 (s, lH),5.37 (s,2H),
5.35 (s,2H),4.08 (br s,4H),3.99 (s,2H),3.50 (br s,4H),3.05 (s,6H)i 3.03 (q. J = `
7.1 Hz,2H),1.28 (t, J = 7.2 Hz,3H). An~. C~lcd for C25H25N305-5/4HCl-7/4
H2O: C,57.24; H,5.72; N,8.01. Found: C,57.17; H,5.33; N,7.62.
- -- = ::
