U.S. patent application number 11/083011 was filed with the patent office on 2005-08-04 for thio-oxindole derivatives.
This patent application is currently assigned to Wyeth. Invention is credited to Edwards, James P., Fensome, Andrew, Jones, Todd K., Koko, Marci C., Melenski, Edward G., Tegley, Christopher M., Wrobel, Jay E., Zhang, Puwen, Zhi, Lin.
Application Number | 20050171186 11/083011 |
Document ID | / |
Family ID | 24203676 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171186 |
Kind Code |
A1 |
Fensome, Andrew ; et
al. |
August 4, 2005 |
Thio-oxindole derivatives
Abstract
This invention relates to methods of co-administering compounds
of formula 1 which are agonists of the progesterone receptor which
have the general structure: 1 wherein: R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and Q.sup.1 are as defined herein, or a
pharmaceutically acceptable salt thereof, with estrogen, an
estrone, or an estrogen receptor agonist for contraception, hormone
replacement therapy, or treating progesterone-related carcinomas
and adenocarcinomas.
Inventors: |
Fensome, Andrew; (Wayne,
PA) ; Zhang, Puwen; (Audubon, PA) ; Koko,
Marci C.; (Bethlehem, PA) ; Zhi, Lin; (San
Diego, CA) ; Jones, Todd K.; (Solana Beach, CA)
; Wrobel, Jay E.; (Lawrenceville, NJ) ; Tegley,
Christopher M.; (Thousand Oaks, CA) ; Edwards, James
P.; (San Diego, CA) ; Melenski, Edward G.;
(Woodlyn, PA) |
Correspondence
Address: |
HOWSON AND HOWSON
CATHY A. KODROFF
ONE SPRING HOUSE CORPORATE CENTER
BOX 457
SPRING HOUSE
PA
19477
US
|
Assignee: |
Wyeth
Madison
NJ
Ligand Pharmaceuticals, Inc.
San Diego
CA
|
Family ID: |
24203676 |
Appl. No.: |
11/083011 |
Filed: |
March 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11083011 |
Mar 17, 2005 |
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10117156 |
Apr 5, 2002 |
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10117156 |
Apr 5, 2002 |
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10022467 |
Oct 30, 2001 |
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6521657 |
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10022467 |
Oct 30, 2001 |
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09552033 |
Apr 19, 2000 |
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6355648 |
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60172259 |
May 4, 1999 |
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Current U.S.
Class: |
514/418 ;
514/414 |
Current CPC
Class: |
A61P 13/08 20180101;
C07D 209/08 20130101; A61P 5/34 20180101; A61P 35/00 20180101; A61P
15/00 20180101; C07D 209/30 20130101; A61P 43/00 20180101; C07D
209/40 20130101; A61P 1/00 20180101; A61P 5/36 20180101; A61P 7/00
20180101; A61P 7/04 20180101 |
Class at
Publication: |
514/418 ;
514/414 |
International
Class: |
A61K 031/404 |
Claims
What is claimed is:
1. A method of providing hormone replacement therapy comprising the
step of delivering to a female a composition comprising a compound
of formula I and an estrogen to said female, wherein formula I is:
64wherein: R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, alkyl, substituted alkyl, OH, O(alkyl),
O(substituted alkyl), O(Acetyl), aryl, substituted aryl,
heterocyclic ring, substituted heterocyclic ring, alkylaryl,
substituted alkylaryl, alkylheteroaryl, substituted
alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl,
and substituted 3-propynyl; or R.sup.1 and R.sup.2 form a double
bond to C(CH.sub.3).sub.2, C(cycloalkyl), O, or C(cycloether);
R.sup.3 is selected from the group consisting of H, OH, NH.sub.2,
C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl,
C.sub.3 to C.sub.6 alkenyl, substituted C.sub.3 to C.sub.6 alkenyl,
alkynyl, substituted alkynyl, and CORA; R.sup.A is selected from
the group consisting of H, C.sub.1 to C.sub.3 alkyl, substituted
C.sub.1 to C.sub.3 alky, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, and
substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.4 is selected from
the group consisting of H, halogen, CN, NH.sub.2, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.1 to
C.sub.6 alkoxy, substituted C.sub.1 to C.sub.6 alkoxy, C.sub.1 to
C.sub.6 aminoalkyl, and substituted C.sub.1 to C.sub.6 aminoalkyl;
R.sup.5 is selected from the group consisting of a), b) and c): a)
a substituted benzene ring having the structure: 65X is selected
from the group consisting of halogen, OH, CN, C.sub.1 to C.sub.3
alkyl, substituted C.sub.1 to C.sub.3 alky, C.sub.1 to C.sub.3
alkoxy, substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
thioalkyl, substituted C.sub.1 to C.sub.3 thioalkyl, C.sub.1 to
C.sub.3 thioalkoxy, substituted C.sub.1 to C.sub.3 thioalkoxy,
S(O)alkyl, S(O).sub.2alkyl, C.sub.1 to C.sub.3 aminoalkyl,
substituted C.sub.1 to C.sub.3 aminoalkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, substituted C.sub.1 to C.sub.3
perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its
backbone 1 to 3 heteroatoms, CONH.sub.2, CSNH.sub.2, CNHNHOH,
CNH.sub.2NOH, CNHNOH, COR.sup.B, CSR.sup.B, OCOR.sup.B, and
NR.sup.CCOR.sup.B; R.sup.B is selected from the group consisting of
H, C.sub.1 to C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl,
aryl, substituted aryl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, and
substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.C is H, C.sub.1 to
C.sub.3 alkyl, or substituted C.sub.1 to C.sub.3 alkyl; Y and Z are
independently selected from the group consisting of H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.3 thioalkyl, and substituted C.sub.1 to
C.sub.3 thioalkyl; b) a five or six membered heterocyclic ring
having in its backbone 1, 2, or 3 heteroatoms selected from the
group consisting of O, S, SO, SO.sub.2 and NR.sup.6 and having one
or two independent substituents selected from the group consisting
of H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.4 alkyl, substituted
C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl,
substituted C.sub.1 to C.sub.3 aminoalkyl, COR.sup.D, CSR.sup.D,
and NR.sup.ECOR.sup.D; R.sup.D is H, NH.sub.2, C.sub.1 to C.sub.3
alkyl, substituted C.sub.1 to C.sub.3 alkyl, aryl, substituted
aryl, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.3 aminoalkyl, or substituted C.sub.1 to
C.sub.3 aminoalkyl; R.sup.E is H, C.sub.1 to C.sub.3 alkyl, or
substituted C.sub.1 to C.sub.3 alkyl; R.sup.6 is H, C.sub.1 to
C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl; or c) an indol-4-yl, indol-7-yl or
benzo-2-thiophene moiety, wherein said moiety is optionally
substituted by from 1 to 3 substituents selected from the group
consisting of halogen, alkyl, substituted alkyl, CN, NO.sub.2,
alkoxy, substituted alkoxy, and CF.sub.3; Q.sup.1 is S, NR.sup.7,
or CR.sup.8R.sup.9; R.sup.7 is selected from the group consisting
of CN, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6
alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic ring,
substituted heterocyclic ring, acyl, substituted acyl, aroyl,
substituted aroyl, SO.sub.2CF.sub.3, OR.sup.11, and
NR.sup.11R.sup.12; R.sup.8 and R.sup.9 are independently selected
from the group consisting of H, C.sub.1 to C.sub.6 alkyl,
substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic ring, substituted heterocyclic ring,
NO.sub.2, CN, and CO.sub.2R.sup.10; R.sup.10 is C.sub.1 to C.sub.3
alkyl or substituted C.sub.1 to C.sub.3 alkyl; or CR.sup.8R.sup.9
comprise a six membered ring having the structure: 66R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic
ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl,
substituted aroyl, sulfonyl, and substituted sulfonyl; or a
tautomer or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein said compound of
formula I is delivered at a daily dosage of about 2 to about 80
mg.
3. The method according to claim 1, wherein said compound is of the
structure: 67wherein: R.sup.5 is (i) or (ii): (i) a substituted
benzene ring having the structure: 68X is selected from the group
consisting of halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to C.sub.3
perfluoroalkyl, 5 membered heterocyclic ring having in its backbone
1 to 3 heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; Y is
selected from the group consisting of H, halogen, CN, NO.sub.2,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and C.sub.1 to
C.sub.3 thioalkyl; or (ii) a six membered ring having the
structure: 69X.sup.1 is N or CX.sup.2; X.sup.2 is halogen, CN,
CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2 or NO.sub.2; or a tautomer or a pharmaceutically
acceptable salt thereof.
4. The method according to claim 1, wherein said compound is of the
structure: 70wherein: R.sup.11 is selected from the group
consisting of H, acyl, substituted acyl, aroyl, substituted aroyl,
sulfonyl, and substituted sulfonyl; R.sup.5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure: 71X is
selected from the group consisting of halogen, CN, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, CNHNHOH, CNH.sub.2NOH, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to C.sub.3
perfluoroalkyl, 5 membered heterocyclic ring having in its backbone
1 to 3 heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; Y is
selected from the group consisting of H, halogen, CN, NO.sub.2,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and C.sub.1 to
C.sub.3 thioalkyl; (ii) a five membered ring having the structure:
72U is O, S, or NR.sup.6; R.sup.6 is H, C.sub.1 to C.sub.3 alkyl,
or C.sub.1 to C.sub.4 CO.sub.2alkyl; X' is selected from the group
consisting of halogen, CN, NO.sub.2, CONH.sub.2, CNHNHOH,
CNH.sub.2NOH, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, C.sub.1 to C.sub.3 alkyl, and C.sub.1 to C.sub.3
alkoxy; Y' is selected from the group consisting of H, F, and
C.sub.1 to C.sub.4 alkyl; or (iii) a six membered ring having the
structure: 73X.sup.1 is N or CX.sup.2; X.sup.2 is halogen, CN,
CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2 or NO.sub.2; or a tautomer or a pharmaceutically
acceptable salt thereof.
5. The method according to claim 1, wherein said compound is of the
structure: 74wherein: R.sup.5 is (i), (ii), or (iii): (i) a
substituted benzene ring having the structure: 75X is selected from
the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
having in its backbone 1 to 3 heteroatoms, and C.sub.1 to C.sub.3
thioalkoxy; Y is selected from the group consisting of H, halogen,
CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl,
and C.sub.1 to C.sub.3 thioalkyl; (ii) a five membered ring having
the structure: 76U is O, S, or NR.sup.6; R.sup.6 is H, C.sub.1 to
C.sub.3 alkyl, or C.sub.1 to C.sub.4 CO.sub.2alkyl; X' is selected
from the group consisting of halogen, CN, NO.sub.2, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, C.sub.1 to C.sub.3 alkyl, and C.sub.1 to C.sub.3
alkoxy; Y' is selected from the group consisting of H, F and
C.sub.1 to C.sub.4 alkyl; or (iii) a six membered ring having the
structure: 77X.sup.1 is N or CX.sup.2; X.sup.2 is halogen, CN,
CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2 or NO.sub.2; or a tautomer or a pharmaceutically
acceptable salt thereof.
6. The method according to claim 1, where said compound is of the
structure: 78wherein: R.sup.15 is selected from the group
consisting of H, CO.sub.2R, acyl, substituted acyl, aroyl,
substituted aroyl, alkyl, substituted alkyl, and CN; R.sup.5 is
(i), (ii), or (iii): (i) a substituted benzene ring having the
structure: 79X is selected from the group consisting of halogen,
CN, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, CNHNOH, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to
C.sub.3 alkyl, NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl, 5
membered heterocyclic ring having in its backbone 1 to 3
heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; Y is a substituent
on the 4' or 5' position selected from the group consisting of H,
halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to
C.sub.4 alkyl, and C.sub.1 to C.sub.3 thioalkyl; (ii) a five
membered ring having the structure: 80U is O, S, or NR.sup.6;
R.sup.6 is H, C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.4
CO.sub.2alkyl; X' is selected from the group consisting of halogen,
CN, NO.sub.2, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl,
CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1 to C.sub.3 alkyl, and
C.sub.1 to C.sub.3 alkoxy; Y' is selected from the group consisting
of H, F and C.sub.1 to C.sub.4 alkyl; (iii) a six membered ring
having the structure: 81X.sup.1 is N or C.sup.2 X.sup.2 is halogen,
CN, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2 or NO.sub.2; or a tautomer or a pharmaceutically
acceptable salt thereof.
7. The method according to claim 1, wherein said compound is of the
structure: 82wherein: R.sup.5 is (i), (ii), or (iii): (i) a
substituted benzene ring having the structure: 83X is selected from
the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
having in its backbone 1 to 3 heteroatoms, and C.sub.1 to C.sub.3
thioalkoxy; Y is a substituent on the 4' or 5' position selected
from the group consisting of H, halogen, CN, NO.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and C.sub.1 to C.sub.3
thioalkyl; (ii) a five membered ring having the structure: 84U is
O, S, or NR.sup.6; R.sup.6 is H, C.sub.1 to C.sub.3 alkyl, or
C.sub.1 to C.sub.4 CO.sub.2alkyl; X' is selected from the group
consisting of halogen, CN, NO.sub.2, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1
to C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; Y' is selected
from the group consisting of H, F, and C.sub.1 to C.sub.4 alkyl;
(iii) a six membered ring having the structure: 85X.sup.1 is Nor
CX.sup.2; X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2 or
NO.sub.2; or a tautomer or a pharmaceutically acceptable salt
thereof.
8. The method according to claim 1, wherein R.sub.5 is a five
membered ring of the structure: 86wherein: U is O, S, or NR.sub.6;
R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.4
CO.sub.2alkyl; X' is selected from the group consisting of halogen,
CN, NO.sub.2, CONH.sub.2, CNHNHOH, CNH.sub.2NOH, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; Y' is selected from
the group consisting of H, F and C.sub.1 to C.sub.4 alkyl; or a
pharmaceutically acceptable salt thereof.
9. The method according to claim 1, wherein R.sub.5 is a thiophene
or furan ring.
10. The method according to claim 1, wherein R.sub.5 is a six
membered ring of the structure: 87wherein: X.sup.1 is N or
CX.sup.2, X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
R.sub.7 is selected from the group consisting of CN, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.8 cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, -heterocyclic, substituted heterocyclic,
and SO.sub.2CF.sub.3; R.sub.10 is C.sub.1 to C.sub.3 alkyl; or
pharmaceutically acceptable salt thereof.
11. The method according to claim 1, wherein the compound is
selected from the group consisting of
3-(1',2'-Dihydro-2'-thioxospiro[cyclohexane-1,3'--
[3H]indol]-5'-yl)benzonitrile;
5'-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[c-
yclohexane-1,3'-[3H]indol]-2'-ylidenecyanamide;
5-(1,2-Dihydro-2-thioxospi-
ro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1
tert-butoxycarbonyl)-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro-
[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-2-carbonitrile;
5-(2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1-methyl-pyrrole-2-c-
arbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl-
)-3-thiophenecarbonitrile;
5-(1,2-Dihydro-thioxospiro(cyclopentane-1,3-[3H-
]indol)-5-yl)-2-thiophenecarbonitrile;
5-(3-Fluoro-4methoxyphenyl)spiro[cy-
clohexane-1,3-[3H]indole]-2(1H)-thione;
5-(2-Amino-5-pyrimidinyl)spiro[cyc-
lohexane-1,3-[3H]indole]-2(1H)-thione;
3-(1,2-Dihydro-2-thioxospiro[cyclop-
entane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile;
3-(1,2-Dihydro-2-thioxos-
piro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-3-pyridinec-
arbonitrile;
5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-
-thione;
5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thi-
one;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-furan-
carbonitrile;
5-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-
-2(1H)-thione;
5-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole-
]-2(1H)-thione;
5-(3,5-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(-
1H)-thione;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)--
4-propyl-2-thiophenecarbonitrile;
5-(3-Fluoro-4-nitrophenyl)spiro[cyclohex-
ane-1,3-[3H]indole]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospiro[cyclohexane-
-1,3-[3H]indol]-5-yl)-2-furancarbonitrile;
5"-(3-Chlorophenyl)spiro[cyclob-
utane-1,3"-[3H]indole]-2"(1"H)-thione;
5"-(2-Chlorophenyl)spiro[cyclohexan-
e-1,3"-[3H]indole]-2"(1"H)-thione;
5"-(4-Chlorophenyl)spiro[cyclohexane-1,-
3"-[3H]indole]-2"(1"H)-thione;
5-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-
-1,3"-[3H]indol]-5"-yl)-4-methyl-2-thiophenecarbonitrile;
5'-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-2-thi-
ophenecarbonitrile;
5"-(3-Fluorophenyl)spiro[cyclohexane-1,3"-[3H]indole]--
2"(1"H)-thione;
5-(3-Hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-
-thione;
5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]i-
ndol]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol-
]-5-yl)-2-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-
-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile;
5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thion-
e;
5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'-[3H]indol]-2-amine;
N-(Acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2"-ami-
ne;
5"-(3-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
5'-(2-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
5'-(4-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
5'-(3,4-Difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-o-
ne oxime;
5'(3-methoxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
5'(3-nitrophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
5'(3-cyanophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
oxime;
3-[1',2'-Dihydro-2'-(hydroxyimino)spiro[cyclohexane-1,3'-[3H]indol-
]-5'-yl]-5-fluorobenzonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hy-
droxyimino)-5'-yl)-4-methyl-2-thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-hydroxyimino)-5'-yl-2-thiophenec-
arbonitrile;
4-Spiro[cyclohexane-1,3'-[3H]indole]-2'-hydroxyimino)-5'-yl)--
2thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyi-
mino)-5'-yl)-1H-pyrrole-1-methyl-2-carbonitrile;
5-(spiro[cyclohexane-1,3'-
-[3H]indol]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole-2-carbonitrile;
4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(acetoxyimino)-5'-yl)-2-thiophen-
ecarbonitrile;
3-Fluoro-N'-hydroxy-5-[2'-(hydroxyamino)spiro[cyclohexane-1-
,3'-[3H]indol]-5'-yl]benzenecarboximidamide;
N'-hydroxy-5-(spiro[cyclohexa-
ne-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-4-methyl-2-thiophenecarboximi-
damide;
N'-Hydroxy-4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-
-5'-yl-2-thiophenecarboximidamide;
N'-Hydroxy-5-(spiro[cyclohexane-1,3'-[3-
H]indol]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarboximidamide;
5'-3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'-ylidenecyanamide;
5'-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'-ylidenecy-
anamide;
5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione;
3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione;
4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile;
5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione;
and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione;
or a pharmaceutically acceptable salt thereof.
