U.S. patent application number 11/955195 was filed with the patent office on 2008-07-03 for aminoalkyl substituted aryl sulfamide derivatives and methods of their use.
This patent application is currently assigned to Wyeth. Invention is credited to Stephen Todd Cohn, Matthew Lantz Crawley, Andrew Fensome, Joel Adam Goldberg, Douglas John Jenkins, Callain Younghee Kim, Paige Erin Mahaney, Charles William Mann, Michael Anthony Marella, Casey Cameron McComas, David John O'Neill, Joseph Peter Sabatucci, Eugene Anthony Terefenko, Eugene John Trybulski, An Thien Vu, Richard Page Woodworth, Puwen Zhang.
Application Number | 20080161366 11/955195 |
Document ID | / |
Family ID | 39273293 |
Filed Date | 2008-07-03 |
United States Patent
Application |
20080161366 |
Kind Code |
A1 |
McComas; Casey Cameron ; et
al. |
July 3, 2008 |
AMINOALKYL SUBSTITUTED ARYL SULFAMIDE DERIVATIVES AND METHODS OF
THEIR USE
Abstract
The present invention is directed to aminoalkyl-substituted aryl
sulfamide derivatives of formula I: ##STR00001## or a
pharmaceutically acceptable salt, stereoisomer or tautomer thereof,
which are monoamine reuptake inhibitors, compositions containing
these derivatives, and methods of their use for the prevention and
treatment of conditions, including, inter alia, vasomotor symptoms,
sexual dysfunction, gastrointestinal disorders and genitourinary
disorder, depression disorders, endogenous behavioral disorders,
cognitive disorders, diabetic neuropathy, pain, and other diseases
or disorders.
Inventors: |
McComas; Casey Cameron;
(Phoenixville, PA) ; Cohn; Stephen Todd; (Spring,
TX) ; Crawley; Matthew Lantz; (Phoenixville, PA)
; Fensome; Andrew; (Wayne, PA) ; Goldberg; Joel
Adam; (Philadelphia, PA) ; Jenkins; Douglas John;
(Cincinnati, OH) ; Kim; Callain Younghee;
(Collegeville, PA) ; Mahaney; Paige Erin;
(Pottstown, PA) ; Mann; Charles William; (Plymouth
Meeting, PA) ; Marella; Michael Anthony; (Limerick,
PA) ; O'Neill; David John; (Collegeville, PA)
; Sabatucci; Joseph Peter; (Collegeville, PA) ;
Terefenko; Eugene Anthony; (Center Valley, PA) ;
Trybulski; Eugene John; (Huntingdon Valley, PA) ; Vu;
An Thien; (Pottstown, PA) ; Woodworth; Richard
Page; (North Wales, PA) ; Zhang; Puwen;
(Audubon, PA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
39273293 |
Appl. No.: |
11/955195 |
Filed: |
December 12, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60869644 |
Dec 12, 2006 |
|
|
|
Current U.S.
Class: |
514/362 ;
548/135 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 3/00 20180101; A61P 25/00 20180101; A61P 25/20 20180101; A61P
21/00 20180101; A61P 9/00 20180101; A61P 13/00 20180101; A61P 25/02
20180101; A61P 25/28 20180101; C07D 417/06 20130101; A61P 15/00
20180101; C07D 417/04 20130101; A61P 29/00 20180101; C07D 285/14
20130101; A61P 1/00 20180101; A61P 7/12 20180101; A61P 7/00
20180101; A61P 25/22 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/362 ;
548/135 |
International
Class: |
A61K 31/433 20060101
A61K031/433; C07D 285/14 20060101 C07D285/14; A61P 15/00 20060101
A61P015/00; A61P 25/00 20060101 A61P025/00; A61P 1/00 20060101
A61P001/00; A61P 3/00 20060101 A61P003/00 |
Claims
1. A compound of formula I: ##STR00171## or a pharmaceutically
acceptable salt, stereoisomer or tautomer thereof; wherein: n is an
integer from 0 to 4; m is an integer from 0 to 6; X is
--CH.sub.2--; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or
arylamido; wherein each aryl or heteroaryl is independently
substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups;
and each arylsulfonamide or arylamido is independently substituted
with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido groups; R.sup.2 is
aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl
optionally substituted with alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl, a
heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of
alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are
indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
2. The compound of claim 1, wherein each R.sup.1 is H.
3. The compound of claim 1, wherein R.sup.2 is: ##STR00172##
wherein, each R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
independently selected from the group consisting of H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, or arylamido.
4. The compound of claim 3, wherein R.sup.7 and R.sup.9 are F.
5. The compound of claim 4, wherein R.sup.5R.sup.6 and R.sup.8 are
H.
6. The compound of claim 3, wherein R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 are independently H, halo, alkyl or alkoxy.
7. The compound of claim 1, wherein R.sup.3 is methyl.
8. The compound of claim 7, wherein R.sup.4 is H.
9. The compound of claim 1, wherein m is 1-2.
10. The compound of claim 1, wherein m is 1.
11. The compound of claim 3, wherein: R.sup.7 and R.sup.9 are F;
and R.sup.5, R.sup.6 and R.sup.8 are H.
12. The compound of claim 1, wherein ring A comprises all carbon
atoms.
13. The compound of claim 1, wherein R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
14. The compound of claim 1, wherein R.sup.2 is phenyl,
fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
15. The compound of claim 1, wherein: each R.sup.1 is H; m is 1;
R.sup.3 is methyl; and R.sup.4 is H.
16. The compound of claim 3, wherein: each R.sup.1 is H; R.sup.7
and R.sup.9 are F; R.sup.5, R.sup.6 and R.sup.8 are H; R.sup.3 is
methyl; R.sup.4 is H; and m is 1.
17. The compound of claim 1, selected from the group consisting of:
##STR00173## ##STR00174## ##STR00175##
18. The compound of claim 1, selected from the group consisting of:
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine;
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-
-amine;
N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]propyl}cyclopropanamine;
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-
propan-1-amine;
3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1--
amine;
3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylpropan-1-amine;
3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine;
N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine;
3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine;
3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine;
3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine;
N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pan-1-amine;
N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pan-1-amine;
N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine;
N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine;
3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-a-
mine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-
an-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylbutan-1-amine;
n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]butan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-
-N-methylbutan-1-amine;
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methy-
lpropan-1-amine;
3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methy-
lpropan-1-amine;
N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine;
3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylpropan-1-amine;
N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine;
N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine;
3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine;
3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine;
3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine;
N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
propan-1-amine;
3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine;
N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzo-thiadiazol-1(3H)-yl-
)propan-1-amine;
3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine;
3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-c-
arbonitrile 2,2-dioxide;
3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine;
3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine;
3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine;
3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-
-yl}-N-methylpropan-1-amine;
3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-
-yl}-N-methylpropan-1-amine;
3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)--
yl}-N-methylpropan-1-amine;
3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine;
3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine;
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanami-
ne;
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylethanamine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-
-amine;
N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylbutan-1-amine;
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]-
propan-1-amine;
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine;
3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylpropan-1-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-
-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpentan-1-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylpentan-1-amine;
3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine;
3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine;
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine;
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine;
3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine;
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N,N-dimethylpropan-1-amine;
4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylbutan-1-amine;
4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine;
4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbutan-1-amine;
N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopropanamine;
N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]propyl}cyclopropanamine;
N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclopropanamine;
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine;
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N,N-dimethylbutan-1-amine;
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpentan-1-amine;
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylpentan-1-amine;
3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylpropan-1-amine;
3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl}phenol;
3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl}phenol;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine;
3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cyclopro-
panamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]propyl}cyclopropanamine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cycloprop-
anamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]butyl}cyclopropanamine;
3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lhexan-1-amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1--
amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
,N-dimethylhexan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]butan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N,N-dimethylbutan-1-amine;
N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]butan-1-amine;
3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine;
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine;
4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbutan-1-amine;
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(-
2,2,2-trifluoroethyl)propan-1-amine;
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,13-benzothiadiazol-1(3H)-yl]-N-
-ethylpropan-1-amine;
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpentan-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pent-
an-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpentan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylpropan-1-amine;
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylbutan-1-amine;
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylbutan-1-amine;
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylbutan-1-amine;
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-i-
sopropylbutan-1-amine;
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclobutanamine;
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclohexanamine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylpropan-1-amine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-i-
sopropylpropan-1-amine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclobutanamine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopentanamine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclohexanamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]ethyl}piperidin-4-amine;
N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-
-4-amine;
2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]propyl}amino) ethanol; and pharmaceutically acceptable salts
thereof.
19. The compound of claim 1, wherein said pharmaceutically
acceptable salt is a hydrochloride or dihydrochloride.
20. A composition, comprising: a. at least one compound of formula
I: ##STR00176## or a pharmaceutically acceptable salt, stereoisomer
or tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is --CH.sub.2--; R.sup.1 is, independently
at each occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,
heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide alkylamido, or arylamido; wherein each aryl or
heteroaryl is independently substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido
is independently substituted with 0-3 alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or
alkylamido groups; R.sup.2 is aryl or heteroaryl substituted with
0-4 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl, a
heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of
alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are
indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N; and b. at least one pharmaceutically
acceptable carrier.
21. A method for treating or preventing a condition selected from
the group consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of: administering to said subject an effective
amount of a compound of formula I: ##STR00177## or a
pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
wherein: n is an integer from 0 to 4; m is an integer from 0 to 6;
X is --CH.sub.2--; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or
arylamido; wherein each aryl or heteroaryl is independently
substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups;
and each arylsulfonamide or arylamido is independently substituted
with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido groups; R.sup.2 is
aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl
optionally substituted with alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl, a
heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of
alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are
indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
22. The method of claim 21, wherein said vasomotor symptom is hot
flush.
23. The method of claim 21, wherein said sexual dysfunction is
desire-related or arousal-related.
24. The method of claim 21, wherein said gastrointestinal disorder
or said genitourinary disorder is stress incontinence or urge
incontinence.
25. The method of claim 21, wherein said condition is chronic
fatigue syndrome or fibromyalgia syndrome.
26. The method of claim 21, wherein said condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
27. The method of claim 21, wherein said condition is diabetic
neuropathy.
28. The method of claim 21, wherein said condition is pain.
29. The method of claim 28, wherein said pain is acute centralized
pain, acute peripheral pain, or a combination thereof.
30. The method of claim 28, wherein said pain is chronic
centralized pain, chronic peripheral pain, or a combination
thereof.
31. The method of claim 28, wherein said pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
32. The method of claim 31, wherein said neuropathic pain is
associated with diabetes, post traumatic pain of amputation, lower
back pain, cancer, chemical injury, toxins, major surgery,
peripheral nerve damage due to traumatic injury compression,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
33. The method of claim 32, wherein said neuropathic pain is
post-herpetic neuralgia.
34. The method of claim 31, wherein said visceral pain is
associated with ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, or a combination thereof.
35. The method of claim 28, wherein said subject is female; and the
pain is female-specific pain.
36. A process for the preparation of a compound of formula I:
##STR00178## or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is --CH.sub.2--; R.sup.1 is, independently
at each occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,
heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide alkylamido, or arylamido; wherein each aryl or
heteroaryl is independently substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido
is independently substituted with 0-3 alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or
alkylamido groups; R.sup.2 is aryl or heteroaryl substituted with
0-4 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl, a
heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of
alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are
indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N; the process comprising: (d) reacting
a compound of formula IA: ##STR00179## with a compound of formula
IB: ##STR00180## wherein, T is an --N(R.sup.3)(R.sup.4) or an
activating group; wherein, if T is --N(R.sup.3)(R.sup.4), then the
compound of formula I is formed; or if T is an activating group,
then a compound of formula IC is formed: ##STR00181## and the
process further comprises: (e) reacting the compound formula IC
with --N(R.sup.4)R.sup.P to form a compound of formula ID:
##STR00182## wherein, R.sup.P is R.sup.4 or a protecting group;
wherein, if R.sup.P is R.sup.3, the compound of formula I is
formed; or if R.sup.P is a protecting group, the process further
comprises: (f) deprotecting the compound of formula ID to form a
deprotected compound; and (g) reacting the deprotected compound
with an activated-R.sup.3 group, provided that R.sup.3 in the
activated-R.sup.3 group is not H; wherein the compound of formula I
is formed.
37. The process of claim 36, wherein step (d) further comprises
contacting the compound of formula IA and IB with dialkyl
azodicarboxylate and triphenylphosphine.
38. The process of claim 37, wherein the dialkyl azodicarboxylate
is diisopropyl azodicarboxylate.
39. The process of claim 36, wherein the activating group is
selected from the group consisting of halo, tosylate, mesylate,
triflate, and oxo.
40. The process of claim 39, wherein the activating group is
Br.
41. The process of claim 36, wherein the protecting group is
selected from the group consisting of BOC, benzyl, acetyl, PMB,
C.sub.1-C.sub.6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and
triphenylmethyl.
42. The process of claim 41, wherein the protecting group is
BOC.
43. The process of claim 36, wherein the deprotecting step is
performed in the presence of at least one agent selected from
hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc,
trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or
aluminum chloride.
44. The process of claim 36, wherein any one of steps (d)-(g) is
performed at or above 30.degree. C. or any one of steps (d)-(g)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
45. The process of any one of claims 36, wherein the
activated-R.sup.3 group is halo-R.sup.3.
46. The process of claim 36, wherein the compound of formula IA is
prepared by: (a) reacting a compound of formula IE: ##STR00183##
wherein R.sup.B is F or Cl; with R.sup.2--NH.sub.2 to form a
compound of formula IF: ##STR00184## (b) hydrogenating the compound
of formula IF to form a compound of formula IG: ##STR00185## and
(c) reacting the compound of formula IG with sulfamide in diglyme
to form the compound of formula IA.
47. The process of claim 46, wherein the hydrogenating step is
performed in the presence of hydrogen (H.sub.2) and Pd/C.
48. The process of claim 46, wherein any one of steps (a)-(c) is
performed at or above 30.degree. C.
49. The process of claim 46, wherein any one of steps (a)-(c)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
50. A process for the preparation of a compound of formula I:
##STR00186## or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is --CH.sub.2--; R.sup.1 is, independently
at each occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl,
heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide alkylamido, or arylamido; wherein each aryl or
heteroaryl is independently substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido
is independently substituted with 0-3 alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or
alkylamido groups; R.sup.2 is aryl or heteroaryl substituted with
0-4 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl, a
heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of
alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are
indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N; the process comprising: (d) reacting
R.sup.2(BOH).sub.2 and a transitional metal salt with a compound of
formula IH: ##STR00187## wherein, R.sup.P is R.sup.3 or a
protecting group; and if R.sup.P is R.sup.3, the compound of
formula I is formed; or if R.sup.P is a protecting group, the
process further comprises: (e) deprotecting the compound of formula
IH to form a deprotected compound; and (f) reacting the deprotected
compound with an activated-R.sup.3 group, provided that R.sup.3
group in the activated-R.sup.3 group is not H; wherein the compound
of formula I is formed.
51. The process of claim 50, wherein the transitional metal salt is
copper(II) acetate.
52. The process of claim 50, wherein the activated-R.sup.3 group is
halo-R.sup.3.
53. The process of claim 50, wherein the protecting group is
selected from the group consisting of BOC, benzyl, acetyl, PMB,
C.sub.1-C.sub.6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and
triphenylmethyl.
54. The process of claim 53, wherein the protecting group is
BOC.
55. The process of claim 50, wherein the deprotecting step is
performed in the presence of at least one agent selected from
hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc,
trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or
aluminum chloride.
56. The process of claim 50, wherein any one of steps (d)-(f) is
performed at or above 30.degree. C. or any one of steps (d)-(f)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
57. The process of claim 50, wherein the compound of formula IH is
prepared by: (a) reacting a compound of formula IJ: ##STR00188##
wherein R.sup.B is F or Cl; with a compound of formula IK:
##STR00189## to form a compound of formula IL: ##STR00190## (b)
hydrogenating the compound of formula IL to form a compound of
formula IM: ##STR00191## and (c) reacting the compound of formula
IM with sulfamide and diglyme to form the compound of formula
IH.
58. The process of claim 57, wherein the hydrogenating step is
performed in the presence of hydrogen (H.sub.2) and Pd/C.
59. The process of claim 57, wherein any one of steps (a)-(c) is
performed at or above 30.degree. C.
60. The process of claim 57, wherein any one of steps (a)-(c)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
61. The process of claim 36, wherein any one of the steps is
performed in: a protic solvent, an aprotic solvent, a polar
solvent, a nonpolar solvent, a protic polar solvent, an aprotic
nonpolar solvent, or an aprotic polar solvent.
62. The process of claim 50, wherein any one of the steps is
performed in: a protic solvent, an aprotic solvent, a polar
solvent, a nonpolar solvent, a protic polar solvent, an aprotic
nonpolar solvent, or an aprotic polar solvent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) to co-pending U.S. Provisional Application Ser. No.
60/869,644, filed Dec. 12, 2006, which is hereby incorporated by
reference in its entirety.
FIELD
[0002] The present invention relates to aminoalkyl-substituted aryl
sulfamide derivatives, which are monoamine reuptake inhibitors,
compositions containing these derivatives, and methods of their use
for the prevention and treatment of diseases or disorders including
vasomotor symptoms, depression disorders, endogenous behavioral
disorders, cognitive disorders, sexual dysfunction, or pain
conditions, in particular vasomotor symptoms.
BACKGROUND
[0003] Vasomotor symptoms (VMS), referred to as hot flushes and
night sweats, are the most common symptoms associated with
menopause, occurring in 60% to 80% of all women following natural
or surgically-induced menopause. VMS are likely an adaptive
response of the central nervous system (CNS) to declining sex
steroids. To date, the most effective therapies for VMS are
hormone-based treatments, including estrogens and/or some
progestins. Hormonal treatments are very effective at alleviating
VMS, but they are not appropriate for all women.
[0004] VMS are caused by fluctuations of sex steroid levels and can
be disruptive and disabling in both males and females. A hot flush
can last up to thirty minutes and vary in their frequency from
several times a week to multiple occurrences per day. The patient
experiences a hot flush as a sudden feeling of heat that spreads
quickly from the face to the chest and back and then over the rest
of the body. It is usually accompanied by outbreaks of profuse
sweating, and may sometimes occur several times an hour, and it
often occurs at night. Hot flushes and outbreaks of sweats
occurring during the night can cause sleep deprivation.
Psychological and emotional symptoms are also observed, such as
nervousness, fatigue, irritability, insomnia, depression, memory
loss, headache, anxiety, nervousness or inability to concentrate,
and are caused by the sleep deprivation following hot flush and
night sweats (Kramer et al., In: Murphy et al., 3.sup.rd Int'l
Symposium on Recent Advances in Urological Cancer Diagnosis and
Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).
[0005] Hot flushes may be even more severe in women treated for
breast cancer for several reasons. Many survivors of breast cancer
are given tamoxifen, the most prevalent side effect of which is hot
flush, and many women treated for breast cancer undergo premature
menopause from chemotherapy Women with a history of breast cancer
are also generally been denied estrogen therapy because of concerns
about potential recurrence of breast cancer (Loprinzi, et al.,
Lancet, 2000, 356(9247): 2059-2063).
[0006] Men also experience hot flushes following steroid hormone
(androgen) withdrawal. This is true in cases of age-associated
androgen decline (Katovich, et al., Proceedings of the Society for
Experimental Biology & Medicine, 1990, 193(2): 129-35) as well
as in extreme cases of hormone deprivation associated with
treatments for prostate cancer (Berendsen, et al., European Journal
of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these
patients will experience persistent and frequent symptoms severe
enough to cause significant discomfort and inconvenience.
[0007] The precise mechanism of these vasomotor symptoms is unknown
but generally is thought to represent disturbances to normal
homeostatic mechanisms controlling thermoregulation and vasomotor
activity (Kronenberg et al., "Thermoregulatory Physiology of
Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol.,
1987, 65:1312-1324).
[0008] The fact that estrogen treatment (e.g. estrogen replacement
therapy) relieves the symptoms establishes the link between these
symptoms and an estrogen deficiency. For example, the menopausal
stage of life is associated with a wide range of other acute
symptoms as described above and these symptoms are generally
estrogen responsive.
[0009] It has been suggested that estrogens may stimulate the
activity of both the norepinephrine (NE) and/or serotonin (5-HT)
systems (J. Pharmacology & Experimental Therapeutics, 1986,
236(3) 646-652). It is hypothesized that estrogens modulate NE and
5-HT levels providing homeostasis in the thermoregulatory center of
the hypothalamus. The descending pathways from the hypothalamus via
brainstem/spinal cord and the adrenals to the skin are involved in
maintaining normal skin temperature. The action of NE and 5-HT
reuptake inhibitors is known to impinge on both the CNS and
peripheral nervous system (PNS). The pathophysiology of VMS is
mediated by both central and peripheral mechanisms and, therefore,
the interplay between the CNS and PNS may account for the efficacy
of dual acting SRI/NRIs in the treatment of thermoregulatory
dysfunction. In fact, the physiological aspects and the CNS/PNS
involvement in VMS may account for the lower doses proposed to
treat VMS (Loprinzi, et al., Lancet, 2000, 356:2059-2063; Stearns
et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat
the behavioral aspects of depression. The interplay of the CNS/PNS
in the pathophysiology of VMS supports the claims that the
norepinephrine system could be targeted to treat VMS.
[0010] Although VMS are most commonly treated by hormone therapy,
some patients cannot tolerate estrogen treatment (Berendsen,
Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996,
383(6598): 306). In addition, hormone replacement therapy is
usually not recommended for women or men with or at risk for
hormonally sensitive cancers (e.g. breast or prostate cancer).
Thus, non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs]
and clonidine) are being evaluated clinically. WO9944601 discloses
a method for decreasing hot flushes in a human female by
administering fluoxetine. Other options have been studied for the
treatment of hot flushes, including steroids, alpha-adrenergic
agonists, and beta-blockers, with varying degree of success
(Waldinger et al., Maturitas, 2000, 36(3): 165-168).
[0011] .alpha..sub.2-Adrenergic receptors play a role in
thermoregulatory dysfunctions (Freedman et al., Fertility &
Sterility, 2000, 74(1): 20-3). These receptors are located both
pre- and post-synaptically and mediate an inhibitory role in the
central and peripheral nervous system. There are four distinct
subtypes of the adrenergic.sub..alpha.2 receptors, i.e., are
.alpha..sub.2A, .alpha..sub.2B, .alpha..sub.2C and .alpha..sub.2D
(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther.,
1995, 68: 175). A non-select .alpha..sub.2-adrenoceptor antagonist,
yohimbine, induces a flush and an .alpha..sub.2-adrenergic receptor
agonist, clonidine, alleviates the yohimbine effect (Katovich, et
al., Proceedings of the Society for Experimental Biology &
Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility &
Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat hot
flush. However, using such treatment is associated with a number of
undesired side effects caused by high doses necessary to abate hot
flush described herein and known in the related arts.
