Note: Descriptions are shown in the official language in which they were submitted.
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THIO-OXINDOLE DERIVATIVES
Field of the Invention
This invention relates to compounds which are agonists of the progesterone
receptor, their preparation and utility.
Background of the Invention
Intracellular receptors (IR) form a class of structurally related gene
regulators
known as "ligand dependent transcription factors" (R. M. Evans, Science, 240,
889,
1988). The steroid receptor family is a subset of the IR family, including
progesterone
receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid
receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but
1 S synthetic compounds, such as medroxyprogesterone acetate or
levonorgestrel, have
been made which also serve as ligands. Once a ligand is present in the fluid
surrounding a cell, it passes through the membrane via passive diffusion, and
binds to
the IR to create a receptor/ligand complex. This complex binds to specific
gene
promoters present in the cell's DNA. Once bound to the DNA the complex
modulates
the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone
is termed an agonist, whilst a compound which inhibits the effect of the
hormone is
an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the
health of women. PR agonists are used in birth control formulations, typically
in the
presence of an ER agonist, alternatively they may be used in conjunction with
a PR
antagonist. ER agonists are used to treat the symptoms of menopause, but have
been
associated with a proliferative effect on the uterus which can lead to an
increased risk
of uterine cancers. Co-administration of a PR agonist reduces/ablates that
risk.
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The compounds of this invention have been shown to act as competitive
inhibitors of progesterone binding to the PR and act as agonists These
compounds
may be used for contraception and post menopausal hormone replacement therapy.
Jones, et al, described in U.S. Patent No. 5,688,810 the PR antagonist
dihydroquinoline A.
N
Me
A
Jones, et al, described the enol ether B (U.S. Patent No. 5,693,646) as a PR
ligand.
F
B
Jones, et al, described compound C (U.S. Patent No. 5,696,127) as a PR
ligand.
Me
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-3-
H
C
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med.
Chem., 41, 291, 1998).
a E
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291,
1998).
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H
G
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem.,
38, 4880, 1995).
F
Br
H
Penman, et. al., described the vitamin D analog I as a PR ligand (Tet.
Letters,
35, 2295, 1994).
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Hamann, et al, described the PR antagonist J (Ann. N. Y. Acad. Sci., 761, 383,
1995).
J
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16'" Int.
Cong. Het. Chem., Montana, 1997).
I
\ ~ci
~",N
S H
N
H
K
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Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997).
L
Kuhla, et al, taught the oxindole M as a cardiotonic (WO 86/03749).
S
H2N I H3C CH
3
N
O
N
H
M
Weber, described the oxindole N for cardiovascular indications (WO 91/06545).
\ N I W
N
H
N
Fischer, et al, claim a preparation for making compounds which include the
generic
structure O (U.S. Patent No. 5,453,516).
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_7_
HzC
O
R = various
Singly et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248,
1994).
N
P
Andreani, et al, described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407,
1990).
N
Q
Binder, et al, described structure R which is an intermediate for preparing
COX II
inhibitors (WO 97/13767).
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_g_
A
N
H
R
Walsh (A.H. Robins) described the oxindole S as an intermediate (U.S. Patent
No.
4,440,785, U.S. Patent No. 4,670,566).
R2
S
R1 = F, C1, Br, alkyl, NHz
R2 = alkyl, alkoxy, F, Cl, NH2, CF3
Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545).
~N
H3C0 ~ / H3C CH3
N
O
N
H
T
Bohm, et al, include the generic structure U (WO 91/04974).
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C~
H
U
JP 63112584 A contains the generic structure V:
Y
N
R~
X
N ~ \ CH~~
N O
R3
V
Boar, et al, described the dioxolane W as an intermediate for preparation of
acetyl-
cholinesterase inhibitors (WO 93/12085 A1).
W
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Kende, et al, described methodology for preparing 3,3-substituted oxindoles,
e.g. X,
that was utilized in the present invention (Synth. Commun., 12, l, 1982).
H
$ X
Description of the Invention
This invention provides compounds of the formulae 1 or 2:
R~ R,
1
or
wherein:
R, and RZ are chosen independently from the group of H, alkyl, substituted
alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted
aryl;
heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-
propynyl;
or 3-propynyl:
or R, and R~ are joined to form a ring comprising one of the following:
-CH2(CHz)nCHz-; -CHzCH2CMe2CH2CHz-; -O(CHZ)mCHr; O(CHZ)PO-;
-CHZCHZOCHzCH2-; or -CHzCH2N(H or alkyl)CHZCHz-;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
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p is an integer from 1 to 4;
or R, and RZ together comprise a double bond to one of the following:
CMe2; C(cycloalkyl), O, C(cyloether).
R3 is selected from H, OH, NH2, C, to C6 alkyl, substituted C, to C6 alkyl, C3
to C6 alkenyl, alkynyl or substituted alkynyl, or COR";
R" is selected from H, C, to C3 alkyl, substituted C, to C3 alkyl, C, to C3
alkoxy, substituted C, to C3 alkoxy, C, to C3 aminoalkyl, or substituted C, to
C3
aminoalkyl;
R4 is selected from H, halogen, CN, NHZ, C, to C6 alkyl, substituted C, to C6
alkyl, C, to C6 alkoxy, substituted C, to C6 alkoxy, C, to C6 aminoalkyl, or
substituted
C, to C6 aminoalkyl;
RS is selected from the groups a), b) or c):
a) RS is a trisubstituted benzene ring containing the substituents X, Y
and Z as shown below:
Y,
X I Z
X is selected from halogen, OH, CN, C, to C3 alkyl, substituted
C, to C3 alkyl, C, to C3 alkoxy, substituted C, to C3 alkoxy, C, to C3
thioalkyl,
substituted C, to C3 thioalkyl, S(O)alkyl, S(O)Zalkyl, C, to C, aminoalkyl,
substituted
C, to C3 aminoalkyl, NOz, C, to C3 perfluoroalkyl, S or 6 membered
heterocyclic ring
containing 1 to 3 heteroatoms, CONHZ, CSNHz, CONHalkyl, CSNHalkyl,
CON(alkyl)2, CSN(alkyl)Z, CORE, OCORB, NR~CORB;
RB is selected from H, C, to C3 alkyl, substituted C, to
C3 alkyl, aryl, substituted aryl, C, to C3 alkoxy, substituted C, to C3
alkoxy, C, to C3
aminoalkyl, or substituted C, to C3 aminoalkyl;
R~ is H, C, to C3 alkyl, or substituted C, to C3 alkyl;
Y and Z are independently selected from H, halogen, CN, NO2,
C, to C3 alkoxy, C, to C3 alkyl, or C, to C3 thioalkyl;
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or
b) RS is a five or six membered heterocyclic ring with l, 2, or 3
heteroatoms selected from O, S, SO, SOZ or NR6 and containing one or two
independent substituents from the group of H, halogen, CN, NOz and C, to C3
alkyl,
C, to C3 alkoxy, C, to C, aminoalkyl, COR°, or NRECOR°;
R° is H, C, to C3 alkyl, substituted C, to C3 alkyl, aryl,
substituted aryl, C, to C3 alkoxy, substituted C, to C3 alkoxy, C, to C3
aminoalkyl, or
substituted C, to C3 aminoalkyl;
RE is H, C, to C3 alkyl, or substituted C, to C3 alkyl;
R6 is H, or C, to C3 alkyl; or
c) RS is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the
moiety being optionally substituted by from 1 to 3 substituents selected from
halogen,
lower alkyl, CN, NO2, lower alkoxy, or CF3;
Q' is S, NR" CRgR9;
R, is selected from the group including CN, C, to C6 alkyl, substituted C, to
C6
alkyl, C3 to C8 cycloalkyl, substituted C, to C8 cycloalkyl, aryl, substituted
aryl,
heterocyclic, substituted heterocyclic, acyl, substituted acyl, aroyl,
substituted aroyl,
SOZCF3, OR" or NR"R'2;
R8 and R, are independent substituents selected from the group of H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to Cg cycloalkyl, substituted C3 to C8
eycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, or
COZR,o,
R,o is C, to C3 alkyl; or
CRBRg comprises a six membered ring as shown by the structure below
0
CH3
CH3
O
QZ is selected from the moieties:
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11 D11 p12 11
-N_p-R12 -'I~'~'NI/~-R13 or -p-N-Rlg.
R", R'z and R'3 are independently selected from H, C, to C6 alkyl, substituted
C, to C6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
acyl,
substituted acyl, aroyl or substituted aroyl or sulfonyl;
or a pharmaceutically acceptable salt thereof.
A preferred list of substituents represented by R", R'z and R'3 in groups of
the
compounds described herein are H, C, to C6 alkyl, substituted C, to C6 alkyl, -
C(O)-
(C, to C6 alkyl), -S(O)z-(C, to C6 alkyl), phenyl or benzyl.
It will be understood that this invention includes all tautomeric forms of the
compounds, chemical formulae and substituents described herein.
Two preferred sets of compounds of this invention is depicted by structures 2
and 3, respectively:
R5
1
2 3
each wherein RS is a disubstituted benzene ring containing the substituents X
and Y as shown below
X
3'
4' ~
5' ~~
Y
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X is selected from halogen, CN, CONHz, CSNH2, CONHalkyl, CSNHalkyl,
CONa1ky12, CSNalkylz, C, to C3 alkoxy, C, to C3 alkyl, NO2, C, to C3
perfluoroalkyl,
membered heterocyclic ring containing 1 to 3 heteroatoms, or C, to C3
thioalkoxy;
Y is a substituent on the 4' or 5'position from the group including H,
halogen,
5 CN, NO2, C, to C3 alkoxy, C, to C4 alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 2 are those wherein RS is a five membered
ring with the structure shown below
X'
Y'
wherein:
U is O, S, or NR6;
R~ is H, or C, to C3 alkyl, or C, to C4 COzalkyl;
X' is selected from halogen, CN, NO~, CONHZ, CSNH2, CONHalkyl,
CSNHalkyl, CONa1ky12, CSNalkyl2, C, to C3 alkyl, or C, to C3 alkoxy;
Y' is from the group of H, F or C, to C4 alkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which RS is
a thiophene or furan ring substituted by X' and Y', as described above.
A further preferred subgroup group of compounds of formulas 2 and 3 are
those wherein RS is a six membered ring with the structure:
X'
N
wherein X' is N or CXZ,
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Xz is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2,
CSNalkylz or NOz;
Q' is S, NR,, CRBR,;
R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C3 to C8 cycloalkyl, substituted C, to C8 cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or SOZCF3;
R8 and R9 are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C, to C8
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN
COZR,o,
R,o is C, to C3 alkyl;
CRBR, are within a six membered ring as shown by the structure below
H3
~3
or pharmaceutically acceptable salt thereof.
Still another preferred group of these compounds includes those having the
general formulae:
R5 R5
or
each wherein RS is a disubstituted benzene ring containing the substituents X
and Y as shown below
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X
3'
4' ~
5' /~
Y
X is selected from halogen, CN, CONHz, CSNHZ, CONHalkyl, CSNHalkyl,
CONa1ky12, CSNa1ky12, C, to C3 alkoxy, C, to C3 alkyl, NOz, C, to C3
perfluoroalkyl,
membered heterocyclic ring containing 1 to 3 heteroatoms, or C, to C3
thioalkoxy;
5 Y is a substituent on the 4' or 5'position from the group including H,
halogen,
CN, NOz, C, to C3 alkoxy, C, to Cq alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup group of compounds of formulae:
or
are those wherein RS is a six membered ring with the structure:
~i
wherein X' is N or CXZ,
XZ is halogen, CN, CONHz, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2,
CSNalkylz or NOz;
QZ is as defined above;
R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C3 to C8 cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or SOZCF3;
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Rg and R, are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NOz, CN
COZR,o,
R,o is C, to C3 alkyl;
CR$Rg are within a six membered ring as shown by the structure below
O
O
CH3
O CH3
O
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by
structure
4,
R5
Rs
H
~Rt4
4a
Wherein R,4 is chosen from the group H, acyl, substituted acyl, aroyl,
substituted amyl, sulfonyl, substituted sulfonyl.
Wherein RS is a disubstituted benzene ring containing the substituents X and
Y as shown below
X
3'
4' ~
5'~~
Y
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X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl,
CON(alkyl)2, CSN(alkyl)z, CNHNHOH, CNHzNOH, C, to C3 alkoxy, C, to C3 alkyl,
NOz, C, to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3
heteroatoms, or C, to C3 thioalkoxy;
Y is a substituent on the 4' or 5'position from the group including H,
halogen,
CN, NOz, C, to C3 alkoxy, C, to C4 alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 4 are those wherein RS is a five membered
ring with the structure shown below
X'
u~~
wherein:
U is O, S, or NR6;
R6 is H, or C, to C3 alkyl, or C, to C4 COZalkyl;
X' is selected from halogen, CN, NOz, CONH2, CNHNHOH, CNH2NOH,
CSNH2, CONHalkyl, CSNHalkyl, CONa1ky12, CSNalkylz, C, to C3 alkyl, or C, to C3
alkoxy;
Y' is from the group of H, F or C, to Cq alkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which RS is
a thiophene or furan ring substituted by X' and Y', as described above.
A further preferred subgroup group of compounds of formula 4 are those
wherein RS is a six membered ring with the structure:
~,i~
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wherein X' is N or CXz,
XZ is halogen, CN, CONH2, CSNHz, CONHalkyl, CSNHalkyl, CONalkylz,
CSNalkylZ or NOZ;
R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C, to C8 cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or SOZCF3;
R8 and R, are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NOz, CN
COZR,o,
R,o is C, to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by
structure
5,
R5
5
Wherein RS is a disubstituted benzene ring containing the substituents X and
Y as shown below
X
3'
4' ~
5'~~
Y
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl,
CONalkylz, CSNalkylz, CNHNOH, C, to Cj alkoxy, C, to C3 alkyl, NO2, C, to C3
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perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or
C, to
C3 thioalkoxy;
Y is a substituent on the 4' or 5'position from the group including H,
halogen,
CN, NO2, C, to C3 alkoxy, C, to C4 alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 5 are those wherein RS is a five membered
ring with the structure shown below
Y'
wherein:
U is O, S, or NR~;
R6 is H, or C, to C3 alkyl, or C, to Cq COZalkyl;
X' is selected from halogen, CN, NOZ, CONH2, CSNHZ, CONHalkyl,
CSNHalkyl, CONa1ky12, CSNalkyl2, C, to C3 alkyl, or C, to C3 alkoxy;
Y' is from the group of H, F or C, to C4 alkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which RS is
a thiophene or furan ring substituted by X' and Y', as described above.
A further preferred subgroup group of compounds of formula 5 are those
wherein RS is a six membered ring with the structure:
X1
N
wherein X' is N or CXz,
Xz is halogen, CN, CONH2, CSNHZ, CONHalkyl, CSNHalkyl, CONa1ky12,
CSNalkylz or NOz;
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R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or SOZCF3;
Rg and R9 are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to Cg
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NOz, CN
COzR,o,
R,o is C, to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by
structure
6,
Rs
6
Wherein R,5 is selected from the group H, Me, COzR, acyl, substituted acyl,
aroyl, substituted aroyl, alkyl, substituted alkyl, CN.
Wherein RS is a disubstituted benzene ring containing the substituents X and
Y as shown below
X
3'
4' ~
5'~~
Y
X is selected from halogen, CN, CONH2, CSNHz, CONHalkyl, CSNHalkyl,
CONalkyl2, CSNalkyl2, CNHNOH, C, to C3 alkoxy, C, to C3 alkyl, NOZ, C, to C3
perfluoroalkyl, S membered heterocyclic ring containing 1 to 3 heteroatoms, or
C, to
C3 thioalkoxy;
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Y is a substituent on the 4' or 5'position from the group including H,
halogen,
CN, NOz, C, to C3 alkoxy, C, to Cq alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 6 are those wherein RS is a five membered
ring with the structure shown below
X'
u~~
wherein:
U is O, S, or NR6;
R6 is H, or C, to C3 alkyl, or C, to Cq COZalkyl;
X' is selected from halogen, CN, NOz, CONHz, CSNHZ, CONHalkyl,
CSNHalkyl, CONalkylz, CSNalkyl2, C, to C3 alkyl, or C, to C3 alkoxy;
Y' is from the group of H, F or C, to CQ alkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which RS is
a thiophene or furan ring substituted by X' and Y', as described above.
A further preferred subgroup group of compounds of formula 6 are those
wherein RS is a six membered ring with the structure:
~.i~
wherein X' is N or CXz,
XZ is halogen, CN, CONHz, CSNH2, CONHalkyl, CSNHalkyl, CONalkylz,
CSNa1ky12 or NOz;
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R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or SOzCF3;
R8 and R, are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN
COZR,o,
R,o is C, to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by
structure
7,
7
Wherein RS is a disubstituted benzene ring containing the substituents X and
Y as shown below
X
3'
4' ~
5'~~
Y
X is selected from halogen, CN, CONH2, CSNHZ, CONHalkyl, CSNHalkyl,
CONalkylz, CSNalkylz, CNHNOH, C, to C, alkoxy, C, to C3 alkyl, NOz, C, to C3
perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or
C, to
C3 thioalkoxy;
Y is a substituent on the 4' or 5'position from the group including H,
halogen,
CN, NOz, C, to C3 alkoxy, C, to CQ alkyl, or C, to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
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Another preferred group of formula 7 are those wherein RS is a five membered
ring with the structure shown below
X'
u~~
wherein:
U is O, S, or NR6;
R6 is H, or C, to C3 alkyl, or C, to C4 COZalkyl;
X' is selected from halogen, CN, NO2, CONH2, CSNH2, CONHalkyl,
CSNHalkyl, CONa1ky12, CSNalkyl2, C, to C3 alkyl, or C, to C3 alkoxy;
Y' is from the group of H, F or C, to C4 alkyl;
or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which RS is
a thiophene or furan ring substituted by X' and Y', as described above.
A further preferred subgroup group of compounds of formula 7 are those
wherein RS is a six membered ring with the structure:
~.i~
wherein X' is N or CX2,
XZ is halogen, CN, CONH2, CSNHZ, CONHalkyl, CSNHalkyl, CONalkylz,
CSNa1ky12 or NOz;
R, is from the group including CN, C, to C6 alkyl, substituted C, to C6 alkyl,
C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, or S02CF3;
Rg and R, are independent substituents from the group including H, C, to C6
alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic, NOZ, CN
COzR,o,
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R,o is C, to C3 alkyl;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and
some of the compounds of this invention may contain one or more asymmetric
centers and may thus give rise to optical isomers and diastereomers. While
shown
without respect to stereochemistry in Formula 1 and 2 the present invention
includes
such optical isomers and diastereomers; as well as the racemic and resolved,
enantiomerically pure R and S stereoisomers; as well as other mixtures of the
R and S
stereoisomers and pharmaceutically acceptable salts thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably
1 to 6
carbon atoms; "alkenyl" is intended to include both straight- and branched-
chain
alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8
carbon
atoms, preferably 2 to 6 carbon atoms; "alkynyl" group is intended to cover
both
straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon
triple
bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.
The term "acyl" refers to a carbonyl substituent, including both straight- and
branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon
atoms,
preferably 1 to 6 carbon atoms. The term "substituted acyl" refers to an acyl
group as
just described optionally substituted with from 1 to 6 groups chosen from the
list
halogen, CN, OH, and N02.
The term "aroyl" also refers to a carbonyl substituent carrying a phenyl group
or a heteroaromatic group. The heteroaromatic groups of this include 2-, 3- or
4-
pyridinyl, 2- and 3-furanyl, 2- or 3-thiophenyl, or 2- or 4-pyrimidinal. The
term
"substituted amyl" also refers to an aroyl group as just described optionally
substituted with from 1 to 6 groups chosen from the list halogen, CN, OH, and
N02,
The terms "substituted alkyl", "substituted alkenyl", and "substituted
alkynyl" refer to alkyl, alkenyl, and alkynyl as just described having one or
more
substituents from the group including halogen, CN, OH, NOz, amino, aryl,
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heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy,
substituted
alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These
substituents may
be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that
the
attachment constitutes a stable chemical moiety.
The term "aryl" is used herein to refer to an aromatic system which may be a
single ring or multiple aromatic rings fused or linked together as such that
at least one
part of the fused or linked rings forms the conjugated aromatic system. The
aryl
groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrohydronaphthyl, phenanthryl.
The term "substituted aryl" refers to aryl as just defined having 1 to 4
substituents from the group including halogen, CN, OH, NO2, amino, alkyl,
cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy,
alkylcarbonyl,
alkylcarboxy, alkylamino, or arylthio.
The term "heterocyclic" is used herein to describe a stable 4- to 7-membered
monocyclic or a stable multicyclic heterocyclic ring which is saturated,
partially
unsaturated, or unsaturated, and which consists of carbon atoms and from one
to four
heteroatoms selected from the group including N, O, and S atoms. The N and S
atoms may be oxidized. The heterocyclic ring also includes any multicyclic
ring in
which any of above defined heterocyclic rings is fused to an aryl ring. The
heterocyclic ring may be attached at any heteroatom or carbon atom provided
the
resultant structure is chemically stable. Such heterocyclic groups include,
for
example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl,
azepinyl,
pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
oxazolyl,
isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term "substituted heterocyclic" is used herein to describe the
heterocyclic
just defined having 1 to 4 substituents selected from the group which includes
halogen, CN, OH, NOz, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy,
alkylcarbonyl,
alkylcarboxy, alkylamino, or arylthio.
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The term "thioalkyl" is used herein to refer to the SR group, where R is alkyl
or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon
atoms.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or
substituted alkyl, containing lto 8 carbon atoms, preferably 1 to 6 carbon
atoms. The
term "aryloxy" is used herein to refer to the OR group, where R is aryl or
substituted
aryl, as defined above. The term "alkylcarbonyl" is used herein to refer to
the RCO
group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms,
preferably 1 to 6 carbon atoms. The term "alkylcarboxy" is used herein to
refer to
the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8
carbon
atoms, preferably 1 to 6 carbon atoms. The term "aminoalkyl" refers to both
secondary and tertiary amines wherein the alkyl or substituted alkyl groups,
containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, which may be
either
the same or different and the point of attachment is on the nitrogen atom. The
term
"halogen" refers to Cl, Br, F, or I.
The compounds of this invention may be prepared according to the methods
described below.
Scheme 1
R: Rz R ....:
Rz
~~ I ~° I ~ °
N
H H
4 H
3 5
R.~' R.~'
R2 Rz
Ar
I ~°
N ~ N
H H
6 7
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According to scheme 1, commercially available oxindole 3 is treated with a
strong organo-metallic base (e.g. butyl lithium, lithium diisopropylamide,
potassium
hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) under
nitrogen at
reduced temperature (ca. -20 °C) (Kende, et al, Synth. Commun., 12, 1,
1982) in the
presence of lithium chloride or N,N,N',N'-tetramethylethylene-diamine. The
resulting
di-anion is then treated with excess electrophile such as an alkyl halide,
preferably an
iodide. If R, and RZ are to be joined such as the product 4 contains a
spirocycle at
position 3, then the electrophile should be bifunctional, i.e. a diiodide.
Subsequent
bromination of 4 proceeds smoothly with bromine in acetic acid (an organic co-
solvent such as dichloromethane may be added as required) in the presence of
sodium
acetate, to afford the aryl bromide 5. The bromide 5 is reacted with a
palladium salt
(e.g. tetrakis(triphenylphoshine)palladium(0) or palladium acetate), in a
suitable
solvent (e.g. THF, dimethoxyethane, acetone, ethanol or toluene) at room
temperature
under an inert atmosphere (argon, nitrogen). The mixture is then treated with
an aryl
or heteroaryl boronic acid or boronic acid ester and a base (sodium carbonate,
triethylamine, potassium phosphate) in water or fluoride source (cesium
fluoride)
under anhydrous conditions. The required product 6 is then isolated and
purified by
standard means.
Reaction of the indoline-2-one derivative 6 with either Lawessen's reagent or
phosphorous pentasulfide in a suitable organic solvent (pyridine, THF,
dioxane,
dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature
between room temperature and the reflux temperature of the solvent provides
access
to the thiocarbonyl derivative 7. An additive such as sodium hydrogen
carbonate may
also be useful.
If R, and RZ are different then the intermediate 4 is prepared by reacting the
dianion of 3 with one equivalent of the electrophile R,-X (X = leaving group
e.g.
iodine). The resultant mono-alkylated compound may then be isolated and re-
subjected to the reaction conditions using Rz-X, or alternatively used in-situ
for the
second alkylation with RZ-X. Alternatively if the desired product 7 is to
contain RZ =
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H, then the isolated mono-alkylated intermediate is taken though the
subsequent
steps.
Scheme 2
R'
Rz
Ar
0
N
H
6
5 Other methodologies are also available for coupling the pendant aryl or
heteroaryl group, Ar, to the oxindole platform, for example reaction of
compound 5
with an aryl or heteroaryl stannane, aryl or heteroaryl zinc, or aryl or
heteroaryl
magnesium halide in the presence of a palladium or nickel catalyst (scheme 2).
The
required aryl or heteroaryl-metallic species described above are formed
through
standard techniques.
Other functionalities can also be installed into the 3-position of the
indoline
platform according to scheme 3. Oxidation of the unsubstituted indoline 8,
preferably
under neutral or acidic conditions (e.g. selenium dioxide in dry dioxane at
reflux)
affords the isatin 9. Compound 9 may be further functionalized to provide a
ketal 11
by treatment with an alcohol and acid catalyst under dehydrating conditions.
Alternatively reaction of 9 with a second ketone under suitable conditions
(piperidine
in toluene at reflux; or TiCl4/Zn in THF at reflux) affords alkylidene
derivatives 11.
Reaction of the isatin 9 with a grignard reagent or organolithium affords
tertiary
alcohols 12 (R = H). These alcohols may then be further functionalized by
alkylation
or acylation procedures.