12. A method of providing hormone replacement therapy comprising
the step of delivering to a female a composition comprising a
compound of formula I and an estrone to said female, wherein
formula I is: 88wherein: R.sup.1 and R.sup.2 are independently
selected from the group consisting of H, alkyl, substituted alkyl,
OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted
aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl,
substituted alkylaryl, alkylheteroaryl, substituted
alkylheteroaryl, 1-propynyl, substituted I-propynyl, 3-propynyl,
and substituted 3-propynyl; or R.sup.1 and R.sup.2 form a double
bond to C(CH.sub.3).sub.2, C(cycloalkyl), O, or C(cycloether);
R.sup.3 is selected from the group consisting of H, OH, NH.sub.2,
C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl,
C.sub.3 to C.sub.6 alkenyl, substituted C.sub.3 to C.sub.6 alkenyl,
alkynyl, substituted alkynyl, and COR.sup.A; R.sup.A is selected
from the group consisting of H, C.sub.1 to C.sub.3 alkyl,
substituted C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 alkoxy,
substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
aminoalkyl, and substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.4
is selected from the group consisting of H, halogen, CN, NH.sub.2,
C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl,
C.sub.1 to C.sub.6 alkoxy, substituted C.sub.1 to C.sub.6 alkoxy,
C.sub.1 to C.sub.6 aminoalkyl, and substituted C.sub.1 to C.sub.6
aminoalkyl; R.sup.5 is selected from the group consisting of a), b)
and c): a) a substituted benzene ring having the structure: 89X is
selected from the group consisting of halogen, OH, CN, C.sub.1 to
C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl, C.sub.1 to
C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to
C.sub.3 thioalkyl, substituted C.sub.1 to C.sub.3 thioalkyl,
C.sub.1 to C.sub.3 thioalkoxy, substituted C.sub.1 to C.sub.3
thioalkoxy, S(O)alkyl, S(O).sub.2alkyl, C.sub.1 to C.sub.3
aminoalkyl, substituted C.sub.1 to C.sub.3 aminoalkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, substituted C.sub.1 to C.sub.3
perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its
backbone 1 to 3 heteroatoms, CONH.sub.2, CSNH.sub.2, CNHNHOH,
CNH.sub.2NOH, CNHNOH, COR.sup.B, CSR.sup.B, OCOR.sup.B, and
NR.sup.CCOR.sup.B; R.sup.B is selected from the group consisting of
H, C.sub.1 to C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl,
aryl, substituted aryl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, and
substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.C is H, C.sub.1 to
C.sub.3 alkyl, or substituted C.sub.1 to C.sub.3 alkyl; Y and Z are
independently selected from the group consisting of H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.3 thioalkyl, and substituted C.sub.1 to
C.sub.3 thioalkyl; b) a five or six membered heterocyclic ring
having in its backbone 1, 2, or 3 heteroatoms selected from the
group consisting of O, S, SO, SO.sub.2 and NR.sup.6 and having one
or two independent substituents from the group consisting of H,
halogen, CN, NO.sub.2, C.sub.1 to C.sub.4 alkyl, substituted
C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl,
substituted C.sub.1 to C.sub.3 aminoalkyl, COR.sup.D, CSR.sup.D,
and NR.sup.ECOR.sup.D; R.sup.D is H, NH.sub.2, C.sub.1 to C.sub.3
alkyl, substituted C.sub.1 to C.sub.3 alkyl, aryl, substituted
aryl, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.3 aminoalkyl, or substituted C.sub.1 to
C.sub.3 aminoalkyl; R.sup.E is H, C.sub.1 to C.sub.3 alkyl, or
substituted C.sub.1 to C.sub.3 alkyl; R.sup.6 is H, C.sub.1 to
C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl; or c) an indol-4-yl, indol-7-yl or
benzo-2-thiophene moiety, wherein said moiety is optionally
substituted by from 1 to 3 substituents selected from the group
consisting of halogen, alkyl, substituted alkyl, CN, NO.sub.2,
alkoxy, substituted alkoxy, and CF.sub.3; Q.sup.1 is S, NR.sup.7,
or CR.sup.8R.sup.9; R.sup.7 is selected from the group consisting
of CN, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6
alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic ring,
substituted heterocyclic ring, acyl, substituted acyl, aroyl,
substituted aroyl, SO.sub.2CF.sub.3, OR.sup.11 and
NR.sup.11R.sup.12; R.sup.8 and R.sup.9 are independently selected
from the group consisting of H, C.sub.1 to C.sub.6 alky,
substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic ring, substituted heterocyclic ring,
NO.sub.2, CN, and CO.sub.2R.sup.10; R.sup.10 is C.sub.1 to C.sub.3
allyl or substituted C.sub.1 to C.sub.3 alkyl; or CR.sup.8R.sup.9
comprise a six membered ring having the structure: 90R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic
ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl,
substituted aroyl, sulfonyl, and substituted sulfonyl; or a
tautomer or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12, wherein said compound is of
the structure: 91wherein: R.sup.5 is (i), (ii), or (iii): (i) a
substituted benzene ring having the structure: 92X is selected from
the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
having in its backbone 1 to 3 heteroatoms, and C.sub.1 to C.sub.3
thioalkoxy; Y is a substituent on the 4' or 5' position selected
from the group consisting of H, halogen, CN, NO.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and C.sub.1 to C.sub.3
thioalkyl; (ii) a five membered ring having the structure: 93U is
O, S, or NR.sup.6; R.sup.6 is H, C.sub.1 to C.sub.3 alkyl, or
C.sub.1 to C.sub.4 CO.sub.2alkyl; X' is selected from the group
consisting of halogen, CN, NO.sub.2, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1
to C.sub.3 alky, and C.sub.1 to C.sub.3 alkoxy; Y' is selected from
the group consisting of H, F, and C.sub.1 to C.sub.4 alkyl; (iii) a
six membered ring having the structure: 94X.sup.1 is N or CX.sup.2;
X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2 or NO.sub.2; or a
tautomer or a pharmaceutically acceptable salt thereof.
14. The method according to claim 12, wherein said compound is of
the structure: 95wherein: R.sup.15 is selected from the group
consisting of H, CO.sub.2R, acyl, substituted acyl, aroyl,
substituted aroyl, alkyl, substituted alkyl, and CN; R.sup.5 is
(i), (ii), or (iii): (i) a substituted benzene ring having the
structure: 96X is selected from the group consisting of halogen,
CN, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, CNHNOH, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to
C.sub.3 alkyl, NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl, 5
membered heterocyclic ring having in its backbone 1 to 3
heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; Y is a substituent
on the 4' or 5' position selected from the group consisting of H,
halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to
C.sub.4 alkyl, and C.sub.1 to C.sub.3 thioalkyl; (ii) a five
membered ring having the structure: 97U is O, S, or NR.sup.6;
R.sup.6 is H, C.sub.1 to C.sub.3 alky, or C.sub.1 to C.sub.4
CO.sub.2alkyl; X' is selected from the group consisting of halogen,
CN, NO.sub.2, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl,
CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1 to C.sub.3 alkyl, and
C.sub.1 to C.sub.3 alkoxy; Y' is selected from the group consisting
of H, F and C.sub.1 to C.sub.4 alkyl; (iii) a six membered ring
having the structure: 98X.sup.1 is Nor CX.sup.2; X.sup.2 is
halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl,
CON(alkyl).sub.2, CSN(alkyl).sub.2 or NO.sub.2; or a tautomer or a
pharmaceutically acceptable salt thereof.
15. The method according to claim 12, wherein said compound is of
the structure: 99wherein: R.sup.5 is (i), (ii), or (iii): (i) a
substituted benzene ring having the structure: 100X is selected
from the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
having in its backbone 1 to 3 heteroatoms, and C.sub.1 to C.sub.3
thioalkoxy; Y is a substituent on the 4' or 5' position selected
from the group consisting of H, halogen, CN, NO.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and C.sub.1 to C.sub.3
thioalkyl; (ii) a five membered ring having the structure: 101U is
O, S, or NR.sup.6; R.sup.6 is H, C.sub.1 to C.sub.3 alkyl, or
C.sub.1 to C.sub.4 CO.sub.2alkyl; X' is selected from the group
consisting of halogen, CN, NO.sub.2, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, C.sub.1
to C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; Y' is selected
from the group consisting of H, F, and C.sub.1 to C.sub.4 alkyl;
(iii) a six membered ring having the structure: 102X.sup.1 is N or
CX.sup.2; X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2 or
NO.sub.2; or a tautomer or a pharmaceutically acceptable salt
thereof.
16. The method according to claim 12, wherein R.sub.5 is the
substituted benzene ring of the structure: 103X is selected from
the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring containing 1
to 3 heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; and Y is a
substituent on the 4' or 5'position selected from the group
consisting of H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, and C.sub.1 to C.sub.3 thioalkyl; and
Q.sup.1 is S, NR.sub.7, or CR.sub.8R.sub.9; or a pharmaceutically
acceptable salt thereof.
17. The method according to claim 12, wherein R.sub.5 is a five
membered ring of the structure: 104wherein: U is O, S, or NR.sub.6;
R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.4
CO.sub.2alkyl; X' is selected from the group consisting of halogen,
CN, NO.sub.2, CONH.sub.2, CNHNHOH, CNH.sub.2NOH, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; Y' is selected from
the group consisting of H, F and C.sub.1 to C.sub.4 alkyl; or a
pharmaceutically acceptable salt thereof.
18. The method according to claim 12, wherein R.sub.5 is a
thiophene or furan ring.
19. The method according to claim 12, wherein R.sub.5 is a six
membered ring of the structure: 105wherein: X.sup.1 is N or
CX.sup.2, X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
R.sub.7 is selected from the group consisting of CN, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.8 cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, -heterocyclic, substituted heterocyclic,
and SO.sub.2CF.sub.3; R.sub.10 is C.sub.1 to C.sub.3 alkyl; or
pharmaceutically acceptable salt thereof.
20. The method according to claim 14, wherein the compound is
selected from the group consisting of
3-(1',2'-Dihydro-2'-thioxospiro[cyclohexane--
1,3'-[3H]indol]-5'-yl)benzonitrile;
5'-(5-Cyano-1-methyl-1H-pyrrol-2-yl)sp-
iro[cyclohexane-1,3'-[3H]indol]-2'-ylidenecyanamide;
5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrol-
e-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]--
5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-
-2-carbonitrile;
5-(2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1-me-
thyl-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-
-[3H]indol]-5-yl)-3-thiophenecarbonitrile;
5-(1,2-Dihydro-thioxospiro(cycl-
opentane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile;
5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thion-
e;
5-(2-Amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione-
;
3-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorob-
enzonitrile;
3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-
-4-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]in-
dol]-2-yl)-3-pyridinecarbonitrile;
5-(3,4-Difluorophenyl)spiro[cyclohexane-
-1,3-[3H]indole]-2(1H)-thione;
5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-
-[3H]indole]-2(1H)-thione;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3[3H-
]indol]-5-yl)-3-furancarbonitrile;
5-(3-Chloro-4-fluorophenyl)spiro[cycloh-
exane-1,3-[3H]indole]-2(1H)-thione;
5-(3-Chloro-5-fluorophenyl)spiro[cyclo-
hexane-1,3-[3H]indole]-2(1H)-thione;
5-(3,5-Difluorophenyl)spiro[cyclohexa-
ne-1,3-[3H]indole]-2(1H)-thione;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane--
1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile;
5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarb-
onitrile;
5"-(3-Chlorophenyl)spiro[cyclobutane-1,3"-[3H]indole]-2"(1"H)-th-
ione;
5"-(2-Chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione-
;
5"-(4-Chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione;
5-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-4-meth-
yl-2-thiophenecarbonitrile;
5'-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-1-
,3"-[3H]indol]-5"-yl)-2-thiophenecarbonitrile;
5"-(3-Fluorophenyl)spiro[cy-
clohexane-1,3"-[3H]indole]-2"(1"H)-thione;
5-(3-Hydroxyphenyl)spiro[cycloh-
exane-1,3-[3H]indole]-2(1H)-thione;
5-[4-Fluoro-3-(trifluoromethyl)phenyl]-
spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospir-
o[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-
-thiophenecarbonitrile;
5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3--
[3H]indole]-2(1H)-thione;
5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,-
3'-[3H]indol]-2-amine;
N-(Acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane--
1,3'-[3H]indol]-2"-amine;
5"-(3-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]in- dol]-2'(1'H)-one
oxime; 5'-(2-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indo-
l]-2'(1'H)-one oxime;
5'-(4-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]- -2'(1'H)-one
oxime; 5'-(3,4-Difluorophenyl)spiro[cyclohexane-1,3'-[3H]indo-
l]-2'(1'H)-one oxime;
5'(3-methoxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]- -2'(1'H)-one
oxime; 5'(3-nitrophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(-
1'H)-one oxime;
5'(3-cyanophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)- -one
oxime;
3-[1',2'-Dihydro-2'-(hydroxyimino)spiro[cyclohexane-1,3'-[3H]i-
ndol]-5'-yl]-5-fluorobenzonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-
-(hydroxyimino)-5'-yl)-4-methyl-2-thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophene-
carbonitrile;
4-(Spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-y-
l)-2-thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydr-
oxyimino)-5'-yl)-1H-pyrrole-1-methyl-2-carbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole--
2-carbonitrile;
4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(acetoxyimino)-5'-
-yl)-2-thiophenecarbonitrile;
3-Fluoro-N'-hydroxy-5-[2'-(hydroxyamino)spir-
o[cyclohexane-1,3'-[3H]indol]-5'-yl]benzenecarboximidamide;
N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-
-4-methyl-2-thiophenecarboximidamide;
N'-Hydroxy-4-(spiro[cyclohexane-1,3'-
-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophenecarboximidamide;
N'-Hydroxy-5-spiro[cyclohexane-1,3'-[3H]indol]2'-(hydroxyimino)-5'-yl)-2--
thiophenecarboximidamide;
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]in-
dol]-2'-ylidenecyanamide;
5'-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1,3-
'-[3H]indol]-2'-ylidenecyanamide;
5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihy- dro-2H-indole-2-thione;
3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2-
H-indole-2-thione;
4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-f-
uronitrile;
5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thion- e;
and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione;
or a pharmaceutically acceptable salt thereof.
21. A method of providing hormone replacement therapy or treating
the symptoms of menopause, comprising the step of delivering to a
female a composition comprising a compound of formula I and an
estrogen receptor agonist to said female, wherein formula I is:
106wherein: R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, alkyl, substituted alkyl, OH, O(alkyl),
O(substituted alkyl), O(Acetyl), aryl, substituted aryl,
heterocyclic ring, substituted heterocyclic ring, alkylaryl,
substituted alkylaryl, alkylheteroaryl, substituted
alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl,
and substituted 3-propynyl; or R.sup.1 and R.sup.2 form a double
bond to C(CH.sub.3).sub.2, C(cycloalkyl), O, or C(cycloether);
R.sup.3 is selected from the group consisting of H, OH, NH.sub.2,
C.sub.1 to C.sub.6 alky, substituted C.sub.1 to C.sub.6 alkyl,
C.sub.3 to C.sub.6 alkenyl, substituted C.sub.3 to C.sub.6 alkenyl,
alkynyl, substituted alkynyl, and CORA; R.sup.A is selected from
the group consisting of H, C.sub.1 to C.sub.3 alkyl, substituted
C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, and
substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.4 is selected from
the group consisting of H, halogen, CN, NH.sub.2, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.1 to
C.sub.6 alkoxy, substituted C.sub.1 to C.sub.6 alkoxy, C.sub.1 to
C.sub.6 aminoalkyl, and substituted C.sub.1 to C.sub.6 aminoalkyl;
R.sup.5 is selected from the group consisting of a), b) and c): a)
a substituted benzene ring having the structure: 107X is selected
from the group consisting of halogen, OH, CN, C.sub.1 to C.sub.3
ally, substituted C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3
alkoxy, substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
thioalkyl, substituted C.sub.1 to C.sub.3 thioalkyl, C.sub.1 to
C.sub.3 thioalkoxy, substituted C.sub.1 to C.sub.3 thioalkoxy,
S(O)alkyl, S(O).sub.2alkyl, C.sub.1 to C.sub.3 aminoalkyl,
substituted C.sub.1 to C.sub.3 aminoalkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, substituted C.sub.1 to C.sub.3
perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its
backbone 1 to 3 heteroatoms, CONH.sub.2, CSNH.sub.2, CNHNHOH,
CNH.sub.2NOH, CNHNOH, COR.sup.B, CSR.sup.B, OCOR.sup.B, and
NR.sup.CCOR.sup.B; R.sup.B is selected from the group consisting of
H, C.sub.1 to C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl,
aryl, substituted aryl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, and
substituted C.sub.1 to C.sub.3 aminoalkyl; R.sup.C is H, C.sub.1 to
C.sub.3 alkyl, or substituted C.sub.1 to C.sub.3 alkyl; Y and Z are
independently selected from the group consisting of H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.3 thioalkyl, and substituted C.sub.1 to
C.sub.3 thioalkyl; b) a five or six membered heterocyclic ring
having in its backbone 1, 2, or 3 heteroatoms selected from the
group consisting of O, S, SO, SO.sub.2 and NR.sup.6 and having one
or two independent substituents selected from the group consisting
of H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.4 alkyl, substituted
C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.3 alkoxy, substituted
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl,
substituted C.sub.1 to C.sub.3 aminoalkyl, COR.sup.D, CSR.sup.D,
and NR.sup.ECOR.sup.D; R.sup.D is H, NH.sub.2, C.sub.1 to C.sub.3
alkyl, substituted C.sub.1 to C.sub.3 alkyl, aryl, substituted
aryl, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3
alkoxy, C.sub.1 to C.sub.3 aminoalkyl, or substituted C.sub.1 to
C.sub.3 aminoalkyl; R.sup.E is H, C.sub.1 to C.sub.3 alkyl, or
substituted C.sub.1 to C.sub.3 alkyl; R.sup.6 is H, C.sub.1 to
C.sub.3 alkyl, substituted C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl; or c) an indol-4-yl, indol-7-yl or
benzo-2-thiophene moiety, wherein said moiety is optionally
substituted by from 1 to 3 substituents selected from the group
consisting of halogen, alkyl, substituted alkyl, CN, NO.sub.2,
alkoxy, substituted alkoxy, and CF.sub.3; Q.sup.1 is S, NR.sub.7,
or CR.sup.8R.sup.9; R.sup.7 is selected from the group consisting
of CN, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6
alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to CS
cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted
heterocyclic ring, acyl, substituted acyl, aroyl, substituted
aroyl, SO.sub.2CF.sub.3, OR.sup.11, and NR.sup.11R.sup.12; R.sup.8
and R.sup.9 are independently selected from the group consisting of
H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl,
C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to C.sub.8
cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted
heterocyclic ring, NO.sub.2, CN, and CO.sub.2R.sup.10; R.sup.10 is
C.sub.1 to C.sub.3 alkyl or substituted C.sub.1 to C.sub.3 alkyl;
or CR.sup.8R.sup.9 comprise a six membered ring having the
structure: 108R.sup.11 and R.sup.12 are independently selected from
the group consisting of H, alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclic ring, substituted heterocyclic ring,
acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and
substituted sulfonyl; or a tautomer or a pharmaceutically
acceptable salt thereof.