[0012] Chronic pain comes in many forms, including visceral,
inflammatory or neuropathic and crosses all therapeutic areas. It
is a debilitating condition that exerts a high social cost in terms
of productivity, economic impact and quality of life and current
therapies have limited efficacy. Currently, first-line
pharmacological treatments for neuropathic pain (i.e., diabetic
neuropathy and post-herpetic neuralgia) and fibromyalgia include
off-label use of the tricyclic (TCA) antidepressants (e.g.,
amytriptyline) and anticonvulsants (e.g., gabapentin) (Collins et
al., J. Pain Symptom Manage. 2000, 20(6):449-58; and Marcus Expert
Opin Pharmacother. 2003, 4(10): 1687-95). However, these therapies
are only effective in 30-50% of patients and produce only a partial
reduction in pain (.about.50%). In addition, the clinical benefits
of these therapies are often outweighed by the side effects,
including dry mouth and sedation. Therefore, newer classes of
compounds including non-TCA antidepressants are being evaluated
preclinically and clinically for chronic pain indications, and
recently duloxetine was approved for the treatment of diabetic
neuropathy. Although more tolerable than the older tricyclic
antidepressants, these newer compounds are not devoid of side
effects that include sexual dysfunction, weight gain and
nausea.
[0013] While the precise pathophysiological mechanisms involved in
the development and maintenance of chronic pain states are not
fully understood, the pathways involved in pain perception and
modulation have been well described and characterized (Gebhart, In:
Yaksh T L, editor. Spinal afferent processing, New York: Plenum,
1986. pp 391-416; Fields, et al., Annual Review of Neuroscience
1991, 14: 219-245; Fields, et al. In: Wall P D, Melzack R, editors.
Textbook of pain, London: Churchill Livingstone, 1999, pp 309-329;
Millan, et al Progress in Neurobiology; 2002, 66:355-474). A major
component of this descending pain inhibitory system involves the
noradrenergic pathway (Zhuo, et al., Brain Research 1991;
550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It is
assumed that norepinephrine (NE), and to a lesser extent serotonin
(5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by
preventing presynaptic reuptake of NE/5-HT leading to increased
postsynaptic NE/5-HT levels and sustained activation of this
descending pain inhibitory pathway. A meta-analysis of
antidepressants and neuropathic pain comparing the efficacy of
known NRIs, mixed NRI/SRIs and SRIs determined that compounds with
NRI activity were more effective in reducing pain, and that select
SRIs did not significantly differ from placebo (Collins et al., J.
Pain Symptom Manage. 2000, 20(6): 449-58). This analysis suggests
that compounds with greater NRI versus SRI activity will be more
effective for the treatment of pain.
[0014] Given the complex multifaceted nature of pain and of
thermoregulation and the interplay between the CNS and PNS in
maintaining thermoregulatory the homeostasis, multiple therapies
and approaches can be developed to target the treatment of pain and
vasomotor symptoms. The present invention provides novel compounds
and compositions containing these compounds directed to these and
other important uses.
SUMMARY
[0015] The present invention is directed to aryl sulfamide
derivatives, which are monoamine reuptake inhibitors, compositions
containing these derivatives, and methods of their use for the
prevention and treatment of conditions, including, inter alia,
vasomotor symptoms (such as hot flush), sexual dysfunction (such as
desire-related or arousal-related dysfunction), gastrointestinal
disorders and genitourinary disorder (such as stress incontinence
or urge incontinence), chronic fatigue syndrome, fibromyalgia
syndrome, depression disorders (such as major depressive disorder,
generalized anxiety disorder, panic disorder, attention deficit
disorder with or without hyperactivity, sleep disturbance, and
social phobia), diabetic neuropathy, pain, and combinations
thereof.
[0016] One aspect of the invention provides a compound of formula
I:
##STR00002## [0017] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof; [0018] wherein: [0019] n is an
integer from 0 to 4; [0020] m is an integer from 0 to 6; [0021] X
is --CH.sub.2--; [0022] R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
alkylamido, or arylamido; wherein each aryl or heteroaryl is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups; and each arylsulfonamide or arylamido is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido
groups; [0023] R.sup.2 is aryl or heteroaryl substituted with 0-4
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; [0024] R.sup.3 and R.sup.4 are, independently, H,
alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein
each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl,
are indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; [0025] and [0026] wherein 1-3 carbon atoms in
ring A may optionally be replaced with N.
[0027] Another aspect of the invention provides a composition,
comprising:
[0028] a. at least one compound of formula I; and
[0029] b. at least one pharmaceutically acceptable carrier.
[0030] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of:
[0031] administering to said subject an effective amount of a
compound of formula I.
[0032] Another aspect of the invention provides a process for the
preparation of a compound of formula I, the process comprising:
[0033] (d) reacting a compound of formula IA:
##STR00003##
[0034] with a compound of formula IB:
##STR00004##
[0035] wherein,
[0036] T is an --N(R.sup.3)(R.sup.4) or an activating group;
[0037] wherein,
[0038] if T is --N(R.sup.3)(R.sup.4), then the compound of formula
I is formed; or
[0039] if T is an activating group, then a compound of formula IC
is formed:
##STR00005##
[0040] and the process further comprises:
[0041] (e) reacting the compound formula IC with
--N(R.sup.4)R.sup.P to form a compound of formula ID:
##STR00006##
[0042] wherein,
[0043] R.sup.P is R.sup.4 or a protecting group;
[0044] wherein,
[0045] if R.sup.P is R.sup.3, the compound of formula I is formed;
or
[0046] if R.sup.P is a protecting group, the process further
comprises:
[0047] (f) deprotecting the compound of formula ID to form a
deprotected compound; and
[0048] (g) reacting the deprotected compound with an
activated-R.sup.3 group, provided that R.sup.3 in the
activated-R.sup.3 group is not H;
[0049] wherein the compound of formula I is formed.
[0050] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
##STR00007## [0051] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof; [0052] wherein: [0053] n is an
integer from 0 to 4; [0054] m is an integer from 0 to 6; [0055] X
is --CH.sub.2--; [0056] R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
alkylamido, or arylamido; wherein each aryl or heteroaryl is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups; and each arylsulfonamide or arylamido is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido
groups; [0057] R.sup.2 is aryl or heteroaryl substituted with 0-4
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; [0058] R.sup.3 and R.sup.4 are, independently, H,
alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein
each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl,
are indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and
[0059] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N;
[0060] the process comprising:
[0061] (d) reacting R.sup.2(BOH).sub.2 and a transitional metal
salt with a compound of formula IH:
##STR00008##
[0062] wherein,
[0063] R.sup.P is R.sup.3 or a protecting group; and
[0064] if R.sup.P is R.sup.3, the compound of formula I is formed;
or
[0065] if R.sup.P is a protecting group, the process further
comprises:
[0066] (e) deprotecting the compound of formula IH to form a
deprotected compound; and
[0067] (f) reacting the deprotected compound with an
activated-R.sup.3 group, provided that R.sup.3 group in the
activated-R.sup.3 group is not H;
[0068] wherein the compound of formula I is formed.
[0069] Another aspect of the invention provides a compound
comprising a compound of formula IA, IB, IC, ID, IE, IF, IG, IH,
IJ, IK, IL or IM.
[0070] Another aspect of the invention provides a composition
comprising: [0071] (a) one or more of the compounds of formula IA,
IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL or IM; and [0072] (b) one or
more of: a base, an acid, a solvent, a hydrogenating agent, a
reducing agent, an oxidizing agent, or a catalyst.
[0073] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating embodiments
of the invention, are given by way of illustration only, since
various changes and modifications within the spirit and scope of
the invention will become apparent to those skilled in the art from
this detailed description.
DETAILED DESCRIPTION
[0074] The following definitions are provided for the full
understanding of terms and abbreviations used in this
specification.
[0075] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include the plural reference unless the
context clearly indicates otherwise. Thus, for example, a reference
to "an antagonist" includes a plurality of such antagonists, and a
reference to "a compound" is a reference to one or more compounds
and equivalents thereof known to those skilled in the art, and so
forth.
[0076] The abbreviations in the specification correspond to units
of measure, techniques, properties, or compounds as follows: "min"
means minutes, "h" means hour(s), ".mu.L" means microliter(s), "mL"
means milliliter(s), "mM" means millimolar, "M" means molar,
"mmole" means millimole(s), "cm" means centimeters, "SEM" means
standard error of the mean and "IU" means International Units.
".DELTA..degree. C." and .DELTA. "ED.sub.50 value" means dose which
results in 50% alleviation of the observed condition or effect (50%
mean maximum endpoint).
[0077] "Norepinephrine transporter" is abbreviated NET.
[0078] "Human norepinephrine transporter" is abbreviated hNET.
[0079] "Serotonin transporter" is abbreviated SERT.
[0080] "Human serotonin transporter" is abbreviated hSERT.
[0081] "Norepinephrine reuptake inhibitor" is abbreviated NRI.
[0082] "Selective norepinephrine reuptake inhibitor" is abbreviated
SNRI.
[0083] "Serotonin reuptake inhibitor" is abbreviated SRI.
[0084] "Selective serotonin reuptake inhibitor" is abbreviated
SSRI.
[0085] "Norepinephrine" is abbreviated NE.
[0086] "Serotonin is abbreviated 5-HT.
[0087] "Subcutaneous" is abbreviated sc.
[0088] "Intraperitoneal" is abbreviated ip.
[0089] "Oral" is abbreviated po.
[0090] In the context of this disclosure, a number of terms are
utilized. The term "treat," "treatment" or "treating" as used
herein includes preventative (e.g., prophylactic), curative or
palliative treatment.
[0091] The term "effective amount," as used herein, refers to an
amount effective, at dosages, and for periods of time necessary, to
achieve the desired result with respect to treatment of a given
disease or disorder. An effective amount is also one in which any
toxic or detrimental effects of the components are outweighed by
the therapeutically beneficial effects. In particular, with respect
to vasomotor symptoms, "effective amount" refers to the amount of
compound or composition of compounds that would increase
norepinephrine levels to compensate in part or total for the lack
of steroid availability in subjects subject afflicted with a
vasomotor symptom. Varying hormone levels will influence the amount
of compound required in the present invention. For example, the
pre-menopausal state may require a lower level of compound due to
higher hormone levels than the peri-menopausal state.
[0092] The effective amount of components of the present invention
will vary from patient to patient not only with the particular
compound, component or composition selected, the route of
administration, and the ability of the components (alone or in
combination with one or more additional active agents) to elicit a
desired response in the individual, but also with factors such as
the disease state or severity of the condition to be alleviated,
hormone levels, age, sex, weight of the individual, the state of
being of the patient, and the severity of the pathological
condition being treated, concurrent medication or special diets
then being followed by the particular patient, and other factors
which those skilled in the art will recognize, with the appropriate
dosage ultimately being at the discretion of the attendant
physician. Dosage regimens may be adjusted to provide the improved
therapeutic response.
[0093] Preferably, the compounds of the present invention are
administered at a dosage and for a time such that the number of hot
flushes is reduced as compared to the number of hot flushes prior
to the start of treatment. Such treatment can also be beneficial to
reduce the overall severity or intensity distribution of any hot
flushes still experienced, as compared to the severity of hot
flushes prior to the start of the treatment. With respect to sexual
dysfunction, gastrointestinal disorder, genitourinary disorder,
chronic fatigue syndrome, fibromyalgia syndrome, depression
disorder, diabetic neuropathy, or pain, the compounds of the
present invention are administered at a dosage and for a time
sufficient to treat the symptom or condition.
[0094] For example, for a patient, compounds of formula I, or a
pharmaceutically acceptable salt thereof, may be administered,
preferably, at a dosage of from about 0.1 mg/day to about 1500
mg/day, dosed one or two times daily, more preferably from about 1
mg/day to about 200 mg/day and most preferably from about 1 mg/day
to 100 mg/day for a time sufficient to reduce and/or substantially
eliminate the number and/or severity of hot flushes or symptom or
condition of the sexual dysfunction, gastrointestinal disorder,
genitourinary disorder, chronic fatigue syndrome, fibromyalgia
syndrome, depression disorder, diabetic neuropathy, or pain.
[0095] The terms "component," "composition," "composition of
compounds," "compound," "drug," or "pharmacologically active agent"
or "active agent" or "medicament" are used interchangeably herein
to refer to a compound or compounds or composition of matter which,
when administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0096] The term "modulation" refers to the capacity to either
enhance or inhibit a functional property of a biological activity
or process; for example, receptor binding or signaling activity.
Such enhancement or inhibition may be contingent on the occurrence
of a specific event, such as activation of a signal transduction
pathway and/or may be manifest only in particular cell types. The
modulator is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein, and
is preferably small molecule, or peptide.
[0097] As used herein, the term "inhibitor" refers to any agent
that inhibits, suppresses, represses, or decreases a specific
activity, such as norepinephrine reuptake activity. The term
"inhibitor" is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein
(preferably small molecule or peptide) that exhibits a partial,
complete, competitive and/or inhibitory effect on mammalian
(preferably the human) norepinephrine reuptake or both serotonin
reuptake and the norepinephrine reuptake, thus diminishing or
blocking (preferably diminishing) some or all of the biological
effects of endogenous norepinephrine reuptake or of both serotonin
reuptake and the norepinephrine reuptake.
[0098] Within the present invention, the compounds of formula I,
may be prepared in the form of pharmaceutically acceptable salts.
As used herein, the term "pharmaceutically acceptable salts" refers
to salts prepared from pharmaceutically acceptable non-toxic acids,
including inorganic salts and organic salts. Suitable non-organic
salts include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
preferred is the hydrochloride salt.
[0099] "Administering," as used herein, means either directly
administering a compound or composition of the present invention,
or administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0100] The term "subject" or "patient" refers to an animal
including the human species that is treatable with the compounds,
compositions, and/or methods of the present invention. The term
"subject" or "subjects" is intended to refer to both the male and
female gender unless one gender is specifically indicated.
Accordingly, the term "patient" comprises any mammal which may
benefit from treatment or prevention of a disease or disorder, such
as a human, especially if the mammal is female, either in the
pre-menopausal, peri-menopausal, or post-menopausal period.
Furthermore, the term patient includes female animals including
humans and, among humans, not only women of advanced age who have
passed through menopause but also women who have undergone
hysterectomy or for some other reason have suppressed estrogen
production, such as those who have undergone long-term
administration of corticosteroids, suffer from Cushing's syndrome
or have gonadal dysgenesis. However, the term "patient" is not
intended to be limited to a woman.
[0101] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as one or more adverse
effects produced by a drug, especially on a tissue or organ system
other then the one sought to be benefited by its administration. In
the case, for example, of high doses of NRIs or NRI/SRI compounds
alone, the term "side effect" may refer to such conditions as, for
example, vomiting, nausea, sweating, and hot flushes (Janowsky, et
al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
[0102] "Vasomotor symptoms," (also called "vasomotor instability
symptoms" and "vasomotor disturbances") include, but are not
limited to, hot flushes (flushes), insomnia, sleep disturbances,
mood disorders, irritability, excessive perspiration, night sweats,
fatigue, and the like, caused by, inter alia, thermoregulatory
dysfunction.
[0103] The term "hot flush" (sometimes called "hot flash") is an
art-recognized term that refers to an episodic disturbance in body
temperature typically consisting of a sudden skin flushing, usually
accompanied by perspiration in a subject.
[0104] The terms "premature menopause" or "artificial menopause"
refer to ovarian failure of unknown cause that may occur before age
40. It may be associated with smoking, living at high altitude, or
poor nutritional status. Artificial menopause may result from
oophorectomy, chemotherapy, radiation of the pelvis, or any process
that impairs ovarian blood supply.
[0105] The term "pre-menopausal" means before the menopause, the
term "peri-menopausal" means during the menopause and the term
"post-menopausal" means after the menopause. "Ovariectomy" means
removal of an ovary or ovaries and can be effected according to
Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
[0106] The term "sexual dysfunction" includes, but is not limited
to, conditions relating to disorders of sexual desire and/or
arousal.
[0107] As used herein, "gastrointestinal and genitourinary
disorders" includes irritable bowel syndrome, symptomatic GERD,
hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest
pain, biliary dyskinesia, sphincter of Oddi dysfunction,
incontinence (i.e., urge incontinence, stress incontinence, genuine
stress incontinence, and mixed incontinence, including the
involuntary voiding of feces or urine, and dribbling or leakage or
feces or urine which may be due to one or more causes including but
not limited to pathology altering sphincter control, loss of
cognitive function, overdistention of the bladder, hyperreflexia
and/or involuntary urethral relaxation, weakness of the muscles
associated with the bladder or neurologic abnormalities),
interstitial cystitis (irritable bladder), and chronic pelvic pain
(including, but not limited to vulvodynia, prostatodynia, and
proctalgia).
[0108] As used herein, "chronic fatigue syndrome" (CFS) is a
condition characterized by physiological symptoms selected from
weakness, muscle aches and pains, excessive sleep, malaise, fever,
sore throat, tender lymph nodes, impaired memory and/or mental
concentration, insomnia, disordered sleep, localized tenderness,
diffuse pain and fatigue, and combinations thereof, whether or not
correlated with Epstein-Barr virus infection.
[0109] As used herein, "fibromyalgia syndrome" (FMS) includes FMS
and other somatoform disorders, including FMS associated with
depression, somatization disorder, conversion disorder, pain
disorder, hypochondriasis, body dysmorphic disorder,
undifferentiated somatoform disorder, and somatoform NOS. FMS and
other somatoform disorders are accompanied by physiological
symptoms selected from a generalized heightened perception of
sensory stimuli, abnormalities in pain perception in the form of
allodynia (pain with innocuous stimulation), abnormalities in pain
perception in the form of hyperalgesia (increased sensitivity to
painful stimuli), and combinations thereof.
[0110] As used herein, the term "depression disorder" includes
major depressive disorder, generalized anxiety disorder, panic
disorder, attention deficit disorder with or without hyperactivity,
sleep disturbance, social phobia, and combinations thereof.
[0111] The compounds of the present invention can also be used to
treat a cognitive disorder or an endogenous behavioral disorder. As
used herein, a "cognitive disorder" includes changes or defects in
alertness; mild cognitive impairment (MCI), characterized by
problems with memory, language, or other mental functions which is
severe enough to be noticeable or be detected by tests, but not
serious enough to significantly interfere with daily life;
cognitive disorder NOS (not otherwise specified), characterized by
a syndrome of cognitive impairment that does not meet the criteria
for delirium, dementia or amnesic disorders; age-related cognitive
decline (ARCD); and cognitive arousal (such as increased arousal
states). A cognition disorder can be idiopathic, or can be caused
by a variety of other factors such as a congenital defect, alcohol
or drug addiction, transient or permanent pharmacologic effects of
drugs, organic or infectious disease (e.g., Alzheimer's disease,
Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or
advanced age. As used herein, an "endogenous behavioral disorder"
includes attention deficit disorder/attention deficit hyperactivity
disorder (ADD/ADHD, including adult and pediatric forms of
predominantly inattentive, predominantly hyperactive, or combined
types), obsessive-compulsive disorder (OCD), oppositional or
oppositional explosive defiant disorder (ODD/OEDD), anxiety and
panic disorders (APD) and temper, rage and outburst behavior
disorder (TROBD).
[0112] As used herein, "pain" includes both acute and chronic
nociceptic or neuropathic pain, which includes centralized pain,
peripheral pain, or combination thereof. The term includes many
different types of pain, including, but not limited to, visceral
pain, musculoskeletal pain, bony pain, cancer pain, inflammatory
pain, and combinations thereof, such as lower back pain, atypical
chest pain, headache such as cluster headache, migraine, herpes
neuralgia, phantom limb pain, pelvic pain, myofascial face pain,
abdominal pain, neck pain, central pain, dental pain, opioid
resistant pain, visceral pain, surgical pain, bone injury pain,
pain during labor and delivery, pain resulting from burns, post
partum pain, angina pain, peripheral neuropathy and diabetic
neuropathy, post-operative pain, and pain which is co-morbid with
nervous system disorders described herein.
[0113] As used herein, the term "acute pain" refers to centralized
or peripheral pain that is intense, localized, sharp, or stinging,
and/or dull, aching, diffuse, or burning in nature and that occurs
for short periods of time.
[0114] As used herein, the term "chronic pain" refers to
centralized or peripheral pain that is intense, localized, sharp,
or stinging, and/or dull, aching, diffuse, or burning in nature and
that occurs for extended periods of time (i.e., persistent and/or
regularly reoccurring), including, for the purposes of the present
invention, neuropathic pain and cancer pain. Chronic pain includes
neuropathic pain, hyperalgesia, and/or allodynia.
[0115] As used herein, the term "neuropathic pain" refers to
chronic pain caused by damage to or pathological changes in the
peripheral or central nervous systems. Examples of pathological
changes related to neuropathic pain include prolonged peripheral or
central neuronal sensitization, central sensitization related
damage to nervous system inhibitory and/or exhibitory functions and
abnormal interactions between the parasympathetic and sympathetic
nervous systems. A wide range of clinical conditions may be
associated with or form the basis for neuropathic pain including,
for example, diabetes, post traumatic pain of amputation (nerve
damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain), lower back pain, cancer,
chemical injury, toxins, other major surgeries, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, or viral or bacterial infections such as
shingles or human immunodeficiency virus (HIV), and combinations
thereof. Also included in the definition of neuropathic pain is a
condition secondary to metastatic infiltration, adiposis dolorosa,
burns, central pain conditions related to thalamic conditions, and
combinations thereof.
[0116] As used herein, the term "hyperalgesia" refers to pain where
there is an increase in sensitivity to a typically noxious
stimulus.
[0117] As used herein, the term "allodynia" refers to an increase
in sensitivity to a typically non-noxious stimulus.
[0118] As used herein, the term "visceral pain" refers to pain
associated with or resulting from maladies of the internal organs,
such as, for example, ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, and combinations thereof.
[0119] As used herein, the term "female-specific pain" refers to
pain that may be acute and/or chronic pain associated with female
conditions. Such groups of pain include those that are encountered
solely or predominately by females, including pain associated with
menstruation, ovulation, pregnancy or childbirth, miscarriage,
ectopic pregnancy, retrograde menstruation, rupture of a follicular
or corpus luteum cyst, irritation of the pelvic viscera, uterine
fibroids, adenomyosis, endometriosis, infection and inflammation,
pelvic organ ischemia, obstruction, intra-abdominal adhesions,
anatomic distortion of the pelvic viscera, ovarian abscess, loss of
pelvic support, tumors, pelvic congestion or referred pain from
non-gynecological causes, and combinations thereof.
[0120] "Alkyl," as used herein, refers to an optionally
substituted, saturated straight, branched, or cyclic hydrocarbon
having from about 1 to about 20 carbon atoms (and all combinations
and subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 1 to about 8 carbon atoms or 1 to 6
carbon atoms (C.sub.1-C.sub.6) being preferred, and with from about
1 to about 4 carbon atoms, herein referred to as "lower alkyl",
being more preferred. Alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl,
isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl,
2,2-dimethylbutyl, and 2,3-dimethylbutyl. A branched alkyl group
has at least 3 carbon atoms (e.g., an isopropyl group), and in
various embodiments, has up to 6 carbon atoms, i.e., a branched
lower alkyl group. A branched alkyl group has at least 3 carbon
atoms (e.g., an isopropyl group), and in various embodiments, has
up to 6 carbon atoms, i.e., a branched lower alkyl group. Examples
of branched lower alkyl groups include, but are not limited to:
##STR00009##
[0121] "Alkenyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more double bonds, wherein
alkyl is as defined herein. Preferred alkenyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkenyl groups can be optionally
substituted.
