U.S. patent application number 12/760666 was filed with the patent office on 2010-08-12 for aryl sulfonamides useful for modulation of the progesterone receptor.
This patent application is currently assigned to Wyeth LLC. Invention is credited to Andrew Fensome, Michael Anthony Marella, Casey Cameron McComas.
Application Number | 20100204228 12/760666 |
Document ID | / |
Family ID | 39719009 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204228 |
Kind Code |
A1 |
McComas; Casey Cameron ; et
al. |
August 12, 2010 |
Aryl Sulfonamides Useful for Modulation of the Progesterone
Receptor
Abstract
In one embodiment, compounds of the following structure are
described, wherein R.sub.1 to R.sub.7 are described herein. Also
provided are methods for preparing these compounds and methods of
contraception; treating or preventing fibroids; treating or
preventing uterine leiomyomata; treating or preventing
endometriosis, dysfunctional bleeding, and polycystic ovary
syndrome; treating or preventing hormone-dependent carcinomas;
providing hormone replacement therapy; stimulating food intake;
synchronizing estrus; and treating cycle-related symptoms using the
compounds described herein. ##STR00001##
Inventors: |
McComas; Casey Cameron;
(Phoenixville, PA) ; Fensome; Andrew; (Wayne,
PA) ; Marella; Michael Anthony; (Limerick,
PA) |
Correspondence
Address: |
HOWSON & HOWSON LLP / WYETH LLC
501 OFFICE CENTER DRIVE, SUITE 210
FORT WASHINGTON
PA
19034
US
|
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
39719009 |
Appl. No.: |
12/760666 |
Filed: |
April 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12041716 |
Mar 4, 2008 |
7723332 |
|
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12760666 |
|
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60905239 |
Mar 6, 2007 |
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Current U.S.
Class: |
514/235.5 ;
514/326; 514/422; 514/427; 544/141; 546/208; 548/518; 548/561 |
Current CPC
Class: |
A61P 5/24 20180101; A61P
25/22 20180101; C07D 207/34 20130101; C07D 417/10 20130101; A61P
15/00 20180101; A61P 35/00 20180101; A61P 25/00 20180101; A61P
15/18 20180101 |
Class at
Publication: |
514/235.5 ;
548/561; 514/427; 514/422; 548/518; 546/208; 514/326; 544/141 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 207/34 20060101 C07D207/34; A61K 31/40 20060101
A61K031/40; A61K 31/4025 20060101 A61K031/4025; C07D 403/12
20060101 C07D403/12; C07D 401/12 20060101 C07D401/12; A61K 31/454
20060101 A61K031/454; C07D 413/12 20060101 C07D413/12; A61P 15/18
20060101 A61P015/18; A61P 15/00 20060101 A61P015/00; A61P 5/24
20060101 A61P005/24; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method of contraception, treating or preventing fibroids,
uterine leiomyomata, endometriosis, dysfunctional bleeding,
polycystic ovary syndrome, or hormone-dependent carcinomas,
providing hormone replacement therapy, stimulating food intake,
synchronizing estrus, or treating cycle-related symptoms, said
method comprising administering to a mammal in need thereof a
compound of formula (I): ##STR00075## wherein: R.sub.1 and R.sub.2
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, heteroaryl, substituted heteroaryl,
heterocycle, substituted heterocycle, C.sub.3 to C.sub.6 alkenyl,
C.sub.3 to C.sub.6 substituted alkenyl, C.sub.3 to C.sub.6 alkynyl,
substituted C.sub.3 to C.sub.6 alkynyl,
--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q, O--C.sub.1 to C.sub.6
alkyl, O--C.sub.1 to C.sub.6 substituted alkyl, and
O--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q; or R.sub.1 and R.sub.2
may be taken together to form a ring of 4 to 8 ring atoms
containing in its backbone carbon atoms and 1 to 4 N, O, S, or
SO.sub.2, and where any C-atom or N-atom of said ring is optionally
substituted with C.sub.1 to C.sub.4 alkyl, F, or CF.sub.3; R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently selected from the
group consisting of H, halogen, CN, C.sub.1 to C.sub.6 alkyl,
substituted C.sub.1 to C.sub.6 alkyl,
--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q, C.sub.3 to C.sub.6
cycloalkyl, substituted C.sub.3 to C.sub.6 cycloalkyl, O--C.sub.1
to C.sub.6 alkyl, O--C.sub.1 to C.sub.6 substituted alkyl, OH,
NH.sub.2, NH--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q,
O--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q,
N--{(CH.sub.mX.sub.n).sub.nCH.sub.pX.sub.q}.sub.2, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocycle,
and substituted heterocycle; X is halogen; m and n are,
independently, 0 to 2, provided that m+n=2; p and q are,
independently, 0 to 3, provided that p+q=3; z is 0 to 10; R.sub.7
is 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.6
cycloalkyl, and substituted C.sub.3 to C.sub.6 cycloalkyl; or a
pharmaceutically acceptable salt, tautomer, metabolite or prodrug
thereof.
2. The method according to claim 1, wherein R.sub.7 is a branched
C.sub.3 to C.sub.6 alkyl.
3. The method according to claim 1, wherein R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are H.
4. The method according to claim 1, wherein R.sub.4 is H or
halogen.
5. The method according to claim 1, wherein R.sub.7 is C.sub.7 to
C.sub.6 alkyl.
6. The method according to claim 1, wherein R.sub.1 is H or C.sub.1
to C.sub.6 alkyl.
7. The method according to claim 1, wherein R.sub.2 is H, C.sub.1
to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.6 cycloalkyl, CF.sub.3, or CH.sub.2--C.sub.3 to C.sub.8
cycloalkyl.
8. The method according to claim 1, wherein R.sub.1 and R.sub.2 are
joined to form tetrahydropyrrole, pyrrolidine, piperidine,
tetrahydropyran, or pyrrole.
9. The method according to claim 1, wherein R.sub.3 is H or
OCF.sub.3.
10. The method according to claim 1, wherein R.sub.4 and R.sub.6
are independently H or F.
11. The method according to claim 1, wherein R.sub.5 is H,
CF.sub.3, N(CH.sub.3).sub.2, or F.
12. The method according to claim 1, wherein: R.sub.1 is H or
C.sub.1 to C.sub.6 alkyl; R.sub.2 is H, C.sub.i to C.sub.6 alkyl,
substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.6
cycloalkyl, or CF.sub.3; or R.sub.1 and R.sub.2 are joined with the
N-atom to form tetrahydropyrrole, piperidine, tetrahydropyran, or
pyrrole; R.sub.3 is H or OCF.sub.3; R.sub.4 and R.sub.6 are
independently H or F; R.sub.5 is H, CF.sub.3, N(CH.sub.3).sub.2, or
F; or R.sub.7 is to C.sub.6 alkyl.
13. The method according to claim 1 which is selected from the
group consisting of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide;
N-(tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide;
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile;
1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile;
1-methyl-5-[4-(morpholin-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulfon-
amide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesul-
fonamide;
1-methyl-5-[4-(1H-pyrrol-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbo-
nitrile;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesul-
fonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromet-
hyl)benzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesu-
lfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromet-
hyl)benzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzen-
esulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesul-
fonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)-
benzenesulfonamide;
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenyl]-1H-pyr-
role-2-carbonitrile;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benz-
enesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hyl)benzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benze-
nesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methylbenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonami-
de;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-3-fluorobenzenesulfonamide-
;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonami-
de;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfona-
mide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-propylbenzenesulfonam-
ide;
5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1H-pyrrole-2--
carbonitrile;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonam-
ide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluoroben-
zenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-fluorobenzenesulfonamide-
;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonami-
de;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfona-
mide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesul-
fonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluo-
robenzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-fluorobenzenesulfonami-
de;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfona-
mide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethoxy)ben-
zenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benz-
enesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesu-
lfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromet-
hoxy)benzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benze-
nesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethoxy)benzenes-
ulfonamide;
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethoxy)phenyl]-1H-py-
rrole-2-carbonitrile;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)ben-
zenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hoxy)benzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benz-
enesulfonamide;
N-tert-butyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benz-
enesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(dimethylamino)-N,N-dimethylbenzene-
sulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-methylbenzenesulfonami-
de;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesul-
fonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2,5-difluorobe-
nzenesulfonamide;
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2,5-difluoroben-
zenesulfonamide; and a pharmaceutically acceptable salt, tautomer,
metabolite or prodrug thereof.
14. The method according to claim 1, wherein said fibroids are
uterine fibroids.
15. The method according to claim 1, wherein said carcinomas are
selected from the group consisting of carcinomas of the
endometrium, breast, uterine, ovarian and prostate cancer.
16. The method according to claim 1, wherein said cycle-related
symptoms comprise psychological symptoms and physical symptoms.
17. The method according to claim 16, wherein said psychological
symptoms comprise mood changes, irritability, anxiety, lack of
concentration, or decrease in sexual desire.
18. The method according to claim 16, wherein said physical
symptoms comprise dysmenorrhea, breast tenderness, bloating,
fatigue, or food cravings.
19. A method for preparing a compound of formula I: ##STR00076##
wherein: R.sub.1 and R.sub.2 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.6 cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocycle, substituted
heterocycle, C.sub.3 to C.sub.6 alkenyl, C.sub.3 to C.sub.6
substituted alkenyl, C.sub.3 to C.sub.6 alkynyl, substituted
C.sub.3 to C.sub.6 alkynyl,
--(CH.sub.mX.sub.n).sub.nCH.sub.pX.sub.q, O--C.sub.1 to C.sub.6
alkyl, O--C.sub.1 to C.sub.6 substituted alkyl, and
O--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q; or R.sub.1 and R.sub.2
may be taken together to form a ring of 4 to 8 ring atoms
containing in its backbone carbon atoms and 1 to 4 N, O, S, or
SO.sub.2, and where any C-atom or N-atom of said ring is optionally
substituted with C.sub.1 to C.sub.4 alkyl, F, or CF.sub.3; R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently selected from the
group consisting of H, halogen, CN, C.sub.1 to C.sub.6 alkyl,
substituted C.sub.1 to C.sub.6 alkyl,
--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q, C.sub.3 to C.sub.6
cycloalkyl, substituted C.sub.3 to C.sub.6 cycloalkyl, O--C.sub.1
to C.sub.6 alkyl, O--C.sub.1 to C.sub.6 substituted alkyl, OH,
NH.sub.2, NH--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q,
O--(C.sub.mX.sub.n).sub.zCH.sub.pX.sub.q,
N--{(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q}.sub.2, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocycle,
and substituted heterocycle; X is halogen; m and n are,
independently, 0 to 2, provided that m+n=2; p and q are,
independently, 0 to 3, provided that p+q=3; z is 0 to 10; R.sub.7
is 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.6
cycloalkyl, and substituted C.sub.3 to C.sub.6 cycloalkyl; or a
pharmaceutically acceptable salt, tautomer, metabolite or prodrug
thereof; said method comprising: (a) reacting HNR.sub.1R.sub.2 and
an arylsulfonyl of the structure: ##STR00077## wherein: LG is a
first leaving group; and D is halogen or sulfonate; (b) coupling
the product of step (a) with a pyrrole comprising a second leaving
group.
20. The method according to claim 19, wherein said first leaving
group is Cl, Br, F, or imidazole.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 12/041,716, filed Mar. 4, 2008, which claims the benefit
of the priority of U.S. Provisional Patent Application No.
60/905,239, filed Mar. 6, 2007, now expired. These priority
applications are incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Progesterone receptor (PR) agonists and antagonists, also
termed PR modulators, have been described for use in contraception
and a variety of other indications.
[0003] What are needed are alternate non-steroidal compounds that
are useful as PR modulators.
SUMMARY OF THE INVENTION
[0004] In one aspect, compounds of the following structure are
described, wherein R.sub.1-R.sub.7 are defined herein.
##STR00002##
[0005] In a further aspect, methods of contraception; treating or
preventing fibroids; treating or preventing uterine leiomyomata;
treating or preventing endometriosis, dysfunctional bleeding, and
polycystic ovary syndrome; treating or preventing hormone-dependent
carcinomas; providing hormone replacement therapy; stimulating food
intake; synchronizing estrus; and treating cycle-related symptoms
using the compounds described herein are provided.