22. The method according to claim 21, wherein R.sub.5 is the
substituted benzene ring of the structure: 109X is selected from
the group consisting of halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring containing 1
to 3 heteroatoms, and C.sub.1 to C.sub.3 thioalkoxy; and Y is a
substituent on the 4' or 5' position selected from the group
consisting of H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, and C.sub.1 to C.sub.3 thioalkyl; and
Q.sup.1 is S, NR.sub.7, or CR.sub.8R.sub.9; or a pharmaceutically
acceptable salt thereof.
23. The method according to claim 21, wherein R.sub.5 is a five
membered ring of the structure: 110wherein: U is O, S, or NR.sub.6;
R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.4
CO.sub.2alkyl; X' is selected from the group consisting of halogen,
CN, NO.sub.2, CONH.sub.2, CNHNHOH, CNH.sub.2NOH, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; Y' is selected from
the group consisting of H, F and C.sub.1 to C.sub.4 alkyl; or a
pharmaceutically acceptable salt thereof.
24. The method according to claim 21, wherein R.sub.5 is a
thiophene or furan ring.
25. The method according to claim 21, wherein R.sub.5 is a six
membered ring of the structure: 111wherein: X.sup.1 is N or
CX.sup.2; X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
R.sub.7 is selected from the group consisting of CN, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.8 cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, -heterocyclic, substituted heterocyclic,
and SO.sub.2CF.sub.3; R.sub.10 is C.sub.1 to C.sub.3 alkyl; or
pharmaceutically acceptable salt thereof.
26. The method according to claim 21, wherein the compound is
selected from the group consisting of
3-(1',2'-Dihydro-2'-thioxospiro[cyclohexane--
1,3'-[3H]indol]-5'-yl)benzonitrile;
5'-(5-Cyano-1-methyl-1H-pyrrol-2-yl)sp-
iro[cyclohexane-1,3'-[3H]indol]-2'-ylidenecyanamide;
5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrol-
e-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]--
5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-
-2-carbonitrile;
5-(2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1-me-
thyl-pyrrole-2-carbonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-
-[3H]indol]-5-yl)-3-thiophenecarbonitrile;
5-(1,2-Dihydro-thioxospiro(cycl-
opentane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile;
5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thion-
e;
5-(2-Amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione-
;
3-(1,2-Dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorob-
enzonitrile;
3-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-
-4-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]in-
dol]-2-yl)-3-pyridinecarbonitrile;
5-(3,4-Difluorophenyl)spiro[cyclohexane-
-1,3-[3H]indole]-2(1H)-thione;
5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-
-[3H]indole]-2(1H)-thione;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3-
H]indol]-5-yl)-3-furancarbonitrile;
5-(3-Chloro-4-fluorophenyl)spiro[cyclo-
hexane-1,3-[3H]indole]-2(1H)-thione;
5-(3-Chloro-5-fluorophenyl)spiro[cycl-
ohexane-1,3-[3H]indole]-2(1H)-thione;
5-(3,5-Difluorophenyl)spiro[cyclohex-
ane-1,3-[3H]indole]-2(1H)-thione;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-
-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile;
5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarb-
onitrile;
5"-(3-Chlorophenyl)spiro[cyclobutane-1,3"-[3H]indole]-2"(1"H)-th-
ione;
5"-(2-Chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione-
;
5"-(4-Chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione;
5-(1",2"-Dihydro-2"thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-4-methy-
l-2-thiophenecarbonitrile;
5'-(1",2"-Dihydro-2"-thioxospiro[cyclohexane-1,-
3"-[3H]indol]-5"-yl)-2-thiophenecarbonitrile;
5"-(3-Fluorophenyl)spiro[cyc-
lohexane-1,3"-[3H]indole]-2"(1"H)-thione;
5-(3-Hydroxyphenyl)spiro[cyclohe-
xane-1,3-[3H]indole]-2(1H)-thione;
5-[4-Fluoro-3-(trifluoromethyl)phenyl]s-
piro[cyclohexane-1,3-[3H]indol]-2(1H)-thione;
4-(1,2-Dihydro-2-thioxospiro-
[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile;
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-
-thiophenecarbonitrile;
5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3--
[3H]indole]-2(1H)-thione;
5-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,-
3'-[3H]indol]-2-amine;
N-(Acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane--
1,3'-[3H]indol]-2"-amine;
5"-(3-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]in- dol]-2'(1'H)-one
oxime; 5'-(2-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indo-
l]-2'(1'H)-one oxime;
5'-(4-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]- -2'(1'H)-one
oxime; 5'-(3,4-Difluorophenyl)spiro[cyclohexane-1,3'-[3H]indo-
l]-2'(1'H)-one oxime;
5'(3-methoxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]- -2'(1'H)-one
oxime; 5'(3-nitrophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(-
1'H)-one oxime;
5'(3-cyanophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)- -one
oxime;
3-[1',2'-Dihydro-2'-(hydroxyimino)spiro[cyclohexane-1,3'-[3H]i-
ndol]-5'-yl]-5-fluorobenzonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-
-(hydroxyimino)-5'-yl)-4-methyl-2-thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophene-
carbonitrile;
4-(Spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-y-
l)-2-thiophenecarbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydr-
oxyimino)-5'-yl)-1H-pyrrole-1-methyl-2-carbonitrile;
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole--
2-carbonitrile;
4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(acetoxyimino)-5'-
-yl)-2-thiophenecarbonitrile;
3-Fluoro-N'-hydroxy-5-[2'-(hydroxyamino)spir-
o[cyclohexane-1,3'-[3H]indol]-5'-yl]benzenecarboximidamide;
N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-
-4-methyl-2-thiophenecarboximidamide;
N'-Hydroxy-4-(spiro[cyclohexane-1,3'-
-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophenecarboximidamide;
N'-Hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)--
2-thiophenecarboximidamide;
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]-
indol]-2'-ylidenecyanamide;
5'-(3-Cyano-5-fluorophenyl)spiro[cyclohexane-1-
,3'-[3H]indol]-2'-ylidenecyanamide;
5-(3-chlorophenyl)-3,3-dimethyl-1,3-di- hydro-2H-indole-2-thione;
3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-
-2H-indole-2-thione;
4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-
-furonitrile;
5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thi- one;
and 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione;
or a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/117,156, filed Apr. 5, 2002, which is a continuation of
U.S. patent application Ser. No. 10/022,467, filed Oct. 30, 2001,
which is a divisional of U.S. patent application Ser. No.
09/552,033, filed Apr. 19, 2000, now U.S. Pat. No. 6,355,648,
issued Mar. 12, 2002, which claims the benefit of the priority of
U.S. Provisional Patent Application No. 60/172,259, filed May 4,
1999, now abandoned.
BACKGROUND OF THE INVENTION
[0002] This invention relates to compounds which are agonists of
the progesterone receptor, their preparation and utility.
[0003] 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).
[0004] The natural hormone, or ligand, for the PR is the steroid
progesterone, but 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.
[0005] 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.
[0006] 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.
[0007] Jones, et al, described in U.S. Pat. No. 5,688,810 the PR
antagonist dihydroquinoline A. 2
[0008] Jones, et al, described the enol ether B (U.S. Pat. No.
5,693,646) as a PR ligand. 3
[0009] Jones, et al, described compound C (U.S. Pat. No. 5,696,127)
as a PR ligand. 4
[0010] Zhi, et al, described lactones D, E and F as PR antagonists
(J. Med. Chem., 41, 291, 1998). 5
[0011] Zhi, et al, described the ether G as a PR antagonist (J.
Med. Chem., 41, 291, 1998). 6
[0012] Combs, et al., disclosed the amide H as a ligand for the PR
(J. Med. Chem., 38, 4880, 1995). 7
[0013] Perlman, et. al., described the vitamin D analog I as a PR
ligand (Tet. Letters, 35, 2295, 1994). 8
[0014] Hamann, et al, described the PR antagonist J (Ann. N.Y.
Acad. Sci., 761, 383, 1995). 9
[0015] Chen, et al, described the PR antagonist K (Chen, et al,
POI-37, 16.sup.th, Int. Cong. Het. Chem., Montana, 1997). 10
[0016] Kurihari, et. al., described the PR ligand L (J.
Antibiotics, 50, 360, 1997). 11
[0017] Kuhla, et al, taught the oxindole M as a cardiotonic (WO
86/03749). 12
[0018] Weber, described the oxindole N for cardiovascular
indications (WO 91/06545). 13
[0019] Fischer, et al, claim a preparation for making compounds
which include the generic structure O (U.S. Pat. No. 5,453,516).
14
[0020] R=various
[0021] Singh, et al, described the PDE III inhibitor P (J. Med.
Chem., 37, 248, 1994). 15
[0022] Andreani, et al, described the cytotoxic agent Q (Acta.
Pharm. Nord., 2, 407, 1990). 16
[0023] Binder, et al, described structure R which is an
intermediate for preparing COX II inhibitors (WO 97/13767). 17
[0024] Walsh (A. H. Robins) described the oxindole S as an
intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566).
18
[0025] R.sub.1=F, Cl, Br, alkyl, NH.sub.2
[0026] R.sub.2=alkyl, alkoxy, F, Cl, NH.sub.2, CF.sub.3
[0027] Bohmn, et al, claim the oxindole T as cardiovascular agents
(WO 91/06545). 19
[0028] Bohm, et al, include the generic structure U (WO 91/04974).
20
[0029] JP 63112584 A contains the generic structure V: 21
[0030] Boar, et al, described the dioxolane W as an intermediate
for preparation of acetylcholinesterase inhibitors (WO 93/12085
A1). 22
[0031] Kende, et al, described methodology for preparing
3,3-substituted oxindoles, e.g. X, that was utilized in the present
invention (Synth. Commun., 12, 1, 1982). 23
DESCRIPTION OF THE INVENTION
[0032] This invention provides compounds of the formulae 1 or 2:
24
[0033] wherein:
[0034] R.sub.1 and R.sub.2 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:
[0035] or R.sub.1 and R.sub.2 are joined to form a ring comprising
one of the following:
[0036] --CH.sub.2(CH.sub.2).sub.nCH.sub.2--;
--CH.sub.2CH.sub.2CMe.sub.2CH- .sub.2CH.sub.2--;
--O(CH.sub.2).sub.mCH.sub.2--; O(CH.sub.2).sub.pO--;
[0037] --CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--; or
--CH.sub.2CH.sub.2N(H or alkyl)CH.sub.2CH.sub.2--;
[0038] m is an integer from 1 to 4;
[0039] n is an integer from 1 to 5;
[0040] p is an integer from 1 to 4;
[0041] or R.sub.1 and R.sub.2 together comprise a double bond to
one of the following:
[0042] CMe.sub.2; C(cycloalkyl), O, C(cyloether).
[0043] R.sub.3 is selected from H, OH, NH.sub.2, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.6
alkenyl, alkynyl or substituted alkynyl, or COR.sup.A;
[0044] R.sup.A is selected from H, C.sub.1 to C.sub.3 alkyl,
substituted C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 alkoxy,
substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
aminoalkyl, or substituted C.sub.1 to C.sub.3 aminoalkyl;
[0045] R.sub.4 is selected from H, halogen, CN, NH.sub.2, C.sub.1
to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.1 to
C.sub.6 alkoxy, substituted C.sub.1 to C.sub.6 alkoxy, C.sub.1 to
C.sub.6 aminoalkyl, or substituted C.sub.1 to C.sub.6
aminoalkyl;
[0046] R.sup.5 is selected from the groups a), b) or c):
[0047] a) R.sup.5 is a trisubstituted benzene ring containing the
substituents X, Y and Z as shown below: 25
[0048] X is selected from halogen, OH, CN, C.sub.1 to C.sub.3
alkyl, substituted C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3
alkoxy, substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
thioalkyl, substituted C.sub.1 to C.sub.3 thioalkyl, S(O)alkyl,
S(O).sub.2alkyl, C.sub.1 to C.sub.3 aminoalkyl, substituted C.sub.1
to C.sub.3 aminoalkyl, NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl,
5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms,
CONH.sub.2, CSNH.sub.2, CONHalkyl, CSNHalkyl, CON(alkyl).sub.2,
CSN(alkyl).sub.2, COR.sup.B, OCOR.sup.B, NR.sup.CCOR.sup.B;
[0049] R.sup.B is selected from H, C.sub.1 to C.sub.3 alkyl,
substituted C.sub.1 to C.sub.3 alkyl, aryl, substituted aryl,
C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.3 aminoalkyl, or substituted C.sub.1 to C.sub.3
aminoalkyl;
[0050] R.sup.C is H, C.sub.1 to C.sub.3 alkyl, or substituted
C.sub.1 to C.sub.3 alkyl;
[0051] Y and Z are independently selected from H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, or
C.sub.1 to C.sub.3 thioalkyl; or
[0052] b) R.sup.5 is a five or six membered heterocyclic ring with
1, 2, or 3 heteroatoms selected from O, S, SO, SO.sub.2 or NR.sup.6
and containing one or two independent substituents from the group
of H, halogen, CN, NO.sub.2 and C.sub.1 to C.sub.3 alkyl, C.sub.1
to C.sub.3 alkoxy, C.sub.1 to C.sub.3 aminoalkyl, COR.sup.D, or
NR.sup.ECOR.sup.D;
[0053] R.sup.D is H, C.sub.1 to C.sub.3 alkyl, substituted C.sub.1
to C.sub.3 alky, aryl, substituted aryl, C.sub.1 to C.sub.3 alkoxy,
substituted C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3
aminoalkyl, or substituted C.sub.1 to C.sub.3 aminoalkyl;
[0054] R.sup.E is H, C.sub.1 to C.sub.3 alkyl, or substituted
C.sub.1 to C.sub.3 alkyl;
[0055] R.sup.6 is H, or C.sub.1 to C.sub.3 alkyl; or
[0056] c) R.sup.5 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, NO.sub.2,
lower alkoxy, or CF.sub.3;
[0057] Q.sup.1 is S, NR.sub.7, CR.sub.8R.sub.9;
[0058] R.sub.7 is selected from the group including CN, C.sub.1 to
C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.8 cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, heterocyclic, substituted heterocyclic,
acyl, substituted acyl, aroyl, substituted aroyl, SO.sub.2CF.sub.3,
OR.sup.11 or NR.sup.11R.sup.12;
[0059] R.sub.8 and R.sub.9 are independent substituents selected
from the group of H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1
to C.sub.6 alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted
C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, NO.sub.2, CN, or
CO.sub.2R.sub.10,
[0060] R.sub.10 is C.sub.1 to C.sub.3 alkyl; or
[0061] CR.sub.8R.sub.9 comprises a six membered ring as shown by
the structure below 26
[0062] Q.sup.2 is selected from the moieties: 27
[0063] R.sup.11, R.sup.12 and R.sup.13 are independently selected
from H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6
alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
acyl, substituted acyl, aroyl or substituted aroyl or sulfonyl;
[0064] or a pharmaceutically acceptable salt thereof.
[0065] A preferred list of substituents represented by R.sup.11,
R.sup.12 and R.sup.13 in groups of the compounds described herein
are H, C.sub.1 to C.sub.6 alky, substituted C.sub.1 to C.sub.6
alkyl, --C(O)--(C.sub.1 to C.sub.6 alkyl), --S(O).sub.2--(C.sub.1
to C.sub.6 alkyl), phenyl or benzyl.
[0066] It will be understood that this invention includes all
tautomeric forms of the compounds, chemical formulae and
substituents described herein.
[0067] Two preferred sets of compounds of this invention is
depicted by structures 2 and 3, respectively: 28
[0068] each wherein R.sub.5 is a disubstituted benzene ring
containing the substituents X and Y as shown below 29
[0069] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring containing 1
to 3 heteroatoms, or C.sub.1 to C.sub.3 thioalkoxy;
[0070] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl;
[0071] or a pharmaceutically acceptable salt thereof.
[0072] Another preferred group of formula 2 are those wherein
R.sub.5 is a five membered ring with the structure shown below
30
[0073] wherein:
[0074] U is O, S, or NR;
[0075] R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl;
[0076] X' is selected from halogen, CN, NO.sub.2, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2,
C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.3 alkoxy;
[0077] Y' is from the group of H, F or C.sub.1 to C.sub.4
alkyl;
[0078] or a pharmaceutically acceptable salt thereof.
[0079] A further preferred subgroup of the compounds above are
those in which R.sub.5 is a thiophene or furan ring substituted by
X' and Y', as described above.
[0080] A further preferred subgroup group of compounds of formulas
2 and 3 are those wherein R.sub.5 is a six membered ring with the
structure: 31
[0081] wherein X.sup.1 is N or CX.sup.2,
[0082] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0083] Q.sup.1 is S, NR.sub.7, CR.sub.8R.sub.9;
[0084] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0085] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3
to C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN CO.sub.2R.sub.10,
[0086] R.sub.10 is C.sub.1 to C.sub.3 alkyl;
[0087] CR.sub.8R.sub.9 are within a six membered ring as shown by
the structure below 32
[0088] or pharmaceutically acceptable salt thereof.
[0089] Still another preferred group of these compounds includes
those having the general formulae: 33
[0090] each wherein R.sub.5 is a disubstituted benzene ring
containing the substituents X and Y as shown below 34
[0091] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring containing 1
to 3 heteroatoms, or C.sub.1 to C.sub.3 thioalkoxy;
[0092] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl;
[0093] or a pharmaceutically acceptable salt thereof.