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Scheme 3
o'~
0
Ar
~o ; I ~o > I ~o
N ~ N ~ N
H H H
8 9 10
R
R
Ar Ar
O
'N H
H
g 11
R
Nu
O ~~ ~ O
N ~ N
H H
g 12
Reaction of the indoline-2-one derivative 6 with either Lawessen's reagent or
phosphorous pentasulfide in a suitable organic solvent (pyridine, THF,
dioxane,
dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature
between room temperature and the reflux temperature of the solvent provides
access
to the thiocarbonyl derivative 7. An additive such as sodium hydrogen
carbonate may
also be useful.
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Scheme 4
(HO
13 14
R'
R2
~S
N
H
7
An alternative mode of preparation is to react compound 5 with either
Lawessen's reagent or phosphorous pentasulfide in a suitable organic solvent
(pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene,
xylene) at a temperature between room temperature and the reflux temperature
of the
solvent, under an inert atmosphere (nitrogen or argon) providing access to the
thiocarbonyl derivative 13. Then reaction of bromide 13 in an anhydrous
solvent (e.g.
THF, EtzO) with a strong base (sodium hydride preferred, sodium
hexamethyldisilazide, potassium hydride) followed by reaction at reduced
temperature (-50 to -20 °C) with n-butyllithium and N,N,N,N'-
tetramethylethylenediamine followed after a suitable period of time by a
trialkylborate (trimethyl or triisopropylborate) gives after acidic work-up
the boronic
acid 14 (scheme 4). Compound 14 may then be reacted under palladium catalyzed
conditions (tetrakis(triphenylphosphine)palladium(0) or palladium acetate,
base
(NaHC03, Na2C03, KZC03, triethylamine, CsF) solvent (toluene/EtOH/water,
THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl or
heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl
trifluoromethane
sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired
compounds 7.
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Alternatively reaction of compound 13 under palladium catalyzed conditions
(tetrakis(triphenylphosphine)palladium(0) or palladium acetate, base (NaHC03,
NazC03, KzC03, triethylamine, CsF) solvent (acetone/water, toluene/EtOH/water,
THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl or
heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl
trifluoromethane
sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired
compounds 7.
Scheme 5
R :~ ;.
Rz ~~H~B Rz
~o > I ~ ~O
N ~N
H H
15
R.~' R:
Rz ~ Rz
~O ~S
N ~ N
H H
Treatment of the bromide 5 in an anhydrous solvent (e.g. THF, Et20) with a
strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium
hydride) followed by reaction at reduced temperature (-50 to -20 °C)
with n-
butyllithium and N,N,N,N'-tetramethylethylenediamine followed after a suitable
period of time by a trialkylborate (trimethyl or triisopropylborate) gives
after acidic
work-up the boronic acid 15 (scheme 5). Compound 15 may then be reacted under
palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(0), base
(NaHC03, NaZC03, KZC03, triethylamine, CsF) solvent (toluene/EtOH/water,
THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl or
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heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl
trifluoromethane
sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired
compounds 6.
An alternative strategy would be to prepare an organo zinc or magnesium
reagent from compound 5 and react it in-situ with an aryl or heteroaryl
bromide, aryl
or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate of aryl or
heteroaryl
fluorosulfonate, under palladium catalyzed conditions to afford compound 6.
Such an
organo zinc or magnesium species could be prepared by treatment of the bromide
57
in an anhydrous solvent (e.g. THF, EtzO) with a strong base (sodium hydride
preferred, sodium hexamethyldisilazide, potassium hydride) followed by
reaction at
reduced temperature (-50 to -20 °C) with n-butyllithium and N,N,N',N'-
tetramethylethylenediamine followed after a suitable period of time by
reaction with
anhydrous zinc chloride or magnesium bromide.
Reaction of the indoline-2-one derivative 6 with either Lawesson's reagent or
phosphorous pentasulfide in a suitable organic solvent (pyridine, THF,
dioxane,
dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature
between room temperature and the reflux temperature of the solvent, under an
inert
atmosphere (nitrogen or argon) provides access to the thiocarbonyl derivative
15. An
additive such as sodium hydrogen carbonate may also be useful.
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Scheme 6
R~ R'
Rz B ~ R2
S > I ~ ~Y
N N
H H
16
Y = CHN4z
= NCN
= NSOzCF3
_ o
0
Me
Me
O
O
According to scheme 6 thioamide derivatives 7 may be converted into enamine
derivatives 16 (Wrobel, et al, J. Med. Chem., 1989, 2493).
Thus reaction of thioamide 7 (Pg = H, 2-(trimethylsilyl)-ethoxymethyl,
benzyl, etc) with triethyloxonium tetrafluoroborate followed by reaction with
a
nucleophile (nitromethane, cyanamide, trifluoromethanesulfonamide, Meldrum's
acid, etc) followed by removal of the protecting group under appropriate
conditions
(e.g. tetrabutylammonium fluoride in THF for Pg = 2-(trimethylsilyl)-
ethoxymethyl)
then gives the enamine derivatives 16. Appropriate solvents for the two steps
are
selected from dichloromethane, THF, dioxane, 1,2-dichloroethane, and the
reaction is
conducted at a temperature from -78 °C to the boiling point of the
solvent under an
inert atmosphere (nitrogen or argon).
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Ar R ~~wynu.~ A ~ Rp. nrk7
~ / ~~~~m
/ H aM
17
y.. Rn..
Ar \ ~z hydroxylamine Ar \ kz
-N
~aky1 H OH
17 Ig
'~. yuy EWG~R \ R ~ ~ R ~ \ R ~anrunuR H
g decarboxylat'ron
EWG ~ H EWG
a<N
17 19 20
Scheme 7
According to Scheme 7, treatment of intermediate 7 with an alkylating agent,
e.g., methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or 4-nitro
fluorobenzene,
in the presence of a suitable base (e.g. an amine base such as pyridine,
triethylamine
or di-iso-propylethylamine or lithium, sodium, potassium or cesium carbonate)
in a
suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a
temperature between -78 °C and the boiling point of the solvent, would
then afford
thioimino ethers 17. Subsequent reaction of intermediates 17 with
hydroxylamine or
an acid salt of hydroxylamine (e.g. the hydrochloride) in a suitable solvent
(for
example but not limited to pyridine methanol, ethanol, iso-propanol, DMF, THF
or
DMSO and optionally in the presence of an additive such as a tertiary amine
base or
sodium or potassium acetate) at a temperature between -78 °C and the
boiling point
of the solvent would then afford the N hydroxyamidines 18.
Similarly treatment of intermediates 17 with a carbon nucleophile such as a
malonate derivative (e.g., malononitrile, a cyano acetate ester, a nitro
acetate ester or
a malonate) in the presence of a suitable base (e.g. an amine base such as
pyridine,
triethylamine or di-iso-propylethylamine or lithium, sodium, potassium or
cesium
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carbonate) or a Lewis acid (e.g. boron trifluoride etherate, a lead II salt,
titanium
tetrachloride, a magnesium II salt, or a silver salt) in a solvent compatible
with the
chosen base or Lewis acid (e.g. DMF, THF, DMSO, dioxane or acetonitrile,
chloroform, benzene, toluene or dichloromethane) would then afford the adduct
19. If
the group R3 in adduct 19 is an ester of a carboxylic acid, then it may be
decarboxylated directly to give the enamine derivative 20 by treatment with,
e.g.
sodium iodide in DMSO at a temperature between room temperature and thee
boiling
point of the solvent. Alternatively the ester may be first hydrolysed to the
carboxylic
acid (by treatment with an aqueous base (e.g. lithium, sodium, or potassium
hydroxide) in a suitable solvent (e.g. THF, dioxane acetonitrile, methanol or
ethanol),
followed by decarboxylation in the presence of an acid (e.g. hydrochloric or
sulfuric
acid) in a suitable solvent (e.g. acetonitrile, THF, dioxane) to afford the
derivatives
20. Alternatively the xanthate ester of the carboxylic acid may be prepared by
reaction with a base such as sodium or potassium hydride in THF, followed by
treatment with carbon disulfide. Subsequent reaction with tributyl tin hydride
at
elevated temperatures in a solvent such as benzene or toluene under an inert
nitrogen
or argon atmosphere in the presence of a radical initiator such as benzoyl
peroxide or
azo-bis-iso-butyronitrile would then give the product 20.
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Rn.' ftn
Br Rz Br ~ Rz
S ~ ~ ~ S
N V N ~ kN
H a
aryl
13 21
Rt c R1 - '' 3
Br '\ Ra hydroxylamine Br \ RZ R' __
_ Br ~ Rz
S~ rkN ~ ~ H N OH / N N OProrectirg
aryl H 9~uD
21 22 23
Rn Rn.'
Ar ~ Rz lv ~ Rz
N '' N
~mbceng ~ ~ N~ ~ H
H gmuG N
24 IS
Scheme 8
An alternative strategy for synthesizing the product 18 is illustrated by
Scheme 8. Thus the bromide 13 (the corresponding chloride, iodide or triflate
ester
may also be employed) is treated with an alkylating agent, eg methyl iodide,
ethyl
iodide, 2,4-dinitrofluoro benzene, or 4-nitro fluorobenzene, in the presence
of a
suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso-
propylethylamine or lithium, sodium, potassium or cesium carbonate) in a
suitable
organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a
temperature
between -78 °C and the boiling point of the solvent, would then afford
thioimino
ethers 21. Subsequent reaction of intermediate 21 with hydroxylamine or an
acid salt
of hydroxylamine (e.g. the hydrochloride, hydrobromide) in a suitable solvent
(for
example but not limited to pyridine methanol, ethanol, iso-propanol, DMF, THF
or
DMSO and optionally in the presence of an additive such as a tertiary amine
base or
sodium or potassium acetate) at a temperature between -78 °C and the
boiling point
of the solvent, would then afford the N hydroxyamidine 22. Intermediate 22
could
then be protected with a compatible group (e.g. benzyl ether, acyl derivative,
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tetrahydropyranyl ether, methoxy methyl ether, silyl ether) to give the
derivative 23.
Alternately compound 21 could be reacted directly with a protected
hydroxlamine
derivative (chosen, but not limited to the protecting groups described above)
to
directly afford derivative 23. Compound 23 may then be reacted with a
palladium salt
(e.g. tetrakis(triphenylphoshine)palladium(0) or palladium acetate), in a
suitable
solvent (e.g. THF, dimethoxyethane, acetone, ethanol or toluene) at room
temperature
under an inert atmosphere (argon, nitrogen). The mixture is then treated with
an aryl
or heteroaryl boronic acid or boronic acid ester and a base (sodium carbonate,
triethylamine, potassium phosphate) in water or fluoride source (cesium
fluoride)
under anhydrous conditions, and the reaction may then be heated to the boiling
point
of the solvent. The required product 24 is then isolated and purified by
standard
means.
Compound 24 may then be de-protected under the conditions prescribed by
the nature of the protecting group. For example if the protecting group is a
benzyl
ether then treatment with boron tribromide or trimethylsilyl iodide in a
suitable
solvent (dichloromethane for example) would afford the compound 18. Other
methods to remove the benzyl ether would involve hydrogenation (hydrogen gas
or
other hydrogen source such as cyclohexadiene or ammonium formate) in the
presence
of a palladium catalyst. Solvents suitable for such a process include
methanol,
ethanol, THF, ethyl acetate and dioxane, at a temperature between room
temperature
and the boiling point of the solvent. If the protecting group was an acetal
derivative
(tetrahydropyranyl or methoxymethyl ethers) then hydrolysis could be effected
under
acidic conditions (hydrochloric acid, sulfuric acid, p-toluene sulfonic acid
or acidic
ion exchange resin) in a solvent such as methanol, ethanol, THF dioxane or
acetonitrile. If the protecting group was an acyl derivative (acetate, or
benzoate for
example) then hydrolysis could be effected under acidic conditions as
described
above or under basic conditions (lithium, sodium or potassium hydroxide) in a
solvent such as an alcohol, THF dioxane or acetonitrile at a temperature
between
room temperature and the boiling point of the solvent. If the protecting group
was a
silyl ether then compound 18 may be prepared by hydrolysing intermediate 24
under
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the acidic conditions described above or alternately by exposing compound 24
to a
fluoride source (eg potassium fluoride, cesium fluoride or tetra butyl
ammonium
fluoride) in a solvent such as an alcohol, THF dioxane or acetonitrile at a
temperature
between room temperature and the boiling point of the solvent. An inert
atmosphere
of nitrogen or argon may be necessary.
Another method of synthesizing compound 18 would be to convert the
protected N-hydroxy amidine 23 into a boronic acid or boronic acid ester (by
lithium
halogen exchange followed by quench with tri-isopropyl borate, or palladium
catalyzed coupling with diboron pinacolate) and then couple this boronic acid
or ester
derivative with an aryl chloride, bromide, iodide or triflate under a suitable
palladium
catalysis system as described previously. Subsequent deprotection as described
for
Scheme 8 would afford the desired compounds 18.
R '~.n
Ar ~ R2 ~
Ar ~ R2
~NH
H ~ H ~ ~ N
H
R~
Ar \ RZ
~N
~GN
27
Scheme 9
According to Scheme 9, treatment of the N-hydroxyamidine 18 under
reducing conditions (e.g. catalytic hydrogenation, iron in acetic acid or
hydrazine-
raney nickel) would then afford intermediate 25. Solvents suitable for such a
process
include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature
between
room temperature and the boiling point of the solvent. Protection of the
secondary
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nitrogen (a tertiary butyl carbamate is shown as a non-limiting example) under
standard conditions would then give compound 26. Reaction of compound 26 with
an
electrophilic cyanating agent (e.g. cyanogen bromide, N-cyanobenzotriazole or
cyanogen bromide/ 4-dimethylaminopyridine complex) in a suitable solvent (THF
acetonitrile or DMF, optionally in the presence of a base such as pyridine or
sodium
hydride or potassium tert-butoxide) may then afford the desired compound 27.
In
some cases the cyanation step may occur with concomitant removal of the
secondary
nitrogen protecting group, if this deprotection does not occur in-situ then a
further
hydrolysis step would be required.
An alternate synthesis of compound 27 may follow that of compound 18,
Scheme 8, where an N-cyanoamidine bromide 28, prepared from compound 22
adopting a similar strategy to the reactions shown in scheme 9, could be
coupled with
a suitable functionalised aryl boronic acid or boronic acid ester to give
compound 27.
In another strategy intermediate 28 may be converted into the corresponding
boronic
1 S acid or boronic acid ester and coupled in a Suzuki or Suzuki type
palladium coupling
with a suitable functionalised aryl bromide.
N
28
The compounds of the present invention can be used in the form of salts
derived from pharmaceutically or physiologically acceptable acids or bases.
These
salts include, but are not limited to, the following salts with inorganic
acids such as
hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the
case may be,
such organic acids as acetic acid, oxalic acid, succinic acid, and malefic
acid. Other
salts include salts with alkali metals or alkaline earth metals, such as
sodium,
potassium, calcium or magnesium in the form of esters, carbamates and other
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conventional "pro-drug" forms, which, when administered in such form, convert
to
the active moiety in vivo.
This invention includes pharmaceutical compositions and treatments which
comprise administering to a mammal a pharmaceutically effective amount of one
or
more compounds as described above, or a pharmaceutically acceptable salt
thereof, as
agonists of the progesterone receptor.
The progesterone receptor agonists of this invention, used alone or in
combination, can be utilized in methods of contraception and the treatment
and/or
prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis;
polycystic
ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary,
breast,
colon, prostate. Additional uses of the invention include stimulation of food
intake.
When the compounds are employed for the above utilities, they may be
combined with one or more pharmaceutically acceptable Garners or excipients,
for
example, solvents, diluents and the like, and may be administered orally in
such
forms as tablets, capsules, dispersible powders, granules, or suspensions
containing,
for example, from about 0.05 to 5% of suspending agent, syrups containing, for
example, from about 10 to 50% of sugar, and elixirs containing, for example,
from
about 20 to 50% ethanol, and the like, or parenterally in the form of sterile
injectable
solutions or suspensions containing from about 0.05 to 5% suspending agent in
an
isotonic medium. Such pharmaceutical preparations may contain, for example,
from
about 25 to about 90% of the active ingredient in combination with the
carrier, more
usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on
the particular compound employed, the mode of administration and the severity
of the
condition being treated. However, in general, satisfactory results are
obtained when
the compounds of the invention are administered at a daily dosage of from
about 0.5
to about 500 mg/kg of animal body weight, preferably given in divided doses
two to
four times a day, or in a sustained release form. For most large mammals, the
total
daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
Dosage
forms suitable for internal use comprise from about 0.5 to 500 mg of the
active
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compound in intimate admixture with a solid or liquid pharmaceutically
acceptable
carrier. This dosage regimen may be adjusted to provide the optimal
therapeutic
response. For example, several divided doses may be administered daily or the
dose
may be proportionally reduced as indicated by the exigencies of the
therapeutic
situation.
These active compounds may be administered orally as well as by
intravenous, intramuscular, or subcutaneous routes. Solid carriers include
starch,
lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin,
while
liquid carriers include sterile water, polyethylene glycols, non-ionic
surfactants and
edible oils such as corn, peanut and sesame oils, as are appropriate to the
nature of the
active ingredient and the particular form of administration desired. Adjuvents
customarily employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents, preserving
agents,
and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of
preparation and administration are solid compositions, particularly tablets
and hard-
filled or liquid-filled capsules. Oral administration of the compounds is
preferred.
These active compounds may also be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a
free base
or pharmacologically acceptable salt can be prepared in water suitably mixed
with a
surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under
ordinary
conditions of storage and use, these preparations contain a preservative to
prevent the
growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous
preparation of
sterile injectable solutions or dispersions. In all cases, the form must be
sterile and
must be fluid to the extent that easy syringe ability exits. It must be stable
under
conditions of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacterial and fungi. The Garner
can
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be a solvent or dispersion medium containing, for example, water, ethanol
(e.g.,
glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof,
and vegetable oil.
This invention is further understood by the following non-limiting examples.
EXAMPLE 1
5'-(3-Chlorophenyl)spiro(cyclohexane-1,3'-]3H]indolel-2'(1'H)-thione
biro[cyclohexane-1,3'-[3Hlindol]-2'-( 1'H)one
A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800
cm3) was cooled to -20°C, then n-butyllithium (2.SM in hexanes, 152
cm', 0.38 mol)
was added slowly followed by N,N,N',N'-tetramethylethylenediamine (51 cm',
0.38
mol,). After 15 min. 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and
the
mixture was allowed to warm to room temperature. After stirring for 16 h.
saturated
aqueous ammonium chloride solution ( 1 L) and EtOAc ( 1 L) were added. After
15
min., the layers were separated and the aqueous phase was extracted with EtOAc
(x2). The combined organic layers were extracted with hydrochloric acid (1N),
then
washed with brine (500 cm3), dried (MgS04), and concentrated to obtain an oil.
The
oil was triturated with hexane (200 cm') and benzene (20 cm'). The precipitate
was
collected and dried in vacuo to obtain the subtitled compound (26.3g, 69.6%)
as
colorless crystals: mp 110-114°C;'H NMR (DMSO-d6) 8 1.67 (m, lOH), 6.84
(d, 1H,
J = 8 Hz) 6.94 (t, 1 H, J = 8 Hz), 7.17 (t, 1 H, J = 8 Hz), 7.44 (d, 1 H, J =
8 Hz), 10.3
(S, 1H).
5'-Bromospiro[cyclohexane-1,3'-[3H] indoll-2'(1'H)-one
To a solution of spiro[cyclohexane-1,3'-[3H]indol]-2' (1'H)-one (17.6 g, 0.09
mol) in acetic acid (300 cm3) was added sodium acetate (8.0 g, 0.1 mol) and
bromine
( 14.6g, 0.091 mol) with stirring. After 30 min. at room temperature, the
reaction
mixture was partitioned between water and EtOAc. The aqueous phase was
extracted
twice with EtOAc. The combined organic layers were washed with water, dried
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(MgS04) and evaporated and the residue was triturated with hexane. The
precipitate
was collected, and dried in vacuo to obtain the subtitled compound (l6.Sg,
67%) as
off white crystals: mp 196 -199 °C; 'H NMR (DMSO-d6) 8 1.62 (m, l OH),
6.8 (d,
1H, J = 6.8 Hz), 7.36 (d, 1H, J= 8.2, 1.8 Hz), 7.58 (dd, 1H, J= 8.2, 1.8 Hz),
10.44 (S,
1 H).
5 ~3-chlorophenyl)spiro [cyclohexane-1,3-[3H~indoll-2( 1 H)-one
A solution of 5'-bromospiro[cyclohexane-1,3'-[3H] indol]-2'(1'H)-one (0.32
g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol)
in
dimethoxyethane (6 cm3) was stirred under Nz for 20 min.. To this mixture was
then
added 3-chlorophenylboronic acid (0.21 g, 1.37 mmol) and sodium carbonate
(0.36 g,
3.4 mmol) in water (3 cm3). The solution was brought to reflux for 6 h then
cooled to
RT, poured into water and extracted with EtOAc (x 3). The combined organic
extracts were washed with water, brine, dried (MgS04), and evaporated. The
residue
was purified by column chromatography (Si02, ethyl acetate: hexane 1:3) to
afford
the subtitled compound (0.28 g, 0.89 mmol, 80%) as a yellow solid: mp. 164-165
°C ,
1H NMR (CDC13) 8 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J= 8.1 Hz,
1H),
7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H);'3C-NMR
((CDC13)
20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94, 124.06, 125.50, 125.79,
125.97,
126.38, 128.96 (d), 132.88, 133.59, 135.60, 139.14, 142.17, 182.89 (s); MS
(EI) m/z
310, 312 (M-H)+; Anal. (C,9H,8C1N0) C, H, N.
To a solution of 5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-
2'(1'H)-one (0.63 g, 2.0 mmol) in dry xylene (20 cm3) under nitrogen was added
2,4-
bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.89 g, 2.2
mmol)
and the mixture heated under reflux. After 72h, the mixture was evaporated and
the
residue subjected to column chromatography (Si02, EtOAc: hexane, gradient
elution)
to afford a solid which was re-crystallized from di-iso-propylether/ hexane to
afford
the title compound as yellow crystals (0.17g, 0.51 mmol, 26%): mp. 223 - 227
C; d
(CDC13) 1.53 - 1.66 (m, 8H), 1.83 - 2.05 (m, 4H), 2.07 - 2.17 (m, 2H), 7.11
(d, 1H, J
= 8.0 Hz) 7.31 - 7.53 (m, 3H), 7.54 (s, 1H), 7.86 (S, 1H), 9.93 (s, 1H, br):
MS
((+APCI) m/z 328 (M + H)+.
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EXAMPLE 2
3-(1',2'-Dihydro-2'-thioxospiro f cyclohexane-1,3'-f3H~indol-5'-yl)
benzonitrile
To a solution of 5'-bromospiro[cyclohexane-1,3'-[3H] indol]-2'(1'H)-one
(1.00 g, 3.57 mmol) in dimethoxyethane (20 cm3) was added
tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol). After 15 min. 3-
formylphenylboronic acid ( 1.00 g, 6.93 g) was added followed by potassium
carbonate (2.90 g, 21 mmol) in water ( 10 cm3). After 20h at reflux, the
mixture was
cooled poured into water and extracted with EtOAc (x3). The combined organic
extract was washed with saturated brine, dried (MgS04) and evaporated. The
residue
was purified by column chromatography (SiOz, EtOAc: hexane, gradient elution)
to
afford the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, 'H NMR
(CDC13) 8 1.65 - 1.85 (m, 6H), 1.86 - 2.08 (m, 4H), 7.22 (d, 1 H, J = 8 Hz),
7.48 (dd,
1 H, J = 8, 2 Hz), 7.61 (t, 1 H, J = 8 Hz), 7.66 (d, 1 H, J = 2 Hz), 7.81 - 7.
8 8 ( m, 2H),
8.06 (t, 1H, J= 2 Hz), 8.30 (s , 1H, br); MS ((+)ESI) mlz 306 (M + H)+.
3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl) benzaldehyde
oxime
To a solution of 3-(1',2'-dihydro-2'-oxospirocyclohexane-1,3'-[3H]indol-5'-yl)
benzaldehyde (0.59 g, 1.95 mmol) in EtOH: H20 (10 cm3, 8:2) was added
hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5
mmol). After 20 min. the mixture was concentrated water was added and the
product
extracted with EtOAc (x2). The combined organic layers were washed with sat.
sodium hydrogen carbonate solution, water, sat. brine, dried (MgS04) and
evaporated
to afford the subtitled oxime (0.63 g, 1.95 mmol, 100%) which was used without
further purification, 'H NMR (CDC13) 8 1.60 - 1.84 (m, 6H), 1.85 - 2.00 (m,
4H), 6.86
(d, 1 H, J = 8 Hz), 7.36 (dd, 1 H, J = 8, 2 Hz), 7.43 - 7.50 (m, 1 H), 7.57 -
7.67 (m, 2H),
7.85 (s, 1H, br), 8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((-
)ESI) m/z 319
(M - H)'.
3-(1',2'-Dihydro-2'-oxospirofcyclohexane-1,3'~3H]indol-5'-yl) benzonitrile
A solution of 3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)
benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform ( 10 cm3) was treated
with
selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the
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mixture was concentrated and the residue purified by column chromatography
(SiOZ,
EtOAc: hexane 1:4) and the product re-crystallized from EtOAc-hexane to afford
the
subtitled compound (0.161 g, 0.53 mmol, 35%) as a white solid: mp. 190 - 191
°C; 'H
NMR (CDC13) 8 1.59 - 1.87 (m, 6H), 1.88 - 2.09 (m, 4H), 7.03 (d, 1H, J= 8 Hz),
7.42
(dd, 1H, J= 8, 2 Hz), 7.54 (t, 1H, J= 8 Hz), 7.58 - 7.65 (m, 2H), 7.78 (dt,
1H, J= 7, 2
Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M + H)+.
Reaction of 3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)
benzonitrile and Lawesson's reagent according to the procedure in example 1
gave
the title compound: mp. >231 °C (decomp.);'H NMR (DMSO-db) 8 1.38 -
1.55 (m,
3H), 1.82 - 1.99 (m, 7H), 7.16 (d, 1H, J= 8.1 Hz), 7.63 - 7.69 (m, 2H), 7.80
(d, 1H, J
= 7.7 Hz), 8.01 (d, 1 H, J = 8 Hz) and 12.76 (s, 1 H); MS ((-)-APCI) m/z 317
[M-H]-.