[0006] In another aspect, methods are described for preparing
compounds the following structure, wherein R.sub.1-R.sub.7 are
defined herein.
##STR00003##
[0007] Other aspects and advantages of the invention will be
readily apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0008] Compounds are provided which are progesterone receptor
modulators. These compounds are those of formula I and have the
structure:
##STR00004##
[0009] wherein, R.sub.1 and R.sub.2 are independently selected from
among 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, heteroaryl, substituted
heteroaryl, heterocycle, substituted heterocycle, C.sub.3 to
C.sub.6 alkenyl, C.sub.3 to C.sub.6 substituted alkenyl, C.sub.3 to
C.sub.6 alkynyl, substituted C.sub.3 to C.sub.6 alkynyl,
--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q, O--C.sub.1 to C.sub.6
alkyl, O--C.sub.i to C.sub.6 substituted alkyl, and
O--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q; or R.sub.1 and R.sub.2
may be taken together to form a ring of 4 to 8 ring atoms
containing in its backbone carbon atoms and 1 to 4 N, O, S, or
SO.sub.2, and where any C-atom or N-atom of the ring is optionally
substituted with C.sub.1 to C.sub.4 alkyl, F, or CF.sub.3; R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently selected from among
H, halogen, CN, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alkyl, --(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q, C.sub.3 to
C.sub.6 cycloalkyl, substituted C.sub.3 to C.sub.6 cycloalkyl,
O--C.sub.1 to C.sub.6 alkyl, O--C.sub.1 to C.sub.6 substituted
alkyl, OH, NH.sub.2, NH--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q,
O--(CH.sub.mX.sub.n).sub.nCH.sub.pX.sub.q,
N--{(CH.sub.mX.sub.n).sub.zCH.sub.p}.sub.2, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocycle, and substituted
heterocycle; X is halogen; m and n are, independently, 0 to 2,
provided that m+n=2; p and q are, independently, 0 to 3, provided
that p+q=3; z is 0 to 10; R.sub.7 is selected from among H, C.sub.1
to C.sub.6 alkyl, substituted C.sub.1 to C.sub.6 alkyl, C.sub.3 to
C.sub.6 cycloalkyl, and substituted C.sub.3 to C.sub.6 cycloalkyl;
or a pharmaceutically acceptable salt, tautomer, metabolite or
prodrug thereof.
[0010] In one embodiment, R.sub.7 is a branched C.sub.1 to C.sub.6
alkyl. In another embodiment, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are H. In a further embodiment, R.sub.4 is H or halogen. In
still a further embodiment, R.sub.5 is H or halogen. In another
embodiment, R.sub.7 is CH.sub.3. In yet another embodiment, R.sub.7
is C.sub.1 to C.sub.6 alkyl. In still a further embodiment, R.sub.1
is H or C.sub.1 to C.sub.6 alkyl. In yet a further embodiment,
R.sub.2 is H, C.sub.1 to C.sub.6 alkyl, substituted C.sub.1 to
C.sub.6 alkyl, C.sub.3 to C.sub.6 cycloalkyl, or CF.sub.3. In
another embodiment, R.sub.2 is CH.sub.2--C.sub.3 to C.sub.o
cycloalkyl. In yet another embodiment, R.sub.3 or R.sub.6 are
NH--(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.p such as NH(C.sub.1 to
C.sub.6 alkyl). In a further embodiment, R.sub.3 or R.sub.6 are
N{(CH.sub.mX.sub.n).sub.zCH.sub.pX.sub.q}.sub.2 such as N{(C.sub.1
to C.sub.6 alkyl)}.sub.2, wherein the C.sub.1 to C.sub.6 alkyl
groups may be same or different. In still another embodiment,
R.sub.1 and R.sub.2 are joined to form a pyrrolidine, piperidine,
tetrahydropyran, morpholine, or pyrrole. In a further embodiment,
R.sub.3 or R.sub.6 is H, halogen, OCF.sub.3, CF.sub.3, or
N(CH.sub.3).sub.2. In yet another embodiment, R.sub.4 and R.sub.6
are independently H or F. In a further embodiment, R.sub.3 is H or
OCF.sub.3. In yet another embodiment, R.sub.4 and R.sub.6 are
independently H or F. In another embodiment R.sub.4 and R.sub.5 are
independently H or F. In still another embodiment, R.sub.5 is H,
CF.sub.3, N(CH.sub.3).sub.2, or F. In a further embodiment, R.sub.1
is H or C.sub.1 to C.sub.6 alkyl; R.sub.2 is H, C.sub.1 to C.sub.6
alkyl, substituted C.sub.1 to C.sub.6 alkyl, or C.sub.3 to C.sub.6
cycloalkyl; or R.sub.1 and R.sub.2 are joined with the N-atom to
form a tetrahydropyrrole, piperidine, tetrahydropyran, morpholine,
or pyrrole; R.sub.4 and R.sub.5 are independently H or F; R.sub.3
and R.sub.6 are independently H, halogen, CF.sub.3, OCF.sub.3, or
N(CH.sub.3).sub.2; or R.sub.7 is C.sub.1 to C.sub.6 alkyl.
[0011] The inventors found that the compounds described herein not
only functioned as effective PR modulators, but they have improved
solubility as compared to other PR modulators in the art. Further,
the compounds described herein have excellent bioavailablity and
are selective over other nuclear hormone receptors when
administered in vivo.
[0012] The compounds as described can contain one or more
asymmetric centers and can thus give rise to optical isomers and
diastereomers. The compounds can include optical isomers and
diastereomers; racemic and resolved enantiomerically pure R and S
stereoisomers; other mixtures of the R and S stereoisomers; and
pharmaceutically acceptable salts thereof.
[0013] The term "alkyl" is used herein to refer to both straight-
and branched-chain saturated aliphatic hydrocarbon groups. In one
embodiment, an alkyl group has 1 to about 8 carbon atoms (i.e.,
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5 C.sub.6, C.sub.7, or
C.sub.8). In another embodiment, an alkyl group has 1 to about 6
carbon atoms (i.e., C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5 or
C.sub.6). In a further embodiment, an alkyl group has 1 to about 4
carbon atoms (i.e., C.sub.2, C.sub.3, or C.sub.4).
[0014] The term "cycloalkyl" is used herein to refer to cyclic,
saturated aliphatic hydrocarbon groups. In one embodiment, a
cycloalkyl group has 3 to about 8 carbon atoms (i.e., C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, or C.sub.8). In another
embodiment, a cycloalkyl group has 3 to about 6 carbon atoms (i.e.,
C.sub.3, C.sub.4, C.sub.5 or C.sub.6).
[0015] The term "alkenyl" is used herein to refer to both straight-
and branched-chain alkyl groups having one or more carbon-carbon
double bonds. In one embodiment, an alkenyl group contains 3 to
about 8 carbon atoms (i.e., C.sub.3, C.sub.4, C.sub.5, C.sub.6,
C.sub.7, or C.sub.8). In another embodiment, an alkenyl groups has
1 or 2 carbon-carbon double bonds and 3 to about 6 carbon atoms
(i.e., C.sub.3, C.sub.4, C.sub.5 or C.sub.6).
[0016] The term "alkynyl" is used herein to refer to both straight-
and branched-chain alkyl groups having one or more carbon-carbon
triple bonds. In one embodiment, an alkynyl group has 3 to about 8
carbon atoms (i.e., C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, or
C.sub.8). In another embodiment, an alkynyl group contains 1 or 2
carbon-carbon triple bonds and 3 to about 6 carbon atoms (i.e.,
C.sub.3, C.sub.4, C.sub.5, or C.sub.6).
[0017] The terms "substituted alkyl", "substituted alkenyl",
"substituted alkynyl", and "substituted cycloalkyl" refer to alkyl,
alkenyl, alkynyl, and cycloalkyl groups, respectively, having one,
two, or more substituents independently selected from among,
without limitation, hydrogen, halogen, CN, OH, NO.sub.2,
cycloalkyl, amino, aryl, heterocyclic, aryl, alkoxy, aryloxy,
alkyloxy, alkylcarbonyl, alkylcarboxy, amino, and arylthio. In one
embodiment, one or more of the carbon atoms in an alkyl has two or
more substituents.
[0018] The term "arylthio" as used herein refers to the S(aryl)
group, where the point of attachment is through the sulfur-atom and
the aryl group can be substituted as noted above. The term "alkoxy"
as used herein refers to the O(alkyl) group, where the point of
attachment is through the oxygen-atom and the alkyl group can be
substituted as noted above. The term "aryloxy" as used herein
refers to the O(aryl) group, where the point of attachment is
through the oxygen-atom and the aryl group can be substituted as
noted above.
[0019] The term "alkylcarbonyl" as used herein refers to the
C(O)(alkyl) group, where the point of attachment is through the
carbon-atom of the carbonyl moiety and the alkyl group can be
substituted as noted above.
[0020] The term "alkylcarboxy" as used herein refers to the
C(O)O(alkyl) group, where the point of attachment is through the
carbon-atom of the carboxy moiety and the alkyl group can be
substituted as noted above.
[0021] The term "alkylamino" as used herein refers to both
secondary and tertiary amines where the point of attachment is
through the nitrogen-atom and the alkyl groups can be substituted
as noted above. The alkyl groups can be the same or different.
[0022] The term "halogen" as used herein refers to Cl, Br, F, or I
groups.
[0023] The term "aryl" as used herein refers to an aromatic,
carbocyclic system, e.g., of about 6 to 14 carbon atoms, which can
include a single ring or multiple aromatic rings fused or linked
together where 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, phenanthryl, indene, benzonaphthyl, and
fluorenyl.
[0024] The term "substituted aryl" refers to an aryl group which is
substituted with one or more substituents including halogen, CN,
OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,
C.sub.1 to C.sub.3 perfluoroalkyl, C.sub.1 to C.sub.3
perfluoroalkoxy, aryloxy, alkyloxy including --O--(C.sub.1 to
C.sub.10 alkyl) or --O--(C.sub.1 to C.sub.10 substituted alkyl),
alkylcarbonyl including --CO--(C.sub.1 to C.sub.10 alkyl) or
--CO--(C.sub.1 to C.sub.10 substituted alkyl), alkylcarboxy
including --COO--(C.sub.1 to C.sub.10 alkyl) or --COO--(C.sub.1 to
C.sub.10 substituted alkyl), --C(NH.sub.2).dbd.N--OH,
--SO.sub.2--(C.sub.1 to C.sub.10 alkyl), --SO.sub.2--(C.sub.1 to
C.sub.10 substituted alkyl), --O--CH.sub.2-aryl, alkylamino,
arylthio, aryl, or heteroaryl, which groups can be substituted.
Desirably, a substituted aryl group is substituted with 1 to about
4 substituents.
[0025] The term "heterocycle" or "heterocyclic" as used herein can
be used interchangeably to refer to a stable, saturated or
partially unsaturated 3- to 9-membered monocyclic or multicyclic
heterocyclic ring. The heterocyclic ring has in its backbone carbon
atoms and one or more heteroatoms including nitrogen, oxygen, and
sulfur atoms. In one embodiment, the heterocyclic ring has 1 to
about 4 heteroatoms in the backbone of the ring. When the
heterocyclic ring contains nitrogen or sulfur atoms in the backbone
of the ring, the nitrogen or sulfur atoms can be oxidized. The term
"heterocycle" or "heterocyclic" also refers to multicyclic rings in
which a heterocyclic ring is fused to an aryl ring of about 6 to
about 14 carbon atoms. The heterocyclic ring can be attached to the
aryl ring through a heteroatom or carbon atom provided the
resultant heterocyclic ring structure is chemically stable. In one
embodiment, the heterocyclic ring includes multicyclic systems
having 1 to 5 rings.
[0026] A variety of heterocyclic groups are known in the art and
include, without limitation, oxygen-containing rings,
nitrogen-containing rings, sulfur-containing rings, mixed
heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. Examples of heterocyclic groups include,
without limitation, tetrahydrofuranyl, piperidinyl,
2-oxopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl,
dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, oxazinyl,
oxathiazinyl, benzopyranyl, benzoxazinyl and xanthenyl.