[0094] A further preferred subgroup group of compounds of formulae:
35
[0095] are those wherein R.sub.5 is a six membered ring with the
structure: 36
[0096] wherein X.sup.1 is N or CX.sup.2,
[0097] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0098] Q.sup.2 is as defined above;
[0099] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alky, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0100] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alky, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN CO.sub.2R.sub.10,
[0101] R.sub.10 is C.sub.1 to C.sub.3 alkyl;
[0102] CR.sub.8R.sub.9 are within a six membered ring as shown by
the structure below 37
[0103] or pharmaceutically acceptable salt thereof.
[0104] A further preferred set of compounds of this invention is
depicted by structure 4, 38
[0105] Wherein R.sub.14 is chosen from the group H, acyl,
substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted
sulfonyl.
[0106] Wherein R.sub.5 is a disubstituted benzene ring containing
the substituents X and Y as shown below 39
[0107] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CON(alkyl).sub.2, CSN(alkyl).sub.2, CNHNHOH,
CNH.sub.2NOH, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl,
NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered
heterocyclic ring containing 1 to 3 heteroatoms, or C.sub.1 to
C.sub.3 thioalkoxy;
[0108] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl; or a
pharmaceutically acceptable salt thereof.
[0109] Another preferred group of formula 4 are those wherein
R.sub.5 is a five membered ring with the structure shown below
40
[0110] wherein:
[0111] U is O, S, or NR.sub.6;
[0112] R.sub.6 is H, or C.sub.1 to C.sub.3 alky, or C.sub.1 to
C.sub.4 CO.sub.2alkyl;
[0113] X' is selected from halogen, CN, NO.sub.2, CONH.sub.2,
CNHNHOH, CNH.sub.2NOH, CSNH.sub.2, CONHalkyl, CSNHalkyl,
CONalkyl.sub.2, CSNalkyl.sub.2, C.sub.1 to C.sub.3 alkyl, or
C.sub.1 to C.sub.3 alkoxy;
[0114] Y' is from the group of H, F or C.sub.1 to C.sub.4
alkyl;
[0115] or a pharmaceutically acceptable salt thereof.
[0116] A further preferred subgroup of the compounds above are
those in which R.sub.5 is a thiophene or furan ring substituted by
X' and Y', as described above.
[0117] A further preferred subgroup group of compounds of formula 4
are those wherein R.sub.5 is a six membered ring with the
structure: 41
[0118] wherein X.sup.1 is N or CX.sup.2,
[0119] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0120] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0121] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3
to C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN CO.sub.2R.sub.10,
[0122] R.sub.10 is C.sub.1 to C.sub.3 allyl;
[0123] or pharmaceutically acceptable salt thereof.
[0124] A further preferred set of compounds of this invention is
depicted by structure 5, 42
[0125] Wherein R.sub.5 is a disubstituted benzene ring containing
the substituents X and Y as shown below 43
[0126] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
containing 1 to 3 heteroatoms, or C.sub.1 to C.sub.3
thioalkoxy;
[0127] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl;
[0128] or a pharmaceutically acceptable salt thereof.
[0129] Another preferred group of formula 5 are those wherein
R.sub.5 is a five membered ring with the structure shown below
44
[0130] wherein:
[0131] U is O, S, or NR.sub.6;
[0132] R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl;
[0133] X' is selected from halogen, CN, NO.sub.2, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2,
C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.3 alkoxy;
[0134] Y' is from the group of H, F or C.sub.1 to C.sub.4
alkyl;
[0135] or a pharmaceutically acceptable salt thereof.
[0136] A further preferred subgroup of the compounds above are
those in which R.sub.5 is a thiophene or furan ring substituted by
X' and Y', as described above.
[0137] A further preferred subgroup group of compounds of formula 5
are those wherein R.sub.5 is a six membered ring with the
structure: 45
[0138] wherein X.sup.1 is N or CX.sup.2,
[0139] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0140] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alky, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0141] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alky, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN CO.sub.2R.sub.10,
[0142] R.sub.10 is C.sub.1 to C.sub.3 alkyl;
[0143] or pharmaceutically acceptable salt thereof.
[0144] A further preferred set of compounds of this invention is
depicted by structure 6, 46
[0145] Wherein R.sub.15 is selected from the group H, Me,
CO.sub.2R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl,
substituted alkyl, CN.
[0146] Wherein R.sub.5 is a disubstituted benzene ring containing
the substituents X and Y as shown below 47
[0147] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
containing 1 to 3 heteroatoms, or C.sub.1 to C.sub.3
thioalkoxy;
[0148] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl;
[0149] or a pharmaceutically acceptable salt thereof.
[0150] Another preferred group of formula 6 are those wherein
R.sub.5 is a five membered ring with the structure shown below
48
[0151] wherein:
[0152] U is O, S, or NR.sub.6;
[0153] R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl;
[0154] X' is selected from halogen, CN, NO.sub.2, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2,
C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.3 alkoxy;
[0155] Y' is from the group of H, F or C.sub.1 to C.sub.4
alkyl;
[0156] or a pharmaceutically acceptable salt thereof.
[0157] A further preferred subgroup of the compounds above are
those in which R.sub.5 is a thiophene or furan ring substituted by
X' and Y', as described above.
[0158] A further preferred subgroup group of compounds of formula 6
are those wherein R.sub.5 is a six membered ring with the
structure: 49
[0159] wherein X.sup.1 is N or CX.sup.2,
[0160] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0161] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0162] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alky, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN CO.sub.2R.sub.10,
[0163] R.sub.10 is C.sub.1 to C.sub.3 alkyl;
[0164] or pharmaceutically acceptable salt thereof.
[0165] A further preferred set of compounds of this invention is
depicted by structure 7, 50
[0166] Wherein R.sub.5 is a disubstituted benzene ring containing
the substituents X and Y as shown below 51
[0167] X is selected from halogen, CN, CONH.sub.2, CSNH.sub.2,
CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2, CNHNOH,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heterocyclic ring
containing 1 to 3 heteroatoms, or C.sub.1 to C.sub.3
thioalkoxy;
[0168] Y is a substituent on the 4' or 5'position from the group
including H, halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkoxy,
C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.3 thioalkyl;
[0169] or a pharmaceutically acceptable salt thereof.
[0170] Another preferred group of formula 7 are those wherein
R.sub.5 is a five membered ring with the structure shown below
52
[0171] wherein:
[0172] U is O, S, or NR.sub.6;
[0173] R.sub.6 is H, or C.sub.1 to C.sub.3 alkyl, or C.sub.1 to
C.sub.4 CO.sub.2alkyl;
[0174] X' is selected from halogen, CN, NO.sub.2, CONH.sub.2,
CSNH.sub.2, CONHalkyl, CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2,
C.sub.1 to C.sub.3 alkyl, or C.sub.1 to C.sub.3 alkoxy;
[0175] Y' is from the group of H, F or C.sub.1 to C.sub.4
alkyl;
[0176] or a pharmaceutically acceptable salt thereof.
[0177] A further preferred subgroup of the compounds above are
those in which R.sub.5 is a thiophene or furan ring substituted by
X' and Y', as described above.
[0178] A further preferred subgroup group of compounds of formula 7
are those wherein R.sub.5 is a six membered ring with the
structure: 53
[0179] wherein X.sup.1 is N or CX.sup.2,
[0180] X.sup.2 is halogen, CN, CONH.sub.2, CSNH.sub.2, CONHalkyl,
CSNHalkyl, CONalkyl.sub.2, CSNalkyl.sub.2 or NO.sub.2;
[0181] R.sub.7 is from the group including CN, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.8
cycloalkyl, substituted C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, or
SO.sub.2CF.sub.3;
[0182] R.sub.8 and R.sub.9 are independent substituents from the
group including H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alkyl, C.sub.3 to C.sub.8 cycloalkyl, substituted C.sub.3
to C.sub.8 cycloalkyl, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, NO.sub.2, CN, or CO.sub.2R.sub.10,
[0183] R.sub.10 is C.sub.1 to C.sub.3 alkyl;
[0184] or pharmaceutically acceptable salt thereof.
[0185] 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.
[0186] 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.
[0187] 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 NO.sub.2.
[0188] 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 aroyl" 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 NO.sub.2.
[0189] 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, NO.sub.2, amino, aryl, 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.
[0190] 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, tetrahydronaphthyl, and phenanthryl.
[0191] The term "substituted aryl" refers to aryl as just defined
having 1 to 4 substituents from the group including halogen, CN,
OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,
aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,
alkylamino, or arylthio.
[0192] 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.
[0193] The term "substituted heterocyclic" is used herein to
describe the heterocyclic group just defined having 1 to 4
substituents selected from the group which includes halogen, CN,
OH, NO.sub.2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl,
substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted
alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
[0194] 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 1 to 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.
[0195] The compounds of this invention may be prepared according to
the methods described below. 54
[0196] 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.degree. 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.sub.1 and R.sub.2 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)palla- dium(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.
[0197] 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.
[0198] If R.sub.1 and R.sub.2 are different then the intermediate 4
is prepared by reacting the dianion of 3 with one equivalent of the
electrophile R.sub.1--X (X=leaving group e.g. iodine). The
resultant mono-alkylated compound may then be isolated and
re-subjected to the reaction conditions using R.sub.2--X, or
alternatively used in-situ for the second alkylation with
R.sub.2--X. Alternatively if the desired product 7 is to contain
R.sub.2.dbd.H, then the isolated mono-alkylated intermediate is
taken though the subsequent steps. 55
[0199] 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.
[0200] 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 TiCl.sub.4/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.dbd.H). These alcohols may then be further functionalized by
alkylation or acylation procedures. 56
[0201] 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. 57
[0202] 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, Et.sub.2O) with a strong base (sodium
hydride preferred, sodium hexamethyldisilazide, potassium hydride)
followed by reaction at reduced temperature (-50 to -20.degree. 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 (NaHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, 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.
[0203] Alternatively reaction of compound 13 under palladium
catalyzed conditions (tetrakis(triphenylphosphine)palladium(0) or
palladium acetate, base (NaHCO.sub.3, Na.sub.2CO.sub.3,
K.sub.2CO.sub.3, 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. 58
[0204] Treatment of the bromide 5 in an anhydrous solvent (e.g.
THF, Et.sub.2O) with a strong base (sodium hydride preferred,
sodium hexamethyldisilazide, potassium hydride) followed by
reaction at reduced temperature (-50 to -20.degree. 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 (NaHCO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
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 6.
[0205] 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 5 in an anhydrous solvent
(e.g. THF, Et.sub.2O) with a strong base (sodium hydride preferred,
sodium hexamethyldisilazide, potassium hydride) followed by
reaction at reduced temperature (-50 to -20.degree. 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.
[0206] 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. 59
[0207] 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.degree. C. to the
boiling point of the solvent under an inert atmosphere (nitrogen or
argon). 60
[0208] 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.degree. 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.degree. C. and the boiling point of the solvent would then
afford the N-hydroxyamidines 18.
[0209] 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 carbonate) or a Lewis acid (e.g. boron
trifluoride etherate, a lead H 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 R.sub.3 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
the 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. 61
[0210] 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.degree. 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.degree. 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, tetrahydropyranyl ether, methoxy methyl ether,
silyl ether) to give the derivative 23. Alternately compound 21
could be reacted directly with a protected hydroxylamine 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.
[0211] 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 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.
[0212] 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. 62
[0213] 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 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.
[0214] 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 acid or boronic acid ester and coupled in a Suzuki or
Suzuki type palladium coupling with a suitable functionalised aryl
bromide. 63
[0215] 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 maleic 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 conventional
"pro-drug" forms, which, when administered in such form, convert to
the active moiety in vivo.
[0216] 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.
[0217] 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.
[0218] 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.
[0219] When the compounds are employed for the above utilities,
they may be combined with one or more pharmaceutically acceptable
carriers 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.
[0220] 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 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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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 carrier can 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.
[0225] This invention is further understood by the following
non-limiting examples.
EXAMPLE 1
5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-thione
Spiro[cyclohexane-1,3'-[3H]indol]-2'-(1'H)one
[0226] A solution of oxindole (25 g, 0.19 mol) in anhydrous
tetrahydrofuran (800 cm.sup.3) was cooled to -20.degree. C., then
n-butyllithium (2.5M in hexanes, 152 cm.sup.3, 0.38 mol) was added
slowly followed by N,N,N',N'-tetramethylethylenediamine (51
cm.sup.3, 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 (.times.2). The combined organic layers were extracted with
hydrochloric acid (1N), then washed with brine (500 cm.sup.3),
dried (MgSO.sub.4), and concentrated to obtain an oil. The oil was
triturated with hexane (200 cm.sup.3) and benzene (20 cm.sup.3).
The precipitate was collected and dried in vacuo to obtain the
subtitled compound (26.3 g, 69.6%) as colorless crystals: mp
110-114.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 1.67 (m,
10H), 6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8
Hz), 7.44 (d, 1H, J=8 Hz), 10.3 (s, 1H).
5'-Bromospiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
[0227] To a solution of
spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one (17.6 g, 0.09 mol) in
acetic acid (300 cm.sup.3) was added sodium acetate (8.0 g, 0.1
mol) and bromine (14.6 g, 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
(MgSO.sub.4) and evaporated and the residue was triturated with
hexane. The precipitate was collected, and dried in vacuo to obtain
the subtitled compound (16.5 g, 67%) as off-white crystals: mp
196-199.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 1.62 (m,
10H), 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, 1H).
5-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0228] 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 cm.sup.3) was stirred under N.sub.2 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 cm.sup.3). The solution was brought to reflux for 6 h then
cooled to RT, poured into water and extracted with EtOAc
(.times.3). The combined organic extracts were washed with water,
brine, dried (MgSO.sub.4), and evaporated. The residue was purified
by column chromatography (SiO.sub.2, ethyl acetate:hexane 1:3) to
afford the subtitled compound (0.28 g, 0.89 mmol, 80%) as a yellow
solid: mp. 164-165.degree. C., .sup.1H NMR (CDCl.sub.3) .delta.
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);
.sup.13C-NMR (CDCl.sub.3) 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).sup.+; Anal. (C.sub.19H.sub.18ClNO) C, H, N.
[0229] To a solution of
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indo- l]-2'(1'H)-one
(0.63 g, 2.0 mmol) in dry xylene (20 cm.sup.3) 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 72 h, the mixture was evaporated and the residue
subjected to column chromatography (SiO.sub.2, 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 (0.17 g, 0.51 mmol, 26%): mp. 223-227.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 2
3-(1',2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)benzonit-
rile
[0230] To a solution of
5'-bromospiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-- one (1.00 g,
3.57 mmol) in dimethoxyethane (20 cm.sup.3) 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 cm.sup.3).
After 20 h at reflux, the mixture was cooled poured into water and
extracted with EtOAc (.times.3). The combined organic extract was
washed with saturated brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by column chromatography (SiO.sub.2,
EtOAc:hexane, gradient elution) to afford the title compound (0.66
g, 2.15 mmol, 60%) as a white solid, .sup.1H NMR (CDCl.sub.3)
.delta. 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz),
7.48 (dd, 1H, J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2
Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS
((+)ESI) m/z 306 (M+H).sup.+.
3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)benzaldehyd-
e Oxime
[0231] To a solution of
3-(1',2'-dihydro-2'-oxospirocyclohexane-1,3'-[3H]i-
ndol-5'-yl)benzaldehyde (0.59 g, 1.95 mmol) in EtOH: H.sub.2O (10
cm.sup.3, 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 (.times.2). The combined organic layers were washed with
sat. sodium hydrogen carbonate solution, water, sat. brine, dried
(MgSO.sub.4) and evaporated to afford the subtitled oxime (0.63 g,
1.95 mmol, 100%) which was used without further purification,
.sup.1H NMR (CDCl.sub.3) .delta. 1.60-1.84 (m, 6H), 1.85-2.00 (m,
4H), 6.86 (d, 1H, J=8 Hz), 7.36 (dd, 1H, J=8, 2 Hz), 7.43-7.50 (m,
1H), 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).sup.-.
3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)benzonitril-
e
[0232] A solution of
3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]ind-
ol-5'-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10
cm.sup.3) was treated with selenium dioxide (0.38 g, 3.50 mmol) and
heated under reflux. After 16 h, the mixture was concentrated and
the residue purified by column chromatography (SiO.sub.2,
EtOAc:hexane 1:4) and the product recrystallized from EtOAc-hexane
to afford the subtitled compound (0.161 g, 0.53 mmol, 35%) as a
white solid: mp. 190-191.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 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).sup.+.
[0233] 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.degree.
C. (decomp.); .sup.1H NMR (DMSO-d.sub.6) .delta. 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, 1H, J=8 Hz) and 12.76 (s, 1H); MS
((-)-APCI) m/z 317 [M-H].sup.-.
EXAMPLE 3
4-(1',2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-2-thiop-
henecarbonitrile
3-(Trimethylstannyl)-2-thiophenecarbonitrile
[0234] 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.sup.3) was heated under reflux for 14 h then cooled to RT. The
reaction mixture was absorbed onto florisil and purified by column
chromatography (SiO.sub.2, methylene chloride: hexane 1:9) to
afford the subtitled compound (1.04 g, 3.8 mmol, 90%) as a clear
viscous oil: .sup.1H NMR (CDCl.sub.3) .delta. 0.35 (s, 9H), 7.56
(d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).
4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarb-
onitrile
[0235] 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 cm.sup.3) was stirred under N.sub.2 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 and
purified by column chromatography (SiO.sub.2, ethyl acetate:hexane
2:3) to afford the subtitled compound (0.43 g, 1.39 mmol, 74%) as
an off white solid: .sup.1H NMR (CDCl.sub.3) .delta. 1.56-2.1 (m,
10H), 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); .sup.13C-NMR (CDCl.sub.3) .delta. 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).sup.+; Anal. (C.sub.18H.sub.16N.sub.2OS)C, H,
N.
[0236] A solution of
4-1,2-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 (5.times.100 mL), dried over MgSO.sub.4, and evaporated. The
product was purified by column chromatography (SiO.sub.2,
EtOAc:Hexane 1:5) to afford the title compound (0.2 g, 20%) as a
pale-yellow solid: m.p. 230-232.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 12.72 (s, 1H), 8.52 (d, 1H, J=1.5 Hz), 8.36
(d, 1H, J=1.5 Hz), 8.00 (d, 1H, J=1.5 Hz), 7.69 (dd, 1H, J=6.4, 1.8
Hz), 7.10 (d, 1H, J=8.3 Hz), 1.98-1.77 (m, 7H), 1.43-1.33 (m, 3H);
MS (EI) M.sup.+ @ m/z 324.
