Note: Descriptions are shown in the official language in which they were submitted.
WO 94/19321 215 ~ ~ 2 ~ PCT/US94/01694
TITLE OF THE INVENTION
IN~BITORS OF HIV REVERSE TRANSCRIPTASE
s This application is a continuation-in-part of co-pending
application U.S. Serial No. 07/866,765 filed April 9, 1992, which itself
is a continuation-in-part of application U.S. Serial No. 07/832,260 filed
February 7, 1992 and now ~b~ndoned, which itself was a contiml~tion-
in-part of application U.S. Serial No. 07/756,013, filed
September 6, 1991, now ~b~n~iQned.
The present invention is concerned with compounds which
inhibit the reverse transcriptase encoded by human i~ odeficiency
ViIUS (HIV) or ph~ ceutically acceptable salts thereof and are of
value in the prevention of infection by HIV, the treatment of infection
by HIV and the tre~tm~nt of the resulting acquired ;,....-...-e deficiency
syndrome (AIDS). It also relates to pharmaceutical compositions
cont~inin~ the compounds and to a method of use of the present
compounds and other agents for the treatment of AIDS and viral
infection by HIV.
BACKGROUND OF THE INVENTION
A retrovirus design~ted hllm~n immunodeficiency virus
(HIV) is the etiological agent of the complex disease that includes
progressive destruction of the immlme system (acquired immlme
2s deficiency syndrome; AIDS) and degeneration of the central and
peripheral nervous system. This virus was previously known as LAV,
HTLV-m, or ARV. A common feature of retrovirus replication is
reverse transcription of the RNA genome by a virally encoded reverse
transcriptase to generate DNA copies of HIV sequences, a required step
30 in viral replication. It is known that some compounds are reverse
transcriptase inhibitors and are effective agents in the treatment of
AIDS and simil~r diseases, e.g., azidothymidine or AZT.
Nucleotide sequencing of HIV shows the presence of a ~1
gene in one open re~ding frame [Ratner, L. et ah, Nature, 313,
277(1985)]. Amino acid sequence homology provides evidence that the
-
WO 94/19321 PCT/US94/01694
21~642o
~1 sequence encodes reverse transcriptase, an endonuclease and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al.,
Science, ~, 1567 (1986); Pearl, L.H. et al., Nature ~2, 351 (1987)].
The compounds of this invention are inhibitors of HIV
reverse transcriptase. Furthermore, the compounds of the present
invention do not require bioactivation to be effective.
BREF DESCRIPTION OF THE ~VENTION
Novel compounds of formula A:
X~ .
\R6
as herein defined, are disclosed. These compounds are useful in the
inhibition of HIV reverse transcriptase, the prevention of infection by
HIV, the treatment of infection by HIV and in the treatment of AIDS
and/or ARC, either as compounds, ph~ ceutically acceptable salts
20 (when al,~ro~"ate), pharmaceutical composition ingredients, whether
or not in combination with other antivirals, anti-infectives,
;,.-.-..~,.omodulators, antibiotics or vaccines. Methods of treating AIDS,
methods of preventing infection by HIV, and methods of treating
infection by HIV are also disclosed.
2s
DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
This invention is concerned with the compounds of formula
A described below, combinations thereof, or pharmaceutically
30 acceptable salts or esters thereof, in the inhibition of HIV reverse
transcriptase, the prevention or treatment of infection by HIV and in the
treatment of the resulting acquired i"-.~ e deficiency syndrome
(AIDS). The compounds of this invention include those with structural
formula A:
WO 94/19321 2 ~ 5 6 4 2 ~ PCT/US94/01694
S R6
wherein
X is -H, -Cl, -F, -Br, -NO2, -CN, -oR2, -NR2R2, -NHSO2-
Cl 3alkyl, or -NHCO-Cl 3alkyl;
Y is S()n or -O-, wherein n is zero, 1 or 2;
Ris
1) -C1 salkyl, unsubstituted or substituted with one or more
of:
a) -C1 salkyl,
b) -Cl ~aLkoxy,
c) -OH, or
d) aryl, unsubstituted or substituted with one or more
of:
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2,
2) aryl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstituted or sul,sliluled with one or
more of:
i) -OH or
ii) -Cl salkoxy,
~, b) -Cl salkoxy,
3 o c) -OH,
d) halogen, or
e) -NR2R2
3) heterocycle, unsubstituted or substituted with one or more
of:
WO 94/19321 PCT/US94/01694
21~iS~?O
a) -Cl salkyl, unsubstituted or substituted wi~ one or
more of:
i) -OH or
ii) -Cl salko~y,
b) -Cl salko~y,
c) -OH,
d) halogen, or
e) -NR2R2, or
4) -NR2R3, provided that Y is ~S(O)n~;
zis
-NR2R3
W,
wherein W is O, S, -N-CN, or -N-OR2,
2) -COR1a,
3) -COOR1b,
4) -CR2R2-s(o)n-R 1 a,
wherein n is defined above,
S) -CR2R2NHR4,
6) -CR2R2-Co-R5,
7) -Cl 3alkyl substituted wi~ one or more of:
a) aryl, unsubstituted or substituted with one or more
of:
i) -Cl saLkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
WO 94/19321 % l ~; 6 4 2 ~ PCT/US94/01694
- v) -NR2R2, or
b) heterocycle, unsubstituted or substituted with one or
more of:
i) -Cl salkyl,
ii) -Cl salko~y,
iii) -OH,
iv) halogen, or
v) -NR2R2, or
8) -CN;
Rl is
1 ) hydrogen,
- 2) -Cl salkyl, unsubstituted or substituted with one or more
of:
a) -Cl salkyl,
b) -Cl salkoxy,
c) -OH,
d) aryl, unsubstituted or substituted with one or more
20 of:
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
2s v) -NR2R2, or
e) heterocycle, unsubstituted or substituted with one or
more of:
i) -Cl salkyl,
ii) -Cl salkoxy,
3 0 iii) -OH,
iv) halogen, or
v) -NR2R2, or
3) aryl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstitl-te~ or substituted with one or
more of:
WO 94/19321 PCT/US94/01694
21~6420
i) -OH or
ii) -Cl salkoxy,
b) -C1 salko~y,
c) -OH,
d) halogen,
e) -CN,
f) -NO2, or
g) -NR2R2; or
4) heterocycle, unsubstituted or substituted with one or more
of:
a) -Cl salkyl, unsubstituted or subsliluled with one or
more of:
i) -OH or
ii) -Cl_5alkoxy,
b) -Cl salkoxy,
c) -OH,
d) halogen, or
g) -NR2R2;
Rla is
1 ) -Cl salkyl, unsubstituted or substituted with one or more
of:
a) -Cl salkyl,
b) -Cl salkoxy,
c) -OH,
d) aryl, unsubstituted or substituted with one or more
of:
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2, or
e) heterocycle, unsubstituted or substituted with one or
more of:
WO 94/19321 215 o 4 2 ~ PCT/US94/01694
Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2, or
2) aryl, unsubstituted or sul,sliluted with one or more of:
a) -Cl salkyl, unsubstituted or subs~ led with one or
more of:
i) -OH or
ii) -Cl salkoxy,
b) -Cl salkoxy,
c) -OH,
d) halogen,
e) -CN,
f) -NO2, or
g) -NR2R2;
3) heterocycle, unsubstituted or substituted with one or more
of:
a) -Cl salkyl, unsubstituted or substituted with one or
more of:
i) -OH or
ii) -Cl salkoxy,
b) -Cl saLkoxy, or
2S C) -OH,
d) halogen, or
e) -NR2R2, or
4) C3 6cycloalkyl;
30 Rlb iS
1) -Cl salkyl subs~ ed with one or more of:
a) -C1 saLkoxy,
b) -OH,
c) aryl, unsubstituted or substituted with one or more
of:
WO 94/19321 PCT/US94/01694
~1564~0
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2, or
d) heterocycle, unsubstituted or substituted with one or
more of:
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2~
2) aryl, unsubstituted or subs~iluled with one or more of:
a) -C1 salkyl, unsubstituted or substituted with one or
more of:
i) -OH or
ii) -Cl salkoxy,
b) -Cl salkoxy,
c) -OH,
d) halogen,
e) -CN,
f) -NO2, or
g) -NR2R2; or
3) heterocycle, unsubstituted or substituted with one or more
of:
a) -Cl salkyl, unsubstituted or subsliluled with one or
more of:
i) -OH or
ii) -Cl saLkoxy,
b) -Cl salko~y,
c) -OH,
d) halogen, or
e) -NR2R2;
WO 94/19321 ~ 1 5 ~S ~ 2 ~ PCT/US94/01694
_ 9 _
- R2is hydrogenorCl 3aLkyl;
R3 is
1) -C1 salkyl, unsubstituted or substituted with one or more
of:
a) -C1 salkyl,
b) -Cl saLkoxy, unsu~sliluted or substituted with -OH,
c) -OH,
d) -oC(o)R7;
e) -COOR2
f) aryl, unsubstituted or substituted with one or more
of:
i) -Cl salkyl, unsubstituted or substituted with
one or more of -OH,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen,
v) -N2,
vi) -NR2R2
vii) -NHCO-C 1 3alkyl, or
viii) -NHS02-Cl 3aLkyl,
g) heterocycle, unsubstituted or substituted with one or
more of:
2s i) -Cl saLkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) C1 3alkyl-NR2R2,
v) halogen,
3 o vi) oxo,
vii) -N2~
viii) -NR2R2
ix) -NHCO-Cl 3aLkyl, or
x) -NHS02-Cl 3alkyl,
h) -NR2R2,
WO 94/19321 PCT/US94/01694
4 2 0
- 10-
i) -C3 6cycloalkyl,
2) aryl, unsubstituted or substituted with one or more of:
a) -Cl saL~yl,
b) -Cl salko~y,
c) -OH,
d) halogen, or
e) -NR2R2,
3) heterocycle, unsubstituted or substituted with one or more
of:
i) -Cl salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2,
4) -Cl salkoxy,
5) -OH,
6) -C3 6cycloalkyl, or
7) hydrogen;
R4 is
1) Rl or
2) -CORl;
R5 is
1) Rl,
2) -Cl salkoxy,
3) -NHRl, or
4) heterocycle, unsubstituted or substituted with one or more
of:
i) -Cl salkyl,
ii) -Cl salko~y,
WO 94/19321 PCT/US94/01694
- ~ 21~6420
- iii) -OH,
iv) halogen, or
v) -NR2R2;
R6 is
1 ) hydrogen,
2) -COR1,
3) -CONHR1;
R7 is
1 ) aryl, unsubsliluled or substituted with one or more of -Cl,
-Br, -OH, -OCH3, or-CN, or
2) -Cl salkyl, unsubstituted or substituted with one or more
of -OH or -NR2R2; and
with the proviso that when X is -H, Y is -S, R is unsubstituted phenyl
and R6 is -H,
Z is not -CH2-SO-Ph, -COH,
\ J or \~ ;
or a pharmaceutically acceptable salt or ester thereof.
One embodiment of this invention encompasses compounds
of Formula A further limited to:
30 X iS -H, -Cl or -F;
Y is -S()n~;
R is -Ph, -tolyl, 3-CI-phenyl, 2-pyridyl or 2-thiazolyl;
R6 is -H; and
WO 94/19321 ~ PCT/US94/01694
~1~6420
- 12 -
zis
-fj-NR2R3 -COOR1b -COR1a,
W
-CR2R2-S(O)n-R1a or
-Cl 3alkyl sul,~liluled with heterocycle.
One class of compounds within the first embodiment is
further limited to compounds wherein
X is -H or -Cl;
Y is -S()n~;
R is -Ph, -tolyl, 3-Cl-phenyl or 2-thiazolyl;
R6 is -H; and
zis
1 ) -fi-NR2R3
W,
wherein R2 is -H and W is -O, -S or -NCN, or
2) -CR2R2-SO-aryl, wherein the aryl group is
unsub~liluled or substituted with one or more of
Cl salkyl.
A sub-class of compounds within ~is class is fi~er
limited to compounds wherein
2s X is -Cl;
Y is -S()n~;
n is 1 or 2;
R is -Ph, 3-Cl-phenyl or 2-thiazolyl;
R6 is -H;
Zis
-f~ NR2R3
W,
wherein R2 is -H, and W is -O, -S or -NCN; and
WO 94/19321 PCT/US94/01694
2 ~
- 13-
- R3 is
1) -Cl saL~yl, unsubstituted or substituted with one or more
of
a) -Cl salkoxy, unsubstituted or substituted with -OH,
b) -OH,
c) -oc(o)R7~
d) aryl, unsubstituted or substituted with one or more
of:
i) -Cl saLkyl, unsub~liluled or substituted with
one or more of -OH,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
V) -NR2R2,
e) heterocycle, unsubstituted or substituted with one or
more of:
i) -Cl saL~yl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2, or
f) C3 6cycloalkyl,
2) heterocycle, unsulusliluled or substituted with one or more
2s of:
i) -C1 salkyl,
ii) -Cl salkoxy,
iii) -OH,
iv) halogen, or
v) -NR2R2,
3) hydrogen, or
4) C3-6 cycloalkyl.
WO 94/19321 PCT/US94/01694
~lS6 ~2~
- 14-
A second embodiment of ~is invention encompasses
compounds of formula A wherein X is selected from the group
consisting of:
1 ) -NR2R2,
2) -NHS02-Cl 3alkyl, and
3) ` -NHCO-Cl 3alkyl.
A third embotlimP-nt of this invention encompasses
compounds of formula A wherein Z is
-Ijj-NR2R3
W
and R3 is selected from the group consisting of:
1 ) C1 3aLkyl sub~liluled with phenyl wherein phenyl is
substituted with one or more of:
a) -NO2,
b) -NR2R2,
c) -NHCO-Cl 3alkyl or
d) -NHS02-Cl 3alkyl, and
2) Cl 3alkyl substituted with heterocycle, wherein heterocycle
is substituted with one or more of:
a) halogen,
b) oxo,
c) -NO2,
d) -NR2R2,
e) -NHCO-Cl 3alkyl, or
f) -NHS02-Cl 3alkyl.
30A fourth embodiment of this invention encompasses
compounds of formula A wherein Y is ~S(O)n- and R is -NR2R3.
The most preferred compounds of this invention are
compounds 1 ~rough 39, shown below.
WO 94/19321 PCT/US94/01694
_ ~156~29
- Compound 1:
SPh
NHCH2CH3
N-e~yl-5-chloro-3 -phenylthioindole-2-carboxamide
Compound 2:
SPh
Cl~ NHCH2CH20H
N-2-hydroxyethyl-5 -chloro-3 -phenylthioindole-2-carboxamide
20 Compound 3:
SPh
Cl~_ ~.NHCH2CH20CH3
H O
N-2-methoxyethyl-5 -chloro-3 -phenylthioindole-2-carboxamide
WO 94/19321 ~ 1 5 ~ o PCT/US94/01694
- 16-
Compound 4:
OCH3
SPh
o N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-carboxamide
Compound 5:
Cl~ NI1
N-4-pyridylmethyl-S -chloro-3 -phenylthioindole-2-carboxamide
Compound 6:
SPh N
CI~NHJ~
N-3 -pyridylmethyl-5 -chloro-3 -phenylthioindole-2-carboxamide
WO 94/19321 2 1 ~ G 4 2 0 PCT/US94/01694
- Compound 7:
SPh
Cl~ N--~3
N-2-furanylmethyl-5 -chloro-3 -phenylthioindole -2-carboxamide
Compound 8:
SPh
Cl~"NH~
N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxarnide
20 Compound 9:
S-Ph
CI~NH
H o
N-[ 1 -(2(R)-hydro~ypropyl)]-5-chloro-3-phenyl-thioindole-2-
carboxamide
WO 94/19321 ~ ~. PCT/US94/01694
~1 5~;~2~
- 18-
Compound 10:
S-Ph
Cl~ NHCH2~
N-(2-pyridyl)methyl-5-chloro-3 -phenylthioindole-2-carboxamide
Compound 11:
S-Ph OCH3
Cl~,NHCH2~N
N-(3 -methoxy~-pyridyl)methyl -5 -chloro -3 -phenylthioindole-2-
carboxamide
Compound 12:
S-Ph CH20H
Cl~NHCH2~
N-(3 -hydroxymethyl)benzyl-5-chloro-3-phenylthioindole -2-
30 carbo~amide
WO 94/19321 PCT/US94/01694
~6~2~
- 19-
- Compound 13:
S-Ph
Cl~[" NH2
S -chloro-3 -phenylthioindole-2-carboxamide
Compound 14:
S-Ph OH
Cl ~ N HC H2
H o
N-(3-hydro~ybenzyl)-5-chloro-3-phenylthioindole-2-carboxamide
20 Compound 15:
S-Ph
C~ ~NHcH
2s H S
N -2-furanylmethyl-5 -chloro-3 -phenylthioindole-2-thiocarboxamide
WO 94/lg321 PCT/US94/01694
6 ~ 2 i~
- 20 -
Compound 16:
S-Ph
Cl~" NH2
5-chloro-3-phenyl~ioindole-2-thiocarbox~mide
Compound 17:
\
S-Ph
Cl~NH2
H o
20 5-chloro-3-phenylsulfinylindole-2-carboxamide
Compound 18:
o
0~ 11
2s CI~NH2
H O
3 5-chloro-3-phenylsulfonylindole-2-carbo~mide.
WO 94/19321 PCT/US94/01694
- 2l~6~2a
Compound 19:
S Cl~0~,NHCH2~/ ~
N-[(l -methylimidazol-2-yl)methyl] -3-phenylsulfonyl-5-
chloroindole-2-carboxamide
Compound 20:
Cl~, NHCH
H CH3
N-[(1 -methylimidazol-2-yl)methyl]-3-phenylsulfinyl-5-chloroindole-2-
carboxamide
W O 94/19321 ~ ~ 5 6 4 2 0 PCTrUS94/01694
Compound 21:
o
~ NHCH2~-~N
N-[(1 -methylimidazol-4-yl)methyl] -3-phenylsulfonyl-5-
chloroindole-2-carboxamide
Compound 22:
O
O=S'
CI~NHCH
H CH3
N-[(1-methylimidazol-5-yl)methyl]-3-phenylsulfonyl-5-
chloroindole-2-carboxamide
WO 94/19321 PCT/US94/01694
2~ ~642~
- 23 -
Compound 23:
Cl
~
Cl~NHCH2~ ~
N-[(1-methylimidazol-2-yl)methyl]-3-(3-chlorophenyl-sulfonyl)-5-
chloroindole-2-carboxamide
Compound 24:
~[~NHCH2CH2~q
25 N-[2-(imidazol~-yl)ethyl]-3-phenylsulfonyl-5-chloroindole-2-
carboxamide
-
WO 94/19321 . PCT/US94/01694
21~6~2~
- 24 -
Compound 25:
s Cl~NHCH2CH2
N-[2-(1 -methylimi~1~7ol-4-yl)ethyl] -3-phenylsulfonyl-S-chloroindole-2-
carboxamide
Compound 26:
0
\\ Ph
Cl~ NH~
N-cyclopropyl-S -chloro-3-phenylsulfonylindole-2-carboxamide
WO 94/19321 PCT/US94/01694
6~2~
- 25 -
- Compound 27:
\\ Ph
CI~NH~
N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-carboxamide
Compound 28:
\\ Ph
Cl ~; NHCH2~;~
N-(3 -pyridylme~yl)-3 -phenylsulfonyl-5-chloroindole-2-carboxamide
WO 94/19321 PCT/US94101694
2 ~
- 26 -
Compound 29:
Cl~ NHCH2~N
o N-(4-pyridylme~yl)-5-chloro-3-phenylsulfinylindole-2-carboxamide
Compound 30:
~O~NHCH2~NH2
N-(3-aminobenzyl)-3-phenylsulfonyl-5 -chloroindole-2-carboxamide
WO 94/19321 2 1 5 ~ ~ 2 ~ PCT/US94/01694
Compound 31:
O S
O=S~N
s CI~NHCH2--Q
N-(3 -methoxybenzyl)-5-chloro-3 -(2-thiazolyl)sulfonyl-indole-2-
carboxamide
Compound 32:
O
~ CH,OH
N-[(S)- 1 -phenyl-2-hydroxyethyl] -5-chloro-3 -phenylsulfonylindole-2-
carboxamide
WO 94/19321 PCTIUS94/01694
- 28 -
Compound 33:
o
o=~ ~h ><~
N-[(R)- 1 -phenylethyl] -5-chloro-3-phenylsulfonylindole-2-carboxamide
Compound 34:
o
~ ~ ;NHCH2 ~ lNHSO2CHj
N-(3-methylsulfonylaminobenzyl)-3 -phenylsulfonyl-S-chloroindole-2-
carboxamide
WO 94/19321 ~ 3 PCT/US94/01694
- 29 -
Compound 35:
Cl~ 2
N-cyano-5 -chloro-3-phenylsulfonylindole -2-carboximid-amide
Compound 36:
O
CH3SO2NH ~NH2
3-phenylsulfonyl-5 -methylsulfonylaminoindole-2-carboxamide
wo 94/19321 PCT/US94/01694
~ S~2~
- 30-
Compound 37:
o
C ~ NHCH2~N--H
4-[(5-chloro-3 -phenylsulfonylindole-2-carboxamido)-methyl]pyridin-
2(1H)-one
Compound 38:
lS
Cl~NHCH2~N
N-(2-amino-4-pyridylmethyl)-5-chloro-3-phenylsulfonyl-indole-2-
carboxamide, and
WO 94/19321 ~ .1 5 ~ 4 2 ~ PCT/US94/01694
~ompound 39:
- Ph
S Cl~ NH <
N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide.