[0027] The term "heteroaryl" as used herein refers to a stable,
aromatic 5- to 14-membered monocyclic or multicyclic
heteroatom-containing ring. The heteroaryl ring has in its backbone
carbon atoms and one or more heteroatoms including nitrogen,
oxygen, and sulfur atoms. In one embodiment, the heteroaryl ring
contains 1 to about 4 heteroatoms in the backbone of the ring. When
the heteroaryl ring contains nitrogen or sulfur atoms in the
backbone of the ring, the nitrogen or sulfur atoms can be oxidized.
The term "heteroaryl" also refers to multicyclic rings in which a
heteroaryl ring is fused to an aryl ring. The heteroaryl ring can
be attached to the aryl ring through a heteroatom or carbon atom
provided the resultant heterocyclic ring structure is chemically
stable. In one embodiment, the heteroaryl ring includes multicyclic
systems having 1 to 5 rings.
[0028] A variety of heteroaryl groups are known in the art and
include, without limitation, oxygen-containing rings,
nitrogen-containing rings, sulfur-containing rings, mixed
heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. Examples of heteroaryl groups include,
without limitation, furyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, thiazolyl,
oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl,
benzofuranyl, thionapthene, indolyl, benzazolyl, purindinyl,
pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl,
quinolinyl, isoquinolinyl, benzodiazonyl, napthylridinyl,
benzothienyl, pyridopyridinyl, acridinyl, carbazolyl, and purinyl
rings.
[0029] The term "substituted heterocycle" and "substituted
heteroaryl" as used herein refers to a heterocycle or heteroaryl
group having one or more substituents including halogen, CN, OH,
NO.sub.2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, C.sub.1 to
C.sub.3 perfluoroalkyl, C.sub.1 to C.sub.3 perfluoroalkoxy, alkoxy,
aryloxy, alkyloxy including --O--(C.sub.1 to C.sub.10 alkyl) or
--O--(C.sub.i to C.sub.10 substituted alkyl), alkylcarbonyl
including --CO--(C.sub.1 to C.sub.10 alkyl) or --CO--(C.sub.1 to
C.sub.10 substituted alkyl), alkylcarboxy including --COO--(C.sub.1
to C.sub.10 alkyl) or --COO--(C.sub.1 to C.sub.10 substituted
alkyl), --C(NH.sub.2).dbd.N--OH, --SO.sub.2--(C.sub.1 to C.sub.10
alkyl), --SO.sub.2--(C.sub.1 to C.sub.10 substituted alkyl),
--O--CH.sub.2-aryl, alkylamino, arylthio, aryl, or heteroaryl,
which groups may be optionally substituted. A substituted
heterocycle or heteroaryl group may have 1, 2, 3, or 4
substituents.
[0030] The compounds may encompass tautomeric forms of the
structures provided herein characterized by the bioactivity of the
drawn structures. Further, the compounds may also be used in the
form of salts derived from pharmaceutically or physiologically
acceptable acids, bases, alkali metals and alkaline earth
metals.
[0031] Pharmaceutically acceptable salts can be formed from organic
and inorganic acids including, e.g., acetic, propionic, lactic,
citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,
malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable
acids. Salts may also be formed from inorganic bases, desirably
alkali metal salts including, e.g., sodium, lithium, or potassium,
and organic bases, such as ammonium salts, mono-, di-, and
trimethylammonium, mono-, di- and triethylammonium, mono-, di- and
tripropylammonium (iso and normal), ethyldimethylammonium,
benzyldimethylammonium, cyclohexylammonium, benzylammonium,
dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,
piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,
1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl
piperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium,
mono-, di- and triethanolammonium, ethyl diethanolammonium,
n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium,
phenylmonoethanolammonium, and the like.
[0032] Physiologically acceptable alkali salts and alkaline earth
metal salts can include, without limitation, sodium, potassium,
calcium and magnesium salts in the form of esters, and
carbamates.
[0033] These salts, as well as other compounds, can be 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. In one embodiment, the prodrugs are esters. In another
embodiment, the prodrugs are carbamates. See, e.g., B. Testa and J.
Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a
Complement to Ligand Design", Medicinal Research Reviews,
16(3):233-241, ed., John Wiley & Sons (1996).
[0034] The compounds discussed herein also encompass "metabolites"
which are unique products formed by processing the compounds by the
cell or subject. Desirably, metabolites are formed in vivo.
[0035] The compounds described herein may be prepared using
reagents and steps that alone are known in the art. However, the
combination of these reagents and steps by the inventors provide
compounds of the following structure, wherein R.sub.1-R.sub.7 are
defined above.
##STR00005##
[0036] In summary, the compounds of formula I are prepared by
combining an arylsulfonyl (1) with an amine (2) to form
arylsulfonamide (3) under a variety of conditions. The
arylsulfonamide may then be coupled with a cyanopyrrole to form the
compounds of formula I. See, Scheme 1.
##STR00006##
[0037] The first step includes reacting an amine, such as
HNR.sub.1R.sub.2, and an arylsulfonyl of the following structure,
wherein R.sub.3-R.sub.6 are defined above, LG is a leaving group
which may be selected from among Cl, Br, F, or imidazole, and D is
a halogen or sulfonate. In one embodiment, D is halogen. In a
further embodiment, D is Br. In another example, D is
sulfonate.
##STR00007##
[0038] An amine, such as HNR.sub.1R.sub.2, where R.sub.1 and
R.sub.2 are defined above, is utilized to prepare the sulfonamide.
In one embodiment, greater than one equivalent of the amine is
utilized. In another embodiment, about 10 equivalents of the amine
are utilized. The reaction is also desirably performed in the
presence of a base. A variety of bases may be selected for use in
this reaction and may be selected by one of skill in the art.
Examples of bases include sodium carbonate, potassium carbonate,
cesium fluoride, potassium fluoride, or potassium phosphate, among
others. The reaction is typically performed in methylene chloride,
however other solvents may be selected by one of skill. By doing
so, a sulfonamide of the following structure is prepared, wherein
R.sub.1-R.sub.6 and D are defined above.
##STR00008##
[0039] The sulfonamide is then coupled with a pyrrole comprising a
leaving group. In one example, the pyrrole comprising a leaving
group is a cyanopyrrole containing a leaving group. In a further
example, the pyrrole comprising a leaving group is a boronic acid
(5) of the following structure, wherein R.sub.7 is defined above.
In another example, the pyrrole comprising a leaving group is a tin
derivative of boronic acid (5) of the following structure, wherein
R.sub.7 and "alkyl" are defined herein.
##STR00009##
[0040] In a further example, the pyrrole comprising a leaving group
may be prepared from lithium diisopropylamide, a trialkyl borate,
and a pyrrole (4) of the following structure, wherein R.sub.7 is
defined above. A variety of trialkyl borates may be selected by one
of skill in the art for use in the coupling. Specific examples of
trialkyl borates include, without limitation, trimethyl borate,
triethyl borate, or triisopropyl borate.
##STR00010##
[0041] The coupling is desirably performed in the presence of a
palladium catalyst. There are a variety of palladium catalysts
available in the art that would be useful in the coupling and
include, without limitation, tetrakis(triphenylphosphine) palladium
(0) or palladium dibenzylidene acetone in the presence of
tributylphosphine (Fu et al., J. Am. Chem. Soc., 2000, 122, 4020),
as well as the catalysts/catalyst systems described in Hartwig et
al. J. Org. Chem. 2002, 67, 5553. A base is also included for the
coupling and may be selected by one of skill in the art. Bases that
may be utilized include, without limitation, sodium carbonate,
potassium carbonate, cesium fluoride, potassium fluoride, and
potassium phosphate. Similarly, a variety of solvents may be
selected for use in the coupling and include, without limitation,
tetrahydrofuran (THF), dimethoxyethane (DME), dioxane, ethanol,
water, toluene, or a combination thereof. Depending on the
reactivity of the coupling partners and reagents, the reaction may
be conducted up to the boiling point of the solvents, or may be
accelerated under microwave irradiation, if necessary, which may
readily be determined by one of skill in the art.
[0042] In one embodiment, the compounds of formula I are prepared
as described in Scheme 2 by reacting bromoarylsulfonyl (1) with
amine (2) to produce sulfonamide (3), which is then coupled with
pyrrole boronic acid (5) or a pyrrole compound prepared using
pyrrole (4).
##STR00011##
[0043] Also provided are pharmaceutical compositions containing one
or more compounds described herein and a pharmaceutically
acceptable carrier or excipient. In one embodiment, the methods of
treatment include administering to a mammal a pharmaceutically
effective amount of one or more compounds as described herein as
progesterone receptor modulators.
[0044] The compounds may be combined with one or more
pharmaceutically acceptable carriers or excipients, e.g., solvents,
diluents and the like. Suitably, the compounds are formulated for
delivery to a subject by any suitable route including, e.g.,
transdermal, mucosal (intranasal, buccal, vaginal), oral,
parenteral, among others. A variety of suitable delivery devices
can be utilized for these delivery routes and include, without
limitation, tablets, caplets, capsules, gel tabs, dispersible
powders, granules, suspensions, injectable solutions, transdermal
patches, topical creams or gels, and vaginal rings, among
others.
[0045] In preparing the compositions described herein, the
compounds may be combined with one or more of a solid carrier,
liquid carrier, adjuvant, suspending agent, syrup, and elixir,
among others, the selection of which dependent on the nature of the
active ingredient and the particular form of administration
desired.
[0046] Solid carriers include, without limitation, starch, lactose,
dicalcium phosphate, microcrystalline cellulose, sucrose and
kaolin.
[0047] Liquid carriers include, without limitation, sterile water,
dimethylsulfoxide (DMSO), polyethylene glycols, non-ionic
surfactants and edible oils such as corn, peanut and sesame
oils.
[0048] Adjuvants can include, without limitation, flavoring agents,
coloring agents, preserving agents, and antioxidants, e.g., vitamin
E, ascorbic acid, butylatedhydroxytoluene (BHT) and
butylatedhydroxyanisole (BHA).
[0049] In one embodiment, the compound may be combined with a
suspending agent, including about 0.05 to about 5% of suspending
agent.
[0050] In another embodiment, the compound may be combined with a
syrup containing, e.g., about 10 to about 50% of sugar.
[0051] In a further embodiment, the compound may be combined with
an elixir containing, e.g., about 20 to about 50% ethanol, and the
like.
[0052] When formulated for oral delivery, the compounds can be in
the form of a tablet, capsule, caplet, gel tab, dispersible powder,
granule, or suspension. One particularly desirable pharmaceutical
composition, from the standpoint of ease of preparation and
administration, are solid compositions, particularly tablets and
hard-filled or liquid-filled capsules.
[0053] The compounds may also be administered parenterally or
intraperitoneally as solutions, suspensions, dispersions, or the
like. Such pharmaceutical preparations may contain, e.g., about 25
to about 90% of the compound in combination with the carrier.
Desirably, the pharmaceutical preparation contains about 5% and 60%
by weight of the compound. In one embodiment, the compounds are
administered in solutions or suspensions, whereby the compounds are
present as free bases or pharmacologically acceptable salts and are
prepared in water suitably mixed with a surfactant such as
hydroxypropylcellulose. In another embodiment, the solutions or
suspensions containing the compound may contain about 0.05 to about
5% of a suspending agent in an isotonic medium. In a further
embodiment, the compounds are administered in dispersions, which
may be prepared in glycerol, liquid, polyethylene glycols and
mixtures thereof in oils.
[0054] 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 utilized in the injectable form
may be a solvent or dispersion medium containing, e.g., water,
ethanol (e.g., glycerol, propylene glycol and liquid polyethylene
glycol), suitable mixtures thereof, and vegetable oil.
[0055] The compounds may also be administered via a vaginal ring.
Suitably, use of the vaginal ring is timed to cycle to which the
compound is being administered, including a 28-day cycle. However,
the vaginal ring can be inserted for longer or shorter periods of
time. See, U.S. Pat. Nos. 5,972,372; 6,126,958; and 6,125,850,
which are hereby incorporated by reference, for formulations of the
vaginal ring that can be used.
[0056] The compounds can also be delivered via a transdermal patch.
Suitably, use of the patch is timed to the length of the cycle,
including a 28 day cycle. However, the patch can remain in place
for longer or shorter periods of time.