EXAMPLE 3
4-(1',2'-Dihydro-2'-thioxospirofcyclohexane-1,3'-[3H~indoll-5'-yl)-2-
thiophenecarbonitrile
3-(Trimeth ls~yl)-2-thiophenecarbonitrile. A solution of 3-bromo-2-
thiophenecarbonitrile (0.8 g, 4.3 mmol),
tetrakis(triphenylphosphine)palladium(0)
(0.25 g, 0.2 mmol) and hexamethylditin ( 1.4 g, 4.3 mmol) in dimethoxyethane
(5
cm') was heated under reflux for 14 h then cooled to RT. The reaction mixture
was
absorbed onto florisil and purified by column chromatography (Si02, methylene
chloride: hexane 1:9) to afford the subtitled compound ( 1.04 g, 3.8 mmol,
90%) as a
clear viscous oil: 'H NMR (CDCl3) 8 0.35 (s, 9H), 7.56 (d, J= 0.9 Hz, 1H),
7.66 (d, J
= 0.9 Hz, 1 H).
4-( 1,2-Dihydro-2-oxospiroCcyclohexane-1,3-(3H]indol]-5-yl)-2-
thiophenecarbonitrile
A solution of the 5'-bromospiro[cyclohexane-1,3'-[3H] indol]-2'(1'H)-one
(0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.1 g, 0.14
mmol)
and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm3) was stirred
under
Nz for 20 minutes. To this mixture was then added 3-(trimethylstannyl)-2-
thiophenecarbonitrile (0.64 g, 2.35 mmol). The solution was brought to reflux
for 32
h. After cooling to room temperature the reaction mixture was absorbed onto
florisil
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and purified by column chromatography (SiOz, ethyl acetate: hexane 2:3) to
afford
the subtitled compound (0.43 g, 1.39 mmol, 74%) as an off white solid: 'H NMR
(CDC13) 8 1.56-2.1 (m, lOH), 6.97 (d, J= 8.0 Hz, 1H), 7.39 (dd, J = 8.03, 1.45
Hz,
1H), 7.57 (d, J= 1.45 Hz, 1H), 7.59 (d, J= 1.4 Hz, 1H), 7.84 (d, J= 1.4 Hz,
1H), 8.32
(br s, 1H); '3C-NMR (CDC13) 8 22.07, 26.56, 34.4 (t), 48.13 (s), 110.18 (d),
111.3,
114.75 (s), 122.92, 126.76 (d), 128.44 (s), 137.55 (d), 138.11, 142.71,
144.49, 182.13
(s); MS (EI) m/z 307 (M-H)+; Anal. (C,8H,6NZOS) C, H, N.
A solution of4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-
thiophenecarbonitrile ( 1.0 g, 3.2 mmol) and Lawesson's Reagent ( 1.3 g, 3.2
mmol) in
o-xylene (20 mL) was heated for two and a half hours. The reaction mixture was
washed with distilled water (5x100 mL), dried over MgS04, and evaporated. The
product was purified by column chromatography (Si02, EtOAc:Hexane 1:5) to
afford
the title compound (0.2 g, 20%) as a pale-yellow solid: m.p. 230-232
°C; 'H-NMR
(DMSO-db) 8 12.72 (s, 1H), 8.52 (d, 1H, J = 1.5 Hz), 8.36 (d, IH, J = 1.5 Hz),
8.00 (d,
1 H, J = 1.5 Hz), 7.69 (dd, 1 H, J = 6.4, 1.8 Hz), 7.10 (d, 1 H, J = 8.3 Hz),
1.98 - 1.77
(m, 7H), 1.43 - 1.33 (m, 3H); MS (EI) M+ @ m/z 324.
EXAMPLE 4
3-(1,2-Dihydro-2-thioxospirolcyclohexane-1,3-l3Hlindoll-5-yl)-5-
fluorobenzonitrile
To a solution of 5'-bromospiro [cyclohexane-1,3'-[3H]indol]-2'-(1'H)-one
(1 lg, 0.04 mol) in dry tetrahydrofuran (200 cm3) was added sodium hydride
(60%
dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 min. stirnng at room
temperature, the mixture was cooled to -78°C and butyl lithium (1.7M in
hexanes,
23.2 cm', 0.04 mol) was added slowly. After 30 min. di-iso-propylborate (25
cm3,
0.11 mol) was added and the mixture was allowed to warm to room temperature.
After 2 hrs. hydrochloric acid (1N, 500 cm3) and ethylacetate (S00 cm3) were
added.
The aqueous phase was extracted with ethylacetate, then the combined organic
layers
were washed with water, brine, dried (MgS04) and evaporated. The residue was
triturated with hexane and the precipitate dried in vacuo to obtain (2'-oxo-2,
3-
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dihydrospiro[cyclohexane-1, 3'- [3H] indol] -5'-yl) boronic acid (8.3 g, 86%)
as an
off white solid that was used without further purification. A sample that was
further
triturated with ethyl acetate had the following properties: mp. 255-
260°C dec.; 'H
NMR (DMSO-d6) 8 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J= 7.72 Hz) 7.66 (d,
1H, J= 7.72 Hz) 7.91 (s, 3H, br), 10.36 (s, 1H);MS ((-)ESI) m/z 244 [M-H].
3-( 1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indoll-5-yl)-5-
fluorobenzonitrile.
To a solution of 3,5-dibromofluorobenzene in diethyl ether ( 100 cm3) at -78
°C was added n-butyl lithium (2.5 M, 8 cm', 20 mmol) dropwise. After 30
min. the
mixture was treated with DMF (20 cm3) in diethyl ether (10 cm3) and stirring
was
continued at -78 °C. After 30 min. the mixture was quenched with dilute
HCl aq.,
separated and the aqueous layer was extracted with EtOAc. The combined organic
layers were combined, washed with water, brine, dried (MgS04) and evaporated
to
give 3-fluoro-S-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: 'H NMR
(CDC13) 8 inter alia 7.50 - 7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS
(EI) mlz
202, 204 [M+]
To a solution of the last cited compound (4.0 g, 19.7 mmol) in ethanol:water
(8:2, 50 cm3), was added sodium acetate (1.72 g, 21 mmol) and hydroxylamine
hydrochloride (1.45 g, 21 mmol), and the mixture was heated under reflux.
After 30
min., the mixture was cooled, evaporated and the residue partitioned between
water
and EtOAc. The aqueous layer was re-extracted with EtOAc and the combined
organic layers were washed with water, saturated sodium hydrogen carbonate
solution, brine, dried (MgS04) and evaporated to give 3-fluoro-5-
bromobenzaldehyde
oxime (3.76 g, 17.24 mmol, 87%) which was used without further purification:
'H
NMR (CDCI3) 8 7.24 - 7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s,
1H); MS
(EI) m/z 217 [M+].
The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were
dissolved in acetonitrile (100 cm') under nitrogen and heated under reflux.
After Sh,
the mixture was evaporated, the residue taken into EtOAc, washed with sulfuric
acid
(1N), water, brine, dried (MgS04) and evaporated to give 3-fluoro-5-
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bromobenzonitrile (3.08 g, 15.39 mmol, 89%) which was used without further
purification.
The above bromide (3.0 g, 15 mmol) and
tetrakis(triphenylphosphine)palladium (0) (0.86 g, 0.75 mmol) were dissolved
in
dimethoxyethane (130 cm3) under nitrogen. After 15 min. (2'-oxo-2,
3-dihydrospiro[cyclohexane-l, 3'- [3H] indol] -5'-yl) boronic acid (2.82 g,
11.5
mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved in water (40 cm3) were
added, and the mixture heated under reflux. After 8h the mixture was cooled,
poured
into water and extracted with EtOAc (x3). The combined organic layers were
then
washed with water, dried (MgS04) and evaporated. The residue was then purified
by
column chromatography (EtOAc: hexane, gradient elution), and the product
recrystallized from methanol to give 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-
[3H]indol]-S-yl)-5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): mp 199 - 205
°C; 'H
NMR (CDC13) 8 1.64 -2.03 (m, lOH), 7.03 (d, 1H, J= 8 Hz), 7.31 (dt, 1H, J= 7.7
and
1.6 Hz), 7.41 (dd, 1 H, J = 8, 1.7 Hz), 7.49 (dt, 1 H, J = 9.6, 2 Hz), 7.5 8
(d, 1 H, J = 2
Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M+].
To a solution of 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-
yl)-5-fluorobenzonitrile (0.32 g, 1.0 mmol) in xylenes (10 cm3) under nitrogen
was
added Lawesson's reagent (0.89 g, 2.22 mmol) and the reaction was heated under
reflux. After 4h., the mixture was cooled, evaporated and the residue
subjected to
column chromatography (Si02, EtOAc: hexane, gradient elution) to afford (0.143
g,
0.42 mmol, 42%) as a white solid: mp. 236-250 °C; 'H NMR (CDCl3) 8 1.54
- 1.66
(m, 3H), 1.86 - 2,18 (m,7H), 7.16 (d, 1H, J= 8.1 Hz), 7.33 - 7.36 (m, 1H),
7.46 - 7.52
(m, 2H), 7.65 (s, 1H), 7.85 (d, 1H, J= 1Hz), 10.05 (s, 1H); MS ((+)-APCI) mlz
337
[M+H]+.
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EXAMPLE 5
4-Methyl-5-(1,2-dihydro-2-thioxospiro(cyclohexane-1,3-(3Hl-indoll-5-xl)-2-
thiophene thioamide
2'-oxo-2',3'-dihydrospiro [cyclohexane-1,3'-[3H]indol]-5'-yl)boronic acid
(2.45 g, 10 mmol), 2-bromo-S-cyano-3-methylthiophene (2.4 g, 12 mmol),
potassium
(4 g, 29 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.5 mmol)
in
dimethoxyethane: water: ethanol (130 cm3, 10:2:1) was heated to 80°C
for 16 h., then
poured into 1 L of water, and extracted with EtOAc. The organic layer was
washed
with brine, dried (MgS04) and concentrated. The crude product was subjected to
column chromatography (Si02, EtOAc:hexane,l:l) to obtain the title compound
(0.9
g, 28%): m.p. 200-203°C; 'H NMR (DMSO-d6) 8 1.63 (m, 8H), 1.87 (m, 2H),
2.27 (s,
3H), 6.95 (d, 1 H, J = 8.13 Hz), 7.34 (dd, 1 H, J = 8.13, 1.98 Hz) 7.54 (d, 1
H, J = 1.98
Hz), 7.82 (S, 1H) 10.50 (S, 1H); MS ((+)APC1) m/z 323 [M + H] +.
A solution of 4-methyl-5-[2'-oxo-2'3'-dihydrospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl)-2-thiophenecarbonitrile (0.61 g, 1.9 mmol) and phosphorous
pentasulfide (0.92 g, 2.1 mmol) in dioxane (17 mL) was heated to 85 °C
for 30
minutes. The reaction mixture was poured into distilled water, and washed with
aqueous NaHC03, distilled water, dried over MgS04, and evaporated to dryness.
The
residue was purified with column chromatography (2.5% MeOH/CHzCl2) to afford
the title compound (O.OSg, 8%) as a orange-brown solid: m.p. 244-249
°C; 'H-NMR
(DMSO-db) b 12.75 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H, J = 1.5
Hz), 7.58
(s, 1H), 7.45 (dd, 1H, J = 6.4, 1.8 Hz), 7.14 (d, 1H, J = 7.9 Hz), 2.26 (s,
3H), 1.98 -
1.89 (m, 7H), 1.83 - 1.81 (m, 3H); MS ((+)APCI) [M+H]+ @ m/z 373.
EXAMPLE 6 - Pharmacology
The progestational activity for the compounds of the current invention was
evaluated in the in-vitro and in-vivo assays described below. In-vitro
potencies lie in
the range 0.01 nM - 10,000 nM, and in-vivo potencies in the range 1 ug/kg to
30
mg/kg.
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A. In-vitro biology
The in-vitro biology is determined by ( 1 ) competitive Radioligand
Binding: using the A-form of the human progesterone receptor with progesterone
as
the radioligand; (2) co-transfection assay, which provides functional activity
expressed as agonist ECSO and Antagonist IC50 values; (3) a T47D cell
proliferation,
which is a further functional assay which also provides agonist and antagonist
data;
and (4) T47D cell alkaline phosphatase assay, which is a further functional
assay
which also provides agonist and antagonist data.
1. hPR Binding a~ssay - This assay is carried out in
accordance with: Pathirana, C.; Stein, R.B.; Bergen T.S.; Fenical, W.; Ianiro,
T.;
Mais, D.E.; Tones, A.; Glodman, M.E., Nonsteroidal human progesterone receptor
modulators from the marine alga cymoplia barbata, J. Steroid Biochem. Mol.
Biol.,
1992, 41, 733-738.
2. PRE-luciferase assay in CV-1 cells
The object of this assay is to determine a compound's
progestational or antiprogestational potency based on its effect on PRE-
luciferase
reporter activity in CV-1 cells co-transfected with human PR and PRE-
luciferase
plasmids. The materials methods used in the assay are as follows.
a. Growth medium: DMEM (BioWhittaker)
containing 10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-
essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM
GlutaMax (GIBCO, BRL). Experimental medium: DMEM (BioWhittaker), phenol
red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-
inactivated), 0.1 mM MEM non-essential amino acids, 100U/ml penicillin,
100mg/ml
streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
b. Cell culture, transfection, treatment, and luciferase
as_ say
Stock CV-1 cells are maintained in growth medium.
Co-transfection is done using 1.2x10' cells, 5 mg pLEM plasmid with hPR-B
inserted
at Sphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the
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luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250
ml. Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene
Pulser II.
After electroporation, cells are resuspended in growth medium and plated in 96-
well
plate at 40,000 cells/well in 200 ~1. Following overnight incubation, the
medium is
changed to experimental medium. Cells are then treated with reference or test
compounds in experimental medium. Compounds are tested for antiprogestational
activity in the presence of 3 nM progesterone. Twenty-four hr. after
treatment, the
medium is discarded, cells are washed three times with D-PBS (GIBCO, BRL).
Fifty
~1 of cell lysis buffer (Promega, Madison, WI) is added to each well and the
plates are
shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).
Luciferase
activity is measured using luciferase reagents from Promega.
c. Analysis of Results:
Each treatment consists of at least 4 replicates. Log
transformed data are used for analysis of variance and nonlinear dose response
curve
fitting for both agonist and antagonist modes. Huber weighting is used to
downweight the effects of outliers. ECSo or ICSO values are calculated from
the
retransformed values. JMP software (SAS Institute, Inc.) is used for both one-
way
analysis of variance and non-linear response analyses.
d. Reference Compounds:
Progesterone and trimegestone are reference
progestins and RU486 is the reference antiprogestin. All reference compounds
are
run in full dose-response curves and the ECSO or ICSo values are calculated.
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Table 1. Estimated ECSp, standard error (SE), and 95% confidence intervals
(CI) for reference progestins from three individual studies
EC50 95% CI
Compound Exp. (nM) SE lower upper
Progesterone 1 0.616 0.026 0.509 0.746
2 0.402 0.019 0.323 0.501
3 0.486 0.028 0.371 0.637
Trimegestone 1 0.0075 0.0002 0.0066 0.0085
2 0.0081 0.0003 0.0070 0.0094
3 0.0067 0.0003 0.0055 0.0082
Table 2. Estimated ICS°, standard error (SE), and 95% confident
interval (CI)
for the antiprogestin, RU486 from three individual studies
IC 50 95%
CI
Compound Exp. (nM) SE lower upper
RU486 1 0.028 0.002 0.019 0.042
2 0.037 0.002 0.029 0.048
3 0.019 0.001 0.013 0.027
Progestational activity: Compounds that increase PRE-luciferase activity
significantly (p<0.05) compared to vehicle control are considered active.
Antiprogestational activity: Compounds that decrease 3 nM progesterone
induced PRE-luciferase activity significantly (p<0.05)
ECS°: Concentration of a compound that gives half maximal increase
PRE-
luciferase activity (default-nM) with SE.
ICS°: Concentration of a compound that gives half maximal decrease
in 3 nM
progesterone induced PRE-luciferase activity (default-nM) with SE.
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3. T47D cell proliferation assay
The objective of this assay is the determination of
progestational and antiprogestational potency by using a cell proliferation
assay in
T47D cells. A compound's effect on DNA synthesis in T47D cells is measured.
The
materials and methods used in this assay are as follows.
a. Growth medium: DMEM: F I 2 ( 1:1 )
(GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat-
inactivated), 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax
(GIBCO, BRL).
b. Treatment medium: Minimum Essential
Medium (MEM) (#51200-038GIBC0, BRL) phenol red-free supplemented with 0.5%
charcoal stripped fetal bovine serum, 100U/ml penicillin, 200 mg/ml
streptomycin,
and 2 mM GlutaMax (GIBCO, BRL).
c. Cell culture
Stock T47 D cells are maintained in growth
medium. For BrdU incorporation assay, cells are plated in 96-well plates
(Falcon,
Becton Dickinson Labware) at 10,000 cells/well in growth medium. After
overnight
incubation, the medium is changed to treatment medium and cells are cultured
for an
additional 24 hr before treatment. Stock compounds are dissolved in
appropriate
vehicle (100% ethanol or 50% ethanol/50% DMSO), subsequently diluted in
treatment medium and added to the cells. Progestin and antiprogestin reference
compounds are run in full dose-response curves. The final concentration of
vehicle is
0.1 %. In control wells, cells receive vehicle only. Antiprogestins are tested
in the
presence of 0.03 nM trimegestone, the reference progestin agonist. Twenty-four
hours after treatment, the medium is discarded and cells are labeled with 10
mM
BrdU (Amersham Life Science, Arlington Heights, IL) in treatment medium for 4
hr.
d. Cell Proliferation Assay
At the end of BrdU labeling, the medium is
removed and BrdU incorporation is measured using a cell proliferation ELISA
kit
(#RPN 250, Amersham Life Science) according to manufacturer's instructions.
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Briefly, cells are fixed in an ethanol containing fixative for 30 min,
followed by
incubation in a blocking buffer for 30 min to reduce background. Peroxidase-
labeled
anti-BrdU antibody is added to the wells and incubated for 60 min. The cells
are
rinsed three times with PBS and incubated with 3,3'5,5'-tetramethylbenzidine
(TMB)
substrate for 10-20 min depending upon the potency of tested compounds. Then
25
~1 of 1 M sulfuric acid is added to each well to stop color reaction and
optical density
is read in a plate reader at 450 nm within 5 min.
e. Analysis of Results:
Square root-transformed data are used for
analysis of variance and nonlinear dose response curve fitting for both
agonist and
antagonist modes. Huber weighting is used to downweight the effects of
outliers.
ECS° or ICS° values are calculated from the retransformed
values. JMP software (SAS
Institute, Inc.) is used for both one-way analysis of variance and non-linear
dose
response analyses in both single dose and dose response studies.
f. Reference Compounds:
Trimegestone and medroxyprogesterone acetate
(MPA) are reference progestins and RU486 is the reference antiprogestin. All
reference compounds are run in full dose-response curves and the ECS°
or ICS° values
are calculated.
Table 3. Estimated ECSp, standard error (SE), and 95% confidence intervals
(CI) for individual studies
ECS° 95% CI
Compound Exp (nM) SE lower upper
Trimegestone 1 0.017 0.003 0.007 0.040
2 0.014 0.001 0.011 0.017
3 0.019 0.001 0.016 0.024
MPA 1 0.019 0.001 0.013 0.027
2 0.017 0.001 0.011 0.024
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Table 4. Estimated ICS°, standard error, and 95% confident interval
for the
antiprogestin, RU486
ICS° 95% CI
Compound Exp (nMl SE lower upper
RU486 1 0.011 0.001 0.008 0.014
2 0.016 0.001 0.014 0.020
3 0.018 0.001 0.014 0.022
ECS°: Concentration of a compound that gives half maximal increase
in BrdU
incorporation with SE; ICS°: Concentration of a compound that gives
half maximal
decrease in 0.1 trimegestone induced BrdU incorporation with SE
4. T47D cell alkaline phosphatase assay
The purpose of this assay is to identify progestins or
antiprogestins by determining a compound's effect on alkaline phosphatase
activity in T47D
cells. The materials and methods used in this assay are as follows.
a. Culture medium: DMEM:F 12 ( 1:1 ) (GIBCO, BRL)
supplemented with 5% (v/v) charcoal stripped fetal bovine serum (not heat-
inactivated),
100U/ml penicillin, 100 pg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
b. Alkaline php osnhatase assay buffer:
I. 0.1 M Tris-HCI, pH 9.8, containing 0.2% Triton X-100; II. 0.1 M Tris-HCI,
pH 9.8
containing 4 mM p-nitrophenyl phosphate (Sigma).
c. Cell Culture and Treatment:
Frozen T47D cells were thawed in a 37°C water
bath and diluted to 280,000 cells/ml in culture medium. To each well in a 96-
well plate
(Falcon, Becton Dickinson Labware), 180 pl of diluted cell suspension was
added.
Twenty pl of reference or test compounds diluted in the culture medium was
then
added to each well. When testing for progestin antagonist activity, reference
antiprogestins or test compounds were added in the presence of 1 nM
progesterone.
The cells were incubated at 37°C in a 5% COz/humidified atmosphere for
24 hr.
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d. Alkaline Phosphatase Enzyme Assay:
At the end of treatment, the medium was removed from
the plate and fifty ~l of assay buffer I was added to each well. The plates
were shaken
in a titer plate shaker for 15 min. Then 150 ~1 of assay buffer II was added
to each
well. Optical density measurements were taken at 5 min intervals for 30 min at
a test
wavelength of 405 nM.
e. Analysis of Results: Analysis of dose-response data
For reference and test compounds, a dose response
curve is generated for dose (X-axis) vs. the rate of enzyme reaction (slope)
(Y-axis).
Square root-transformed data are used for analysis of variance and nonlinear
dose
response curve fitting for both agonist and antagonist modes. Huber weighting
is used
to downweight the effects of outliers. ECso or ICSO values are calculated from
the
retransformed values. JMP software (SAS Institute, Inc.) is used for both one-
way
analysis of variance and non-linear dose response analyses in both single dose
and dose
response studies.
f. Reference Compounds:
Progesterone and trimegestone are reference
progestins and RU486 is the reference antiprogestin. All reference compounds
are run
in full dose response curves and the ECso or ICSO values are calculated.
Table 5. Estimated ECSp, standard error (SE), and 95% confidence intervals
(CI) for reference progestins from three independent experiments
EC50 95% CI
Compound Exp (nM) SE lower upper
Progesterone 1 0.839 0.030 0.706 0.996
2 0.639 0.006 0.611 0.669
3 1.286 0.029 1.158 1.429
Trimegestone 1 0.084 0.002 0.076 0.091
2 0.076 0.001 0.072 0.080
3 0.160 0.004 0.141 0.181
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Table 6. Estimated ICSp, standard error, and 95% confident interval for the
reference antiprogestin RU486 from three independent experiments
IC SO 95% CI
Compound Exp (nM) SE lower ~uer
RU486 1 0.103 0.002 0.092 0.11
S
2 0.120 0.001 0.115 0.126
3 0.094 0.007 0.066 0.134
B. In-vivo Biology
The primary in-vivo assay is the rat decidualization model which may be used
to determine progestational effects of both agonists and antagonists. The
secondary
in-vivo assay is the rat ovulation inhibition model which is under development
and
hence the protocol is un-available.
1. Rat decidualization assay: The objective of this procedure is
used to evaluate the effect of progestins and antiprogestins on rat uterine
decidualization and compare the relative potencies of various test compounds.
The
materials and methods used in this assay are as follows.
a. Methods: Test compounds are dissolved in 100%
ethanol and mixed with corn oil (vehicle). Stock solutions of the test
compounds in
oil (MazolaTM) are then prepared by heating (~80 oC) the mixture to evaporate
ethanol. Test compounds are subsequently diluted with 100% corn oil or 10%
ethanol in corn oil prior to the treatment of animals. No difference in
decidual
response was found when these two vehicles were compared.
b. Animals (RACUC protocol #5002
Ovariectomized mature female Sprague-Dawley rats (~60-day old and 230g)
are obtained from Taconic (Taconic Farms, NY) following surgery. Ovariectomy
is
performed at least 10 days prior to treatment to reduce circulating sex
steroids.
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Animals are housed under 12 hr light/dark cycle and given standard rat chow
and
water ad libitum.
c. Treatment
Rats are weighed and randomly assigned to groups of 4
or 5 before treatment. Test compounds in 0.2 ml vehicle are administered by
subcutaneous injection in the nape of the neck or by gavage using 0.5 ml. The
animals are treated once daily for seven days. For testing antiprogestins,
animals are
given the test compounds and a EC50 dose of progesterone (5.6 mg/kg) during
the
first three days of treatment. Following decidual stimulation, animals
continue to
receive progesterone until necropsy four days later.
d. Dosing
Doses are prepared based upon mg/kg mean group body
weight. In all studies, a control group receiving vehicle is included.
Determination of
dose-response curves is carried out using doses with half log increases (e.g.
0.1, 0.3,
1.0, 3.0 mg/kg...).
e. Decidual induction
Approximately 24 hr after the third injection, decidualization
is induced in one of the uterine horns by scratching the antimesometrial
luminal
epithelium with a blunt 21 G needle. The contralateral horn is not scratched
and
serves as an unstimulated control. Approximately 24 hr following the final
treatment,
rats are sacrificed by C02 asphyxiation and body weight measured. Uteri are
removed and trimmed of fat. Decidualized (D-horn) and control (C-horn) uterine
horns are weighed separately.
f. Analysis of Results:
The increase in weight of the decidualized uterine horn is
calculated by D-horn/C-horn and logarithmic transformation is used to maximize
normality and homogeneity of variance. The Huber M-estimator is used to down
weight the outlying transformed observations for both dose-response curve
fitting and
one-way analysis of variance. JMP software (SAS Institute, Inc.) is used for
both one-
way ANOVA and non-linear dose-response analyses.