The compounds of the present invention may have
asymmetric cellters and occur as racemates, racemic mixtures,
5 individual diastereomers, or enantiomers, with all isomeric forms being
included in the present invention.
When any variable (e.g., aryl, heterocycle, R1, R2, R3,
etc.) occurs more than one time in any constituent or in formula A of
this invention, its definition on each occurrence is independent of its
20 definition at eve y other oc~ ce. Also, combinations of substituents
and/or variables are permissible only if such combinations result in
stable compounds.
As used herein except where noted, "alkyl" is intended to
include both branched- and straight-chain saturated aliphatic
2s hydrocarbon groups having the specified number of carbon atoms;
"aLkoxy" represents an alkyl group of indicated number of carbon atoms
attached through an oxygen bridge. "Halogen" or "halo" as used herein,
means fluoro, chloro, bromo and iodo.
- As used herein, wi~ exceptions as noted, "aryl" is intended
30 to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to
7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-
naphthyl, biphenyl.
WO 94/19321 PCTtUS94tO1694
~15642G
The term heterocycle or heterocyclic, as used herein except
where noted, represents a stable 5- to 7-membered monocyclic or stable
8- to 1 l-membered bicyclic heterocyclic ring which is either saturated
5 or lms~tllrated, and which consists of carbon atoms and from one to
three heteroatoms selected from the group consisting of N, O and S, and
wherein the nitrogen and sulfur heteroatoms may optionally be
oxidized, and the nitrogen heteroatom may optionally be quaterni7ed,
and including any bicyclic group in which any of the above-defined
o heterocyclic rings is fused to a benzene ring. The heterocyclic ring may
be attached at any heteroatom or carbon atom which results in the
creation of a stable structure. Examples of such heterocyclic elements
include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-
oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,
15 pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,
quinolinyl, isoquinolinyl, ben7imidazolyl, thi~di~70yl, benzopyranyl,
20 benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, benzofuranyl,
tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,
~iamorpholinyl sulfoxide, thiamorpholinyl sulfone, and ox~di~7.01yl.
Further abbreviations that may appear in this application
are as follows:
Me methyl
Et ethyl
Ph phenyl
BuLi butyllithium
n-Bu3P tri-n-butyl phosphine
LAH lil~.;l.,,l ~ll.. i.-.. -. hydride
DMF dimethylformamide
THF tetrahydrofuran
Et3N tri-ethyl~mine
MMPP monoperoxyphthalic acid, m~nesium salt
WO 94/19321 2~ ~z5 6 4 2 0 PCT/US94/01694
BOP-reagent ben_otria_ol- 1 -yloxytris-(dimethyl-
amino)phosphonium hexafluorophosphate
mp or m.p. melting point
The ph~rm~ceutically-acceptable salts of the novel
compounds of this invention that are capable of salt formation (in the
forrn of water- or oil- soluble or dispersible products) include the
conventional non-toxic salts or the quaternary ammonium salts of these
o compounds, which are formed, e.g., from inorganic or organic acids or
bases. F.~mples of such acid addition salts include ~cet~te, adipate,
~lgin~te, aspartate, ben70~te, ben7~nesulfonate, bissulfate, butyrate,
citrate, camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
15 glycerophosphate, hemisulfate, heptanoate, hex~no~te, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,
pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the
20 basic nitrogen-co.~t~ ig groups may be quaternized with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride,
bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;
and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl
and phenethyl bromides and others. Esters are also encompassed by the
present invention, and include those which would readily occur to the
skilled artisan, for example, Cl~ alkyl esters.
Schemes I-VIII for pr~il~g the novel con~l,out~ds of ~is
invention are presented below. Tables I - VII which follow the schemes
- 3 o illustrate the compounds that can be synthesized by Schemes I-VIII, but
Schemes I - VIII are not limiterl by the compounds in the tables nor by
- any ~li.;.llar substituents employed in the sch~mes for illustrativepurposes. The examples specifically illustrate the application of the
following schPmes to specific compounds.
WO 94/19321 PCT/US94/01694
2156~2~
- 34 -
Scheme I, below, is a general route for synthesizing, e.g., the
compounds shown in Table I, infra. The substituent groups (e.g., X, R,
Rl, etc.) employed in Scheme I correspond to the substituent groups as
5 de~lned in Table I, but Scheme I is not limite~l by the defined
substit~ t~ or compounds of Table I.
SCHEME I
SPh
X~ NaH, PhSSPh X~--CO2H
1 ) (co)2cl2~
CHCI3, ~ BOP-reagent,
or R2R3NH, DMF
2) R2R3NH
SPh
x~N\R32
111
As shown in Scheme I, commercially available indole-2-
carbo~ylic acid (or 5-chloro, 5-fluoro or 5-methoxyindole-2-carbo~ylic
acid) I is treated with an excess of sodium hydride in dimethyl-
formamide in the presence of an aryl disulfide such as phenyldisulfide at
0C to 60C, according to the general procedure described by
Atkinson, et al., in Synthesis, p. 480-481 (1988). The resulting product
II is reacted with oxalyl chloride in refluxing chloroform for about 30
WO 94/19321 2 ~ ~ 6 ~ 2 0 PCT/US94/01694
- 35 -
- millu~es to 1 hour to produce the corresponding acid chloride which is
then reacted with a primary or secondary amine in chlorofo.lll at 0C to
20C to give the amide m. Alternatively, amide m can be produced
g directly from II by treatment with BOP reagent (benzotriazol-1-
yloxytris-(dimethylamino)-phosphonium hexafluorophosphate) in the
presence of the desired primary or secondary amine and triethyl~mine,
in a solvent such as dimethyl-form~mide. Other carboxyl group
activating reagents such as l,l'-c~l,ollyl-diimidazole can also be used
for this step. Saponification of ethyl 5-chloro-3-benzylindole-2-
carboxylate (prepared as described below) by methods f~mili~r to those
skilled in ~e art, yields 5-chloro-3-benzylindole-2-carboxylic acid,
which can be converted to the desired amides in the m~nner described
for the synthesis of arnides m.
The compounds shown in Table II infra, are generally
synthesized as in Scheme I, except R1OH is used in place of R2R3NH, as
depicted in Scheme II below. The substituent groups employed in
Scheme II correspond to the substituent groups as defined in Table II,
but Scheme II is not limited by the defined substituents or compounds of
20 Table II.
WO 94/19321 : PCT/US94/01694
2:1 5 ~ 4 ? U
- 36 -
SCHEME II
X"~N C07H 2) R10H ~OR
H H o
Il IV
/ PhS-N
,~
~OR1 BF3-Et20/CHCI3
As shown in Scheme II, 3-phenylthioindole-2-carboxylic
acid II can be converted to the corresponding acid chloride with oxalyl
chloride in refluxing chloroform, and reacted with an alcohol to give
the ester IV. In an alternative procedure, Ia may be converted to IV by
reaction with N-phenylthio-succinimide in chloroform at room
2s ten.l,eldture with a Lewis acid, such as boron trifluoride etherate, as
catalyst (as shown in Scheme II). The con-yound ethyl 5-chloro-3-
benzylindole-2-carboxylate was ylc~&~ed according to the procedure
described by Inaba, et ah, in Chem. Pharm. Bull., 24, p. 1076-1082
(1 976).
Scheme m, below, is a general route for synthesizing, e.g.,
the compounds shown in Table m, infra. The substituent groups
employed in Scheme m correspond to the substituent groups as defined
in Table m, but Scheme m is not limited by the defined substituents or
compounds of Table m.
WO 94/19321 2 ~ 3 ~ 4 ~ G PCT/US94/01694
scHEME m
X~--C0 C H LAH X~CH20H
V Vl
n-Bu3P X~ CH2SPh
o PhSSPh,THF ~NH PhSSPh, DMF
SPh SPh
X~CH2SPh X~CH2SPh
NH CH30H-CHCI3 NRX 0
~Llll X Rx is H or CH3)
NaH
CH31, DMF / MMPP
/ CH30H-CHCI3
SPh
X~CH2SPh
CH3
IX
As shown in Scheme m commercially available ethyl
indole-2-carboxylate (compound V wherein X is -H) or ethyl 5-
chloroindole-2-carbo~ylate (compound V wherein X is -Cl), was
reduced to the primary alcohol VI with an e~cess of li~liu~il aluminum
hydride in tetrahydrofuran at 0C. Compound Vl was converted to the
sulfide VII by treatment with an excess of tri-n-butylphosphine and an
WO 94/19321 . PCT/US94/01694
~6 ~120
- 38 -
aryldisulfide such as phenyl-disulfide in tetrahydrorul~u. at 0C to 20C
for 6-24 hours. Reaction of sulfide VII with sodium hydride, an
aryldisulfide such as phenyldisulfide, in dimethylformamide at 0C to
5 20C for 1 to 18 hours produces bis-sulfide vm. Aryl disulfides which
were not commercially available were obtained by oxidation of the
commercially available aryl merc~tal- with dimethyl sulfoxide and
iodine, according to the procedure described by Orville G. Lowe in L
Or~. Chem.. 40, p. 2096-2098 (1975). Compound vm can be N-
aL~ylated, if desired, by methods f~mili~r to those trained in the art,
e.g., by treatment with sodium hydride in dimethylfonn~mide at 0C in
the presence of an alkylating agent such as iodomethane, to give
compound IX. Thereafter, compound vm (or IX) is treated with one
equivalent of peracid such as monoperoxyphthalic acid, magnesium salt
15 (MMPP), or meta-chloroperoxy-benzoic acid in methanol or
chloroform-methanol at 0C for 30 mimltes to 3 hours, to give
predomin~tely sulfoxide X.
Schemes IV-A and IV-B, below, show a general route for
synthesizing, e.g., the compounds shown in Tables IV-A and IV-B,
20 infra. The substituent groups employed in Schemes IV-A and IV-B,
respectively, correspond to the substituent groups as defined in Tables
IV-A and IV-B, respectively, but Schemes IV-A and IV-B are not
limited by the defined substituents or compounds of Tables IV-A and
IV-B.
WO 94/19321 ,2~1 5 6 4 2 ~ PCT~S94/01694
- 39 -
SCHEME IV-A
SPh SPh
~ BH, DMS
¦ `~ NHRl 3 ~ `~CH2NHR
--N T~ THF A ~ N
H o H
Xl 2~11
SCHEME IV-B
SPh 1I SPh H
pyridinc. CHCI3 ~CH2NCR
XII-A 2~Lll
As shown in Scheme IV-A, 3-phenylthioindole-
2-carboxamides XI can be reduced to primary or secondary amines XII
by reaction with an excess of borane-dimethylsulfide complex in
2s reflu~ing tetrahydrofuran for 6-24 hours. As shown in Scheme IV-B,
the ~lill-aly amine XII-A can be acylated with an acid chloride, such as
benzoyl chloride, in chloroform in the presence of pyridine, to give the
amide XIII.
- Scheme V, below, is a general route for synthesizing, e.g.,
30 the compounds shown in Table V-A and Table V-B, infra. The
substituent groups employed in Scheme V correspond to the substituent
groups as defined in Tables V-A and V-B, but Scheme V is not limited
by the defined substituents or compounds of Tables V-A and V-B.
WO 94/19321 PCT/US94/01694
- ~1S6~2~
- 40 -
SCHEME V
s ~CH3 NaH, PhSSPh~CH
o 1 ) n-BuLi
2) CO2
SPh SPh
1) t-BuLi ~CH3
XvlllH O 3 ~ CO2Li
_ _
1 ) t-BuLi
2) R1-NCO/H+
SPh
~ e
R6
XVII
WO 94/19321 2 ~ 5 ~ PCT/US94/01694
- 41 -
- As shown in Scheme V, commercially available 2-methyl-indole XIV can be treated with sodium hydride in dimethylform~mide
- in the presence of an aryldisulfide such as phenyldisulfide to give
5 compound XV. Compound XV can be converted to the monoanion with
n-butyl-li~hiull- in tetrahydrorul~l at -78C, and then reacted with
carbon dioxide to give carboxylate XVI. The dianion formed by the
reaction of XVI with t-butyllitl~ n could be reacted with an isocyanate,
such as phenyliso-cyanate, to give a mi~ture of monoacylated product
and diacylated product XVII (see Table V-B). Alternatively, the
dianion fonned by the reaction of XVI with t-butyllithium could be
reacted with an N-methoxy-N-methyl amide such as N-methoxy-N-
methyl-furan-2-carboxamide (prepared in a manner f~mili~r to those
skilled in the art, e.g., by the methods described in Scheme 1) to
produce ketones xvm. The methodology described above is essentially
that used by A. J. Katritsky and K. ~hlt~g~wa to prepare 2-indoleacetic
acids, and is published in J. Am. Chem. Soc.. 108, 6808 (1986).
Scheme VI, below, is a general route for synthesizing, e.g.,
the compounds shown in Table VI, infra. The substituent groups
20 employed in Scheme VI correspond to the substituent groups as defined
in Table VI, but Scheme VI is not limited by the defined substituents or
compounds of Table VI.
SCHEME VI
SPh SPh
3 -78Cto20C ~R
2~ 2Q~
As shown in Scheme VI, N-methoxy-N-methyl-3-phenyl-
thioindole-2-carboxamide XIX (or N-methoxy-N-methyl-5-chloro-3-
phenyl~ioindole-2-carboxamide) (prepared as in Scheme 1) can be
reacted with Grignard reagents (wherein Rl is not hydrogen) such as
WO 94tl9321 PCT/US94/01694
4 2 ~
- 42 -
phenylm~nesium chloride, in tetrahyrodrofuran at -78C to 20C for
18-48 hours, or XIX can be reacted with other organometallic reagents
well known in the art to one of ordinary skill, to produce ketones XX.
The compounds shown in Table VII infra, can generally be
synthesized by those of ordinary skill in the art according to methods
described in Sçhemçs I through VI, with the exception of 2-(2-
benzoxazol-2-ylethyl)-3-phenyl~ioindole (compound XXIV), the
synthesis of which is described below in Scheme VII.
SCHEME VII
SPh SPh
5~OCH -0C to 20C ~CH0
XXII
2eq.
THF ~_N
O
2s SPh SPh
H2, CH30H ~
N~-- ~ Pd/C ~ N~ N
H 0y~/ ~ H 0_~
\~/ XXIII \~/
As shown in Scheme VII, N-methoxy-N-methyl-3-
phenylthioindole-2-carbo~mille XXI can be reduced to aldehyde XXII
with lilhiuln ~ .., hydride in tetrahyd~fur~l at 0C to 20C for 2-
4 hours. Aldehyde XXII could be reacted wi~ the li~ ll salt of
WO 94/19321 ~15 6 4 ;~ C PCT/US94/01694
- 43 -
- [(benzoxal-2-yl)methyl]diethyl-phosphonate to produce olefin XXIII,
which is then hydrogenated in the presence of 10% palladium on
charcoal in methanol under one atmosphere of hydrogen to give
5 compound XXIV.
The compound 5-chloro-2-cyano-3-phenylthioindole in
Table VII can be prepared by dehydro-sulfurization of 5-chloro-3-
phenyl-thioindole-2-thiocarboxamide with, e.g., Hg(OAc)2.
Using methods well-known to those skilled in the art,
compounds of formula A where Y is -SO- or -SO2- can be synthesized
by treatment of compounds where Y is -S- with a suitable oxidizing
agent such as, for example, meta-chloroperoxybenzoic acid (MCPBA),
sodium periodate or hydrogen peroxide in an a~ro~liate solvent such
as MeOH, CHCl3 or acetic acid, or potassium persulfate in a solvent
15 such as MeOHlH2O.
Alternative routes to amide derivatives of forrnula A where
Y = -SO- or -S02- are shown in Scheme vm. Intermediate acid II can
be oxidized (with for example meta-chloroperoxybenzoic acid
(MCPBA) in CHCl3) to the Y = -SO- or -SO2- acid derivative XXV
20 which can then be converted to the corresponding arnide derivatives
XXVII employing the amide forming conditions indicated in Scheme I.
In another useful sequence, interm~ te ester IVa can be oxidized to the
Y = -SO- or -S02- ester intenne~i~te XXVI which on reaction with
ammonia or a primary amine with heating is converted to compounds of
25 formula XXVII.
WO 94/19321
PCT/IJS94/01694
2 ~ 0
- 44 -
SCHEME vm
SPh
S X~ H2O2/HOAc ~ 5~ h
S(O)nPh See SCHEME I
X~ C~o N R2R3
lS H
XXVII
~NR2R3
\
SPh
S()nPh
20 X~l H2O2/HOAc X~CO2Et
~B H
XXVI
WO 94/19321215 6 4 ;~ O PCT/US94/01694
~ `_
- 45 -
TABLE I
Y-Ph
s X~N/ RR3
X Y R2 R3 m.p.
H S CH3 CH3 194-195C
H S H CH2Ph 179-181C
- l 5 H S H Ph 194-196C
H S H n-C4Hg 161 -163C
H S H CH2CH2Ph 147-149C
Cl S CH3 OCH3 57-59C
Cl S H ~) 255-256C
H S H CH3 197-199C
Cl S H nC3H7 210-212C
Cl S H --CH2~ 240-241 C
Cl S H {~ 255-256C
WO 94/19321 PCT/US94/01694
2 3
- 46 -
TABLE I. Cont'd
X Y R2 R3 m.p.
F S H ~ 239-241 C
Cl S H ~OH 232-233C
Cl CH~ H --CH~ 243-244C
Cl S H ~ 221 C
OCH3
Cl S H --CH2~ 21 4C
Cl S HCH2CH2CH2OH 21 5C
Cl S H ~OCH3 229C
Cl S H CH3 220-221 C
WO 94/19321 ~ 4 2 ~ PCT/US94/01694
- 47 -
TABLE I. Cont'd
X Y R2 R3 m.p.
Cl S H CH2CH2CH2OCH3 170-171C
OCH3
Cl S H CH2~OCH3 1 84C
Cl S H CH2~ 259-260C
lS NH (HCI salt)
Cl S H CH2CH2--N~N 256C
\=/ (HCI salt)
Cl S H CH(CH3)2 193-1 94C
Cl S CH3 Ph 191-1 92C
Cl S H CH2CH2CH2N(CH3)2 229-230C
(HCI salt)
WO 94/19321 ` PCT/US94/01694
4 2 t3
- 48 -
TABLE I. Cont'd
X Y R2 R3 m.p.
s
Cl S HC2H5 210-211 C
Cl S H Ph 245-246C
OCH3
Cl S HCH2~ 1 72C
Cl S HCH2CH2CHz--N O 162-164C
Cl S HCH2 A 219-21 9.5C
Cl S HCH2Ph 222C
Cl S H CH2~OCH3 1 98C
Cl S H CH2CH2OCH2CH2OH 161.5-162.5C
WO 94/19321 PCT/US94/01694
_ 215~;~20
- 49 -
- TABLE I. Cont'd
X Y R2 R3 m.p.
Cl S H ~OH ~300C
Cl S H CH2CH2OCH3 216-217.5C
Cl S H CH2CH2Oc2Hs 165.5-167C
Cl S H CH2~ 182-183C
Cl S H CH2~ 201C
CH30
Cl S H CH2CI HCH3 205C
OH
,~
Cl S H --CH2~N 228-229C
Cl S H CH2CH2OH 222-223.5C
Cl S H CH2~CH2N~ 151-152C
WO 94/19321 PCT/US94/01694
2 3
- so
TABLE I~ Cont'd
X Y- R2 R3 m.p.
Ci S H OCH3 179-180C
-CH-CH2CH3
l o Cl S H CH2OH 153-154C
o
l 5 Cl S H CH2COC2Hs 215-215.2C
-CHCH20CH3
Cl S H CH3 168-169C
OH
Cl S H _CH2"~` 202-203C
Cl S H - CH2~ 209-210C
Cl S H - CH2CH2CH2 - N~N HCI 188-189C
OH
Cl S H - CH2~ 201 -206C
Cl S H - ~CHCH2CH3 138-139C
CH20H
WO 94119321 2 1 S 6 4 2 ~ PCTIUS94/01694
TABLE I. Cont'd
- X Y R2 R3 m.p.