[0057] The compounds may be utilized in methods of contraception,
hormone replacement therapy, and the treatment and/or prevention of
benign and malignant neoplastic disease; cycle-related symptoms;
fibroids, including uterine fibroids; leiomyomata; polycystic ovary
syndrome; endometriosis; benign prostatic hypertrophy; carcinomas
and adenocarcinomas of the endometrium, ovary, breast, colon,
prostate, pituitary, meningioma and other hormone-dependent tumors;
dysmenorrhea; dysfunctional uterine bleeding; symptoms of
premenstrual syndrome and premenstrual dysphoric disorder; and for
inducing amenorrhea. Additional uses of the present progesterone
receptor modulators include stimulating food intake and the
synchronization of estrus in livestock. In one embodiment, the
neoplastic disease is hormone-dependent.
[0058] The term "cycle-related symptoms" refers to psychological
symptoms (e.g., mood change, irritability, anxiety, lack of
concentration, or decrease in sexual desire) and physical symptoms
(e.g., dysmenorrhea, breast tenderness, bloating, fatigue, or food
cravings) associated with a woman's menstrual cycle. Cycle-related
symptoms include, but are not limited to, dysmenorrhea and moderate
to severe cycle-related symptoms.
[0059] When utilized for these purposes, the compounds can be
administered in combination with other agents, as well as in
combination with each other. Such agents include, without
limitation, progestins, antiprogestins, estrogens, antiestrogens,
selective estrogen receptor modulators (SERMS), among others.
Progestins can include, without limitation, tanaproget,
levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel,
norethindrone, gestodene, norethindrone acetate, norgestimate,
osaterone, cyproterone acetate, trimegestone, dienogest,
drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Estrogens
can include, without limitation, ethinyl estradiol. The compounds
described herein can be combined with one or more of these agents,
delivered concurrently therewith one or more of these agents,
delivered prior to one or more of these agents, or delivered
subsequent to one or more of these agents.
[0060] A patient or subject being treated is a mammalian subject
and typically a female. Desirably, the subject is a human. However,
as used herein, a female can include non-human mammals, e.g.,
cattle or livestock, horses, pigs, domestic animals, etc.
[0061] The effective dosage of the compound 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 are
administered at a daily dosage of about 0.5 to about 500 mg/kg of
animal body weight, about 1 to about 400 mg/kg, about 5 to about
300 mg/kg, about 10 to about 250 mg/kg, about 50 to about 200
mg/kg, or about 100 to 150 mg/kg. For most large mammals, the total
daily dosage is from about 1 to 100 mg. In one embodiment, the
total daily dosage is from about 2 to 80 mg. 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.
[0062] As previously noted, the compounds may be administered via a
vaginal ring. In one embodiment, the ring is inserted into the
vagina and it remains in place for 3 weeks. During the fourth week,
the vaginal ring is removed and menses occurs. The following week,
a new ring is inserted to be worn another 3 weeks until it is time
for the next period. In another embodiment, the vaginal ring is
inserted weekly and is replaced for 3 consecutive weeks. Then,
following 1 week without the ring, a new ring is inserted to begin
a new regimen. In yet another embodiment, the vaginal ring is
inserted for longer or shorter periods of time.
[0063] Further, the previously mentioned transdermal patch is
applied via a suitable adhesive on the skin, where it remains in
place for at least one week. In one embodiment, the transdermal
patch remains in place for one week and is replaced weekly for a
total of 3 weeks. In another embodiment, the transdermal patch
remains in place for two weeks. In a further embodiment, the
transdermal patch remains in place for three weeks. During the
fourth week, no patch is applied and menses occurs. The following
week, a new patch is applied to be worn to begin a new regimen. In
yet another embodiment, the patch remains in place for longer or
shorter periods of time.
[0064] When used for contraception, the method typically includes
delivering a daily dosage unit containing a compound for 28
consecutive days to a female of child-bearing age. Desirably, the
method includes delivering the compound over a period of 21 to 27
consecutive days followed by 1 to 7 consecutive days in which no
effective amount or no amount of the compound is delivered.
Optionally, the period of 1 to 7 days in which no effective amount
of the compound is delivered to the subject can involve delivery of
a second phase of daily dosage units of 1 to 7 days of a
pharmaceutically acceptable placebo. Alternatively, during this
"placebo period", no placebo is administered. The compound may
optionally be administered in combination with a progestin,
antiprogestin, estrogen, or combination thereof.
[0065] In another embodiment, the method includes delivering a
compound for 21 consecutive days, followed by 7 days in which no
effective amount of the compound is delivered. Optionally, during
these 7 days, a second phase of 7 daily dosage units of an orally
and pharmaceutically acceptable placebo can be delivered. The
compound may optionally be administered in combination with a
progestin, antiprogestin, estrogen, anti-estrogen, SERM or
combination thereof.
[0066] In a further embodiment, the method includes delivering a
compound for 23 consecutive days, followed by 5 days in which no
effective amount of the compound is delivered. Optionally, during
these 5 days, a second phase of 5 daily dosage units of an orally
and pharmaceutically acceptable placebo can be delivered. The
compound may optionally be administered in combination with a
progestin, antiprogestin, estrogen, anti-estrogen, SERM or
combination thereof.
[0067] In yet another embodiment, the method includes delivering a
compound for 25 consecutive days, followed by 3 days in which no
effective amount of the compound is delivered. Optionally, during
these 3 days, a second phase of 3 daily dosage units of an orally
and pharmaceutically acceptable placebo can be delivered. The
compound may optionally be administered in combination with a
progestin, antiprogestin, estrogen, anti-estrogen, SERM, or
combination thereof.
[0068] In still a further embodiment, the method includes
delivering a compound for 27 consecutive days, followed by 1 day in
which no effective amount of the compound is delivered. Optionally,
a second phase of 1 daily dosage unit of an orally and
pharmaceutically acceptable placebo can be delivered. The compound
may optionally be administered in combination with a progestin,
antiprogestin, estrogen, anti-estrogen, SERM, or combination
thereof.
[0069] In another embodiment, a method of contraception includes
administering to a female of child bearing age for 28 consecutive
days: (a) a first phase of from 14 to 24 daily dosage units of a
progestational agent equal in progestational activity to about 35
to about 100 .mu.g levonorgestrel; (b) a second phase of from 1 to
11 daily dosage units, at a daily dosage of from about 2 to 50 mg,
of a compound described herein; and (c) optionally, a third phase
of daily dosage units of an orally and pharmaceutically acceptable
placebo for the remaining days of the 28 consecutive days in which
no antiprogestin, progestin or estrogen is administered; wherein
the total daily dosage units of the first, second and third phases
equals 28.
[0070] In yet a further embodiment, a method of contraception
includes administering to a female of child bearing age for 28
consecutive days: (a) a first phase of from 14 to 24 daily dosage
units of a compound described herein; (b) a second phase of from 1
to 11 daily dosage units of an antiprogestin; and (c) optionally, a
third phase of daily dosage units of an orally and pharmaceutically
acceptable placebo for the remaining days of the 28 consecutive
days in which no antiprogestin, progestin, estrogen, anti-estrogen
or SERM is administered; wherein the total daily dosage units of
the first, second and third phases equals 28.
[0071] In yet a further embodiment, a method of contraception is
provided and includes administering to a female of child bearing
age for 28 consecutive days: (a) a first phase of from 14 to 24
daily dosage units of a progestational agent equal in
progestational activity to about 35 to about 100 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units, at a daily dosage of from about 2 to 50 mg, of a compound
described herein; and (c) optionally, a third phase of daily dosage
units of an orally and pharmaceutically acceptable placebo for the
remaining days of the 28 consecutive days in which no
antiprogestin, progestin or estrogen is administered; wherein the
total daily dosage units of the first, second and third phases
equals 28.
[0072] In another embodiment, a method of contraception is provided
and includes administering to a female of child bearing age for 28
consecutive days: (a) a first phase of from 14 to 24 daily dosage
units of a compound described herein; (b) a second phase of from 1
to 11 daily dosage units of an antiprogestin; and (c) optionally, a
third phase of daily dosage units of an orally and pharmaceutically
acceptable placebo for the remaining days of the 28 consecutive
days in which no antiprogestin, progestin, estrogen, anti-estrogen
or SERM is administered; wherein the total daily dosage units of
the first, second and third phases equals 28.
[0073] Also provided are kits or packages of pharmaceutical
formulations designed for use in the regimens described herein.
Suitably, the kits contain one or more compounds as described
herein.
[0074] Advantageously, for use in the kits, the compound is
formulated for the desired delivery vehicle and route. For example,
the compound can be formulated for oral delivery, parenteral
delivery, vaginal ring, transdermal delivery, or mucosal delivery,
as discussed in detail above. The kit is preferably a pack (e.g. a
blister pack) containing daily doses arranged in the order in which
they are to be taken.
[0075] In each of the regimens and kits described herein, it is
preferred that the daily dosage of each pharmaceutically active
component of the regimen remain fixed in each particular phase in
which it is administered. It is also understood that the daily dose
units described are to be administered in the order described, with
the first phase followed in order by the optional phases, including
any second and third phases. To help facilitate compliance with
each regimen, it is also preferred that the kits contain the
placebo described for the final days of the cycle. It is further
preferred that each package or kit contain a pharmaceutically
acceptable package having indicators for each day of the 28-day
cycle, such as a labeled blister package, dial dispenser, or other
packages known in the art.
[0076] These dosage regimens may be adjusted to provide the optimal
therapeutic response. For example, several divided doses of each
component may be administered daily or the dose may be
proportionally increased or reduced as indicated by the exigencies
of the therapeutic situation. In the descriptions herein, reference
to a daily dosage unit may also include divided units which are
administered over the course of each day of the cycle
contemplated.
[0077] In one embodiment, the kit is designed for daily oral
administration over a 28-day cycle, desirably for one oral
administration per day, and organized so as to indicate a single
oral formulation or combination of oral formulations to be taken on
each day of the 28-day cycle. Desirably each kit will include oral
tablets to be taken on each the days specified; desirably one oral
tablet will contain each of the combined daily dosages indicated.
For example, a kit can contain 21 to 27 daily dosage units of an
effective amount of the compound, optionally, 1 to 7 daily dosage
units of a placebo and other appropriate components including,
e.g., instructions for use.
[0078] In another embodiment, the kit is designed for weekly or
monthly administration via a vaginal ring over a 28-day cycle.
Suitably, such a kit contains individual packaging for each of the
vaginal rings, i.e. one to three, required for a monthly cycle and
other appropriate components, including, e.g., instructions for
use.
[0079] In a further embodiment, the kit is designed for weekly or
monthly administration via a transdermal patch over a 28-day cycle.
Suitably, such a kit contains individual packaging for each of the
patches, i.e. one to three, required for a monthly cycle and other
appropriate components including, e.g., instructions for use.
[0080] In still another embodiment, the kit is designed for
parenteral delivery of the compound. Such a kit is typically
designed for delivery at home and may include needles, syringes,
and other appropriate packaging and instructions for use.
[0081] In yet another embodiment, the kit contains the compound in
a gel or cream formulation. Optionally, the kit can include
appropriate packaging such as a tube or other container, an
applicator, and/or instructions for use.
[0082] In a further embodiment, the kit includes (a) a first phase
of from 14 to 21 daily dosage units of a progestational agent equal
in progestational activity to about 35 to about 150 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units of a compound described herein; and (c) a third phase of
daily dosage units of an orally and pharmaceutically acceptable
placebo; wherein the total number of the daily dosage units in the
first phase, second phase and third phase equals 28.
[0083] In still another embodiment, a kit contains (a) a first
phase of from 14 to 21 daily dosage units of a compound described
herein; (b) a second phase of from 1 to 11 daily dosage units of an
antiprogestin compound; and (c) a third phase of daily dosage units
of an orally and pharmaceutically acceptable placebo; wherein the
total number of the daily dosage units in the first phase, second
phase and third phase equals 28.
[0084] The following examples are illustrative only and are not
intended to be a limitation on the present invention.
EXAMPLES
Example 1
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide
##STR00012##
[0086] Step 1: Preparation of
4-bromo-N-methylbenzenesulfonamide
General Procedure A for Preparation of Sulfonamides from Sulfonyl
Chlorides
[0087] 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and
methylamine (10 mL, 33% in ethanol) were stirred in a sealed tube
for 16 hours. The reaction mixture was concentrated in vacuo onto
the Celite.RTM. reagent. The crude product was purified via Isco
chromatography (the Redisep.TM. column, silica, gradient 0-3% ethyl
acetate-dichloromethane) to provide
4-bromo-N-methylbenzenesulfonamide (0.11 g, 28%). MS (ESI) m/z 250.