EXAMPLE 4
3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenz-
onitrile
[0237] To a solution of
5'-bromospiro[cyclohexane-1,3'-[3H]indol]-2'-(1'H)- -one (11 g,
0.04 mol) in dry tetrahydrofuran (200 cm.sup.3) was added sodium
hydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30
min. stirring at room temperature, the mixture was cooled to
-78.degree. C. and butyl lithium (1.7M in hexanes, 23.2 cm.sup.3,
0.04 mol) was added slowly. After 30 min. di-iso-propylborate (25
cm.sup.3, 0.11 mol) was added and the mixture was allowed to warm
to room temperature. After 2 hrs., hydrochloric acid (1N, 500
cm.sup.3) and ethylacetate (500 cm.sup.3) were added. The aqueous
phase was extracted with ethylacetate, then the combined organic
layers were washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was triturated with hexane and the
precipitate dried in vacuo to obtain
(2'-oxo-2,3-dihydrospiro[cyclohe-
xane-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.degree. C. dec.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 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]indol]-5-yl)-5-fluorobenzoni-
trile
[0238] To a solution of 3,5-dibromofluorobenzene in diethyl ether
(100 cm.sup.3) at -78.degree. C. was added n-butyl lithium (2.5 M,
8 cm.sup.3, 20 mmol) dropwise. After 30 min. the mixture was
treated with DMF (20 cm.sup.3 diethyl ether (10 cm.sup.3 stirring
was continued at -78.degree. 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 (MgSO.sub.4) and evaporated to give
3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil:
.sup.1H NMR (CDCl.sub.3) 6 inter alia 7.50-7.53 (m, 2H), 7.82 (s,
1H) and 9.93 (m, 1H); MS (EI) m/z 202, 204 [M.sup.+].
[0239] To a solution of the last cited compound (4.0 g, 19.7 mmol)
in ethanol:water (8:2, 50 cm.sup.3), 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 (MgSO.sub.4) and
evaporated to give 3-fluoro-5-bromobenzalde- hyde oxime (3.76 g,
17.24 mmol, 87%) which was used without further purification:
.sup.1H NMR (CDCl.sub.3) .delta. 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.sup.+].
[0240] The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate
(370 mg) were dissolved in acetonitrile (100 cm.sup.3) under
nitrogen and heated under reflux. After 5 h, the mixture was
evaporated, the residue taken into EtOAc, washed with sulfuric acid
(1N), water, brine, dried (MgSO.sub.4) and evaporated to give
3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%) which was
used without further purification.
[0241] The above bromide (3.0 g, 15 mmol) and
tetrakis(triphenylphosphine)- palladium (0) (0.86 g, 0.75 mmol)
were dissolved in dimethoxyethane (130 cm.sup.3) under nitrogen.
After 15 min. (2'-oxo-2,3-dihydrospiro[cyclohex-
ane-1,3'-[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
cm.sup.3) were added, and the mixture heated under reflux. After 8
h the mixture was cooled, poured into water and extracted with
EtOAc (.times.3). The combined organic layers were then washed with
water, dried (MgSO.sub.4) 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]-5-y-
l)-5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): mp
199-205.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 1.64-2.03 (m,
10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41
(dd, 1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2
Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M.sup.+].
[0242] To a solution of
3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indo-
l]-5-yl)-5-fluorobenzonitrile (0.32 g, 1.0 mmol) in xylenes (10
cm.sup.3) under nitrogen was added Lawesson's reagent (0.89 g, 2.22
mmol) and the reaction was heated under reflux. After 4 h., the
mixture was cooled, evaporated and the residue subjected to column
chromatography (SiO.sub.2, EtOAc:hexane, gradient elution) to
afford (0.143 g, 0.42 mmol, 42%) as a white solid: mp.
236-250.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 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=1 Hz), 10.05 (s,
1H); MS ((+)-APCI) m/z 337 [M+H].sup.+.
EXAMPLE 5
4-methyl-5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]-indol]-5-yl)-2--
thiophene Thioamide
[0243]
2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boronic
acid (2.45 g, 10 mmol), 2-bromo-5-cyano-3-methylthiophene (2.4 g,
12 mmol), potassium (4 g, 29 mmol), and
tetrakis(triphenylphosphine)palladiu- m(0) (0.6 g, 0.5 mmol) in
dimethoxyethane: water: ethanol (130 cm.sup.3, 10:2:1) was heated
to 80.degree. C. for 16 h., then poured into 1 L of water, and
extracted with EtOAc. The organic layer was washed with brine,
dried (MgSO.sub.4) and concentrated. The crude product was
subjected to column chromatography (SiO.sub.2, EtOAc:hexane, 1:1)
to obtain the title compound (0.9 g, 28%): m.p. 200-203.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.63 (m, 8H), 1.87 (m, 2H), 2.27
(s, 3H), 6.95 (d, 1H, J=8.13 Hz), 7.34 (dd, 1H, J=8.13, 1.98 Hz)
7.54 (d, 1H, J=1.98 Hz), 7.82 (s, 1H) 10.50 (s, 1H); MS ((+)APCI)
m/z 323 [M+H].sup.+.
[0244] 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.degree. C. for 30 minutes. The reaction mixture was
poured into distilled water, and washed with aqueous NaHCO.sub.3,
distilled water, dried over MgSO.sub.4, and evaporated to dryness.
The residue was purified with column chromatography (2.5%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound (0.05 g, 8%) as
a orange-brown solid: m.p. 244-249.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 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].sup.+ @ m/z 373.
EXAMPLE 6
Pharmacology
[0245] 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 .mu.g/kg to 30 mg/kg.
[0246] A. In-vitro biology
[0247] 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 EC50
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.
[0248] 1. hPR Binding assay--This assay is carried out in
accordance with: Pathirana, C.; Stein, R. B.; Berger, T. S.;
Fenical, W.; Ianiro, T.; Mais, D. E.; Torres, A.; Glodman, M. E.,
Nonsteroidal human progesterone receptor modulators from the marine
alga cymoplia barbata, J. Steroid Biochem. Mol. Biol., 1992, 41,
733-738.
[0249] 2. PRE-luciferase assay in CV-1 cells
[0250] 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.
[0251] a. Growth medium: DMEM (BioWhittaker) containing 10% (v/v)
fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential
amino acids, 100 U/ml penicillin, 100 mg/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, 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM
GlutaMax (GIBCO, BRL).
[0252] b. Cell culture, transfection, treatment, and luciferase
assay
[0253] Stock CV-1 cells are maintained in growth medium.
Co-transfection is done using 1.2.times.10.sup.7 cells, 5 mg pLEM
plasmid with hPR-B inserted at Sph1 and BamH1 sites, 10 mg pGL3
plasmid with two PREs upstream of the 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 .mu.l. 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 .mu.l of cell
lysis buffer (Promega, Madison, Wis.) 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.
[0254] c. Analysis of Results:
[0255] 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.
EC.sub.50 or IC.sub.50 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.
[0256] d. Reference Compounds:
[0257] Progesterone and trimegestone are reference progestins and
RU486 is the reference antiprogestin. All reference compounds are
run in full dose-response curves and the EC.sub.50 or IC.sub.50
values are calculated.
1TABLE 1 Estimated EC.sub.50, 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
[0258]
2TABLE 2 Estimated IC.sub.50, 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
[0259] Progestational activity: Compounds that increase
PRE-luciferase activity significantly (p<0.05) compared to
vehicle control are considered active.
[0260] Antiprogestational activity: Compounds that decrease 3 nM
progesterone induced PRE-luciferase activity significantly
(p<0.05).
[0261] EC.sub.50: Concentration of a compound that gives
half-maximal increase PRE-luciferase activity (default-nM) with
SE.
[0262] IC.sub.50: Concentration of a compound that gives
half-maximal decrease in 3 nM progesterone induced PRE-luciferase
activity (default-nM) with SE.
[0263] 3. T47D cell proliferation assay
[0264] 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.
[0265] a. Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented
with 10% (v/v) fetal bovine serum (not heat-inactivated), 100 U/ml
penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO,
BRL).
[0266] b. Treatment medium: Minimum Essential Medium (MEM)
(#51200-038GIBCO, BRL) phenol red-free supplemented with 0.5%
charcoal stripped fetal bovine serum, 100 U/ml penicillin, 200
mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
[0267] c. Cell culture
[0268] 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, Ill.) in treatment medium for 4 hr.
[0269] d. Cell Proliferation Assay
[0270] 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. 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 .mu.l 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.
[0271] e. Analysis of Results:
[0272] 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. EC.sub.50 or IC.sub.50 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.
[0273] f. Reference Compounds:
[0274] 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
EC.sub.50 or IC.sub.50 values are calculated.
3TABLE 3 Estimated EC.sub.50, standard error (SE), and 95%
confidence intervals (CI) for individual studies EC.sub.50 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
[0275]
4TABLE 4 Estimated IC.sub.50, standard error, and 95% confident
interval for the antiprogestin, RU486 IC.sub.50 95% CI Compound Exp
(nM) 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 EC.sub.50: Concentration of a
compound that gives half-maximal increase in BrdU incorporation
with SE; IC.sub.50: Concentration of a compound that gives
half-maximal decrease in 0.1 trimegestone induced BrdU
incorporation with SE
[0276] 4. T47D cell alkaline phosphatase assay
[0277] 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.
[0278] a. Culture medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented
with 5% (v/v) charcoal stripped fetal bovine serum (not
heat-inactivated), 100 U/ml penicillin, 100 .mu.g/ml streptomycin,
and 2 mM GlutaMax (GIBCO, BRL).
[0279] b. Alkaline phosphatase assay buffer:
[0280] I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100; II.
0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate
(Sigma).
[0281] c. Cell Culture and Treatment:
[0282] Frozen T47D cells were thawed in a 37.degree. 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 .mu.l of
diluted cell suspension was added. Twenty .mu.l 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.degree. C. in a 5%
CO.sub.2/humidified atmosphere for 24 hr.
[0283] d. Alkaline Phosphatase Enzyme Assay:
[0284] At the end of treatment, the medium was removed from the
plate and fifty .mu.l of assay buffer I was added to each well. The
plates were shaken in a titer plate shaker for 15 min. Then 150
.mu.l 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.
[0285] e. Analysis of Results: Analysis of dose-response data
[0286] 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. EC.sub.50 or IC.sub.50 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.
[0287] f. Reference Compounds:
[0288] Progesterone and trimegestone are reference progestins and
RU486 is the reference antiprogestin. All reference compounds are
run in full dose response curves and the EC.sub.50 or IC.sub.50
values are calculated.
5TABLE 5 Estimated EC.sub.50, 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
[0289]
6TABLE 6 Estimated IC.sub.50, standard error, and 95% confident
interval for the reference antiprogestin RU486 from three
independent experiments IC 50 95% CI Compound Exp (nM) SE lower
upper RU486 1 0.103 0.002 0.092 0.115 2 0.120 0.001 0.115 0.126 3
0.094 0.007 0.066 0.134
[0290] B. In-vivo Biology
[0291] 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.
[0292] 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.
[0293] a. Methods: Test compounds are dissolved in 100% ethanol and
mixed with corn oil (vehicle). Stock solutions of the test
compounds in oil (Mazola.TM.) are then prepared by heating
(.about.80.degree. C.) 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.
[0294] b. Animals (RACUC protocol #5002)
[0295] Ovariectomized mature female Sprague-Dawley rats (-60-day
old and 230 g) are obtained from Taconic (Taconic Farms, N.Y.)
following surgery. Ovariectomy is performed at least 10 days prior
to treatment to reduce circulating sex steroids. Animals are housed
under 12 hr light/dark cycle and given standard rat chow and water
ad libitum.
[0296] c. Treatment
[0297] 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 EC.sub.50 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.
[0298] d. Dosing
[0299] 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).
[0300] e. Decidual induction
[0301] 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 CO.sub.2 asphyxiation and body
weight measured. Uteri are removed and trimmed of fat. Decidualized
(D-horn) and control (C-horn) uterine horns are weighed
separately.
[0302] f. Analysis of Results:
[0303] 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.
[0304] g. Reference Compounds:
[0305] All progestin reference compounds were run in full
dose-response curves and the EC.sub.50 for uterine wet weight were
calculated.
7TABLE 7 Estimated EC.sub.50, standard error (SE), and 95%
confidence intervals for individual studies EC.sub.50 95% CI
Compound Exp (mg/kg, s.c.) SE lower upper Progesterone 1 5.50 0.77
4.21 7.20 2 6.21 1.12 4.41 8.76 3-Ketodesogestrel 1 0.11 0.02 0.07
0.16 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
[0306]
8TABLE 8 Estimated average EC.sub.50, standard error, and 95%
confidence intervals for dose-response curves of 3 reference
compounds EC50 95% CI Compound (mg/kg, s.c.) SE lower upper
Progesterone 5.62 0.62 4.55 7.00 3-Ketodesogestrel 0.10 0.02 0.07
0.14 Levonorgestrel 0.10 0.01 0.08 0.12
[0307]
9TABLE 9 Estimated IC.sub.50, standard error, and 95% confident
interval for the antiprogestin, RU 486 IC.sub.50 95% CI Compound
Exp. (mg/kg, p.o.) SE lower upper RU 486 1 0.21 0.07 0.05 0.96 2
0.14 0.02 0.08 0.27
[0308] Concentration: Compound concentration in assay
(default-mg/kg body weight)
[0309] Route of administration: Route the compound is administered
to the animals
[0310] Body weight: Mean total animal body weight (default-kg)
[0311] D-horn: Wet weight of decidualized uterine horn
(default-mg)
[0312] C-horn: Wet weight of control uterine horn (default-mg)
[0313] Decidual response: [(D-C)/C].times.100%
[0314] Progestational activity: Compounds that induce
decidualization significantly (p<0.05) compared to vehicle
control are considered active
[0315] Antiprogestational activity: Compounds that decrease
EC.sub.50 progesterone induced decidualization significantly
(p<0.05)
[0316] EC.sub.50 for uterine weight: Concentration of compound that
gives half-maximal increase in decidual response
(default-mg/kg)
[0317] IC.sub.50 for uterine weight: Concentration of compound that
gives half-maximal decrease in EC.sub.50 progesterone induced
decidual response (default-mg/kg)
10TABLE 10 Data for Representative Compounds Ovulation CV-1
inhibition Example # Ki/nM EC50/nM IC100 mg/kg 5 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-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-
-2-carbonitrile
[0318]
5-(2'-Oxo-2',3'-dihydrospiro[cyclopentane-1,3'-[3H]indol]-5'-yl-2-c-
yanopyrrole: A solution of
5'-bromospiro[cyclopentane-1,3'-[3H]indol]-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.degree. C. for 3 h and allowed to cool. The
reaction mixture was poured into water (50 mL) and extracted with
ethyl acetate (3.times.50 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'-[3H]indol]-5'-yl)-1H-pyrro-
le-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white
powder, mp 179-180.5.degree. C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, J=1.8, 3.3
Hz), 6.22 (`t`, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1H, J=7.9 Hz), 7.08
(dd, 1H, J=1.8, 7.9 Hz), 7.14 (`d`, 1H, J=1.5 Hz), 7.28 (dd, J=1.9,
3.3 Hz), 10.30 (s, 1H). MS (EI) m/z 352 [M.sup.+]. Anal. Calcd for
C.sub.21H.sub.24N.sub.2O.sub.3: C, 71.57; H, 6.86; N, 7.95. Found:
C, 71.08; H, 6.83; N, 7.74.
[0319] 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.degree. 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.times.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-cyanopy-
rrole-1-carboxylic acid, tert-butyl ester (1.7 g, 75%) as white
crystals, mp 167-9.degree. C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H, J=3.7 Hz),
6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1H, J=1.8, 7.9 Hz), 7.28 (`t`,
2H), 10.41 (s, 1H). MS (ESI) m/z 376 [M-H].sup.-. Anal. Calcd. for
C.sub.22H.sub.23N.sub.3O.sub.3: C, 70.01; H, 6.14; N, 11.13. Found:
C, 69.67; H, 6.38; N, 11.04.
[0320]
5-(2'-Oxo-2',3'-dihydrospiro[cyclopentane-1,3'-[3H]indol]-5'-yl-2-c-
yanopyrrole-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.degree. 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.degree.
C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.75-2.03 (m, 8H),
6.60 (dd, 1H, J=2.4, 3.7 Hz), 6.84 (d, 1H, J=8.1 Hz), 6.94 (dd, 1H,
J=2.4, 3.7 Hz), 7.52 (dd, 1H, J=1.8, 8.1 Hz), 7.60 (d, 1H, J=1.8
Hz), 10.38 (s, 1H), 12.45 (s, 1H). MS (ESI) m/z 276 [M-H].sup.-.
Anal. Calcd. For C.sub.17H.sub.15N.sub.3O: C, 73.63; H, 5.45; N,
15.15. Found: C, 73.24; H, 5.34; N, 14.96.
[0321] 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.degree. C. (dec.). .sup.1H NMR (d.sub.6-DMSO, 300 MHz)
.delta. 1.81-2.16 (m, 8H), 6.69 (dd, 1H, J=2.3, 3.7 Hz), 6.98 (dd,
1H, J=1.8, 3.7 Hz), 7.04 (d, 1H, J=8.2 Hz), 7.63 (dd, 1H, J=1.6,
8.2 Hz), 7.72 (d, 1H, J=1.3 Hz), 12.57 (s, 1H), 12.65 (s, 1H). MS
(ESI) [M-H].sup.-=292. Anal. Calculated (cald.) for
C.sub.17H.sub.15N.sub.3S: 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-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-buto-
xycarbonyl)-pyrrole-2-carbonitrile
[0322] 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, 5 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 K.sub.2CO.sub.3 (2.3 eq,
3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The
solution was heated to 80.degree. C. for 3 h and allowed to cool.
The reaction mixture was poured into water (200 mL) and extracted
with EtOAc (2.times.100 mL). The organic layers were combined,
washed with brine (150 mL) and dried over MgSO.sub.4. 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[cycl-
ohexane-1,3'-[3H]indol]-5'-yl)-1H-pyrrole-1-carboxylic acid,
tert-butyl ester (3.4 g, 76%) as a white powder, mp 177.degree. C.