--CHCH2CH3
Cl S H _ 137.5-1 39C
CH20H
OH
Cl S H --CH2CHCH2OH 219-221 C
Cl S H ~ ~CH~ 208-21 0C
CH3
Cl S H --CH~ 223-226C
CH20H
Cl S H ~ ~CH~ 223-226C
CH20H
Cl S H --CH~ 208-21 0C
CH3
OCH3
Cl S H --CH2~N 227-228C
WO 94/19321 PCT/US94/01694
2156~12~
TABLE I. Cont'd
X Y R2 R3 m.p.
Cl S CH20H 229 230C
- CH2~
CH2CH20H
~=~
Cl S H--CH2~) 217-219C
- OH
Cl S H--CH2~ 214-21 6C
OH
Cl S H--CH2~ 193-1 95.5C
` 20 ~
Cl S H - H 213-21 5C
Cl SO2 H H 255-257C
3 0 Cl so2 H--CH2~ 249-251 C
WO 94/19321 21 5 6 4 2 ~ PCT/US94/01694
- 53 -
TABLE I. Cont'd
X Y R2 R3 m.p.
Cl so2 H - CH2CH2OH 1 98-200C
Cl so2 H --CH2~N
OCH3
l 5 Cl S2 H - CH2~3 212-21 5C
Cl S2 H --CH2~N 21 1-21 5C
S CH3
Cl so2 H --CH2~3F 275-278C
Cl so2 H --CH2~ 265-270C
Cl Cl
S2 CH3~ 1 49C
-
WO 94/19321 PCT/US94/01694
~15~
- 54 -
TABLE I. Cont'd
X Y R2 R3 m.p.
Cl SO2 H ~ \ ~ 175C
CH3
Cl SO2 H --CH2~N 278-281C
WO 94tl9321 ~ PCT/US94/01694
- TABLE II
X~OR~ b
X Y R R1b m.p.
H S Ph CH3 179-180C
H S ~ CH3 195-1 97C
CH30
OCH3 S Ph CH3 211-21 2C
Cl S Ph CH3 193-1 96C
Cl S Ph CH2Ph 154-1 55C
Cl S Ph C2H5 163-164C
Cl CH2 Ph C2H5 196-1 97C
3 F S Ph C2H5 1 49C
WO 94/19321 _ PCT/US94/01694
~ ~ ~ G42~
- 56 -
TABLE m
S-R
~N ~;
R ()n
x
X R R~ n Rx m.p.
- 10
H Ph Ph 1 H 71-74C
H Ph Ph 0 H
H Ph Ph 2 H 168-1 69C
H ~ Ph 1 H 166-1 67C
CH3
H ~CH3 Ph 1 H 164.5-166.5C
OCH3 Ph Ph 1 H 70-80C
H ~ Ph 1 H 171.5-1 72.5C
CH3
H Ph Ph 0 CH3 98-99C
WO 94/19321 PCT/US94/01694
-- 2156~2~
- ~7 -
- TABLE m. Cont'd
X R R1a n Rx m.p.
H Ph Ph 1 CH3 177-1 78C
l 0 H Ph~OCH3 1 H
H PhCH3 1 H 164-1 68C
H Ph ~ 0 H ---
CH3
H Ph~--CH3 H
CH3
H Ph ~-CH3 H
CH3
H Ph ~ 1 H ---
CH3
H Ph`~1 H _
WO 94/19321 PCT/US94/01694
21 56~2~
- 58 -
TABLE m. Cont'd
X R R1a n Rx m.p.
OCH3
H Ph ~ 1 H ---
0 H Ph ~}> 1 H 138-1 40C
OCH3
H Ph ~OH 0 H --
H Ph ~ ~OH 1 H 219-220C
Cl Ph Ph 1 H 158-1 62C
OH
H Ph ~ 1 H ---
WO 94/19321 215 ~ 4 2 ~ PCT/US94/01694
_ 59 _
TABLE IV-A
SPh
s ~CH2NHR1
NH
R1 m.p.
-CH2Ph 199-201 C
-Ph 167-1 70C
-n-C4Hg 177-1 79C
-H
TABLE IV-B
SPh H
~CH2N ICIR
H O
2s
R1 m.p.
-CH3 ~--
- -Ph 64-65C
WO 94/19321 PCT/US94/01694
21~6~2(~
- 60 -
TABLE V-A
SPh
X~CH2lCIR5
R6
X R5 R6 m.p.
H -CH2Ph H
l 5 H -Ph H 154-1 55C
H -CH3 H 101.5-1 03.5C
H ~ H 87-90C
o
H ~D H 127-1 29C
Cl -OC2H5 H 99-1 03C
WO 94/19321 215 ~ 4 2 ~ PCT/US94101694
- 61 -
TABLE V-B
SPh
s X~CH~ICINHR
X R1 R6 m.p.
H -Ph H 66-68C
H -Ph-IClNHPh 123-125C
WO 94/19321 PCT/US94/01694
2 a
- 62 -
TABLE VI
Y-Ph
S X~o~ R 1 a
X YR1a m.p.
Cl S -Ph 154-155C
Cl S-CH2Ph 219-220C
H S -Ph 121.5-123.5C
H S ~CI 142-149C
Cl S-C2H5 196-197C
Cl S ~CI 214-215C
Cl S -CH3 178C
CH2 -C2H5 203-205C
Cl CH2 -Ph 161 -163C
Cl SO2 cyclopropy 224-226C
Cl SO2 -C2H5 226-227C
Cl SO2 -CH3 184-187.5C
WO 94/19321 ~ 1 ~ 6 4 ~ ~ PCT/US94/01694
- 63 -
- TABLE VII
SPh
X~Rx
N~R6
X Rx R6 m.p.
H -CH3 H 128-130C
l 5 H -CH3 - IlNHPh 157-159C
H -CH3 - IlPh 124-125C
H -CH2CH2Ph H 117-120.5C
N ~
H --CH2CH2~/ ,I~d H 92-193C
Cl -CN H 172-174C
~ NHCH2~ H 143-144C
- -NH2 H 217
I l (decomp.)
WO 94/19321 PCT/US94/01694
~69?~
- 64 -
The compounds of the present invention are useful in the
inhibition of HIV reverse transcriptase, the prevention or treatment of
infection by the human immlmodeficiency virus (HIV) and the treatment
of consequent pathological conditions such as AIDS. Treating AIDS or
preventing or treating infection by HIV is defined as including, but not
limited to, treating a wide range of states of HrV infection: AIDS, ARC
(AIDS related complex), both symptomatic and asymptomatic, and
actual or potential exposure to HIV. For example, the compounds of
this invention are useful in treating infection by HIV after suspected past
exposure to HrV by, e.g., blood transfusion, organ transplant, exchange
of body fluids, bites, accidental needle stick, or exposure to patient
blood during surgery.
The compounds of this invention are also useful in the
preparation and execution of screening for antiviral compounds. For
example, the compounds of this invention are useful for isolating
enzyme mutants, which are excellent screening tools for more powerful
antiviral compounds. Furthermore, the compounds of this invention are
useful in establichin~ or determining the binding site of other antivirals
to HIV reverse transcriptase e.g., by competitive inhibition. Thus the
compounds of this invention are commercial products to be sold for
these purposes.
For inhibition of HIV reverse transcriptase, the prevention
or treatment of infection by HIV and the treatment of AIDS or ARC,
the compounds of the present invention may be ~-lminictered orally,
parenterally (including subcutaneous injections, intravenous,
intramuscular, intrasternal injection or infusion techniques), by
inh~l~tion spray, or rectally, in dosage unit formulations cont~ining
conventional non-toxic ph~rm~celltiç~lly-acceptable carriers, adjuvants
and vehicles.
Thus, in accordance with the present invention there is
further provided a method of treating and a ph~rm~ceutical composition
for treating HIV infection and AIDS. The treatment involves
~lminictering to a patient in need of such treatment a pharmaceutical
composition comprising a pharmaceutical carrier and a therapeutically-
WO 94/19321 215 6 4 2 5 PCT/US94/01694
- 65 -
effective amount of a compound of the present invention.
These pharmaceutical compositions may be in the form of
orally-~lmini~trable suspensions or tablets; nasal sprays; sterile
injectable preparations, for example, as sterile injectable aqueous or
oleagenous suspensions or suppositories.
When ~tlmini~tered orally as a suspension, these
compositions are l ~aled according to techniques well-known in the
art of ph~rm~ceutical form~ tion and may contain microcryst~lline
0 cellulose for impa~ting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enh~ncer, and
sweetners/flavonng agents known in the art. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, m~gnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents and
lubricants known in the art.
When ~dmini~tered by nasal aerosol or inh~l~tion, these
compositions are ~lel)a~d according to techniques well-known in the
art of pharmaceutical formulation and may be ~lepa ed as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons, and/or
other solubilizing or di~e~sillg agents known in the art.
The injectable solutions or suspensions may be form~ tt-d
according to known art, using suitable non-toxic, parenterally-
2s acceptable diluents or solvents, such as m~nnitol, 1,3-butanediol, water,
Ringer's solution or isotonic sodium chloride solution, or suitable
disye.~ing or wetting and suspen~lin~ agents, such as sterile, bland, fixed
oils, including synthetic mono- or diglycerides, and fatty acids,
including oleic acid.
When rectally ~lmini~tered in the form of suppositories,
these compositions may be prepared by mixing the drug with a suitable
non-illiLati~g excipient, such as cocoa butter, synthetic glyceride esters
or polyethylene glycols, which are solid at ordinary temperatures, but
liquidify and/or dissolve in the rectal cavity to release the drug.
WO 94tl9321 PCTtUS94/01694
2~5~42~ -
- 66 -
The compounds of this invention can be ~tlmini~tered orally
to hnm~n~ in a dosage range of l to 100 mg/kg body weight in divided
doses. One preferred dosage range is 1 to l0 mg/kg body weight orally
in divided doses. Another ~lefelled dosage range is 1 to 20 mg/kg
body weight orally in divided doses. It wiIl be understood, however,
that the specific dose level and frequency of dosage for any particular
p~ti~nt may be varied and will depend upon a variety of factors
including the activity of the specific compound employed, the metabolic
stability and length of action of that compound, the age, body weight,
general health, sex, diet, mode and time of ~rlmini~tration, rate of
excretion, drug combination, the severity of the particular condition,
and the host undergoing therapy.
The present invention is also directed to combinations of
the HIV reverse transcriptase inhibitor compounds with one or more
agents useful in the treatment of AIDS. The compounds of this
invention can be ~tlmini~tered in combination with other compounds
that are HIV reverse transcriptase inhibitors, and/or with compounds
that are HIV protease inhibitors. For example, the compounds of this
invention may be effectively ~lmini~tered, whether at periods of pre-
exposure and/or post-exposure, in combination with effective amounts
of the AIDS antivirals, such as those in the following Table vm.
When used in a combination tre~tment with compounds of
the instant invention, dosage levels of HIV protease inhibitors of the
order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment
or prevention of the above-indicated conditions, with oral doses two-to-
five time higher. For example, infection by HrV is effectively treated
by the ~-lminictMtion of from 10 to 50 milligrams of the HIV protease
inhibitor per kilogram of body weight from one to three times per day.
It will be understood, however, that the speci~lc dose level and
frequency of dosage for any particular patient may be varied and will
depend upon a variety of factors including the activity of the specific
compound employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and
time of ~tlmini~tration, rate of excretion, drug combination, the severity
WO 94/19321 2 1 S 6 4 2 ~ PCT/US94/01694
~ _ .
- 67 -
- of the particular condition, and the host undergoing therapy.
Dosages of HIV reverse transcriptase inhibitors, when used
in a combination tre~tment with compounds of the instant invention, are
s comparable to those dosages specified above for the instant compounds.
It will be understood that the scope of` combinations of the
compounds of this invention with AIDS antivirals is not limited by
Table VIII but includes in principle any combination with any pharma-
ceutical composition useful for the treatment of AIDS.
TABLE VIII
Dru Name Manufacturer Indication
ddI Bristol-Myers AIDS, ARC
Dideoxyinosine (New York, NY)
Dideoxycytidine; Hoffman-La Roche AIDS, ARC
ddC (Nutley, NJ)
Zidovudine; AZT Burroughs Wellcome AIDS, adv, ARC
(Rsch. Triangle Park, pediatric AIDS,
NC) Kaposi's sarcoma,
asymptomatic HIV
infection, less severe
HIV disease,
neurological
involvement, in
combination with other
therapies
L-697,661 Merck AIDS, ARC,
(Rahway, NJ) asymptomatic HIV
positive, also in
combination with AZT.
- .
WO 94/19321 ~ d PCT/US94/01694
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TABLE VIII (Cont'd)
Drute Name Manufacturer Indication
L-696,229 Merck AIDS~,ARC,
(Rahway, NJ) asymptomatic HIV
positive, also in
combination with AZT.
L-735,524 Merck AIDS, ARC,
(Rahway, NJ) asymptomatic HIV
positive, also in
combination with AZT.
L-738,372 Merck AIDS, ARC,
(Rahway, NJ) asymptomatic HIV
positive, also in
combination with AZT.
L-738,872 Merck AIDS, ARC,
(Rahway, NJ) asymptomatic HIV
positive, also in
combination with AZT.
Compounds of Table VIII are the following: L-697,661 is
3-([(4,7-dichloro-1,3-benzoxazol-2-yl)-methyl]-amino)-5-ethyl-6-
methyl-pyridin-2(1H)-one; L-696,229 is 3-[2-(1,3-benzoxazol-2-
yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one; L-735,524 is an HIV
protease inhibitor with the chemical name N-(2(R)-hydroxy-1(S)-
30 indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-
2(S)-N'-(t-butylcarboxamido)piperazinyl))pent~ne~mide; L-738,372 is
6-chloro-4(S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)-ethynyl)-
quinazolin-2(1H)-one; L-738,872 is N-tert-butyl-1-[2'-(R)-hydroxy-4'-
phenyl-3'(S)-[3 "(R)-[1 "',1 "'-dioxo-2"'(R)-methylethyl]tetrahydro-
thienyloxycarbonylamino] -butyl] -4-[4'-(2" -chloro-6 "-methyl)pyridyl-
WO 94/19321 2 ~ ~ 6 ~ PCT/US94/01694
- 69 -
methyl] -piperazine-2(S)-carboxamide.
REVERSE TRANSCRIPTASE ASSAY
The assay measures the incorporation of tritiated deoxy-
guanosine monophosphate by recombinant HIV reverse transcriptase
(HIV RTR) (or other RT) into acid-precipitable cDNA at the Km values
of dGTP and poly r(C)-oligo d(G)12 18. The inhibitors of the present
invention inhibit this incorporation.
Thirty ~L of a reaction mixhlre cont~inin~ equal volumes
of: 500 mM Tris-HCl (pH 8.2), 300 mM MgCl2, 1200 mM KCl, 10 mM
DTT, 400 ~g/mL poly r(c)-oligo d(G) [~ &~d by dissolving 1.5 mg
(25 U) poly r(C)-oligo d(G) in 1.5 ml sterile distilled H2O and diluting
to 400 ~lg/ml], 0.1 IlCi/~ll [3H] dGTP, 160 ~M dGTP, was added to 10
~ll sterile distilled H20, 2.5 ~ll of potential inhibitor and 10 ~L of 5 nM
purified HIV RTR in tubes. The mixture was incubated at 37C for 45
mimltes.
After incubation is complete, the tubes were cooled in ice
for5 ~ ltes. Ice-cold 13% TCA cont~ining 10mMNaPPi (200
are added and the ~ ule incubated on ice for 30 mimltes. The
precipitated cDNA is removed by filtration using presoaked glass filters
[TCA, NaPPi]. The precipitate is then washed with lN HCl, 10 mM
NaPPi-
The filter discs are then counted in a scintill~tion counter.
Under these conditions [dGTP] and poly r(C)-oligo
d(G)12 18 each are approximately equal to the ~r~liate Km value.
Approximately 5-6,000 cpm of [3H] dGMP are incorporated into acid-
precipitable material. The RT reaction is concentration- and time-
dependent. DMSO (up to 5%) does not affect enzyme activity.
3 o Calc~ te-l IC50 values for the tested compounds of this invention vary
from about 3 nM to more than 300 ~lM. The IC50 values of the most
preferred compounds range from about 3 nM to about 35 nM.
WO 94/19321 PCT/US94/01694
21~6~20
- 70 -
INHIBll ION OF VIRUS SPREAD
A. r~e~a-dtion of HIV-infected MT-4 Cell Suspension
MT cells were infected at Day O at a concentration of
250,000 per ml with a 1:2000 dilution of HIV-1 strain IIIb` stock (final
125 pg p24/ml; sufficient to yield < 1% infected cells on day 1 and 25-
100% on day 4). Cells were infected and grown in the following
me~ m RPMl 1640 (Whin~ker BioProducts), 10% inactivated fetal
0 bovine serum, 4 mM glul~l..i..ç (Gibco Labs) and 1:100 Penicillin-
Streptomycin (Gibco Labs).
The mix~re was incubated ovemight at 37C in 5% CO2
atmosphere.
lS B. Treatment with Inhibitors
Serial two-fold dilutions of compound were prepared in
cell culture medium. At Day 1, aliquots of 125 111 of compound were
added to equal volumes of HIV-infected MT~ cells (50,000 per well) in
a 96-well microtiter cell culture plate. Incubation was continued for 3
days at 37C in 5% CO2 atmosphere.
C. Measurement of Virus Spread
Using a multich~nnel pipettor, the settled cells were
resuspended and a 125 ,ul haIvested into a separate microtiter plate.
25 After the settling of the cells, the plates were frozen for subsequent
assay of the ~uye...~t~nt for HIV p24 antigen.
The conce--l-dtion of HIV p24 antigen was measured by an
enzyme ;.--....oassay, described as follows. Aliquots of p24 antigen to
be measured were added to microwells coated with a monoclonal
30 antibody specific for HIV core antigen. The microwells were washed at
this point, and at other a~l,ro~.iate steps ~at follow. Biotinylated HIV-
specific antibody was then added, followed by conjllg~te~ streptavidin-
horseradish peroxidase. A color reaction occurs from the added
hydrogen peroxide and tetramethylbenzidine substrate. Color intensity
is proportional to ~e concentration of HIV p24 antigen.
WO 94/19321 215642 ~ PCT/US94/01694
The cell culture inhibitory concentration (ClCgs) for each
compound is defined as that concentration which inhibited by greater
than 95% the spread of infection, as assessed by a greater than 95%
reduction in p24 antigen production relative to untreated controls. The
tested compounds of the present invention were found to have CICgs
values r~nging from about 3 nM to about 400 nM for preferred species,
and up to about 40 IlM for others.
EXAMPLE 1
Preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthioindole-2-
carboxamide
Step A: 5-Chloro-3-phenylthioindole-2-carbo~ylic acid
To a suspension of sodium hydride (3.0 g, 60% dispersion
in oil, 0.076 mol) in dimethylfonn~mi(le (125 mL) was added 5-
chloroindole-2-carbo~ylic acid (5.0 g, 0.0255 mol) and phenyldi-
sulfide (6.1 g, 0.028 mol). The reaction was he~te-l under nitrogen at
50C overnight. The reaction was cooled, and additional sodium
hydride (1.8 g) and phenyldisulfide (3.6 g) were added and heating
continued for 1 h. The reaction was cooled and the dimethylformamide
tille-l in vaCuo. 'rhe residue was partitioned between ethyl acetate
and water. The aqueous layer was separated and the pH ad~usted to pH1
with 10% aqueous hydrochloric acid. The aqueous phase was extracted
with ethyl acetate, and the ethyl ~Get~te e~tract was washed with water
and saturated brine, and dried over m~gnesium sulfate. The crude
product was recryst~lli7ed from ethyl acetate in hexane to afford the
title compound as an off-white solid.
Step B: N-(3-pyridylmethyl)-5-chloro-3-phenylthioindole-2-
carboxamide
Benzotria_ol- 1 -yloxytris(dimethylamino)phosphonium
hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5-
chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 rnmol), 3-
WO 94/19321 2 1 5 6 ~ 2 ~ PCT/US94/01694
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aminomethylpyridine (0.35 g, 3.2 mmol) and triethyl~mine (0.50 mL,
3.2 mmol) in degassed dimethylfonn~mide (25 mL). The reaction was
stirred at room temperature overni~ht. The precipitated product was
s filtered and the filter cake washed well with water. The solid was
triturated with 30% ethyl acetate in hexane, filtered and dried at 60C in
vacuo for 72 h. The title compound was obtained as an off-white solid,
mp 240-241C.
Analysis calculated for C2lHl6clN3os-o.25 H20:
C, 63.31; H, 4.17; N, 10.54
Found: C, 63.34; H, 4.06; N, 10.71
NMR (DMSO-d6): ~ 12.54 (lH, s), 8.91 (lH, t, J=6 Hz), 8.51 (lH, s),
8.42 (lH, d, J=S Hz), 7.58 (2H, m), 7.45 (lH, m), 7.25 (4H, m), 7.15
(lH, t, J=7 Hz), 7.04 (2H, d, J=8 Hz), 4.58 (2H, d, J=6 Hz).