[0122] "Alkynyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more triple bonds, wherein
alkyl is as defined herein. Preferred alkynyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkynyl groups can be optionally
substituted.
[0123] "Alkylenyl", "alkenylenyl", "alkynylenyl", and "arylenyl"
refer to the subsets of alkyl, alkenyl, alkynyl and aryl groups,
respectively, as defined herein, including the same residues as
alkyl, alkenyl, alkynyl, and aryl but having two points of
attachment within a chemical structure. Examples of
C.sub.1-C.sub.6alkylenyl include methylenyl (--CH.sub.2--),
ethylenyl (--CH.sub.2CH.sub.2--), propylenyl
(--CH.sub.2CH.sub.2CH.sub.2--), and dimethylpropylenyl
(--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--). Likewise, examples of
C.sub.2-C.sub.6alkenylenyl include ethenylenyl (--CH.dbd.CH-- and
propenylenyl (--CH.dbd.CH--CH.sub.2--). Examples of
C.sub.2-C.sub.6alkynylenyl include ethynylenyl (--C.ident.C--) and
propynylenyl (--C.dbd.C--CH.sub.2--). Examples of arylenyl groups
include phenylenyl;
##STR00010##
Preferably, arylenyl groups contain 6 carbon atoms (C.sub.6).
[0124] "Halo," as used herein, refers to chloro, bromo, fluoro, and
iodo.
[0125] "Aryl" as used herein, refers to an optionally substituted,
mono-, di-, tri-, or other multicyclic aromatic ring system having
from about 5 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbons (C.sub.6-C.sub.10)
being preferred. Non-limiting examples include, for example,
phenyl, naphthyl, anthracenyl, and phenanthrenyl.
[0126] "Heteroaryl," as used herein, refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aromatic ring
system that includes at least one, and preferably from 1 to about 4
heteroatom ring members selected from sulfur, oxygen and nitrogen.
Heteroaryl groups can have, for example, from about 3 to about 50
carbon atoms (and all combinations and subcombinations of ranges
and specific numbers of carbon atoms therein), with from about 4 to
about 10 carbons being preferred. Non-limiting examples of
heteroaryl groups include, for example, pyrryl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,
thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0127] "Heterocyclic ring," as used herein, refers to a stable 4-
to 12-membered monocyclic or bicyclic or 7- to 10-membered bicyclic
heterocyclic ring that is saturated, partially unsaturated or
unsaturated (aromatic), and which contains carbon atoms and from 1
to 4 heteroatoms independently selected from the group consisting
of N, O and S and including any bicyclic group in which any of the
above defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen atom in the heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds one, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than two. Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl,
.alpha.-, .beta.-, or .gamma.-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles
include, but are not limited to, pyridinyl, furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[0128] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group, as defined herein. Preferred alkoxy groups have
from 1 to 6 carbon atoms (C.sub.1-C.sub.6).
[0129] "Arylalkyl," as used herein, refers to the group R'--R--
where R' is an aryl group, as defined herein, and R is an alkyl
group, as defined herein. Preferred arylalkyl groups have from 7 to
16 carbon atoms (C.sub.7-C.sub.16).
[0130] "Heteroarylalkyl," as used herein, refers to the group
R''--R-- where R'' is a heteroaryl group, as defined herein, and R
is an alkyl group, as defined herein.
[0131] "Heteroarylmethyl," as used herein, refers to the group
R''--CH.sub.2-- where R'' is a heteroaryl group, as defined
herein.
[0132] "Alkanoyloxy," as used herein, refers to the group
R--C(.dbd.O)--O-- where R is an alkyl group, as defined herein, of
1 to 5 carbon atoms (C.sub.1-C.sub.5).
[0133] "Alkylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R, where R is alkyl, as defined herein.
Preferred alkysulfoxide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0134] "Arylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R', where R' is aryl, as defined herein.
Preferred arylsulfoxide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0135] "Alkylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R, where R is alkyl, as defined herein.
Preferred alkylsulfone groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0136] "Arylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R', where R' is aryl, as defined herein.
Preferred arylsulfone groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0137] "Alkylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R, where each R is independently, alkyl, as
defined above, or the NR part may also be NH. Preferred
alkylsulfonamide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0138] "Arylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R', where R is H or alkyl, as defined
herein, and R' is aryl, as defined herein. Preferred
arylsulfonamide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0139] "Heteroarylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R'', where R is H or alkyl, as defined
herein, and R'' is aryl, as defined herein.
[0140] "Alkylamido," as used herein, refers to --NR--C(.dbd.O)--R,
where each R is independently, alkyl, as defined above, or the NR
part may also be NH. Preferred alkylamido groups have from 1 to 6
carbon atoms (C.sub.1-C.sub.6).
[0141] "Arylamido," as used herein, refers to --NR--C(.dbd.O)--R'',
where R is H or alkyl, as defined herein, and R'' is aryl, as
defined herein. Preferred arylamido groups have from 6 to 10 carbon
atoms (C.sub.6-C.sub.10).
[0142] "Phenylamido," as used herein, refers to
--NR--C(.dbd.O)-phenyl, where R is H or alkyl, as defined
above.
[0143] As used herein, the terms "optionally substituted" or
"substituted or unsubstituted" are intended to refer to the
optional replacement of up to four hydrogen atoms with up to four
independently selected substituent groups as defined herein. Unless
otherwise specified, suitable substituent groups independently
include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl,
aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl,
formyl, alkyl, perfluoroalkyl, alkyamino, dialkylamino, alkoxy,
alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, aryl,
heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl,
carboxyalkyl, haloalkyl, alkenyl, alkynyl, arylalkyl, aryloxy,
heteroaryloxy, heteroarylalkyl, and the like. Substituent groups
that have one or more available hydrogen atoms can in turn
optionally bear further independently selected substituents, to a
maximum of three levels of substitutions. For example, the term
"optionally substituted alkyl" is intended to mean an alkyl group
that can optionally have up to four of its hydrogen atoms replaced
with substituent groups as defined above (i.e., a first level of
substitution), wherein each of the substituent groups attached to
the alkyl group can optionally have up to four of its hydrogen
atoms replaced by substituent groups as defined above (i.e., a
second level of substitution), and each of the substituent groups
of the second level of substitution can optionally have up to four
of its hydrogen atoms replaced by substituent groups as defined
above (i.e., a third level of substitution).
[0144] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkoxycabonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--.
[0145] It is understood that the above definitions are not intended
to include impermissible substitution patterns (e.g., methyl
substituted with 5 fluoro groups). Such impermissible substitution
patterns are well known to the skilled artisan.
[0146] At various places in the present specification, substituents
of compounds are disclosed in groups or in ranges. It is
specifically intended that the description include each and every
individual subcombination of the members of such groups and ranges.
For example, the term "C.sub.1-6 alkyl" is specifically intended to
individually disclose C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4,
C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.6, C.sub.2-C.sub.5,
C.sub.2-C.sub.4, C.sub.2-C.sub.3, C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.4-C.sub.5, and
C.sub.5-C.sub.6 alkyl. By way of another example, the term "5-9
membered heteroaryl group" is specifically intended to individually
disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7,
5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
[0147] The term "protecting group" or "G.sub.p" with respect to
amine groups, hydroxyl groups and sulfhydryl groups refers to forms
of these functionalities which are protected from undesirable
reaction with a protecting group known to those skilled in the art,
such as those set forth in Protective Groups in Organic Synthesis,
Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York,
N.Y., (3rd Edition, 1999) which can be added or removed using the
procedures set forth therein. Examples of protected hydroxyl groups
include, but are not limited to, silyl ethers such as those
obtained by reaction of a hydroxyl group with a reagent such as,
but not limited to, t-butyldimethyl-chlorosilane,
trimethylchlorosilane, triisopropylchlorosilane,
triethylchlorosilane; substituted methyl and ethyl ethers such as,
but not limited to methoxymethyl ether, methythiomethyl ether,
benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl
ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether,
benzyl ether; esters such as, but not limited to, benzoylformate,
formate, acetate, trichloroacetate, and trifluoracetate. Examples
of protected amine groups include, but are not limited to, amides
such as, formamide, acetamide, trifluoroacetamide, and benzamide;
carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB,
benzyl, and dithiosuccinimide; and others. Examples of protected or
capped sulfhydryl groups include, but are not limited to,
thioethers such as S-benzyl thioether, and S-4-picolyl thioether;
substituted S-methyl derivatives such as hemithio, dithio and
aminothio acetals; and others.
[0148] Reference to "activated" or "an activating group" or
"G.sub.a" as used herein indicates having an electrophilic moiety
bound to a substituent, capable of being displaced by a
nucleophile. Examples of preferred activating groups are halogens,
such as Cl, Br or I, and F; triflate; mesylate, or tosylate;
esters; aldehydes; ketones; epoxides; and the like. An example of
an activated group is acetylchloride, which is readily attacked by
a nucleophile, such as piperidine group to form a
N-acetylpiperidine functionality.
[0149] The term "deprotecting" refers to removal of a protecting
group, such as removal of a benzyl or BOC group bound to an amine.
Deprotecting may be preformed by heating and/or addition of
reagents capable of removing protecting groups. In preferred
embodiments, the deprotecting step involves addition of an acid,
base, reducing agent, oxidizing agent, heat, or any combination
thereof. One preferred method of removing BOC groups from amino
groups is to add HCl in ethyl acetate. Many deprotecting reactions
are well known in the art and are described in Protective Groups in
Organic Synthesis, Greene, T. W., John Wiley & Sons, New York,
N.Y., (1st Edition, 1981), the entire disclosure of which is herein
incorporated by reference.
[0150] One aspect of the invention provides a compound of formula
I:
##STR00011## [0151] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof; [0152] wherein: [0153] n is an
integer from 0 to 4; [0154] m is an integer from 0 to 6; [0155] X
is --CH.sub.2--; [0156] R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
alkylamido, or arylamido; wherein each aryl or heteroaryl is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups; and each arylsulfonamide or arylamido is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido
groups; [0157] R.sup.2 is aryl or heteroaryl substituted with 0-4
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; [0158] R.sup.3 and R.sup.4 are, independently, H,
alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein
each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl,
are indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; [0159] and [0160] wherein 1-3 carbon atoms in
ring A may optionally be replaced with N.
[0161] In another embodiment, each R.sup.1 is H.
[0162] In another embodiment, R.sup.2 is:
##STR00012##
[0163] wherein,
[0164] each R.sup.5, R.sup.3, R.sup.7, R.sup.8 and R.sup.9 are
independently selected from the group consisting of H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, or arylamido.
[0165] In another embodiment, R.sup.7 and R.sup.9 are F. In another
embodiment, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H. In another
embodiment, R.sup.9 is F. In another embodiment, R.sup.5, R.sup.6
and R.sup.8 are H. In another embodiment R.sup.5 is H or F, R.sup.6
is H or F, R.sup.7 is H or F, R.sup.3 is H or F and R.sup.9 is H or
F. In another embodiment, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.9 are H, halo, alkyl or alkoxy.
[0166] In another embodiment, R.sup.3 is alkyl. More particularly,
methyl.
[0167] In another embodiment, R.sup.4 is H.
[0168] In another embodiment, m is an integer from 2 to 6. More
particularly, m is 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4,
2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, or 4 to 5. In another
embodiment, m is 1, m is 2, m is 3, m is 4, m is 5 or m is 6.
[0169] In another embodiment, ring A comprises all carbon
atoms.
[0170] In another embodiment, R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
[0171] In another embodiment, R.sup.2 is phenyl, fluoro-phenyl,
difluoro-phenyl, trifluorophenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
[0172] In another embodiment:
[0173] each R.sup.1 is H;
[0174] m is 1;
[0175] R.sup.3 is methyl; and
[0176] R.sup.4 is H.
[0177] In another embodiment:
[0178] each R.sup.1 is H;
[0179] R.sup.7 and R.sup.9 are F;
[0180] R.sup.5, R.sup.6 and R.sup.8 are H;
[0181] R.sup.3 is methyl;
[0182] R.sup.4 is H; and
[0183] m is 1.
[0184] Another aspect of the invention provides a compound is
selected from the group consisting of:
##STR00013## ##STR00014## ##STR00015##
[0185] Another aspect of the invention provides a compound selected
from the group consisting of: [0186]
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0187]
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-
-amine; [0188]
N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]propyl}cyclopropanamine; [0189]
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-
propan-1-amine; [0190]
3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1--
amine; [0191]
3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0192]
3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine; [0193]
N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0194]
3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine; [0195]
3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0196]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0197]
3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0198]
N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pan-1-amine; [0199]
N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]propan-1-amine; [0200]
N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0201]
N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0202]
3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine; [0203]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-a-
mine; [0204]
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine; [0205]
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylbutan-1-amine; [0206]
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylbutan-1-amine; [0207]
n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
butan-1-amine; [0208]
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-ethyl-N-methylbutan-1-amine; [0209]
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methy-
lpropan-1-amine; [0210]
3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methy-
lpropan-1-amine; [0211]
N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine; [0212]
N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine; [0213]
3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine; [0214]
3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylpropan-1-amine; [0215]
N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine; [0216]
3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine; [0217]
N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine; [0218]
N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine; [0219]
3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine; [0220]
3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine; [0221]
3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine; [0222]
3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine; [0223]
N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
propan-1-amine; [0224]
3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine; [0225]
N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzo-thiadiazol-1(3H)-yl-
)propan-1-amine; [0226]
3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine; [0227]
3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0228]
3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-c-
arbonitrile 2,2-dioxide; [0229]
3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine; [0230]
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0231]
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0232]
3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine; [0233]
3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0234]
3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-
-yl}-N-methylpropan-1-amine; [0235]
3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-
-yl}-N-methylpropan-1-amine; [0236]
3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)--
yl}-N-methylpropan-1-amine; [0237]
3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0238]
3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine; [0239]
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanami-
ne; [0240]
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylethanamine; [0241]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-
-amine; [0242]
N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine; [0243]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine; [0244]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylbutan-1-amine; [0245]
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0246]
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0247]
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0248]
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0249]
3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylpropan-1-amine; [0250]
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-
-amine; [0251]
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpentan-1-amine; [0252]
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylpentan-1-amine; [0253]
3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine; [0254]
3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine; [0255]
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropan-1-amine; [0256]
3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0257]
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine; [0258]
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine; [0259]
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine; [0260]
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0261]
3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0262]
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine; [0263]
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine; [0264]
3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine; [0265]
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N,N-dimethylpropan-1-amine; [0266]
4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylbutan-1-amine; [0267]
4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine; [0268]
4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbutan-1-amine; [0269]
N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopropanamine; [0270]
N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopropanamine; [0271]
N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclopropanamine; [0272]
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine; [0273]
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbutan-1-amine; [0274]
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpentan-1-amine; [0275]
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylpentan-1-amine; [0276]
3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylpropan-1-amine; [0277]
3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl}phenol; [0278]
3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl}phenol; [0279]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine; [0280]
3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0281]
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cyclopro-
panamine; [0282]
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}cyclopropanamine; [0283]
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cycloprop-
anamine; [0284]
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl-
}cyclopropanamine; [0285]
3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine; [0286]
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lhexan-1-amine; [0287]
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1--
amine; [0288]
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylhexan-1-amine; [0289]
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine; [0290]
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]butan-1-amine; [0291]
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbutan-1-amine; [0292]
N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]butan-1-amine; [0293]
3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine; [0294]
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0295]
4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylbutan-1-amine; [0296]
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(-
2,2,2-trifluoroethyl)propan-1-amine; [0297]
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1
(3H)-yl]-N-ethylpropan-1-amine; [0298]
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine; [0299]
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine; [0300]
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpentan-1-amine; [0301]
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pent-
an-1-amine; [0302]
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpentan-1-amine; [0303]
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpropan-1-amine; [0304]
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylpropan-1-amine; [0305]
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylbutan-1-amine; [0306]
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylbutan-1-amine; [0307]
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylbutan-1-amine; [0308]
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-i-
sopropylbutan-1-amine; [0309]
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclobutanamine; [0310]
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclohexanamine; [0311]
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylpropan-1-amine; [0312]
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-i-
sopropylpropan-1-amine; [0313]
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclobutanamine; [0314]
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopentanamine; [0315]
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclohexanamine; [0316]
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine; [0317]
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine; [0318]
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine; [0319]
N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-
-4-amine; [0320]
2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
yl}amino) ethanol; and
[0321] pharmaceutically acceptable salts thereof.
[0322] In another embodiment, said pharmaceutically acceptable salt
is a hydrochloride or dihydrochloride.
[0323] Another aspect of the invention provides a composition,
comprising:
[0324] a. at least one compound of formula I; and
[0325] b. at least one pharmaceutically acceptable carrier.
[0326] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of:
[0327] administering to said subject an effective amount of a
compound of formula I.
[0328] In certain embodiments, the vasomotor symptom is hot
flush.
[0329] In certain embodiments, the sexual dysfunction is
desire-related or arousal-related.
[0330] In certain embodiments, the gastrointestinal disorder or the
genitourinary disorder is stress incontinence or urge
incontinence.
[0331] In certain embodiments, the condition is chronic fatigue
syndrome.
[0332] In certain embodiments, the condition is fibromyalgia
syndrome.
[0333] In certain embodiments, the condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
[0334] In certain embodiments, the disorder is an endogenous
behavioral disorder or a cognitive disorder.
[0335] In certain embodiments, the condition is diabetic
neuropathy.
[0336] In certain embodiments, the condition is pain.
[0337] In certain embodiments, the pain is acute centralized pain,
acute peripheral pain, or a combination thereof.
[0338] In certain embodiments, the pain is chronic centralized
pain, chronic peripheral pain, or a combination thereof.
[0339] In certain embodiments, the pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
[0340] In certain embodiments, the neuropathic pain is associated
with diabetes, post traumatic pain of amputation, lower back pain,
cancer, chemical injury, toxins, major surgery, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
[0341] In certain embodiments, the neuropathic pain is
post-herpetic neuralgia.
[0342] In certain embodiments, the visceral pain is associated with
ulcerative colitis, irritable bowel syndrome, irritable bladder,
Crohn's disease, rheumatologic (arthralgias), tumors, gastritis,
pancreatitis, infections of the organs, biliary tract disorders, or
a combination thereof.
[0343] In certain embodiments, the pain is female-specific
pain.
[0344] The present invention provides a treatment for vasomotor
symptoms by methods of recovering the reduced activity of
norepinephrine. Without wishing to be bound by any theory,
norepinephrine activity in the hypothalamus or in the brainstem can
be elevated by (i) blocking the activity of the NE transporter,
(ii) blocking the activity of the presynaptic adrenergic
.sub..alpha.2 receptor with an antagonist, or (iii) blocking the
activity of 5-HT on NE neurons with a 5-HT.sub.2a antagonist.
[0345] The compounds of the invention are also useful to prevent
and treat pain. The pain may be, for example, acute pain or chronic
pain. The pain may also be centralized or peripheral.
[0346] Examples of pain that can be acute or chronic and that can
be treated in accordance with the methods of the present invention
include inflammatory pain, musculoskeletal pain, bony pain,
lumbosacral pain, neck or upper back pain, visceral pain, somatic
pain, neuropathic pain, cancer pain, pain caused by injury or
surgery such as burn pain or dental pain, or headaches such as
migraines or tension headaches, or combinations of these pains. One
skilled in the art will recognize that these pains may overlap one
another. For example, a pain caused by inflammation may also be
visceral or musculoskeletal in nature.
[0347] In a preferred embodiment of the present invention the
compounds useful in the present invention are administered in
mammals to treat chronic pain such as neuropathic pain associated
for example with damage to or pathological changes in the
peripheral or central nervous systems; cancer pain; visceral pain
associated with for example the abdominal, pelvic, and/or perineal
regions or pancreatitis; musculoskeletal pain associated with for
example the lower or upper back, spine, fibromyalgia,
temporomandibular joint, or myofascial pain syndrome; bony pain
associated with for example bone or joint degenerating disorders
such as osteoarthritis, rheumatoid arthritis, or spinal stenosis;
headaches such migraine or tension headaches; or pain associated
with infections such as HIV, sickle cell anemia, autoimmune
disorders, multiple sclerosis, or inflammation such as
osteoarthritis or rheumatoid arthritis.
[0348] In a more preferred embodiment, the compounds useful in this
invention are used to treat chronic pain that is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain or
inflammatory pain or combinations thereof, in accordance with the
methods described herein. Inflammatory pain can be associated with
a variety of medical conditions such as osteoarthritis, rheumatoid
arthritis, surgery, or injury. Neuropathic pain may be associated
with for example diabetic neuropathy, peripheral neuropathy,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, or nerve damage cause by injury resulting in peripheral
and/or central sensitization such as phantom limb pain, reflex
sympathetic dystrophy or postthoracotomy pain, cancer, chemical
injury, toxins, nutritional deficiencies, or viral or bacterial
infections such as shingles or HIV, or combinations thereof. The
methods of use for compounds of this invention further include
treatments in which the neuropathic pain is a condition secondary
to metastatic infiltration, adiposis dolorosa, burns, or central
pain conditions related to thalamic conditions.
[0349] As mentioned previously, the methods of the present
invention may be used to treat pain that is somatic and/or visceral
in nature. For example, somatic pain that can be treated in
accordance with the methods of the present invention include pains
associated with structural or soft tissue injury experienced during
surgery, dental procedures, burns, or traumatic body injuries.
Examples of visceral pain that can be treated in accordance with
the methods of the present invention include those types of pain
associated with or resulting from maladies of the internal organs
such as ulcerative colitis, irritable bowel syndrome, irritable
bladder, Crohn's disease, rheumatologic (arthralgias), tumors,
gastritis, pancreatitis, infections of the organs, or biliary tract
disorders, or combinations thereof. One skilled in the art will
also recognize that the pain treated according to the methods of
the present invention may also be related to conditions of
hyperalgesia, allodynia, or both. Additionally, the chronic pain
may be with or without peripheral or central sensitization.
[0350] The compounds useful in this invention may also be used to
treat acute and/or chronic pain associated with female conditions,
which may also be referred to as female-specific pain. Such groups
of pain include those that are encountered solely or predominately
by females, including pain associated with menstruation, ovulation,
pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde
menstruation, rupture of a follicular or corpus luteum cyst,
irritation of the pelvic viscera, uterine fibroids, adenomyosis,
endometriosis, infection and inflammation, pelvic organ ischemia,
obstruction, intra-abdominal adhesions, anatomic distortion of the
pelvic viscera, ovarian abscess, loss of pelvic support, tumors,
pelvic congestion or referred pain from non-gynecological
causes.
[0351] Another aspect of the invention provides a process for the
preparation of a compound of formula I, the process comprising:
[0352] (d) reacting a compound of formula IA:
##STR00016##
[0353] with a compound of formula IB:
##STR00017##
[0354] wherein,
[0355] T is an --N(R.sup.3)(R.sup.4) or an activating group;
[0356] wherein,
[0357] if T is --N(R.sup.3)(R.sup.4), then the compound of formula
I is formed; or
[0358] if T is an activating group, then a compound of formula IC
is formed:
##STR00018##
[0359] and the process further comprises:
[0360] (e) reacting the compound formula IC with
--N(R.sup.4)R.sup.P to form a compound of formula ID:
##STR00019##
[0361] wherein,
[0362] R.sup.P is R.sup.4 or a protecting group;
[0363] wherein,
[0364] if R.sup.P is R.sup.3, the compound of formula I is formed;
or
[0365] if R.sup.P is a protecting group, the process further
comprises:
[0366] (f) deprotecting the compound of formula ID to form a
deprotected compound; and
[0367] (g) reacting the deprotected compound with an
activated-R.sup.3 group, provided that R.sup.3 in the
activated-R.sup.3 group is not H;
[0368] wherein the compound of formula I is formed.