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g. Reference Compounds:
All progestin reference compounds were run in full dose-
response curves and the ECSO for uterine wet weight were calculated.
Table 7. Estimated ECSO, standard error (SE), and 95% confidence intervals for
individual studies
ECS° 95% CI
Compound Exp (m,~/k~, s.c.) SE lower upper
Progesterone 1 5.50 0.77 4.21 7.20
2 6.21 1.12 4.41 8.76
20
3-Ketodesogestrel 0.11 0.02 0.07 0.16
1
2 0.10 0.05 0.11 0.25
3 0.06 0.03 0.03 0.14
Levonorgestrel 1 0.08 0.03 0.04 0.16
2 0.12 0.02 0.09 0.17
3 0.09 0.02 0.06 0.13
4 0.09 0.02 0.06 0.14
MPA 1 0.42 0.03 0.29 0.60
2 0.39 0.05 0.22 0.67
3 0.39 0.04 0.25 0.61
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Table 8. Estimated average ECso~ standard error, and 95% confidence
intervals for dose-response curves of 3 reference compounds
EC50 95% CI
Compound (m /g-kg SE lower upper
s.c.)
Progesterone 5.62 0.62 4.55 7.00
3-Ketodesogestrel0.10 0.02 0.07 0.14
Levonorgestrel 0.10 0.01 0.08 0.12
Table 9. Estimated ICSO, standard error, and 95% confident interval for the
antiprogestin, RU 486
ICS° 95% CI
Compound Exp. (m~~p.o.) SE lower upper
RU 486 1 0.21 0.07 0.05 0.96
1 S 2 0.14 0.02 0.08 0.27
Concentration: Compound concentration in assay(default-mg/kg body
weight)
Route of administration: Route the compound is administered to the animals
Body weight: Mean total animal body weight (default-kg)
D-horn: Wet weight of decidualized uterine horn (default-mg)
C-horn: Wet weight of control uterine horn (default-mg)
Decidual response: [(D-C)/C]x100%
Progestational activity: Compounds that induce decidualization significantly
(p<0.05) compared to vehicle control are considered active
Antiprogestational activity: Compounds that decrease ECS°
progesterone
induced decidualization significantly (p<0.05)
ECS° for uterine weight: Concentration of compound that gives half
maximal
increase in decidual response (default-mg/kg)
ICS° for uterine weight: Concentration of compound that gives half
maximal
decrease in ECSO progesterone induced decidual response (default-mg/kg)
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Table 10. Data for Representative Compounds
Example Ki/nM CV-1 EC50/nM Ovulation
#
inhibition
IC 100
mg/kg
S 0.3
3 0.1 0.2
1 0.2 0.8
4 0.06 0.1 0.1
Example 7
5-(1,2-Dihydro-2-thioxospirolcyclopentane-1,3-(3Hlindoll-5'-yl)-1H-pyrrole-2
carbonitrile
5-(2'-Oxo-2',3'-dihydrospiro[cyclopentane-1 3'-[3HJindol]-5'-yl-2-
cyanopyrrole: A solution of 5'-bromospiro[cyclopentane-1,3'-[3HJ indolJ-
2'(1'H)-
one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg,
0.3
mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of
nitrogen
for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-
boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in
water (10
mL). The mixture was heated to 80 °C for 3 h and allowed to cool. The
reaction
mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x SO
mL).
The organic layers were combined, washed with brine (30 mL) and dried over
magnesium sulfate. The solution was filtered and concentrated in vacuo.
Crystallization from 20% ethyl acetate/hexane gave 2-( 1',2'-dihydro-2'-
oxospiro[cyclopentane-1,3'-[3HJindolJ-5'-yl)-1H-pyrrole-1-carboxylic acid,
tert-butyl
ester (2.2 g, 83%) as a white powder, mp 179-180.5 °C. 'H NMR (DMSO-d6,
400
MHz) 8 1.30 (s, 9H), 1.75-1.98 (m, 8 H), 6.16 (dd, 1 H, J= 1.8, 3.3 Hz), 6.22
('t', 1
H, J= 3.3, 3.3 Hz), 6.79 (d, 1 H, J= 7.9 Hz), 7.08 (dd, 1 H, J= 1.8, 7.9 Hz),
7.14
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('d', 1 H, J= 1.5 Hz), 7.28 (dd, J= 1.9, 3.3 Hz),10.30 (s, 1 H). MS (EI) mlz
352
[M+]. Anal. Calcd for CZ,HZqN203: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08;
H,
6.83; N, 7.74.
To a solution of 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-
yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 6.0 mmol) in THF
(anhydrous, 25 mL) was added at -78 °C chlorosulfonyl isocyanate (0.63
mL, 7.0
mmol). After 90 min, dimethylformamide ( 11 mL, 140 mmol) was added and the
reaction was allowed to warm to room temperature. The reaction mixture was
poured
into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic
layers
were combined, washed with brine (50 mL), dried over magnesium sulfate,
filtered
and concentrated in vacuo. Purification via flash column chromatography on
silica
gel (30% ethyl acetate/hexane) gave 5-(2'-oxo-2',3'-dihydrospiro[cyclopentane-
1,3'-
[3H]indol]-5'-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (1.7 g,
75%) as
white crystals, mp 167-9 °C. 'H NMR (DMSO-db, 400 MHz) 8 1.34 (s, 9H),
1.75-
1.98 (m, 8 H), 6.39 (d, 1 H, J= 3.7 Hz), 6.84 (d, 1 H, J= 7.9 Hz), 7.17 (dd, 1
H, J=
1.8, 7.9 Hz), 7.28 ('t', 2 H), 10.41 (s, 1 H). MS (ESI) m/z 376 [M-H]-. Anal.
Calcd.
for CZZH23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,
11.04.
5-(2'-Oxo-2',3'-dihydrospiro[cyclopentane-1,3'-[3H]indol]-5'-yl-2
cyanopyrrole-1-carboxylic acid, tert-butyl ester (1 g, 2.7 mmol) was placed in
a 25
mL round bottomed flask stoppered with a rubber septum and equipped with
nitrogen
inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was
maintained as the flask was placed in an oil bath and heated to 165 °C.
After 20 min
at this temperature, the flask was removed from the oil bath and allowed to
cool.
Crystallization from ethyl ether gave the title compound (600 mg, 79%) as a
yellow
powder, mp 285-286 °C. 'H NMR (DMSO-db, 400 MHz) 8 1.75-2.03 (m, 8 H),
6.60
(dd, 1 H, J= 2.4, 3.7 Hz), 6.84 (d, 1 H, J= 8.1 Hz), 6.94 (dd, 1 H, J= 2.4,
3.7 Hz),
7.52 (dd, 1 H, J= 1.8, 8.1 Hz), 7.60 (d, 1 H, J= 1.8 Hz), 10.38 (s, 1 H),
12.45 (s, 1
H). MS (ESI) m/z 276 [M-H]-. Anal. Calcd. For C"H,SN30: C, 73.63; H, 5.45; N,
15.15. Found: C, 73.24; H, 5.34; N, 14.96.
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To 5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-
pyrrole-2-carbonitrile (0.18 g, 0.7 mmol, 1 eq) in p-xylene (20 mL) was added
Lawesson's reagent (0.14 g, 0.36 mmol, 0.5 eq) and the reaction was heated to
reflux
for 1 hour. The reaction was cooled to room temperature and adsorbed onto
silica
gel. Purification by flash column chromatography (20% ethyl acetate/hexane) on
silica gel gave the product as an orange powder. Further purification by HPLC
gave
the title compound as a green solid (0.144 g, 70%), mp 275-276 °C
(dec.). 'H NMR
(db-DMSO, 300 MHz) 8 1.81-2.16 (m, 8 H), 6.69 (dd, 1 H, J= 2.3, 3.7 Hz), 6.98
(dd,
1 H, J = 1.8, 3.7 Hz), 7.04 (d, 1 H, J = 8.2 Hz), 7.63 (dd, 1 H, J = 1.6, 8.2
Hz), 7.72
(d, 1 H, J= 1.3 Hz), 12.57 (s, 1 H), 12.65 (s, 1 H). MS (ESI) [M-H)-= 292.
Anal.
Calculated (cald.) for C"H,SN3S: C, 69.6; H, 5.15; N, 14.32. Found: C, 69; H,
5.31;
N, 13.81.
Example 8
5-(1,2-DihYdro-2-thioxospirolcyclohexane-1,3-f3Hlindoll-5-yl)-1-(tert-
butoxycarbon~)-pyrrole-2-carbonitrile
To a solution of 5'-bromo-spiro[cyclohexane-1,3'-indolin]-2'-one (3.4 g, 12
mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added
tetrakis(triphenylphospine)palladium(0) (70 mg, S mol%). After 15 min, 2-
borono-
1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol)
and a
solution of KZC03 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added
sequentially. The solution was heated to 80 °C for 3 h and allowed to
cool. The
reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 x
100
mL). The organic layers were combined, washed with brine (150 mL) and dried
over
MgS04. The solution was filtered, concentrated in vacuo, and the residue was
purified by flash column chromatography on silica gel (eluting with 30%
EtOAc/hexane) to give 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-
5'-
yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white
powder, mp
177 °C. 'H NMR (CDC13; 300 MHz) 8 1.38 (s, 9 H), 1.59-1.93 (m, 10 H),
6.18 (m, 1
H), 6.23 ('t', 1H, 3 Hz), 6.91 (d, 1 H, J--8 Hz), 7.21 (d, 1 H, J--8 Hz), 7.34
(m, 1 H),
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7.44 (s, 1 H), 8.33 (br s, 1 H, DZOex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal.
Calcd for Cz2H26N2~3~ C~ 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N,
7.5.
To a solution of 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-
yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (0.75 g, 2 mmol) in THF
(anhydrous, 20 mL) at -78 °C was added chlorosulfonyl isocyanate (1.15
eq, 0.23 mL,
2.3 mmol). After 90 min, DMF (20 eq, 3.6 mL, 46 mmol) was added and the
reaction
was allowed to warm to room temperature. The reaction mixture was poured into
water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layers
were
combined, washed with brine (50 mL), dried over magnesium sulfate, filtered
and
concentrated in vacuo. Purification via flash column chromatography on silica
gel
(30% ethyl acetate/hexane) gave 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (0.5 g,
63%) as an
oil which crystallized from acetone to give white crystals, mp 156 °C.
'H NMR (db
DMSO, 400 MHz) 8 1.32 (s, 9H), 1.50 (m, 3 H), 1.60-1.70 (m, 5 H), 1.75-1.85
(m, 2
H), 6.38 (d, 1 H, J= 3.7 Hz), 6.87 (d, 1 H, J= 7.9 Hz), 7.18 (dd, 1 H, J= 1.5,
7.9 Hz),
7.27 (d, 1 H, J= 3.7 Hz), 7.48 (d, 1 H, J= 1.8 Hz), 10.42 (bs, 1 H). MS (EI)
m/z 391
(M+). Anal. Calcd for CZ3HZSN3O3: C, 70.57; H, 6.44; N, 10.73. Found: C,
69.82; H,
6.46; N, 10.43.
To a solution oft-Cyano-5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-
[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (0.7 g, 1.8
mmol, 1 eq)
in toluene (70 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq)
and the
reaction was heated to reflux for 1 hour. The reaction was cooled to room
temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x
100
mL). The organic layers were combined, washed with brine (50 mL), dried over
magnesium sulfate, filtered and concentrated in vacuo. Purification by flash
column
chromatography (20-30% ethyl acetate/hexane) on silica gel gave title compound
as a
yellow solid (0.7 g, 96 %). 'H NMR (db-DMSO, 500 MHz) 8 1.30-1.98 (m, 19 H),
6.45 (d, 1 H, J= 3.7 Hz), 7.09 (d, 1 H, J= 7.9 Hz), 7.31-7.34 (m, 2 H), 7.81
(d, 1 H, J
= 1.4 Hz), 12.74 (s, 1 H). MS (ESI) [M-H]- = 406. Anal. calcd. for
Cz3HzsN3OzS: C,
67.79; H, 6.18; N, 10.31. Found: C, 67.86; H, 5.99; N, 10.25.
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Example 9
5-~-Dihydro-2-thioxospiro[cyclohexane-1,3-[3Hlindol]-S~r~-1-H-pyrrole-2-
rarhnnitrilP
To a solution of 5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-
yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile (0.5 g, 1.2 mmol, 1 eq) in
THF (5
mL) was added NaOEt (0.25 g, 3.6 mmol, 3 eq) in EtOH (5 mL) and the reaction
was
heated to 80°C for 24 h. The solvents were removed in vacuo and the
residue
partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate (50 mL). The
organic layers were combined, washed with brine (50 mL), dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by flash column
chromatography (30% ethyl acetate/hexane) on silica gel gave the title
compound
(0.27g, 68%) as a yellow powder. 'H NMR (db-DMSO, 500 MHz) 8 1.32-1.99 (m, 10
H), 6.71 (d, 1 H, J= 3.7 Hz), 7.00 (d, 1 H, J= 3.7 Hz), 7.09 (d, 1 H, J= 8.4
Hz), 7.70
(dd, 1 H, J= 1.6, 8.4 Hz), 8.05 (d, 1 H, J= 1.1 Hz), 12.67 (s, 1 H), 12.73 (s,
1 H). MS
(ESI) [M-H]-= 306. Anal. calcd. for C,BH"N3S: C, 70.33; H, 5.57; N, 13.67.
Found:
C, 69.64; H, 5.79; N, 13.04.
Example 10
5-(2'-thioxospiro[cyclohexane-1,3'-(3Hlindoll-5'-yl~ 1-meth,~pyrrole-2-
carbonitrile
To a solution of 5-(2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1-methyl-
pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 eq) in toluene (50 mL) was added
Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated to
80 °C
for 1 hour. The reaction was cooled to room temperature, poured into water
(100 mL)
and extracted with ethyl acetate (2 x 100 mL). The organic layers were
combined,
washed with brine (50 mL), dried over magnesium sulfate, filtered and
concentrated
in vacuo. Purification by flash column chromatography on silica gel gave the
product
as a white solid (0.32 g, 55 %). 'H NMR (d6-DMSO, 500 MHz) 8 1.36-1.99 (m, 10
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H), 3.7 (s, 3 H), 6.35 (d, 1 H, J= 4.2 Hz), 7.05 (d, 1 H, J= 4.2 Hz), 7.16 (d,
1 H, J=
7.9 Hz), 7.44 (dd, 1 H, J= 1.6, 8.1 Hz), 7.83 (d, 1 H, J= 1.6 Hz), 12.75 (s, 1
H). MS
(ESI) [M-H]-= 320. Anal. calcd. for C,9H,9N3S: C, 70.99; H, 5.96; N, 13.07.
Found:
C, 68.69; H, 5.36; N, 12.27.
Example 11
5-(1,2-Dihydro-2-thioxospirolc~lopentane-1,3-f3Hlindoll-5-vl)-3-
thiophenecarbonitrile
5-Bromo-2-thiophenecarbonitrile: A mixture of S-bromo-2-
thiophenecarboxaldehyde (96.Og, 500 mmol), hydroxylamine hydrochloride ( 111.9
g,
S00 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen
at
reflux for two hours. The reaction mixture was cooled to ambient temperature
and
concentrated in vacuo to give an oil. The crude product was triturated twice
with ice
water and the solid obtained was collected on a filter. A mixture of a portion
of the
above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21
mmol) in
acetonitrile ( 1.4L) was heated at reflux for three hours. The solvent was
removed in
vacuo and the residue was dissolved in ethyl acetate. The solution was washed
with
5% aqueous sulfuric acid (2X30 mL), water (2X30 mL), brine (20 mL), and dried
(MgS04). The solvent was removed in vacuo and the residue was dissolved in a
minimum amount of chloroform ( 1 L) and allowed to crystallize. The crystal
obtained
was collected on a filter and the filtrate was concentrated and purified by a
chromatography (silica gel, chloroform) to give the subtitled compound as an
off
white solid (3l.Sg combined, 58%). IR (film) cm' 2200. 'H-NMR (CDCI3) 8 7.39-
7.38 (d, 1H, J= 4. 1 Hz), 7.10 (d, 1H, J= 4.0 Hz); MS (EI) mlz 187 (M+, 98%)
189(M+, 100%).
5-( 1,2 -dihydro-2-oxospiro[ cyclopentane-1,3-[ 3H]indole]-5-yl)-3-
thiophenecarbonitrile was prepared according to the procedure for Example 5
using 5-
bromo-2-thiophenecarbonitrile and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl) boronic acid: mp. 225-228°C; 'H NMR (DMSO-db) 8 1.63
(m, 8H),
1.90 (m, 2H) 6.91 (d, 1H, J= 8.13 Hz), 7.55 (dd, 1H, J= 8.13 , 1.76Hz), 7.60
(d, 1H,
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J= 4.17 Hz), 7.75 (d, 1H, J= 1.76 Hz), 7.93 (d, 1H, J= 4.17 Hz), 10.51 (s,
1H); MS
((+)APC1) m/z 309 [M + H]+.
A solution of 5-( 1,2 -dihydro-2-oxospiro[ cyclopentane-1,3-[ 3H]indole]-5-
yl)-3-thiophenecarbonitrile (0.66 g, 2.4 mmol ), and 2,4-bis (4-methoxyphenyl
)-1,3-
dithia-2,4-diphosphetane-2,4-disulfide ( 0.97 g, 2.4 mmol ) in toluene (250
ml) was
stirred at 80°C for 2 hours. The solution was concentrated in vacuo.
The residue was
extracted with ethylacetate, the ethylacetate solution was washed with water,
dried
over magnesium sulfate, and concentrated. The residue was purified by column
chromatography (silica gel, ethylacetate, hexane 20/80) to afford the title
compound,
m.p. 269-272 °C (0.24 g, 32% ). 'H-NMR ( DMSO-db ) 8 2.09 ( m, 8H ),
7.05 (d,
J--8.1 Hz, 1H ), 7.55 ( dd, J--8.1, 1.7 Hz, 1H ), 7.7 (d, J--1.7 Hz, 1H ),
7.95 (d, J--1.3
Hz,IH ),8.49 ( d, J--1.3 Hz, 1H ), 8.49 (d, J--1.3 Hz, 1H ), 12.68 (s, 1H );
MS ( EI
NEG ) m/z 309 ( M-H )-.
Example 12
1,2-Dihydro - thioxos~ro ( cyclopentane - 1,3-f3 H lindol) - 5- 1
thiophenecarbonitrile
The title compound was prepared from 5- (1,2-dihydro-
oxospiro(cyclopentane - 1,3- [3 H ] indol )-5 yl ~2-thiophenecarbonitrile (2 g
,6.8
mmol ) and Lawesson's reagent (3.32 g ,8.2 mmol ) heated to reflux in toluene
( 150
mL ) for 3 hours. Yield 1.5 g (48.3 % ).m.p. 250-253~C.'H NMR (DMSO-d6) 8
12.75
( S,1H),7.98-7.97(d, 1 H,J=3.9Hz),7.71-7.70(d, 1 H,J=5.2Hz),7.65-7.62(
d, 1 HJ--8.1 Hz),7.09-7.07(d, 1 H,J=8.1 Hz)2.132.08(m, 6H), 1.99-1.85(
m, 2 H ); MS. [ M-H]- = 309 .IR ( SP ATR ) 1430,1620,2220
crri'.Anal.C"H,4NzSz.
calc C,65.77;H,4.55; N , 9.02. obs'd C65.27; H,4.41 ; N , 8.84.
Example 13
5-I 3-Fluoro-4-methoxyphen~piro[cYClohexane-1,3-f3Hlindolel-2(1H)-thione
5-(3-Fluoro-4-methoxyphen~)spiro[cyclohexane-1,3-[3H]indol]-2( 1 H)-one:
Prepared from 4-bromo-2-fluoroanisole and (2'-oxo-2',3'-
dihydrospiro[cyclohexane-
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1,3'-[3H]indol]-5'-yl) boronic acid according to the procedure for example 5
to afford
the subtitled compound as a white solid, mp. 178 - 180 °C; 'H-NMR (DMSO
- db) 8
10.4 (s, 1H), 7.65 (d, 1H, J= 1.1 Hz), 7.5 - 7.4 (m, 3H), 7.2 (t, 1H, J= d J=
8.8
Hz), 3.9 (s, 3H), 1.9 (m, 2H) 1.7 - 1.6 (m, 8H); MS (APCI (-)) m/z 324 [M-H]~;
Anal.
Calc. For CzoHz°FNOz. : C, 73.83, H, 6.20, N, 4.30. Found: C, 73.55, H,
6.23, N, 4.40.
The title compound was prepared by refluxing overnight a mixture of 5-(3-
Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-one and an
equal
weight of phosphorus pentasulfide in pyridine. Removal of the pyridine in
vacuo
followed by treatment of the residue with 5N hydrochloric acid solution and
subsequent recrystallization in ethanol gave a grey solid, mp 228-
229°C; 'H-NMR
(DMSO-d6) 8 12.7 (s, 1H), 7.9 (s, 1H), 7.6 - 7.5 (m, 2H), 7.5 - 7.4 (m, 1H),
7.2 (t, 1H,
J= 8.8 Hz), 7.1 (d, 1H, J= 8.1 Hz), 3.9 (s, 3H), 1.9 - 1.8 (m, 7H), 1.4 - 1.3
(m, 3H);
MS (APCI (-)) [M-H]-m/z 324. Anal. Cal. for CzoHzoFNOS. 0.25 H20 C, 69.44; H,
5.97; N, 4.05. Found: C, 69.43; H, 5.75; N, 4.32.
Example 14
5-(2-Amino-5-pyrimidin~piro[cyclohexane-1,3-[3Hl indole]-2(1H)-thione
Prepared by refluxing overnight a mixture of 5-(2-amino-5-
pyrimidinyl)spiro[cyclohexane-1,3-[3H]-indole]-2(1H)-one and an equal weight
of
phosphorus pentasulfide in pyridine. Removal of the pyridine in vacuo followed
by
treatment of the residue with 5N hydrochloric acid solution and subsequent
recrystallization in ethanol gave a grey solid; mp 274 - 277 °C (dec.);
'H-NMR
(DMSO-db) 8 12.7 (s, 1H), 8.6 (s, 2H), 7.9 (s, 1H), 7.5 (d,lH, J= 8.1 Hz), 7.1
(d, 1H,
J= 8.1 Hz), 6.8 (s, 2H), 1.9 -1.8 (m, 7H), 1.4 - 1.3 (m, 3H). MS (APCI (-)) [M-
H]~ m/z
309.
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Example 15
3-(1,2-Dihydro-2-thioxospirofcyclopentane-1,3-[3Hjindoll-5-X1L
fluorobenzonitrile
Spiro(cyclopentane-1,3'-[3H]indol]-2'(1'H)-one
To a -25 °C solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of
anhydrous
THF under NZ was added n-butyllithium ( 1.6 M in hexanes, 19.7 cm3, 31.5 mmol)
drop-wise. To the resulting milky solution was added N,N,N',N'-
tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of
1,4-
diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction
mixture
was allowed to warm to RT and stirred for 14 h. The reaction mixture was
poured into
water, extracted with EtOAc (x 2), the combined organic layers were washed
with
dilute HCl (pH 1) and water (x 2), dried (MgS04) and evaporated. The residue
was
purified by column chromatography (Si02, EtOAc: hexane 1:4) to afford the
subtitled
compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 'H NMR (CDCI3) 8 1.8-2.2 (m,
8H),
6.94 (dd, J= 7.5, 1.0 Hz, 1H), 7.01 (dd, J7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H),
9.30
(br s, 1 H).
S-Bromo-spiro[cyclopentane-1,3'-(3H]indol]-2'( 1'H)-one
A solution of spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one (0.27 g, 1.4
mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid ( 10 cm3) was
treated
with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the
mixture
was poured into sat. sodium hydrogen carbonate solution and extracted with
EtOAc
(x 2), the combined organic layers were washed with water, sat. sodium
hydrogen
carbonate solution, water, dried (MgS04), and evaporated to give the subtitled
compound (0.37 g, 1.47 mmol, 96 %) as an off white solid which was used
without
further purification: 'H NMR (CDC13) 8 1.8-2.27 (m, 8H), 6.79 (d, J= 8 Hz,
1H),
7.30-7.39 (m, 2H), 8.63 (br s, 1H).
5'-(3-Cyano-5-fluorophenyl)-spiro [cyclopentane-1,3'-[3H]indol]-2'( 1'H)-one:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis
(triphenylphosphine) palladium(0) (0.2 g) in ethylene glycol dimethyl ether
(20 cm3)
was stirred under Nz for 20 minutes. To this mixture was then
(spiro[cyclopentane-
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1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium
carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to
reflux for
18 hours and then cooled to room temperature, poured into 2N NaOH and
extracted
with EtOAc (x 3). The combined extracts were washed with water, brine, dried
(MgS04), and evaporated. The residue was purified by column chromatography
(Si02, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white
needles. mp: 235 - 237 °C; 'H NMR (DMSO-db) 8 10.5 (s, 1H), 8.1 (s,
1H), 8.0 (dt,
1 H, J = 1.7, 2.0, 7.0 Hz), 7.8 - 7.7 (m, 2H), 7.6 (dd, 1 H, J = 1.8, 6.4 Hz),
6.9 (d, 1 H, J
= 8.1 Hz), 2.0 - 1.9 (m, 8H); MS (EI) M+ @ m/z 306.
General Procedure A
The title compound was prepared from S'-(3-Cyano-5-fluorophenyl)-
spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one (40 mg) and Lawesson's reagent
(50
mg) in toluene ( 10 ml) at reflux in a sealed tube for 16 h. The mixture was
concentrated and the residue dissolved in a minimal amount of THF, then
purified by
HPLC (SiOZ, 30 cm x 2.5 cm, EtOAc-Hexane 2:8 at 20 ml/min.) to afford the
title
compound (0.022 g) as an off white solid: mp. 236 - 238 °C; 'H NMR
(DMSO-db) 8
12.66 (br s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, J= 10.1 and 2.2 Hz), 7.79 - 7.76
(m, 2H),
7.68 (dd, 1H, J= 8.1 and 1.7 Hz), 7.07 (d, 1H, J= 8.1 Hz), 2.10 - 2.05 (m, 6H)
and
1.97 - 1.88 (m, 2H); MS (EI) m/z 322 [M]+.