EXAMPLE 2
Preparation of Methyl 5-chloro-3-phenylthioindole-2-carboxylate
Oxalyl chloride (0.70 mL, 9.6 mmol) was added to a
solution of 5-chloro-3-phenylthioindole-2-carboxylic acid (0.97 g, 3.2
mmol) in chloroform (50 mL) under nitrogen. The reaction was
refluxed for 3 h, cooled and reduced to dryness in vacuo. The resulting
solid was dissolved in chloroform and added to methanol at 0C. The
methanol was removed in vacuo and the crude product chromato-
graphed on silica gel with 20% ethyl acetate in hexane. The title
compound was obtained as a solid, mp 193-196C.
Analysis calculated for C16H12ClN2S
C,60.47;H,3.81;N,4.42
Found: C, 60.09; H, 3.50; N, 4.67
EXAMPLE 3
Preparation of Ethyl 5-chloro-3-benzylindole-2-carboxylate
The title compound was prepared according to the
procedure described by Inaba, S., et al., Chem. Pharm. Bull., 24, 1076-
1082 (1976). Recryst~11i7~tion from ben~ene gave the title compound as
WO94/19321 ~ A~ 3 :~, 2~ PCT/US94/01694
pale yellow needles, mp 196-197C.
Analysis calculated for C18H16ClN2
C, 68.90; H, 5.13; N, 4.46
Found: C, 68.64; H, 5.10; N, 4.56
EXAMPLE 4
Preparation of 2-Phenylsulfinylmethyl-3-phenylthioindole
o Step A: 2-Hydroxymethylindole
A suspension of lithium alllmimlm hydride (2.0 g, 0.20
mol) in tetrahydrofuran (100 mL) was cooled with stirring to 0C
under nitrogen. A solution of ethyl indole-2-carboxylate (10.0 g, 0.052
mol) in tetrahydrofuran was added dropwise, m~ t~ ing the reaction
~m~e,ature between 0-5C. After 1 h, the reaction was quenched with
saturated sodium potassium tartrate solution. The reaction was filtered
and the filter cake washed well with tetrahydroruldll. The tetrahydro-
furan was evaporated in vacuo and the residue partitioned between ethyl
acetate and water. The ethyl acetate solution was washed with water,
20 saturated brine, dried over magnesium sulfate, ~lltered and freed of
solvent. The title compound was obtained as a yellowish solid.
NMR (CDCl3): ~ 8.18 (lH, bs), 7.57 (lH, d, J=8 Hz), 7.35 (lH, d, J=8
Hz),7.26(1H,s),7.18(1H,dt,J=1,8 Hz),7.10(1H,dt,J=1,8Hz),
6.41 (lH, bs), 4.84 (2H, s).
Step B: 2-Phenylthiome~ylindole
2-Hydroxymethylindole (6.94 g, 0.047 mol) and
phenyldisulfide (10.8 g, 0.049 mol) were dissolved in tetrahydrofuran
(200 mL) and cooled to 0C under nitrogen. Tri-n-butylphosphine
30 (11.7 mL, 0.047 mol) was added and the reaction stirred for 1 h.
Additional phenyldisulfide (1.5 g, 0.007) and tri-n-butylphosphine (5.1
mL, 0.20 mol) was ~ e~l, and the reaction stirred at room temperature
until complete. The tetrahydrofuran was removed in vacuo and the
residue chromatographed on silica gel eluting with 5% ethyl acetate in
hexane. The title compound was obtained as clear colorless plates, mp
WO 94/19321 21 5 6 ~ 2 a PCT/US94/01694
- 74 -
100-101.5C.
AI~alysis calculated for C1sH13NS
C, 75.27, H, 5.47, N, 5.85
Found: C, 74.52, H, 5.39, N, 5.95
Step C: 3-Phenylthio-2-phenylthiomethylindole
A suspension of sodium hydride (0.37 g 60% dispersion in
oil, 9.4 mmol) in dimethylform~mide (50 mL) was cooled to 0C.
2-Phenylthiomethylindole (1.5 g, 6.3 mmol) was added portionwise, and
lO the reaction stirred at 0C for 15 min. Phenyldisulfide (1.5 g, 6.9
mmol) was added and the reaction stirred at 20C for 6 h. The reaction
was quenched with water and e~tracted with ethyl ~cet~te. The organic
extract was washed with water, saturated brine and dried over
m~gnPsium sulfate. Filtration and evaporation of solvent left an oil
which was purified by medium pressure chromatography on silica gel
using 5% ethyl ~cet~te in hexane. The title compound was obtained as
an oil.
Analysis calculated for C2lHl7Ns2-H2o-o.l5-c4H8o2
C, 68.50; H, 5.33; N 3.60
Found: C, 68.40; H, 4.65; N, 3.86
Step D: 2-Phenylsulfinylmethyl-3-phenylthioindole
A solution of 3-phenylthio-2-phenylthiomethylindole
(0.750 g, 2.94 mmol) in methanol (100 mL) was cooled to 0C with
stirring. Monoperoxyphthalic acid m~nesium salt (0.908 g, 80%
peracid) in methanol (50 mL) was added slowly dropwise. After
addition, the reaction was stirred an additional 30 min., then quenched
with 10% aqueous sodium thiosulfate (2 mL). The methanol was
removed in vacuo, and the residue partitioned between ethyl acetate and
water. The organic phase was washed successively with water and
saturated brine, then dried over m~nesium sulfate. Filtration and
concentration of the filtrate in vacuo gave an oil which was purified by
chromatography on silica gel using 20-30% ethyl ~cet~te in hexane.
The title compound was obt~inP-l as a foam, mp 71-74C.
Exact mass calculated for C21H17NOS2: 364.082982.
WO 94/19321 2 1 ~ ~ 4 2 ~ PCT/US94/01694
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Found: 364.084549.
NMR (DMSO-d6) â 11.82 (lH, s), 7.50 (6H, m), 7.23 (lH, d, J=8 Hz),
- 7.15 (3 H, m) 7.05 (2H, m) 6.90 2H, m), 4.43 (lH, d, J=13 Hz), 4.38
5 (lH, d, J=13 Hz).
EXAMPLE 5
P~ al ~tion of 2-Phenylcarboxamidomethyl-3 -phenylthioindole
Step A: 3-Phenythioindole-2-carboxamide
The title compound was prepared from 3-phenylthioindole-
2-carboxylic acid (~ aled according to the procedure described by
Atkinson, J.G. et al., Synthesis, p. 480-481 (1988), (4.01 g, 0.015 mol),
15 ammonia (large e~cess), and benzotriazol-1-yloxytris(dimethyl-
amino)phosphonium hexafluorphosphate (7.2 g, 0.016 mol) in
dimethylform~mide according to the general procedure described in
Fx~mple 1 for the ~r~a ation of N-(3-pyridylmethyl)-5-chloro-3-
phenylthio-2-carboxamide. The title compound was obtained as a pale
20 yellow solid.
Step B: 2-Aminomethyl-3-phenylthioindole
A solution of 3-phenylthioindole-2-carboxamide (1.9 g, 7.1
mmol) in tetrahydror~ was cooled under nitrogen to 0C and treated
25 with neat boranetlime.thylsulfide complex (7.1 mL, 0.070 mol). The
reaction was reflu~ed for 7 h, cooled to 0C and qll~nclletl with 10%
aqueous hydrochloric acid. The solution was adjusted to pH 8 with 20%
aqueous sodium hydro~ide. The reaction was e~tracted with ethyl
~cet~te and the organic e~tract washed with saturated brine, and dried
3 o over m~pnesium sulfate. The title compound was obtained as a pale
yellow oil.
Step C: 2-Phenylcarboxamidomethyl-3-phenylthioindole
2-Aminomethyl-3-phenylthioindole (0.85 g, 3.3 mmol) was
dissolved in chloroform (15 mL) and cooled under nitrogen to 0C.
WO 94/19321 PCT/US94101694
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- 76 -
Pyridine (2.7 mL, 33 mmol) was added, followed by benzoyl chloride
(1.1 mL, 10 mmol). The reaction was stirred at 20C for 1 h and 10%
aqueous hydrochloric acid added. The layers were separated and the
5 organic phase washed successively with water, saturated sodium
bicarbonate and saturated brine. The chloroform solùtion was dried
over m~gn~sium sulfate, filtered and evaporated to dryness. The
resulting oil was chromatographed on silica gel with 5% ethyl acetate in
methylene chloride. The title compound was obtained as a solid, mp 64-
65C.
Analysis calculated for C22H18N2OS 0 2 H2O
C, 73.00; H, 5.08; N, 7.74
Found: C, 72.93; H, 5.02; N, 7.66
EXAMPLE 6
15Preparation of 2-(N-Phenylacetamido)-3-phenyl-thioindole and 2-(N-
Phenylacetamido)- 1 -(phenyl-carbamoyl)-3-phenylthioindole
2-Methyl-3-phenylthioindole (0.50 g, 2.1 mmol) (prepared
according to the procedure described by Atkinson, J. G., et aL,
20 Synthesis, p. 480-481 (1988), was dissolved in dry tetrahydrofuran and
cooled under nitrogen to -78C. A solution of n-butyllithium in hexane
(0.83 mL, 2.5 M) was added via syringe. Carbon dio~ide was bubbled
into the reaction mixture over a period of several minlltes; unreacted
carbon dioxide was removed by freezing the reaction at liquid nitrogen
25 tenl~elature under high vacuum and warming to -78C. A solution of
t-butylli~iunl in hexane was added (1.35 mL, 1.7 M) and the reaction
stirred for 20 min. Phenylisocyanate (0.23 mL, 2.1 mmol) in
tetrahydrofuran (1.5 mL) was added and the reaction stirred at 20C
oven~ight. The reaction was diluted with water and extracted with ethyl
30 ~cet~te. The organic phase was washed with saturated brine and dried
over magnesium sulfate. Filtration and evaporation of solvent left an
amber oil. The crude products were chromatographed on silica gel
eluting successively with 15%, 20%, and 40% ether in hexane. 2~
Phenylacetamido)-3-phenylthioindole was isolated as a solid, mp 66-
68C.
WO 94/19321 21~6 4 2 0 PCT/US94/01694
`~. .,
Analysis calculated for C22H 1 gN2OS
C, 72.98; H, 5.01; N, 7.73
Found: C, 72.99; H, 4.87; N, 7.52
Later fractions contained 2-(N-phenylacetamido)-1-
(phenylc~-13allloyl3-3-phenyl~ioindole, mp 123-125C.
Analysis calculated for C29H23N302S
C, 70.28, H, 4.67, N, 8.47
Found: C, 70.37, H, 4.61; N, 8.34
EXAMPLE 7
Preparation of 2-(2-Oxo-2-furan-3-yl)ethyl-3-phenylthioindole
Step A: N-Methoxy-N-methylfuran-3-carboxamide
The title compound was prepared from furan-3-carboxylic
acid (3.4 g, 0.030 mol), N,O-dimethylhydroxyl~mine hydrochloride
hydrochloride (2.9 g, 0.û30 mol) triethyl~mine (8.3 mL, 0.060 mol)
and benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorphosphate (13.3 g, 0.030 mol) according to the general
procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-
phenylthio-2-carboxamide .
NMR (DMSO-d6) ~ 8.25 (lH, s), 7.75 (lH, s), 3.70 (3H, s), 3.22
(3H, s).
Step B: 2-(2-Oxo-2-furan-3-yl)ethyl-3-phenylthioindole
The title compound was ~ ~ed from N-methoxy-N-
methylfuran-3-carboxamide (0.32 g, 2.1 mmol), and 2-methyl-3-
phenylthioindole (0.50 g, 2.1 mmol) according to the general procedure
described in Example 6 for the preparation of 2-(N-phenylacetamido)-
3-phenyl-thioindole. The crude product was chromatographed on silica
gel with chloroform. The title compound was obtained as a pale yellow
solid, mp 127-129C.
Analysis calculated for C20H15N2S
C, 72.05; H, 4.54; N, 4.20
Found: C, 72.08; H, 4.57; N, 4.24
-
WO 94/19321 PCT/US94/01694
2 0
- 78 -
EXAMPLE 8
Preparation of 2-Benzoyl-5-chloro-3-phenylthioindole
Step A: N-Methoxy-N-methyl-5-chloro-3-phénylthioindole-2-
carboxamide
The title compound was prepared from 5-chloro-3-phenyl-
thioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethyl-
o hydroxyl~mine hydrochloride (0.64 g, 6.6 mmol), triethyl~mine (1.0mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylform~mi~e
according to the general procedure described in Example 1 for the
preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-
carboxamide.
Step B: 2-Benzoyl-5-chloro-3-phenylthioindole
N-Methoxy-N-methyl-5 -chloro-3-phenylthioindole-2-
carboxamide (0.24 g, 0.69 mmol) was dissolved in dry tetrahydrofuran
20 (5 mL) and cooled to -78C under nitrogen. A solution of
phenylm~gnesium chloride in tetrahydrofuran (0.81 mL, 2M) was
added via syringe and the reaction warmed to 20C overnight Water
and ethyl ~cet~te were added to the reaction and then separated. The
organic phase was washed with water, 5% aqueous hydrochloric acid,
2s saturated sodium bicarbonate, saturated brine, and dried over
m~ sium sulfate. Filtration and evaporation of solvent gave the clude
product which was chromatographed on silica gel with 10% ether in
hexane. The title compound was obtained as a solid, mp 154-155C.
Analysis calculated for C21H14ClNOS
C, 69.32; H, 3.88; N, 3.85
Found: C, 68.61; H, 3.83; N, 3.83
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EXAMPLE 9
Preparation of 2-(2-Benzoxazol-2-ylethyl)-3-phenylthioindole
StepA: N-Methoxy-N-methyl-3-phenylthioindole-2-~;a~ lide
The title compound was prepared from 3-phenylthioindole-
2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxyl~min~o
hydrochloride (0.54 g, 5.5 mmol), triethyl~mine (1.5 mL, 11 mmol)
o and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium
hexafluorphosphate (1.64 g, 3.7 mmol) according to the procedure
described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-
2-carboxamide.
lS Step B: 3-Phenylthioindole-2-carboxaldehyde
N-Methoxy-N-methyl-3 -phenylthioindole-2-carboxamide
(1.57 g, 5.26 mmol) was dissolved in tetrahydroruldn (150 mL) and
cooled to 0C under nitrogen. A solution of lithium aluminum hydride
in tetrahydroru-dn (5.76 mL, lM) was added slowly via syringe and the
20 reaction stirred a total of 1.5 h. Ethyl acetate (30 mL) was added,
followed by saturated sodium potassium tartrate solution. The layers
were separated and the organic phase washed with saturated brine and
dried over m~gnesium sulfate. Filtration and evaporation of solvent
gave the title compound as a yellow solid.
Step C: trans-2-(2-Benzoxazol-2-ylethenyl)-3-phenylthioindole
n-Butylli~hil.... in he~ne (3.47 mL, 2.5 M) was added to a
solution of [(benzoxal-2-yl)-methyl]diethylphosphonate (2.34 g, 8.68
mmol) in tetrahydrorul~l (50 mL) at -78C under nitrogen. The
30 reaction was stirred for 20 min., and warmed to -20C. A solution of
3-phenylthioindole-2-carboxaldehyde (1.10 g, 4.34 mmol) in
- tetrahydrofuran (30 mL) was added and the reaction stirred at 20C
ovemight. Ethyl acetate and water were added and the layers separated.
The organic layer was washed with saturated brine and dried over
m~gnesium sulfate. The cIude product was triturated with 1:1 hexane
WO 94/19321 PCT/US94/01694
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ethyl acetate and collected by filtration. The title compound was
obtained as a yellow solid, mp 260C.
Analysis calculated for C23H16N2S
C,72,32;H,4.58;N,7.33
Found: C, 72.41; H, 4.50; N, 7.44
Step D: 2-(2-Benzoxazol-2-ylethyl)-3-phenylthioindole
A solution of trans-2-(2-benzoxazol-2-ylethenyl)-3-
phenylthioindole (0.420 g, 1.14 mmol) in 1:1 methanol/tetrahydrorulan
lO (250 mL) was stirred under 1 atmosphere of hydrogen in the presence
of 10% p~ m on charcoal (100 mg). Additional catalyst was added
as needed to drive the reaction to completion. The catalyst was
removed by filtration, and the filtrate concentrated in vacuo. The
resulting solid was triturated with 10% ethyl ~cet~te in hexane and
lS collected by filtration to afford the title co~ ound, mp 192-193C.
Analysis calculated for C23H18N2S
C, 72.80; H, 5.04; N, 7.38
Found: C, 72.78; H, 4.95; N,7.45
EXAMPLE 10
Preparation of N-2-Furanylmethyl-5-chloro-3-phenylthioindole-2-
carboxamide
The title compound was lJl~ar~,d according to the
procedure described in Example 1, Step B, e~cept subslil..li..,e 2-
aminomethylfuran for 3-aminomethylpyridine. The
dimethylformamide was removed in vacuo, and the residue triturated
with 1 :1 ethyl acetate-hP~ne and filtered. Reclyst~11i7~tion from
acetonitrile gave the title compound, mp 214C.
Analysis calculated for C20H15CIN22S
C, 62.74; H, 3.95; N, 7.32
Found: C, 62.27; H, 3.88; N,7.41
NMR (DMSO-d6): ~ 12.55 (lH, s), 8.72 (lH, t, J=6 Hz),7.55 (1H, m),
7.54 (lH, d, J=8 Hz), 7.45 (lH, d, J=2 Hz),7.15 (lH, tt, J=7,1 Hz),
7.08 (lH, s), 7.06 (lH, d, J= 8 Hz), 6.35 (lH, m), 6.18 (lH, m), 4.56
(2H, d, J=6 Hz).
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EXAMPLE 11
5 Preparation of N-3-Pyridyl-5-chloro-3-phenylthioindole-2-carboxamide
The title compound was yl~ed according to the
procedure described in Example 1, Step B, except subsl;l..li..g 3-
aminopyridine for 3-aminomethyl-pyridine. The dimethylformamide
was removed in vacuo, and the residue triturated with 1:1 ethyl acetate-
hexane and filtered. Chromatography on silica gel with 40% ethyl
acetate in hexane gave the title compound, mp 255-256C.
Analysis calculated for C20H15ClN3S
C, 63.24; H, 3.98; N, 10.74
Found: C, 62.59; H, 3.86; N, 11.06
NMR (DMSO-d6): ~ 12.72 (lH, s), 10.55 (lH, s), 8.85 (lH, d, J=3 Hz),
15 8.35 (lH, dd, J=5, 1 Hz), 8.14 (lH, dm, Jd=8 Hz), 7.60 (lH, d, J=9 Hz),
7.48 (lH, d, J=2 Hz), 7.40 (lH, dd, J=9, 2 Hz), 7.25 (2H, t, J=7 Hz),
7.16 (lH, m), 7.11 (2H, t, J=7 Hz).
EXAMPLE 12
Preparation of N-Ethyl-5-chloro-3-phenylthioindole-2-carboxamide
The title compound was prepared according to the
procedure described in F.x~mple 1, Step B, except sub~
ethyl~mine for 3-aminomethylpyridine. The dimethylfo~n~mide was
25 removed in vacuo, and the residue triturated with 1:1 ethyl acetate-
hexane and ~lltered. Recryst~lli7~tion from 2% methanol in ethyl
acetate gave the title compound, mp 210-211C.
Analysis calculated for C17H15ClN2OS-0 S H20
- C, 60.08; H, 4.74; N, 8.24
30 Found: C, 60.00; H, 4.18; N, 8.52
NMR (DMSO-d6): ~ 12.49 (lH, s), 8.31(1H, t, J=6 Hz), 7.54 (lH, d,
J=9 Hz), 7.43 (lH, d, J= 2 Hz), 7.27 (3H, m), 7.15 (lH, tt, J=7, 2 Hz),
7.07 (2H, m), 3.35(4H, m), 1.06 (3H, t, J=7 Hz).
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EXAMPLE 13
Preparation of N-3-Metho~ybenzyl-5-chloro-3-phenylthioindole-2-
carboxamide
The title compound was prepared according to the
procedure described in F.x~mple 1, Step B, except subs~ 3-
methoxybenzylamine for 3-amino-methylpyridine. The dimethyl-
formamide was removed in Yacuo~ and the residue triturated with 1:1
ethyl acetate-hexane and filtered. Recryst~11i7~tion from acetonitrile
gave the title compound, mp 172C.
Analysis calculated for C23H19ClN22S- 3 H20
C, 64.48; H, 4.61; N, 6.54
Found: C, 64.41; H, 4.38; N, 6.75
NMR (DMSO-d6): ~ 12.55 (lH, s), 8.80 (lH, m), 7.55 (lH, d, J=8 Hz),
7.44 (lH, s), 7.25 (3H, m), 7.15 (2H, m), 7.05 (2H, d, J=7 Hz), 6.80
(3H, m), 4.54 (2H, d, J=6 Hz).