[0369] In another embodiment, step (d) further comprises contacting
the compound of formula IA and IB with dialkyl azodicarboxylate and
triphenylphosphine.
[0370] In another embodiment, the dialkyl azodicarboxylate is
diisopropyl azodicarboxylate.
[0371] In another embodiment, the activating group is selected from
the group consisting of halo, tosylate, mesylate, triflate, and
oxo.
[0372] In another embodiment, the activating group is Br.
[0373] In another embodiment, the protecting group is selected from
the group consisting of BOC, benzyl, acetyl, PMB, C.sub.1-C.sub.6
alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
[0374] In another embodiment, the protecting group is BOC.
[0375] In another embodiment, the deprotecting step is performed in
the presence of at least one agent selected from hydrochloric acid
(HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic
acid (TFA), tosic acid, a halotrimethylsilane, or aluminum
chloride.
[0376] In another embodiment, any one of steps (d)-(g) is performed
at or above 30.degree. C. or any one of steps (d)-(g) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0377] In another embodiment, the activated-R.sup.3 group is
halo-R.sup.3.
[0378] In another embodiment, the compound of formula IA is
prepared by:
[0379] (a) reacting a compound of formula IE:
##STR00020##
[0380] wherein R.sup.B is F or Cl;
[0381] with R.sup.2--NH.sub.2 to form a compound of formula IF:
##STR00021##
[0382] (b) hydrogenating the compound of formula IF to form a
compound of formula IG:
##STR00022##
[0383] and (c) reacting the compound of formula IG with sulfamide
in diglyme to form the compound of formula IA.
[0384] In another embodiment, the hydrogenating step is performed
in the presence of hydrogen (H.sub.2) and Pd/C.
[0385] In another embodiment, any one of steps (a)-(c) is performed
at or above 30.degree. C.
[0386] In another embodiment, any one of steps (a)-(c) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0387] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
##STR00023## [0388] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof; [0389] wherein: [0390] n is an
integer from 0 to 4; [0391] m is an integer from 0 to 6; [0392] X
is --CH.sub.2--; [0393] R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
alkylamido, or arylamido; wherein each aryl or heteroaryl is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups; and each arylsulfonamide or arylamido is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido
groups; [0394] R.sup.2 is aryl or heteroaryl substituted with 0-4
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; [0395] R.sup.3 and R.sup.4 are, independently, H,
alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein
each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl,
are indepently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups, provided that neither R.sup.3 or R.sup.4 contain an
aminoalkyl group; and
[0396] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N;
[0397] the process comprising:
[0398] (d) reacting R.sup.2(BOH).sub.2 and a transitional metal
salt with a compound of formula IH:
##STR00024##
[0399] wherein,
[0400] R.sup.P is R.sup.3 or a protecting group; and
[0401] if R.sup.P is R.sup.3, the compound of formula I is formed;
or
[0402] if R.sup.P is a protecting group, the process further
comprises:
[0403] (e) deprotecting the compound of formula IH to form a
deprotected compound; and
[0404] (f) reacting the deprotected compound with an
activated-R.sup.3 group, provided that R.sup.3 group in the
activated-R.sup.3 group is not H;
[0405] wherein the compound of formula I is formed.
[0406] In another embodiment, the transitional metal salt is
copper(II) acetate.
[0407] In another embodiment, the activated-R.sup.3 group is
halo-R.sup.3.
[0408] In another embodiment, the protecting group is selected from
the group consisting of BOC, benzyl, acetyl, PMB, C.sub.1-C.sub.6
alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
[0409] In another embodiment, the protecting group is BOC.
[0410] In another embodiment, the deprotecting step is performed in
the presence of at least one agent selected from hydrochloric acid
(HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic
acid (TFA), tosic acid, a halotrimethylsilane, or aluminum
chloride.
[0411] In another embodiment, any one of steps (d)-(f) is performed
at or above 30.degree. C. or any one of steps (d)-(f) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0412] In another embodiment, the compound of formula IH is
prepared by:
[0413] (a) reacting a compound of formula IJ:
##STR00025##
[0414] wherein R.sup.B is F or Cl;
[0415] with a compound of formula IK:
##STR00026##
[0416] to form a compound of formula IL:
##STR00027##
[0417] (b) hydrogenating the compound of formula IL to form a
compound of formula IM:
##STR00028##
[0418] and (c) reacting the compound of formula IM with sulfamide
and diglyme to form the compound of formula IH.
[0419] In another embodiment, the hydrogenating step is performed
in the presence of hydrogen (H.sub.2) and Pd/C.
[0420] In another embodiment, any one of steps (a)-(c) is performed
at or above 30.degree. C.
[0421] In another embodiment, any one of steps (a)-(c) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0422] In another embodiment, any one of the steps is performed in:
a protic solvent, an aprotic solvent, a polar solvent, a nonpolar
solvent, a protic polar solvent, an aprotic nonpolar solvent, or an
aprotic polar solvent.
[0423] In another embodiment, any one of the steps is performed in:
a protic solvent, an aprotic solvent, a polar solvent, a nonpolar
solvent, a protic polar solvent, an aprotic nonpolar solvent, or an
aprotic polar solvent.
[0424] Another aspect of the invention provides a compound
comprising a compound of formula IA, IB, IC, ID, IE, IF, IG, IH,
IJ, IK, IL or IM.
[0425] Another aspect of the invention provides a composition
comprising:
[0426] (a) one or more of the compounds of formula IA, IB, IC, ID,
IE, IF, IG, IH, IJ, IK, IL or IM; and
[0427] (b) one or more of: a base, an acid, a solvent, a
hydrogenating agent, a reducing agent, an oxidizing agent, or a
catalyst.
[0428] Some of the compounds of the present invention may contain
chiral centers and such compounds may exist in the form of
stereoisomers (i.e. enantiomers or diastereomers). The present
invention includes all such stereoisomers and any mixtures thereof
including racemic mixtures. Racemic mixtures of the stereoisomers
as well as the substantially pure stereoisomers are within the
scope of the invention. The term "substantially pure," as used
herein, refers to at least about 90 mole %, more preferably at
least about 95 mole %, and most preferably at least about 98 mole %
of the desired stereoisomer is present relative to other possible
stereoisomers. Preferred enantiomers may be isolated from racemic
mixtures by any method known to those skilled in the art, including
high performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described
herein. See, for example, Jacques, et al., Enantiomers, Racemates
and Resolutions (Wiley
[0429] Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of
Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed.,
University of Notre Dame Press, Notre Dame, Ind. 1972), the entire
disclosures of which are herein incorporated by reference.
[0430] The present invention includes prodrugs of the compounds of
formula I. "Prodrug," as used herein, means a compound which is
convertible in vivo by chemical or metabolic means (e.g. by
hydrolysis) to a compound of formula I. Various forms of prodrugs
are known in the art, for example, as discussed in Bundgaard,
(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),
Methods in Enzymology, vol. 4, Academic Press (1985);
Krogsgaard-Larsen, et al., (ed). "Design and Application of
Prodrugs," Textbook of Drug Design and Development, Chapter 5,
113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews,
1992, 8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988,
77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel
Drug Delivery Systems, American Chemical Society (1975), the entire
disclosures of which are herein incorporated by reference.
[0431] Further, the compounds of formula I may exist in unsolvated
as well as in solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the
solvated forms are considered equivalent to the unsolvated forms
for the purpose of the present invention.
[0432] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0433] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Protecting groups that may be
employed in accordance with the present invention may be described
in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic
Synthesis 2d. Ed., Wiley & Sons, 1991, the entire disclosure of
which is herein incorporated by reference.
[0434] Compounds of the present invention are suitably prepared in
accordance with the following general description and specific
examples. Variables used are as defined for formula I, unless
otherwise noted. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
In accordance with this invention, compounds of formula I may be
produced by the following reaction schemes (Schemes 1-3).
[0435] The compounds of this invention contain chiral centers,
providing for various stereoisomeric forms such as diastereomeric
mixtures, enantiomeric mixtures as well as optical isomers. The
individual optical isomers can be prepared directly through
asymmetric and/or stereospecific synthesis or by conventional
chiral separation of optical isomers from the enantiomeric
mixture.
##STR00029## ##STR00030##
[0436] Following Scheme 1, an appropriate fluoronitroarene 1 may be
substituted with an aryl amine using a base under standard
conditions to provide an aminonitroarene 2. Typically conditions
for this reaction a base such as sodium hydride in DMF or an
organometallic base such as butyllithium in THF. Reduction of the
nitro group in structure 2 is accomplished under standard
conditions using hydrogen and a suitable catalyst such as palladium
or Raney nickel to provide a dianiline 3. Nitro reduction is a
common transformation and one could employ a number of alternative
procedures including reduction conditions using metal salts such as
aqueous HCl with tin(II) chloride or aqueous ammonium chloride with
zinc metal. The dianiline 3 is then treated a suitable sulfate
containing reagent to form arylsulfamide of structure 4. In a
typical example, 3 was heated with sulfamide in diglyme to provide
the cyclized product 4. The acidic nitrogen is then combined with a
suitably substituted side chain providing products 5 or 6 defending
on the structure of the desired side chain. An effective method for
attaching the side chain to sulfamide 4 is the Mitsunobu reaction
in which an alcohol is activated and displaced by treating with a
phosphine and an activating reagent. In accordance with the
embodiment of the invention, typical conditions for effecting the
attachment of the sulfamide to the alcohol containing side chain
were treatment with diisopropyl azodicarboxylate and
triphenylphosphine in THF. Another suitable method for
accomplishing side chain attachment is direct nucleophilic
substitution of a leaving group containing side chain with the
sulfamide and can be facilitated by addition of a base in a
suitable solvent. Typically compounds of structure 5 with a bromine
containing side chain were treated with an excess of the desired
amine to provide the desired compounds of formula I. An alternative
method for the synthesis of compounds of formula I is possible from
6 where the side chain is attached with the amine present in
protected form (the protecting group is represented by the letter
P). Any suitable amine protecting group, t-butoxycarbonyl in a
typical example, may be used. The protecting group is then removed,
in the case of t-butoxycarbonyl using an acid such as hydrochloric
acid, to give compounds of formula I.
##STR00031## ##STR00032##
[0437] An additional method for the synthesis of compounds of
formula I is described in Scheme 2. An appropriate fluoronitroarene
is substituted with an amine bearing the desired side chain to give
compounds of structure 7. Reduction of the nitro group under
conditions described in Scheme 1 provides 8. Compounds of structure
8 can be converted to arylsulfamide of structure 9 by treatment
with a suitable sulfate containing reagent. In a typical example, 8
was heated with sulfamide in diglyme to provide the cyclized
product 9. An aryl group may then be attached to the sulfamide 9
using conventional methods for formation of an aryl-nitrogen bond.
In a typical example an aryl boronic acid forms an aryl-nitrogen
bond in the presence of a transition metal salt such as copper(II)
acetate to provide 6. Subsequent deprotection of the protecting
group P in 6 affords compounds of formula I. As described in Scheme
1, the protecting group t-butoxycarbonyl was useful for this
purpose and is readily removed using an acid such as hydrochloric
acid to give compounds of formula I.
[0438] In other embodiments, the invention is directed to
pharmaceutical compositions, comprising: [0439] a. at least one
compound of formula I, or pharmaceutically acceptable salt thereof;
and [0440] b. at least one pharmaceutically acceptable carrier.
[0441] Generally, the compound of formula I, or a pharmaceutically
acceptable salt thereof, will be present at a level of from about
0.1%, by weight, to about 90% by weight, based on the total weight
of the pharmaceutical composition, based on the total weight of the
pharmaceutical composition. Preferably, the compound of formula I,
or a pharmaceutically acceptable salt thereof, will be present at a
level of at least about 1%, by weight, based on the total weight of
the pharmaceutical composition. More preferably, the compound of
formula I, or a pharmaceutically acceptable salt thereof, will be
present at a level of at least about 5%, by weight, based on the
total weight of the pharmaceutical composition. Even more
preferably, the compound of formula I, or a pharmaceutically
acceptable salt thereof will be present at a level of at least
about 10%, by weight, based on the total weight of the
pharmaceutical composition. Yet even more preferably, the compound
of formula I, or a pharmaceutically acceptable salt thereof, will
be present at a level of at least about 25%, by weight, based on
the total weight of the pharmaceutical composition.
[0442] Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's
Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro,
Mack Publishing Company, Easton, Pa. (1985), the entire disclosure
of which is herein incorporated by reference. Pharmaceutically
acceptable carriers are those that are compatible with the other
ingredients in the formulation and biologically acceptable.
[0443] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances that may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or an
encapsulating material. In powders, the carrier is a finely divided
solid that is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to about 99% of the
active ingredient. Suitable solid carriers include, for example,
calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin, starch, gelatin, cellulose, methyl cellulose, sodium
carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes
and ion exchange resins.
[0444] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers, or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[0445] Liquid pharmaceutical compositions for parenteral
administration, which are sterile solutions or suspensions, can be
administered by, for example, intramuscular, intraperitoneal or
subcutaneous injection. Sterile solutions can also be administered
intravenously. Oral administration may be either liquid or solid
composition form.
[0446] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form.
[0447] In another embodiment of the present invention, the
compounds useful in the present invention may be administered to a
mammal with one or more other pharmaceutical active agents such as
those agents being used to treat any other medical condition
present in the mammal. Examples of such pharmaceutical active
agents include pain relieving agents, anti-angiogenic agents,
anti-neoplastic agents, anti-diabetic agents, anti-infective
agents, or gastrointestinal agents, or combinations thereof.
[0448] The one or more other pharmaceutical active agents may be
administered in a therapeutically effective amount simultaneously
(such as individually at the same time, or together in a
pharmaceutical composition), and/or successively with one or more
compounds of the present invention.
[0449] The term "combination therapy" refers to the administration
of two or more therapeutic agents or compounds to treat a
therapeutic condition or disorder described in the present
disclosure, for example hot flush, sweating,
thermoregulatory-related condition or disorder, or other condition
or disorder. Such administration includes use of each type of
therapeutic agent in a concurrent manner. In either case, the
treatment regimen will provide beneficial effects of the drug
combination in treating the conditions or disorders described
herein.
[0450] The route of administration may be any enteral or parenteral
route which effectively transports the active compound of formula
I, or a pharmaceutically acceptable salt thereof, to the
appropriate or desired site of action; such as oral, nasal,
pulmonary, transdermal, such as passive or iontophoretic delivery,
or parenteral, e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intrathecal, intra-articular,
intranasal, ophthalmic solution or an ointment. Furthermore, the
administration of compound of formula I, or pharmaceutically
acceptable salt thereof, with other active ingredients may be
separate, consecutive or simultaneous.
[0451] The present invention is further defined in the following
Examples, in which all parts and percentages are by weight and
degrees are Celsius, unless otherwise stated. It should be
understood that these examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only. From the above discussion and these examples, one skilled in
the art can ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
EXAMPLES
Example 1
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine
##STR00033##
[0453] Genera Procedure A for Synthesis of Sulfamides of Structure
I;
[0454] Step 1: Dry diglyme (10 mL) was added to a flask equipped
with a dropping funnel under a nitrogen atmosphere and brought to a
vigorous reflux. N-(4-chlorophenyl)-benzene-1,2-diamine (1.09 g,
5.0 mmol) and sulfamide (0.58 g, 6.0 mmol) were dissolved in 5 mL
of diglyme and placed in the dropping funnel. The mixture was added
dropwise to the flask over 15 minutes and then refluxing was
continued for an additional 15 minutes. The mixture was cooled to
ambient temperature and diluted with ether, washed with water, 2N
HCl, water, brine, dried over anhydrous magnesium sulfate, and
concentrated. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 5-50% (ethyl acetate
containing 2% formic acid) in hexane) to afford
1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
0.66 g (47%).
[0455] MS (ESI) m/z 279
[0456] HPLC purity 94.7% at 210-370 nm, 9.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0457] Step 2:
1-(4-Chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.28 g, 1.0 mmol) was dissolved in THF (10 mL). Triphenylphosphine
(314 mg, 1.2 mmol) and 3-bromopropanol (0.089 mL, 1.0 mmol) were
added followed by diisopropylazodicarboxylate (0.23 mL, 1.2 mmol).
The mixture was stirred for 16 hours and then concentrated.
Purification via Isco chromatography (Redisep, silica, gradient
5-50% ethyl acetate in hexane) afforded 0.13 g (32%)
1-(3-bromo-propyl)-3-(4-chlorophenyl)-1,3-dihydro-benzo[1,2,5]thiadiazole
2,2-dioxide which was immediately carried on to the next step.
[0458] Step 3: 1-(3-Bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydro
benzo[1,2,5]thia-diazole 2,2-dioxide (0.12 g, 0.29 mmol) was
dissolved in 8N methylamine in methanol (20 mL) and stirred for 16
hours in a sealed flask. The mixture was concentrated in vacuo to
give the crude product. The crude product was purified via
chromatography (silica, 5% methanol saturated with ammonia in
chloroform) to give 70 mg of
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine. The free base was dissolved in ether (2 mL) and
treated with 1N hydrochloric acid in ether (1 equivalent). The
white precipitate was collected and dried under vacuum to give 70
mg (71%) of
3-=3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl-N-methylpropan-1-amine hydrochloride. HPLC purity 100% at
210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5,
acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
[0459] HRMS: calculated for
C.sub.16H.sub.18ClN.sub.3O.sub.2S+H.sup.+, 352.08810; found (ESI,
[M+H].sup.+), 352.0875
Example 2
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1--
amine
##STR00034##
[0461]
1-(3-Bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thia--
diazole 2,2-dioxide (0.10 g, 0.25 mmol) was dissolved in 7N ammonia
in methanol (20 mL), heated to 60.degree. C. and stirred for 16
hours in a sealed flask. The mixture was cooled and concentrated in
vacuo to give the crude product. The crude product was purified via
chromatography (silica, 5% methanol saturated with ammonia in
chloroform) to give 73 mg (87%) of
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine. The free base was dissolved in ether (2 mL) and
treated with 1N hydrochloric acid in ether (1 equivalent). The
white precipitate was collected, dissolved in water, and
lyophilized to give 56 mg of
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-
-amine hydrochloride.
[0462] MS (ES) m/z 337.9;
[0463] HPLC purity 100% at 210-370 nm, 7.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 3
N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl-
}cyclopropanamine
##STR00035##
[0465] In an analogous manner to General Procedure A, Step 3,
1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole
2,2-dioxide (0.10 g, 0.25 mmol) was treated with cyclopropyl amine
to provide
N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]propyl}cyclopropanamine (87 mg).
[0466] MS (ES) m/z 378
[0467] HPLC purity 100% at 210-370 nm, 8.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 4
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylp-
ropan-1-amine
##STR00036##
[0469] In an analogous manner to General Procedure A, Step 3,
1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole
2,2-dioxide (0.06 g, 0.15 mmol) was treated with ethyl amine to
provide
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-
propan-1-amine (42 mg).
[0470] MS (ES) m/z 366.1;
[0471] HPLC purity 92.4% at 210-370 nm, 8.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 5
3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-a-
mine
##STR00037##
[0473] Step 1: In an analogous manner to General Procedure A, Step
1, N-phenyl-o-phenylenediamine (0.10 g, 5.4 mmol) was treated with
sulfamide (0.63 g, 6.5 mmol) to provide
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.90
g).
[0474] MS (ES) m/z 244.9;
[0475] HPLC purity 97.7% at 210-370 nm, 8.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0476] Step 2: In an analogous manner to General Procedure A, Step
2, 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (246 mg,
1.0 mmol) was treated with triphenylphosphine (0.31 g, 1.2 mmol),
3-bromopropanol (0.087 mL, 1 mmol), and diisopropylazodicarboxylate
(0.23 mL, 1.2 mmol) to provide
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.19 g).
[0477] MS (ES) m/z 367.0;
[0478] HPLC purity 98.5% at 210-370 nm, 10.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0479] Step 3: In an analogous manner to General Procedure A, Step
3, 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.17 g, 0.46 mmol) was treated with methylamine to
provide
3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1--
amine (120 mg).
[0480] MS (ES) m/z 318.0;
[0481] HPLC purity 99.5% at 210-370 nm, 6.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 6
3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine
##STR00038##
[0483] Step 1: 4-Fluoroaniline (5.5 g, 50 mmol) was dissolved in
DMF (100 mL) and sodium hydride (1.9 g, 50 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (4.4 mL,
42 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ethyl acetate and ether. The mixture was washed with water, brine,
dried over anhydrous magnesium sulfate, and concentrated. The crude
product was purified via Isco chromatography (Redisep, silica,
gradient 5-25% ethyl acetate in hexane) to afford 3.2 g of
N-(4-fluorophenyl)-N-(2-nitrophenyl)amine that was carried on
directly to the next step.
[0484] HRMS: calculated for C.sub.12H.sub.9FN.sub.2O2+H.sup.+,
233.07208; found (ESI.sup.+, [M+H].sup.+), 233.07207
[0485] Step 2: N-(4-fluorophenyl)-N-(2-nitrophenyl)amine (3.0 g,
12.9 mmol) was dissolved in ethyl acetate (30 mL) and 10% palladium
on activated carbon (250 mg) was added. The mixture was shaken
under a hydrogen atmosphere (40 psi) for 1 hour. The mixture was
filtered through a pad of Celite and concentrated to give
N-(4-fluorophenyl)benzene-1,2-diamine (2.6 g) that was carried on
directly to the next step.
[0486] MS (ES) m/z 203.1;
[0487] HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0488] Step 3: in an analogous manner to General Procedure A, Step
1, N-(4-fluorophenyl)benzene-1,2-diamine (2.4 g, 11.9 mmol) was
treated with sulfamide (1.36 g, 14.3 mmol) to provide
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(2.2 g).
[0489] MS (ES) m/z 263.0;
[0490] HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0491] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.2 g, 8.3 mmol) was treated with triphenylphosphine
(2.62 g, 10 mmol), 3-bromopropanol (0.72 mL, 8.3 mmol), and
diisopropylazodicarboxylate (1.94 mL, 10 mmol) to provide
1-(3-bromopropyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.3 g).
[0492] MS (ES) m/z 385.3;
[0493] HPLC purity 100.0% at 210-370 nm, 10.6 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0494] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.3 g, 6 mmol) was treated with methylamine to provide
3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine (1.65 g).
[0495] MS (ES) m/z 335.9;
[0496] HPLC purity 100.0% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 7
3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine
##STR00039##
[0498] Step 1: p-Anisidine (1.0 g, 8.1 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.31 g, 8.1 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (0.86 mL,
8.1 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ethyl acetate and ether. The mixture was washed with water, brine,
dried over anhydrous magnesium sulfate, and concentrated. The crude
product was purified via Isco chromatography (Redisep, silica,
gradient 5-25% ethyl acetate in hexane) to afford 0.4 g of
N-(4-methoxyphenyl)-2-nitroaniline that was carried on directly to
the next step.