Example 16
5-(3-chloropheny_l~l-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione
5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one. 5-bromo-1,3-dihydro-
3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and
tetrakis(triphenylphosphine)palladium(0) (0.239 g) were stirred under an
atmosphere
of nitrogen in dimethoxyethane (35 cm'). After 1 S min., 3-chlorophenylboronic
acid
(1.27 g, 8.13 mol) was added, followed by potassium carbonate (3.40 g, 45
mmol) in
water (15 cm3). The reaction was heated to reflux for 2 hours and then stirred
at room
temperature overnight. The mixture was diluted with sat. ammonium chloride and
extracted with EtOAc (x3). The combined organic layers were dried (MgS04),
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filtered, and evaporated. The residue was purified by column chromatography
(Si02,
EtOAc: hexane, 1:3) to afford the subtitled compound (0.284 g, 25%): mp 188 -
189
°C; 'H NMR (DMSO-db) 8 3.34 (s, 6 H), 6.93 (d, 1 H, J= 8.04 Hz), 7.38-
7.35 (m, 1
H), 7.53-7.43 (m, 2 H), 7.61 (d, 1 H, J= 7.68 Hz), 7.70 (s, 2 H), 10.40 (s, 1
H); IR
(KBr) 3420, 3150, 3050, 1700 cm'; MS (EI) m/z 270 (M-H)-; CHN calculated for
C,6H,4C1N0 + O.1C4H80z: C, 70.21; H, 5.32; N, 4.99; Found: C, 70.3; H, 5.44;
N,
4.93.
The title compound was prepared from 5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-
dihydro-indol-2-one ( 100 mg) and Lawesson's reagent ( 120 mg) in toluene ( 10
ml) at
reflux, according to General Procedure A, to afford the title compound (0.031
g) as an
off white solid: mp. 158 - 160 °C;'H NMR (CDC13) 8 9.67 (br s, 1H),
7.55 (s, 1H),
7.47 - 7.43 (m, 3H), 7.40 - 7.30 (m, 2H), 7.08 (d, 1H, J= 8.7 Hz) and 1.50 (s,
6H);
MS (EI) m/z 287/289 [M]+.
Example 17
3-Benzyl-5-(3-chlorophenyl~-3-methyl-1,3-dihydro-2H-indole-2-thione
The title compound was prepared from 3-benzyl-5-(3-chloro-phenyl)-3-
methyl-1,3-dihydro-indol-2-one (100 mg) and Lawesson's reagent (120 mg) in
toluene (10 ml) at reflux, according to General Procedure A, to afford the
title
compound (0.022 g) as an off white solid: mp. 168 - 170 °C; 'H NMR
(CDC13) 8
9.23 (br s, 1H), 7.49 (s, 1H), 7.49 - 7.30 (m, 4H), 7.21 (s, 1H), 7.15 - 7.09
(m, 3H),
6.96 - 6.94 (m, 2H), 6.89 (d, 1H, J= 8.0 Hz), 3.19 (dd, 2H, J= 40.5 and 13 Hz)
and
1.57 (s, 3H); MS (EI) m/z 363/365 [M]+.
Example 18
4-(3,3-dimethvl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile
4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-furan-2-carbonitrile.
Prepared according to the procedure for Example 5 using (2'-oxo-[2, 3-dihydro-
3,3-
dimethyl -l, 3'- [3H] indol] -5'-yl) boronic acid (354 mg, 1.7 mmol) and 4-
bromo-
furan-2-carbonitrile (200 mg, 1.2 mmol) to afford the subtitled compound (76
mg, 0.3
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mmol, 26 %) as a white solid: mp.199.6-201.4 °C , 'H NMR (DMSO-db) 8
1.28 (s,
6H), 6.89 (d, J= 8.0 Hz, 1H), 7.48 (dd, J= 8.0, 1.8 Hz, 1H), 7.65 (d, J= 1.5
Hz, 1H),
8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m/z 251 (M-H)-; Anal.
C, SH, ZN202Ø6 H20
The title compound was prepared from 4-(3,3-Dimethyl-2-oxo-2,3-dihydro-
1H-indol-5-yl)-furan-2-carbonitrile (73 mg) and Lawesson's reagent (120 mg) in
toluene ( 10 ml) at reflux, according to General Procedure A, to afford the
title
compound (0.003 g) as an off white solid: mp. 188 - 191 °C; 'H NMR
(CDC13) b
9.63 (br s, 1H), 7.83 (s, 1H), 7.36 - 7.33 (m, 3H), 7.06 (d, 1H, J= 7.9 Hz)
and 1.48 (s,
6H); MS (EI) m/z 268 [M]+.
Example 19
5-(3-methoxYphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione
5-bromo-1.3-dihydro-3,3-dimethyl-2H-indol-2-one: 3,3-dimethyl-indol-2-one
(0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in
acetic
acid (5 cm3) then bromine (0.66 g, 4.13 mmol) in acetic acid (S cm3) was added
drop-
wise to the reaction mixture. The reaction was stirred for SO min., then
poured into
water. The mixture was basified with sodium carbonate, extracted with ethyl
acetate
(x3), dried (MgS04), filtered, and evaporated to give the subtitled compound
(0.89 g,
92%)'H NMR (DMSO-db) 8 1.21 (s, 6 H), 6.76 (d, 1 H, J= 8.22 Hz), 7.29 (dd, 1
H, J
= 2.12 Hz, 8.23 Hz), 7.49 (d, 1 H, J= 2.03 Hz), 10.4 (s, 1H).
5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under an
atmosphere
of nitrogen in dimethoxyethane ( 12 cm3). After 1 S minutes, 3-
methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium
carbonate ( 1.15 g, 8.34 mmol) in water (5 cm3). The reaction was heated to
reflux for
S hours, and then cooled to room temperature. Saturated aqueous ammonium
chloride and EtOAc were added and the mixture was filtered. The aqueous layer
was extracted with EtOAc (x2), and the combined organic layers were dried
(MgS04), filtered, and evaporated. The residue was purified by column
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chromatography (SiOz, EtOAc: hexane 1:3) to afford 5-(3-methoxy-phenyl)-3,3-
dimethyl-1,3-dihydro-indol-2-one (0.1 lg, 31%), mp = 157-158 °C; 'H NMR
(DMSO-
db) 8 3.34 (s, 6 H), 3.82 (s, 3 H), 6.87 - 6.93 (m, 2 H), 7.20-7.15 (m, 2 H),
7.37-7.32
(m, 1 H), 7.49-7.46 (m, 1 H), 7.63 (d, 1 H, J= 1.14 Hz), 10.4 (s, 1 H); MS
(EI) mlz
266 (M-H)-; CHN calculated for C"H"NO2: C, 76.38; H, 6.41; N, 5.24; Found: C,
76.02; H, 6.49; N, 5.02.
The title compound was prepared from 5-(3-methoxy-phenyl)-3,3-dimethyl-
1,3-dihydro-indol-2-one ( 100 mg) and Lawesson's reagent ( 120 mg) in toluene
( 10
ml) at reflux, according to General Procedure A, to afford the title compound
(0.022
g) as an off white solid: mp. 149 - 150 °C; 'H NMR (CDC13) 8 9.69 (br
s, 1H), 7.49 -
7.46 (m, 2H), 7.37 (t, 1H, J= 8.0 Hz), 7.16 (d, 1H, J= 7.7 Hz), 7.09- 7.06 (m,
2H),
6.90 (dd, 1H, J= 8.2 and 2.3 Hz) 3.88 (s, 3H) and 1.50 (s, 6H); MS (EI) mlz
283
[M]+.
Example 20
3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-l3Hlindol]'-5-yl~-4-
tluorobenzonitrile
3-( 1,2-Dihydro-2-oxospirof cyclohexane-1,3-[3H]indol]-5-yl)-4-
fluorobenzonitrile
Prepared according to the procedure for Example 5: m.p. 205 - 206
°C. 'H
NMR (DMSO-db) 8 10.47 (s,lH), 8.08 - 8.06 (dd, 1H), 7.89 - 7.85 (m, 1H), 7.65
(s,
1 H), 7.54 -7.49 (m, 1 H), 7.43 - 7.40 (tt, 1 H), 6.95 - 6.93 (d, 1 H J = 7.9
Hz), 1.97 -
1.83 (m, 2H), 1.69 - 1.55 (m, 8H); MS (EI) m/z 320 (M+).
The title compound was prepared from 3-(1,2-Dihydro-2-
oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile (100 mg) and
Lawesson's reagent ( 120 mg) in toluene ( 10 ml) at reflux, according to
General
Procedure A, to afford the title compound (0.037 g) as an off white solid: mp.
230 -
233 °C; 'H NMR (CDCl3) 8 9.82 (br s, 1H), 7.86 (s, 1H), 7.77 (dd, 1H,
J= 7.0 and
1.8 Hz), 7.68 - 7.63 (m, 1 H), 7.45 (d, 1 H, J = 8.0 Hz), 7.31 (d, 1 H, J =
9.0 Hz), 7.15
(d, 1H, J= 8.1 Hz), 2.17 - 1.84 (m, 7 H) and 1.60 - 1.54 (m, 3H); MS (EI) mlz
336
[M]+.
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Example 21
5-(1,2-Dihydro-2-thioxospirofcyclohexane-1,3-l3Hlindoll-5-yl)-3
pyridinecarbonitrile
A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol),
hexamethylditin (5.00 g, 15.26 mmol) and
tetrakis(triphenylphosphine)palladium(0)
(0.20 g, 0.17 mmol) in anhydrous dimethoxyethane (30 cm3) under Nz was heated
under reflux.. After 16 h the mixture was concentrated and purified by column
chromatography (Si02, EtOAc: hexane 5:95) to afford 3-cyanopyridine-5-
trimethylstannane (2.82 g, 10.55 mmol, 69%): 'H NMR (CDC13) 8 0.40 (s, 9H),
8.01
(m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z 269 (M + H)+.
A solution of 5'-bromospiro[cyclohexane-1,3'-[3H] indol]-2'(1'H)-one (1.97
g, 7.05 mmol), 3-cyanopyridine-5-trimethylstannane (2.26 g, 8.46 mmol),
bis(triphenylphosphine)palladium(II)chloride (0.33 g, 0.47 mmol) and lithium
chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm3) was heated under
reflux.
After 16h the mixture was cooled, partitioned between EtOAc and water, the
aqueous
layer was re-extracted with EtOAc (x 2), the combined organic extracts were
washed
with water, dried (MgS04) and evaporated. The residue was subjected to column
chromatography (Si02, EtOAc: hexane, 1:2) and then further purified by
preparative
LC (Primesphere C18, 10 micron, 50 x 250 mm, MeCN: H20 1:1, 100 cm3/min., RT
7.92 min.) to afford 3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-
5'-
yl)pyridine carbonitrile. as white crystals (0.56 g, 1.84 mmol, 26%): mp. 232 -
234
°C, 'H NMR (CDC13) 8 1.68 - 1.89 (m, 6H), 1.93 - 2.13 (m, 4H), 7.12 (d,
1H, J= 8
Hz), 7.49 (dd, 1 H, J = 8, 2 Hz), 7.66 (d, 1 H, 2 Hz), 8.15 (t, 1 H, J = 2
Hz), 8.39 (s, 1 H,
br), 8.89 (d, 1 H, J = 2 Hz), 9.06 (d, 1 H, J = 2 Hz); MS ((+)-ESI) m/z 304 (M
+ H)+;
Anal. C,9H"N30 CHN.
The title compound was prepared from 3-( 1',2'-Dihydro-2'-
oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)pyridine carbonitrile (100 mg) and
Lawesson's reagent (120 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the title compound (0.004 g) as a yellow solid: mp. 237
- 238
°C; 'H NMR (CDC13) 8 9.56 (br s, 1 H), 9.03 (d, 1 H, J = 1.9 Hz), 8.87
(d, 1 H, J = 1.4
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Hz), 8.12 (s, 1H), 7.87 (s, 1H), 7.50 (d, 1H, J= 8.1 Hz), 7.17 (d, 1H, J= 8.1
Hz), 2.19
- 1.85 (m, 7H) and 1.59 - 1.54 (m, 3H); MS ((-)-APCI) m/z 318 [M-H]-.
Example 22
5-(3,4-Difluorophenyl)spirofcyclohexane-1,3-[3Hlindolej-2(1H)-thione
5'-(3,5-DifluorophenylZspirojcyclohexane-1,3'-(3H] indolj-2' ( 1'H)-one:
Prepared according to the procedure for Example 5: mp 180-183 °C;
'H-NMR
(CDCl3) 8 8.35 (s, 1H), 7.59 (d, IH, J= 2.0 Hz), 7.40 (dd, 1H, J= 6.2, 2.0
Hz), 7.10 -
7.03 (m, 2H), 6.99 (d, IH, J= 8.1 Hz), 7.76 (tt, 1 H, J= 4.3, 2.3 Hz), 2.05 -
1.62 (m,
l OH); MS ((+)APCI) m/z 314 [M+H]+.
The title compound was prepared from 5'-(3,5-
difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(I'H)-one (100 mg) and
Lawesson's reagent (120 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the product (0.020 g) as a yellow solid: mp. 232 - 233
°C; 'H
1 S NMR (CDCl3) 8 10.05 (br s, 1 H), 7.83 (s, 1 H), 7.44 (dd, 1 H, J = 8.1 and
1.4 Hz),
7.3 8 - 7.30 (m, 1 H), 7.26 - 7. I 9 (m, 3H), 7.11 (d, 1 H, J = 8.1 Hz), 2.17 -
1.82 (m,
7H) and 1.66 - 1.53 (m, 3H); MS ((-)-APCI) m/z 328 [M-H]-.
Example 23
5-(5-Chloro-2-thien~)spirolcyclohexane-1,3-f3Hlindolej-2(1H)-thione
5-(S-Chloro-2-thienyl)spirofcyclohexane-1,3-[3Hl indol)-2(1H)-one:
Prepared according to the procedure for Example 5: m.p. 191-192°C ,
'H NMR
(CDC13) 8 1.6-2.1 (m, lOH), 6.85-6.95 (m, 2H), 6.98 (d, J= 4.0 Hz, 1H), 7.36
(dd, J=
7.5, 1.6 Hz, 1H), 7.53 (d, J= 0.9 Hz, 1H), 7.80 (br s, 1H);'3C-NMR (THF-d8) 8
21.35, 25.33, 33.12 (t), 48.32 (s), 110.40, 121.66, 121.96, 125.44, 127.25
(d), 128.17,
128.43, 136.92, 140.20, 143.43, 183.72 (s); MS (EI) m/z 318 (M+H)+; Anal.
(C"H,6C1NOS) C, H, N.
The title compound was prepared from 5-(5-Chloro-2-thienyl)spiro
[cyclohexane-1,3-[3H] indol]-2(1H)-one (100 mg) and Lawesson's reagent (120
mg)
in toluene (10 ml) at reflux, according to General Procedure A, to afford the
product
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(0.041 g) as a yellow solid: mp. 231 - 232 °C; 'H NMR (CDCl3) 8 9.75
(br s, 1H),
7.82 (d, 1H, J= 1.2 Hz), 7.43 (dd, 1H, J= 8.1 and 1.6 Hz), 7.04 - 7.02 (m,
2H), 6.89
(d, 1H, J= 3.8), 2.15 - 1.84 (m, 7H) and 1.59 - 1.52 (m, 3H); MS ((-)-APCI)
mlz
332/334 [M-H]-.
Example 24
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3Hlindoll-5-~)-3-
furancarbonitrile
5-( 1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H] indol]-5'-yl)-3-
furancarbonitrile:
Prepared according to the procedure for Example 5: m.p. 243 - 245
°C. 'H-
NMR (DMSO-d6) 8 10.48 (s, 1H), 8.62 (d, 1H J= 0.7 Hz), 7.76 (d, 1H J= 1.5 Hz),
7.58 -7.55 (dd, 1H), 7.33 (d, 1H J= 0.7 Hz), 6.92 - 6.90 (d, 1H J= 8.1 Hz),
1.87 -
1.83 (m, 2H), 1.73 - 1.53 (m, 8H). MS ((+)EI) m/z 292 (M+).
The title compound was prepared from 5-(1',2'-dihydro-2'-
oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-3-furancarbonitrile (100 mg) and
Lawesson's reagent ( 120 mg) in toluene ( 10 ml) at reflux, according to
General
Procedure A, to afford the product (0.020 g) as a yellow solid: mp. 264 - 268
°C; 'H
NMR (CDC13) 8 9.66 (br s, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, J= 8.2 and 1.5 Hz),
7.08
(d, 1H, J= 8.2 Hz), 6.78 (s, 1H), 2.16 - 1.85 (m, 7H) and 1.56 - 1.52 (m, 2H):
MS ((-
-APCI) m/z 307 [M-H]~.
Example 25
5-(3-Chloro-4-fluorophenyl)spiro f cyclohexane-1,3-f 3H1 indolel-2(1H)- thione
5'-(3-Chloro-4-fluorophen~pirojcyclohexane-1,3'-[3Hlindol]-2'(1'H)-one.
Prepared according to the procedure for Example 5: mp 188-189 °C;
'H-NMR
(CDC13) 8 7.97 (s, 1H), 7.57 - 7.54 (m, 2H), 7.41 - 7.34 (m, 2H), 7.20 (t, 1H,
J= 8.7
Hz), 9.96 (d, 1H, J= 8.1 Hz), 2.04 - 1.65 (m, lOH); MS ((+)APCI) mlz 330
[M+H]+.
The title compound was prepared from 5'-(3-Chloro-4-fluorophenyl)
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spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one (100 mg) and Lawesson's reagent
( 100 mg) in toluene ( 10 ml) at reflux, according to General Procedure A, to
afford the
product (0.036 g) as an off white solid: 'H NMR (DMSO-db) 8 12.74 (br s, 1H),
7.92
(d, 1 H, J = 1.4 Hz), 7.87 (dd, 1 H, J = 7.1 and 2.3 Hz), 7.70 - 7.65 (m, 1
H), 7.61 (dd,
1H, J= 7.1 and 1.5 Hz), 7.49 (t, 1H, J= 8.9 Hz), 7.14 (d, 1H, J= 8.1 Hz), 1.99
- 1.82
(m, 7H) and 1.40 - 1.37 (m, 3H): MS ((-)-APCI) mlz 344/346 [M-H]-.
Example 26
~3-Chloro-5-lluorophenylLpiro[cyclohexane-1,3-f3Hlindolel-2(1H)-thione
5'-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3'-f3H]indol]-2'(1'H)-one:
Prepared according to the procedure for Example 5: mp 178-180 °C;
'H-NMR
(CDC13) 8 8.50 (s, 1H), 7.57 (d, 1H, J= 1.8 Hz), 7.39 (dd, 1H, J= 6.2, 1.9
Hz), 7.33 -
7.32 (m, 1 H), 7.15 (dq, 1H, J= 5.7, 1.7, 0.7 Hz), 7.06 (dq, 1 H, J= 4.2, 1.9,
0.4 Hz),
7.00 (d, 1H, J= 8.1 Hz), 2.05 - 1.64 (m, lOH); MS ((-)ESI) [M-H]- @ m/z 328.
The title compound was prepared from 5'-(3-chloro-S-fluorophenyl)spiro
[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one (100 mg) and Lawesson's reagent (100
mg) in toluene ( 10 ml) at reflux, according to General Procedure A, to afford
the
product (0.039 g) as an off white solid: 'H NMR (DMSO-db) 8 12.76 (br s, 1 H),
7.97
(d, 1H, J= 1.1 Hz), 7.67 (dd, 1H, J= 8.1 and 1.4 Hz), 7.60 - 7.54 (m, 2H),
7.40 (dt,
1H, J= 8.65 and 2.0 Hz), 7.14 (d, 1H, J= 8.1 Hz), 1.99 - 1.83 (m, 7H) and 1.41
-
1.38 (m, 3H): MS ((-)-APCI) m/z 344/346 [M-H]-.
Example 27
5-(3,5-Difluorophenyl~lspirofcyclohexane-1,3-[3H)indolel-2(1H~I-thione
5'-(3,5-Difluorophenyl)spiro[c~rclohexane-1,3'-[3H]indol]-2'(1'H)-one:
Prepared according to the procedure for Example 5: mp 180-183 °C;
'H-NMR
(CDC13) 8 8.35 (s, 1 H), 7.59 (d, 1 H, J = 2.0 Hz), 7.40 (dd, 1 H, J = 6.2,
2.0 Hz), 7.10 -
7.03 (m, 2H), 6.99 (d, 1H, J= 8.1 Hz), 7.76 (tt, 1 H, J= 4.3, 2.3 Hz), 2.05 -
1.62 (m,
l OH); MS ((+)APCI) mlz 314 [M+H]+.
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The title compound was prepared from 5'-(3,5-
difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one (100 mg) and
Lawesson's reagent (100 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the title compound 0.029 g as an off white solid: 'H
NMR
(DMSO-db) 8 12.76 (br s, 1H), 7.84 (s, 1H), 7.64 - 7.56 (m, 1H), 7.46 (d, 1H,
J= 8.1
Hz), 7.40 - 7.32 (m, 1H), 7.22 - 7.15 (m, 2H), 1.99 - 1.80 (m, 7H) and 1.38 -
1.35
(m, 3H); MS ((-)-APCI) m/z 328 [M-H]-.
Example 28
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-l3Hlindoll-5-ylLpropyl-2-
thiophenecarbonitrile
5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl- 2-
thiophenecarbonitrile. The title compound was prepared in a manner similar to
Example 5 from 5-bromo-4-n-propyl thiophene-2-carbonitrile ( 1.17 g, 5 mmol ),
(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H] indol)-5-boronic acid ( 1.24 g, 5
mmol
), tetrakis(triphenylphosphine) palladium, potassium carbonate ( 2.75 g,21
mmol),
water ( 10 mL ), and dimethoxyethane (50 mL) heated at reflux over night, to
afford
the product (0.7 g, 40%): m.p.168-171 °C;'H NMR ( DMSO-db) 8 10.56 (
s,lH ),
7.93 ( s, 1 H ) 7.52-7.51 (d, 1 H, J = 1.5 Hz), 7.33 - 7.29 (dd, 1 H, J = 1.6
Hz), 7.00-
6.96 (d, 1H, J= 8.0 Hz), 2.62-2.57 (t, 2H), 1.86 (m, 2H), 1.70-1.56 (m, 11 H),
0.88-
0.84 (t, H); MS m/z (APCI (+)) 351 [M+H)+. IR (KBr) 1620,1700,2200 crri'..-
.Anal.
Cz,H22N20S~1/2 Hz0 calc. C,70.2; H, 6.39; N, 7.79. Observed. C,70.67; H,6.34;
N,7.62.
The title compound was prepared from 5-(1,2-dihydro-2-
oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl- 2-thiophenecarbonitrile
(90 mg)
and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux, according to
General
Procedure A, to afford the title compound (0.037 g) as an orange solid: 'H NMR
(DMSO-db) b 12.83 (br s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J= 7.7
Hz),
7.19 (d, 1H, J= 8.0 Hz), 2.60 (t, 2H, J= 8.0 Hz), 1.98 - 1.79 (m, 7H), 1.64 -
1.56 (m,
2H), 1.39 - 1.35 (m, 2H) and 0.87 (t, 3H, J= 7.3 Hz):MS ((-)-APCI) mlz 365 [M-
H]-.
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Example 29
5-(3-Fluoro-4-nitrophen~piro ~ cyclohexane-1,3-f 3Hl indolel-2(1 H)-thione
5-(3-Fluoro-4-nitrophenyl)spirofcyclohexane-1,3-[3H]indol]-2(1H -one:
Prepared from (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-
yl)boronic
acid (3.2 g, 12.5 mmol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) as
described for example 5, to afford the title compound (0.7 g, 16%) as a yellow
solid:
mp. 213-215 °C; 'H NMR (DMSO-db) 8 1.5 - 1.8 (m, 8H), 1.8 - 2.0 (m,
2H), 6.96 (d,
1H, J = 8.13 Hz), 7.68 (dd, 1H, J= 8.13, 1.76 Hz), 7.74 (dd, 1 H, J= 8.68,
1.76 Hz),
7.86 (d, 1 H, J = 1.98 Hz), 7.92 (dd, 1 H, J = 13.4, 1.76 Hz), 8.18 (t, 1 H, J
= 8.46 Hz)
and 10.52 (s, 1H); MS (EI) m/z = 340 (M+)
The title compound was prepared from 5-(3-fluoro-4-nitrophenyl)spiro
[cyclohexane-1,3-[3H]indol]-2(1H)-one (90 mg) and Lawesson's reagent (90 mg)
in
toluene ( 10 ml) at reflux, according to General Procedure A, to afford the
product
(0.021 g) as a yellow solid: 'H NMR (DMSO-db) 8 12.82 (br s, 1H), 8.21 (t, 1H,
J=
8.4 Hz), 8.07 (d, 1 H, J = 1 Hz), 7.98 (dd, 1 H, J = 13.1 Hz), 7.79 (dt, 1 H,
J = 8.1 and
2.6 Hz), 7.19 (1H, J= 8.2 Hz), 1.99 - 1.83 (m, 7H) and 1.42 - 1.39 (m, 3H): MS
((-)-
APCI) m/z 355 [M-H]-.
Example 30
X1,2-Dihydro-2-thioxospiro cyclohexane-1,3-f3Hlindol]-5-yll-2-
furancarbonitrile
4-( 1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-
furancarbonitrile: A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol), and
tetrakis(triphenylphosphine) palladium(0) (0.4 g) in ethylene glycol dimethyl
ether
(20 cm3) was stirred under NZ for 20 minutes. To this mixture was then added
(spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid (1.6 g, 6.5
mmol)
and sodium acetate ( 1.4 g, 13.1 mmol) in water (5 cm3). The solution was
brought to
reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH
and
extracted with EtOAc (x 3). The combined extracts were washed with water,
brine,
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dried (MgS04), and evaporated. The residue was purified by column
chromatography
(SiOZ, EtOAc, hexane) to afford the product (0.45 g, 36%) as an off white
solid. mp:
240 - 242 °C; 'H NMR (DMSO-db) 8 10.4 (s, 1H), 8.5 (s, 1H), 8.2 (s,
1H), 7.7 (s, 1H),
7.5 (dd, 1H, J= 1.5 6.5 Hz), 6.9 (d, 1H, J= 8.0 Hz), 2.0 - 1.6 (m, lOH); MS
(EI) M+
@ m/z 292.