EXAMPLE 14
Preparation of N-2-Methoxyethyl-5-chloro-3-phenyl-thioindole-2-
carboxamide
The title compound was prepared according to the
procedure described in E~ample 1, Step B, except sul,s~ 2-
2s methoxyethyl~min~ for 3-amino-methylpyridine. The ~lim~thyl-
fo~mide was removed in vacuo, and the residue t~ ated with 1:1
e~yl acetate-he~ane and filtered to give the title compound, mp 216-
217C.
Analysis calculated for C18H17ClN22S: 0-25 H2O
C,59.17;H,4.83;N,7.67
Found: C, 59.11; H, 4.75? N, 7.82
NMR (DMSO-d6): ~ 12.54 (lH, s), 8.44 (lH, t, J=6 Hz), 7.54 (lH, d,
J=9 Hz), 7.48 (lH, d, J=2 Hz), 7.28 (3H, m), 7.17 (lH, t, J=7 Hz), 7.10
(2H, m), 3.49 (2H, q, J=6 Hz), 3.37 (2H, t, J=6 Hz), 3.16 (3H, s).
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EXAMPLE lS
- ~e~a ation of N-4-Pyridylmethyl-5-chloro-3-phenyl-thioindole-2-
carbo~amide
The title compound was l~lcl~al~d according to the
procedure described in ~mple 1, Step B, except su~s~ g 4-
aminomethylpyridine for 3-amino-methylpyridine. The
dimethylform~mide was removed in vacuo, and the residue triturated
with 1 :1 ethyl acetate-hexane and filtered. Recryst~11i7~tion from
acetonitrile gave the title compound, mp 228-229C.
Analysis calculated for C2lHl6clN3os: 0-2 H2O
C, 63.45; H, 4.16; N, 10.57
Found: C, 63.33; H, 4.02; N, 10.50
NMR (DMSO-d6): ~ 12.56 (lH, s), 8.92 (lH, t, J= 6 Hz), 8.38 (lH, d,
lS J=4 Hz), 7.55 (lH, d, J=8 Hz), 7.47 (lH, s), 7.31 (lH, dd, J=8, 2 Hz),7.25 (lH, d, J=7 Hz), 7.17 (2H, m), 7.05 (lH, d, J=7 Hz), 4.58 (2H, d,
J=6 Hz).
EXAMPLE 16
Plcyal~tion of N-2-Hydroxyethyl-S-chloro-3-phenylthioindole-2-
carboxamide
The title compound was ~le~a~cd according to the
procedure described in P.x~mple 1, Step B, except subs~ 2-
hydroxyethyl~mine for 3-amino-methylpyridine. The dimethyl-
fonn~mide was removed in vacuo, and the residue triturated with 1:1
ethyl acetate-h~x~n~- and filtered. Chromatography on silica gel with
2% methanol in chloroform gave the title compound, mp 222-223C.
Analysis calculated for C17H15ClN202S: 0.3 H20
C, 57.96; H, 4.46; N, 7.95
Found: C, 57.99; H, 4.26; N, 7.90
NMR (DMSO-d6): ~ 12.50 (lH, s), 8.46 (lH, m), 7.55 (lH, d, J=9 Hz),
7.45 (lH, d, J=1 Hz), 7.28 (3H, m), 7.17 (lH, t, J=6 Hz), 7.13 (2H, m),
4.85 (lH, t), 3.49 (lH, m), 3.43 (lH, m).
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EXAMPLE 17
Preparation of 5-Chloro-3-phenylthioindole-2-carbo~amide
The title compound was prepared accordillg to the
procedure described in F~mple 1, Step B, except ~ul~slilulil~g an excess
of ammonia gas for 3-aminomethylpyridine and triethyl~mine. The
dimethylformamide and excess ammonia were removed in vacuo and
the residue partitioned between ethyl ~cet~te and 10% hydrochloric
o acid. The organic phase was washed with water, 5% sodium hydroxide
and saturated brine, and then dried over m~n~sium sulfate. Filtration
and evaporation gave a crude product which was chromatographed on
silica gel with 30% ethyl acetate in hexane. The title compound was
obtained as a white solid mp 213-215C.
Analysis calculated for ClsH11ClN2OS-1/3H2O
C,S8.35;H,3.81;N,9.07
Found: C, 58.33; H, 3.64; N, 9.11
NMR (DMSO-d6): ~ 12.52 (lH, bs), 8.06 (lH, s), 7.76 (lH, s), 7.55
(lH, d, J=9 Hz), 7.44 (lH, s), 7.28 (3H, m), 7.15 (lH, t, J=6 Hz), 7~06
(2H, d, J=8 Hz).
EXAMPLE 18
Pl~yalalion of S-Chloro-3-phenylthioindole-2-thiocarboxamide
A solution of S-chloro-3-phenylthioindole-2-carboxamide
(3.8 g, 12.5 mmol) and [2,4-bis(4-methoxyphenyl3-1,3-dithia-2,4-
diphosphetane-2,4-disulfide (Lawesson's reagent) (5.0 g, 12.5 mmol) in
dry THF (110 mL) was reflu~ed under nitrogen for 16 h. The solvent
was removed in vacuo and the residue chromatographed on silica gel
with 10% ethyl acetate in hexane. The chromatographed product was
30 lliluldted with hexane and the yellowish solid collected and dried to
give the title compound, mp 217C (decomposed).
Analysis calculated for ClSH11ClN2S
C, 56.50; H, 3.48; N, 8.79
Found: C, 56.75; H, 3.64; N, 8.59
NMR (DMSO-d6): ~ 12.22 (lH, s), 10.31 (lH, s), 9.48 (lH, s), 7.50
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(lH, d, J=8 Hz), 7.39 (lH, s), 7.25 (3H, m), 7.13 (lH, t, J=7 Hz), 7.01
(2H, d, J=7 Hz).
EXAMPLE 19
Preparation of N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-
thiocarboxamide
The title compound was l,lel,~ed according to the
o procedure described for 5-chloro-3-phenyl-thioindole-2-
thiocarboxamide except subsliluling N-2-furanylmethyl-5-chloro-3-
phenylthioindole-2-carbo~amide for 5-chloro-3-phenylthioindole-2-
carboxamide. The crude product was chromatographed on silica gel
with 3% ethyl acetate in hexane. The title compound was obtained as a
bright yellow solid, mp 143-144C.
Analysis calculated for C2oHlsclN2os2-H2o
C, 57.61; H, 3.62; N, 6.72
Found: C, 57.56; H, 3.58; N, 6.52
NMR (DMSO-d6): ~ 12.27 (lH, s), 10.73 (lH, s), 7.55 (2H, m), 7.39
(lH, s), 7.21 (4H, m), 6.98 (2H, d, J=7 Hz), 6.36 (2H, 4.96 (2H, s).
EXAMPLE 20
Preparation of N-[1-(2(R)-hydroxypropyl)]-5-chloro-3-phenylthio-
indole-2-carboxamide
The title compound was l~lG~alGd according to the
procedure described in F.x~mrle 1, Step B, except sub~lilulillg 2(R)-
hydroxy-l-propyl~min~ for 3-amino-methylpyridine. The
dime~ylfomlamide was removed in vacuo and the residue triturated
first with 20% ethyl ~ret~te in hexane then by acetonitrile. The title
30 compound was obtained as an off-white solid, mp 202-203C.
Analysis calc~ e~l for Cl8H17ClN22S--3 H20
C, 59.01; H, 4.67; N, 7.65
Found: C, 58.91; H, 4.59; N, 7.50
NMR (DMSO-d6): ~ 12.52 (lH, s), 8.45 (lH, t, J=5 Hz), 7.55 (lH, d,
J=8 Hz), 7.46 (lH, s), 7.25 (3H, m), 7.15 (3H, m), 4.89 (lH, d, J=5 Hz),
WO 94/19321 PCT/US94/01694
21~ 86-
3.74 (lH, m), 3.38 (lH, m), 3.23 (lH, m), 1.00 (3H, d, J=6 Hz).
EXAMPLE 21
5 Preparation of N-(2-pyridyl)methyI-S-chloro-3-phenylthioi~dole-2-
~carboxamide
The title compound was prepared accordillg to the
procedure described in Example 1, Step B, except sub~ 2-
pyridylmethylamine for 3-aminomethylpyridine. The dimethyl-
o form~mi~e was removed in vacuo and the residue triturated first with30% ethyl acetate in hexane, then with acetonitrile. The title compound
was obtained as a white solid, mp 209-210C.
Analysis calc~ teA for C21H16ClN3OS
C, 64.03; H, 4.10; N, 10.67
l5 Found: C, 63.51; H, 3.97; N, 10.41
NMR (DMSO-d6): o 12.58 (lH, s), 9.15 (lH, t, J=S Hz), 8.46 (lH, d,
J=S Hz), 7.66 (lH, t, J=8 Hz), 7.57 (lH, d, J=8 Hz), 7.50 (lH, s), 7.25
(5H, m), 7.12 (3H, m), 4.68 (2H, d, J=5 Hz).
EXAMPLE 22
Preparation of N-(3-methoxy-4-pyridyl)methyl-S-chloro-3-phenyl-
thioindole-2-carboxamide
25 Step 1: Preparation of 4-cyano-2-methoxypyridine
A solution of 2-chloro-4-cyanopyridine (1.25 g, 9.1
mmol), prepared as described by D. Libenn~nn, N. Rist, F. Grumbach,
S. Cals, M. Moyeux and A. Rouaix, Bull. Soc. Chim. France, 694
(1958), in methanol was treated with sodium me~oxide (0.58 g, 10.9
30 mmol) and refluxed for 30 ~ es. The reaction mixture was cooled,
~lltered and the filtrate concentrated in vacuo to obtain the clude
product as an off-white solid. The clude product was chromatographed
on silica gel with 20% ethyl ~cet~te in hexane. The title compound was
obtained as a white powder.
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Step2: Preparation of 4-aminomethyl-2-methoxypyridine
A solution of 4-cyano-2-methoxypyridine (0.55 g, 4.1
mmol) in ethanol was hydrogen~te-l at 60 psi H2 in the presence of 10%
Pd/C (100 mg). After 3.5 h the catalyst was removed by filtration
~rough Super-Cel and the filtrate evaporated to give the titre compound~
as a foam.
Step 3: Preparation of N-(3-methoxy-4-pyridylmethyl)-5-chloro-3-
o phenylthioindole-2-carboxamide
The title compound was prepared according to the
procedure described in Example 1, Step B, except subslilutillg 4-
aminomethyl-2-methoxypyridine for 3-aminomethylpyridine. The
dimethylforrn~mide was removed in vacuo and the crude product
purified by chromatography on silica gel with 2040% ethyl acetate in
hexane. The title compound was obtained as a white solid, mp 227-
228C.
Analysis calc~ tecl for C22H1gClN3O2S
C, 62.33; H, 4.28; N, 9.91
Found: C, 62.63; H, 4.21; N, 9.92
NMR (DMSO-d6): ~ 12.58 (lH, s), 8.93 (lH), 8.37 (2H, d), 7.~6 (lH,
d), 7.47 (lH, s), 7.27 (3H, m), 7.18 (2H, m), 7.05 (2H, d), 4.59 (2H, d),
3.30 (3H, s).
EXAMPLE 23
Preparation of N-(3-hydroxymethyl)benzyl-5-chloro-3-phenylthio-
indole-2-carboxamide
The title compound was prepared according to the
- procedure described in F.x~mple 1, Step B, except sulJ~ ulil.g 3-
30 hydroxymethylbenzyl~mine for 3-amino-methylpyridine. The
dimethylforrn~mide was removed in vacuo and the crude product
recryst~lli7e~ from acetonitrile. The title compound was obtained as a
white solid, mp 229-230C.
WO 94/19321 PCT/US94/01694
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Analysis calc~ te~l for C22H17C1N22S
C,64.61;H,4.19;N,6.85
Found: C, 64.20; H, 4.09; N, 6.85
NMR (DMSO-d6): o 12.69 (lH, s), 10.33 (lH, s), 7.60 (3H, m), 7.49
S ~1-~ s~ 7.30 (4H,-m), 7.15 (AH, m), 5.22 (lH, t, J=7 Hz), 4.50 (2H, d,
l=7 Hz).
EXAMPLE 24
Preparation of N-(3 -hydro~ybenzyl)-5-chloro-3 -phenylthioindole-2-
carboxamide
The title compound was prepared according to the
procedure described in Example 1, Step B, except subs~ 3-
hydroxybenzyl~mine for 3-aminomethyl-pyridine. The dimethyl-
formamide was removed in vacuo and the crude product was
chromatographed on silica gel with 10% methanol in chloroform. The
title compound was obtained as a white solid, mp 214-216C.
Analysis calculated for C22Hl7clN2o2s-o.3 H2O
C, 63.77; H, 4.04; N, 6.76
Found: C, 63.92; H, 3.88; N, 6.49
NMR (DMSO-d6): ~ 12.55 (lH, s), 9.34 (lH, s), 8.75 (lH, t, J=5 Hz),
7.53 (lH, d, J=8 Hz), 7.45 (lH, s), 7.1-7.65 (4H, m), 7.06 (2H, d, J=7
Hz), 7.01 (lH, t, J=8 Hz), 6.70 (lH, s), 6.62 (2H, m), 4.48 (2H, d, J=5
Hz).
EXAMPLE 25
Preparation of S-Chloro-3-phenylsulfonylindole-2-carbo~amide
(Compound 18)
3 0 5-Chloro-3-phenylthioindole-2-carbo~amide (0.177 g,
0.584 mmol) was dissolved in 25 mL chloroform and cooled to 0C.
50% by weight meta-chloro~elo~ybenzoic acid (503 mg, 1.46 mmol)
was added and the reaction stirred at 20C for 6 hours. A 10% aqueous
solution of sodium ~iosulfate was added and the reaction vigorously
stirred for 10 ..,i....tes. The layers were separated and the organic phase
WO 94/19321 21 5 ~ 4 ~ O PCT/US94/01694
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washed with saturated sodium chloride then dried over magnesium
sulfate. The crude product was chromatographed over silica gel eluting
with 40% ethyl acetate in he~ane. The title compound was obtained as a
white powder, mp 255-257C.
NMR (300 MHz, DMSO-d6~- ~ 13.05~ (lH,s), 8.48(1H,s), 8.25~1H,s),
8.03(2H,d,J=8 Hz), 7.95(1H,s), 7.60(4H,m), 7.34(1H,d,J=8 Hz).
Analysis calculated for Cl5Hl lClN23S
C, 53.82; H, 3.31; N, 8.37
Found: C, 53.74; H, 3.29; N, 8.34
EXAMPLE 26
Preparation of 5-Chloro-3-phenylsulfinylindole-2-carboxamide
(Compound 17)
A solution of m~gnesium monoperoxyphthalic acid (85%
peracid) (11.8 mg, 0.024 mmol) in methanol (2 mL) was added
dropwise to a solution of 5-chloro-3-phenylthioindole-2-carboxamide
(14.5 mg, 0.048 mmol) in methanol (2 mL) at O~C. The reaction was
stirred at 20C for 4 hours. A solution of 10% aqueous sodium
20 thiosulfate was added and the reaction stirred vigorously for 10
lules. Methanol was removed in vacuo and the residue partitioned
between ethyl ~cet~te and water. The ethyl acetate extract was washed
with brine and dried over m~nesium sulfate. The crude product was
purified by column cllrulllatography on silica gel with 30-40% ethyl
25 ~cet~te in hexane. The title compound was obt~ine~l as a white solid.
NMR (DMSO-d6, 300 MHz) ~ 12.53(1H, s), 8.35(1H,br s), 8.08(1H,br
s), 7.83(1H,d,l=2 Hz), 7.71(2H,d,l=8 Hz), 7.52(4H,m),
7.30(1H,dd,J=9,2 Hz).
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EXAMPLE 27
Preparation of N-(2,6-difluorobenzyl)-5-chloro-3-phenyl-sulfonyl-
5~ indole-2-carboxamide
Step A: 5-chloro-3-phenylsulfonylindole-2-carboxylic acid
To a suspension of 5-chloro-3-phenylthio-indole-2-
carbo~ylic acid (4.84 g, 0.016 mol) in chloroform (1200 mL) was
added 55% m-chloroperoxybenzoic acid (12.5 g, 0.04 mol). The
mixture was allowed to stir at room temperature for 40 hours.
Filtration afforded the title compound as a colorless solid, mp 277-
280C (dec). On partial evaporation a second crop of product was
obtained.
Step B: Product of reaction of 5-chloro-3-phenyl-sulfonylindole-
2-carboxylic acid with oxalyl chloride
To a suspension of 5-chloro-3-phenylsulfonyl-indole-2-
carboxylic acid (5.04 g, 0.015 mol) in chloroform (200 mL) was added
oxalyl chloride (3.81 g, 0.03 mol). After addition of a catalytic amount
of dimethylformamide (0.1 mL) the mixtllre was h~te-l at a bath
temperature of 60C for 50 min~ltes. After cooling, the solid product,
mp >300C, was utilized directly without further purification. While
based on mass spectral and NMR data, this product appears to be a
symmetrical dimer, it behaves as a typical acid chloride in reactions
with primary ~mines.
Step C: N-(2,6-difluorobenzyl)-5-chloro-3-phenyl-sulfonylindole-
2-carboxamide
2,6-Difluorobenzylamine (0.430 g, 3.0 mmol) was added
dropwise to the solution of the "acid chloride equivalent" from Step B
(0.354 g, 1.0 mmol) in tetrahydrofuran solution (10 mL) cooled in an
ice-acetone bath. The reaction mixture was allowed to warm to room
tempelalure and left overnight. For work-up, ethyl acetate and water
were ~ le~ The ethyl acetate phase was washed well with dilute
WO 94tlg321 ~ 1 5 ~ ~ 2 ~ PCT/US94/01694
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hydrochloride acid, saturated aqueous sodium bicarbonate, and brine.
Mer dIying over m~gnesium sulfate and evaporation of the solvent, the
residue was slurried with ethyl acetate and filtered to give the title
compound, mp 274-280C.
Analysis calculated for C22Hl5clF2N2o3s-o~5H2o
C, 56.24; H, 3.43; N, 5.96
Found: C, 56.12; H, 3.31; N, 5.97
NMR (DMSO-d6) o 13.06 (lH, s), 9.41 (lH, t, J=S.SHz), 7.95 (3H, m),
7.41-7.67 (m, 5H), 7.34 (lH, dd, J=9, 2Hz), 7.18 (2H, t, J=8Hz), 4.64
(2H, d, J=5.5Hz).
EXAMPLE 28
Pre~,a~ation of N-(4-pyridylmethyl)-5-chloro-3-phenyl-sulfinylindole-
15 2-carboxamide (29)
Step A: Preparation of 5-chloro-3-phenylsulfinyl-indole-2-
carboxylic acid
To a suspension of 5-chloro-3-phenylthioindole-2-
20 carboxylic acid (2.14 g, 0.007 mol) in chloroform (600 mL) was added55% m-chloropero~ybenzoic acid (2.32 g, 0.0074 mol). The n~i~ur~
cleared briefly and then solids appeared. After stirring overnight at
room temperature, the title compound was obt~in~l in pure form on
filtration, mp 183-185C.
Step B: N-(4-pyridylmethyl)-5-chloro-3-phenylsulfinylindole-2-
carboxamide
To a mi~ture of 5-chloro-3-phenylsulfinylindole-2-
carboxylic acid (0.096 g, 0.3 mmol), triethyl~mine (0.061 g, 0.6
30 mmol), 4-aminomethylpyridine (0.043 g, 0.4 mmol) in dry
dimethylfo~mide was added benzotriazol-l-ylo~ytris(dimethyl-
amino)phosphonium he~afluorophosphate (BOP reagent) (0.155 g, 0.35
mmol). The mi~tu~ was stirred at room temperature under nitrogen
for three days. Following evaporation, the residue was partitioned
between ethyl acetate and water. The ethyl acetate phase was separated
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and washed with dilute hydrochloric acid. The acidic extract was
neutralized with aqueous sodium bicarbonate and the product extracted
into ethyl acetate. The ethyl acetate extract was washed well with
5 aqueous sodium bicarbonate, then brine, and dried over m~nesium
sulfate. Evaporation afforded a soIid residue which was recryst~lli7ed
from ethyl acetate to give the title cGnllJoulld, mp 233-235C.
Analysis calc~ te~l for C21H16ClN32S
C, 61.54; H, 3.93; N, 10.25
Found: C, 61.39; H, 3.95; N, 10.36
10 NMR (DMSO-d6) o 9.62 (lH, t, J=6 Hz), 8.53 (2H, d, J=6Hz), 7.80
(lH, d, J=2 Hz), 7.67 (2H, m), 7.64 (2H, d, J=9 Hz), 7.44-7.54 (3H, m),
7.33 (3H, m), 4.60 (2H, dq, l=9, 6 Hz).