[0499] HRMS: calculated for C.sub.13H.sub.12N.sub.2O.sub.3+H.sup.+,
245.09207; found (ESI.sup.+, [M+H].sup.+), 245.09144;
[0500] Step 2: N-(4-methoxyphenyl)-2-nitroaniline (0.4 g, 1.6 mmol)
was dissolved in ethyl acetate (15 mL) and 10% palladium on
activated carbon (100 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered
through a pad of Celite and concentrated to give
N-(4-methoxyphenyl)benzene-1,2-diamine (0.34 g) that was carried on
directly to the next step.
[0501] HRMS: calculated for C.sub.13H.sub.14N.sub.2O+H.sup.+,
215.11789; found (ESI.sup.+, [M+H].sup.+), 215.11733
[0502] Step 3: In an analogous manner to General Procedure A, Step
1, N-(4-methoxyphenyl)benzene-1,2-diamine (0.34 g, 1.6 mmol) was
treated with sulfamide (0.18 g, 1.9 mmol) to provide
1-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.17 g).
[0503] MS (ES) m/z 275.0;
[0504] HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0505] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.13 g, 0.47 mmol) was treated with triphenylphosphine
(146 mg, 0.56 mmol), 3-bromopropanol (0.041 mL, 0.47 mmol), and
diisopropylazodicarboxylate (0.11 mL, 0.56 mmol) to provide
1-(3-bromopropyl)-3-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.12 g).
[0506] MS (ES) m/z 396.8;
[0507] HPLC purity 98.1% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0508] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (100 mg, 0.25 mmol) was treated with methylamine to
provide
3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine (70 mg).
[0509] MS (ES) m/z 347.9;
[0510] HPLC purity 100.0% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 8
N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine
##STR00040##
[0512] Step 1: p-Toluidine (1.4 g, 13 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ethyl acetate and ether. The mixture was washed with water, brine,
dried over anhydrous magnesium sulfate, and concentrated. The crude
product was purified via Isco chromatography (Redisep, silica,
gradient 5-30% ethyl acetate in hexane) to afford 0.6 g
N-(4-methylphenyl)-N-(2-nitrophenyl)amine that was carried on
directly to the next step.
[0513] HRMS: calculated for C.sub.13H.sub.12N.sub.2O.sub.2+H.sup.+,
229.09715; found (ESI.sup.+, [M+H].sup.+), 229.09737
[0514] Step 2: N-(4-methylphenyl)-N-(2-nitrophenyl)amine (0.59 g,
2.6 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium
on activated carbon (50 mg) was added. The mixture was shaken under
a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-(4-methylphenyl)benzene-1,2-diamine (0.5 g) that was carried on
directly to the next step.
[0515] HRMS: calculated for C.sub.13H.sub.14N.sub.2+H.sup.+,
199.12297; found (ESI.sup.+, [M+H].sup.+), 199.12318
[0516] Step 3: In an analogous manner to General Procedure A, Step
1, N-(4-methylphenyl)benzene-1,2-diamine (0.5 g, 2.5 mmol) was
treated with sulfamide (0.29 g, 3.0 mmol) to provide
1-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.31 g).
[0517] MS (ES) m/z 259.0;
[0518] HPLC purity 95.5% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0519] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.24 g, 0.92 mmol) was treated with triphenylphosphine
(0.288 g, 1.1 mmol), 3-bromopropanol (0.081 mL, 0.92 mmol), and
diisopropylazodicarboxylate (0.21 mL, 1.1 mmol) to provide
1-(3-bromopropyl)-3-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.26 g).
[0520] HPLC purity 98.4% at 210-370 nm, 10.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0521] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (240 mg, 0.63 mmol) was treated with methylamine to
provide
N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine (190 mg).
[0522] MS (ES) m/z 331.9;
[0523] HPLC purity 100.0% at 210-370 nm, 6.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 9
3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine
##STR00041##
[0525] Step 1: o-Anisidine (1.7 mL, 15 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.7 g
N-(2-methoxyphenyl)-N-(2-nitrophenyl)amine that was carried on
directly to the next step.
[0526] HRMS: calculated for C.sub.13H.sub.12N.sub.2O.sub.3+H.sup.+,
245.09207; found (ESI.sup.+, [M+H].sup.+), 245.09187
[0527] Step 2: N-(2-methoxyphenyl)-N-(2-nitrophenyl)amine (0.66 g,
2.7 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium
on activated carbon (50 mg) was added. The mixture was shaken under
a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-(2-methoxyphenyl)benzene-1,2-diamine (0.56 g) that was carried on
directly to the next step.
[0528] HRMS: calculated for C.sub.13H.sub.14N.sub.2O+H.sup.+,
215.11789; found (ESI.sup.+, [M+H].sup.+), 215.11761
[0529] Step 3: In an analogous manner to General Procedure A, Step
1, N-(2-methoxyphenyl)benzene-1,2-diamine (0.56 g, 2.6 mmol) was
treated with sulfamide (0.30 g, 3.1 mmol) to provide
1-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.41 g).
[0530] MS (ES) m/z 275.0;
[0531] HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0532] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.35 g, 1.27 mmol) was treated with triphenylphosphine
(400 mg, 1.5 mmol), 3-bromopropanol (0.11 mL, 1.27 mmol), and
diisopropylazodicarboxylate (0.29 mL, 1.5 mmol) to provide
1-(3-bromopropyl)-3-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.44 g).
[0533] MS (ES) m/z 397.0;
[0534] HPLC purity 100.0% at 210-370 nm, 10.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0535] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (410 mg, 1.0 mmol) was treated with methylamine to
provide
3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine (330 mg).
[0536] MS (ES) m/z 347.9;
[0537] HPLC purity 100.0% at 210-370 nm, 6.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 10
3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
##STR00042##
[0539] Step 1: 3-Fluoro-2-methylaniline (1.7 mL, 15 mmol) was
dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was
added and the mixture was stirred for 30 minutes.
2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture
was stirred for 16 hours. The mixture was quenched with saturated
NH.sub.4Cl and diluted with ether. The mixture was washed with
water, brine, dried over anhydrous magnesium sulfate, and
concentrated. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 5-30% ethyl acetate in
hexane) to afford 1.2 g
(3-fluoro-2-methyl-phenyl)-(2-nitro-phenyl)-amine that was carried
on directly to the next step.
[0540] Step 2: (3-Fluoro-2-methyl-phenyl)-(2-nitro-phenyl)-amine
(1.1 g, 4.5 mmol) was dissolved in ethyl acetate (20 mL) and 10%
palladium on activated carbon (100 mg) was added. The mixture was
shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture
was filtered through a pad of Celite and concentrated to give
N-(3-Fluoro-2-methyl-phenyl)-benzene-1,2-diamine (0.86 g) that was
carried on directly to the next step.
[0541] Step 3: In an analogous manner to General Procedure A, Step
1, N-(3-Fluoro-2-methyl-phenyl)-benzene-1,2-diamine (0.86 g, 4.0
mmol) was treated with sulfamide (0.46 g, 4.8 mmol) to provide
1-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.48 g).
[0542] MS (ES) m/z 277.0;
[0543] HPLC purity 98.8% at 210-370 nm, 10.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0544] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.43 g, 1.55 mmol) was treated with triphenylphosphine
(470 mg, 1.8 mmol), 3-bromopropanol (0.134 mL, 1.55 mmol), and
diisopropylazodicarboxylate (0.34 mL, 1.8 mmol) to provide
1-(3-bromopropyl)-3-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.43 g).
[0545] HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0546] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (420 mg, 1.0 mmol) was treated with methylamine
to provide
3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]-N-methylpropan-1-amine (350 mg).
[0547] MS (ES) m/z 350.0;
[0548] HPLC purity 100.0% at 210-370 nm, 7.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 11
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine
##STR00043##
[0550] Step 1: 2-Fluoroaniline (1.45 mL, 15 mmol) was dissolved in
DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 1.4 g
2-fluoro-N-(2-nitrophenyl)aniline that was carried on directly to
the next step.
[0551] MS (ES) m/z 232.9
[0552] Step 2: 2-fluoro-N-(2-nitrophenyl)aniline (1.4 g, 6.0 mmol)
was dissolved in ethyl acetate (20 mL) and 10% palladium on
activated carbon (150 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered
through a pad of Celite and concentrated to give
N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g) that was carried on
directly to the next step.
[0553] MS (ES) m/z 203.0
[0554] Step 3: In an analogous manner to General Procedure A, Step
1, N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g, 6.0 mmol) was
treated with sulfamide (0.69 g, 7.2 mmol) to provide
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.37 g).
[0555] MS (ES) m/z 263.0;
[0556] HPLC purity 100.0% at 210-370 nm, 8.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0557] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.37 g, 1.4 mmol) was treated with triphenylphosphine
(440 mg, 1.68 mmol), 3-bromopropanol (0.12 mL, 1.4 mmol), and
diisopropylazodicarboxylate (0.33 mL, 1.68 mmol) to provide
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.41 g).
[0558] MS (ES) m/z 384.9
[0559] HPLC purity 99.4% at 210-370 nm, 10.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0560] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.4 g, 1.04 mmol) was treated with methylamine to
provide
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine (350 mg).
[0561] MS (ES) m/z 335.9;
[0562] HPLC purity 99.2% at 210-370 nm, 8.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 12
3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine
##STR00044##
[0564] Step 1: 3-Fluoroaniline (1.43 mL, 15 mmol) was dissolved in
DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.77 g
N-(3-fluorophenyl)-N-(2-nitrophenyl)amine that was carried on
directly to the next step.
[0565] HRMS: calculated for C.sub.12H.sub.9FN.sub.2O.sub.2,
232.06481; found (EI, M.sup.+), 232.06482
[0566] Step 2: N-(3-fluorophenyl)-N-(2-nitrophenyl)amine (0.77 g,
3.3 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium
on activated carbon (50 mg) was added. The mixture was shaken under
a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-(3-fluorophenyl)benzene-1,2-diamine (0.64 g) that was carried on
directly to the next step.
[0567] HRMS: calculated for C.sub.12H.sub.11FN.sub.2+H.sup.+,
203.09790; found (ESI.sup.+, [M+H].sup.+), 203.09795
[0568] Step 3: In an analogous manner to General Procedure A, Step
1, N-(3-fluorophenyl)benzene-1,2-diamine (0.64 g, 3.2 mmol) was
treated with sulfamide (0.36 g, 3.8 mmol) to provide
1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.17 g).
[0569] MS (ES) m/z 263.0;
[0570] HPLC purity 97.4% at 210-370 nm, 8.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0571] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.16 g, 0.61 mmol) was treated with triphenylphosphine
(190 mg, 0.73 mmol), 3-bromopropanol (0.053 mL, 0.61 mmol), and
diisopropylazodicarboxylate (0.14 mL, 0.73 mmol) to provide
1-(3-bromopropyl)-3-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.15 g).
[0572] MS (ES) m/z 385
[0573] HPLC purity 97.9% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0574] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.14 g, 0.36 mmol) was treated with methylamine to
provide
3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine (120 mg).
[0575] MS (ES) m/z 336.0;
[0576] HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 13
N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine
##STR00045##
[0578] Step 1: 1-naphthylamine (2.14 g, 15 mmol) was dissolved in
DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.41 g
N-(2-nitrophenyl)naphthalen-1-amine that was carried on directly to
the next step.
[0579] MS (ES) m/z 265.0;
[0580] HPLC purity 100.0% at 210-370 nm, 11.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0581] Step 2: N-(2-nitrophenyl)naphthalen-1-amine (0.41 g, 1.55
mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on
activated carbon (50 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-Naphthalen-1-yl-benzene-1,2-diamine (0.36 g) that was carried on
directly to the next step.
[0582] Step 3: In an analogous manner to General Procedure A, Step
1, N-Naphthalen-1-yl-benzene-1,2-diamine (0.36 g, 1.55 mmol) was
treated with sulfamide (0.18 g, 1.86 mmol) to provide
1-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28
g).
[0583] MS (ES) m/z 295.0
[0584] HPLC purity 94.3% at 210-370 nm, 9.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0585] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.25 g, 0.84 mmol) was treated with triphenylphosphine (262 mg,
1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and
diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide
1-(3-bromopropyl)-3-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.12 g).
[0586] MS (ES) m/z 416.8
[0587] HPLC purity 99.4% at 210-370 nm, 11.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0588] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.12 g, 0.28 mmol) was treated with methylamine to
provide
N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pan-1-amine (110 mg).
[0589] MS (ES) m/z 367.9;
[0590] HPLC purity 99.5% at 210-370 nm, 7.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 14
N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine
##STR00046##
[0592] Step 1: 2-naphthylamine (1.0 g, 7 mmol) was dissolved in DMF
(5 mL) and sodium hydride (0.27 g, 7 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (0.61 mL,
5.8 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.37 g
N-(2-nitrophenyl)naphthalen-2-amine that was carried on directly to
the next step.
[0593] MS (ES) m/z 265.0;
[0594] HPLC purity 100.0% at 210-370 nm, 11.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0595] Step 2: N-(2-nitrophenyl)naphthalen-2-amine (0.36 g, 1.4
mmol) was dissolved in ethyl acetate (10 mL) and 10% palladium on
activated carbon (50 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-Naphthalen-2-yl-benzene-1,2-diamine (0.32 g) that was carried on
directly to the next step.
[0596] Step 3: In an analogous manner to General Procedure A, Step
1, N-Naphthalen-2-yl-benzene-1,2-diamine (0.32 g, 1.36 mmol) was
treated with sulfamide (0.16 g, 1.63 mmol) to provide
1-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.29
g).
[0597] MS (ES) m/z 295.0
[0598] HPLC purity 99.2% at 210-370 nm, 9.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH-3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0599] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.25 g, 0.84 mmol) was treated with triphenylphosphine (262 mg,
1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and
diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide
1-(3-bromopropyl)-3-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.14 g).
[0600] MS (ES) m/z 415.9
[0601] HPLC purity 98.4% at 210-370 nm, 11.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0602] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.12 g, 0.28 mmol) was treated with methylamine to
provide
N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pan-1-amine (100 mg).
[0603] MS (ES) m/z 368.0;
[0604] HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 15
N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine
##STR00047##
[0606] Step 1: m-Toluidine (1.6 mL, 15 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.95 g
N-(3-methylphenyl)-2-nitroaniline that was carried on directly to
the next step.
[0607] HRMS: calculated for C.sub.13H.sub.12N.sub.2O.sub.2+H.sup.+,
229.09715; found (ESI.sup.+, [M+H].sup.+), 229.09727
[0608] Step 2: N-(3-methylphenyl)-2-nitroaniline (0.93 g, 4.1 mmol)
was dissolved in ethyl acetate (20 mL) and 10% palladium on
activated carbon (50 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-(3-methylphenyl)benzene-1,2-diamine (0.81 g) that was carried on
directly to the next step.
[0609] HRMS: calculated for C.sub.13H.sub.14N.sub.2+H.sup.+,
199.12297; found (ESI.sup.+, [M+H].sup.+), 199.1232
[0610] Step 3: In an analogous manner to General Procedure A, Step
1, N-(3-methylphenyl)benzene-1,2-diamine (0.81 g, 4.1 mmol) was
treated with sulfamide (0.47 g, 4.9 mmol) to provide
1-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.035 g).
[0611] MS (ES) m/z 259.0
[0612] HPLC purity 94.8% at 210-370 nm, 9.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0613] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.03 g, 0.12 mmol) was treated with triphenylphosphine
(37 mg, 0.14 mmol), 3-bromopropanol (0.001 mL, 0.12 mmol), and
diisopropylazodicarboxylate (0.027 mL, 0.14 mmol) to provide
1-(3-bromopropyl)-3-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (14 mg) that was carried on to the next step.
[0614] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (14 mg, 0.04 mmol) was treated with methylamine to
provide
N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine (9 mg).
[0615] MS (ES) m/z 332.0;
[0616] HPLC purity 100.0% at 210-370 nm, 7.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 16
N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine
##STR00048##
[0618] Step 1: o-Toluidine (1.6 mL, 15 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 0.75 g
(2-Nitro-phenyl)-o-tolyl-amine.
[0619] Step 2: (2-Nitro-phenyl)-o-tolyl-amine (0.75 g, 3.3 mmol)
was dissolved in ethyl acetate (20 mL) and 10% palladium on
activated carbon (50 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-o-tolyl-benzene-1,2-diamine (0.65 g) that was carried on directly
to the next step.
[0620] Step 3: In an analogous manner to General Procedure A, Step
1, N-o-Tolyl-benzene-1,2-diamine (0.65 g, 3.3 mmol) was treated
with sulfamide (0.38 g, 4.0 mmol) to provide
1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.24 g).
[0621] MS (ES) m/z 261.0;
[0622] HPLC purity 92.8% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0623] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.22 g, 0.84 mmol) was treated with triphenylphosphine
(262 mg, 1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and
diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide
1-(3-bromopropyl)-3-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.29 g).
[0624] HPLC purity 95.3% at 210-370 nm, 10.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0625] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.27 g, 0.7 mmol) was treated with methylamine to
N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine (220 mg).
[0626] MS (ES) m/z 331.9;
[0627] HPLC purity 100.0% at 210-370 nm, 7.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 17
3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine
##STR00049##
[0629] Step 1: m-Anisidine (1.7 mL, 15 mmol) was dissolved in DMF
(10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 1.3 g
N-(3-methoxyphenyl)-N-(2-nitrophenyl)amine.
[0630] HRMS: calculated for C.sub.13H.sub.12N.sub.2O.sub.3+H.sup.+,
245.09207; found (ESI.sup.+, [M+H].sup.+), 245.0919
[0631] Step 2: N-(3-methoxyphenyl)-N-(2-nitrophenyl)amine (1.27 g,
5.2 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium
on activated carbon (50 mg) was added. The mixture was shaken under
a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered
through a pad of Celite and concentrated to give
N-(3-methoxyphenyl)benzene-1,2-diamine (1.11 g) that was carried on
directly to the next step.
[0632] HRMS: calculated for C.sub.13H.sub.14N.sub.2O+H.sup.+,
215.11789; found (ESI.sup.+, [M+H].sup.+), 215.11774
[0633] Step 3: In an analogous manner to General Procedure A, Step
1, N-(3-methoxyphenyl)benzene-1,2-diamine (1.1 g, 5.1 mmol) was
treated with sulfamide (0.59 g, 6.2 mmol) to provide
1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.3 g).
[0634] MS (ES) m/z 276.9;
[0635] HPLC purity 99.4% at 210-370 nm, 8.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0636] Step 4: In an analogous manner to General Procedure A, Step
2, 1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.3 g, 1.09 mmol) was treated with triphenylphosphine
(340 mg, 1.3 mmol), 3-bromopropanol (0.095 mL, 1.09 mmol), and
diisopropylazodicarboxylate (0.25 mL, 1.3 mmol) to provide
1-(3-bromopropyl)-3-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.22 g).
[0637] MS (ES) m/z 396.9;
[0638] HPLC purity 100.0% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0639] Step 5: In an analogous manner to General Procedure A, Step
3,
1-(3-bromopropyl)-3-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.21 g, 0.5 mmol) was treated with methylamine to give
3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-meth-
ylpropan-1-amine (170 mg).
[0640] MS (ES) m/z 347.9;
[0641] HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 18
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-am-
ine
##STR00050##
[0643] Step 1: 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (110 mg, 0.45 mmol) was dissolved in DMF (2 mL) and
1,4-dibromobutane (0.27 mL, 2.25 mmol) was added followed by cesium
carbonate (0.22 g, 0.68 mmol). The mixture was stirred for 16 hours
then diluted with ether and washed with 1N HCl, water, and
saturated brine. The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified via Isco chromatography (Redisep,
silica, gradient 2-30% ethyl acetate in hexane) to afford 0.155 g
of 1-(4-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide.
[0644] HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0645] Step 2:
1-(4-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.14 g, 0.37 mmol) was dissolved in 8N methylamine in
methanol (20 mL) and stirred for 16 hours in a sealed flask. The
mixture was concentrated in vacuo to give the crude product. The
crude product was purified via chromatography (silica, 5% methanol
saturated with ammonia in chloroform) to give 110 mg of
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-a-
mine. The free base was dissolved in ether (2 mL) and treated with
1N hydrochloric acid in ether (1 equivalent). The white precipitate
was collected and dried under vacuum to give 120 mg of
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-a-
mine hydrochloride.
[0646] HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 19
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-a-
mine
##STR00051##
[0648] Step 1: Cesium carbonate (0.29 g, 0.9 mmol) was added to a
solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.25 g, 0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6
mmol) in dry DMF (5.0 mL) under nitrogen. After 3 h, the reaction
mixture was diluted with diethyl ether and washed with water and
brine. The ether layer was dried over magnesium sulfate, filtered
and concentrated in vacuo to give 0.41 g of crude product. The
crude product was pre-adsorbed onto Celite and purified via Isco
chromatography (Redisep, silica, gradient 5-30% ethyl acetate in
hexane) to afford 0.22 g (59%) of
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide.
[0649] mp 65-68.degree. C.
[0650] HPLC purity 100.0% at 210-370 nm, 11.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH-3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0651] Step 2: 10 mL of ammonia (ca. 7N in methanol) was added to a
pressure tube containing
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (50 mg, 0.12 mmol). The vessel was sealed and the
mixture was stirred at 60.degree. C. overnight then concentrated to
give the crude product. The crude product was pre-adsorbed onto
Celite and purified via Isco chromatography (Redisep, silica,
gradient 1-8% methanol in dichloromethane) to afford 33 mg (78%) of
product. Further purification by reverse phase HPLC(X-terra MS
C.sub.18 19.times.150 mm, using a gradient of 10-100%
water-acetonitrile with 0.1% TFA at a rate of 20 mL/minute at 254
nm) gave 11 mg (20%) of
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine as the TFA salt.
[0652] MS (ESI) m/z 352.0844
[0653] HPLC purity 97.0% at 210-370 nm, 9.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium
Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4
minutes
Example 20
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-1-amine
##STR00052##
[0655] 10 mL of Methylamine (ca. 8M in ethanol) was added to a
round bottom flask containing (50 mg, 0.12 mmol) of
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. The reaction flask was covered with a septum and
stirred overnight at room temperature. The reaction solution was
concentrated in vacuo and the crude product was pre-adsorbed onto
Celite and purified via Isco chromatography (Redisep, silica,
gradient 1-8% methanol in dichloromethane with ammonia) to afford
33 mg (78%) of product. Further purification by reverse phase
HPLC(X-terra MS C.sub.18 19.times.150 mm, using a gradient of
10-100% water-acetonitrile with 0.1% TFA at a rate of 20 mL/minute
at 254 nm) gave 24 mg (41%) of
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine as the TFA salt.