The title compound was prepared from 4-(1,2-dihydro-2-
oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2- furancarbonitrile (67 mg) and
Lawesson's reagent (67 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the title compound (0.018 g) as a yellow solid: 'H NMR
(DMSO-db) 8 12.74 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd,
1H, J=
8.0 and 1.0 Hz), 7.10 (s, 1H, J= 8.1 Hz), 1.94 - 1.78 (m, 7H) and 1.35 - 1.32
(m,
3H): MS ((-)-APCI) m/z 307 [M-H]-.
Example 31
5"-(3-Chlorophenyl)spirofcyclobutane-1,3"-f3Hlindolel-Z"(1"H?-thione
5-Bromospirojcyclobutane-1,3-[3Hlindoll-2(1H)-one: To a stirred solution of
spiro[cyclobutane-1,3'-[3H]indol]-2'(1'I~-one (J. Med. Chem. 1987, 824-9) (1.0
g, 6
mmol) in glacial acetic acid ( 10 mL) was added dropwise at room temperature a
solution of bromine (0.30 mL, 6 mmol) in glacial acetic acid (6 mL). After
stirnng
for 10 min, anhydrous sodium acetate (0.47 g, 6 mmol) was added and the
solution
was concentrated in vacuo. The residue was dissolved in ethyl ether (50 mL)
and
washed sequentially with water (50 mL), aqueous saturated sodium bicarbonate
solution (50 mL), water (50 mL) and brine (30 mL). The organic layer was dried
over magnesium sulfate, filtered and concentrated in vacuo. Crystallization
from ethyl
ether yielded the product as a white fluffy solid (1.1 g, 73%), mp 235-7
°C. 'H NMR
(DMSO-d6, 300 MHz) 2.15-2.41 (m, 6 H), 6.74 (d, 1 H, J= 8.2 Hz), 7.33 (dd, 1
H, J
= 2, 8.2 Hz), 7.75 (d, 1 H, J = 2 Hz), 10.36 (bs, 1 H). MS (EI) m/z 251 [M+].
Anal.
Calcd for C"H,oBrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 51.98; H, 4.24; N,
5.42.
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To a solution of 5-bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6 g,
2 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogen atmosphere
was
added tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). To the
solution
was added sequentially 3-chlorophenyl boronic acid (0.48 g, 3 mmol) and
potassium
carbonate (0.76 g, 5 mmol) in water (5 mL). The mixture was heated to 80
°C for 3 h
and allowed to cool. The reaction mixture was poured into water ( 100 mL) and
extracted with ethyl acetate (3 x 100 mL). The organic layers were combined,
washed with brine (50 mL) and dried over magnesium sulfate. The solution was
filtered, concentrated in vacuo, and the residue was purified by HPLC (Zorbax
PRO,
C18, 10u, 15A, 50 X 250mm; 35% Water/65% AcCN; 254NM; AMB. temp.) to give
5-(3-chlorophenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one (200 mg, 35%) as
a
white powder, mp 199.5-201 °C. 'H NMR (DMSO-d6, 300 MHz) 2.21-2.28m, 2
H),
2.40-2.45 (m, 4 H), 6.87 (d, 1 H, J= 8.1 Hz), 7.37 ('d', 1 H), 7.44-7.52 (m, 2
H), 7.65
(bd, 1 H, J= 7.8 Hz), 7.76 (bs, 1 H), 7.92 (bs, 1 H), 10.35 (s, 1 H). MS (EI)
mlz 283
[M+]. Anal. Calcd for C"H,QC1N0: C, 71.96; H, 4.97; N, 4.94. Found: C, 70.75;
H,
5.07; N, 4.68.
The title compound was prepared from 5-(3-Chlorophenyl)spiro[cyclobutane-
1,3-[3H]indole]-2(1H)-one (55 mg) and Lawesson's reagent (55 mg) in toluene
(10
ml) at reflux, according to General Procedure A, to afford the title compound
0.016 g
as an orange solid: 'H NMR (DMSO-db) 8 12.58 (br s, 1H), 8.07 (d, 1H, J= 1.5
Hz),
7.82 (t, 1 H, J = 1.7 Hz), 7.70 (d, 1 H, J = 7.74 Hz), 7.60 (dd, 1 H, J = 8.12
and 1.71
Hz), 7.49 (t, 1 H, 7.9 Hz), 7.41 (d, 1 H, J = 8.32 Hz), 7.05 (d, 1 H, J = 8.14
Hz) and
2.57 - 2.27 (m, 6H); MS ((-)-APCI) m/z 298/300 [M-H]-.
Example 32
5"-(2-Chlorophenyl)spirofcyclohexane-1,3"-[3Hlindole]-2"(1"H]-thione
The title compound was prepared from 5"-(2-
Chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione (90 mg) and
Lawesson's reagent (90 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the product 0.042 g as an off white solid: 'H NMR (DMSO-
db)
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8 12.75 (br s, 1H), 7.80 (d, 1H, J= 1.1 Hz) 7.58 - 7.55 (m, 1H), 7.48 - 7.36
(m, 4H),
7.16 (d, 1H, J= 8.0 Hz) ; MS ((-)-APCI) mlz 326/328 [M-H]-.
Exam lp a 33
5"-(4-Chlorophenyl)spirofcyclohexane-1,3"-f3Hlindole-2"(1"H)-thione
The title compound was prepared from 5-(4-chlorophenyl)spiro[cyclohexane-
1,3-[3H]indol]-2(1H)-one (90 mg) and Lawesson's reagent (90 mg) in toluene (10
ml) at reflux, according to General Procedure A, to afford the product 0.035 g
as an
off white solid: 'H NMR (DMSO-db) 8 12.74 (br s, 1H), 7.91 (d, 1H, J= 1.3 Hz),
7.69 (d, 2H, J= 5.5 Hz), 7.60 (dd, 1H, J= 8.1 and 1.4 Hz), 7.50 (d, 2H, J= 8.5
Hz),
7.15 (d, 1H, J= 8.1 Hz), 1.99 - 1.83 (m, 7H) and 1.50 - 1.36 (m, 3H); MS ((-)-
APCI)
m/z 326/328 [M-H]~.
Example 34
5-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-1,3"-f3HJindoll-5"-xl)- 4-methyl-
2-thiophenecarbonitrile
5-Bromo-4-methyl-2-thiophene carboxaldehyde: To a solution of
diethylamine (28g, 0.383 mol) in anhydrous THF (400 mL) was added at -40
°C
under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane.
After
addition, the solution was stirred at -40 °C under nitrogen for 30
minutes, cooled to -
78 °C and treated dropwise with a solution of 2-bromo-3-methylthiophene
(45g,
0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at -78
°C
for 30 minutes and treated with anhydrous DMF (100 mL). The mixture was
allowed
to warm to ambient temperature and was quenched with 1N aqueous hydrochloride
solution (1L). The solution was extracted with ethyl acetate (3x450 mL) and
the
extracts washed with water, brine and dried (MgS04). After removal of solvent
in
vacuo, the title compound was obtained as a white solid (46g, 88.3%). A sample
of
the product was crystallized from hexane: mp 63-65 °C; IR (KBr) 1654 cm-
'. 'H-
NMR (CDCI3) 8 9.75 (S, 1H), 7.45 (S, 1H), 2.26 (S, 3H); MS (EI) m/z 204/206
(M+).
Anal. Calc. For C6HSBrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.
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5-Bromo-4-methyl-2-thiophenecarbonitrile: Prepared from 5-bromo-4-
methyl-2-thiophene carboxaldehyde using the procedure of Example 5. White
solid:
mp 40-42 °C; IR (KBr) 2200 cm'; 'H-NMR (CDC13) 8 7.29 (S, 1H), 2.21 (S,
3H).
MS (EI) m/z 201/203 (M+, 98%/100%); Anal. Calc. For C6H4BrNS: C, 35.66; H,
1.99; N, 6.93. Found: C, 36.00; H, 2.14; N, 6.76.
Prepared according to the procedure for Example 5 using (2'-oxo-[2, 3-
dihydro-3,3-dimethyl -l, 3'- [3H] indol] -5'-yl) boronic acid (357 mg, 1.7
mmol) and
5-bromo-4-methylthiophene-2-carbonitrile (295 mg, 1.5 mmol) to afford 5-(3,3-
Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methyl thiophene-2-carbonitrile
(227
mg, 0.8 mmol, 55 %) as a white solid: mp. 192.3-193 °C , 'H NMR (DMSO-
db) b 1.29
(s, 6H), 2.29 (s, 3H), 6.97 (d, J= 8.0 Hz, 1H), 7.34 (dd, J= 8.0, 1.8 Hz, 1H),
7.49 (d,
J= 1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) mlz 282 (m)+; Anal.
C,6H,4NZOS.
The title compound was prepared from 5-(3,3-dimethyl-2-oxo-2,3-dihydro-
1H-indol-5-yl)-4-methyl thiophene-2-carbonitrile (0.77 g, 2.39 mmol) and
phosphorous pentasulfide (0.42 g, 0.96 mmol) in toluene (20 ml) at reflux.
After 3 h,
the reaction was cooled and partitioned between water and EtOAc, the organic
layer
was separated, dried (MgS04) and evaporated. The residue was purified by
column
chromatography (Si02, EtOAc- hexane gradient elution) to afford the product
(0.25 g,
0.73 mmol, 30%) as an orange solid: 'H NMR (DMSO-db) 8 12.82 (br s, 1H), 7.88
(s,
1 H), 7.82 (d, 1 H, 2 Hz), 7.49 (dd, 1 H, J = 8.1, 1.6 Hz), 7.18 (d, 1 H, J =
8.1 Hz), 1.99
- 1.80 (m, 7H) and 1.40 - 1.36 (m, 3H); MS ((-)-APCI) m/z 321 [M-H]-.
Example 35
5-(1",2"-Dihydro-2"-thioxospirofcyclohexane-1,3"-l3Hlindoll-5"- 1~)- 2-
thiophenecarbonitrile
5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-
thiophenecarboxaldehyde (96.Og, 500 mmol), hydroxylamine hydrochloride ( 111.9
g,
500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen
at
reflux for two hours. The reaction mixture was cooled to ambient temperature
and
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concentrated in vacuo to give an oil. The crude product was triturated twice
with ice
water and the solid obtained was collected on a filter. A mixture of a portion
of the
above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21
mmol) in
acetonitrile ( 1.4L) was heated at reflux for three hours. The solvent was
removed in
vacuo and the residue was dissolved in ethyl acetate. The solution was washed
with
S% aqueous sulfuric acid (2X30 mL), water (2X30 mL), brine (20 mL), and dried
(MgS04). The solvent was removed in vacuo and the residue was dissolved in a
minimum amount of chloroform ( 1 L) and allowed to crystallize. The crystals
obtained was collected on a filter and the filtrate was concentrated and
purified by a
chromatography (silica gel, chloroform) to give the subtitled compound as an
off
white solid (3l.Sg combined, 58%). IR (film) cm' 2200. 'H-NMR (CDC13) 8 7.39-
7.38 (d, 1H, J= 4. 1 Hz), 7.10 (d, 1H, J= 4.0 Hz); MS (EI) mlz 187 (M+, 98%)
189(M+, 100%).
5-(2'-Oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'yl-2-
thiophenecarbonitrile was prepared according to the procedure for Example 5
using 5-
bromo-2-thiophenecarbonitrile and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl) boronic acid: mp. 225-228°C;'H NMR (DMSO-db) 8 1.63
(m, 8H),
1.90 (m, 2H) 6.91 (d, 1H, J= 8.13 Hz), 7.55 (dd, 1H, J= 8.13 , 1.76Hz), 7.60
(d, 1H,
J = 4.17 Hz), 7.75 (d, 1 H, J = 1.76 Hz), 7.93 (d, 1 H, J = 4.17 Hz), 10.51
(s, 1 H); MS
((+)APC 1 ) m/z 309 [M + H]+.
The title compound was prepared from 5-(2'-oxo-2',3'-
dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'yl-2-thiophenecarbonitrile (0.69 g)
and
phosphorous pentasulfide (0.4 g) in toluene (20 ml) at reflux. After 3 h. the
reaction
was cooled, poured into sat. aqueous sodium hydrogen carbonate solution, and
extracted with EtOAc. The organic layer was separated, dried (MgS04) and
evaporated. The residue was purified by column chromatography (Si02, EtOAc-
hexane gradient elution) to afford the title compound (0.215 g) as an orange
solid: 'H
NMR (DMSO-db) 8 12.82 (br s, 1H), 8.00 - 7.98 (m, 2H), 7.74 (d, 1H, J= 4.1
Hz),
7.69 (dd, 1H, J= 8.2 and 1.6 Hz), 7.14 (d, 1H, J= 8.1 Hz), 1.99 - 1.83 (m, 7H)
and
1.40 - 1.37 (m, 3H); MS ((-)-APCI) m/z 323 [M-H]-.
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Example 36
5"-(3-Fluorophen~piro(cyclohexane-1,3"-(3Hlindolel-2"(1 "H)-thione
5'-(3-Fluorophenyl)spiro(cyclohexane-1 3'-(3H]indol]-2'(1'H)-one' Prepared
according to the procedure for Example 5: mp 171-172 °C; 'H-NMR (CDCl3)
8 8.43
(s, 1 H), 7.62 (d, 1 H, J = 1.8 Hz), 7.42 (dt, 1 H, J = 6.2, 2.0 Hz), 7.3 9 -
7.3 7 (m, 1 H),
7.33 (dt, 1H, J= 5.1, 1.3 Hz), 7.26 (dq, 1 H, J= 5.9, 2.1 Hz), 7.05 - 6.99 (m,
2H),
2.03 - 1.64 (m, lOH); MS ((+)APCI) m/z 296 [M+H]+.
The title compound was prepared from 5'-(3-fluorophenyl)spiro[cyclohexane-
1,3'-[3H]indol]-2'(1'H)-one (0.70 g) and phosphorous pentasulfide (0.4 g) in
toluene
(20 ml) at reflux. After 3 h. the reaction was cooled, poured into sat.
aqueous sodium
hydrogen carbonate solution, and extracted with EtOAc, the organic layer was
separated, dried (MgS04) and evaporated. The residue was purified by column
chromatography (SiOz, EtOAc-hexane gradient elution) to afford the product
(0.42 g)
as an off white solid: 'H NMR (DMSO-db) 8 12.75 (br s, 1H), 7.95 (d, 1H, J=
1.5
Hz), 7.64 (dd, 1H, J= 8.13 and 1.5 Hz), 7.53 - 7.48 (m, 3H), 7.21 - 7.14 (m,
2H),
1.99 - 1.83 (m, 7H) and 1.40 - 1.37 (m, 3H); MS ((-)-APCI) m/z 310 [M-H]-.
Example 37
5-(3-Hydroxyphenyl)spiro(cyclohexane-1,3-(3Hjindole]-2(1H)-thione
5'-(3-Hydroxyphenyl)spiro[cyclohexane-1 3'~3H]indol)-2'(1'H)-one' Prepared
according to the procedure for example 5: mp. 213 - 216 °C; 'H NMR
(CDCl3) 8 1.60-
1.96 (m, lOH), 6.78 - 6.82 (m, 1H), 6.94 (d, 1H, J= 8 Hz), 7.01 - 7.04 (m,
2H), 7.23
(t, 1 H, J = 7.7 Hz), 7.3 8 (d, 1 H, J = 8 Hz), 7.61 (s, 1 H), 8.91 (s, 1 H)
and 9.73 (s, 1 H,
br); MS ((+)-APCI) m/z 294 [M+H]+.
The title compound was prepared from 5'-(3-
hydroxyphenyl)spiro[cyclohexane-1,3'-[3H]indol)-2'(1'H)-one (100 mg) and
Lawesson's reagent (110 mg) in toluene (10 ml) at reflux, according to General
Procedure A, to afford the title compound (0.0045 g) as an off white solid: 'H
NMR
(CDC13) 8 9.59 (br s, 1H), 7.89 (s, 1H), 7.49 (dd, 1H, J= 8.1 and 1.5 Hz),
7.33 (t, 1H,
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J= 7.9 Hz), 7.15 - 7.10 (m, 3H), 6.84 (dd, 1H, J= 8.0 and 2.2 Hz), 2.17 - 2.05
(m,
2H), 1.98 - 1.88 (m, 5H) and 1.57 - 1.53 (m, 3H): MS ((-)-APCI) m/z 308 [M-H]-
.
Example 38
5-(3-chlorophenyl)-3,3-diethyl-1 3-dih~dro-2H-indole-2-thione
A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under Nz was
cooled to -25 °C and treated drop wise with n-butyl lithium (2.SM in
hexanes, 240 ml,
0.6 mol). To the resulting solution was added N,N,N',N'-
tetramethylethylenediamine
(90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and
the
reaction mixture was allowed to warm to room temperature and stirred over
night.
The reaction mixture was poured into aqueous NH4C1 solution, extracted with
EtOAc
(2x) and the combined organic layers were washed with dil. HCI, water, brine,
dried
(MgS04) and concentrated. The residual oil was triturated with hexane to
afford the
crude product (24.5 g, 51 %). A sample (3 g) was recrystallized from
EtOAc/hexane
to obtain 3-ethyl-indol-2-one (1.4 g), m.p. 100 - 101 °C; 'H-NMR (DMSO-
db) 8 0.76
(t, 3H, J = 7.5 Hz), 1.8 - 2.0 (m, 2H), 3.38 (t, 3H, J = 5.7 Hz), 6.8 (dt, 1
H, J = 7.69,
0.45 Hz), 6.93 (dt, 1 H, J = 7.45, 1.10 Hz), 7.15 (m, 1 H), 7.22 (m, 1 H),
10.3 (s, 1 H);
MS (ESI) m/z 270 [M+H].
A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 ml) under
Nz was cooled to -25 °C and treated drop wise with n-butyllithium (2.5M
in hexanes,
80 ml, 0.2 mol). To the resulting solution was added N,N,N',N'
tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min. iodoethane (8 ml,
0.1
mol) was added and the reaction mixture was allowed to warm to RT and stirred
over
night. The reaction mixture was poured into an aqueous NH4C1 solution,
extracted
with EtOAc (2x) and the combined organic layers were washed with dil. HCI,
water,
brine, dried (MgS04) and concentrated. The residual oil was triturated with
hexane to
afford 3,3-diethylindol-2-one (9 g, 45%), m.p. 156 - 159 °C; 'H NMR
(DMSO-db) 8
10.44 (s, l H), 7.70 - 7.69 (t, l H), 7.62 - 7.59 (m, 1 H), 7.58 (d, l H J--
1.7Hz), 7.53-7.50
(m, 1H), 7.45 - 7.41 (t,lH), 7.36 - 7.35 (m,lH), 7.34 - 7.33 (m,lH), 6.91 -
6.89 (d,lH
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J--8.2Hz), 1.87 - 1.80 (m,2H), 1.77 - 1.70 (m, 2H), 0.54 - 0.50 (t, 6H); MS
(+ESI) m/z
190 (M+H).
A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g,
48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol).
After
30 min. the mixture was diluted with water and extracted with EtOAc (2x); the
combined organic layers were washed with water, sat. sodium hydrogen carbonate
solution, then brine, dried (MgS04) and evaporated to afford the crude product
(7.6 g,
75%). A sample was recrystallized from EtOAc/hexane to obtain 5-bromo-1,3-
dihydro-3,3-diethyl-[2H]-indol-2-one, m. p. 164 - 165 °C; 'H-NMR (DMSO-
db) 8
10.45 (s, 1 H), 7.41-7.40(d, 1 H, J = 2.2Hz), 7.34 - 7.31 (m, 1 H), 6.78 -
6.76 (d, 1 H J =
8.2 Hz), 1.78-1.65 (m, 4H), 0.50 - 0.46 (m, 6H); MS (-ESI) m/z 266/268 (M-H).
A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g, 10
mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4 g,
30
mmol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmol) in
dimethoxyethane ( 100 ml), ethanol (25 ml), and water (25 ml) was heated to
reflux
for 6 hours. After cooling to room temperature, the mixture was diluted with
water
and extracted with EtOAc (2x). The combined organic extracts were washed with
water, then brine, dried (MgS04) and evaporated. The residue was purified by
column chromatography (Si02, EtOAc:hexane 1:3) to afford 5-(3-chloro-phenyl)-
3,3-
diethyl-1,3-dihydro-indol-2-onecompound (0.8 g, 27%), m.p. 195 - 197
°C; 'H-NMR
(DMSO-db) 8 7.70 (t, 1H, J= 2 Hz), 7.62 - 7.60 (m, 1H), 7.58 (d, 1H, J= 1.7
Hz),
7.52, (dd, 1H, J= 8.1, 2 Hz), 7.43 (t, 1H, 7.9 Hz), 7.36 - 7.33 (m, 1H), 6.90
(d, 1H, J
= 8.1 Hz), 1.87 - 1.70 (m, 4H) and 0.52 (t, 6H, J= 7.4 Hz); MS (+APCI) mlz
300/302
(M-H).
The title compound was prepared from 5-(3-chloro-phenyl)-3,3-diethyl-1,3-
dihydro-indol-2-onecompound (100 mg) and Lawesson's reagent (100 mg) in
toluene
( 10 ml) at reflux, according to General Procedure A, to afford the product
(0.023 g) as
a yellow solid: 'H NMR (DMSO-db) 8 12.73 (br s, 1H), 7.77 (t, 1H, J= 1.8 Hz),
7.75
(d, 1 H, J = 1.6 Hz), 7.68 - 7.62 (m, 2H), 7.48 (t, 1 H, J = 7.9 Hz), 7.40 (d,
1 H, J = 8.3
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Hz), 7.09 (d, 1H, J= 8.1 Hz), 2.07 - 2.00 (m, 2H), 1.86 - 1.79 (m, 2H) and
0.37 (t,
6H, J= 7.3 Hz): MS ((-)-APCI) mlz 314/316 [M-H]-.
Examine 39
S 5-f4-Fluoro-3-(trifluoromethyl?phenyl)spirofcYClohexane-1,3- [3Hlindoll
2(1H)
thione
5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3- [3H]indol]-
2(1H)-one was prepared from (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-
[3H]indol]-
5'-yl)boronic acid (2.5 g, 10 mmol) and 5-bromo-2-fluoro-
trifluoromethylbenzene (2
g, 8 mmol) as described for Example 5, to afford the title compound (0.87 g,
30%) as
a solid: mp. 222 °C; 'H NMR (DMSO-db) 8 1.5 - 1.8 (m, 8 H), 1.8 - 2.0
(m, 2 H), 6.92
(d, 1 H, J = 8.13 Hz), 7.51 (dd, 1 H, J = 8.13, 1.76 Hz), 7.55 (dd, 1 H, J =
10.54, 9.01
Hz) 7.72 (d, 1 H, J = 1.76 Hz), 7.90 (dd, 1 H, J = 7.03, 2.20 Hz), 7.98 (m, 1
H) and
10.39 (s, 1 H); MS (EI) m/z 363 (M+)
The title compound was prepared from 5-[4-Fluoro-3-(trifluoromethyl)phenyl]
spiro[cyclohexane-1,3- [3H]indol]-2(1H)-one (90 mg) and Lawesson's reagent (90
mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford
the
product (0.016 g) as a yellow solid: 'H NMR (DMSO-db) 8 12.75 (br s, 1H), 8.06
-
8.00 (m, 1H), 7.96 - 7.92 (m, 2H), 7.66 - 7.56 (m, 2H), 7.16 (d, 1H, J= 8.1
Hz), 1.99
- 1.83 (m, 7H) and 1.41 - 1.38 (m, 3H): MS ((-)-APCI) m/z 378 [M-H]-.
Example 40
4-(1,2-Dihydro-2-thioxospiro f cyclohexane-1,3-l3Hl indoll-5-y1L
lluorobenzonitrile
The title compound was prepared from 4-(1,2-dihydro-2-
oxospiro[cyclohexane-1,3-[3H]indol]-S-yl)-2-fluorobenzonitrile (90 mg) and
Lawesson's reagent (90 mg) in toluene ( 10 ml) at reflux, according to General
Procedure A, to afford the title compound (0.050 g) as an orange solid: 'H NMR
(DMSO-db) 8 12.80 (br s, 1H), 8.04 (d, 1H, J= 1.3 Hz), 7.98 (t, 1H, J= 7.5
Hz), 7.92
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(dd, 1 H, J = 1 I .3 and 1.3 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.18 (d, I H, J =
8.2 Hz), 1.99
- I .82 (m, 7H) and 1.40 - 1.38 (m, 3H); MS ((-)-APCI) m/z 335 [M-H]-.
Example 41
5-( 1,2-Dihydro-2-thioxospiro(cyclohexane-1,3-[3Hl indolj-5-yl) 4-n-but
thiophenecarbonitrile
The title compound was prepared in a manner similar to Example 5 from 5-
bromo-4-n-butyl thiophenecarbonitrile (1.24 g, 5.1 mmol), (1,2-dihydro -2-
oxospiro[cyclohexane-1,3-[3H] indol)-5-boronic acid (1.24 g, 5.05 mmol),
tetrakis(triphenylphosphine) palladium (0.25 g), potassium carbonate (2.75 g,
21
mmol), water ( 10 mL),and dimethoxyethane (50 mL) heated at reflux for 5 hours
to
afford 5-( 1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H] indol]-5-yl) 4-n-butyl-
2-
thiophenecarbonitrile (1 g, 54%), m.p.130-132° C. 'H NMR ( DMSO-db ) 8
10.56 (s,
IH), 7.92 (s, 1H) , 7.52-7.51 (d, 1H, J= 1.2 Hz ), 7.32-7.29 (dd, 1H, J= 1.5
Hz), 6.98
- 6.96 (d, IH, J= 8.0 Hz), 2.64 - 2.59 (t, 2H), 1.99 - 1.86 (m, 2H), 1.70 -
1.50 (m, 11
H), 1.32 - 1.22 (m, 2H) , 0.86 - 0.82 (t, 3H ); MS (APCI (+)) m/z 365 [M+H]+;
IR
(KBr) 1620,1700;2200 cm'; Anal. Cz2Hz4NzOS~1/4 H20. calc. C, 71.61; H, 6.69; N
7.59. observed C, 71.13; H, 6.61; N, 6.91.