.sup.1H NMR (CDCl.sub.3; 300 MHz) .delta. 1.38 (s, 9H), 1.59-1.93
(m, 10H), 6.18 (m, 1H), 6.23 (`t`, 1H, J=3 Hz), 6.91 (d, 1H, J=8
Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s,
1H, D.sub.2Oex). MS ((+)-APCI) m/z 367 [(M+H).sup.+]. Anal. Calcd
for C.sub.22H.sub.26N.sub.2O.sub.3: C, 72.11; H, 7.15; N, 7.64.
Found: C, 71.7; H, 7.16; N, 7.5.
[0323] 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.degree. 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.times.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-cyanopyrr-
ole-1-carboxylic acid, tert-butyl ester (0.5 g, 63%) as an oil
which crystallized from acetone to give white crystals, mp
156.degree. C. .sup.1H NMR (d.sub.6-DMSO, 400 MHz) .delta. 1.32 (s,
9H), 1.50 (m, 3H), 1.60-1.70 (m, 5H), 1.75-1.85 (m, 2H), 6.38 (d,
1H, J=3.7 Hz), 6.87 (d, 1H, J=7.9 Hz), 7.18 (dd, 1H, J=1.5, 7.9
Hz), 7.27 (d, 1H, J=3.7 Hz), 7.48 (d, 1H, J=1.8 Hz), 10.42 (bs,
1H). MS (EI) m/z 391 (M.sup.+). Anal. Calcd for
C.sub.23H.sub.25N.sub.3O.sub.3: C, 70.57; H, 6.44; N, 10.73. Found:
C, 69.82; H, 6.46; N, 10.43.
[0324] To a solution of
2-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.times.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%). .sup.1H NMR (d.sub.6-DMSO, 500 MHz)
.delta. 1.30-1.98 (m, 19H), 6.45 (d, 1H, J=3.7 Hz), 7.09 (d, 1H,
J=7.9 Hz), 7.31-7.34 (m, 2H), 7.81 (d, 1H, J=1.4 Hz), 12.74 (s,
1H). MS (ESI) [M-H].sup.-=406. Anal. calcd. for
C.sub.23H.sub.25N.sub.3O.sub.2S: C, 67.79; H, 6.18; N, 10.31.
Found: C, 67.86; H, 5.99; N, 10.25.
EXAMPLE 9
5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole--
2-carbonitrile
[0325] To a solution of
5-(1,2-Dihydro-2-thioxospiro[cyclohexane-1,3-[3H]i-
ndol]-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.degree. 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
(0.27 g, 68%) as a yellow powder. .sup.1H NMR (d.sub.6-DMSO, 500
MHz) .delta. 1.32-1.99 (m, 10H), 6.71 (d, 1H, J=3.7 Hz), 7.00 (d,
1H, J=3.7 Hz), 7.09 (d, 1H, J=8.4 Hz), 7.70 (dd, 1H, J=1.6, 8.4
Hz), 8.05 (d, 1H, J=1.1 Hz), 12.67 (s, 1H), 12.73 (s, 1H). MS (ESI)
[M-H].sup.-=306. Anal. calcd. for C.sub.18H.sub.17N.sub.3S: 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'-[3H]indol]-5'-yl)-1-methyl-pyrrole-2-ca-
rbonitrile
[0326] 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.degree. C. for 1 hour. The
reaction was cooled to room temperature, poured into water (100 mL)
and extracted with ethyl acetate (2.times.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%). .sup.1H NMR (d.sub.6-DMSO, 500 MHz)
.delta. 1.36-1.99 (m, 10H), 3.7 (s, 3H), 6.35 (d, 1H, J=4.2 Hz),
7.05 (d, 1H, J=4.2 Hz), 7.16 (d, 1H, J=7.9 Hz), 7.44 (dd, 1H,
J=1.6, 8.1 Hz), 7.83 (d, 1H, J=1.6 Hz), 12.75 (s, 1H). MS (ESI)
[M-H].sup.-=320. Anal. calcd. for C.sub.19H.sub.19N.sub.3S: 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-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-3-thiophene-
carbonitrile
[0327] 5-Bromo-2-thiophenecarbonitrile: A mixture of
5-bromo-2-thiophenecarboxaldehyde (96.0 g, 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 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 (1.4 L)
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 (2.times.30 mL), water
(2.times.30 mL), brine (20 mL), and dried (MgSO.sub.4). 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
(31.5 g combined, 58%). IR (film) 2200 cm.sup.-1. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H,
J=4.0 Hz); MS (EI) m/z 187 (M.sup.+, 98%) 189(M.sup.+, 100%).
[0328]
5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indole]-5-yl)-3-thio-
phenecarbonitrile was prepared according to the procedure for
Example 5 using 5-bromo-2-thiophenecarbonitrile and
(2'-oxo-2',3'-dihydrospiro[cycl-
ohexane-1,3'-[3H]indol]-5'-yl)boronic acid: mp. 225-228.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.63 (m, 8H), 1.90 (m, 2H) 6.91
(d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H,
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 ((+)APCI) m/z 309 [M+H].sup.+.
[0329] 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.degree. 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.degree. C. (0.24 g, 32%). .sup.1H-NMR (DMSO-d.sub.6)
.delta. 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, 1H), 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).sup.-.
EXAMPLE 12
5-(1,2-dihydro-thioxospiro(cyclopentane-1,3-[3H]indol)-5-yl)-2-thiopheneca-
rbonitrile
[0330] The title compound was prepared from
5-(1,2-dihydro-oxospiro(cyclop-
entane-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile (2 g, 0.8 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.degree. C. .sup.1H NMR (DMSO-d.sub.6) .delta. 12.75 (s,
1H), 7.98-7.97 (d, 1H, J=3.9 Hz), 7.71-7.70 (d, 1H, J=5.2 Hz),
7.65-7.62 (d, 1H, J=8.1 Hz), 7.09-7.07 (d, 1H, J=8.1 Hz) 2.13-2.08
(m, 6H), 1.99-1.85 (m, 2H); MS.[M-H].sup.-=309 IR (SP ATR)
1430,1620,2220 cm.sup.-1. Anal. calcd. for
C.sub.17H.sub.14N.sub.2S.sub.2. C, 65.77; H, 4.55; N, 9.02. obs'd
C, 65.27; H, 4.41; N, 8.84.
EXAMPLE 13
5-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0331]
5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)--
one: Prepared from 4-bromo-2-fluoroanisole and
(2'-oxo-2',3'-dihydrospiro[-
cyclohexane-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.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta.
10.4 (s, 1H), 7.65 (d, 1H, J=1.1 Hz), 7.5-7.4 (m, 3H), 7.2 (t, 1H,
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].sup.-; Anal. Calc. For C.sub.20H.sub.20FNO.sub.2: C,
73.83, H, 6.20, N, 4.30. Found: C, 73.55, H, 6.23, N, 4.40.
[0332] 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.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 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].sup.- m/z 324. Anal. Cal. for
C.sub.20H.sub.20FNOS.0.25H.sub.2.degree. 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-pyrimidnyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0333] 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.degree. C. (dec.);
.sup.1H-NMR (DMSO-d.sub.6) .delta. 12.7 (s, 1H), 8.6 (s, 2H), 7.9
(s, 1H), 7.5 (d, 1H, 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].sup.- m/z
309.
EXAMPLE 15
3-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluoroben-
zonitrile
Spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one
[0334] To a -25.degree. C. solution of oxindole (2.0 g, 15.0 mmol)
in 40 (cm.sup.3) of anhydrous THF under N.sub.2 was added
n-butyllithium (1.6 M in hexanes, 19.7 cm.sup.3, 31.5 mmol)
drop-wise. To the resulting milky solution was added
N,N,N'N'-tetramethylethylenediamine (4.75 cm.sup.3, 31.5 mmol).
After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in
THF (3 cm.sup.3) 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 (.times.2), the combined organic
layers were washed with dilute HCl (pH 1) and water (.times.2),
dried (MgSO.sub.4) and evaporated. The residue was purified by
column chromatography (SiO.sub.2, EtOAc:hexane 1:4) to afford the
subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: .sup.1H
NMR (CDCl.sub.3) .delta. 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz,
1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s,
1H).
5-Bromo-spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one
[0335] 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 cm.sup.3) was treated with bromine (0.24 g, 1.51 mmol) in
acetic acid (2 cm.sup.3). After 30 min. the mixture was poured into
sat. sodium hydrogen carbonate solution and extracted with EtOAc
(.times.2), the combined organic layers were washed with water,
sat. sodium hydrogen carbonate solution, water, dried (MgSO.sub.4),
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: .sup.1H NMR (CDCl.sub.3) .delta. 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
[0336] 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 cm.sup.3) was stirred under
N.sub.2 for 20 minutes. To this mixture was then added
(spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-o- ne-5-yl) boronic
acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in
water (5 cm.sup.3). The solution was brought to reflux for 18 hours
and then cooled to room temperature, poured into 2N NaOH and
extracted with EtOAc (.times.3). The combined extracts were washed
with water, brine, dried (MgSO.sub.4), and evaporated. The residue
was purified by column chromatography (SiO.sub.2, EtOAc, hexane) to
afford the subtitled compound (0.35 g, 44%) as white needles. mp:
235-237.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 10.5 (s,
1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m,
2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9
(m, 8H); MS (EI) M.sup.+ @ m/z 306.
[0337] General Procedure A
[0338] The title compound was prepared from
5'-(3-Cyano-5-fluorophenyl)-sp-
iro[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 (SiO.sub.2, 30
cm.times.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.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.+.
EXAMPLE 16
5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione
5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one
[0339] 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.sup.3). After 15 min., 3-chlorophenylboronic acid (1.27 g, 8.13
mol) was added, followed by potassium carbonate (3.40 g, 45 mmol)
in water (15 cm.sup.3). 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
(.times.3). The combined organic layers were dried (MgSO.sub.4),
filtered, and evaporated. The residue was purified by column
chromatography (SiO.sub.2, EtOAc:hexane, 1:3) to afford the
subtitled compound (0.284 g, 25%): mp 188-189.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 3.34 (s, 6H), 6.93 (d, 1H, J=8.04 Hz),
7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d, 1H, J=7.68 Hz), 7.70
(s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700 cm.sup.-1;
MS (EI) m/z 270 (M-H).sup.-; CHN calculated for
C.sub.16H.sub.14ClNO+0.1C.sub.4H.- sub.8O.sub.2: C, 70.21; H, 5.32;
N, 4.99; Found: C, 70.3; H, 5.44; N, 4.93.
[0340] The title compound was prepared from
5-(3-Chloro-phenyl)-3,3-dimeth- yl-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.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 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].sup.+.
EXAMPLE 17
3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione
[0341] 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.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 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].sup.+.
EXAMPLE 18
4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile
4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile
[0342] Prepared according to the procedure for Example 5 using
(2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3'-[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 mmol, 26%)
as a white solid: mp.199.6-201.4.degree. C., .sup.1H NMR
(DMSO-d.sub.6) .delta. 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).sup.-; Anal.
C.sub.15H.sub.12N.sub.2O.sub.2.0.6H.sub.2O.
[0343] The title compound was prepared from
4-(3,3-Dimethyl-2-oxo-2,3-dihy-
dro-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.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.
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].sup.+.
EXAMPLE 19
5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione
[0344] 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 cm.sup.3) then
bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm.sup.3) was added
drop-wise to the reaction mixture. The reaction was stirred for 50
min., then poured into water. The mixture was basified with sodium
carbonate, extracted with ethyl acetate (.times.3), dried
(MgSO.sub.4), filtered, and evaporated to give the subtitled
compound (0.89 g, 92%) .sup.1H NMR (DMSO-d.sub.6) .delta. 1.21 (s,
6H), 6.76 (d, 1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz),
7.49 (d, 1H, J=2.03 Hz), 10.4 (s, 1H).
[0345] 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
cm.sup.3). After 15 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 cm.sup.3). The reaction was heated to reflux for
5 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 (.times.2),
and the combined organic layers were dried (MgSO.sub.4), filtered,
and evaporated. The residue was purified by column chromatography
(SiO.sub.2, EtOAc:hexane 1:3) to afford
5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (0.11 g,
31%), mp=157-158.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H),
7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14 Hz), 10.4
(s, 1H); MS (EI) m/z 266 (M-H).sup.-; CHN calculated for
C.sub.17H.sub.17NO.sub.2: C, 76.38; H, 6.41; N, 5.24; Found: C,
76.02; H, 6.49; N, 5.02.
[0346] The title compound was prepared from
5-(3-methoxy-phenyl)-3,3-dimet- hyl-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.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 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)
m/z 283 [M].sup.+.
EXAMPLE 20
3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenz-
onitrile
3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzoni-
trile
[0347] Prepared according to the procedure for Example 5: m.p.
205-206.degree. C. .sup.1H NMR (DMSO-d.sub.6) .delta. 10.47 (s,1H),
8.08-8.06 (dd, 1H), 7.89-7.85 (m, 1H), 7.65 (s, 1H), 7.54-7.49 (m,
1H), 7.43-7.40 (tt, 1H), 6.95-6.93 (d, 1H J=7.9 Hz), 1.97-1.83 (m,
2H), 1.69-1.55 (m, 8H); MS (EI) m/z 320 (M.sup.+).
[0348] The title compound was prepared from
3-(1,2-Dihydro-2-oxospiro[cycl-
ohexane-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.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 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, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.31
(d, 1H, J=9.0 Hz), 7.15 (d, 1H, J=8.1 Hz), 2.17-1.84 (m, 7H) and
1.60-1.54 (m, 3H); MS (EI) m/z 336 [M].sup.+.
EXAMPLE 21
5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-pyridineca-
rbonitrile
[0349] A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26
mmol), hexamethylditin (5.00 g, 15.26 mmol) and
tetrakis(triphenylphosphine)pall- adium(0) (0.20 g, 0.17 mmol) in
anhydrous dimethoxyethane (30 cm.sup.3) under N.sub.2 was heated
under reflux. After 16 h the mixture was concentrated and purified
by column chromatography (SiO.sub.2, EtOAc:hexane 5:95) to afford
3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%):
.sup.1H NMR (CDCl.sub.3) .delta. 0.40 (s, 9H), 8.01 (m, 1H), 8.80
(m, 2H); MS ((+) APCI) m/z 269 (M+H).sup.+.
[0350] 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
cm.sup.3) was heated under reflux. After 16 h the mixture was
cooled, partitioned between EtOAc and water, the aqueous layer was
re-extracted with EtOAc (.times.2), the combined organic extracts
were washed with water, dried (MgSO.sub.4) and evaporated. The
residue was subjected to column chromatography (SiO.sub.2,
EtOAc:hexane, 1:2) and then further purified by preparative LC
(Primesphere C18, 10 micron, 50.times.250 mm, MeCN: H.sub.2O 1:1,
100 cm.sup.3/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.degree. C., .sup.1H NMR (CDCl.sub.3) .delta. 1.68-1.89 (m,
6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8 Hz), 7.49 (dd, 1H, J=8, 2
Hz), 7.66 (d, 1H, J=2 Hz), 8.15 (t, 1H, J=2 Hz), 8.39 (s, 1H, br),
8.89 (d, 1H, J=2 Hz), 9.06 (d, 1H, J=2 Hz); MS ((+)-ESI) m/z 304
(M+H).sup.+; Anal. C.sub.19H.sub.17N.sub.3O CHN.
[0351] The title compound was prepared from
3-(1',2'-Dihydro-2'-oxospiro[c-
yclohexane-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.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 9.56 (br s, 1H), 9.03 (d, 1H, J=1.9 Hz), 8.87 (d, 1H, J=1.4
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].sup.-.
EXAMPLE 22
5-(3,4-difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0352]
5'-(3,5-Difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-on-
e: Prepared according to the procedure for Example 5: mp
180-183.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 8.35 (s, 1H),
7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H, J=6.2, 2.0 Hz), 7.10-7.03 (m,
2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H, J=4.3, 2.3 Hz),
2.05-1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H].sup.+.
[0353] The title compound was prepared from
5'-(3,5-difluorophenyl)spiro[c-
yclohexane-1,3'-[3H]indol]-2'(1'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.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 10.05 (br s,
1H), 7.83 (s, 1H), 7.44 (dd, 1H, J=8.1 and 1.4 Hz), 7.38-7.30 (m,
1H), 7.26-7.19 (m, 3H), 7.11 (d, 1H, J=8.1 Hz), 2.17-1.82 (m, 7H)
and 1.66-1.53 (m, 3H); MS ((-)-APCI) m/z 328 [M-H].sup.-.
EXAMPLE 23
5-(5-chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0354]
5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one:
Prepared according to the procedure for Example 5: mp.
191-192.degree. C., .sup.1H NMR (CDCl.sub.3) .delta. 1.6-2.1 (m,
10H), 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); .sup.13C-NMR
(THF-d.sub.8) .delta. 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).sup.+; Anal.
(C.sub.17H.sub.16ClNOS)C, H, N.
[0355] 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
(0.041 g) as a yellow solid: mp. 231-232.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 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
Hz), 2.15-1.84 (m, 7H) and 1.59-1.52 (m, 3H); MS ((-)-APCI) m/z
332/334 [M-H].sup.-.
EXAMPLE 24
5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-furancarbo-
nitrile
5-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-3-furancar-
bonitrile
[0356] Prepared according to the procedure for Example 5: m.p.
243-245.degree. C. .sup.1H-NMR (DMSO-d.sub.6) .delta. 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.sup.+).
[0357] The title compound was prepared from
5-(1',2'-dihydro-2'-oxospiro[c-
yclohexane-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.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.
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].sup.-.
EXAMPLE 25
5-(3-chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0358]
5'-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'-
H)-one. Prepared according to the procedure for Example 5: mp
188-189.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 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, 10H); MS ((+)APCI) m/z 330
[M+H].sup.+.
[0359] The title compound was prepared from
5'-3-Chloro-4-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 (0.036 g) as an off
white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 12.74 (br s, 1H),
7.92 (d, 1H, J=1.4 Hz), 7.87 (dd, 1H, J=7.1 and 2.3 Hz), 7.70-7.65
(m, 1H), 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) m/z 344/346 [M-H].sup.-.
EXAMPLE 26
5-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
5'-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
[0360] Prepared according to the procedure for Example 5: mp
178-180.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 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,
1H), 7.15 (dq, 1H, J=5.7, 1.7, 0.7 Hz), 7.06 (dq, 1H, J=4.2, 1.9,
0.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 2.05-1.64 (m, 10H); MS ((-)ESI)
[M-H].sup.- @m/z 328.