[0656] HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0657] HRMS: calculated for
C.sub.17H.sub.20ClN.sub.3O.sub.2S+H.sup.+, 366.10375; found (ESI,
[M+H].sup.+), 366.1019
Example 21
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dime-
thylbutan-1-amine
##STR00053##
[0659] In an analogous manner to Example 2, dimethylamine (10 mL,
[.about.5.6 M]) and
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (50 mg, 0.12 mmol) were stirred overnight to prepare 9
mg (16%) of
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbutan-1-amine as the TFA salt. HPLC purity 100.0% at
210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5,
acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
[0660] HRMS: calculated for
C.sub.18H.sub.22ClN.sub.3O.sub.2S+H.sup.+, 380.11940; found (ESI,
[M+H].sup.+), 380.1177
Example 22
n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utan-1-amine
##STR00054##
[0662] In an analogous manner to Example 2, butylamine (2.0 mL,
20.2 mmol) and
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (50 mg, 0.12 mmol) was stirred overnight to prepare
13 mg (21%) of
n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]butan-1-amine as the TFA salt.
[0663] HPLC purity 100.0% at 210-370 nm, 9.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0664] HRMS: calculated for
C.sub.20H.sub.26ClN.sub.3O.sub.2S+H.sup.+, 408.15070; found (ESI,
[M+H].sup.+), 408.1506
Example 23
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-ethyl-N--
methylbutan-1-amine
##STR00055##
[0666] In an analogous manner to Example 2, N-ethylmethylamine (3
mL, 35 mmol) and
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (35 mg, 0.08 mmol) were stirred overnight to
prepare 4 mg (10%) of
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-
-N-methyl butan-1-amine as the TFA salt.
[0667] MS (ESI) m/z 394.132;
[0668] HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 24
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methyl-
propan-1-amine
##STR00056##
[0670] Step 1: A mixture of 2-chloro-3-nitropyridine (5.0 g, 31.5
mmol) and aniline (5.8 mL, 63.1 mmol) was heated to 140.degree. C.
for 90 minutes. After cooling to ambient temperature, the mixture
was diluted with water (200 mL) and extracted with three portions
(50 mL each) of dichloromethane. The combined extracts were dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo. The crude solids were recrystallized from isopropyl alcohol
to afford 3.50 g of 3-nitro-N-phenylpyridin-2-amine.
[0671] HRMS: calculated for C.sub.11H.sub.9N.sub.3O.sub.2+H.sup.+,
216.07675; found (ESI, [M+H].sup.+), 216.0787 HPLC purity 100.0% at
210-370 nm, 9.5 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5,
acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
[0672] Step 2: A mixture of 3-nitro-N-phenylpyridin-2-amine (3.50
g, 16.3 mmol), zinc powder (16.0 g, 244 mmol) and ammonium chloride
(4.35 g, 81.3 mmol) in 60% aqueous ethanol (250 mL) was heated to
50.degree. C. for 1 hour. The mixture was cooled to ambient
temperature, filtered through a plug of Celite and the plug was
rinsed with ethyl acetate (100 mL). The filtrate was partitioned
against ethyl acetate (75 mL) and the layers separated. The aqueous
layer was further extracted with ethyl acetate. The combined
organic portions were washed once with water and once with brine
(100 mL each), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 0-100% ethyl acetate in
hexane) to afford 2.6 g of N.sup.2-phenylpyridine-2,3-diamine.
[0673] HPLC purity 99.4% at 210-370 nm, 6.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium
Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4
minutes.
[0674] Step 3: A mixture of N.sup.2-phenylpyridine-2,3-diamine (1.0
g, 5.4 mmol) and sulfamide (0.78 g, 8.1 mmol) in diglyme (15 mL)
was heated to 160.degree. C. for 90 minutes. The mixture was cooled
to ambient temperature, loaded directly onto silica gel and
immediately purified via Isco chromatography (Redisep, silica,
gradient 0-100% ethyl acetate in hexane). The material obtained was
re-chromatographed via Isco chromatography (Redisep, silica,
isocratic 25% ethyl acetate in hexane for 15 minutes, then gradient
15-100% ethyl acetate in hexane to afford 0.19 g of
1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine
2,2-dioxide.
[0675] Step 4: To a solution of
1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide
(190 g, 0.76 mmol), tert-butyl 3-hydroxypropyl(methyl)carbamate
(198 mg, 1.0 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in
tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate
(0.19 mL, 1.0 mmol). The mixture was stirred at ambient temperature
for 30 minutes and then concentrated in vacuo. The residue was
filtered through a plug of silica and rinsed through with 50% ethyl
acetate in hexane. The filtrate was concentrated and the residue
purified via Supercritical Fluid Chromatography using the
conditions described below.
TABLE-US-00001 SFC Instrument: Berger MuitiGram Prep SFC (Berger
Instruments, Inc. Newark, DE) Column: Kromasil DIOL; 5 .mu.m; 250
mm L .times. 21 mm ID (EKA Chemicals, Dobbs Ferry, NY) Column
temperature: 35.degree. C. SFC Modifier: 15% MeOH/85% CO2 Flow
rate: 50 mL/min Detector: UV at 220 nm
[0676] The residue obtained was taken up in 4M HCl/dioxane (5 mL)
and stirred at ambient temperature for 2 hours. The mixture was
diluted with water (15 mL) and lyophilized. The resulting oil was
triturated with diethyl ether until solids formed. The off-white
solids were collected and dried under vacuum to give 96 mg of
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methy-
lpropan-1-amine dihydrochloride.
[0677] HRMS: calculated for
C.sub.15H.sub.18N.sub.4O.sub.2S+H.sup.+, 319.12232; found (ESI,
[M+H].sup.+), 319.1227
[0678] HPLC purity 100.0% at 210-370 nm, 5.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 25
3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methyl-
propan-1-amine
##STR00057##
[0680] Step 1: A mixture of 4-chloro-3-nitropyridine (5.0 g, 31.5
mmol) and aniline (5.8 mL, 63.1 mmol) was stirred at ambient
temperature. Within a few minutes, a strong exotherm was observed.
At ten minutes, the mixture had become solid. The solids were
dissolved in dichloromethane (50 mL) and partitioned against water
(200 mL). The layers were separated and the aqueous layer was
extracted with two additional portions (50 mL each) of
dichloromethane. The combined extracts were dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to afford
5.7 g of 3-nitro-N-phenylpyridin-4-amine, which was used without
further purification.
[0681] Step 2: A mixture of 3-nitro-N-phenylpyridin-4-amine (5.70
g, 26.5 mmol), zinc powder (26.0 g, 397 mmol) and ammonium chloride
(7.10 g, 132 mmol) in 60% aqueous ethanol (250 mL) was heated to
50.degree. C. for 1 hour. The mixture was cooled to ambient
temperature, filtered through a plug of Celite and the plug was
rinsed with ethyl acetate (100 mL). The filtrate was partitioned
against ethyl acetate (75 mL) and the layers separated. The aqueous
layer was extracted with one additional portion of ethyl acetate
(75 mL). The combined organic portions were washed once with water
and once with brine (100 mL each), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via Isco chromatography (Redisep, silica, gradient 0-100%
ethyl acetate in hexane) to afford 2.2 g of
N.sup.4-phenylpyridine-3,4-diamine.
[0682] HRMS: calculated for C.sub.11H.sub.11N.sub.3+H.sup.+,
186.10257; found (ESI, [M+H].sup.+), 186.1036
[0683] HPLC purity 98.6% at 210-370 nm, 4.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0684] Step 3: A mixture of N.sup.4-phenylpyridine-3,4-diamine
(1.18 g, 6.37 mmol) and sulfamide (0.918 g, 9.55 mmol) in diglyme
(15 mL) was heated to 160.degree. C. for 90 minutes. The mixture
was cooled to ambient temperature, loaded directly onto silica gel
and immediately purified via Isco chromatography (Redisep, silica,
gradient 0-100% ethyl acetate in hexane) to afford 0.35 g of
1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-c]pyridine
2,2-dioxide.
[0685] HPLC purity 98.4% at 210-370 nm, 4.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0686] Step 4: To a solution of
1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-c]pyridine 2,2-dioxide
(300 g, 1.21 mmol), tert-butyl 3-hydroxypropyl(methyl)carbamate
(300 mg, 1.58 mmol) and triphenylphosphine (414 mg, 1.58 mmol) in
tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate
(0.31 mL, 1.58 mmol). The mixture was stirred at ambient
temperature for 45 minutes and then concentrated in vacuo. The
residue was filtered through a plug of silica and rinsed through
with 50% ethyl acetate in hexane. The filtrate was concentrated and
the residue purified via Supercritical Fluid Chromatography using
the conditions described below.
TABLE-US-00002 SFC Instrument: Berger MultiGram Prep SFC (Berger
Instruments, Inc. Newark, DE) Column: Kromasil DIOL; 5 .mu.m; 250
mm L .times. 21 mm ID (EKA Chemicals, Dobbs Ferry, NY) Column
temperature: 35.degree. C. SFC Modifier: 10% MeOH/90% CO2 Flow
rate: 50 mL/min Detector: UV at 220 nm
[0687] The residue obtained was taken up in 4M HCl/dioxane (5 mL)
and stirred at ambient temperature for 2 hours. The mixture was
diluted with water (15 mL) and lyophilized. The resulting oil was
triturated with diethyl ether until solids formed. The beige solids
were collected and dried under vacuum to give 127 mg of
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-1(3H)-yl)-N-methy-
lpropan-1-amine dihydrochloride.
[0688] HRMS: calculated for
C.sub.15H.sub.18N.sub.4O.sub.2S+H.sup.+, 319.12232; found (ESI,
[M+H].sup.+), 319.1197 HPLC purity 98.6% at 210-370 nm, 4.7
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for
10 minutes, hold 4 minutes.
Example 26
N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propan-1-amine hydrochloride
##STR00058##
[0690] General Procedure B for Synthesis of Sulfamides of Structure
I:
[0691] Step 1: In an analogous manner to Example 6, Step 1,
5-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from
2-amino-5-picoline as an orange solid.
[0692] MS (ES) m/z 230.0 ([M+H].sup.+).
[0693] Step 2: 5-methyl-N-(2-nitrophenyl)pyridin-2-amine (0.74 g,
3.2 mmol) was dissolved in ethanol (50 ml) and treated with 10%
palladium on carbon. The reaction mixture was placed under 50 psi
of hydrogen on a Parr shaker for 3 hours. The reaction mixture was
then filtered through a Celite pad and the filtrate was
concentrated in vacuo. The crude product was crystallized from
ethyl acetate by adding a minutesimum amount of diethyl ether to
yield (5-methylpyridin-2-yl)benzene-1,2-diamine (0.66 g, 98%) as a
white solid.
[0694] MS (ES) m/z 200.0 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.13N.sub.3+H.sup.+, 200.11822; found (ESI,
[M+H].sup.+), 200.125.
[0695] Step 3: (5-methylpyridin-2-yl)benzene-1,2-diamine (0.66 g,
3.3 mmol) was dissolved in diglyme (5 ml) and stirred at reflux for
5 minutes. To this was added sulfamide (0.32 g, 3.3 mmol) in
diglyme (5 ml) dropwise through a dropping funnel in a period of 5
minutes. Additional sulfamide (0.32 g, 3.3 mmol) in diglyme (5 ml)
was added in a same manner and the mixture was further stirred at
reflux for 5 minutes. The reaction mixture was then placed in an
ice-water bath and partitioned between water and a solution of
dichloromethane/isopropanol (3/1). The separated organic layer was
washed with water and brine, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
via Biotage Horizon (Flash 40 M, silica, gradient from 0% to 60% of
10% methanol-dichloromethane in dichloromethane) to yield
1-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
(0.71 g, 83%) as a white solid.
[0696] MS (ES) m/z 261.8 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.11N.sub.3O.sub.2S+H.sup.+, 262.06447; found (ESI,
[M+H].sup.+), 262.0642.
[0697] Step 4: A heterogeneous mixture of
1-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
(0.71 g, 2.7 mmol), potassium carbonate (0.33 g, 5.4 mmol) and
cesium carbonate (0.88 g, 2.7 mmol) in anhydrous acetonitile (30
ml) was stirred at room temperature under nitrogen. To this was
added excess of 1-bromo-3-chloropropane (2.7 ml, 27 mmol) and the
reaction mixture was heated at 70.degree. C. for 3 hours. The
resulted mixture was then partitioned between water and ethyl
acetate. The separated organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was purified via Biotage
Horizon (Flash 40 M, silica, gradient from 0% to 60% of ethyl
acetate in hexane) to yield
1-(3-chloropropyl)-3-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide (0.55 g, 74%) as an oil.
[0698] MS (ES) m/z 337.7 ([M+H].sup.+); HRMS: calculated for
C.sub.15H.sub.16ClN.sub.3O.sub.2S+H.sup.+, 338.07245; found (ESI,
[M+H].sup.+), 338.0724.
[0699] Step 5:
1-(3-chloropropyl)-3-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide (0.55 g, 1.6 mmol) was treated with a solution of
methylamine in ethanol (2.0 M, 8 ml, 16 mmol) and the solution was
heated at 50.degree. C. in a sealed vessel for 15 hours. After
dilution with a saturated aqueous solution of sodium bicarbonate,
the mixture was extracted with a solution of
dichloromethane/isopropanol (3/1). The extract was washed with
water and brine, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was crystallized from
dichloromethane by adding minutesimum amount of ethyl acetate and
diethyl ether to afford the title compound,
N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine hydrochloride as a light tan solid.
[0700] MS (ES) m/z 333.0 ([M+H].sup.+); HRMS: calculated for
C.sub.16H.sub.20N.sub.4O.sub.2S+H.sup.+, 333.13797; found (ESI,
[M+H].sup.+), 333.1383; HPLC purity 100% at 210-370 nm, 6.2
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 ml/min,
85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for
10 minutes, hold 4 minutes.
Example 27
N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propan-1-amine hydrochloride
##STR00059##
[0702] In an analogous manner to General Procedure B. Step 1,
3-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from
2-amino-3-picoline as an orange solid.
[0703] MS (ES) m/z 230.0 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.1N.sub.3O.sub.2+H.sup.+, 230.09240; found (ESI,
[M+H].sup.+), 230.0923.
[0704] In an analogous manner to General Procedure B, Step 2,
N-(3-methylpyridin-2-yl)benzene-1,2-diamine was prepared from
3-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES)
m/z 200 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.13N.sub.3+H.sup.+, 200.11822; found (ESI,
[M+H].sup.+), 200.
[0705] In an analogous manner to General Procedure B, Step 3,
1-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(3-methylpyridin-2-yl)benzene-1,2-diamine as a
white solid. MS (ES) m/z 261.8; HRMS: calculated for
C.sub.12H.sub.11N.sub.3O.sub.2S+H.sup.+, 262.06447; found (ESI,
[M+H].sup.+), 262.0644.
[0706] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide was prepared from
1-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 337.7 ([M+H].sup.+).
[0707] In an analogous manner to General Procedure B, Step 5,
N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide as light tan solid. MS (ES) m/z 332.9; HPLC
purity 100% at 210-370 nm, 5.3 minutes; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 ml/min, 85/15-5195 (ammonium formate
buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 28
3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylpropan-1-amine hydrochloride
##STR00060##
[0709] In an analogous manner to General Procedure B, Step 1,
6-methoxy-N-(2-nitrophenyl)pyridin-3-amine was prepared from
5-amino-2-methoxypyridine as an orange oil. MS (ES) m/z 245.9
([M+H].sup.+).
[0710] In an analogous manner to General Procedure B, Step 2,
N-(6-methoxypyridin-3-yl)benzene-1,2-diamine was prepared from
6-methoxy-N-(2-nitrophenyl)pyridin-3-amine as an off white solid.
MS (ES) m/z 216.0 ([M+H].sup.+);
[0711] HRMS: calculated for C.sub.12H.sub.13N.sub.3O+H.sup.+,
216.11314; found (ESI, [M+H].sup.+), 216.1128.
[0712] In an analogous manner to General Procedure B, Step 3,
1-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(6-methoxylpyridin-3-yl)benzene-1,2-diamine
without further purification. MS (ES) m/z 278 ([M+H].sup.+).
[0713] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide was prepared from
1-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 353.7.
[0714] In an analogous manner to General Procedure B, Step 5,
3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-(6-methoxylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothia-
diazole-2,2-dioxide as a white solid. MS (ES) m/z 348.9
([M+H].sup.+); HRMS: calculated for
C.sub.16H.sub.20N.sub.4O.sub.3S+H.sup.+, 349.13289; found (ESI,
[M+H].sup.+), 349.1385; HPLC purity 100% at 210-370 nm, 6.6
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 ml/min,
85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for
10 minutes, hold 4 minutes.
Example 29
3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride
##STR00061##
[0716] In an analogous manner to General Procedure B, Step 1,
5-ethyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from
6-amino-3-ethylpyridine as an oil. MS (ES) m/z 243.5 ([M+H].sup.+);
HRMS: calculated for C.sub.13H.sub.13N.sub.3O.sub.2+H.sup.+,
244.10805; found (ESI, [M+H].sup.+), 244.1068.
[0717] In an analogous manner to General Procedure B, Step 2,
N-(5-ethylpyridin-2-yl)benzene-1,2-diamine was prepared from
5-ethyl-N-(2-nitrophenyl)pyridin-2-amine as an oily solid. MS (ES)
m/z 214.0 ([M+H].sup.+).
[0718] In an analogous manner to General Procedure B, Step 3,
1-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(5-ethylpyridin-2-yl)benzene-1,2-diamine
without further purification. MS (ES) m/z 276 ([M+H].sup.+).
[0719] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide was prepared from
1-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 351.7 ([M+H].sup.+).
[0720] In an analogous manner to General Procedure B, Step 5,
3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylpropan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide as a white solid. MS (ES) m/z 346.9 ([M+H].sup.+);
HRMS: calculated for C.sub.17H.sub.22N.sub.4O.sub.2S+H.sup.+,
347.15362; found (ESI, [M+H].sup.+), 347.1536; HPLC purity 94.9% at
210-370 nm, 8.3 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 ml/min, 85/15-5195 (ammonium formate buffer pH=3.5,
acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
Example 30
N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propan-1-amine hydrochloride
##STR00062##
[0722] In an analogous manner to General Procedure B, Step 1,
4-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from
2-amino-4-picoline as an orange solid. MS (ES) m/z 230.0
([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.11N.sub.3O.sub.2+H.sup.+, 230.09240; found (ESI,
[M+H].sup.+), 230.0923.
[0723] In an analogous manner to General Procedure B, Step 2,
N-(4-methylpyridin-2-yl)benzene-1,2-diamine was prepared from
4-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES)
m/z 200 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.13N.sub.3+H.sup.+, 200.11822; found (ESI,
[M+H].sup.+), 200.1217.
[0724] In an analogous manner to General Procedure B, Step 3,
1-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(4-methylpyridin-2-yl)benzene-1,2-diamine
without further purification. MS (ES) m/z 262 ([M+H].sup.+).
[0725] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide was prepared from
1-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 338 ([M+H].sup.+).
[0726] In an analogous manner to General Procedure B, Step 5,
3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylpropan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide as a white solid. MS (ES) m/z 333.0
([M+H].sup.+); HRMS: calculated for
CO.sub.6H.sub.20N.sub.4O.sub.2S+H.sup.+, 333.13797; found (ESI,
[M+H].sup.+), 333.1366; HPLC purity 100% at 210-370 nm, 5.3
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 ml/min,
85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for
10 minutes, hold 4 minutes.
Example 31
3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylprop-
an-1-amine hydrochloride
##STR00063##
[0728] In an analogous manner to General Procedure B, Step 1,
N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-aminopyridine
as an orange solid. MS (ES) m/z 216.1 ([M+H].sup.+).
[0729] In an analogous manner to General Procedure B, Step 2,
N-pyridin-2-ylbenzene-1,2-diamine was prepared from
N-(2-nitrophenyl)pyridin-2-amine as a white solid.
[0730] MS (ESI) m/z 186 ([M+H].sup.+).
[0731] In an analogous manner to General Procedure B, Step 3,
1-(N-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-pyridin-2-ylbenzene-1,2-diamine without further
purification. MS (ES) m/z 248 ([M+H].sup.+).
[0732] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-pyridin-2-yl-1,3-dihydro-2,1,3-benzothiadiazole-2,2--
dioxide was prepared from
1-(N-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 323.7 ([M+H].sup.+); HRMS: calculated for
C.sub.14H.sub.4ClN.sub.3O.sub.2S+H.sup.+, 324.05680; found (ESI,
[M+H].sup.+), 324.0574.
[0733] In an analogous manner to General Procedure B, Step 5,
3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide as a white solid. MS (ES) m/z 318.9 ([M+H].sup.+); HRMS:
calculated for C.sub.15H.sub.18N.sub.4O.sub.2S+H.sup.+, 319.12232;
found (ESI, [M+H].sup.+), 319.122; HPLC purity 98.7% at 210-370 nm,
5.5 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5,
acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
Example 32
N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propan-1-amine hydrochloride
##STR00064##
[0735] In an analogous manner to General Procedure B, Step 1,
6-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from
2-amino-6-picoline as an orange solid. MS (ES) m/z 230.0
([M+H].sup.+).
[0736] In an analogous manner to General Procedure B, Step 2,
N-(6-methylpyridin-2-ylbenzene-1,2-diamine was prepared from
6-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES)
m/z 200 ([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.13N.sub.3+H.sup.+, 200.11822; found (ESI,
[M+H].sup.+), 200.1248.
[0737] In an analogous manner to General Procedure B, Step 3,
1-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(6-methyl)pyridin-2-ylbenzene-1,2-diamine
without further purification. MS (ES) m/z 262 ([M+H].sup.+).
[0738] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide was prepared from
1-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 337.7 ([M+H].sup.+).
[0739] In an analogous manner to General Procedure B, Step 5,
N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide as a white solid. MS (ES) m/z 332.9 ([M+H].sup.+);
HPLC purity 100% at 210-370 nm, 6.9 minutes; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate
buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 33
N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propan-1-amine hydrochloride
##STR00065##
[0741] In an analogous manner to General Procedure B, Step 1,
4-methyl-N-(2-nitrophenyl)pyridin-3-amine was prepared from
3-amino-4-methylpyridine as an orange solid. MS (ES) m/z 229.9
([M+H].sup.+); HRMS: calculated for
C.sub.12H.sub.11N.sub.3O.sub.2+H.sup.+, 230.09240; found (ESI,
[M+H].sup.+), 230.09.
[0742] In an analogous manner to General Procedure B, Step 2,
N-(4-methylpyridin-3-ylbenzene-1,2-diamine was prepared from
4-methyl-N-(2-nitrophenyl)pyridin-3-amine as a white solid. MS (ES)
m/z 200 ([M+H].sup.+).
[0743] In an analogous manner to General Procedure B, Step 3,
1-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-(4-methylpyridin-3-yl)benzene-1,2-diamine
without further purification. MS (ES) m/z 262 ([M+H].sup.+).
[0744] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide was prepared from
1-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 337.7 ([M+H].sup.+).
[0745] In an analogous manner to General Procedure B, Step 5,
N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]propan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide as a light tan solid. MS (ES) m/z 332.9
([M+H].sup.+); HPLC purity 100% at 210-370 nm, 5.3 minutes; Xterra
RP18, 3.5u, 150.times.4.6 mm column, 1.2 ml/min, 85/15-5/95
(ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes,
hold 4 minutes.
Example 34
3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylprop-
an-1-amine hydrochloride
##STR00066##
[0747] In an analogous manner to General Procedure B, Step 1,
N-(2-nitrophenyl)pyridin-3-amine was prepared from 3-aminopyridine
as an orange solid. MS (ES) m/z 216.1 ([M+H].sup.+). HRMS:
calculated for C.sub.11H.sub.9N.sub.3O.sub.2+H.sup.+, 216.07675;
found (ESI, [M+H].sup.+), 216.0783.