The title compound was prepared from S-( 1,2-dihydro-2-
oxospiro[cyclohexane-1,3-[3H] indol]-5-yl) 4-n-butyl-2-thiophenecarbonitrile
(90
mg) and Lawesson's reagent (90 mg) in toluene (10 ml) at reflux, according to
General Procedure A, to afford the product (0.050 g) as an orange solid: 'H
NMR
(DMSO-db) 8 12.83 (br s, 1 H), 7.95 (s, 1 H), 7.77 (s, I H), 7.44 (d, 1 H, J =
8.1 Hz),
7.18 (d, 1 H, J = 8. I Hz), 2.63 (t, 1 H, J .79= 8.0 Hz), 1.99 - 1.77 (m, 7H),
I .60 - 1.50
(m, 2H), 1.39 - 1.35 (m, 3 H), 1.29 - 1.22 (m, 2H) and 0.81 (t, 3H, 7.3 Hz):
MS ((-)-
APCI) m/z 379 [M-H]-.
Example 42
5-(3-Fluoro-5-methoxyphen~)spirolcyclohexane-1,3-f3Hlindolel-2(1H)-thione
The title compound was prepared from 5-(3-Fluoro-5-methoxyphenyl)spiro
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[cyclohexane-1,3-[3H]indole]-2(1H)-one (90 mg) and Lawesson's reagent (90 mg)
in
toluene ( 10 ml) at reflux, according to General Procedure A, to afford the
product
(0.043 g) as an off white solid: 'H NMR (DMSO-d6) 8 12.74 (br s, 1H), 7.90 (s,
1H),
7.63 (dd, 1 H, J = 8.1 and 1.2 Hz), 7.13 (d, 1 H, J = 8.1 Hz), 7.08 (d, 1 H, J
= 10 Hz),
S 7.01 (s, 1H), 6.83 (dt, 1H, J= 11 and 2.0 Hz), 1.99 - 1.83 (m, 7H) and 1.40 -
1.37 (m,
3H): MS ((-)-APCI) m/z 340 [M-H]~.
Example 43
5-(3-Chlorophenyl)-N-hydroxyspiro(cyclohexane-1,3'-(3Hlindoll-2-amine
To a solution of 5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-
2'(1'H)-thione (0.74 g, 2.25 mmol) in dry THF (15 ml) was added sodium hydride
(60% in oil, 0.1 g, 2.5 mmol) at room temperature. After 15 min., methyl
iodide (0.18
ml, 2.88 mmol) was added. After lh, the reaction mixture was partitioned
between
water and EtOAc, the organic layer was washed with brine, dried (MgS04) and
evaporated to give 5-(3-chlorophenyl)-2-(methylthio)spiro[cyclohexane-1,3'
[3H]indole] (0.80 g, 100%) which was used without further purification:
To a solution of the last cited compound (1.96 g, 5.73 mmol) in DMSO (20
ml) was added hydroxylamine (60% in water, 5 ml) and the mixture was heated to
120 oC. After lh., the reaction was cooled, partitioned between diethyl ether
and
saturated aqueous ammonium chloride solution. The organic layer was washed
with
water and brine and then dried (MgS04) and evaporated. The crude product was
then
crystallized from MeOH to afford the title compound ( 1.67 g, 5.08 mmol, 89%)
as a
white solid: 'H NMR (CDCl3) 8 7.52 (t, 1H, J= 1.7 Hz), 7.43 - 7.28 (m, 7H),
6.83
(d, 1H, J= 8 Hz) and 1.98 - 1.51 (m, lOH); MS (ESI (+)) mlz 327/329 [M+H]+.
Example 44
N-(Acetyloxy)-5'-(3-chlorophenvl)spiro(cyclohexane-1,3'-(3Hlindoll-2"amine
To a solution of 5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'
[3H]indol]-2-amine (0.23 g, 0.71 mmol) in methylene chloride-methanol (9:1, 10
ml)
was added acetic anhydride (0.08 ml, 0.8 mmol) and 4-dimethylaminopyridine
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(catalytic amount) under a nitrogen atmosphere. After 20 min., the reaction
was
evaporated and the product purified by column chromatography (Si02, methanol:
methylene chloride 5:95). The product was then triturated with di-iso-
propylether to
afford the title compound (0.12 g, 0.32 mmol, 45%): 'H NMR (CDC13) 8 7.52 -
7.51
(m, 2H), 7.43 - 7.27 (m, SH), 6.88 (d, 1H, J = 8 Hz), 2.27 (s, 3H), 2.04 -
1.92 (m,
4H), 1.84 - 1.74 (m, 4H) and 1.72 - 1.57 (m, 2H); MS (ESI (+)) m/z 369/371
[M+H]+; C21 H21 C1N2O2. 0.5 H20 requires C 66.98: H 5.64: N 7.34. Found C
66.74:
H 5.86: N 7.41.
Example 45
5'-(3-Fluorophenyl)spirofcyclohexane-1,3'-f3Hlindol-2'(1'H)-one oxime
Prepared according to the method for Example 43 from 5'-(3-fluorophenyl)
spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-thione (0.59 g, 1.90 mmol) to
afford the
title compound (0.053 g, 0.17 mmol, 10%): 'H NMR (DMSO-d6) 8 9.59 (s, 1H),
9.40 (s, 1H), 7.57 (d, 1H, J = 1.5 Hz), 7.46 - 7.39 (m, 4H), 7.11 - 7.05 (m,
1H), 6.80
(d, 1H, J = 8.1 Hz), 2.04 -1.97 (m, 2H), 1.82 - 1.74 (m, 2H) and 1.66 - 1.42
(m, 6H):
MS (ESI (-)) m/z 309 [M-H]', C19H19FN20 requires C: 73.53, H: 6.17, N: 9.03.
Found C: 73.33, H: 6.07, N: 8.83.
Exam Ip a 46
5'-(2-Fluorophenyl)spiro[cyclohexane-1,3'-f3H]iindol-2'(1'H)-one oxime
5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O- benzyloxime).
5'-Bromo-2'-(methylthio)spiro[cyclohexane-1,3'-[3H]indole] (9.0 g, 28.98 mmol)
and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol) were combined in
methanol ( 150 mL) and heated to 45°C for 6 hours. Methanol was
evaporated in
vacuo. Ethyl acetate was added to the residue and this mixture was washed with
ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate,
ethyl
acetate collected evaporated in vacuo and the residue was flash
chromatographed on
alumina 90 (9:1 Hexane/EtOAc) to the desired product (6.5 g, 60%).
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1H NMR (DMSO-db, 300 MHz) b 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s,
2H), 6.71 (d, 1 H, J = 8.26 Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1 H).
Procedure A
5'-(2-Fluorophenyl)-spiro[cyclohexane-1,3'-[3H]indol}-2'(1H)-one 2(O-
benzyloxime). 5'-Bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O-
benzyloxime) (1.0 g, 2.6 mmol), and tetrakistriphenyl phosphine Pd (0) (0.14
g, 0.12
mmol) were stirred under an atmosphere of nitrogen in ethylene glycol dimethyl
ether
(23 mL). After 15 minutes, 2-flurophenyl boronic acid (0.72 mg, 5.2 mmol) was
added, followed by sodium carbonate ( 1.6 g, 15.6 mmol) in water (6.0 mL). The
reaction was heated to reflux overnight, cooled to room temperature and
filtered
through a Celite plug. Saturated ammonium chloride was added. The water layer
was
extracted with ethyl acetate (3 X 100 mL). The combined organic layers were
dried
(MgS04), filtered, and the solvent removed in vacuo. The product was purified
by
flash silica gel chromatography; (eluant: 10:0.5 hexane: ethyl acetate) to
give the
desired target compound (0.75 g, 1.8 mmol, 72%) as a viscous oil. 'H NMR (500
MHz, DMSO-db) 8 1.44 - 1.73 (8H, m) 1.93 - 2.06 ( 2H, q) 5.00 (2H, s) 6.88
(1H, d,
J-- 8.1 Hz) 7.24 - 7.38 (6H, m) 7.44 - 7.56 (5H, m) 9.64 (1H, s); MS (ESI(+
ve)) mlz
399 (M-H)'.
Procedure B
A solution of 5'-(2-Fluorophenyl)-spiro[cyclohexane-1,3'-[3H]indol}-2'(1H)-
one 2(O-benzyloxime) (0.55 g, 1.37 mmol) in ethanol(15 mL) was added to
Palladium on carbon ( 10%, 0.11 g) in ethanol ( 10 mL). The mixture was
stirred under
an atmosphere of hydrogen (balloon) for 24 h at room temperature. The reaction
mixture was filtered through a Celite plug and the filtrate was concentrated
in vacuo.
The product was purified by flash silica gel chromatography (hexane: ethyl
acetate,
gradient elutions) to give the title compound (0.45 g, 1.12 mmol, 82%), mp.
200 -
203 °C; 'H NMR (500 MHz, DMSO-db) 8 1.45 - 1.73 (8H, m) 1.96 - 2.00
(2H, q) 6.83
(1H, d, J-- 7.9) 7.23 - 7.50 (6H, m) 9.42 (1H, s) 9.58 (1H, s); MS (ESI(+ ve))
m/z 311
(M+H)+.
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Example 47
5'-(4-Fluorophenyl)spirofcyclohexane-1,3' [3H~'indol 2' 1'H) one oxime
5'-(4-Fluorophenyl)-spiro[cyclohexane-1,3'-[3H)indol}-2' (1'H)-one 2'(O-
benzyloxime). Prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-
one 2'(O- benzyloxime) ( 1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid
(0.72 g,
5.2 mmol) according to Example 46 procedure A. The product was purified by
flash
silica gel chromatography; (eluant: 10:0.5 hexane: ethyl acetate) to give the
desired
product (0.70 g, 1.7 mmol, 67 %) as a viscous oil. 'H NMR (500 MHz, DMSO-db) 8
1.42 - 1.77 (8H, m) 1.95 - 1.99 (2H, q) 5.00 (2H, s) 6.84 (1H, d, J-- 8.1 Hz)
7.21 -
7.63 (1H, m) 9.58 (1H, s); MS (ESI(- ve)) m/z 399 (M-H)-.
The product was synthesized using 5'-(4-Fluorophenyl)-spiro[cyclohexane-
1,3'-[3H]indol}-2' (1'H)-one 2'(O-benzyloxime) (0.70 g, 1.74 mmol), according
to
Example 45 procedure B. The product was purified by flash silica gel
chromatography; (hexane: ethyl acetate, gradient elution) to give the title
compound
(0.44 g, 1.4 mmol, 81 %), Mp. 205 - 208°C; 'H NMR (500 MHz, DMSO-db) 8
1.43 -
1.77 (8H, m) 2.00 - 2.05 (2H, q) 6.80 (1H, d, J-- 8.2 Hz) 7.21 - 7.24 (2H, m)
7.33 -
7.35 (1H, dd, J-- 1.9 Hz) 7.49 (1H, s) 7.60 - 7.63 (2H, m) 9.35 (1H, s) 9.56
(1H, s);
MS (ESI(+ ve)) m/z 311 (M+H)+.
Example 48
5'-(3 4-difluorophenyl)spiro[cyclohexane-1,3' [3Hlindol 2'(1'H) one oxime
5'-(3,4-Difluorophenyl)-spiro[cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O-
benzyloxime). Prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-
one 2'(O- benzyloxime) ( 1.0 g, 2.6 mmol) and 3,4 -diflurophenyl boronic acid
( 1.6 g,
5.2 mmol of a 50 % solution of acid in THF/water) according to Example 46
procedure A. The product was purified by flash silica gel chromatography
(eluant: 10:
0.5 hexane: ethyl acetate) to give the desired product (0.75 g, 1.7 mmol, 69
%) as a
viscous oil. 'H NMR (500 MHz, DMSO-db) 8 1.41 - 1.78 (8H, m) 1.95 - 1.99 (2H,
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q) 5.00 (2H, s) 6.82 ( 1 H, d) 7.28 - 7.46 (8H, m) 7.58 ( 1 H, q) 7.67 - 7.71
( 1 H, m) 9.61
(1H, s); MS (ESI(- ve)) m/z 417 (M-H)-.
Reaction of the last cited compound (0.70 g, 1.6 mmol) according to Example
45 procedure B, afforded the title compound (0.44 g, 1.3 mmol, 80 % ), 'H NMR
(500 MHz, DMSO-db) 8 1.42 - 1.79 (8H, m) 2.01 - 2.05 (2H, q) 6.78 - 6.80 (1H,
d)
7.39 - 7.46 (3H, m) 7.55 (1H, s) 7.70 (1H, m) 9.10 (1H, s) 9.59 (1H, s); MS
(ESI(+
ve)) m/z 329 (M+H)+.
Exam In a 49
5'-(3-methoxyphenYlLpirolcyclohexane-1,3'-f3Hlindol-2'(1'H)-one oxime
5'-(3-Methoxyphenyl)-spiro[cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O-
benzyloxime). Prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-
one 2'(O- benzyloxime) ( 1.0 g, 2.6 mmol) and 3-methoxyphenyl boronic acid
(0.79 g,
5.2 mmol) according to Example 46 procedure A. The product was purified by
flash
silica gel chromatography; (eluant: 10:0.5 hexane: ethyl acetate) to give the
desired
product (0.80 g, 1.9 mmol, 75 %) as a viscous oil. 'H NMR (500 MHz, DMSO-db) 8
1.43 - 1.78 (8H, m) 1.95 - 2.00 (2H, q) 3.80 (3H, s) 5.00 (2H, s) 6.82 - 6.86
(2H, m)
7.10 - 7.16 (2H, m) 7.28 - 7.53 (IOH, m) 9.57 (1H, s); MS (ESI(- ve)) m/z 411
(M-H)-
Reaction of the last cited compound (0.80 g, 1.9 mmol) according to Example
46 procedure B, afforded the title compound (0.48 g, 1.4 mmol, 77 %), as a
white
solid. Mp. 101 - 104°C; 'H NMR (500 MHz, DMSO-db) 8 1.44 - 1.78 (8H, m)
1.99 -
2.03 (2H, q) 3.81 (3H, s) 6.78 (1H, d) 6.85 (1H, d) 7.10 - 7.16 (2H, m) 7.30 -
7.38
(2H, m) 7.50 (1H, d) 9.35 (1H, s) 9.56 (1H, s); MS (ESI(+ ve)) m/z 323 (M+H)+.
Example 50
5'-(3-nitrophenyl)spirofcyclohexane-1,3'-l3Hlindol-2'(1'H)-one oxime
5'-(3-Nitrophenyl)-spiro[cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O-
benzyloxime). Prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-
one 2'(O- benzyloxime) ( 1.0 g, 2.6 mmol) and 3-Nitrophenyl boronic acid (0.86
g, 5.2
mmol) according to Example 46 procedure A. Purification by flash silica gel
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chromatography (eluant : 10:0.5 hexane: ethyl acetate) afforded the desired
compound (0.60 g, 1.4 mmol, 55 %) as a viscous oil. 'H NMR (500 MHz, DMSO-
db) 8 1.42 - 1.82 (8H, m) 2.02 - 2.04 (2H, q) 5.01 (2H, s) 6.88 (1H, d) 7.28-
7.71 (8H,
m) 8.08 - 8.13 (2H, m ) 8.38 (1H, d) 9.69 (1H, s); MS (ESI(- ve)) m/z 426 (M-
H) -.
Procedure C
The last cited compound (0.54 g, 1.26 mmol) was dissolved in dry methylene
chloride (25 mL) and cooled to -78 °C under nitrogen. Boron tribromide
(3.8 mL, 3.8
mmol, 1.0 M in methylene chloride) was added drop-wise over 5 minutes. After
30
minutes the reaction was quenched with saturated sodium bicarbonate (5 mL).
The
reaction mixture was allowed to warm to room temperature, the layers were
separated
and the aqueous layer was extracted with methylene chloride. The combined
organic
layers were dried (NazS04), filtered, and the solvent removed in vacuo. The
product
was purified by flash silica gel chromatography (eluant: 8:1 hexane: ethyl
acetate) to
give afford the title compound (0.33 g, 0.9 mmol, 78 %). Mp. 221 - 224
°C; 'H
NMR (500 MHz, DMSO-db) 8 1.42 - 1.83 (8H, m) 1.99 - 2.07 (2H, q) 6.84 - 6.85
(1H, dd) 7.50 - 7.52 (1H, m) 7.67 - 7.71 (2H, m) 8.08 - 8.12 (2H, m) 8.37 -
8.38 (1H,
d) 9.48 (1H, s) 9.64 (1H, s); MS (ESI(+ ve)) m/z 338 (M+H)+.
Example 51
5'-( 3-c,~phen~l?spiro[cyclohexane-1,3'-[3Hlindol-2'(1'H)-one oxime
3-Lpiro Lcyclohexane-1 3'-f 3H]indol]-( 1'H)-one-2'-(O-
benzyloxime)lbenzonitrile f3H]indol]-5-yllbenzonitrile. Prepared from 5'-
bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O- benzyloxime) (1.0 g,
2.6
mmol) and 3-cyanophenyl boronic acid (0.76 g, 5.2 mmol) according to Example
46
procedure A. The product was purified by flash silica gel chromatography
(eluant: 10:
0.5 hexane: ethyl acetate) to give the desired product (0.75 g, 1.8 mmol, 71
%) as a
viscous oil.'H NMR (500 MHz, DMSO-db) 8 1.41 - 1.81 (8H, m) 1.96 - 2.03 (2H,
q)
5.01 (2H,s)6.86(lH,d)7.28-7.33(9H,m)7.95-7.97(lH,d)8.12(lH,s)9.65
(1H, s); MS (ESI(- ve)) mlz 406 (M-H)-.
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Reaction of the last cited compound (0.17 g, 0.43 mmol) and boron tribromide
(1.2 mL, 1.2 mmol) according to Example SO procedure C afforded the title
compound (0.06 g, 0.2 mmol, 47 %) as a white solid, Mp. 198 - 200°C; 'H
NMR
(500 MHz, DMSO-db) 8 1.41 - 1.80 (8H, m) 1.97 - 2.04 (2H, q) 6.80 (1H, q) 7.45
-
7.69 (4H, m) 7.93 - 7.95 ( 1 H, dd) 8.10 ( 1 H, s) 9.42 ( 1 H, s) 9.59 ( 1 H,
s); (ESI(+ ve))
mlz 318 (M+H)+.
Example 52
3-11',2'-Dihydro-2'-(hydrox 'mino)spiro[cyclohexane-1,3'-f3H]indoll-5'x11-5-
fluorobenzonitrile
To a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) in dry
DMF ( 10 ml) was added diboron pinacolate ester (0.63 g, 2.5 mmol), potassium
acetate (0.65 g, 6.7 mmol) and PdClz (dppf) (0.2. g) and the reaction was
heated to 80
°C under a nitrogen atmosphere. After 8 h. from 5'-
bromospiro{cyclohexane-1,3'-
[3H]indol}-2' (1'H)-one 2'(O- benzyloxime) (0.2 g, 0.5 mmol), PdCl2 (dppf)
(0.05 g)
and sodium carbonate (1.30 g, 12.5 mmol) were added and heating at 80
°C was
continued. After 8h. the reaction was cooled and partitioned between water and
ethyl
acetate, the organic layer was washed with brine, dried (MgS04) and
evaporated. The
residue was purified by column chromatography (Si02, EtOAc:hexane 1:20) to
give
the desired product (0.14 g, 0.33 mmol, 66%).
Reaction of the last cited compound (0.14 g, 0.33 mmol) and boron tribromide
( 1.0 ml, 1.0 mmol) according to Example 50 procedure C afforded the title
compound
(0.019 g, 0.05 mmol, 17%): 'H NMR (300 MHz, DMSO-db) 8 9.65 (s, 1H), 9.49 (s,
1 H), 8.04 (m, 1 H), 7.89 (dt, 1 H, J = 10.5 and 2 Hz), 7.72 - 7.68 (m, 2H),
7.54 (d, 1 H,
J= 8.1 Hz), 6.80 (d, 1H, J= 8.1 Hz), 2.05 - 1.99 (m, 2H), 1.84 - 1.76 (m, 2H)
and
1.65 - 1.44 (m, 6H): MS (ESI(+ ve)) m/z 336 (M+H)+.
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Examine 53
5-(Spiro f cyclohexane-1,3'-(3Hl indoll-2'-(hvdroxvimino)-5'-yl)-4-methyl-2
thiophenecarbonitrile
4-Methyl-5-trimethylstannanyl-thiophene-2-carbonitrile Prepared from 5-
bromo-4-methyl-thiophene-2-carbonitrile (3.08 g, 15.2 mmol), tetrakistriphenyl
phosphine Pd (0) (0.82 g, 0.71 mmol), hexamethylditin (5.0 g, 15.2 mmol) and
ethylene glycol dimethyl ether (20 mL) under nitrogen. The mixture was heated
to
reflux for 14 hours. The reaction mixture was concentrated in vacuo and
purified
using flash silica gel chromatography (eluant: 2% MeOH: methylene chloride) to
recover the desired roduct (2.8 g, 0.01 mmol, 67 %) as a runny oil. 1H NMR
(300
MHz, DMSO-db) 8 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).
The last cited compound (0.20 g, 0.50 mmol), dichlorobis
(triphenylphosphine) palladium(II) (0.02 g, 0.03 mmol) and triphenylarsine
(0.03 g,
0.13 mmol) in DME (8.0 mL) were stirred under nitrogen for 20 minutes. 5'-
Bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-one 2'(O- benzyloxime) (0.18
g,
0.64 mmol) was added in a solution of DME (2.0 mL). The solution was heated to
reflux overnight. The reaction solution was concentrated in vacuo and purified
by
flash silica gel chromatography (eluant 12:1 hexane : ethyl acetate) to give
the crude
product(0.10 g, 0.25 mmol, 50%) which was used without further purification
Boron tribromide (2.6 mL, 2.6 mmol of a 1.0 M solution in methylene
chloride) was added to a solution of the last product (0.37 g, 0.86 mmol) in
dry
methylene chloride ( 1.7 mL) at -78°C. The solution was stirred for 30
minutes and
quenched with saturated sodium bicarbonate (10 mL). The mixture was allowed to
warm to room temperature and the layers were separated. The organic layer was
dried
(NazS04), filtered and concentrated in vacuo to give crude product which was
purified
by flash silica gel chromatography (eluant: 6:1 hexane: ethyl acetate) to give
the title
compound (0.02 g, 24 %): Mp. 173-176 °C; 'H NMR (500 MHz, DMSO-db) 8
1.44 -
1.73 (8H, m), 1.96 - 2.00 (2H, m), 2.28 (3H, s), 6.82 - 6.84 (1H, m), 7.24 -
7.26 (1H,
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dd, J-- 1.7 Hz), 7.3 8 ( 1 H, m) 7.82 ( 1 H, m) 9.51 ( 1 H, m) 9.66 ( 1 H, m);
MS (ESI(+ ve))
m/z 338 (M+H)+.
Example 54
5-(Spiro[cyclohexane-1,3'-f3Hlindole]-2'(hydroxyimino)-5'-yl)-2-
thiophenecarbonitrile
To a solution of 2-cyanothiophene ( 1.0 g, 9.16 mmol) and tri-iso-propylborate
(2.3 ml, 10 mmol) in dry THF (30 ml) under nitrogen at -78 °C was
added, dropwise,
lithium hexamethyldisilazide (1M in THF, 10 ml, 10 mmol). After 30 min., the
reaction was quenched with 1N HCI, then extracted with ethyl acetate, the
organic
layer was washed with water, dried (Na2S04) and evaporated to the product
(1.25g,
8.17 mmol, 89%) which was used without further purification: 'H NMR (500 MHz,
DMSO-db) 8 8.75 (br s, 2H), 7.97 (d, 1H, J= 8 Hz) and 7.73 (d, 1H, J= 8 Hz):
MS
(ESI(- ve)) m/z 152 (M-H)-.
Prepared from the last cited product (0.91 g, 5.95 mmol) and 5'-
bromospiro{cyclohexane-1,3'-[3H)indol}-2' (1'H)-one 2'(O- benzyloxime) (1.53
g,
3.97 mmol) according to Example 46 procedure A. Purification by flash silica
gel
chromatography (eluant: 5: 1 hexane: THF) gave the desired product (0.66 g,
1.59
mmol) which was used without further purification: MS (ESI(- ve)) m/z 412 (M-
H)-.
Reaction of the last cited compound (0.60 g, 1.45 mmol) and boron
tribromide (1M in dichloromethane, S mL, 5 mmol) according to Example 50
procedure C afforded the title compound (0.036 g, 0.11 mmol, 8 %): 'H NMR (300
MHz, DMSO-db) 8 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J= 3.9 Hz), 7.63 (d,
1H, J
= 1.5 Hz), 7.54 (d, 1H, J = 3.9 Hz), 7.47 (dd, 1H, J= 8.1 and 1.6 Hz), 6.78
(d, 1H, J
= 8.1 Hz), 2.13 - 1.90 (m, 2H) and 1.78 - 1.60 (m, 6H): MS (ESI(+ ve)) m/z 324
(M+H)+.