[0361] The title compound was prepared from
5'-(3-chloro-5-fluorophenyl)sp-
iro[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:
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.76 (br s, 1H), 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].sup.-.
EXAMPLE 27
5-(3,5-difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
5'-(3,5-Difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
[0362] Prepared according to the procedure for Example 5: mp
180-183.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 8.35 (s, 1H),
7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H, J=6.2, 2.0 Hz), 7.10-7.03 (m,
2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H, J=4.3, 2.3 Hz),
2.05-1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H].sup.+.
[0363] The title compound was prepared from
5'-(3,5-difluorophenyl)spiro[c-
yclohexane-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: .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-.
EXAMPLE 28
5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-t-
hiophenecarbonitrile
[0364]
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-bo- ronic 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.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
10.56 (s,1H), 7.93 (s, 1H) 7.52-7.51 (d, 1H, J=1.5 Hz), 7.33-7.29
(dd, 1H, 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].sup.+. IR (KBr) 1620, 1700, 2200. Anal. calc. for
C.sub.21H.sub.22N.sub.2OS.1/2H.sub.2.de- gree. C., 70.2; H, 6.39;
N, 7.79. Observed. C, 70.67; H, 6.34; N, 7.62.
[0365] The title compound was prepared from
5-(1,2-dihydro-2-oxospiro[cycl-
ohexane-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: .sup.1H NMR (DMSO-d.sub.6) .delta.
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) m/z 365 [M-H].sup.-.
EXAMPLE 29
5-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0366]
5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-on-
e: Prepared from
(2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-y-
l)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.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 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, 1H, J=8.68, 1.76 Hz), 7.86 (d, 1H, J=1.98 Hz), 7.92 (dd, 1H,
J=13.4, 1.76 Hz), 8.18 (t, 1H, J=8.46 Hz) and 10.52 (s, 1H); MS
(EI) m/z=340 (M.sup.+).
[0367] The title compound was prepared from
5-(3-fluoro-4-nitrophenyl)spir-
o[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:
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.82 (br s, 1H), 8.21 (t, 1H,
J=8.4 Hz), 8.07 (d, 1H, J=1 Hz), 7.98 (dd, 1H, J=13.1 Hz), 7.79
(dt, 1H, 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].sup.-.
EXAMPLE 30
4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbo-
nitrile
[0368]
4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furanc-
arbonitrile: 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 cm.sup.3) was stirred under
N.sub.2 for 20 minutes. To this mixture was then added
(spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-on- e-5-yl)boronic acid
(1.6 g, 6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) in water (5
cm.sup.3). The solution was brought to reflux for 18 hours and then
cooled to room temperature, poured into 2N NaOH and extracted with
EtOAc (.times.3). The combined extracts were washed with water,
brine, dried (MgSO.sub.4), and evaporated. The residue was purified
by column chromatography (SiO.sub.2, EtOAc, hexane) to afford the
product (0.45 g, 36%) as an off-white solid. mp: 240-242.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 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, 10H); MS (EI) M.sup.+ @ m/z 292.
[0369] The title compound was prepared from
4-(1,2-dihydro-2-oxospiro[cycl-
ohexane-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: .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-.
EXAMPLE 31
5"-(3-chlorophenyl)spiro[cyclobutane-1,3"-[3H]indole]-2"(1"H)-thione
[0370] 5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one: To a
stirred solution of spiro[cyclobutane-1,3'-[3H]indol]-2'(1'H)-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
stirring 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.degree. C. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.15-2.41 (m, 6H), 6.74 (d, 1H,
J=8.2 Hz), 7.33 (dd, 1H, J=2, 8.2 Hz), 7.75 (d, 1H, J=2 Hz), 10.36
(bs, 1H). MS (EI) m/z 251 [M.sup.+]. Anal. Calcd for C.sub.11
H.sub.10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 51.98; H, 4.24;
N, 5.42.
[0371] 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.degree. C. for 3 h and allowed to cool. The reaction mixture
was poured into water (100 mL) and extracted with ethyl acetate
(3.times.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.times.250 mm; 35% Water/65%
AcCN; 254NM; AMB. temp.) to give 5-(3-chlorophenyl)spiro[cyclob-
utane-1,3-[3H]indole]-2(1H)-one (200 mg, 35%) as a white powder, mp
199.5-201.degree. C. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
2.21-2.28m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H, J=8.1 Hz), 7.37
(`d`, 1H), 7.44-7.52 (m, 2H), 7.65 (bd, 1H, J=7.8 Hz), 7.76 (bs,
1H), 7.92 (bs, 1H), 10.35 (s, 1H). MS (EI) m/z 283 [M.sup.+]. Anal.
Calcd for C.sub.17H.sub.14ClNO: C, 71.96; H, 4.97; N, 4.94. Found:
C, 70.75; H, 5.07; N, 4.68.
[0372] The title compound was prepared from
5-(3-Chlorophenyl)spiro[cyclob- utane-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: .sup.1H NMR (DMSO-d.sub.6) .delta.
12.58 (br s, 1H), 8.07 (d, 1H, J=1.5 Hz), 7.82 (t, 1H, J=1.7 Hz),
7.70 (d, 1H, J=7.74 Hz), 7.60 (dd, 1H, J=8.12 and 1.71 Hz), 7.49
(t, 1H, J=7.9 Hz), 7.41 (d, 1H, J=8.32 Hz), 7.05 (d, 1H, J=8.14 Hz)
and 2.57-2.27 (m, 6H); MS ((-)-APCI) m/z 298/300 [M-H].sup.-.
EXAMPLE 32
5"-(2-chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione
[0373] The title compound was prepared from
5"-(2-Chlorophenyl)spiro[cyclo-
hexane-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:
.sup.1H NMR (DMSO-d.sub.6) .delta. 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) m/z 326/328 [M-H].sup.-.
EXAMPLE 33
5"-(4-chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione
[0374] The title compound was prepared from
5-(4-chlorophenyl)spiro[cycloh- exane-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: .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-.
EXAMPLE 34
5-(1",2"-dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-4-methy-
l-2-thiophenecarbonitrile
[0375] 5-Bromo-4-methyl-2-thiophene carboxaldehyde: To a solution
of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was
added at -40.degree. 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.degree. C. under nitrogen for 30 minutes, cooled to
-78.degree. C. and treated dropwise with a solution of
2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450
mL). The reaction solution was stirred at -78.degree. 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 (1 L). The solution was extracted
with ethyl acetate (3.times.450 mL) and the extracts washed with
water, brine and dried (MgSO.sub.4). After removal of solvent in
vacuo, the title compound was obtained as a white solid (46 g,
88.3%). A sample of the product was crystallized from hexane: mp
63-65.degree. C.; IR (KBr) 1654 cm.sup.-1. .sup.1H-NMR (CDCl.sub.3)
.delta. 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z
204/206 (M.sup.+). Anal. Calc. For C.sub.6H.sub.5BrOS: C, 35.14; H,
2.46. Found: C, 35.00; H, 2.44.
[0376] 5-Bromo-4-methyl-2-thiophenecarbonitrile: Prepared from
5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure of
Example 5. White solid: mp 4042.degree. C.; IR (KBr) 2200
cm.sup.-1; .sup.1H-NMR (CDCl.sub.3) .delta. 7.29 (s, 1H), 2.21 (s,
3H). MS (EI) m/z 201/203 (M.sup.+, 98%/100%); Anal. Calc. For
C.sub.6H.sub.4BrNS: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H,
2.14; N, 6.76.
[0377] Prepared according to the procedure for Example 5 using
(2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3'-[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.degree. C. .sup.1H NMR (DMSO-d.sub.6) .delta. 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) m/z 282 (M).sup.+; Anal. C.sub.16H.sub.14N.sub.2OS.
[0378] The title compound was prepared from
5-(3,3-dimethyl-2-oxo-2,3-dihy- dro-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 (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography
(SiO.sub.2, EtOAc-hexane gradient elution) to afford the product
(0.25 g, 0.73 mmol, 30%) as an orange solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.82 (br s, 1H), 7.88 (s, 1H), 7.82 (d, 1H,
J=2 Hz), 7.49 (dd, 1H, J=8.1, 1.6 Hz), 7.18 (d, 1H, J=8.1 Hz),
1.99-1.80 (m, 7H) and 1.40-1.36 (m, 3H); MS ((-)-APCI) m/z 321
[M-H].sup.-.
EXAMPLE 35
5-(1",2"-dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-2-thiop-
henecarbonitrile
[0379] 5-Bromo-2-thiophenecarbonitrile: A mixture of
5-bromo-2-thiophenecarboxaldehyde (96.0 g, 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 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 (1.4 L)
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 (2.times.30 mL), water
(2.times.30 mL), brine (20 mL), and dried (MgSO.sub.4). 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
(31.5 g combined, 58%). IR (film) 2200 cm.sup.-1. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H,
J=4.0 Hz); MS (EI) m/z 187 (M.sup.+, 98%) 189(M.sup.+, 100%).
[0380]
5-(2'-Oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'yl-2-thi-
ophenecarbonitrile was prepared according to the procedure for
Example 5 using 5-bromo-2-thiophenecarbonitrile and
(2'-oxo-2',3'-dihydrospiro[cycl-
ohexane-1,3'-[3H]indol]-5'-yl)boronic acid: mp. 225-228.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.63 (m, 8H), 1.90 (m, 2H) 6.91
(d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H,
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 ((+)APCI) m/z 309 [M+H].sup.+.
[0381] The title compound was prepared from
5-(2'-oxo-2',3'-dihydrospiro[c-
yclohexane-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 (MgSO.sub.4) and evaporated. The residue
was purified by column chromatography (SiO.sub.2, EtOAc-hexane
gradient elution) to afford the title compound (0.215 g) as an
orange solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-.
EXAMPLE 36
5"-(3-fluorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione
[0382]
5'-(3-Fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one:
Prepared according to the procedure for Example 5: mp
171-172.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 8.43 (s, 1H),
7.62 (d, 1H, J=1.8 Hz), 7.42 (dt, 1H, J=6.2, 2.0 Hz), 7.39-7.37 (m,
1H), 7.33 (dt, 1H, J=5.1, 1.3 Hz), 7.26 (dq, 1H, J=5.9, 2.1 Hz),
7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H); MS ((+)APCI) m/z 296
[M+H].sup.+.
[0383] The title compound was prepared from
5'-(3-fluorophenyl)spiro[cyclo- hexane-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 (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography
(SiO.sub.2, EtOAc-hexane gradient elution) to afford the product
(0.42 g) as an off white solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
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].sup.-.
EXAMPLE 37
5-(3-hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0384]
5'-(3-Hydroxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one:
Prepared according to the procedure for example 5: nip.
213-216.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 1.60-1.96 (m,
10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8 Hz), 7.01-7.04 (m, 2H),
7.23 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8 Hz), 7.61 (s, 1H), 8.91
(s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) m/z 294
[M+H].sup.+.
[0385] 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: .sup.1H NMR (CDCl.sub.3)
.delta. 9.59 (br s, 1H), 7.89 (s, 1H), 7.49 (dd, 1H, J=8.1 and 1.5
Hz), 7.33 (t, 1H, 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].sup.-.
EXAMPLE 38
5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione
[0386] A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml)
under N.sub.2 was cooled to -25.degree. C. and treated drop wise
with n-butyl lithium (2.5M 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 NH.sub.4Cl solution, extracted with EtOAc (2.times.)
and the combined organic layers were washed with dil. HCl, water,
brine, dried (MgSO.sub.4) 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.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 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, 1H, J=7.69, 0.45 Hz), 6.93 (dt,
1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS
(ESI) m/z 270 [M+H].
[0387] A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF
(200 ml) under N.sub.2 was cooled to -25.degree. 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 NH.sub.4Cl solution, extracted
with EtOAc (2.times.) and the combined organic layers were washed
with dil. HCl, water, brine, dried (MgSO.sub.4) and concentrated.
The residual oil was triturated with hexane to afford
3,3-diethylindol-2-one (9 g, 45%), m.p. 156-159.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 10.44 (s,1H), 7.70-7.69 (t,1H),
7.62-7.59 (m, 1H), 7.58 (d,1H J=1.7 Hz), 7.53-7.50 (m, 1H),
7.45-7.41 (t,1H), 7.36-7.35 (m,1H), 7.34-7.33 (m,1H), 6.91-6.89
(d,1H J=8.2 Hz), 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).
[0388] 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 (2.times.); the
combined organic layers were washed with water, sat. sodium
hydrogen carbonate solution, then brine, dried (MgSO.sub.4) 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.degree. C.; .sup.1H-NMR (DMSO-d.sub.6) .delta. 10.45 (s,
1H), 7.41-7.40(d, 1H, J=2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d,
1H J=8.2 Hz), 1.78-1.65 (m, 4H), 0.50-0.46 (m, 6H); MS (-ESI) m/z
266/268 (M-H).
[0389] 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 (2.times.). The combined organic extracts were washed with
water, then brine, dried (MgSO.sub.4) and evaporated. The residue
was purified by column chromatography (SiO.sub.2, EtOAc:hexane 1:3)
to afford 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one
compound (0.8 g, 27%), m.p. 195-197.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6) .delta. 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,
J=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) m/z 300/302 (M-H).
[0390] The title compound was prepared from
5-(3-chloro-phenyl)-3,3-diethy- l-1,3-dihydro-indol-2-one compound
(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: .sup.1H NMR (DMSO-d.sub.6) .delta.
12.73 (br s, 1H), 7.77 (t, 1H, J=1.8 Hz), 7.75 (d, 1H, J=1.6 Hz),
7.68-7.62 (m, 2H), 7.48 (t, 1H, J=7.9 Hz), 7.40 (d; 1H, J=8.3 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) m/z 314/316 [M-H].sup.-.
EXAMPLE 39
5-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1-
H)-thione
[0391]
5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]ind-
ol]-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-triflu- oromethylbenzene (2 g, 8 mmol) as
described for Example 5, to afford the title compound (0.87 g, 30%)
as a solid: mp. 222.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, J=8.13 Hz), 7.51
(dd, 1H, J=8.13, 1.76 Hz), 7.55 (dd, 1H, J=10.54, 9.01 Hz) 7.72 (d,
1H, J=1.76 Hz), 7.90 (dd, 1H, J=7.03, 2.20 Hz), 7.98 (m, 1H) and
10.39 (s, 1H); MS (EI) m/z 363 (M.sup.+).
[0392] 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: .sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-.
EXAMPLE 40
4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenz-
onitrile
[0393] The title compound was prepared from
4-(1,2-dihydro-2-oxospiro[cycl-
ohexane-1,3-[3H]indol]-5-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: .sup.1H NMR (DMSO-d.sub.6) .delta. 12.80 (br s,
1H), 8.04 (d, 1H, J=1.3 Hz), 7.98 (t, 1H, J=7.5 Hz), 7.92 (dd, 1H,
J=11.3 and 1.3 Hz), 7.76 (d, 2H, J=8.0 Hz), 7.18 (d, 1H, J=8.2 Hz),
1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H); MS ((-)-APCI) m/z 335
[M-H].sup.-.
EXAMPLE 41
5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)
4-n-butyl-2-thiophenecarbonitrile
[0394] 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[cyclohex- ane-1,3-[3H]indol]-5-yl)
4-n-butyl-2-thiophenecarbonitrile (1 g, 54%), m.p. 130-132.degree.
C. .sup.1H NMR (DMSO-.sub.6) .delta. 10.56 (s, 1H), 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, 1H, J=8.0 Hz), 2.64-2.59 (t, 2H), 1.99-1.86 (m, 2H),
1.70-1.50 (m, 11H), 1.32-1.22 (m, 2H), 0.86-0.82 (t, 3H); MS (APCI
(+)) m/z 365 [M+H].sup.+; IR (KBr) 1620, 1700, 2200 cm.sup.-1;
Anal. calc. C.sub.22H.sub.24N.sub.2OS.1/4H.sub.2O. C, 71.61; H,
6.69; N 7.59. Observed C, 71.13; H, 6.61; N, 6.91.
[0395] The title compound was prepared from
5-(1,2-dihydro-2-oxospiro[cycl- ohexane-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:
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.83 (br s, 1H), 7.95 (s, 1H),
7.77 (s, 1H), 7.44 (d, 1H, J=8.1 Hz), 7.18 (d, 1H, J=8.1 Hz), 2.63
(t, 1H, J=8.0 Hz), 1.99-1.77 (m, 7H), 1.60-1.50 (m, 2H), 1.39-1.35
(m, 3H), 1.29-1.22 (m, 2H) and 0.81 (t, 3H, J=7.3 Hz): MS
((-)-APCI) m/z 379 [M-H].sup.-.
EXAMPLE 42
5-(3-fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione
[0396] The title compound was prepared from
5-(3-Fluoro-5-methoxyphenyl)sp- iro
[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:
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.74 (br s, 1H), 7.90 (s, 1H),
7.63 (dd, 1H, J=8.1 and 1.2 Hz), 7.13 (d, 1H, J=8.1 Hz), 7.08 (d,
1H, J=10 Hz), 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].sup.-.
EXAMPLE 43
5-(3-chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'-[3H]indol]-2-amine
[0397] To a solution of
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indo-
le]-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
1 h, the reaction mixture was partitioned between water and EtOAc,
the organic layer was washed with brine, dried (MgSO.sub.4) 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:
[0398] 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.degree. C. After 1 h., 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 (MgSO.sub.4) 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: .sup.1H NMR
(CDCl.sub.3) .delta. 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, 10H); MS (ESI (+)) m/z
327/329 [M+H].sup.+.
EXAMPLE 44
N-(acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2"amine
[0399] 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 (catalytic amount) under a
nitrogen atmosphere. After 20 min., the reaction was evaporated and
the product purified by column chromatography (SiO.sub.2,
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%): .sup.1H NMR (CDCl.sub.3) .delta. 7.52-7.51 (m, 2H),
7.43-7.27 (m, 5H), 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].sup.+; C.sub.21H.sub.21ClN.sub.2O.sub.2.0.5H.sub.2O
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)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0400] Prepared according to the method for Example 42 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%):
.sup.1H NMR (DMSO-d.sub.6) .delta. 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].sup.-,
C.sub.19H.sub.19FN.sub.2O requires C, 73.53, H, 6.17, N, 9.03.
Found C, 73.33, H, 6.07, N, 8.83.