[0748] In an analogous manner to General Procedure B, Step 2,
N-pyridin-3-ylbenzene-1,2-diamine was prepared from
N-(2-nitrophenyl)pyridin-3-amine as a white solid.
[0749] MS (ESI) m/z 186 ([M+H].sup.+). HRMS: calculated for
C.sub.11H.sub.11N.sub.3+H.sup.+, 186.10257; found (ESI,
[M+H].sup.+), 186.1083.
[0750] In an analogous manner to General Procedure B, Step 3,
1-(N-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
was prepared from N-pyridin-3-ylbenzene-1,2-diamine without further
purification. MS (ES) m/z 248 ([M+H].sup.+).
[0751] In an analogous manner to General Procedure B, Step 4,
1-(3-chloropropyl)-3-pyridin-3-yl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(N-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
as an oil. MS (ES) m/z 323.7 ([M+H].sup.+).
[0752] In an analogous manner to General Procedure B, Step 5,
3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpro-
pan-1-amine hydrochloride was prepared from
1-(3-chloropropyl)-3-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide as a white solid. MS (ES) m/z 318.9 ([M+H].sup.+); HPLC
purity 100% at 210-370 nm, 5.6 minutes; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate
buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
Example 35
3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine
[0753] General Procedure C for Synthesis of Sulfamides of Formula
I:
[0754] Step 1: 4-fluoro-2-nitro-N-phenylaniline: A solution of
2,5-difluoronitrobenzene (1.59 g, 10.0 mmol), aniline (0.96 mL,
10.5 mmol), and triethylamine (2.78 mL, 20.0 mmol) in DMF (5.0 mL)
were heated in a sealed tube in the microwave at 200.degree. C. for
1 hour. The solution was allowed to cool to room temperature and
was diluted with ethyl acetate (75 mL). The organic layer was
washed with water (75 mL), brine (75 mL), and dried over sodium
sulfate. After concentration in vacuo silica gel chromatography
(5-15% ethyl acetate in hexanes) afforded product as an orange oil
(2.21 g, 95%).
[0755] HPLC purity 94.8% at 210-370 nm, 10.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 233.1.
[0756] Step 2: 4-fluoro-N.sup.1-phenylbenzene-1,2-diamine: A
solution of 4-fluoro-2-nitro-N-phenylaniline (1.04 g, 4.48 mmol) in
ethanol (100 mL) was added to a solution of ammonium chloride (1.20
g, 22.4 mmol) in water (50 mL). The solution was heated to
60.degree. C. and zinc powder (4.39 g, 67.2 mmol) was added. The
suspension was stirred for 2 hours at 60.degree. C. The suspension
was allowed to cool to room temperature and was filtered through a
pad of Celite using ethyl acetate washing (3.times.100 mL). The
organic layer was separated and washed with water (100 mL), brine
(100 mL), and dried over sodium sulfate. After concentration in
vacuo silica gel chromatography (10-30% ethyl acetate in hexanes)
afforded a slightly red powder (0.90 g, 99%).
[0757] HPLC purity 97.3% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.12H.sub.11FN.sub.2+H.sup.+,
203.09790; found (ESI, [M+H].sup.+), 203.0975.
[0758] Step 3: 5-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide: Sulfamide (961 mg, 10.0 mmol) was added to a solution
of 4-fluoro-N.sup.1-phenylbenzene-1,2-diamine (404 mg, 2.00 mmol)
in diglyme (10 mL). The solution was heated open to the air at
160.degree. C. for 3 hours. The reaction was allowed to cool to
room temperature, was diluted with ethyl acetate (100 mL) and
washed with water (100 mL) and brine (100 mL). After the organic
layer was dried over sodium sulfate, the solution was concentrated
in vacuo. Silica gel chromatography (5-25% ethyl acetate in
hexanes) afforded product as an orange solid (418 mg, 79%).
[0759] MS (ES) [M+H].sup.+ m/z 264.3;
[0760] Step 4:
tert-butyl[3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate: A solution of
5-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(135 mg, 0.510 mmol),
3-(N-tert-butoxycarbonyl-N-methylamino)propanol (189 mg, 1.00
mmol), and triphenylphosphine (262 mg, 1.00 mmol) in THF was
treated with diisobutylazodicarboxylate (202 mg, 1.00 mmol). After
stirring for 1 hour at room temperature, the solution was diluted
with ethyl acetate (50 mL) and washed with water (100 mL). The
organic layer was dried over sodium sulfate and the concentrated in
vacuo. Silica gel chromatography (0-10% ethyl acetate in hexanes)
afforded product as a slightly yellow oil (162 mg, 73%).
[0761] HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for
C.sub.21H.sub.26FN.sub.3O.sub.4S+H.sup.+, 436.17008; found (ESI,
[M+H].sup.+), 436.1688.
[0762] Step 5:
3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine:
tert-Butyl[3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate (91 mg, 0.207 mmol) was treated with 4N
HCl in dioxane (5 mL) and stirred at room temperature for 1 hour.
The solution was concentrated to 1 mL in vacuo, diluted with water
(9 mL), frozen, and placed under vacuum to afford the HCl salt of
product as a white powder (74 mg, 96%).
[0763] HPLC purity 100.0% at 210-370 nm, 7.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for
C.sub.16H.sub.18FN.sub.3O.sub.2S+H.sup.+, 336.11765; found (ESI,
[M+H].sup.+), 336.1169.
Example 36
3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine
[0764] Step 1: 4-chloro-2-nitro-N-phenylaniline.
4-chloro-2-nitro-N-phenylaniline was obtained commercially from the
Sigma-Aldrich company.
[0765] Step 2: 4-chloro-N.sup.2-phenylbenzene-1,2-diamine.
Following the General Procedure C, Step 2, starting with
4-chloro-2-nitro-N-phenylaniline (2.49 g, 10.0 mmol) afforded
product as a brown solid (2.17 g, 99%).
[0766] HPLC purity 95.7% at 210-370 nm, 9.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium
Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4 minutes.
HRMS: calculated for C.sub.12H.sub.11ClN.sub.2+H+, 219.06835; found
(ESI, [M+H].sup.+), 219.0671.
[0767] Step 3: 6-chloro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3,
4-chloro-N.sup.2-phenylbenzene-1,2-diamine (437 mg, 2.00 mmol)
afforded product as a slightly red solid (417 mg, 74%).
[0768] HPLC purity 98.6% at 210-370 nm, 9.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 278.9.
[0769] Step 4:
tert-butyl[3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate. Following the General Procedure C, Step
4, starting with
6-chloro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(417, 1.49 mmol) afforded product as a yellow oil (604 mg,
89%).
[0770] HPLC purity 98.9% at 210-370 nm, 11.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.21H.sub.26ClN.sub.3O.sub.4S+H+,
452.14053; found (ESI, [M+H].sup.+), 452.1465.
[0771] Step 5:
3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine. Following the General Procedure C, Step 5, starting
with
tert-butyl[3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]-methylcarbamate (226 mg, 0.500 mmol) afforded product HCl
salt as a off-white powder (193 mg, 99%).
[0772] HPLC purity 99.0% at 210-370 nm, 8.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes.
[0773] HRMS: calculated for C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+,
352.08810; found (ESI, [M+H].sup.+), 352.0861.
Example 37
3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpr-
opan-1-amine
[0774] Step 1: 4-bromo-2-nitro-N-phenylaniline. Following the
General Procedure C, Step 1, starting with
4-bromo-1-fluoro-2-nitrobenzene (2.20 g, 10.0 mmol) afforded
product as an orange solid (2.90 g, 99%).
[0775] MS (ES) [M+H].sup.+ m/z 293.0.
[0776] Step 2: 4-bromo-N.sup.1-phenylbenzene-1,2-diamine. Following
the General Procedure C, Step 2, starting with
4-bromo-2-nitro-N-phenylaniline (2.90 g, 9.90 mmol) afforded
product as an off-white solid (2.10 g, 80%).
[0777] HPLC purity 98.2% at 210-370 nm, 10.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.12H.sub.1BrN.sub.2+H+,
263.01783; found (ESI, [M+H].sup.+), 263.0178.
[0778] Step 3: 5-bromo-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3, starting
with 4-bromo-N.sup.1-phenylbenzene-1,2-diamine (1.05 g, 4.00 mmol)
afforded product as a purple solid (664 mg, 51%).
[0779] HPLC purity 100.0% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M-H].sup.+ m/z 322.8.
[0780] Step 4:
tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)propyl]methylcarbamate. Following the General Procedure C, Step 4,
starting with 5-bromo-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (423 mg, 1.30 mmol) afforded product as a colorless oil
(522 mg, 81%).
[0781] HPLC purity 100.0% at 210-370 nm, 11.3 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+hours-Boc].sup.+ m/z 395.8.
[0782] Step 5:
3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine. Following the General Procedure C, Step 5, starting
with
tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)propyl]-methylcarbamate (100 mg, 0.201 mmol) afforded the HCl salt
of product as a white powder (87 mg, 99%).
[0783] HPLC purity 100.0% at 210-370 nm, 8.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.16H.sub.18BrN.sub.3O.sub.2S+H+,
396.03758; found (ESI, [M+H].sup.+), 396.0371.
Example 38
N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)p-
ropan-1-amine
[0784] Step 1: 4-methyl-2-nitro-N-phenylaniline. Following the
General Procedure C, Step 1, starting with 3-fluoro-4-nitrotoluene
(2.33 g, 15.0 mmol) afforded product as an orange solid (3.09 g,
90%).
[0785] MS (ES) [M+H].sup.+ m/z 229.1.
[0786] Step 2: 4-methyl-N'-phenylbenzene-1,2-diamine. Following the
General Procedure C, Step 2, 4-methyl-2-nitro-N-phenylaniline (1.18
g, 5.17 mmol) afforded product as a brown solid (1.02 g, 99%).
[0787] MS (ES) [M+H].sup.+ m/z 199.1.
[0788] Step 3: 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3,
4-methyl-N.sup.1-phenylbenzene-1,2-diamine (397 mg, 2.00 mmol)
afforded product as a tan solid (422 mg, 81%).
[0789] MS (ES) [M-H].sup.+ m/z 259.2.
[0790] Step 4: tert-butyl
methyl[3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)pr-
opyl]carbamate. Following the General Procedure C, Step 4, starting
with 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (381 mg, 1.46 mmol) afforded product as a colorless gel
(592 mg, 94%).
[0791] HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.22H.sub.29N.sub.3O.sub.4S+H+,
432.19515; found (ESI, [M+H].sup.+), 432.1967.
[0792] Step 5:
N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
propan-1-amine. Following the General Procedure C, Step 5, starting
with tert-butyl
methyl[3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)pr-
opyl]carbamate (432 mg, 1.00 mmol) afforded the HCl salt of product
as a tan powder (367 mg, 100%).
[0793] HPLC purity 100.0% at 210-370 nm, 7.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.17H.sub.21N.sub.3O.sub.2S+H+,
332.14272; found (ESI, [M+H].sup.+), 332.1422.
Example 39
3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine
[0794] Step 1: 3-fluoro-2-nitro-N-phenylaniline. Following a
modification of the General Procedure C, Step 1,
2,6-difluoronitrobenzene (1.59 g, 10.0 mmol), at a changed
microwave temperature of 150.degree. C., afforded product as an
orange solid (1.86 g, 80%).
[0795] MS (ES) [M+H].sup.+ m/z 233.2.
[0796] Step 2: 3-fluoro-N.sup.1-phenylbenzene-1,2-diamine.
Following the General Procedure C, Step 2, starting with
3-fluoro-2-nitro-N-phenylaniline (1.80 g, 7.74 mmol) afforded
product as a red solid (1.12 g, 65%).
[0797] HPLC purity 100.0% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.12H.sub.11FN.sub.2+H+,
203.09790; found (ESI, [M+H].sup.+), 203.0907.
[0798] Step 3: 4-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3, starting
with 3-fluoro-N.sup.1-phenylbenzene-1,2-diamine (606 mg, 3.00 mmol)
afforded product as a rose colored solid (294 mg, 37%).
[0799] HPLC purity 100.0% at 210-370 nm, 8.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M-H].sup.+ m/z 263.0.
[0800] Step 4:
tert-butyl[3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate. Following the General Procedure C, Step
4, starting with
4-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(201 mg, 0.760 mmol) afforded product as a tan oil (281 mg,
85%).
[0801] HPLC purity 100.0% at 210-370 nm, 10.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.21H.sub.26FN.sub.3O.sub.4S+H+,
436.17008; found (ESI, [M+H].sup.+), 436.1713.
[0802] Step 5:
3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine. Following the General Procedure C, Step 5, starting
with
tertbutyl-[3-(7-fluoro-2,2-dioxido-3-phenyl-2,3-benzothiadiazol-1(3H)-yl)-
propyl]-methyl carbamate (248 mg, 0.570 mmol) afforded product as a
white powder (212 mg, 100%).
[0803] HPLC purity 100.0% at 210-370 nm, 7.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C, H.sub.18FN.sub.3O.sub.2S+H+,
336.11765; found (ESI, [M+H].sup.+), 336.1154.
Example 40
N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)p-
ropan-1-amine
[0804] Step 1: 4-methyl-2-nitro-N-phenylaniline. Following the
General Procedure C, Step 1, starting with 4-fluoro-3-nitrotoluene
(2.32 g, 15.0 mmol) afforded product as an orange oil (2.38 g,
67%).
[0805] MS (ES) [M+H].sup.+ m/z 229.2.
[0806] Step 2: 4-methyl-N.sup.1-phenylbenzene-1,2-diamine.
Following the General Procedure C, Step 2, starting with
4-methyl-2-nitro-N-phenylaniline (2.28 g, 10.0 mmol) afforded
product as a white solid (1.32 g, 67%).
[0807] MS (ES) [M+H].sup.+ m/z 199.1.
[0808] Step 3: 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3, starting
with 4-methyl-N.sup.1-phenylbenzene-1,2-diamine (397 mg, 2.00 mmol)
afforded product as a colorless oil (107 mg, 21%).
[0809] HPLC purity 96.8% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.13H.sub.14N.sub.2+H+,
199.12297; found (ESI, [M+H].sup.+), 199.1209;
[0810] Step 4: tert-butyl
methyl[3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)pr-
opyl]carbamate. Following the General Procedure C, Step 4, starting
with 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (78 mg, 0.300 mmol) afforded product as a colorless oil
(93 mg, 72%).
[0811] HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.22H N.sub.3O.sub.4S+H+,
432.19515; found (ESI, [M+H].sup.+), 432.1977.
[0812] Step 5:
N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
propan-1-amine. Following the General Procedure C, Step 5, starting
with tert-butyl
methyl[3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)pr-
opyl]-carbamate (61 mg, 0.140 mmol) afforded product as a white
powder (51 mg, 99%).
[0813] HPLC purity 100.0% at 210-370 nm, 7.6 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.17H.sub.21N.sub.3O.sub.2S+H+,
332.14272; found (ESI, [M+H].sup.+), 332.1478.
Example 41
3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine
[0814] Step 1: 2-fluoro-6-nitro-N-phenylaniline. Following the
General Procedure C, Step 1, starting with 2,3-difluoronitrobenzene
(2.80 g, 17.6 mmol) afforded product as an orange oil (3.21 g,
79%).
[0815] HPLC purity 97.5% at 210-370 nm, 9.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 233.0.
[0816] Step 2: 3-fluoro-N.sup.2-phenylbenzene-1,2-diamine.
Following the General Procedure C, Step 2, starting with
2-fluoro-6-nitro-N-phenylaniline (3.00 g, 12.9 mmol) afforded
product as an off-white solid (2.14 g, 82%).
[0817] HPLC purity 98.3% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.12H.sub.11FN.sub.2+H+,
203.09790; found (ESI, [M+H].sup.+), 203.0973.
[0818] Step 3: 7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3, starting
with 3-fluoro-1-phenylbenzene-1,2-diamine (607 mg, 3.00 mmol)
afforded product as a red oil (318 mg, 40%).
[0819] HPLC purity 94.3% at 210-370 nm, 8.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.12H FN.sub.2O.sub.2S+H++Na+,
288.03337; found (ESI, [M+H+Na].sup.+), 297.0687.
[0820] Step 4:
tert-butyl[3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate. Following the General Procedure C, Step
4, starting with
7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(200 mg, 0.757 mmol) afforded product as a tan oil (228 mg,
69%).
[0821] HPLC purity 96.4% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.21H.sub.26FN.sub.3O.sub.4S+H+,
436.17008; found (ESI, [M+H].sup.+), 436.17102.
[0822] Step 5;
3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine. Following the General Procedure C, Step 4, starting
with
tert-butyl[3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]-methylcarbamate (161 mg, 0.370 mmol) afforded product as
a white solid (136 mg, 99%).
[0823] HPLC purity 98.1% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.16H.sub.18FN.sub.3O.sub.2S+H+,
336.11765; found (ESI, [M+H].sup.+), 336.1186.
Example 42
3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
[0824] Step 1: 3-fluoro-2-nitro-N-(3-fluorophenyl)aniline.
Following a modified General Procedure C, Step 1, starting with
2,6-difluoronitrobenzene (2.39 g, 15.0 mmol) and replacing aniline
with 3-fluoroaniline (1.67 g, 15.0 mmol) afforded product as an
orange oil (2.43 g, 90% pure, 72%).
[0825] MS (ES) [M+H].sup.+ m/z 251.2.
[0826] Step 2:
3-fluoro-N.sup.1-(3-fluorophenyl)benzene-1,2-diamine. Following the
General Procedure C, Step 2, starting with
3-fluoro-2-nitro-N-(3-fluorophenyl)aniline (2.20 g, 8.00 mmol)
afforded product as a yellow oil (1.32 g, 75%).
[0827] HPLC purity 99.3% at 210-370 nm, 9.6 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 221.
[0828] Step 3:
5-methyl-1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. Following the General Procedure C, Step 3, starting
with 3-fluoro-N.sup.1-(3-fluorophenyl)benzene-1,2-diamine (881 mg,
4.00 mmol) afforded product as a red oil (418 mg, 37%).
[0829] MS (ES) [M+H].sup.+ m/z 283.1.
[0830] Step 4: tert-butyl
{3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]propyl}methylcarbamate. Following the General Procedure C, Step 4
starting with
5-methyl-1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (186 mg, 0.660 mmol) afforded product as a white solid
(162 mg, 54%).
[0831] HPLC purity 98.4% at 210-370 nm, 11.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 353.8.
[0832] Step 5:
3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine. Following the General Procedure C, Step
5, starting with tert-butyl
{3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]propyl}methylcarbamate (89 mg, 0.200 mmol) afforded the HCl salt
of product as a white solid (76 mg, 97%).
[0833] HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes; MS (ES) [M+H].sup.+ m/z 353.8.
Example 43
3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-ca-
rbonitrile 2,2-dioxide
[0834] Step 1:
tert-butyl[3-(6-cyano-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)propyl]methylcarbamate. A solution of
tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)propyl]methylcarbamate (118 mg, 0.24 mmol), zinc(II) cyanide (56
mg, 0.48 mmol), and palladium tetrakis-triphenylphosphine (58 mg,
0.050 mmol) in DMF (2 mL) was heated in the microwave at
150.degree. C. for 0.25 hours. The solution was diluted with ethyl
acetate (25 mL) and washed with water (25 mL) and brine (25 mL).
The organic layer was dried over sodium sulfate and concentrated in
vacuo. Silica gel chromatography (5-30% ethyl acetate in hexanes)
afforded product as a white foam (105 mg, 99%).
[0835] HPLC purity 100.0% at 210-370 nm, 10.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.22H.sub.26N.sub.4O.sub.4S+H+,
443.17475; found (ESI, [M+H].sup.+), 443.1788.
[0836] Step 2:
3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-c-
arbonitrile 2,2-dioxide.
tert-Butyl[3-(6-cyano-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)propyl]methylcarbamate (81 mg, 0.183 mmol) was treated with a
solution of 3N hydrochloric acid in dioxane (5 mL) and stirred 3
hours at room temperature. The solution was concentrated to 1 mL,
diluted with water (9 mL), frozen, and placed under vacuum to
afford the HCl salt of product as a white powder (66 mg, 96%).
[0837] HPLC purity 100.0% at 210-370 nm, 6.9 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS; calculated for C.sub.17H.sub.18N.sub.4O.sub.2S+H+,
343.12232; found (ESI, [M+H].sup.+), 343.1236.
Example 44
3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylp-
ropan-1-amine
##STR00067##
[0839] Step 1: tert-Butyl
{3-[(2-nitro-4-fluorophenyl)amino]propyl}methylcarbamate. A
solution of 2,5-difluoronitrobenzene (3.18 g, 20.0 mmol),
3-(N-tert-butoxycarbonyl-N-methylamino)propylamine (4.14 g, 22.0
mmol), and diisopropylethylamine (5.23 mL, 30.0 mmol) in DMF (50
mL) was stirred at 50.degree. C. for 2 hours. The solution was
diluted with ethyl acetate (200 mL) and washed with water (200 mL)
and brine (200 mL). The organic layer was dried over sodium sulfate
and concentrated in vacuo. Silica gel chromatography (10-50% ethyl
acetate in hexanes) afforded product as an orange oil (6.08 g,
93%).
[0840] MS (ES) [M+H].sup.+ m/z 233.2.
[0841] Step 2: tert-Butyl
{3-[(2-amino-4-fluorophenyl)amino]propyl}methylcarbamate. A
solution of tert-butyl
{3-[(2-nitro-4-fluorophenyl)amino]propyl}methylcarbamate (5.70 g,
17.4 mmol) in ethanol (150 mL) was added to a solution of ammonium
chloride (4.65 g, 87.0 mmol) in water (100 mL). The suspension was
heated to 50.degree. C. and zinc powder (17.1 g, 261 mmol) was
added in portions over 15 minutes. The solution was allowed to stir
at 50.degree. C. for 1 hour. The solution was diluted with ethyl
acetate (200 mL) and filtered through Celite with ethyl acetate
washing (2.times.200 mL). The organic layer was washed with water
(200 mL) and brine (200 mL). The organic layer was dried over
sodium sulfate and concentrated in vacuo. Silica gel chromatography
(5-30% ethyl acetate in hexanes) afforded product as a white solid
(4.03 g, 78%).
[0842] HPLC purity 100.0% at 210-370 nm, 9.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 198.
[0843] Step 3:
tert-butyl[3-(5-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-
methylcarbamate. A solution of tert-Butyl
{3-[(2-amino-4-fluorophenyl)amino]propyl}methylcarbamate (892 mg,
3.00 mmol) in diglyme (10 mL) was treated with sulfamide (432 mg,
4.50 mmol) and heated to 160.degree. C. with stirring for 1 hour.
The solution was allowed to cool to room temperature and was
diluted with diethyl ether (100 mL). The diethyl ether solution was
directly concentrated onto silica gel and dried under vacuum.
Silica gel chromatography (15-40% ethyl acetate in hexanes)
afforded product as a colorless oil (905 mg, 84%).
[0844] HPLC purity 100.0% at 210-370 nm, 9.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.15H.sub.22FN.sub.3O.sub.4S+H+,
360.13878; found (ESI, [M+H-tBoc].sup.+), 260.0627.