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Example 55
4-(Spiro(cyclohexane-1,3'-l3Hlindole)-2'(h~yimino~l-5'-y1L
thiophenecarbonitrile
4-(Trimethylstann~)-2-thiophenecarbonitrile A solution of 3-bromo-2-
thiophenecarbonitrile (0.8 g, 4.3 mmol),
tetrakis(triphenylphosphine)palladium(0)
(0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5
cm3) was heated under reflux for 14 h then cooled to RT. The reaction mixture
was
absorbed onto florisil and purified by column chromatography (Si02, methylene
chloride: hexane 1:9) to afford the subtitled compound ( 1.04 g, 3.8 mmol,
90%) as a
clear viscous oil: 1H NMR (CDC13) 8 0.35 (s, 9H), 7.56 (d, J= 0.9 Hz, 1H),
7.66 (d, J
= 0.9 Hz, 1 H).
To a solution of 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2' (1'H)-one
2'(O- benzyloxime) (1.65 g, 4.28 mmol), 4-(trimethylstannyl)-2-
thiophenecarbonitrile
(1.48 g, 5.44 mmol), triphenylarsine (330 mg) in dry dimethoxy ethane (20 ml),
under
1 S a nitrogen atmosphere was added bis(triphenylphosphine)palladium (II)
chloride, and
the mixture was heated under reflux for 16 h. After cooling to room
temperature the
mixture was evaporated, and the residue purified by column chromatography
(Si02,
EtOAc:hexane, gradient elution) to afford the desired product (0.61 g, 1.47
mmol,
56%).
Reaction of the last cited compound (0.61 g, 1.47 mmol) and boron
tribromide (1M in dichloromethane, 4.5 mL, 4.5 mmol) according to Example 50
procedure C afforded the title compound (0.084 g, 0.26 mmol, 18 %): 'H NMR
(300
MHz, DMSO-db) 8 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.65
(s, 1H),
7.48 (dd, 1 H, J = 8.1 and 0.9 Hz), 6.76 (d, 1 H, J = 8.1 Hz), 2.03 - 1.96 (m,
2H) and
1.78 - 1.42 (m, 6H): MS (ESI(+ ve)) m/z 324 (M+H)+.
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Example 56
5-(Spirolcyclohexane-1,3'-l3Hlindolel-2'(h~yimino)-5'-yl)- 1H-pyrrole-1-
methyl-2-carbonitrile
2- {S'[spiro[cyclohexane-1,3'-[3H]indol]-( 1'H)-one-2'(O-benzyloxime)] } -1 H-
pyrrole-1-carboxylic acid, tert-butyl ester. A solution of S'-
bromospiro{cyclohexane-
1,3'-[3H]indol}-2' (1'H)-one 2'(O- benzyloxime) (7.4 g, 19.17 mmol) and
tetrakis
(triphenylphosphine)palladium (0) (2.5 g, 2.00 mmol) in DME ( 100 ml) was
stirred
under nitrogen for 15 minutes. To the solution was added 1-tert-
butoxycarbonylpyrrole boronic acid (5.5 g, 26 mmol) and 1M sodium carbonate
(50
ml). The mixture was heated to 80° C for 6 hours and allowed to cool.
The reaction
mixture was poured into water and extracted with ethyl acetate (3 x 100 ml).
The
organic layers were combined and dried over magnesium sulfate. The solution
was
filtered, concentrated in vacuo, and the residue was purified by flash
chromatography
on silica gel (4.5:1 Hexane/ ethylacetate) to give the product (7.7 g, 88 %)
as a
white solid. 'H NMR (DMSO-d6, 300 MHz) 8 1.28 (s, 9H), 1.55 - 1.66 (m, 8H),
1.83 - 1.98 (m, 2H), 4.99 (s, 2H), 6.12 - 6.14 (m, 1H), 6.22 (t, 1H, J= 3.26
Hz), 6.76
(d, 1H, J= 7.9 Hz), 7.02 (dd, 1H, J= 7.98, 1.4 Hz), 7.19 (s, 1H) 7.27 -7.31
(m, 2H) ,
7.35 (t, 1H, J-- 6.8 Hz), 7.43 (d, 1H, J= 8 Hz ), 9.55 (s, 1H).
5'-( 1-tert-Butoxycarbonyl-1 H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-
2'-(1'H)one-2'-(O-benzyloxime)-1'-carboxylic acid, tert-butyl ester. To a
solution of
2- {5'[spiro[cyclohexane-1,3'-[3H]indol]-( 1'H)-one-2'(O-benzyloxime)] } -1 H-
pyrrole-
1-carboxylic acid, tert-butyl ester (7.7 g, 16.38 mmol) in THF (anhydrous, 100
mL)
was added sodium hydride (0.665 g, 17 mmol) after hydrogen evolution ceased di-
tert-butyldicarbonate (10.9 g, 50 mmol) and DMAP( 0.20 g) was added and the
reaction stirred at 65 °C for 18 hours. The reaction mixture was poured
into water
and extracted with ethyl acetate. The organic layers were combined, and dried
over
magnesium sulfate. The solution was filtered , concentrated in vacuo, to give
the
product ( 9.0 g, 15.76 mmol) which was taken directly to the next step.
To a solution of 5'-(1-tert-Butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-
1,3'-[3H]indol]-2'-(1'H)one-2'-(O-benzyloxime)-1'-carboxylic acid, tert-butyl
ester
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(9.0 g, 15.76 mmol) in THF (anhydrous, 75 mL) at -78° C was added
chlorosulfonyl
isocyanate (l.SSmL, 17.54 mmol). After 90 minutes, DMF (21 mL, 275 mmol) was
added and the reaction was allowed to warm to room temperature. The reaction
was
poured into water (200 mL) and extracted with ethyl acetate (2 X 100 mL). The
organic layers combined and dried over magnesium sulfate, filtered and
concentrated
in vacuo. Purification by flash column chromatography on silica gel (10% ethyl
acetate/ Hexane) gave 5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-
yl)spiro[cyclohexane-1,3'-[3H]indol]-2'( 1'H)one-2'(O-benzyloxime)-1'-
carboxylic
acid, tert-butyl ester (7.6 g, 82%) as a white powder. 'H NMR (DMSO-dy,
300MHz)
8 1.30 (s, 9H), 1.38 (s, 9H), 1.58-1.83 (m, 8H), 1.72-1.73 (m, 2H), 5.0 (s,
2H), 6.44-
6.45 (d, 1H, J= 3.76), 7.25-1.46 (m, lOH).
5'-(5-Cyano-1 H-pyrrol-2-yl)spiro[cylohexane-1,3'-[3H]indol]-2'( 1'H)one-2'-
(O-benzyloxime)-1'-carboxylic acid, tert-butyl ester. To a solution of 5'-(5-
cyano-1-
tert-butoxycarbonyl-1 H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2'(
1'H)one-
2'(O-benzyloxime)-1'-carboxylic acid, tent-butyl ester (7.6 g, 3.25 g, 48
mmol) in
THF (anhydrous, 30 mL) was added a solution of sodium ethoxide in ethanol (120
mL). The reaction mixture was heated to 80° C and stirred overnight.
The mixture
was cooled to room temperature and concentrated in vacuo. The residue was
dissolved in ethyl acetate and washed with water, brine, and dried over
magnesium
sulfate. The solvent was evaporated in vacuo to afford the product (6.1 g,
95%). 'H
NMR (DMSO, 500 MHz ) 8 1.38 (s, 9H), 1.63-1.74 (m, 8H), 1.88-1.97 (m, 2H),
5.08
(s, 2H) 6.69-6.7 (d, 1H, J= .BHz), 6.98-6.99 (d, 1H, J= .7 Hz), 7.29-7.37 (m,
1H),
7.35 (m, 2H), 7.42 (m, 3H), 7.63 (dd, 1H, J= 1.8, .3 Hz), 7.76 (d, 1H, J= .4
Hz).
5'-(5-Cyano-1-methyl-1 H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-
(O-benzyloxime)-1'-carboxylic acid, tent-butyl ester. To 5'-(5-cyano-1H-pyrrol-
2-
yl)spiro[cylohexane-1,3'-[3H]indol]-2'( 1'H)one-2'-(O-benzyloxime)-1'-
carboxylic
acid, tert-butyl ester (6.1 g, 12.29 mmol) in DMF (75 mL) was added potassium
carbonate (6.5 g, 47 mmol) and MeI ( 1 mL, 15.4 mmol) and the reaction mixture
was
stirred at room temperature for 2.5 hours. The reaction mixture was poured
into
water and extracted with ethyl acetate. The organic layer was washed with
brine and
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the solvent was concentrated in vacuo. To give the desired product (6.1 g,
12.29
mmol) which was carried on to the next step without further purification. 'H
NMR
DMSO, 300 MHz) 8 1.38 (s, 9H), 1.62-1.98 (m,IOH), 3.71 (s, 3H), 5.08 (s, 2H),
6.34
(d, 1 H, J = 4.1 ), 7.03 (d, 1 H, J = 3.99), 7.30-7.53 (m, 8H).
5-{5'-Spiro[cyclohexane-1,3'-[3H]indol]-(1'H)-one-2'-(O-benzyloxime)]}-1H-
pyrrole-1-methyl-2-carbonitrile. 5'-(5-Cyano-1-methyl-1 H-pyrrol-2-
yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-(O-benzyloxime)-1'-carboxylic acid,
tert-
butyl ester (6.1 g,12.29 mmol) was dissolved in dioxane (5 mL) and 4 M HCl in
dioxane ( 10 mL) was added and the reaction heated to 45 °C for 3.5
hours. The
mixture was carefully neutralized with sodium bicarbonate (sat.). The reaction
mixture was poured into water and extracted with ethyl acetate. The organic
layer
was washed with brine and dried over magnesium sulfate. The solvent was
evaporated in vacuo. Purification by column chromatography on silica gel (5%
ethyl
acetate/hexane) gave the product (4.36 g, 94%). 'H NMR (DMSO-d6, 300MHz) 8
1.57-1.7 (m, 8H), 1.9-2.05 (m, 2H), 3.68 (s, 3H), 5.00 (s, 2H), 6.25 (d, 1H,
J= 3.92),
6.85 (d,lH, J= 8.03), 7.00 (d, 1H, J= 4.08), 7.2-7.44 (m, 7H), 9.7 (s, 1H)
To 5-{5'-spiro[cyclohexane-1,3'-[3H]indol]-(1'H)-one-2'-(O-benzyloxime)]}-
1H-pyrrole-1-methyl-2-carbonitrile (4.36g, 10.6 mmol) in methylene chloride
(50
mL) was added 1M boron tribromide (35 mL, in methylene chloride) at -
78° C. The
reaction mixture was allowed to warm to room temperature. After 4 hours, the
reaction mixture was quenched with saturated sodium bicarbonate ( 100 mL). The
organic layer was collected and the aqueous layer was extracted with ethyl
acetate
(2X 100 mL), organic layers combined, washed with brine, dried over magnesium
sulfate, and the solvent evaporated in vacuo. The residue was purified by
flashed
chromatography on silica gel (7:3 hexane/ethylacetate) to give the title
compound
(1.35g, 40%) as a white solid. 'H NMR (DMSO-d6, 300 MHz) 8 1.58 - 1.71 (m,
8H),
1.99 - 2.00 (m, 2H), 3.69 (s, 3H) 6.24 (d, 1H, J= 4.07 Hz), 6.8 (d, 1H, J=
8.05 Hz),
6.99 (d, 1H, J= 4.01 Hz), 7.20 (dd, 1H, J= 8.04, 1.57 Hz), 7.36 (d, 1H, J=
1.12 Hz),
9.48 (s, 1H), 9.62 (s, 1H).
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Example 57
~spiro f cyclohexane-1,3'-[3H] indoll-2'-(hvdroxyimino)-5'-yl)-1H-pyrrole-2
carbonitrile
5-(spiro[cyclohexane-1,3'-[3]indole]-2' ( 1 H)-(O-benyloxime))-1 H-pyrrole-2-
carbonitrile. Prepared from 5'-(5-Cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-
[3H]indol]-2'(1'H)one-2'-(O-benzyloxime)-1'-carboxylic acid, tert-butyl ester
(0.395
g, 0.796 mmol) dissolved in 2mL of THF and 4M HCl Dioxane/water (10 mL)
following the procedure used to prepare 5-{5'-spiro[cyclohexane-1,3'-
[3H]indol]-
(1'H)-one-2'-(O-benzyloxime)]}-1H-pyrrole-1-methyl-2-carbonitrile the desired
product was obtained (0.220 g, 0.745 mmol, 95%). ' H NMR (DMSO-d6, 500 MHz)
8 1.44 - 1.50 (m, 1H), 1.61 - 1.70 (m, 7H), 1.94 - 1.99 (m, 2H), S.0 (s, 2H),
6.55 (d,
1 H, J = 4 Hz), 6.79 (d, 1 H, J = 8.0 Hz), 6.95 (d, 1 H, J = 4 Hz), 7.27 -
7.31 (m, 1 H),
7.34 - 7.37 (m, 2H), 7.42 - 7.43 (m, 2H), 7.47 (dd, 1H, J = 8.0 , 1.4 Hz),
7.65 (d, 1H,
J = 1.5 Hz), 9.65 (s, 1 H), 12.4 (s, 1 H).
The title compound was prepared from 5-(spiro[cyclohexane-1,3'-[3]indole]-
2'(IH)-(O-benyloxime))-1H-pyrrole-2-carbonitrile (0.325 g, 0.82mmol) and 1M
Boron tribromide (6mL in methylene chloride), following the procedure for 5-
(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)- IH-pyrrole-1-
methyl-
2-carbonitrile, to obtain the product as an off white solid (0.110 g, 0.326
mmol, 44%).
' H NMR (DMSO-d6, 500 MHz) 8 1.46 - I.5 (m, 1H), 1.62 - 1.71 (m, 7H), 1.95 -
2.05
(m, 2H), 6.55 (d, 1 H, J = 4.0 Hz), 6.75 (d, 1 H, J = 8.0 Hz), 6.94 (d, l H, J
= 3.47 Hz),
7.45 (dd, 1H, J= 8.1, 1.73 Hz), 7.63 (d, 1H, J= 1.73), 9.42 (s, 1H), 9.59 (s,
IH),
12.39 (s, 1H).
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Examele 58
4-(Spiro(cYclohexane-1,3'-(3Hlindolel-2'(acetoxyimino)-5'-Xl)-2-
thiophenecarbonitrile
S
To a solution of 4-(Spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyimino)-5'-
yl)-2-thiophenecarbonitrile (2.21 g, 6.83 mmol) and acetic anhydride ( 1 ml)
in
dichloromethane-pyridine (30 ml, 9:1 ) was added 4-dimethylaminopyridine (250
mg)
at room temperature. After 3h., the mixture was diluted with dichloromethane,
washed with water, dil. Hydrochloric acid, water, dried (MgS04), and
evaporated.
The residue was purified by column chromatography (EtOAc: hexane, gradient
elution) to afford the title compound (0.84 g, 2.29 mmol, 33%) as a white
solid: MS
(ESI (+ ve)) m/z 366 [M+H]+.
Example 59
3-Fluoro-N'-hydroxy-5-(2'-(hydrox a~)spiro(cyclohexane-1,3'-(3Hlindoll-5'-
benzenecarboximidamide
5'-(3-Cyano-5-fluorophenyl)-2-(methylthio)spiro[cyclohexane-1,3'-
[3H]indole]. Prepared from 3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl)-5-fluorobenzonitrile (0.451 g, 1.34 mmol) according to the
procedure described in Example 43 to afford the desired product (0.316 g, 0.90
mmol,
67%): 'H NMR (DMSO, 300 MHz) 8 7.74 (d, 1H, J= 1.7 Hz), 7.68 (t, 1H, J= 1.4
Hz), 7.5 8 (d, 1 H, J = 8.0 Hz), 7.54 (t, 1 H, J = 2.3 Hz), 7.50 (dd, 1 H, J =
8.0 and 1.9
Hz), 7.33 - 7.29 (m, 1H), 2.67 (s, 3H), 2.04 - 1.78 (m, 7H) and 1.58 - 1.50
(m, 3H);
MS (ESI(+ ve)) m/z 351 (M+H)+.
To a solution of the last cited product (0.30 g, 0.88 mmol) in DMSO ( 10 ml)
was added hydroxylamine (SO% aqueous solution, 1 ml), and the reaction was
heated
to 120 °C. After lh., the mixture was cooled, partitioned between
saturated aqueous
ammonium chloride and ethylacetate. The organic layer was washed with water,
brine, dried (MgS04) and evaporated. The residue was purified by column
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chromatography (Si02, 5% MeOH in dichloromethane) to afford the title compound
(0.079 g, 0.23 mmol, 26%) as a white foam: 'H NMR (DMSO, 300 MHz) 8 9.79 (s,
1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.73 (s, 1H), 7.61 (d, 1H, J= 1.3 Hz), 7.46
(dd, 1H, J
= 8.3 and 1.5 Hz), 7.34 (d, 1H, J= 10 Hz), 6.81 (d, 1H, J= 8.0 Hz), 6.01 (s,
2H), 2.11
- 2.02 (m, 2H) and 1.81 - 1.56 (m, 8H): MS (ESI(+ ve)) m/z 369 (M+H)+.
Example 60
N'-Hydroxy-5-(suiro(cyclohexane-1,3'-(3Hlindolel-2'(hydroxyimino)-5'- lyl)-4-
methyl-2-thiophenecarboximidamide
4-Methyl-5-(spiro[cyclohexane-1,3'[3H]indol] 2'-(methylthio)-5'-yl]-2-
thiophenecarbonitrile. To potassium tert-butoxide (0.32g, 2.6 mmol) in THF was
added 5-(1',2'-Dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-4-
methyl-
2-thiophenecarbonitrile (0.84 g, 2.5 mmol). After 15 minutes, methyl iodide
(0.50 g,
3.48 mmol) was added. After 3 hours, reaction was poured into ammonium
chloride
(sat.) and extracted with ethylacetate. The organic layers were combined and
dried
over magnesium sulfate. The solution was filtered, concentrated in vacuo, and
the
residue was purified by flash chromatography on silica gel (4:1 Hexane/ethyl
acetate)
to give the desired product (0.530 g, 85%). (DMSO, 300 MHz) 8 1.48 (m, 3H),
1.70
(m, 2H), 1.81 (m, 5H), 2.32 (s, 3H), 2.62 (s, 3H), 7.48 (dd, 1H, J= 7.87 Hz,
1.46 Hz),
7.5 (d, 1H, J= 8.05 Hz), 7.77 (d, 1H, J= 1.46 Hz), 7.88 (s, 1H).
To 4-methyl-5-(spiro[cyclohexane-1,3'[3H] indol]2'-(methylthio)-5'-yl]-2-
thiophenecarbonitrile (.450 g, 1.3 mmol) in DMSO (1 mL) was added
hydroxylamine
hydrochloride (2 mL, 50% sol. in water) and heated to 100° C for 2.5
hours. Water
added until solution became slightly turbid, allowed the mixture to cool to
room
temperature. The white solid was filtered, collected and dissolved in ethyl
acetate
and dried over magnesium sulfate. The solution was filtered, concentrated in
vacuo,
giving (0.320 g, 69%). (DMSO-d6, 500 MHz) 8 1.4-1.74 (m, 8H), 1.94-2.4 9m,
2H),
2.54 (s, 3H), 5.8 (s, 1H), 6.79 (d, 1H, J = 8.0), 7.16 (dd, 1H, J= 8.12,
1.83), 7.39 (m,
2H), 9.42 (s, 1H), 9.56 (s, 1H), 9.58 (s, 1H).
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Example 61
N'-Hydroxy-4-(spiro[~cyclohexane-1,3'-f3Hlindole]-2' 9hydroxyimino)-5'-yl-2-
thiophenecarboximidamide
4-(Spiro[cyclohexane-1,3'-[3H]indol]-2'-(methylthio)-5'-yl]-2-
thiophenecarbonitrile (0.077 g, .237 mmol) was reacted with 50% solution of
hydroxylamine ( 1 mL) following the procedure for Example 60 to afford the
title
compound (0.016g, 0.044 mmol, 20 %). MS (ESI, (+VE)) m/z 357 [M+H]+.
Example 62
N'-Hey-~spirolcyclohexane-1,3'-(3Hjindoll-2'-(hydrox~mino)-5'-ylj-2-
thiophenecarboxidamide
The title compound was prepared from 5-(spiro[cyclohexane-1,3'-
[3H]indol]2'-(methylthio)-5'-yl]-2-thiophenecarbonitrile (0.500 g, 1.5 mmol)
and a
50% solution of hydroxylamine (2 mL, excess) following the procedure for
Example
60, to afford the product (0.200 g, 0.56 mmol, 56%). 'H NMR (DMSO-d6, S00
MHz) 8 1.45-1.75 (m, 8H), 1.97-2.06 (m, 2H), 5.89 (s,lH), 6.74 (d, 1H, J = 8
Hz),
7.3 (d, 1H, J= 3.9 Hz), 7.34 (dd, 1H, J= 8.06, 1.46 Hz), 7.4 (d, 1H, J= 8.0
Hz), 7.5
(d, 1 H, 1.95 Hz), 9.44 (s, l H), 9.58 (s, 1 H), 9.6 (s, 1 H).
Example 63
5'-(3-Chlorophen~piro f cyclohexane-1,3'-(3Hl indoll-2'-cyanamide
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'-amine. To a turbid
solution of S'-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3-[3H]indol]-2-
amine ( 0.500 g; 1.53 mmol) in 25 mL of ethanol was added hydrazine hydrate
(0.600
mL; 12.24 mmol). The solution was warmed to 55° C, where Raney-nickel
(50% in
water) was added to the reaction to keep a constant evolution of gas. After 45
minutes, the hot reaction mixture was filtered through a Celite plug and
rinsed with a
copious amount of hot methanol. The filtrate was concentrated in vacuo to give
0.890
g of an opaque solid. The product was purified by flash silica gel
chromatography;
(eluant, 2% to 8 % methanol-methylene chloride with 0.1 % ammonium hydroxide)
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to afford 0.310 g (65%) of the desired product as a white solid. Mp. 118-
120° C. 'H
NMR 8 (300 MHz, DMSO-db) 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H),
7.1
(br, 2H, 2NH), 7.31-7.34 (dt, 1H, J= 8 Hz), 7.41-7.46 (t, 2H), 7.55-7.58 (d,
1H), 7.62
(s, 1H), 7.72 (s, 1H); MS (ECI(+ve)) m/z 311 (M+H)+.
1-tert-butoxycarbonyl-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-
2'-amine. To a solution of 5'-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-
2'-
amine (0.310 g; 0.96 mmol) in dry methylene chloride at 0° C was added
Di-tert-butyl
dicarbonate (0.252 g; 1.15 mmol) and 4-dimethylaminopyridine (0.117 g; 0.96
mmol). The solution was allowed to warm to room temperature and stir 24 h. The
reaction solution was diluted with water(SO mL) and the layers were separated.
The
organic layer was dried over Na2S04 , filtered and concentrated in vacuo to
give 0.355
g of a yellow oil. The product was purified by flash silica gel
chromatography;
(eluant, 1 %to 3 % methanol- methylene chloride) to afford the desired product
(0.081
g, 20%) as a white solid. 'H NMR 8 (300 MHz, DMSO-db) 1.58 (m, 2H), 1.63 (s,
9H,
Boc), 1.77-1.79 (m, 8H), 7.42-7.48 (m, 2H), 7.64-7.68 (m, 3H), 7.70-7.80(m,
2H),
9.72 (s, 1H, NH). MS (ECI(+ve)) m/z 411 (M+H)+.
1'-tent-Butoxycarbonyl-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-
[3H]indol]-2'-amine (0.120 g; 0.29 mmol) in 2.0 mL of dry DMF was added to a
solution of 4- dimethylaminopyridine (0.089 g; 0.73 mmol) and cyanogen bromide
(0.077 g; 0.73 mmol) in 4.0 mL of dry DMF at 0° C. The yellow solution
was heated
to 40° C for 16 h. Work-up included pouring the reaction solution into
0.1 N NaHC03
(50 mL) and extracting with ethyl acetate (3 x 50 mL). The combined organic
layers
were dried over anhydrous NaZS04, filtered and concentrated in vacuo to give
0.091 g
of a yellow residue. The product was purified by flash silica gel
chromatography;
(stepwise gradient of 5:1 to 3:1 hexane : ethyl acetate) to afford 0.031 g
(32%) of the
product as a bright yellow solid. Mp. 225°C (dec.). 'H NMR 8 (500 MHz,
DMSO-db)
1.46-1.73 (m, 8H), 1.89-1.90 (m, 2H), 7.13-7.16 (d, 1H), 7.38-7.41 (dt, 1H, J=
8Hz),
7.45-7.50 (m, 1H), 7.60-7.63 (dd, 2H, J= 6.4 Hz), 7.71 (s, 1H), 7.85 (s, 1H),
12.1 (s,
1H, NH); MS (ECI(-ve)) m/z 336 (M-H)-.
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Other desirable compounds, which can be made according to the methods
described herein, include 5'-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3'-
[3H]indol]-2'-cyanamide, S'-(5-Cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-
[3H]indol]-2-cyanamide, 5'-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-
1,3'-[3H]indol]-2'-cyanamide cyanamide, 5'-(S-Cyano-thiophen-2-yl)
spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanamide, 5'-(5-Cyano-3-methyl-thiophen-
2-
yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanamide, 5'-(5-Cyano-thiophen-3-
yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanamide, 3-(2'-Cyanomethylene-
spiro[cyclohexane-1,3'-[3H]indol-5'-yl])-5-fluoro-benzonitrile, 5-(2'-
Cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol-5'-yl])-1H-pyrrole-2-
carbonitrile,
5-(2'-Cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol-5'-yl])-1-methyl-1 H-
pyrrole-2-carbonitrile, 5-(2'-Cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol-
5'-
yl])-thiophene-2-carbonitrile, 5-(2'-Cyanomethylene-spiro[cyclohexane-1,3'-
[3H]indol-5'-yl])-4-methyl-thiophene-2-carbonitrile, 4-(2'-Cyanomethylene-
spiro[cyclohexane-1,3'-[3H]indol-5'-yl])-thiophene-2-carbonitrile.
All publications cited in this specification are incorporated herein by
reference herein. While the invention has been described with reference to a
particularly preferred embodiment, it will be appreciated that modifications
can be
made without departing from the spirit of the invention. Such modifications
are
intended to fall within the scope of the appended claims.