EXAMPLE 29
Preparation of N-[(S)-1-phenyl-2-hydroxyethyl]-5-chloro-3-phenyl-
sulfonylindole-2-carboxamide (32)
To a solution of the acid chloride dimer product from
Example 27, Step B, (0.354 g, 1.0 mmol) in tetrahydrofuran (10 mL),
20 cooled in an ice-acetone bath, was added a solution of (S)-(+)-2-
phenylglycinol (0.343 g, 2.5 mmol). The ~ u~e, after w~nnin~
gradually to room ~enl~elature, was allowed to sit overnight. Ethyl
~et~te and water were ~-1de-1 The ethyl ~cet~te phase was washed
successively with dilute hydrochloric acid, water, saturated sodium
25 bicarbonate and brine. After drying over m~n~sium sulfate and
evaporation, the product was chromatographed on a 20 mm column
co.~ 6 inches of 230-400 mesh silica gel. Elution with 40% ethyl
~çet~te-methylene chloride gave pure title compound which, after
evaporation, was crystallized from e~yl acetate-he~ane to give the title
30 compound, mp 155-160C.
Analysis calculated for C23Hl9CIN24S
C, 60.72; H, 4.21; N, 6.16
Found: C, 60.33; H, 4.13; N, 6.16
NMR (DMSO-d6): o 13.05 (lH, s), 9.52 (lH, d, J=7.5 Hz), 7.95-8.48
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(3H, m), 7.26-7.68 (lOH, m), 5.13 (lH, q, J=7.5 Hz), 5.07 (lH, t=6 Hz),
3.75 (2H, 6Hz).
EXAMPLE 30
N-(3 -methoxybenzyl)-S-chloro-3 -(2-thiazolyl)sulfonyl-indole-2-
carboxamide (31)
o Step A: Preparation of S-Chloro-3-(2-thiazolyl)thioindole-2-
carboxylic Acid
Using the procedure of F.x~mrle 1, Step A, but sub~liluling
di-(2-thiazolyl)disulfide for phenyl-lic~ de, there was obtained the title
compound, mp 242-244C.
Step B: Preparation of S-Chloro-3-(2-thiazolyl)-sulfonylindole-
2-carboxylic Acid
Using the procedure of F.x~mple 27, Step A, but
sub~ ulillg S-chloro-3-(2-thiazolyl)thioindole-2-carboxylic acid for 5-
20 chloro-3-phenylthioindole-2-carboxylic acid, there was obtained the title
compound, mp 260-261C.
Step C: Product of Reaction of S-Chloro-3-(2-thiazolyl)sulfonyl-
indole-2-carboxylic Acid with Oxalyl Chloride
2s Using the procedure of Fx~mrle 27, Step B, but
sul,slilulillg S-chloro-3-(2-thiazolyl)sulfonylindole-2-carboxylic acid for
S-chloro-3-phenylsulfonylindole-2-carboxylic acid, there was obtained a
solid product, mp>290C, which was ~tili7ed directly in the next step.
Step D: N-(3-medloxybenzyl)-S-chloro-3-(2-thiazolyl-~ulfonyl)-
indole -2-carboxamide
To a solution of the 'acid chloride' product from Step C
(0.181 g, 0.5 mmol) in tetrahydrofuran (5 mL), cooled in an ice-
acetone bath, was added 3-methoxybenzyl~mine (0.205 g, l.S mmol).
The mi~lu-e was allowed to warm to room temperature and then was
WO 94/19321 PCTIUS94/01694
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left overnight with stirring. Ethyl acetate and water were added. The
e~yl acetate layer, after separation, was washed with dilute
hydrochloric acid, saturated sodium bicarbonate, and brine. After
drying (magnesium sulfate) and evaporation, the solid residue was
allowed to stand in a small volume of ethyl acetate. Filtration gave the
title product, mp 205-209C.
Analysis calc~ te~l for C20H16ClN34S2
C, 52.00, H, 3.49, N, 9.10
Found: C, 51.88, H, 3.42, N, 9.07
o (DMSO-d6) ~ 9.43 (lH, t, J=6 Hz), 8.18 (lH, d, J=3 Hz), 8.02 (lH, d,
J=3 Hz), 8.00 (lH, d, J=2 Hz), 7.58 (lH, d, J=8.5 Hz), 7.40 (lH, dd,
J=8.5, 2 Hz), 7.28 (lH, t, J=8 Hz), 6.98-7.05 (2H, m), 6.85 (lH, dd,
J=8, 2.5 Hz), 4.54 (2H, d, J=3.76 Hz).
l 5 EXAMPLE 31
5 -Chloro-3 -(2-thiazolyl)sulfonylindole-2-carboxamide
A solution of the 'acid chloride' product of Example 30,
Step C, (0.50 g, 1.4 mmol) in tetrahydloru~ (25 mL) was added
20 slowly to a solution of tetrahydrofuran saturated with ammonia at
-10C. The reaction mi~ture was allowed to warm gradually to room
tempelalule and then was stirred overnight. After evaporation of the
solvent, the residue was partitioned between ethyl acetate and water.
The e~yl acetate e~tract was washed wi~ saturated sodium bicarbonate
25 and bnne, and dried with m~gnesium sulfate. After evaporation of
solvent, the residue was slurried in e~yl acetate and filtered to give the
title compound, mp 292-294C (dec).
Analysis calculated for C12H8ClN33S2
C, 42.17; H, 2.36; N, 12.29
30 Found: C, 42.23; H, 2.35; N, 11.85
NMR (DMSO-d6) ~ 8.39 (lH, br s), 8.34 (lH, br s), 8.24 (lH, d, J=3
Hz), 8.07 (lH, d, J=3 Hz), 8.00 (lH, dd, J=2, 0.6 Hz), 7.57 (lH, dd,
J=9, 0.6 Hz), 7.40 (lH, dd, J=9, 2Hz).
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EXAMPLE 32
5-Chloro-3-phenylsulfonylindole-2-thiocarboxamide
Reaction of 5-chloro-3-phenylsulfonylindole-2-
carboxamidè with 2,4-bis~4-met~o~yphenyl)-1,3-dithia-2,4-
diphosphetane (Lawesson's reagent) according to the procedure of
Example 18 gave the title compound. Clllomatographic purification on
silica gel was carried out using 30% ethyl acetate-methylene chloride,
followed by 50% ethyl acetate-methylene chloride. The pure product
had mp 207-210C.
Analysis calculated for C15Hl lClN22S2
C,51.35;H,3.16;N,7.98
Found: C, 50.84; H, 3.08; N, 8.04
NMR (DMSO-d6) ~ 12.90 (lH, s), 10.71 (lH, s), 10.70 (lH, s), 8.0-8.6
5 (2H, m), 7.84 (lH, d, J=2Hz), 7.54-7.66 (3H, m), 7.46 (lH, d, J=8.5Hz),
7.30 (lH, dd, J=8.5, 2Hz).
EXAMPLE 33
20 Preparation of 3-phenylsulfonyl-5-chloroindole-2-carboxamide
Step A: N-(phenylthio)succinimide
To a partial solution of N-chlorosucci~ lide (3.34 g, 25
mmol) in dry methylene chloride (30 mL), cooled in an ice bath and
25 under an inert atmosphere, was added thiophenol (2.05 mL, 20 mmol)
via syringe. After stirring for 1 hour, additional N-chlorosuccinimide
(0.40 g, 3 mmol) was ~ e~l. After 2.5 hours total, triethyl~mine (3.9
mL, 28 mmol) was added dropwise. Within 15 mimltes the reaction
mixtllre was ~lil-lte~l with methylene chloride, ~e solvent washed wi~
30 dilute aq. HCl and the solvent then dried ~a2SO4), filtered through a
pad of charcoal and evaporated. The residue was triturated with diethyl
ether and the product collected by filtration to yield the title compound
mp 115-116C [lit. mp 115-116C, J. Org. Chem.. 34, 51 (1969)]. This
material was used as is.
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Step B: Ethyl 3-phenylthio-5-chloroindole-2-carboxylate
To a partial suspension of ethyl 5-chloroindole-2-
carboxylate (698 mg, 3.1 mmol) and N-(phenylthio)succi~ nide (683
mg, 3.3 mmol) in anhydrous methylene chloride (20 mL) at ambient
tempe~lule under-an inert gas atmosphere was added boron trifluoride
etherate (0.12 mL, 1.0 mmol). The reaction was monitored by tlc (thin
layer chromatography) until complete. After 2 hours, the reaction was
diluted with chloroform and neutralized with aq. NaHCO3. The
organic layer was dried (Na2S04)j filtered through a pad of charcoal,
and the solvents evaporated. The residue was triturated with hexanes as
the product crystallized out to yield the title product, mp 160-162C [see
Table II, mp 163-164C]. This material was used as is.
Step C: Ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate
Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642 mg,
1.94 mmol) was dissolved in chloroform (35 mL) and a dried (Na2SO4)
solution of m-chloro~ero~ybenzoic acid (55% pure, 1.30 g, 4.1 mmol)
in chloroform (20 mL) was added dropwise. The progress of the
oxidation was monitored by tlc until complete. After 5 hours, the
reaction was diluted with chloroform and some methanol and the
solution washed with aq. NaHCO3 and aq. Na2CO3. The dried
(Na2SO4) organic layer was filtered through a pad of charcoal and the
solvents removed under reduced pressure. The residue was triturated
with diethyl ether to yield the product. Cryst~11i7~tion from methylene
chloride and diethyl ether gave analytically pure material, mp 201-
202C.
lH NMR (CDC13) ~ 9.63 (br s, lH), 8.58 (t, lH, J=0.7 Hz), 8.07 (d, 2H,
J=7 Hz), 7.46-7.56 (m, 3H), 7.40 (m, 2H), 4.39 (ABq, 2H, J=7 Hz),
0 1.35 (t, 3H, J=7 Hz).
3 Analysis calculated for C17H14ClN04S
C, 56.12; H, 3.88; N, 3.85
Found: C, 55.91; H, 3.95; N, 3.91
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Step D: 3-Phenylsulfonyl-5-chloroindole-2-carboxamide
(Compound 18)
A suspension of ethyl 3-phenylsulfonyl-5-chloroindole-2-
carboxylate (596 mg, 1.64 mmol) in aqueous conc. ammonium
hydroxide (10 mL) co--t?i-~ g ammonium chloride (28 mg) was heated
at 100C for 3 hours in a sealed screw-top tube. The sealed tube was
cooled in an ice bath as product cryst~lli7e!1 out. The product was
o collected by filtration, rinsed with ice water, and dried to give the
product, mp 253-254C.
EXAMPLE 34
Preparation of N-[(imidazol-2-yl)methyl]-3-phenyl-sulfonyl-5-
chloroindole-2-carboxamide
A suspension of 2-aminomethylimidazole dihydrochloride
(256 mg, 1.5 mmol) [prepared as described in J. OrP. Chem.. 43, 1603
(1978)] in dry tetrahydroru~ul (6 mL) cont~inin~ triethyl~min~o (.42
20 mL, 3.0 mmol) was stirred at room temperature under an inert
atmosphere for one hour. The dimeric acid chloride (179 mg, 0.25
mmol) [see Example 27, Step B] was ~d~ed, followed by additional
triethyl~mine (0.07 mL, 0.5 mmol) and the mi~lre was stirred for 12-
20 hours. The ~ Lule was diluted with water and the product
25 extracted into ethyl ~cet~te. This organic layer was dried (Na2SO4),
filtered, and the solvents evaporated. The residue was triturated with
ethyl acetate to give the product. Recryst~11i7~tion from hot ethyl
acetate gave analytically pure product, mp 276-278C.
lH NMR (DMSO-d6) ~ 9.50 (br t, lH, J=5.4 Hz), 8.07 (s, lH), 8.05
30 (S, lH), 8.00 (d, lH, J=1.2 Hz), 7.52-7.67 (m, 4H), 7.37 (dd, lH, J=1.5,
9 Hz), 7.03 (br s, 2H), 4.61 (d, 2H, J=5.4 Hz).
Analysis calculated for ClgHlsClN4O3S
C, 55.00; H, 3.64; N, 13.50
Found: C, 54.67; H, 3.36; N, 13.37
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EXAMPLE 35
Preparation of N-[(l-methylimidazol-2-yl)methyl]-3-phenylsulfonyl-5-
5 chloroindole-2-carboxamide (19)
Step A: 2-Aminomethyl-l-methylimidazole
To a suspension of lilhiulll al.l.~ hydride (114 mg, 3.0-
mmol) in dry tetrahydrofuran (15 mL) at room temperature in an inert
atmosphere was added solid 1-methylimidazole-2-carboxamide (185 mg,
1.5 mmol) [l~le~a~ed according to J. Or~. Chem., 52, 4379 (1987)] in
portions. After stirring the reaction llli~lule for 0.5 hour, the
temperature was raised to 50C for 3.5 hours. After cooling this
reaction, satd. aq. Na2SO4 (2 mL) was added to quench reaction and
15 then powdered anhyd. Na2SO4. Filtration of this mi~tlllre to remove
salts gave a dry solution of 2-aminomethyl-1-methyl-imidazole in
tetrahydro~u~ (~25 mL) which was used as is.
Step B: N-[(l-methylimidazol-2-yl)methyl]-3-phenyl-sulfonyl-5-
2 0 chloroindole-2-carboxamide
A solution of the dimeric indole acid chloride (see Example
27, Step B) (358 mg, 0.5 mmol) in dry tetrahydrofuran (7 mL) was
added dropwise to the above solution of 2-aminomethyl-1-methyl-
imidazole in tetrahydror~ l, which was cooled in an ice bath. After 15
min. triethyl~mine (0.2 mL, 1.4 mmol) was added and the reaction
.,.ixl~..e slowly warmed to room temperature over 12-20 hours. The
reaction was ~lilllte~l with water and the product e~tracted into 10%
methanol/ethyl ~cet~te. The e~tract was dried (Na2S04), filtered
through charcoal, and the solvents evaporated. The residue was
30 ~ ated with ethyl ~cet~te and the product collected by filtration.
Recryst~11i7~tion from hot methanol/ethyl acetate gave analytically pure
material, mp 273-275C.
lH NMR (DMSO-d6) o 9.48 (br t, lH, J=5 Hz), 8.05 (d, 2H, J=7 Hz),
7.98 (d, lH, J=2 hz), 7.52-7.67 (m, 4H), 7.35 (dd, lH, J=2, 9 Hz), 7.18
215~420
WO 94/19321 PCT/US94/01694
_ 99 _
(d, lH, J=1 Hz), 6.88 (d, lH, J=l Hz), 4.66 (d, 2H, J=5 Hz), 3.71
(s, 3H).
Analysis calculated for C20H17ClN43S
C, 56.00; H, 4.00; N, 13.06
s Found: C, 55.77; H, 3.97; N, 13.41
The hydroc~hloride salt was obtained by addition of one
equivalent of ethanolic HCl to the free base, mp 284-285C with
decomposition.
Analysis calculated for C20H17ClN43S-
C, 51.62; H, 3.90: N, 12.04
Found: C, 51.21; H, 3.92; N, 11.55
EXAMPLE 36
15 Alternate Preparation of N-[(l-methylimidazol-2-yl)-methyl] 3-
phenylsulfonyl-5 -chloroindole-2-carboxamide
To a partial suspension of N-[(imi~701-2-yl)-methyl] 3-
phenylsulfonyl-S-chloroindole-2-carboxamide (Example 35) (42 mg,
0.1 mmol) in 1:1 methanoVtetrahydrofuran (4 mL) was added
20 iodomethane (.05 mL, 0.8 mmol). The reaction was stirred for three
days at room tempelalule. The solvents were removed under reduced
pressure, aq. NaHCO3 added and the product extracted into ethyl
acetate/methanol. The organic layer was dried (Na2SO4), filtered, and
the solvents evaporated. The residue was purified by chromatography
25 and the product eluted with 3% methanoVchloroform. A~l~.~liate
fractions were combined, the solvents ev~olated, and ~e residue
u~ated with me~ylene chloride to give pure product.
EXAMPLE 37
Preparation of N-[2-(imidazol4-yl)ethyl]-3-phenyl-sulfonyl-5-chloro-
indole-2-carboxamide (24)
Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a
solution of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid (Example
27, Step A) (336 mg, 0.5 mmol) cooled in an ice bath under an inert
WO 94/19321 2 I 5 64 ~ o PCT/US94/01694
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atmosphere. After 0.5 hours, hist~mine (125 mg, 1.12 mmol) was
added to the yellow solution. After S hours the reaction was diluted
with water and the product extracted into ethyl ~cet~te. This organic
layer was washed with dilute aq. NaHCO3, dried (Na2SO4), filtered
through charcoal and the solvents evaporated. Tii~ ation of this
residue with methylene chloride gave the crude product. Cryst~11i7~tion
from hot ethyl ~cet~te gave analytically pure product, mp 220-221.5C.
H NMR (DMSO-d6) ~ 9.11 (br t, lH, J=5.4 Hz), 8.00 (s, lH), 7.98
o (s, lH), 7.95 (d, lH, J=2.1 Hz), 7.52-7.67 ~m, SH), 7.35 (dd, lH, J=2.1,
8.7 Hz), 6.94 (s, lH), 3.60 (q, 2H, J=7.2 Hz), 2.83 (t, 2H, J=7.2 Hz).
Analysis calculated for C20H17ClN43S
C, 56.00; H, 4.00; N, 13.05
Found: C, 55.74; H, 4.04; N, 13.35
EXAMPLE 38
Preparation of N-(3-methoxybenzyl)-3-phenylsulfonyl-S-chloroindole-
2-carboxamide
A solution of dimeric acid chloride (Example 27, Step B)
20 (1.77 g, 2.5 mmol) in dry tetrahydrofu.a" (25 mL) was added dropwise
to a solution of 3-methoxybenzyl~mine (1.3 mL, 10 mmol) in dry
tetrahydrorul~l (20 mL) cooled with an ice acetone bath. The reaction
was stiITed for 12-20 hours and then ~ teA with 10% methanol/ethyl
~cet~te. This organic layer was washed with dilute HCl, dried
25 (Na2so4)~ filtered, and the solvents evaporated. The residue was
triturated with diethyl ether to give flocculent white product.
Recryst~11i7~tion from hot m~th~novethyl acetate gave analytically pure
product, mp 203-204C.
lH NMR (DMSO-d6) ~ 9.47 (br t, lH, J=6 Hz), 8.03 (s, lH), 8.01
30 (S, lH), 7.94 (d, lH, J=2.1 Hz), 7.63 (t, lH, J=6.9 Hz), 7.52-7.58 (m,
3H), 7.35 (dd, lH, J=2.1, 8.7 Hz), 7.29 (t, lH, J=7.8 Hz), 7.06 (s, lH),
7.05 (d, lH, J=6.6 Hz), 6.86 (dd, lH, J=2.7, 7.5 Hz), 4.57 (q, 2H, J=6
Hz), 3.76 (s, 3H).
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Analysis calculated for C23H1gClN2O4S
C, 60.72; H, 4.21; N, 6.16
Found: C, 60.60; H, 4.17; N, 6.12
5 - EXAMPLE 39
Preparation of N-(3-hydro~ybenzyl)-3-phenylsulfonyl-S-chloroindole-
2-carboxamide
To a saturated solution of N-(3-methoxybenzyl) 3-
o phenylsulfonyl-5-chloroindole-2-carboxamide (1.37 g, 3.0 mmol) in
dry methylene chloride (140 mL) under an inert atmosphere was added
boron tribromide in hexane (1 M, 10 mL, 10 mmol). After stirring for
12-20 hours, the reaction was neutralized by addition of aq. NaHCO3.
After two hours, the solution was made weakly acidic by addition of
15 dilute HCl. The preci~ilated product was collected by filtration and
then the aqueous filtrate extracted with ethyl acetate. The organic layer
was dried (Na2SO4), filtered, and the solvent evaporated. The residue
was triturated with diethyl ether to give additional product. The solids
were combined and crystallized from hot methanoVethyl acetate to give
20 analytically pure product, mp 273.5-274.5C.
lH NMR (DMSO-d6) ~ 9.43 (t, lH, J=6 Hz), 8.01 (s, lH), 7.98 (s, lH),
7.97 (d, lH, J=2.1 Hz), 7.63 (t, lH, J=6 Hz), 7.52-7.58 (m, 3H), 7.35
(dd, lH, J=2, 1, 9 Hz), 7.17 (t, lH, J=7.8 Hz), 6.89 (s, lH), 6.86 (s, lH),
6.84 (s, lH), 6.70 (dd, lH, J=2.1, 8.4 Hz), 4.50 (d, 2H, J=6 Hz).