High performance liquid chromatography (HPLC) purity 100.0% at
210-370 nm, 7.4 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/Acetonitrile (ACN)+MeOH) for 10 min., hold 4 min.
General Procedure B for Coupling of Aryl Bromides and Boronic
Acids
[0088] Step 2
[0089] 4-Bromo-N-methylbenzenesulfonamide (100 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours. The
reaction mixture was filtered through silica and rinsed with ethyl
acetate. The solvent was concentrated in vacuo to provide the crude
product. The crude product was pre-adsorbed onto the Celite.RTM.
reagent and purified via Isco chromatography (the Redisep.TM.
column, silica, gradient 5-50% ethyl acetate in hexane) to afford
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide (28
mg, 25%). MS (ESI) m/z 275. HPLC purity 100.0% at 210-370 nm, 9.0
min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 2
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide
##STR00013##
[0091] Step 1: In an analogous manner to General Procedure A,
4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and
dimethylamine (10 mL, 33% in ethanol) were stirred together for 16
hours. 4-bromo-N,N-dimethylbenzenesulfonamide (0.11 g) was provided
after purification. MS (ESI) m/z 264. HPLC purity 100.0% at 210-370
nm, 8.3 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6
mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0092] Step 2: In an analogous manner to General Procedure B,
4-bromo-N,N-dimethylbenzenesulfonamide (105 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide
(30 mg, 26%) was provided after purification. HRMS: calcd for
C.sub.14H.sub.15N.sub.3O.sub.2S+H.sup.+, 290.09577; found (ESI,
[M+H].sup.+), 290.0964. HPLC purity 100.0% at 210-370 nm, 9.8 min.;
the Xterra.RTM. RP18 column, 3.5.mu. column, 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 3
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide
##STR00014##
[0094] Step 1: Following general procedure A, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and ethylamine (5 mL, [2,0M],
10 mmol) were stirred together for 16 hours.
4-bromo-N-ethylbenzenesulfonamide (0.11 g) was provided after
purification. MS (ESI) m/z 264. HPLC purity 100.0% at 210-370 nm,
8.1 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0095] Step 2: In an analogous manner to general procedure B,
4-bromo-N-ethylbenzenesulfonamide (105 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide (15
mg, 13%) was provided after purification. MS (ESI) m/z 289. HPLC
purity 100.0% at 210-370 nm, 9.6 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 4
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide
##STR00015##
[0097] Step 1: General Procedure C for Formation of Sulfonamides
from Sulfonyl Chlorides
[0098] 4-Bromobenzene sulfonyl chloride (0.40 g, 1.5 mmol) and
propylamine (0.32 mL, 3.90 mmol) were dissolved in dry
dichloromethane (5 mL) in a sealed tube. The mixture was stirred
for 16 hours then concentrated in vacuo onto the Celite.RTM.
reagent. The crude product was purified via Isco chromatography
(the Redisep.TM. column, silica, gradient 0-3% ethyl
acetate-dichloromethane) to provide
4-bromo-N-propylbenzenesulfonamide (0.12 g, 28%). MS (ESI) m/z 278.
HPLC purity 100.0% at 210-370 nm, 8.8 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0099] Step 2: According to general procedure B,
4-bromo-N-propylbenzenesulfonamide (111 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide (21
mg, 17%) was provided after purification. MS (ESI) m/z 303. HPLC
purity 100.0% at 210-370 nm, 10.2 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 5
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropylbenzenesulfonamide
##STR00016##
[0101] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and isopropylamine (0.33 mL,
3.90 mmol) were stirred together with dry dichloromethane (5 mL)
for 16 hours. 4-bromo-N-isopropylbenzenesulfonamide (0.12 g, 28%)
was provided after purification. MS (ESI) m/z 278. HPLC purity
100.0% at 210-370 nm, 8.7 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0102] Step 2: According to general procedure B,
4-bromo-N-isopropylbenzenesulfonamide (111 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropylbenzenesulfonamide
(15 mg, 12%) was provided after purification. MS (ESI) m/z 303.
HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 6
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide
##STR00017##
[0104] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and isobutylamine (0.39 mL,
3.90 mmol) were stirred together with dry dichloromethane (5 mL)
for 16 hours. 4-bromo-N-isobutylbenzenesulfonamide (0.12 g, 28%)
was provided after purification. MS (ESI) m/z 292. HPLC purity
100.0% at 210-370 nm, 9.4 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0105] Step 2: According to general procedure B,
4-bromo-N-isobutylbenzenesulfonamide (117 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide
(11 mg, 9%) was provided after purification. MS (ESI) m/z 317. HPLC
purity 100.0% at 210-370 nm, 10.8 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 7
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide
##STR00018##
[0107] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and N-Ethyl-N-methylamine
(0.33 mL, 3.90 mmol) were stirred together in dry dichloromethane
(5 mL) for 16 hours. 4-bromo-N-ethyl-N-methylbenzenesulfonamide
(0.12 g, 28%) was provided after purification. MS (ESI) m/z 278.
HPLC purity 99.2% at 210-370 nm, 8.9 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0108] Step 2: According to general procedure B,
4-bromo-N-ethyl-N-methylbenzenesulfonamide (111 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide
(17 mg, 14%) was provided after purification. MS (ESI) m/z 303.
HPLC purity 99.5% at 210-370 nm, 10.3 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 8
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide
##STR00019##
[0110] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and diethylamine (0.40 mL,
3.90 mmol) were stirred together in dry dichloromethane (5 mL) for
16 hours. 4-bromo-N,N-diethylbenzenesulfonamide (0.12 g) was
provided after purification. MS (ESI) m/z 293. HPLC purity 99.2% at
210-370 nm, 9.4 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0111] Step 2: According to general procedure B,
4-bromo-N,N-diethylbenzenesulfonamide (117 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide
(27 mg, 21%) was provided after purification. MS (ESI) m/z 317.
HPLC purity 100.0% at 210-370 nm, 10.8 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 9
Preparation of
N-(tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide
##STR00020##
[0113] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and tert-butylamine (0.41 mL,
3.90 mmol) were stirred together in dry dichloromethane (5 mL) for
16 hours. 4-bromo-N-(tert-butyl)benzenesulfonamide (0.12 g) was
provided after purification. MS (ESI) m/z 292. HPLC purity 100.0%
at 210-370 nm, 9.2 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0114] Step 2: According to general procedure B,
4-bromo-N-(tert-butyl)benzenesulfonamide (117 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
N-(tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide
(19 mg, 15%) was provided after purification. MS (ESI) m/z 317.
HPLC purity 100.0% at 210-370 nm, 10.5 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 10
Preparation of
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
##STR00021##
[0116] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and pyrrolidine (0.32 mL,
3.90 mmol) were stirred together in dry dichloromethane (5 mL) for
16 hours. 1-[(4-bromophenyl)sulfonyl]pyrrolidine (0.12 g) was
provided after purification. HRMS: calcd for
C.sub.14N.sub.12BrNO.sub.2S+H.sup.+, 289.98449; found (ESI,
[M+H].sup.+), 289.9847. HPLC purity 99.1% at 210-370 nm, 8.9 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0117] Step 2: According to general procedure B,
1-[(4-bromophenyl)sulfonyl]pyrrolidine (116 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
(7 mg, 6%) was provided after purification. HRMS: calcd for
C.sub.16H.sub.17N.sub.3O.sub.2S+H.sup.+, 316.11142; found (ESI,
[M+H].sup.+), 316.1114. HPLC purity 100.0% at 210-370 nm, 10.3
min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 11
Preparation of
1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
##STR00022##
[0119] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and piperidine (0.38 mL, 3.90
mmol) were stirred together in dry dichloromethane (5 mL) for 16
hours. 1-[(4-bromophenyl)sulfonyl]piperidine (0.13 g) was provided
after purification. HRMS: calcd for
C.sub.11H.sub.14BrNO.sub.2S+H.sup.+, 304.00014; found (ESI,
[M+H].sup.+), 304.0009. HPLC purity 99.2% at 210-370 nm, 9.8 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0120] Step 2: According to general procedure B,
1-[(4-bromophenyl)sulfonyl]piperidine (121 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
(11 mg, 8%) was provided after purification. MS (ESI) m/z 329. HPLC
purity 100.0% at 210-370 nm, 11.1 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 12
Preparation of
1-methyl-5-[4-(morpholin-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
##STR00023##
[0122] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and morpholine (0.34 mL, 3.90
mmol) were stirred together in dry dichloromethane (5 mL) for 16
hours. 4-[(4-bromophenyl)sulfonyl]morpholine (0.13 g, 28%) was
provided after purification. MS (ESI) m/z 306. HPLC purity 100.0%
at 210-370 nm, 8.2 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0123] Step 2: According to general procedure B,
4-[(4-bromophenyl)sulfonyl]morpholine (122 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(morpholin-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
(11 mg, 8%) was provided after purification. MS (ESI) m/z 331. HPLC
purity 100.0% at 210-370 nm, 9.7 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 13
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide
##STR00024##
[0125] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and cyclobutylamine (0.33 mL,
3.90 mmol) were stirred together in dry dichloromethane (5 mL) for
16 hours. 4-bromo-N-cyclobutylbenzenesulfonamide (0.13 g) was
provided after purification. MS (ESI) m/z 290. HPLC purity 95.6% at
210-370 nm, 9.1 min.; the Xterra.RTM.RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0126] Step 2: According to general procedure B,
4-bromo-N-cyclobutylbenzenesulfonamide (117 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide
(20 mg, 16%) was provided after purification. MS (ESI) m/z 315.
HPLC purity 98.8% at 210-370 nm, 10.4 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 14
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide
##STR00025##
[0128] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylamine (0.27
mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL)
for 16 hours. 4-bromo-N-cyclopropylbenzenesulfonamide (0.12 g) was
provided after purification. MS (ESI) m/z 276. HPLC purity 100.0%
at 210-370 nm, 8.4 min.; the Xterra.RTM.RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0129] Step 2: According to general procedure B,
4-bromo-N-cyclopropylbenzenesulfonamide (110 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide
(34 mg, 28%) was provided after purification. MS (ESI) m/z 301.
HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 15
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide
##STR00026##
[0131] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and cyclohexylamine (0.46 mL,
3.90 mmol) were stirred together in dry dichloromethane (5 mL) for
16 hours. 4-bromo-N-cyclohexylbenzenesulfonamide (0.13 g) was
provided after purification. MS (ESI) m/z 318. HPLC purity 100.0%
at 210-370 nm, 10.0 min.; the Xterra.RTM.RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0132] Step 2: According to general procedure B,
4-bromo-N-cyclohexylbenzenesulfonamide (127 mg, 0.40 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide
(2 mg, 1%) was provided after purification. MS (ESI) m/z 343. HPLC
purity 99.1% at 210-370 nm, 11.3 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 16
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulfon-
amide
##STR00027##
[0134] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and 2,2,2-trifluoroethylamine
(0.32 mL, 3.90 mmol) were stirred together in dry dichloromethane
(5 mL) for 16 hours.
4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (0.13 g) was
provided after purification. MS (ESI) m/z 318. HPLC purity 100.0%
at 210-370 nm, 8.7 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0135] Step 2: According to general procedure B,
4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (127 mg, 0.40
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48
mmol), potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1'-1-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulf-
onamide (57 mg, 42%) was provided after purification. MS (ESI) m/z
343. HPLC purity 97.2% at 210-370 nm, 10.1 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
Example 17
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesulfonann-
ide
##STR00028##
[0137] Step 1: According to general procedure C, 4-Bromobenzene
sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylmethylamine
(0.35 mL, 3.90 mmol) were stirred together in dry dichloromethane
(5 mL) for 16 hours.
4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (0.12 g) was
provided after purification. MS (ESI) m/z 290. HPLC purity 100.0%
at 210-370 nm, 9.0 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0138] Step 2: According to general procedure B,
4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (116 mg, 0.40
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48
mmol), potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesulfonami-
de (6 mg, 5%) was provided after purification. MS (ESI) m/z 315.
HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 18
Preparation of
1-methyl-5-[4-(1H-pyrrol-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
##STR00029##
[0140] Step 1: Pyrrole (1.05 mL, 15.0 mmol) was added to a slurry
of sodium hydride (0.71 g, 60% in mineral oil, 17.8 mmol) in dry
THF (10 mL) at room temperature. 4-Bromobenzene sulfonyl chloride
(1.5 g, 6.0 mmol) dissolved in dry THF (5 mL) was added dropwise.
The reaction mixture was stirred overnight. The reaction was
quenched with saturated ammonium chloride and diluted with ethyl
acetate. The layers were separated and the organic layer was washed
with water and brine. The organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to give the
crude product. The crude product was purified via Isco
chromatography (the Redisep.TM. column, silica, gradient 5-50%
ethyl acetate in hexane) to give
1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (0.27 g, 16%). MS (ESI) m/z
286. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
[0141] Step 2: According to general procedure B,
1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (250 mg, 0.87 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol),
potassium fluoride (76 mg, 1.3 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.0 mL)
was added. Tri-t-butylphosphine (60 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(1H-pyrrol-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile
(81 mg, 30%) was provided after purification. MS (ESI) m/z 311.
HPLC purity 100.0% at 210-370 nm, 11.6 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 19
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide
##STR00030##
[0143] Step 1: 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride
(0.50 g, 1.54 mmol) and ammonia (10 mL, ca. 7 N in methanol) were
stirred in a sealed tube for 16 hours. The reaction solution was
concentrated in vacuo onto the Celite.RTM. reagent. The crude
product was purified via Isco chromatography (the Redisep.TM.
column, silica, gradient 5-50% ethyl acetate in hexane) to recover
4-bromo-2-(trifluoromethyl)benzenesulfonamide (0.46 g, 96%). MS
(ESI) m/z 304. HPLC purity 99.8% at 210-370 nm, 7.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0144] Step 2: According to general procedure B,
4-bromo-2-(trifluoromethyl)benzenesulfonamide (170 mg, 0.56 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol),
potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide
(34 mg, 18%) was provided after purification. MS (ESI) m/z 329.
HPLC purity 98.6% at 210-370 nm, 9.1 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 20
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benze-
nesulfonamide
##STR00031##
[0146] Step 1: In an analogous manner to General Procedure A,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in
sealed tube for 16 hours.
4-bromo-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (0.41 g,
80%) was provided after purification. MS (ESI) m/z 332. HPLC purity
100.0% at 210-370 nm, 9.3 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0147] Step 2: According to general procedure B,
4-bromo-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (186 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benze-
nesulfonamide (115 mg, 58%) was provided after purification. MS
(ESI) m/z 357. HPLC purity 98.4% at 210-370 nm, 10.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 21
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesu-
lfonamide
##STR00032##
[0149] Step 1: In an analogous manner to General Procedure A,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and methylamine (10 mL, 33% in ethanol) were stirred in
sealed tube for 16 hours. 4-bromo-N-methyl-2
(trifluoromethyl)benzenesulfonamide (0.44 g, 90%) was provided
after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370
nm, 8.5 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6
mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0150] Step 2: According to general procedure B,
4-bromo-N-methyl-2(trifluoromethyl)benzenesulfonamide (178 mg, 0.56
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67
mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesu-
lfonamide (90 mg, 47%) was provided after purification. MS (ESI)
m/z 343. HPLC purity 99.2% at 210-370 nm, 9.7 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
Example 22
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzen-
esulfonamide
##STR00033##
[0152] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and diethylamine (0.40 mL, 3.85 mmol) were stirred together
in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N,N-diethyl-2
(trifluoromethyl)benzenesulfonamide (0.46 g, 83%) was provided
after purification. MS (ESI) m/z 360. HPLC purity 100.0% at 210-370
nm, 10.1 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6
mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0153] Step 2: According to general procedure B,
4-bromo-N,N-diethyl-2(trifluoromethyl)benzenesulfonamide (201 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzen-
esulfonamide (100 mg, 46%) was provided after purification. MS
(ESI) m/z 385. HPLC purity 100.0% at 210-370 nm, 11.2 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
ml/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 23
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzen-
esulfonamide
##STR00034##
[0155] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and isopropylamine (0.35 mL, 3.85 mmol) were stirred together
in dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g,
95%) was provided after purification. MS (ESI) m/z 346. HPLC purity
100.0% at 210-370 nm, 9.6 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0156] Step 2: According to general procedure B,
4-bromo-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (193 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzen-
esulfonamide (91 mg, 44%) was provided after purification. MS (ESI)
m/z 371. HPLC purity 100.0% at 210-370 nm, 10.6 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 24
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesul-
fonamide
##STR00035##
[0158] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and ethylamine (2.0 mL, 2.0 M in THF, 4.00 mmol) were stirred
together in dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g, 98%)
was provided after purification. MS (ESI) m/z 332. HPLC purity
100.0% at 210-370 nm, 9.1 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0159] Step 2: According to general procedure B,
4-bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (186 mg, 0.56
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67
mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesul-
fonamide (90 mg, 45%) was provided after purification. MS (ESI) m/z
357. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
Example 25
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesu-
lfonamide
##STR00036##
[0161] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and propylamine (0.32 mL, 3.85 mmol) were stirred together in
dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g,
100%) was provided after purification. MS (ESI) m/z 346. HPLC
purity 100.0% at 210-370 nm, 9.7 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0162] Step 2: According to general procedure B,
4-bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (193 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesu-
lfonamide (68 mg, 33%) was provided after purification. MS (ESI)
m/z 371. HPLC purity 100.0% at 210-370 nm, 10.7 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 26
Preparation of
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenyl]-1H-pyr-
role-2-carbonitrile
##STR00037##
[0164] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and pyrrolidine (0.32 mL, 3.85 mmol) were stirred together in
dry dichloromethane (2 mL) for 16 hours.
1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (0.53 g,
96%) was provided after purification. MS (ESI) m/z 358. HPLC purity
100.0% at 210-370 nm, 9.8 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0165] Step 2: In analogous manner to general procedure B,
1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (200 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenyl]-1H-pyr-
role-2-carbonitrile (117 mg, 54%) was provided after purification.
HRMS: calcd for C.sub.17H.sub.16F.sub.3N.sub.3O.sub.2S+H.sup.+,
384.09881; found (ESI, [M+H].sup.+), 384.0991, HPLC purity 100.0%
at 210-370 nm, 10.9 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 27
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benz-
enesulfonamide
##STR00038##
[0167] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and cyclopropylamine (0.27 mL, 3.85 mmol) were stirred
together in dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (0.51
g, 96%) was provided after purification. MS (ESI) m/z 344. HPLC
purity 100.0% at 210-370 nm, 9.3 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0168] Step 2: According to general procedure B,
4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (193
mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100
mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benz-
enesulfonamide was provided (87 mg, 42%) after purification. MS
(ESI) m/z 369. HPLC purity 99.6% at 210-370 nm, 10.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 28
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hyl)benzenesulfonamide
##STR00039##
[0170] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and cyclopropylmethylamine (0.34 mL, 3.85 mmol) were stirred
together in dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)-benzenesulfonamide
(0.50 g, 91%) was provided after purification. MS (ESI) m/z 358.
HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0171] Step 2: In analogous manner to general procedure B,
4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)benzenesulfonamide
(200 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid
(100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hyl)-benzenesulfonamide (106 mg, 53%) was provided after
purification. MS (ESI) m/z 383. HPLC purity 100.0% at 210-370 nm,
10.8 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 29
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benze-
nesulfonamide
##STR00040##
[0173] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54
mmol) and cyclobutylamine (0.33 mL, 3.85 mmol) were stirred
together in dry dichloromethane (2 mL) for 16 hours.
4-bromo-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g,
96%) was provided after purification. MS (ESI) m/z 358. HPLC purity
100.0% at 210-370 nm, 9.9 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0174] Step 2: According to general procedure B,
4-bromo-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (200 mg,
0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg,
0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (83 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benze-
nesulfonamide (122 mg, 57%) was provided after purification. MS
(ESI) m/z 383. HPLC purity 99.3% at 210-370 nm, 10.9 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
ml/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 30
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide
##STR00041##
[0176] Step 1: According to general procedure A,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
ammonia (20 mL, ca. 7N in methanol) were stirred together for 16
hours. 4-bromo-3-fluorobenzenesulfonamide was provided after
purification (0.23 g, 61%). HRMS: calcd for
C.sub.6H.sub.5BrFNO.sub.2S, 252.92084; found (El, M.sup.+),
252.9201. HPLC purity 100.0% at 210-370 nm, 7.5 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0177] Step 2: According to general procedure B,
4-bromo-3-fluorobenzenesulfonamide (150 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide (29
mg, 18%) was provided after purification. MS (ESI) m/z 279. HPLC
purity 100.0% at 210-370 nm, 8.6 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 31
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methylbenzenesulfonamide
##STR00042##
[0179] Step 1: According to general procedure A,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
methylamine (10 mL, 33% in ethanol) were stirred together for 16
hours. 4-bromo-3-fluoro-N-methylbenzenesulfonamide (0.33 g, 85%)
was provided after purification. HRMS: calcd for
C.sub.7H.sub.7BrFNO.sub.2S, 266.93649; found (El, M.sup.+.),
266.9376. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0180] Step 2: According to general procedure B,
4-bromo-3-fluoro-N-methylbenzenesulfonamide (158 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methylbenzenesulfonamide
(53 mg, 31%) was provided after purification. HRMS: calcd for
C.sub.13H.sub.12FN.sub.3O.sub.2S, 293.06342; found (El, M.sup.+.),
293.0627. HPLC purity 99.5% at 210-370 nm, 8.2 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 32
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonami-
de
##STR00043##
[0182] Step 1: According to general procedure A,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
dimethylamine (10 mL, 33% in ethanol) were stirred together for 16
hours. 4-bromo-3-fluoro-N,N-dimethylbenzenesulfonamide (0.36 g,
89%) was provided after purification. HRMS: calcd for
C.sub.8H.sub.9BrFNO.sub.2S, 280.95214; found (El, M.sup.+.),
280.9516. HPLC purity 98.9% at 210-370 nm, 9.6 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0183] Step 2: According to general procedure B,
4-bromo-3-fluoro-N,N-dimethylbenzenesulfonamide (166 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonami-
de (51 mg, 28%) was provided after purification. HRMS: calcd for
C.sub.14H.sub.14FN.sub.3O.sub.2S, 307.07907; found (El, M.sup.+.),
307.0786. HPLC purity 99.3% at 210-370 nm, 8.8 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 33
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-3-fluorobenzenesulfonamide
##STR00044##
[0185] Step 1: According to general procedure A,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred together
for 16 hours. 4-bromo-N-ethyl-3-fluorobenzenesulfonamide (0.38 g,
92%) was provided after purification. HRMS: calcd for
C.sub.8H.sub.9BrFNO.sub.2S, 280.95214; found (El, M.sup.+.),
280.951. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the
Xterra.RTM. RF18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0186] Step 2: According to general procedure B,
4-bromo-N-ethyl-3-fluorobenzenesulfonamide (166 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-3-fluorobenzenesulfonamide
(44 mg, 24%) was provided after purification. HRMS: calcd for
C.sub.14H.sub.14FN.sub.3O.sub.2S, 307.07907; found (El, M.sup.+.),
307.0792. HPLC purity 99.5% at 210-370 nm, 8.7 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 34
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamid-
e
##STR00045##
[0188] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (0.41 g, 90%) was
provided after purification. HRMS: calcd for
C.sub.10H.sub.13BrFNO.sub.2S, 308.98344; found (El M.sup.+.),
308.9822. HPLC purity 100.0% at 210-370 nm, 10.9 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0189] Step 2: According to general procedure B,
4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (183 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamid-
e (46 mg, 23%) was provided after purification. HRMS: calcd for
C.sub.16H.sub.18FN.sub.3O.sub.2S+H.sup.+, 336.11765; found (ESI,
[M+H].sup.+), 336.117. HPLC purity 99.7% at 210-370 nm, 9.7 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 35
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamid-
e
##STR00046##
[0191] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
isopropylamine (0.31 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (0.40 g, 93%) was
provided after purification. HRMS: calcd for
C.sub.9H.sub.11BrFNO.sub.2S, 294.96779; found (El, M.sup.+.),
294.9665. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0192] Step 2: According to general procedure B,
4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (174 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamid-
e (35 mg, 19%) was provided after purification. HRMS: calcd for
C.sub.15H.sub.16FN.sub.3O.sub.2S, 321.09472; found (El, M.sup.+.),
321.0948. HPLC purity 100.0% at 210-370 nm, 9.1 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 36
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-propylbenzenesulfonamide
##STR00047##
[0194] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
propylamine (0.30 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-3-fluoro-N-propylbenzenesulfonamide (0.39 g, 90%) was
provided after purification. HRMS: calcd for
C.sub.9H.sub.11BrFNO.sub.2S, 294.96779; found (El, M.sup.+.),
294.9684. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0195] Step 2: According to general procedure B,
4-bromo-3-fluoro-N-propylbenzenesulfonamide (174 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-propylbenzenesulfonamide
was provided after purification. HRMS: calcd for
C.sub.15H.sub.16FN.sub.3O.sub.2S, 321.09472; found (El, M.sup.+.),
321.0947. HPLC purity 99.7% at 210-370 nm, 9.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 37
Preparation of
5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1H-pyrrole-2-carb-
onitrile
##STR00048##
[0197] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
pyrrolidine (0.30 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
1-[(4-bromo-3-fluorophenyl)sulfonyl]pyrrolidine (0.43 g, 96%) was
provided after purification. HRMS: calcd for
C.sub.10H.sub.11BrFNO.sub.2S, 306.96779; found (El, M.sup.+.),
306.968. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0198] Step 2: According to general procedure B,
1-[(4-bromo-3-fluorophenyl)sulfonyl]pyrrolidine (182 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1H-pyrrole-2-carb-
onitrile (61 mg, 31%) was provided after purification. HRMS: calcd
for C.sub.16H.sub.16FN.sub.3O.sub.2S+H.sup.+, 334.10200; found
(ESI, [M+H].sup.+), 334.1035. HPLC purity 100.0% at 210-370 nm, 9.3
min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 38
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonam-
ide
##STR00049##
[0200] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with
dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (0.37 g, 86%) was
provided after purification. HRMS: calcd for
C.sub.9H.sub.9BrFNO.sub.2S-H.sup.+, 291.94486; found (ESI, [M-H]-),
291.9462. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0201] Step 2: According to general procedure B,
4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (175 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonam-
ide (26 mg, 14%) was provided after purification. MS (ESI) m/z 319.