EXAMPLE 46
5'-(2-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0401] 5'-bromospiro{cyclohexane-1,3'-[3H]indol}-2'(1'H)-one
2'(O-benzyloxime).
5'-Bromo-2'-(methylthio)spiro[cyclohexane-1,3'-[3H]ind- ole] (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.degree. 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%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H),
6.71 (d, 1H, J=8.26 Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).
Procedure A
[0402]
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.times.100 mL). The combined organic layers were
dried (MgSO.sub.4), 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. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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)) m/z 399 (M-H).sup.-.
Procedure B
[0403] 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.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.45-1.73 (8H, m) 1.96-2.00 (2H, q) 6.83 (1H,
d, J=7.9 Hz) 7.23-7.50 (6H, m) 9.42 (1H, s) 9.58 (1H, s); MS (ESI(+
ve)) m/z 311 (M+H).sup.+.
EXAMPLE 47
5'-(4-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0404]
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 45 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. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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).sup.-.
[0405] The product was synthesized using
5'-4-Fluorophenyl)-spiro[cyclohex- ane-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.degree. C.;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 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).sup.+.
EXAMPLE 48
5'-(3,4-difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0406]
5'-(3,4-Difluorophenyl)-spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-o-
ne 2'(O-benzyloxime). Prepared from
5'-bromospiro{cyclohexane-1,3'-[3H]ind- ol}-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 45 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. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.41-1.78
(8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.82 (1H, d) 7.28-7.46 (8H,
m) 7.58 (1H, q) 7.67-7.71 (1H, m) 9.61 (1H, s); MS (ESI(- ve)) m/z
417 (M-H).sup.-.
[0407] 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%), .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 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).sup.+.
EXAMPLE 49
5'-(3-methoxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0408]
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 45 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. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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 (10H,
m) 9.57 (1H, s); MS (ESI(- ve)) m/z 411 (M-H).sup.-.
[0409] Reaction of the last cited compound (0.80 g, 1.9 mmol)
according to Example 45 procedure B, afforded the title compound
(0.48 g, 1.4 mmol, 77%), as a white solid. Mp. 101-104.degree. C.;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 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).sup.+.
EXAMPLE 50
5'-(3-nitrophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0410]
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 45 procedure A.
Purification by flash silica gel chromatography (eluant:10:0.5
hexane:ethyl acetate) afforded the desired compound (0.60 g, 1.4
mmol, 55%) as a viscous oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 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).sup.-.
Procedure C
[0411] The last cited compound (0.54 g, 1.26 mmol) was dissolved in
dry methylene chloride (25 mL) and cooled to -78.degree. 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
(Na.sub.2SO.sub.4), 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.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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).sup.+.
EXAMPLE 51
5'-(3-cyanophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one
Oxime
[0412]
3-[Spiro[cyclohexane-1,3'-[3H]indol]-1'H)-one-2'-(O-benzyloxime)]be-
nzonitrile [3H]indol]-5-yl]benzonitrile. 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 45 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. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.41-1.81 (8H, m) 1.96-2.03 (2H, q) 5.01 (2H, s) 6.86 (1H,
d) 7.28-7.33 (9H, m) 7.95-7.97 (1H, d) 8.12 (1H, s) 9.65 (1H, s);
MS (ESI(- ve)) m/z 406 (M-H).sup.-.
[0413] Reaction of the last cited compound (0.17 g, 0.43 mmol) and
boron tribromide (1.2 mL, 1.2 mmol) according to Example 49
procedure C afforded the title compound (0.06 g, 0.2 mmol, 47%) as
a white solid, Mp. 198-200.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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 (1H, dd) 8.10 (1H, s) 9.42 (1H, s)
9.59 (1H, s); (ESI(+ ve)) m/z 318 (M+H).sup.+.
EXAMPLE 52
3-[1',2'-dihydro-2'-(hydroxyimino)spiro[cyclohexane-1,3'-[3H]indol]-5'yl]--
5-fluorobenzonitrile
[0414] 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 PdCl.sub.2
(dppf) (0.2 g) and the reaction was heated to 80.degree. 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), PdCl.sub.2 (dppf) (0.05 g) and
sodium carbonate (1.30 g, 12.5 mmol) were added and heating at
80.degree. C. was continued. After 8 h., the reaction was cooled
and partitioned between water and ethyl acetate, the organic layer
was washed with brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by column chromatography (SiO.sub.2,
EtOAc:hexane 1:20) to give the desired product (0.14 g, 0.33 mmol,
66%).
[0415] Reaction of the last cited compound (0.14 g, 0.33 mmol) and
boron tribromide (1.0 ml, 1.0 mmol) according to Example 49
procedure C afforded the title compound (0.019 g, 0.05 mmol, 17%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.65 (s, 1H), 9.49 (s,
1H), 8.04 (m, 1H), 7.89 (dt, 1H, J=10.5 and 2 Hz), 7.72-7.68 (m,
2H), 7.54 (d, 1H, 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).sup.+.
EXAMPLE 53
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)-4-methyl-2-t-
hiophenecarbonitrile
[0416] 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 (O) (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 product (2.8 g, 0.01
mmol, 67%) as a runny oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).
[0417] 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.
[0418] 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.degree. 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 (Na.sub.2SO.sub.4), 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.degree. C.;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 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,
dd, J=1.7 Hz), 7.38 (1H, m) 7.82 (1H, m) 9.51 (1H, m) 9.66 (1H, m);
MS (ESI(+ ve)) m/z 338 (M+H).sup.+.
EXAMPLE 54
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyimino)-5'-yl)-2-thiophenec-
arbonitrile
[0419] 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.degree. C. was added, dropwise, lithium
hexamethyldisilazide (1M in THF, 10 ml, 10 mmol). After 30 min.,
the reaction was quenched with 1N HCl, then extracted with ethyl
acetate, the organic layer was washed with water, dried
(Na.sub.2SO.sub.4) and evaporated to the product (1.25 g, 8.17
mmol, 89%) which was used without further purification: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 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).sup.-.
[0420] 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 45
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).sup.-.
[0421] Reaction of the last cited compound (0.60 g, 1.45 mmol) and
boron tribromide (1M in dichloromethane, 5 mL, 5 mmol) according to
Example 49 procedure C afforded the title compound (0.036 g, 0.11
mmol, 8%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+.
EXAMPLE 55
4-(spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyimino)-5'-yl)-2-thiophenec-
arbonitrile
[0422] 4-(Trimethylstannyl)-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.sup.3)
was heated under reflux for 14 h then cooled to RT. The reaction
mixture was absorbed onto florisil and purified by column
chromatography (SiO.sub.2, methylene chloride: hexane 1:9) to
afford the subtitled compound (1.04 g, 3.8 mmol, 90%) as a clear
viscous oil: .sup.1H NMR (CDCl.sub.3) .delta. 0.35 (s, 9H), 7.56
(d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).
[0423] 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-thiophe- necarbonitrile (1.48 g, 5.44 mmol),
triphenylarsine (330 mg) in dry dimethoxy ethane (20 ml), under 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 (SiO.sub.2, EtOAc:hexane,
gradient elution) to afford the desired product (0.61 g, 1.47 mmol,
56%).
[0424] 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 49 procedure C afforded the title compound
(0.084 g, 0.26 mmol, 18%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H),
7.65 (s, 1H), 7.48 (dd, 1H, J=8.1 and 0.9 Hz), 6.76 (d, 1H, 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).sup.+.
EXAMPLE 56
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyimino)-5'-yl)-1H-pyrrole-1-
-methyl-2-carbonitrile
[0425]
2-{5'[spiro[cyclohexane-1,3'-[3H]indol]-(1'H)-one-2'(O-benzyloxime)-
]}-1H-pyrrole-1-carboxylic acid, tert-butyl ester. A solution of
5'-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.degree. C. for 6 hours and allowed to cool. The reaction mixture
was poured into water and extracted with ethyl acetate (3.times.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. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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).
[0426]
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. To a solution of
2-{5'[spiro[cyclohexane-1,3'-[3H]indol]-(1'H)-one-
-2'(O-benzyloxime)]}-1H-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.degree. 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.
[0427] To a solution of
5'-(1-tert-Butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyc-
lohexane-1,3'-[3H]indol]-2'-(1'H)one-2'-(O-benzyloxime)-1'-carboxylic
acid, tert-butyl ester (9.0 g, 15.76 mmol) in THF (anhydrous, 75
mL) at -78.degree. C. was added chlorosulfonyl isocyanate (1.55 mL,
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.times.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-butoxycarbo-
nyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)one-2'(O-benzy-
loxime)-1'-carboxylic acid, tert-butyl ester (7.6 g, 82%) as a
white powder. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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 Hz), 7.25-1.46 (m, 10H).
[0428]
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. To a
solution of
5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cycloh-
exane-1,3'-[3H]indol]-2'(1'H)one-2'(O-benzyloxime)-1'-carboxylic
acid, tert-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.degree. 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%).
.sup.1H NMR (DMSO, 500 MHz) .delta. 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=0.8 Hz),
6.98-6.99 (d, 1H, J=0.7 Hz), 7.29-7.37 (m, 1H), 7.35 (m, 2H), 7.42
(m, 3H), 7.63 (dd, 1H, J=1.8, 0.3 Hz), 7.76 (d, 1H, J=0.4 Hz).
[0429]
5'-5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol-
]-2'-(O-benzyloxime)-1'-carboxylic acid, tert-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 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. .sup.1H NMR (DMSO,
300 MHz) .delta. 1.38 (s, 9H), 1.62-1.98 (m, 10H), 3.71 (s, 3H),
5.08 (s, 2H), 6.34 (d, 1H, J=4.1 Hz), 7.03 (d, 1H, J=3.99 Hz),
7.30-7.53 (m, 8H).
[0430]
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-1H-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.degree. 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%). .sup.1H NMR (DMSO-d.sub.6,300 MHz) .delta.
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 Hz), 6.85 (d, 1H, J=8.03 Hz), 7.00 (d, 1H,
J=4.08 Hz), 7.2-7.44 (m, 7H), 9.7 (s, 1H).
[0431] To
5-{5'-spiro[cyclohexane-1,3'-[3H]indol]-(1'H)-one-2'-(O-benzylox-
ime)}-1H-pyrrole-1-methyl-2-carbonitrile (4.36 g, 10.6 mmol) in
methylene chloride (50 mL) was added 1M boron tribromide (35 mL, in
methylene chloride) at -78.degree. 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 (2.times.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 (1.35 g, 40%) as a white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 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).
EXAMPLE 57
5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole-2-
-carbonitrile
[0432]
5-(spiro[cyclohexane-1,3'-[3]indole]-2'(1H)-(O-benzyloxime))-1H-pyr-
role-2-carbonitrile. Prepared from
5'-(5-Cyano-1H-pyrrol-2-yl)spiro[cycloh-
exane-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 2 mL 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%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. 1.44-1.50 (m, 1H), 1.61-1.70 (m, 7H), 1.94-1.99 (m, 2H),
5.0 (s, 2H), 6.55 (d, 1H, J=4 Hz), 6.79 (d, 1H, J=8.0 Hz), 6.95 (d,
1H, J=4 Hz), 7.27-7.31 (m, 1H), 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,
1H), 12.4 (s, 1H).
[0433] The title compound was prepared from
5-(spiro[cyclohexane-1,3'-[3]i-
ndole]-2'(1H)-(O-benyloxime))-1H-pyrrole-2-carbonitrile (0.325 g,
0.82 mmol) and 1M Boron tribromide (6 mL in methylene chloride),
following the procedure for
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'--
yl)-1H-pyrrole-1-methyl-2-carbonitrile, to obtain the product as an
off white solid (0.110 g, 0.326 mmol, 44%).
.sup.1H-NMR(DMSO-d.sub.6, 500 MHz) .delta. 1.46-1.5 (m, 1H),
1.62-1.71 (m, 7H), 1.95-2.05 (m, 2H), 6.55 (d, 1H, J=4.0 Hz), 6.75
(d, 1H, J=8.0 Hz), 6.94 (d,1H, J=3.47 Hz), 7.45 (dd, 1H, J=8.1,
1.73 Hz), 7.63 (d, 1H, J=1.73 Hz), 9.42 (s, 1H), 9.59 (s, 1H),
12.39 (s, 1H).
EXAMPLE 58
4-(spiro[cyclohexane-1,3'-[3H]indole]-2'(acetoxyimino)-5'-yl)-2-thiophenec-
arbonitrile
[0434] To a solution of
4-(Spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyim-
ino)-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 3 h.,
the mixture was diluted with dichloromethane, washed with water,
dil. Hydrochloric acid, water, dried (MgSO.sub.4), 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].sup.+.
EXAMPLE 59
3-fluoro-N'-hydroxy-5-[2'-(hydroxyamino)spiro[cyclohexane-1,3'-[3H]indol]--
5'-yl]benzenecarboximidamide
[0435]
5'-(3-Cyano-5-fluorophenyl)-2-(methylthio)spiro[cyclohexane-1,3'-[3-
H]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 42 to afford the desired
product (0.316 g, 0.90 mmol, 67%): .sup.1H NMR (DMSO, 300 MHz)
.delta. 7.74 (d, 1H, J=1.7 Hz), 7.68 (t, 1H, J=1.4 Hz), 7.58 (d,
1H, J=8.0 Hz), 7.54 (t, 1H, J=2.3 Hz), 7.50 (dd, 1H, 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).sup.+.
[0436] To a solution of the last cited product (0.30 g, 0.88 mmol)
in DMSO (10 ml) was added hydroxylamine (50% aqueous solution, 1
ml), and the reaction was heated to 120.degree. C. After 1 h., the
mixture was cooled, partitioned between saturated aqueous ammonium
chloride and ethylacetate. The organic layer was washed with water,
brine, dried (MgSO.sub.4), and evaporated. The residue was purified
by column chromatography (SiO.sub.2, 5% MeOH in dichloromethane) to
afford the title compound (0.079 g, 0.23 mmol, 26%) as a white
foam: .sup.1H NMR (DMSO, 300 MHz) .delta. 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).sup.+.
EXAMPLE 60
N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'(Hydroxyimino)-5'-YL)-4-
-methyl-2-thiophenecarboximidamide
[0437]
4-Methyl-5-(spiro[cyclohexane-1,3'[3H]indol]2'-(methylthio)-5'-yl)--
2-thiophenecarbonitrile. To potassium tert-butoxide (0.32 g, 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) .delta. 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).
[0438] To
4-methyl-5-(spiro[cyclohexane-1,3'[3H]indol]2'-(methylthio)-5'-y-
l)-2-thiophenecarbonitrile (0.450 g, 1.3 mmol) in DMSO (1 mL) was
added hydroxylamine hydrochloride (2 mL, 50% sol. in water) and
heated to 100.degree. C. for 2.5 hours. Water was 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-d.sub.6, 500 MHz) .delta. 1.4-1.74 (m, 8H), 1.94-2.4
(m, 2H), 2.54 (s, 3H), 5.8 (s, 1H), 6.79 (d, 1H, J=8.0 Hz), 7.16
(dd, 1H, J=8.12, 1.83 Hz), 7.39 (m, 2H), 9.42 (s, 1H), 9.56 (s,
1H), 9.58 (s, 1H).
EXAMPLE 61
N'-hydroxy-4-(spiro[cyclohexane-1,3'-[3H]indole]-2'(hydroxyimino)-5'-yl-2--
thiophenecarboximidamide
[0439]
4-(Spiro[cyclohexane-1,3'-[3H]indol]-2'-(methylthio)-5'-yl]-2-thiop-
henecarbonitrile (0.077 g, 0.237 mmol) was reacted with 50%
solution of hydroxylamine (1 mL) following the procedure for
Example 59 to afford the title compound (0.016 g, 0.044 mmol, 20%).
MS (ESI, (+VE)) m/z 357 [M+H].sup.+.
EXAMPLE 62
N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-(hydroxyimino)-5'-yl)-2-
-thiophenecarboximidamide
[0440] 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 59, to afford the product (0.200 g, 0.56
mmol, 56%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.45-1.75
(m, 8H), 1.97-2.06 (m, 2H), 5.89 (s, 1H), 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, 1H, J=1.95 Hz), 9.44 (s,1H), 9.58 (s, 1H), 9.6
(s, 1H).
EXAMPLE 63
5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanamide
[0441]
5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'-amine. To a
turbid solution of
5'-(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.degree. 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)
to afford 0.310 g (65%) of the desired product as a white solid.
Mp. 118-120.degree. C. .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6)
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).sup.+.
[0442]
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.degree. 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(50 mL) and the layers were
separated. The organic layer was dried over Na.sub.2SO.sub.4,
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. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.58 (m, 2H), 1.63 (s, 9H, Boc),
1.77-1.79 (, 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).sup.+.
[0443]
1'-tert-Butoxycarbonyl-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3-
H]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.degree. C. The yellow solution was heated to 40.degree. C. for 16
h. Work-up included pouring the reaction solution into 0.1 N
NaHCO.sub.3 (50 mL) and extracting with ethyl acetate (3.times.50
mL). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, 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.degree. C. (dec.). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 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=8 Hz), 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).sup.-.
[0444] Other desirable compounds, which can be made according to
the methods described herein, include
5'-(3-Cyano-5-fluorophenyl)spiro[cycloh-
exane-1,3'-[3H]indol]-2'-ylidenecyanamide,
5'-(5-Cyano-1H-pyrrol-2-yl)spir-
o[cyclohexane-1,3'-[3H]indol]-2-ylidenecyanamide,
5'-(5-Cyano-1-methyl-1H--
pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-ylidenecyanamide,
5'-(5-Cyanothien-2-yl)
spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidenecyana- mide,
5'-(5-Cyano-3-methyl-thien-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2'-
-ylidenecyanamide,
5'-(5-Cyano-thien-3-yl)spiro[cyclohexane-1,3'-[3H]indol-
]-2'-ylidenecyanamide,
3-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(cyanometh-
ylene)-5'-yl)-5-fluorobenzonitrile,
5-(spiro[cyclohexane-1,3'-[3H]indole]--
2'-(Cyanomethylene)-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile,
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(Cyanomethylene)-5'-yl)-thiophen-
e-2-carbonitrile,
5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(Cyanomethylene-
)-5'-yl)-4-methyl-thiophene-2-carbonitrile,
4-(spiro[cyclohexane-1,3'-[3H]-
indole]-2'-(Cyanomethylene)-5'-yl)-thiophene-2-carbonitrile.
[0445] 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.
* * * * *