25 Analysis calculated for C22H17ClN24S
C,59.93;H,3.89;N,6.36
Found: C, S9.91; H, 3.86; N, 6.51
EXAMPLE 40
Preparation of N-(3-nitrobenzyl)-3-phenylsulfonyl-S-chloroindole-2-
carboxamide
Using the procedure described in Example 34, except for
subslilu~ g 3-nitrobenzylamine hydrochloride for 2-aminomethyl-
imidazole dihydrochloride and adjusting the amount of triethylarnine
WO 94/19321 PCT/US94/01694
21 56~20
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accordingly, the title compound was obt~in~l, mp 253-254C.
Analysis calc~ te~l for C22H16ClN3OsS
C, 56.23; H, 3.43; N, 8.94
Found: C, 55.98; H, 3.37; N, 8.85
EXAMPLE 41
Preparation of N-(3-aminobenzyl)-3-phenylsulfonyl-5-chloroindole-2-
carboxamide (30)
- lO A solution of N-(3-nitrobenzyl) 3-phenyl-sulfonyl-5-
chloroindole-2-carboxamide (353 mg, 0.75 mmol) in tetrahydrofuran
(25 mL) and methanol (10 mL) co.-t~ g pl~i.,.. oxide (70 mg) was
hydrogenated with an atmospheric pressure of hydrogen for 3 hours.
The deg~se-l solution was filtered to remove catalyst and the solvents
evaporated. The residue was triturated with diethyl ether to give the
product. Cryst~11i7~tion from acetonitrile gave analytically pure
product, mp 247-249C.
lH NMR (DMSO-d6) o 9.38 (t, lH, J=6 Hz), 7.98 (s, lH), 7.96 (d, lH,
J=2.1 Hz), 7.53-7.60 (m, 4H), 7.35 (dd, lH, J=2.1, 9 Hz), 7.02 (t, lH,
20 J=7.5 Hz), 6.61 (s, lH), 6.60 (d, lH, J=6 Hz), 6.50 (dd, lH, J=2.1, 8.1
Hz), 4.43 (d, 2H, J=6 Hz).
Analysis calculated for C22Hl8clN3o3s-o.2sH2o
C, 59.45; H, 4.20; N, 9.46
Found: C, 59.43; H, 4.08; N, 9.54
EXAMPLE 42
Preparation of N-(2-methoxybenzyl)-3-phenylsulfonyl-5-chloroindole-
2-carbo~amide
Using the procedure described in F.x~mple 38, except
sul,~liluli.,p 2-methoxybenzyl~min~ for 3-metho~ybenzyl~min~, the title
compound was obt~ine~l, mp 235-237C.
lH NMR (DMSO-d6) ~ 9.39 (t, lH, J=6 Hz), 7.99 (d, lH, J=2.1 Hz),
7.95 (s, lH), 7.93 (s, lH), 7.63 (t, lH, J=7.2 Hz), 7.50-7.57 (m, 3H),
7.29-7.44 (m, 3H), 7.06 (d, lH, J=7.5 Hz), 6.97 (dt, lH, J=0.9, 7.2 Hz),
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4.55 (d, 2H, J=5.7 Hz), 3.85 (s, 3H).
Analysis calc~ te~l for C23Hl9clN2o4s-o.2H2o
C, 60.24; H, 4.26; N, 6.11
Found: C, 60.19; H, 4.40; N, 6.11
EXAMPLE 43
Preparation of N-(2-hydroxybenzyl)-3-phenylsulfonyl-S-chloroirldole-
2-carboxamide
o Using the procedure described in F.x~mple 39, except
subslilulillg the 2-me~oxy isomer (Example 42) for the 3-methoxy
isomer described, the title compound was obtained, mp 243-244.5C.
lH NMR (DMSO-d6) ~ 7.99 (d, lH, J=3 Hz), 7.98 (s, lH), 7.97 (s, lH),
7.63 (t, lH, J=6 Hz), 7.51-7.57 (m, 3H), 7.33-7.38 (m, 2H), 7.14
5 (dt, lH, J=1.2, 7.8 Hz), 6.89 (d, lH, J=7.2 Hz), 6.81 (t, lH, J=7.2 Hz),
4.52 (s, 2H).
Analysis calculated for C22H17C~N24S- 2H20
C, 59.44; H, 3.95; N, 6.30
Found: C, 59.38; H, 3.70; N, 6.39
EXAMPLE 44
Preparation of N-(4-methoxybenzyl)-3-phenylsulfonyl-S-chloroindole-
2-carboxamide
Using the procedure described in Example 38, except
sub~lilutillg 4-methoxybenzyl~mine for 3-methoxy~l~yl~mine, the title
compound was obtained, mp 205-206C.
lH NMR (DMSO-d6) ~ 9.42 (br t, lH, J=6 Hz), 8.01 (s, lH), 7.98
(s, lH), 7.95 (d, lH, J=1.8 Hz), 7.64 (t, lH, J=7.2 Hz), 7.52-7.58
30 (m, 3H), 7.33-7.40 (m, 3H), 6.95 (d, 2H, J=9 Hz), 4.51 (d, 2H, J=6 Hz),
3.76 (s, 3H).
Analysis calculated for C23Hl9ClN24S
C, 60.72; H, 4.21, N, 6.16
Found: C, 60.59; H, 4.14; N, 6.11
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EXAMPLE 45
Preparation of N-(4-hydro~ybenzyl)-3-phenylsulfonyl-5-chloroindole-
2-carbo~amide
Using the procedure described in Example 39, e~cept
subs~ g the 4-metho~y isomer (Fx~mrle 44) for the metho~y
isomer described, the title compound was obtained, mp 249-250C.
H NMR (DMSO-d6) ~ 9.35 (t, lH, J=6 Hz), 7.95-7.99 (m, 3H), 7.62
(t, lH, J=6.9 Hz), 7.52-7.57 (m, 3H), 7.35 (dd, lH, J=1.8, 8.7 Hz), 7.25
(d, 2H, J=8.7 Hz), 6.76 (d, 2H, J=8.1 Hz), 4.46 (d, 2H, J=6 Hz).
Analysis calculated for C22H17CIN24S
C, 59.93; H, 3.89; N, 6.36
Found: C, 59.37; H, 3.85; N, 6.25
EXAMPLE 46
Preparation of N-(3-acetylaminobenzyl)-3-phenyl-sulfonyl-5-chloro-
indole-2-carboxamide
A solution of N-(3-aminobenzyl) 3-phenyl-sulfonyl-5-
20 chloroindole-2-carboxamide (Example 41) (176 mg, 0.4 mmol) in dry
tetrahydroru,~n (7 mL) co.lt~ g acetic anhydride (0.05 mL, 0.5
mmol) was stirred at room temperature for 16 hours. The reaction was
diluted with water and extracted with ethyl ~t~et~te. The organic layer
was dried (Na2SO4), filtered through charcoal, and the solvents
25 evaporated. The residue was triturated ~,vith methylene chloride and the
solid collected by filtration to give the product, mp 249-250C.
lH NMR (DMSO-d6) ~ 9.98 (br s, lH), 9.39 (v br s, lH), 7.96-8.00 (m,
3H), 7.51-7.62 (m, 6H), 7.30 (t, 2H, J=8 Hz), 7.14 (d, lH, J=8 Hz), 4.53
(br s, 2H), 2.04 (s, 3H).
30 Analysis calc~ te-l for C24H20CIN304S
C, 59.81; H, 4.18; N, 8.72
Found: C, 59.41; H, 4.09; N, 8.62
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EXAMPLE 47
Preparation of N-(3-methylsulfonylaminobenzyl)-3-phenyl-sulfonyl-5-
chloroindole-2-carboxamide (34)
To a solution of`N-(3-aminobenzyl) 3-phenyl-sulfonyl-5-
chloroindole-2-carboxamide (174 mg, 0.4 mmol) in dry tetrahydro-
furan (7 mL) at room temperature under an inert atmosphere was addedmethanesulfonyl chloride (.035 mL, .45 mmol) and triethyl~mine (0.7
mL, .50 mmol). Over a period of 20 hours, the reaction progress was
monitored by tlc. Additional equivalents of methanesulfonyl chloride
and triethyl~mine were added twice over this period to obtain complete
reaction with the carboxamide. The reaction was diluted with water,
acidified with dilute HCl, and the product extracted into chloroform.
This organic layer was dried (Na2SO4), filtered, and the solvent
evaporated. The residue was purified by chromatography on silica gel.
Elution with 1% methanol/chloroform gave the bis-sulfonylated product
as evidenced by two methyl group resonances in the NMR at ~ 3.47 and
2.98.
This material was dissolved in dimethoxyether (3 mL) and
water (2 mL) and lithium hydroxide monohydrate (66 mg, 1.57 mmol)
was added. The solution was heated at 60C for two hours. The cooled
reaction was acidified with dilute HCl. Upon stirring for 2-3 hours, the
product cryst~lli7e~ out and was collected by filtration and dried.
Recryst~11i7~tion from hot meth~novethyl ~cet~te gave analytically pure
product, mp 252-253C.
H N~R (DMSO-d6) ~ 9.48 (br t, lH,J=5.4 Hz),8.01(s,lH),7.98(s,
lH),7.95 (d, lH,J=1.8 Hz),7.63 (t, lH,J=7.2Hz),7.52-7.58(m,3H),
7.33-7.38 (m, 2H),7.27 (br s, lH),7.23 (br d, lH,J=7.8 Hz),7.15 (d,
lH,J=7.8 Hz),4.55 (d, 2H,J=5.4 Hz),3.00(S,3H).
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Analysis calculated for C23H20ClN3O5S2
C, 53.33; H, 3.89; N, 8.11
Found: C, 53.26; H, 3.86; N, 8.12
EXAMPLE 48
Pl~alation of N-benzyl-3-phenylsulfonyl-5-chloroindole-2-
carboxamide
A solution of the dimeric acid chloride (Example 27, Step
B) (170 mg, 0.25 mmol) in dry tetrahydroruldll (2 mL) was added
dropwise to a solution of benzyl~minç (.28 mL, 2.5 mmol) in dry
tetrahydrorul~ul (3 mL) cooled in an ice/acetone bath. The reaction
llli~lUl~ was left to stir for 12-20 hours as the temperature rose to
ambient. The solvents were removed under vacuum and the residue
15 partitioned between ethyl acetate and water. The ethyl acetate layer was
washed with brine, dried (Na2SO4), and the solvent evaporated. The
residue was crystallized from ethyl ~cet~te/methanol to give analytically
pure product, mp 249-251C.
lH NMR (DMSO-d6) ~ 9.47 (t, lH, J=6 Hz), 8.02 (s, lH), 8.00 (s, lH),
20 7.95 (d, lH, J=2.1 Hz), 7.33-7.57 (m, 10 H), 4.59 (d, 2H, J=6 Hz).
Analysis calculated for C22H17ClN23S
C, 62.19; H, 4.03; N, 6.59
Found: C, 62.14; H, 4.13; N, 6.62
EXAMPLE 49
Preparation of N-(3-pyridylmethyl)-3-phenylsulfonyl-5-chloroindole-
2-carboxamide (28)
Using the procedure in F.x~mple 48, except subsl;l~.l;.-g 3-
30 aminomethylpyridine for benzylamine, the title compound was obtained,
mp 263-264C.
Analysis calculated for C21H16ClN33S
C, 59.22; H, 3.79; N, 9.87
Found: C, 59.01; H, 3.79; N, 9.87
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EXAMPLE 50
P~a~dtion of N-(2-pyridylmethyl)-3-phenylsulfonyl-5-chloroindole-
2-carboxamide
Using the procedure described in P.~mple 48, e~cept
sub~ ;..g 2-aminomethylpyridine for benzyl~mine, the title compound
was obtained, mp 250-251C.
Analysis calculated for C21H16ClN33S
C, 59.22; H, 3.79; N, 9.87
o Found: C, 59.04; H, 3.73; N, 10.06
EXAMPLE 51
Preparation of N-[2-(pyridin4-yl)ethyl]-3-phenyl-sulfonyl-5- .
lS chloroindole-2-carboxamide
Using the procedure described in Example 48, except
subslilulillg 4-(2-aminoethyl)pyridine for benzyl~minP, the title
compound was obt~ine~, mp 258-260C.
Analysis calculated for C22H18CIN303S
C, 60.07; H, 4.12; N, 9.55
Found: C, 59.68; H, 3.84; N, 9.30
EXAMPLE 52
25 Preparation of N-(2-hydroxyethyl)-3-phenylsulfonyl-5-chloroindole-2-
carboxamide
Using the procedure described in F.~mple 48, except
sub~ g 2-hydro~yethyl~min~ for benzyl~minP, ~e title compound
was obt~in~l, mp 198-200C.
Analysis calculated for C17H1sClN2O4S
C, 53.90; H, 3.99; N, 7.39
Found: C, 54.09; H, 3.94; N, 7.25
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EXAMPLE 53
Preparation of N-ethyl-3-phenylsulfonyl-5-chloroindole-2-carboxamide
Using the procedure described in Example 48, except
SUI;JS~ Ig ethyl~mine for benzyl~ ;..e, the title compound was -
obtained, mp 259-260C.
Analysis calculated for C17H15ClN23S
C,56.28;H,4.17;N,7.72
Found: C, 56.07; H, 4.11; N, 7.73
EXAMPLE 54
Preparation of N-[(2-chloropyridin-4-yl)methyl]-3-phenylsulfonyl-5-
~ chloroindole-2-carboxamide
Using the procedure described in Example 35, Step B,
except sub~lil..li..~ 2-chloro-4-~minomethyl-pyridine for 2-
~minomethyl-l-methylimidazole, the title compound was obtained, mp
263-265C.
Analysis calculated for C21H15Cl2N33S
C, 54.79; H, 3.28; N, 9.13
Found: C, 54.38; H, 3.18; N, 9.03
EXAMPLE 55
2 5 Pl e~al ation of N-cyclopropyl-5-chloro-3-phenylsulfonyl-indole-2-
carboxamide (26)
Using the procedure described in Fx~mple 48, e~cept
sulJslilu~ g cyclopropyl~mine for benzyl~mine, the title compound was
obtained, mp 242-243C.
Analysis calculated for C18H15ClN23S
C, 57.68; H, 4.03; N, 7.47
Found: C, 57.40; H, 3.94; N, 7.43
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EXAMPLE 56
Preparation of N-(cyclopropylmethyl)-3-phenylsulfonyl-S-chloroindole-
2-carboxamide
Using ~e procedure described in Example 48, except
subslil.l~ cyclopropylme~yl~mine for benzyl~mine, the title
compound was obt~in~-l, mp 232-234C.
Analysis calculated for C19H17ClN23S
C, 57.88; H, 4.50; N, 7.11
o Found: C, 57.92; H, 4.34; N, 7.09
EXAMPLE 57
P~a~ation of 3-(4-chlorophenylsulfonyl)-5-chloro-indole-2-
15 carboxamide
Using the procedure described in Fx~mple 30 and 31,
except sub~lillllillg bis(4-chlorophenyl)disul~de for di(2-thiazolyl)-
disulfide, the title compound was obt~ine~l, mp 275-277C.
Analysis calculated for ClSH10C12N203S
C, 48.32; H, 2.81; N, 7.51
Found: C, 48.23; H, 2.84; N, 7.91
EXAMPLE 58
25 Preparation of 3-(3-chlorophenylsulfonyl)-5-chloro-indole-2-
carboxamide
Using the procedure described in F.x~mple 30 and 31,
except sub~lil..li.-~ bis(3-chlorophenyl)disullSde for di(2-thiazolyl)-
disulfide, ~e title compound was obt~ine~l, mp 272-273C.
Analysis calculated for ClSH10C12N203S
C, 48.79; H, 2.73; N, 7.59
Found: C, 48.39; H, 2.70; N, 7.44
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EXAMPLE 59
Preparation of 3-(3,5-dichlorophenylsulfonyl)-S-chloro-indole-2-
carboxamide
Using the procedu~e described in F~mple 30 and 31~
except sulJslilulillg bis(3,5-dichlorophenyl)-disulfide for di(2-thiazolyl)-
disulfide, the title compound was obt~in~-~l, mp 258-260C.
Analysis calculated for ClsHgCl3N2O3S
C, 44.63; H, 2.25; N, 6.94
o Found: C, 44.49; H, 2.24; N, 7.04
EXAMPLE 60
Preparation of 3-(2-chlorophenylsulfonyl)-S-chloro-indole-2-
15 carboxamide
Using the procedure described in F.x~mple 33, except
sub~lil..l;.~g 2-chlorothiophenol for thiophenol, the title compound was
obtained, mp 267C.
Analysis calculated for C15H10Cl2N23S
C, 48.79; H, 2.73; N, 7.59
Found: C, 48.69; H, 2.73; N, 7.62
EXAMPLE 61
25 Preparation of 3-(pyridin-2-ylsulfonyl)-5-chloroindole-2-carboxamide
Using the procedure described in F.x~mrle 30 and 31,
except subslil.~li..g bis(pyridin-2-yl)disulfide for di(2-thiazolyl)-
disulfide, the title compound was obt~in~l, mp 244-246C.
Analysis calculated for C14H10ClN33S
C, 50.08; H, 3.00; N, 12.51
Found: C, 50.31; H, 3.00; N, 12.55
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EXAMPLE 62
Preparation of 3-(pyridin-3-ylsulfonyl)-5-chloroindole-2-carboxamide
5Using the procedure described in Example 30 and 31,
except ~ubslil..li..g bis(pyridin-3-yl)disulfide for di(2-thiazolyl)-
disulfide, the title compound was obtained, mp 300C dec.
FAB mass spectrum: m/e = 336 (M+1)
EXAMPLE 63
Preparation of 3-(pyridin-4-ylsulfonyl)-5-chloroindole-2-carboxamide
Using the procedure described in Example 30 and 31,
except subslilu~ g bis(pyridin4-yl)disulfide for di(2-thiazolyl)-
disulfide, the title compound was obt~ine!l, mp>260C dec.
FAB mass spectrum: m/e = 336 (M+1)
EXAMPLE 64
20 Preparation of 3-[(1-methylimidazol-2-yl)sulfonyl]-5-chloroindole-2-
carboxamide
Using the procedure described in Example 30 and 31,
except subs~ i..g bis(1-methylimidazol-2-yl)-disulfide for di(2-
thiazolyl)disulfide, the title compound was obt~ine~, mp 255-2S6C dec.
Analysis calculatedforC13H11clN4O3s
C, 46.09; H, 3.27; N, 16.54
Found: C, 46.02; H, 3.28; N, 16.27
EXAMPLE 65
30 Preparation of N-(3-methoxybenzyl-3-(3-chlorophenylsulfonyl)-5-
chloroindole-2-carboxamide
Using the procedure described in Example 38, except
subsliLu~ g the dimeric acid chloride derived from 3-(3-
cniorophenylsulfonyl)-5-chloroindole-2-carboxylic acid for that derived
from 3-(phenyl-sulfonyl)-5-chloroindole-2-carboxylic acid, the title
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compound was obtained, mp 225-226.5C.
Analysis calculated for C23H18C12N24S
C, 56.45; H, 3.71; N, 5.73
Found: C, 56.52; H, 3.70; N, 5.83
s
EXAMPLE 66
Preparation of N-(3-hydroxybenzyl)-3-(3-chlorophenylsulfonyl)-5-
chloroindole-2-carboxamide
o Using the procedure described in F.x~mple 39, N-(3-
methoxybenzyl)-3-(3-chlorophenylsulfonyl)-5-chloroindole-2-
carbo~amide was demethylated to obtain the title compound, mp 230-
231C.
Analysis calculated for C22H16C12N24S
S C, 55.58; H, 3.39; N, 5.89
Found: C, 55.59; H, 3.36; N, 5.66
EXAMPLE 67
20 Preparation of N-[( l -methylimidazol-2-yl)methyl]-3-(3-chloro-
phenylsulfonyl)-5-chloroindole-2-carboxamide (23)
Using the procedure described in F.~mple 35, except for
substituting the dimeric acid chloride derived from 3-(3-chlorophenyl-
sulfonyl)-5-chloroindole-2-carboxylic acid for that derived from 3-
2s (phenylsulfonyl)-5-chloroindole-2-carboxylic acid, the title compound
was obtained, mp 232-234C.
Analysis calculated for C20H16C12N43S
C, 51.84; H, 3.48; N, 12.09
Found: C, 51.46; H, 3.38; N, 11.78
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EXAMPLE 68
Preparation of 2-carbo~amido-5-chloroindole-3-cyclo-propyl-
5 sulfonamide
Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-
sulfonic acid
Concentrated sulfuric acid (2.50 ml, 90 mmol) was added
dropwise over 5 min at 0C to a stirred solution of 2-carboethoxy-5-
chloro-1-phenylsulfonylindole (7.28 g, 20.0 mmol) in acetic anhydride
(10 ml) and dry dichloromethane (50 ml). The resulting tan solution
was warmed to RT (room temperature) and after 3 hours was poured
onto ice and the mi~ re was e~tracted with ethyl acetate. The ethyl
acetate layer was washed with brine, dried (Na2S04) and evaporated in
vacuo to a syrup. Residual acetic anhydride was removed by
a_eotroping with toluene (3 x 50 ml), and the residue was cryst~lli7e(1
from dichloromethane. The dichloromethane was evaporated in vacuo
to give the title compound as a tan powder:
20 lH NMR (d6 DMSO) ~ 1.33 (t, J=7.1 Hz, 3H), 4.33 (q, J=7.1 Hz, 2H),
7.44 (dd, J=8.9 and 2.2 Hz, lH), 7.63 (t, J=7.6 Hz, 2H), 7.73 (t, J=7.4
Hz, lH), 7.77 (d, J=2.2 Hz, lH), 7.96 (d, J=8.9 Hz, lH), 8.00 (d, J=7.6
Hz, 2H).