HPLC purity 100.0% at 210-370 nm, 8.9 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 39
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzene-
sulfonamide
##STR00050##
[0203] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclopropylmethylamine (0.32 mL, 3.65 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (0.25 g,
55%) was provided after purification. HRMS: calcd for
C.sub.10H.sub.1BrFNO.sub.2S-H.sup.+, 305.96051; found (ESI,
[M-H].sup.-), 305.9603. HPLC purity 100.0% at 210-370 nm, 10.5
min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0204] Step 2: According to general procedure B,
4-bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (182 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg,
0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzene-
sulfonamide (26 mg, 13%) was provided after purification. HRMS:
calcd for C.sub.16H.sub.16FN.sub.3O.sub.2S+H.sup.+, 334.10200;
found (ESI, [M+H].sup.+), 334.1024. HPLC purity 100.0% at 210-370
nm, 9.4 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6
mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 40
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-3-fluorobenzenesulfonami-
de
##STR00051##
[0206] Step 1: According to general procedure C,
4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclobutylamine (0.31 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclobutyl-3-fluorobenzenesulfonamide (0.40 g, 89%) was
provided after purification. MS (ESI) m/z 308. HPLC purity 98.2% at
210-370 nm, 10.6 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0207] Step 2: According to general procedure B,
4-bromo-N-cyclobutyl-3-fluorobenzenesulfonamide (182 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-3-fluorobenzenesulfonami-
de (28 mg, 14%) was provided after purification. HRMS: calcd for
C.sub.16H.sub.16FN.sub.3O.sub.2S-H.sup.+, 332.08745; found (ESI,
[M-H]-), 332.0867. HPLC purity 96.9% at 210-370 nm, 9.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 41
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonamid-
e
##STR00052##
[0209] Step 1: According to general procedure C,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-N,N-diethyl-2-fluorobenzenesulfonamide (0.19 g, 43%) was
provided after purification. HRMS: calcd for
C.sub.10H.sub.13BrFNO.sub.2S+H.sup.+, 309.99071; found (ESI,
[M+H].sup.+), 309.9917. HPLC purity 100.0% at 210-370 nm, 9.6 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0210] Step 2: According to general procedure B,
4-bromo-N,N-diethyl-2-fluorobenzenesulfonamide (183 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonamid-
e (63 mg, 32%) was provided after purification. MS (ESI) m/z 335.
HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 42
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfonamid-
e
##STR00053##
[0212] Step 1: According to general procedure C,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
isopropylamine (0.31 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-2-fluoro-N-isopropylbenzenesulfonamide (189 mg, 44%) was
provided after purification. MS (ESI) m/z 296. HPLC purity 100.0%
at 210-370 nm, 10.6 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0213] Step 2: According to general procedure B,
4-bromo-2-fluoro-N-isopropylbenzenesulfonamide (177 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfonamid-
e (24 mg, 13%) was provided after purification. MS (ESI) m/z 321.
HPLC purity 100.0% at 210-370 nm, 9.0 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 43
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonam-
ide
##STR00054##
[0215] Step 1: According to general procedure C,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with
dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (190 mg, 44%) was
provided after purification. MS (ESI) m/z 294. HPLC purity 98.6% at
210-370 nm, 10.2 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0216] Step 2: According to general procedure B,
4-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (176 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonam-
ide (45 mg, 24%) was provided after purification. MS (ESI) m/z 319.
HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 44
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzene-
sulfonamide
##STR00055##
[0218] Step 1: According to general procedure C,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclopropylmethylamine (0.31 mL, 3.65 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (0.18 g,
40%) was provided after purification. MS (ESI) m/z 308. HPLC purity
97.7% at 210-370 nm, 10.7 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonium
Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min., hold 4 min.
[0219] Step 2: According to general procedure B,
4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (181 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg,
0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzene-
sulfonamide (20 mg, 10%) was provided after purification. MS (ESI)
m/z 333. HPLC purity 100.0% at 210-370 nm, 11.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 45
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-fluorobenzenesulfonami-
de
##STR00056##
[0221] Step 1: According to general procedure C,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
cyclobutylamine (0.31 mL, 3.65 mmol) were stirred together with dry
dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (192 mg, 43%) was
provided after purification. MS (ESI) m/z 308. HPLC purity 90.7% at
210-370 nm, 11.2 min.; the Xterra.RTM. RP18 column, 3.5.mu.,
150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate
buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0222] Step 2: According to general procedure B,
4-bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (185 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-fluorobenzenesulfonami-
de (25 mg, 13%) was provided after purification. MS (ESI) m/z 333.
HPLC purity 99.6% at 210-370 nm, 9.3 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 46
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamid-
e
##STR00057##
[0224] Step 1: According to general procedure A,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and ammonia (10 mL, ca. 7N in methanol) were stirred together
for 16 hours. 4-bromo-2-(trifluoromethoxy)benzenesulfonamide (0.33
g, 100%) was provided after purification. MS (ESI) m/z 320. HPLC
purity 100.0% at 210-370 nm, 8.0 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0225] Step 2: According to general procedure B,
4-bromo-2-(trifluoromethoxy)benzenesulfonamide (192 mg, 0.59 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol),
potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamid-
e (50 mg, 24%) was provided after purification. MS (ESI) m/z 345.
HPLC purity 100.0% at 210-370 nm, 8.4 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
Example 47
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethoxy)benzenes-
ulfonamide
##STR00058##
[0227] Step 1: According to general procedure A,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and methylamine (10 mL, 33% in ethanol) were stirred in
sealed tube for 16 hours.
4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (0.21 g,
61%) was provided after purification. MS (ESI) m/z 334. HPLC purity
98.0% at 210-370 nm, 8.8 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0228] Step 2: According to general procedure B,
4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (200 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethoxy)benzenes-
ulfonamide (61 mg, 28%) was provided after purification. MS (ESI)
m/z 359. HPLC purity 99.6% at 210-370 nm, 9.0 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
Example 48
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benz-
enesulfonamide
##STR00059##
[0230] Step 1: According to general procedure A,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in
sealed tube for 16 hours.
4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (0.29 g,
81%) was provided after purification. Mp. 55-58.degree. C. MS (ESI)
m/z 348.14.
[0231] Step 2: According to general procedure B,
4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (209 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benz-
enesulfonamide (73 mg, 32%) was provided after purification. MS
(ESI) m/z 373. HPLC purity 99.1% at 210-370 nm, 9.7 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 49
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesu-
lfonamide
##STR00060##
[0233] Step 1: According to general procedure A,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred
together for 16 hours.
4-bromo-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide (0.23 g,
64%) was provided after purification. MS (ESI) m/z 348. HPLC purity
100.0% at 210-370 nm, 9.3 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0234] Step 2: According to general procedure B,
4-bromo-N-ethyl-2(trifluoromethoxy)benzenesulfonamide (208 mg, 0.59
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71
mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesu-
lfonamide (40 mg, 18%) was provided after purification. MS (ESI)
m/z 373. HPLC purity 99.4% at 210-370 nm, 9.4 min.; the Xterra.RTM.
RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min.,
85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min.,
hold 4 min.
Example 50
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethoxy)benze-
nesulfonamide
##STR00061##
[0236] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and diethylamine (0.26 mL, 2.57 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (0.38 g,
98%) was provided after purification. MS (ESI) m/z 376. HPLC purity
100.0% at 210-370 nm, 10.4 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0237] Step 2: According to general procedure B,
4-bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (225 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethoxy)benze-
nesulfonamide (98 mg, 42%) was provided after purification. MS
(ESI) m/z 401. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 51
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benze-
nesulfonamide
##STR00062##
[0239] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and isopropylamine (0.21 mL, 2.57 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.29 g,
78%) was provided after purification. MS (ESI) m/z 362. HPLC purity
100.0% at 210-370 nm, 9.8 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0240] Step 2: According to general procedure B,
4-bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (217 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benze-
nesulfonamide (79 mg, 35%) was provided after purification. MS
(ESI) m/z 387. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 52
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethoxy)benzenes-
ulfonamide
##STR00063##
[0242] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and propylamine (0.21 mL, 2.57 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (0.37 g,
91%) was provided after purification. MS (ESI) m/z 362. HPLC purity
100.0% at 210-370 nm, 9.9 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0243] Step 2: According to general procedure B,
4-bromo-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (217 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethoxy)benzenes-
ulfonamide (66 mg, 29%) was provided after purification. MS (ESI)
m/z 387. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 53
Preparation of
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethoxy)phenyl]-1H-py-
rrole-2-carbonitrile
##STR00064##
[0245] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and pyrrolidine (0.21 mL, 2.57 mmol) were stirred together
with dry dichloromethane (5 mL) for 16 hours.
1-{[4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}pyrrolidine (0.25
g, 65%) was provided after purification. MS (ESI) m/z 374. HPLC
purity 100.0% at 210-370 nm, 10.1 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0246] Step 2: According to general procedure B,
4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}pyrrolidine (224 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethoxy)phenyl]-1H-py-
rrole-2-carbonitrile (98 mg, 42%) was provided after purification.
MS (ESI) m/z 399. HPLC purity 100.0% at 210-370 nm, 10.0 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 54
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)ben-
zenesulfonamide
##STR00065##
[0248] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and cyclopropylamine (0.17 mL, 2.57 mmol) were stirred
together with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.25
g, 68%) was provided after purification. MS (ESI) m/z 360. HPLC
purity 100.0% at 210-370 nm, 9.5 min.; the Xterra.RTM. RP18 column,
3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
[0249] Step 2: According to general procedure B,
4-bromo-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (216
mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107
mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)ben-
zenesulfonamide (65 mg, 29%) was provided after purification. MS
(ESI) m/z 385. HPLC purity 99.2% at 210-370 nm, 9.5 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 55
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hoxy)benzenesulfonamide
##STR00066##
[0251] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and cyclopropylmethylamine (0.21 mL, 2.57 mmol) were stirred
together with dry dichloromethane (5 mL for 16 hours.
4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide
(0.35 g, 91%) was provided after purification. MS (ESI) m/z 374.
HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min
[0252] Step 2: According to general procedure B,
4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide
(224 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid
(107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromet-
hoxy)benzenesulfonamide (56 mg, 24%) was provided after
purification. MS (ESI) m/z 399. HPLC purity 99.1% at 210-370 nm,
9.9 min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 56
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benz-
enesulfonamide
##STR00067##
[0254] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and cyclobutylamine (0.21 mL, 2.57 mmol) were stirred
together with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (0.23
g, 61%) was provided after purification. MS (ESI) m/z 374. HPLC
purity 100.0% at 210-370 nm, 10.1 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 ml/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0255] Step 2: According to general procedure B,
4-bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (224
mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107
mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benz-
enesulfonamide (56 mg, 24%) was provided after purification. MS
(ESI) m/z 399. HPLC purity 99.4% at 210-370 nm, 10.0 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 57
Preparation of
N-tert-butyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benz-
enesulfonamide
##STR00068##
[0257] Step 1: According to general procedure C,
4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03
mmol) and tert-butylamine (0.21 mL, 2.57 mmol) were stirred
together with dry dichloromethane (5 mL) for 16 hours.
4-bromo-N-tert-butyl-2-(trifluoromethoxy)benzenesulfonamide (0.33
g, 85%) was provided after purification. MS (ESI) m/z 376. HPLC
purity 100.0% at 210-370 nm, 10.2 min.; the Xterra.RTM. RP18
column, 3.5.mu., 150.times.4.6 mm column, 1.2 mL/min., 85/15-5/95
(ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4
min.
[0258] Step 2: According to general procedure B,
4-bromo-N-tert-butyl-2-(trifluoromethoxy)benzenesulfonamide (225
mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107
mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
N-tert-butyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benz-
enesulfonamide (44 mg, 19%) was provided after purification. MS
(ESI) m/z 401. HPLC purity 99.0% at 210-370 nm, 10.1 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
ml/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 58
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(dimethylamino)-N,N-dimethylbenzenes-
ulfonamide
##STR00069##
[0260] Step 1: According to general procedure A,
4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and
dimethylamine (10 mL, 33% in ethanol) were stirred in a sealed tube
for 16 hours.
4-bromo-2-(dimethylamino)-N,N-dimethylbenzenesulfonamide (0.19 g,
42%) was provided after purification. HRMS: calcd for
C.sub.10H.sub.15BrN.sub.2O.sub.2S+H.sup.+, 307.01103; found (ESI,
[M+H].sup.+), 307.012. HPLC purity 100.0% at 210-370 nm, 9.4 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
[0261] Step 2: According to general procedure B,
4-bromo-2-(dimethylamino)-N,N-dimethylbenzenesulfonamide (180 mg,
0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg,
0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.4 mL)
was added. Tri-t-butylphosphine (89 .mu.L, 0.02 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(dimethylamino)-N,N-dimethylbenzene-
sulfonamide (28 mg, 14%) was provided after purification. MS (ESI)
m/z 332. HPLC purity 100.0% at 210-370 nm, 9.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min.
Example 59
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-methylbenzenesulfonami-
de
##STR00070##
[0263] Step 1: According to general procedure C,
4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol)
and methylamine were stirred together in dichloromethane (1 mL) for
16 hours. The reaction afforded
4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (0.17 g) after
purification. HPLC purity 100.0% at 210-370 nm, 9.2 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.7H.sub.6BrF.sub.2NO.sub.2S-H.sup.+, 283.91979; found
(ESI-FTMS, [M-H].sup.1-), 283.92003
[0264] Step 2: According to general procedure B,
4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (143 mg, 0.5 mmol),
5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60 mmol),
potassium fluoride (96 mg, 1.65 mmol), and
tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.3 mL)
was added. Tri-t-butylphosphine (75 .mu.L, 0.026 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
Purification afforded
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-methylbenzenesulfonami-
de (24 mg). HPLC purity 87.6% at 210-370 nm, 8.4 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.13H.sub.11F.sub.2N.sub.3O.sub.2S-H.sup.+, 310.04673; found
(ESI-FTMS, [M-H].sup.1-), 310.04692
Example 60
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfon-
amide
##STR00071##
[0266] Step 1: According to general procedure C,
4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol)
and isopropylamine were stirred together in dichloromethane (1 mL)
for 16 hours. The reaction afforded
4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (0.16 g) after
purification. HPLC purity 96.6% at 210-370 nm, 10.7 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.9H.sub.10BrF.sub.2NO.sub.2S-H.sup.+, 311.95109; found
(ESI-FTMS, [M-H].sup.1-), 311.95114
[0267] Step 2: According to general procedure B,
4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (150 mg, 0.5
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60
mmol), potassium fluoride (96 mg, 1.65 mmol), and
tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.3 mL)
was added. Tri-t-butylphosphine (75 .mu.L, 0.026 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
Purification afforded
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfon-
amide (24 mg) HPLC purity 97.2% at 210-370 nm, 9.3 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.15H.sub.15F.sub.2N.sub.3O.sub.2S-H.sup.+, 338.07803; found
(ESI-FTMS, [M-H].sup.1-), 338.07811
Example 61
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2,5-difluorobenzenesulf-
onamide
##STR00072##
[0269] Step 1: According to general procedure C,
4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol)
and cyclopropylamine were stirred together in dichloromethane (1
mL) for 16 hours. The reaction afforded
4-bromo-N-cyclopropyl-2,5-difluorobenzenesulfonamide (0.17 g) after
purification. HPLC purity 99.2% at 210-370 nm, 10.2 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.9H.sub.8BrF.sub.2NO.sub.2S+H.sup.+, 309.93544; found
(ESI-FTMS, [M-H].sup.1-), 309.93545
[0270] Step 2: According to general procedure B,
4-bromo-N-cyclopropyl-2,5-difluorobenzenesulfonamide (150 mg, 0.5
mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60
mmol), potassium fluoride (96 mg, 1.65 mmol), and
tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.3 mL)
was added. Tri-t-butylphosphine (75 .mu.L, 0.026 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
Purification afforded
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2,5-difluorobenzenesulf-
onamide (33 mg) HPLC purity 99.0% at 210-370 nm, 9.1 min.; the
Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.18H.sub.13F.sub.2N.sub.3O.sub.2S-H.sup.+, 336.06238; found
(ESI-FTMS, [M-H].sup.1-), 336.06247
Example 62
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2,5-difluoroben-
zenesulfonamide (WYE-100761)
##STR00073##
[0272] Step 1: According to general procedure C,
4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol)
and cyclopropylmethylamine were stirred together in dichloromethane
(1 mL) for 16 hours. The reaction afforded
4-bromo-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (0.17
g) after purification. HPLC purity 95.0% at 210-370 nm, 9.3 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.10H.sub.10BrF.sub.2NO.sub.2S-H.sup.+, 323.95109; found
(ESI-FTMS, [M-H].sup.1''), 323.95103
[0273] Step 2: According to general procedure B,
4-bromo-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (150
mg, 0.5 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg,
0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and
tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were
placed in an oven dried flask under nitrogen and dry THF (1.3 mL)
was added. Tri-t-butylphosphine (75 .mu.L, 0.026 mmol, 10 wt % in
hexane) was added and the reaction was stirred for 16 hours.
Purification afforded
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2,5-difluoroben-
zenesulfonamide (47 mg). HPLC purity 98.2% at 210-370 nm, 9.5 min.;
the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm column, 1.2
mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 min., hold 4 min. HRMS: calcd for
C.sub.16H.sub.15F.sub.2N.sub.3O.sub.2S-H.sup.+, 350.07803; found
(ESI-FTMS, [M-H].sup.1''), 350.07826
Example 63
Preparation of
4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzene-sulfonamide
##STR00074##
[0275] According to general procedure B, 4-bromobenzenesulfonamide
(472 mg, 2.0 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid
(360 mg, 2.4 mmol), potassium fluoride (350 mg, 6.0 mmol), and
tris(dibenzylideneacetone)-dipalladium (48 mg, 0.05 mmol) were
placed in an oven dried flask under nitrogen and dry THF (5 mL) was
added. Tri-t-butylphosphine (0.30 mL, 0.1 mmol, 10 wt % in hexane)
was added and the reaction was stirred for 16 hours. Purification
afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzene-sulfonamide
(190 mg). MS (ES) m/z 261.8; HPLC purity 99.6% at 210-370 nm, 7.1
min.; the Xterra.RTM. RP18 column, 3.5.mu., 150.times.4.6 mm
column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 64
Effects of Progestins and Antiprogestins on Alkaline Phosphatase
Activity in T47D Cells
[0276] This example was performed to identify progestins or
antiprogestins by determining a compound's effect on alkaline
phosphatase activity in T47D cells.
Materials and Methods:
[0277] A. Reagents: [0278] 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 the GlutaMax.TM. reagent (GIBCO, BRL).
[0279] Alkaline phosphatase assay buffer: [0280] I. 0.1 M Tris-HCl,
pH 9.8, containing 0.2% the Triton.RTM. X-100 [0281] reagent [0282]
II. 0.1M Tris-HCl, pH 9.8, containing 4 mM p-nitrophenyl phosphate
(Sigma).
[0283] B. Cell Culture and Treatment: [0284] 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 hours. NOTE: For high
throughput screening, one concentration of each compound was tested
at 0.3 .mu.g/mL. Based on an average molecular weight of 300 g/mol
for the compounds in the library, the concentration was
approximately 1 .mu.M. Subsequently, active compounds were tested
in dose response assays to determine EC.sub.50 and IC.sub.50.
[0285] C. Alkaline Phosphatase Enzyme Assay:
[0286] At the end of treatment, the medium was removed from the
plate. Fifty .mu.L of assay buffer I was added to each well. The
plates were shaken in a titer plate shaker for 15 minutes. 150
.mu.L of assay buffer II was then added to each well. Optical
density measurements were taken at 5 minute intervals for 30
minutes at a test wavelength of 405 nM.
Analysis of Results--Analysis of Dose-Response Data
[0287] For reference and test compounds, a dose response curve was
generated for dose (X-axis) vs. the rate of enzyme reaction (slope)
(Y-axis). Square root-transformed data was used for analysis of
variance and nonlinear dose response curve fitting for both agonist
and antagonist modes. Huber weighting was used to down-weight the
effects of outliers. EC.sub.50 or IC.sub.50 values were calculated
from the retransformed values. JMP software (SAS Institute, Inc.)
was used for both one-way analysis of variance and non-4 linear
dose response analysis in both single dose and dose response
studies.
REFERENCE COMPOUNDS
[0288] Progesterone and trimegestone are reference progestins known
in the art and typically show an EC.sub.50 of about 0.1 nM to about
2.0 nM. RU486 is a reference antiprogestin known in the art and
typically shows an IC.sub.50 of about 0.1 nM to about 2.0 nM.
TABLE-US-00001 Example Active Dose (nM) IC.sub.50 (nM) 1 13.9 2
81.3 3 11.4 4 23.8 5 27.5 6 47.9 7 66.1 8 48.4 9 10000 10 146.5 11
132.2 12 189.1 13 13.9 14 6.6 15 58.9 16 40.8 17 27.6 18 48.1 19
35.8 20 81.9 21 22 80.4 23 77.1 24 45.8 25 17.3 26 115.1 27 38.2 28
34.9 29 17 30 91 31 8.5 32 127.8 33 13.1 34 65.6 35 26.8 36 26.5 37
150.7 38 9.7 39 40.4 40 18.1 41 62.2 42 48.1 43 30 44 45.6 45 99.4
46 75.8 47 48 62.7 49 121.5 50 101.1 51 32.5 52 8.4 53 22.7 54 71.7
55 12.3 56 30 57 30 58 25.9 59 36.1 60 49.3 61 30 62 163.8 63
99.5
[0289] All publications cited in this specification are
incorporated herein by reference. While the invention has been
described with reference to particular embodiments, 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.
* * * * *