25 Step B: 2-Carboethoxy-5-chloro-1-phenylsulfonyl-indole-3-
cyclopropylsulfonamide
Oxalyl chloride (0.90 ml, 10.3 mmol) was added to a
stirred solution of 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-
sulfonic acid (1.505 g, 3.39 mmol) in dry dichloromethane (15 ml) at
30 0C. DMF (2 drops) was added and the solution was warmed to room
temperature. More DMF (1 drop) was added and the reaction was
- heated to reflux. After 2 hours, the solution was cooled and evaporated
in vacuo to give the sulfonylchloride as a tan solid. This was dissolved
in dichloromethane (15 ml) and cyclopropyl~min~ (0.94 ml, 13.56
mmol) and pyridine (0.5 ml) were ~d(lecl. The solution was heated to
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5~fl~ J
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reflux and after 15 min was cooled, r~ te~l with ethyl acetate and was
washed with 1 M HCl solution, sodium hydrogen c~bollate solution and
brine, dried (Na2S04) and evaporated in vacuo to a gum. Methanol (5
ml) was added to give a colorless solid, and the mixture was stirred and
5 h~te~l to reflux for 5 min. The solids were filtered cold, w~.chin~ with
cold methanol (3xS ml), and were dried in vacuo to give the title
compound as colorless crystals: mp 189-191C;
H NMR (CDCl3) o 0.61 (m, 4H), 1.48 (t, J=7.1 Hz, 3H), 2.26 (m, lH),
4.58 (q, J=7.1 Hz, 2H), 5.06 (br s, lH), 7.42 (dd, J=9.0 and 2.0 Hz, lH),
7.54 (t, J=7.6 Hz, 2H), 7.66 (t, J=7.5 Hz, lH), 7.97 (d, J=9.0 Hz, lH),
7.98 (d, J=2.0 Hz, lH), 8.09 (d, J=7.6 Hz, 2H).
Step C: 2-Carboxamido-5-chloroindole-3-cyclopropyl-sulfonamide
A ...i,~ re of 2-carboethoxy-5-chloro-1-phenyl-sulfonyl-
indole-3-cyclopropylsulfonamide (0.42 g, 0.870 mmol) and 2:1:1 10%
potassium hydroxide solution/methanolm~ (20 ml) was heated to
reflux to give a clear tan solution. After 0.5 hour reflux the solution
was cooled and was concentrated in vacuo to 1/2 volume. The solution
20 was acidified with 1 M HCl, and the resulting ~ e was extracted
with ethyl ~cet~te, washed with brine, dried (Na2S04) and evaporated
in vacuo to a gum. The crude product was dissolved in 2% sodium
hydroxide solution which was acidified with 1 M HCl. The solid
material was collected by filtration, washed with 1 M HCl solution, and
2s dried in vacuo to give 3-cyclopropylsulfonamido-5-chloroindole-2-
carboxylic acid. Oxalyl chloride (0.58 ml, 6.65 mmol) and DMF
(1 drop) were added to a stirred suspension of the acid in dry
dichloromethane (10 ml). After 1 hour at room tem~eldluIe the
lu~ was he~e~l to reflux for 1 hour, cooled and evaporated in
30 vacuo to a tan solid. The solid was suspended in acetone (10 ml) and
9:1 ammonium hydroxide/acetone solution (20 ml) was ~ e~l~ After 15
min the solution was eva~oldted in vacuo to 2 ml in volume and the
residue was acidified with 1 M HCl solution and the mixture was
e~tracted with ethyl acetate. The ethyl acetate layer was washed with
sodium hydrogen carbonate solution, dried (Na2S04) and evaporated in
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vacuo. The resulting tan solid was purified by flash chromatography on
silica (dry loaded, eluting with a chlorofo~n/methanol gradient, 2-10%
methanol), to give the title compound as colorless c~rstals (from ethyl
acetate/he~anes): mp236-238C;
lH NM~. (d6 DMSO) ~ 0.40 (m, 4H), 2.07 (m, lH), 7.35 (dd, J=8.7 and
2.1 Hz, lH), 7.56 (d, J=8.7 Hz, lH), 8.01 (d, J=1.7 Hz, lH), 8.10
(d, J=2.1 Hz, lH), 8.22 (br s, lH), 8.47 (br s, lH).
EXAMPLE 69
Preparation of 2-carboxarnido-S-chloroindole-3-phenyl-sulfonamide
Step A: 2-Carboethoxy-S-chloro-l-phenylsulfonylindole-3-
phenylsulfonamide
In the manner olltline~ in F.x~mple 68, Step B, ~niline (0.63
ml, 6.91 mmol) was added to 2-carboethoxy-S-chloro-l-phenyl-
sulfonylindole-3-sulfonylchloride to give, after flash column
chromatography on silica (dry loaded, eluting with an ethyl
acetate/he~anes gradient, 20-30% ethyl acetate) the title compound as
colorless crystals;
lH NMR (CDCl3) ~ 1.47 (t, J=7.1 Hz, 3H), 4.58 (q, J=7.1 Hz, 2H), 6.74
(br s, lH), 7.11 (m, SH), 7.31 (dd, J=9.0 and 2.2 Hz, lH), 7.51 (t, J=8.1
Hz, 2H), 7.57 (d, J=1.7 Hz, lH), 7.65 (t, J=7.5 Hz, lH), 7.87 (d, J=9.0
Hz, lH), 7.99 (d, J=7.6 Hz, 2H).
Step B: S-Chloro-3-phenylsulfonamidoindole-2-carboxylic acid
2-Carboethoxy-S-chloro- 1 -phenylsulfonylindole-3-
phenylsulfonamide (0.39 g, 0.75 mmol) was dissolved in 2:1:1 10%
- 30 sodium hydroxide solution/methanoUI~lF (20 ml) and after 2 hours the
solution was acidified with 1 M HCl, and the resulting ."i~lll.e was
e~tracted with ethyl ~cet~te, washed with bnne, dried ~a2SO4) and
evaporated in vacuo to a glass. Dichloromethane (S ml) was added to
give a colorless solid, and the mixture was stirred and heated to reflux
for S min. The solids were filtered cold, washing with cold dichloro-
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methane, and were dried in vacuo to give the title compound as
colorless crystals;
lH NMR (d6 DMSO) ~ 7.28 (t, J=7.1 Hz, lH), 7.4 (d, J=7.2 Hz, 2H),
7.51 (t, J=7.1 Hz, 2H), 7.72 (dd, J=8.8 and 2.1 Hz, lH), 7.86 (d, J=8.8
Hz, lH), 8.43 (d, J=2.1 Hz, lH), 10.25 (br s, lH).
Step C: 2-Carboxamido-5-chloroindole-3-phenyl-sulfonamide
Oxalyl chloride (0.087 ml, 1.00 mmol) and DMF (1 drop)
were added to a stirred solution of 5-chloro-3-phenylsulfonamido-
indole-2-carbo~ylic acid (123 mg, 0.35 mmol) in dry THF (3 ml) at
0C. After 1 hour at room t~ erature the solution was evaporated in
vacuo to give a tan solid. The solid was dissolved in acetone (1 ml) and
9:1 ammonium hydroxide/acetone solution (2 ml) was ~ le-l After 0.5
hours the solution was evaporated in vacuo to a gum which was
dissolved in ethyl acetate, washed with 1 M HCl and brine, dried
(Na2SO4) and evaporated in vacuo. The resulting tan solid was purified
by flash column chromatography on silica (dry loaded, eluting with an
ethyl acetate/he~n~s gr~lient, 20-70% ethyl acetate) to give the title
compound as colorless crystals (from dichloromethane); mp 225-227C:
lH NMR (d6 DMSO) ~ 7.00 (m, 3H), 7.17 (t, J=7.3 Hz, 2H), 7.30 (dd,
J=8.8 and 2.0 Hz, lH), 7.48 (d, J=8.8 Hz, lH), 7.93 (d, J=2.0 Hz, lH),
8.21 (br s, lH), 8.28 (br s, lH), 10.34 (br s, lH).
EXAMPLE 70
cl ~ation of 2-carbo~amido-5-chloroindole-3-methyl-(phenyl)-
sulfon-amide
30 Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-
methyl(phenyl)sulfonamide
In the manner olltlin~ in F.x~mple 68, Step B, N-methyl-
~niline was added to 2-carboethoxy-5-chloro-1-phenyl-sulfonylindole-3-
sulfonylchloride to give, after flash column chromatography on silica
(dry loaded, eluting with an ethyl ~cet~te/hexanes gradient, 10-30%
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ethyl acetate) the title compound as colorless crystals (from
dichloromethane/hexanes);
lH NMR (CDC13) ~ 1.46 (t, J=7.1 Hz, 3H), 3.30 (s, 3H), 4.55 (q, J=7.1
Hz, 2H), 6.69 (d, J=2.0 Hz, lH), 7.11 (d, J=7.0 Hz, 2H), 7.26 (m, 4H),
7.54 (t, l=7.6 Hz, 2H), 7.66 (t, J=7.4 Hz, lH), 7.87 (d, J=8.8 Hz, lH),
8.08 (d, J-7.6 Hz, 2H).
Step B: 5-Chloro-3-methyl(phenyl)sulfonamidoindole-2-
carboxylic acid
In the m~nner olltlin~l in Example 69, Step B, 2-
carboethoxy-5-chloro-1-phenylsulfonylindole-3-methyl-(phenyl)-
sulfonamide (0.39 g, 0.75 mmol) was hydrolysed in 2:1:1 10% sodium
hydroxide solution/methanol~IF (20 ml, 14 h at RT (room
telnpelature) followed by 5 min at reflux), to give the title compound
(from ethyl acetate);
lH NMR (d6 DMSO) ~ 3.26 (s, 3H), 7.03 (d, J=2.2 Hz, lH), 7.21
(m, 6H), 7.46 (d, J=8.8 Hz, lH).
Step C: 2-Carboxamido-5-chloroindole-3-methyl(phenyl)-
sulfonamide
In the m~nn~r outlined in Example 69, Step C, starting with
5-chloro-3-methyl(phenyl)sulfonamidoindole-2-carboxylic acid, and
after purification by flash column chromatography on silica (dry
loaded, eluting with 2% meth~nouchloroform)~ the title compound was
obtained as colorless crystals (from ethyl acetate); mp 240-242C.
1H NMR (d6 DMSO) ~ 3.13 (s, 3H), 7.06 (d, J=2.1 Hz, lH), 7.09
(m, 2H), 7.23 (dd, J=8.8 and 2.1 Hz, lH), 7.26 (m, 3H), 7.48
(d, J=8.8 Hz, lH), 8.01 (br s, lH), 8.06 (br s, lH).
EXAMPLE 71
Preparation of N-[2-(1-methylimidazol~-yl)ethyl]-3-phenylsulfonyl-
5-chloroindole-2-carboxamide (25)
Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic
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acid with 1-methylhistamine under the conditions of F.x~mple 37
provides the title compound.
EXAMPLE 72
P~e~al~tion of N-[2-(3-methylimidazol-4-yl)ethyl]-3-phenylsulfonyl-
5 -chloroindole-2-carbo~amide
Reaction of 3-phenylsulfonyl-S-chloroindole-2-carboxylic
acid with 3-methylhist~min~ under the conditions of Example 37 gave
the title compound, mp 257-258.5C.
EXAMPLE 73
lS Pl~yal~tion of N-[(imi~7ol-4-yl)methyl]-3-phenylsulfonyl-5-
chloroindole-2-carbo~amide
Reaction of the dimeric acid chloride (F.x~mple 27, Step B)
with 4-aminomethylimidazole under the conditions of F.x~mple 34
provides the title compound.
EXAMPLE 74
Preparation of N-~3-(imidazol-1-yl)propyl]-3-phenylsulfonyl-5-
chloroindole-2-carbo~amide
Reaction of the 3-phenylsulfonyl-S-chloroindole-2-
carboxylic acid with 1-(3-aminopropyl)-imidazole under the conditions
of Example 37 gave the title compound, mp 216-217.5C.
EXAMPLE 75
Preparation of 3-phenylsulfonyl-S-methylsulfonylamino-indole-2-
carboxamide (36)
Step A: 3-Phenylsulfonyl-S-nitroindole-2-carboxamide
Reaction of ethyl S-n.lloil~dole-2-carboxylate (J. Amer.
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Chem. Soc. 80, 4621 (1958)) with N-(phenyl-thio)succinimide under the
conditions of Example 33, Step B, followed by oxidation to the sulfonyl
product (Step C) provides a product which may be converted to the title
compound with ammonium hydroxide at elevated te.l,l,e~ture and
pressure.
Step B: 3-Phenylsulfonyl-5-aminoindole-2-carboxamide
Reduction of 3-phenylsulfonyl-S-l~ ,dole-2-carbox-
o amide with hydrogen under the conditions of Example 41 provides the
title compound.
Step C: 3-Phenylsulfonyl-5-methylsulfonylaminoindole-2-
carboxamide
Reaction of 3-phenylsulfonyl-S-aminoindole-2-carboxamide
with methanesulfonyl chloride under the conditions of Example 47
provides the title compound.
EXAMPLE 76
Preparatlon of 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamido)-
methyllpyridin-2( 1 H)-one (37)
Step A: N-(2-methoxy-4-pyridylmethyl)-S-chloro-3-phenyl-
2 5 sulfonylindole-2-carboxamide
Reaction of the 'acid chloride dimer' product of Example
27, Step B, with 2-methoxy-4-pyridylmethyl~mine under the conditions
of Example 27, Step C, provides the title compound.
Step B: 4-[(S-Chloro-3-phenylsulfonylindole-2-carboxamido)-
methyll -pyridin-2( 1 H)-one
Reaction of N-(2-methoxy-4-pyridylmethyl)-5-chloro-3-
phenylsulfonylindole-2-carboxamide with boron tribromide in
methylene chloride at 0C to room tempel~lule, according to the
procedure described in Example 39, provides the title compound.
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EXAMPLE 77
5 Preparation of N-(2-amino-4-pyridylmethyl)-5-chloro-3-phenyl-
sulfonylindole-2-carboxamide (38)
Step A: 2-Amino-4-aminomethylpyridine
2-Aminopyridine-4-carbonitrile (L.W. Deady et ah, Aust.
o 1. Chem., 35, 2025 (1982)) is reduced catalytically according to the
procedure of D.E. Beattie et al. for the preparation of 2-amino-3-
aminomethyl pyridine (J. Med. Chem., 20, 718, (1977)) to give the title
compound.
Step B: N-(2-Amino-4-pyridyl~nethyl)-5-chloro-3-phenylsulfonyl-
indole -2-carboxamide
Reaction of 2-amino-4-aminomethylpyridine with the
dimeric acid chloride from Fx~mple 27, Step B, according to the
procedure of Example 27, Step C, provides the title compound.
EXAMPLE 78
Preparation of N-(2-aminothiazol-4-ylmethyl)-5-chloro-3-phenyl-
sulfonyl-indole-2-carboxamide
2s Reaction of the dimeric acid chloride from Example 27,
Step B, with 2-aminothiazol-4-ylmethyl~mine (Chem. Ab. 58, 4534
(1962)) under the conditions of F.x~mple 27, Step C, provides the title
compound.
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EXAMPLE 79
Preparation of N-cyano-5-chloro-3-phenylsulfonylindole-2-carbox-
5 imid-amide (35)
Step A: 5-Chloro-3-phenylsulfonylindole-2-carbonitrile
5-Chloro-3-phenylsulfonylindole-2-carboxamide reacts
with methyl (carboxysulfamoyl)triethylammonium hydroxide inner salt
(Burgess reagent) in tetrahydrofiuan (IHF) solvent as described by
D.A. Claremon and B.T. Phillips (Tetrahedron Lett., ~2, 2155 (1988))
to provide the title compound.
Step B: Ethyl 5-chloro-3-phenylsulfonylindole-2-carboximidate
5-Chloro-3-phenylsulfonylindole-2-call,o~ ileis allowed
to react with ethanol saturated with hydrogen chloride at 0-10C for 7
days. Evaporation to dryness affords the title compound as a
hydrochloride salt. The title compound is obtained as a free base by
~dclin.~ the reaction ~ e to an ice cold solution of excess potassium
20 carbonate and extracting the product with chloroform.
Step C: N-Cyano-5-chloro-3-phenylsulfonylindole-2-carboximid-
amide
Ethyl 5-chloro-3-phenylsulfonylindole-2-car~oximidate is
2s reacted with an equimolar amount of cyanamide in absolute meth~nol
(according to the procedure of K.R. Hllffm~n and F.C. Schaefer (~.
Org. Chem.. 28, 1812 (1963)). After 30-60 ~ tes the solvent is
removed and the residue purified by silica gel chromatography to
afford the title compound.
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EXAMPLE 80
Preparation of N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-
carboxamide (27)
Using the procedure of Example 48 but sub~li~..li..~
cyclobutyl~mine for benzyl~min~, there is obtained the title compound.
EXAMPLE 81
Preparation of N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-
carboxamide (39)
Using the procedure of Example 28, Step B, but
sub~lilulillg cyclopropyl~mine for 4-aminomethylpyridine, there is
obtained the title compound.
EXAMPLE 82
Preparation of N-[(1-methylimidazol-2-yl)methyl]-3-phenylsulfinyl-5-
20 chloroindole-2-carboxamide (20)
Using the procedure of Fx~mple 28, Step B, but
subsl it..l i..g 2-aminomethyl-1 -methylimi~7ole for 4-aminomethyl-
pyridine, there is obtained the title compound.
EXAMPLE 83
2s
~le~ tion of N-[(1-methylimidazol-4-yl)methyl-3-phenylsulfonyl-5-
chloroindole-2-carbo~amide (21) and N-[(1-methylimidazol-5-
yl)me~yll-3-phenylsulfonyl-5-chloroindole-2-carboxamide (22)
Step A: N-[(Imidazol-4(or 5)-ylmethyl]-3-phenylsulfonyl-5-
chloroindole-2-carboxamide
Employing the procedure of F.x~mple 34, but substituting
4(or 5)-aminomethylimidazole dihydrochloride for 2-aminomethyl-
imidazole dihydrochloride, there is obtained the title compound.
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Step B: N-[(1-methylimidazol-4-yl)methyl]-3-phenylsulfonylindole-
f 5-chloroindole-2-carboxa~ide; N-[(1-methylimi~1~7Ol-5-
yl)methyll-3-phenylsulfonyl-5-chloroindole-2-carboxamide
Employing the procedure of E~ample 36, but sub~
N-[(imidazol-4(or 5)-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-
carboxamide for N-[(imidazol-2-yl)methyl]-3-phenylsulfonyl-5-
chloroindole-2-carboxamide, there is obtained each of the title
compounds which are obtained pure by chromatography on silica gel.
EXAMPLE 84
r~epa~ation of N-[(R)-1-phenylethyl]-5-chloro-3-phenylsulfonyl-
indole-2-carboxamide (33)
Employing the procedure of Example 29, but substitlltin~
(R)-(+)-a-methylbenzyl~mine for (S)-(+)-2-phenylglycinol, there was
obtained the title compound, mp 149C.
Analysis calculated for C23H1gC1N2O3S-0.15 C2H4O2-0.15H2O
C, 62.32; H, 4.54; N, 6.16
Found: C,62.39;H,4.54;N,6.01
lH NMR (DMSO-d6) o 3.06 (lH, s); 9.43 (lH, d, J=8Hz); 7.94-8.02
(3H, m); 7.46-7.67 (6H, m); 7.25-7.42 (4H, m); 5.21 (lH, q,J =7Hz);
1.53 (3H, d, J=7Hz).
EXAMPLE 85
r~a dlion of N-[(1-ethylimirl~7O1-2-yl)methyl]-3-phenylsulfonyl-5-
chloroindole-2-carbo~amide
Using ~e procedure described in F~mrle 35, e~cept
30 sub~ ulil~g 2-aminomethyl-1-ethylimidazole for the 2-aminomethyl-1-
methylimidazole (Step A), the title compound was obtained, mp 204-
205.5C.
While the foregoing specification teaches the pnnciples of
the present invention, with examples provided for the purpose of
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illustration, it will be understood that the practice of the invention
encompasses all of the usual variations, adaptations, and modifications,
as come wi~in the scope of the following claims and its equivalents.
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