[0845] Step 4:
tert-butyl[3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-1-
-yl)propyl]methylcarbamate. A suspension of
tert-butyl[3-(5-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-
methylcarbamate (719 mg, 2.00 mmol), phenyl boronic acid (732 mg,
6.00 mmol), copper(II) acetate (545 mg, 3.00 mmol), and 4 A
molecular sieves in methylene chloride (20 mL) was treated with
pyridine (316 mg, 4.00 mmol) and allowed to stir under an
atmosphere of air for 8 hours. The solution was filtered through
Celite with methylene chloride washing (3.times.50 mL) and then
concentrated in vacuo. Silica gel chromatography (0-25% ethyl
acetate in hexanes) afforded product as a colorless oil (374 mg,
43%).
[0846] HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. HRMS: calculated for C.sub.21H.sub.26FN.sub.3O.sub.4S+H+,
436.17008; found (ESI, [M+H-tBoc].sup.+), 336.1128.
[0847] Step 5:
3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methyl-
propan-1-amine.
tert-Butyl[3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)propyl]methylcarbamate (184 mg, 0.422 mmol) was treated with a
solution of 4N hydrochloric acid in dioxane (5 mL) and allowed to
stir at room temperature for 1 hour. The solution was concentrated
to 1 mL volume and then diluted with 9 mL of water. The solution
was frozen and placed under vacuum to afford product as a white
powder (155 mg, 99%).
[0848] HPLC purity 100.0% at 210-370 nm, 8.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4
minutes. MS (ES) [M+H].sup.+ m/z 335.9.
Example 45
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00068##
[0850] General Procedure D for Synthesis of Sulfamides of Structure
I:
[0851] Step 1: To a mixture of 2,6-difluoroaniline (6.90 g, 35.4
mmol) in tetrahydrofuran (75 mL) at -78.degree. C. was added a
solution of tert-butyllithium (1.7 M in pentane, 30 mL, 51.4 mmol)
dropwise via a syringe and the reaction mixture was stirred for 10
minutes at -78.degree. C. After warming to 0.degree. C.,
1-fluoro-2-nitrobenzene (5.00 g, 35.4 mmol) was added dropwise via
a syringe. The reaction mixture immediately turned deep purple. It
was stirred for an additional 30 minutes while warming to room
temperature. The reaction mixture was quenched with saturated
aqueous ammonium chloride solution (40 mL), then and water (150
mL), and extracted with diethyl ether (3.times.150 mL). The
combined organic extracts were washed with water, brine, dried
(anhydrous sodium sulfate) and concentrated. The crude product was
recrystallized from hot hexane, cooled to -30.degree. C. to give
6.05 g (68%) of pure 2,6-difluoro-N-(2-nitrophenyl)aniline as
orange crystals. MS (EI) m/z 250 (M.sup.+.quadrature.).
[0852] Step 2: To a solution of
2,6-difluoro-N-(2-nitrophenyl)aniline (5.80 g, 23.2 mmol) in
ethanol (200 mL) was added Raney Nickel (0.60 g). The mixture was
shaken on a Parr apparatus for 1 hour under hydrogen pressure (40
psi). Reaction color turned from orange to colorless indicated
complete consumption of starting material. The reaction mixture was
filtered through Celite and concentrated to dryness to give 5.02 g
(98%) of pure N-(2,6-difluorophenyl)benzene-1,2-diamine as an
off-white solid. MS (ESI) m/z 221.0 ([M+H].sup.+); HRMS: calculated
for C.sub.12H.sub.10F.sub.2N.sub.2+H.sup.+, 221.0885; found (ESI,
[M+H].sup.+), 221.0888.
[0853] Step 3: A mixture of sulfamide (1.31 g, 13.6 mmol) and
N-(2,6-difluorophenyl)benzene-1,2-diamine (2.50 g, 11.4 mmol) in
diethylene glycol dimethyl ether (15 mL) was added dropwise over 15
minutes to refluxing diethylene glycol dimethyl ether (13 mL) in a
reaction flask. The reaction mixture was stirred at reflux for an
additional 15 minutes, cooled to room temperature, diluted with
ether (30 mL), then washed with 1N HCl (30 mL) and brine. The
organic layer was dried (anhydrous sodium sulfate) and
concentrated. The residue was purified by Isco flash column
chromatography (silica gel, 10-35% ethyl acetate/hexane) to give
1.00 g (31%) of
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as white crystals. MS (ESI) m/z 280.9
([M-H].sup.-).
[0854] Step 4: To a solution of
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (282 mg, 1.00 mmol), triphenylphosphine (315 mg, 1.20
mmol), and 3-bromo-1-propanol (153 mg, 1.10 mmol) in
tetrahydrofuran (4 mL) at 0.degree. C. was added diisopropyl
azodicarboxylate (0.23 mL, 1.20 mmol) dropwise. The reaction
mixture was warmed to ambient temperature, stirred for 12 h, and
concentrated. The residue was and purified by Isco flash column
chromatography (silica gel, 0-25% ethyl acetate/hexane) to give 362
mg (90%) of
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide as a viscous, colorless liquid. MS (ESI) m/z 338.9
([M+H-SO.sub.2].sup.+).
[0855] Step 5: Ethanolic methylamine (33% in ethanol, 20 mL) was
added to
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (320 mg, 0.790 mmol). The reaction mixture was
sealed tightly and stirred for 12 h, then concentrated. The residue
was dissolved in dichloromethane (50 mL), washed with aqueous
potassium carbonate, water, brine, dried (anhydrous sodium
sulfate), and concentrated. The residue was purified by Isco flash
column chromatography (silica gel, 0-20%
methanol/dichloromethane/with 1% triethylamine) to give 238 mg
(85%) of
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine. This free base was dissolved in a minimum
amount of dichloromethane (2 mL), and treated with an ethereal
hydrochloric acid solution (1.0 in diethyl ether, 2 mL). To the
mixture was added diethyl ether until it became cloudy. The mixture
was stored at -30.degree. C. for 12 hours. The white crystals
formed were collected by decantation and dried in vacuo to yield 95
mg (31%)
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride. MS (ESI) m/z 354.0
([M+H].sup.+).
Example 46
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00069##
[0857] In an analogous manner to General Procedure D, Step 1,
2,3-difluoro-N-(2-nitrophenyl)aniline was prepared from
2,3-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals.
MS (ESI) m/z 250.9 ([M+H].sup.+).
[0858] In an analogous manner to General Procedure D, Step 2,
N-(2,3-difluorophenyl)benzene-1,2-diamine was prepared from
2,3-difluoro-N-(2-nitrophenyl)aniline as an off-white solid. MS
(ESI) m/z 221.0 ([M+H].sup.+). HRMS: calculated for
C.sub.12H.sub.10F.sub.2N.sub.2+H.sup.+, 221.0885; found (ESI,
[M+H]+), 221.0895.
[0859] In an analogous manner to General Procedure D, Step 3,
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-(2,3-difluorophenyl)benzene-1,2-diamine as white crystals. MS
(ESI) m/z 280.9 ([M-H].sup.-).
[0860] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide was prepared from
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
MS (ESI) m/z 338.9 ([M+H-SO.sub.2].sup.+).
[0861] In an analogous manner to General procedure D, Step 5,
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide as white crystals. MS (ESI) m/z 354.0
([M+H].sup.+).
Example 47
3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00070##
[0863] In an analogous manner to General Procedure D, Step 1,
3,5-difluoro-N-(2-nitrophenyl)aniline was prepared from
3,5-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals.
MS (ESI) m/z 248.9 ([M-H].sup.-).
[0864] In an analogous manner to General Procedure D, Step 2,
N-(3,5-difluorophenyl)benzene-1,2-diamine was prepared from
3,5-difluoro-N-(2-nitrophenyl)aniline as an off-white solid. MS
(ESI) m/z 221.0 ([M+H].sup.+). HRMS: calculated for
C.sub.12H.sub.10F.sub.2N.sub.2+H.sup.+, 221.0885; found (ESI,
[M+H].sup.+), 221.0874.
[0865] In an analogous manner to General Procedure D, Step 3,
1-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-(3,5-difluorophenyl)benzene-1,2-diamine as white crystals. MS
(ESI) m/z 280.9 ([M-H].sup.-).
[0866] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide was prepared from
1-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless
liquid.
[0867] In an analogous manner to General Procedure D, Step 5,
3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide as white crystals. MS (ESI) m/z 354.1
([M+H].sup.+).
Example 48
3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00071##
[0869] In an analogous manner to General Procedure D, Step 1,
2,5-difluoro-N-(2-nitrophenyl)aniline was prepared from
2,5-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals.
MS (ESI) m/z 250.9 ([M+H].sup.+).
[0870] In an analogous manner to General Procedure D, Step 2,
N-(2,5-difluorophenyl)benzene-1,2-diamine was prepared from
2,5-difluoro-N-(2-nitrophenyl)aniline as an off-white solid. MS
(ESI) m/z 221.0 ([M+H].sup.+). HRMS: calculated for
C.sub.12H.sub.10F.sub.2N.sub.2+H.sup.+, 221.0885; found (ESI,
[M+H].sup.+), 221.0898.
[0871] In an analogous manner to General Procedure D, Step 3,
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-(2,5-difluorophenyl)benzene-1,2-diamine as white crystals. MS
(ESI) m/z 280.9 ([M-H].sup.-).
[0872] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide was prepared from
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
MS (ESI) m/z 338.9 ([M+H-SO.sub.2].sup.+).
[0873] In an analogous manner to General Procedure D, Step 5,
3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide as white crystals. MS (ESI) m/z 354.1
([M+H].sup.+).
Example 49
3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)--
yl}-N-methylpropan-1-amine hydrochloride
##STR00072##
[0875] In an analogous manner to General Procedure D, Step 1,
2-nitro-N-[3-(trifluoromethoxy)phenyl]aniline was prepared from
3-(trifluoromethoxy)aniline and 1-fluoro-2-nitrobenzene as an
orange oil. MS (ESI) m/z 298.7 ([M+H].sup.+).
[0876] In an analogous manner to General Procedure D, Step 2,
N-[3-(trifluoromethoxy)phenyl]benzene-1,2-diamine was prepared from
2-nitro-N-[3-(trifluoromethoxy)phenyl]aniline as an off-white
solid. MS (ESI) m/z 269.0 ([M+H].sup.+). HRMS: calculated for
C.sub.13H.sub.11F.sub.3N.sub.2O+H.sup.+, 269.0896; found (ESI,
[M+H].sup.+), 269.0908.
[0877] In an analogous manner to General Procedure D, Step 3,
1-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-[3-(trifluoromethoxy)phenyl]benzene-1,2-diamine as white
crystals. MS (ESI) m/z 328.8 ([M-H].sup.-).
[0878] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide was prepared from
1-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
MS (ESI) m/z 387.0 ([M+H-SO.sub.2].sup.+).
[0879] In an analogous manner to General Procedure D, Step 5,
3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-
-yl}-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 402.1
([M+H].sup.+).
Example 50
3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)--
yl}-N-methylpropan-1-amine hydrochloride
##STR00073##
[0881] In an analogous manner to General Procedure D, Step 1,
2-nitro-N-[2-(trifluoromethoxy)phenyl]aniline was prepared from
2-(trifluoromethoxy)aniline and 1-fluoro-2-nitrobenzene as an
orange oil. MS (ESI) m/z 298.7 ([M+H].sup.+). HRMS: calculated for
C.sub.13H.sub.9F.sub.3N.sub.2O.sub.3+H.sup.+, 299.0638; found (ESI,
[M+H].sup.+), 299.0648.
[0882] In an analogous manner to General Procedure D, Step 2,
N-[2-(trifluoromethoxy)phenyl]benzene-1,2-diamine was prepared from
2-nitro-N-[2-(trifluoromethoxy)phenyl]aniline as an off-white
solid. MS (ESI) m/z 269.0 ([M+H].sup.+). HRMS: calculated for
C.sub.13H.sub.11F.sub.3N.sub.2O+H.sup.+, 269.0896; found (ESI,
[M+H].sup.+), 269.0882.
[0883] In an analogous manner to General Procedure D, Step 3,
1-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-[2-(trifluoromethoxy)phenyl]benzene-1,2-diamine as white
crystals. MS (ESI) m/z 328.8 ([M-H].sup.-).
[0884] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide was prepared from
1-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
MS (ESI) m/z 387.0 ([M+H-SO.sub.2].sup.+).
[0885] In an analogous manner to General Procedure D, Step 5,
3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1
(3H)-yl}-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 402.1
([M+H].sup.+).
Example 51
3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)-y-
l}-N-methylpropan-1-amine hydrochloride
##STR00074##
[0887] In an analogous manner to General Procedure D, Step 1,
(2-nitrophenyl)[3-(trifluoromethyl)phenyl]amine was prepared from
3-(trifluoromethyl)aniline and 1-fluoro-2-nitrobenzene as orange
crystals. MS (ESI) m/z 282.8 ([M+H].sup.+).
[0888] In an analogous manner to General Procedure D, Step 2,
N-[3-(trifluoromethyl)phenyl]benzene-1,2-diamine was prepared from
(2-nitrophenyl)[3-(trifluoromethyl)phenyl]amine as an off-white
solid. MS (ESI) m/z 252.9 ([M+H].sup.+). HRMS: calculated for
C.sub.13H.sub.11F.sub.3N.sub.2+H.sup.+, 253.0947; found (ESI,
[M+H].sup.+), 253.0963.
[0889] In an analogous manner to General Procedure D, Step 3,
1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-[3-(trifluoromethyl)phenyl]benzene-1,2-diamine as white crystals.
MS (ESI) m/z 312.8 ([M-H].sup.-).
[0890] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide was prepared from
1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless
liquid.
[0891] In an analogous manner to General Procedure D, Step 5,
3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1
(3H)-yl}-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 386.1
([M+H].sup.+).
Example 52
3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine hydrochloride
##STR00075##
[0893] In an analogous manner to General Procedure D, Step 1,
2-chloro-N-(2-nitrophenyl)aniline was prepared from 2-chloroaniline
and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 248.8
([M+H].sup.+).
[0894] In an analogous manner to General Procedure D, Step 2,
N-(2-chlorophenyl)benzene-1,2-diamine was prepared from
2-chloro-N-(2-nitrophenyl)aniline as an off-white solid. MS (ESI)
m/z 219.0 ([M+H].sup.+). HRMS: calculated for
C.sub.12H.sub.11ClN.sub.2+H.sup.+, 219.0684; found (ESI,
[M+H].sup.+), 219.0693.
[0895] In an analogous manner to General Procedure D, Step 3,
1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
was prepared from N-(2-chlorophenyl)benzene-1,2-diamine as white
crystals. MS (ESI) m/z 278.8 ([M-H].sup.-).
[0896] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 3-bromo-1-propanol as a viscous, colorless liquid. MS (ESI) m/z
336.9 ([M+H--SO.sub.2].sup.+).
[0897] In an analogous manner to General Procedure D, Step 5,
3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-[2-chlorophenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as white crystals. MS (ESI) m/z 351.9
([M+H].sup.+).
Example 53
3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylp-
ropan-1-amine hydrochloride
##STR00076##
[0899] In an analogous manner to General Procedure D, Step 1,
N-(3-bromophenyl)-2-nitroaniline was prepared from 3-bromoaniline
and 1-fluoro-2-nitrobenzene as orange crystals. MS (EI) m/z 291.9
(M.sup.+.cndot.). HRMS: calculated for
C.sub.12H.sub.9BrN.sub.2O.sub.2, 291.9847; found (EI, M.sup.+),
291.9841.
[0900] In an analogous manner to General Procedure D, Step 2,
N-(3-bromophenyl)benzene-1,2-diamine was prepared from
N-(3-bromophenyl)-2-nitroaniline as an off-white solid. MS (ESI)
m/z 262.8 ([M+H].sup.+). HRMS: calculated for
C.sub.12H.sub.11BrN.sub.2+H.sup.+, 263.0178; found (ESI,
[M+H].sup.+), 263.0185.
[0901] In an analogous manner to General Procedure D, Step 3,
1-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
was prepared from N-(3-bromophenyl)benzene-1,2-diamine as white
crystals.
[0902] MS (ESI) m/z 322.8 ([M-H].sup.-).
[0903] In an analogous manner to General Procedure D, Step 4,
1-(3-bromopropyl)-3-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 3-bromo-1-propanol as a viscous, colorless liquid. MS (ES I)
m/z 380.9 ([M+H-SO.sub.2].sup.+).
[0904] In an analogous manner to General Procedure D, Step 5,
3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-[3-bromophenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as white crystals. MS (ESI) m/z 396.0
([M+H].sup.+).
Example 54
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanamin-
e
##STR00077##
[0906] Step 1: Diisopropyl azodicarboxylate (0.50 mL, 2.57 mmol)
was added to a solution of
1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.60 g, 2.14 mmol), 2-bromo-ethanol (0.15 mL, 2.14 mmol),
triphenylphosphine (0.67 g, 2.57 mmol) in dry THF (21 mL) under
nitrogen. The solution was stirred overnight at room temperature.
The reaction was concentrated in vacuo to provide the crude
product. The crude product was pre-adsorbed onto Celite and
purified via Isco chromatography (redisep, silica gradient 5-50%
ethyl acetate in hexane) to afford 0.70 g (84%) of
1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. mp 86-89.degree. C. HPLC purity 100% at 210-370 nm,
10.6 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5 acetonitrile/MeOH)
for 10 minutes, hold 4 minutes.
[0907] Step 2: In an analogous manner to Example 19, Step 2,
1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (68 mg, 0.17 mmol) and ammonia (10 mL, ca. 7N in
methanol) were stirred overnight at 60.degree. C. 14 mg (25%) of
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanami-
ne was provided after purification. Treatment of the free base with
1.0 M HCl in diethyl ether afforded 6 mg of the HCl salt. HRMS:
calcd for C.sub.14H.sub.14ClN.sub.3O.sub.2S+H+, 324.05680; found
(ESI, [M+H]+), 324.0566. HPLC purity 91.9% at 210-370 nm, 7.4
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 minutes,
hold 4 minutes.
Example 55
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
ethanamine
##STR00078##
[0909] In an analogous manner to Example 20,
1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (68 mg, 0.17 mmol) and methylamine (15 mL, 8M in
ethanol) were stirred for 16 hours. 31 mg (53%) of
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lethanamine was provided after purification. Treatment with 1.0 M
HCl in diethyl ether afforded 3 mg of the salt. HRMS: calcd for
C.sub.15H.sub.16ClN.sub.3O.sub.2S+H+, 338.07245; found (ESI,
[M+H]+), 338.0727. HPLC purity 100% at 210-370 nm, 7.4 minutes;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 minutes, hold 4
minutes.
Example 56
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1--
amine
##STR00079##
[0911] This compound was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and (3-hydroxy-propyl)-carbamic acid tert-butyl ester according to
General Procedure C.
[0912] MS (ESI) m/z 322.1026
[0913] HPLC purity 98.7% at 210-370 nm, 6.6 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4
minutes
Example 57
N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropan-1-amine
##STR00080##
[0915] This compound was prepared according to the General
Procedure A.
[0916] MS (ESI) m/z 350.135
[0917] HPLC purity 100% at 210-370 nm, 7.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4
minutes
Example 58
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-a-
mine
##STR00081##
[0919] Step 1: To a stirring solution of
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(770 mg, 2.91 mmol) and cesium carbonate (1.42 g, 4.37 mmol) in
anhydrous dimethylformamide was added 1,4-dibromobutane (1.72 mL,
14.6 mmol) and the solution was stirred, under nitrogen, at room
temperature for 18 hours. The reaction was transferred to a
separatory funnel with ethyl acetate and washed with a saturated
solution of ammonium chloride, water, brine and dried (MgSO.sub.4),
filtered, the solvent removed and the material adsorbed onto silica
and purified using column chromatography (Isco: 0-20% ethyl acetate
in hexane) to afford
1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as a clear oil (960 mg, 83% Yield).
[0920] Step 2:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine was prepared from
1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide according to the General Procedure A.
[0921] MS (ESI) m/z 335.0552
[0922] HPLC purity 100% at 210-370 nm, 10.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium
bicarbonate buffer pH=9.5, acetonitrile/MeOH) for 10 minutes hold 4
minutes
Example 59
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-1-amine
##STR00082##
[0924]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylbutan-1-amine was prepared using
1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide according to the General Procedure A.
[0925] MS (ESI) m/z 350.13331
[0926] HPLC purity 100% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4
minutes
Example 60
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine hydrochloride
##STR00083##
[0928] Step 1: In an analogous manner to Example 6, step 1, 5.2 g
of N-(2-Chloro-4-fluorophenyl)-N-(2-nitrophenyl)amine was prepared
from 2-chloro-4-fluoro aniline (5.0 g, 34.5 mmol) and
2-Fluoronitrobenzene (4.9 g, 34.5 mmol). MS (ES) m/z 266.8
[0929] Step 2: N-(2-chloro-4-fluorophenyl)-N-(2-nitrophenyl)amine
(4.0 g, 15.0 mmol) was dissolved in ethanol (50 mL) and 10%
palladium on activated carbon (250 mg) was added. The mixture was
shaken under a hydrogen atmosphere (50 psi) for 2 hour. The mixture
was filtered through a pad of celite and concentrated to give
N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine (3.3 g) that was
carried on directly to the next step.
[0930] Step 3: In an analogous manner to general procedure A, step
1, N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine (4.1 g, 17.3
mmol) was treated with sulfamide (2.5 g, 26.0 mmol) to provide
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.1 g). MS (ESI) m/z 296.8 (M-H).sup.-.
[0931] Step 4: In an analogous manner to general procedure A, step
2, 1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.25 g, 0.85 mmol) was treated with triphenylphosphine
(0.36 g, 1.4 mmol), 3-bromopropanol (0.18 g, 1.4 mmol), and
diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide
1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.22 g).
[0932] Step 5: In an analogous manner to general procedure A, step
3,
1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.20 g, 0.46 mmol) was treated with
methylamine to provide
3-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]-N-methylpropan-1-amine hydrochloride (0.18 g). HRMS:
calculated for C.sub.16H.sub.17ClFN.sub.3O.sub.2S+H+, 370.07868;
found (ESI, [M+H].sup.+), 370.0788
[0933] HPLC purity 96.7% at 210-370 nm, 7.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
Example 61
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine hydrochloride
##STR00084##
[0935] Step 1: In an analogous manner to general procedure A, step
2, 1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.25 g, 0.85 mmol) (See Example 60, step 3) was
treated with triphenylphosphine (0.36 g, 1.4 mmol), 3-BOC amino
propanol (0.25 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28
g, 1.4 mmol) to provide 0.19 g of product used as is in the next
step.
[0936] Step 2 The residue isolated from Step 1 was dissolved in
ether:methanol (10:1) and 2 mL of 2N HCl in ether added. The
solution was allowed to stand for 16 hours whereupon the solid was
collected by filtration to provide 0.16 g of
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine hydrochloride. HRMS: calculated for
C.sub.15H.sub.15ClFN.sub.3O.sub.2S+H.sup.+, 356.06303; found (ESI,
[M+H].sup.+), 356.0631, HPLC purity 99.3% at 210-370 nm, 7.4
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes
hold 4 minutes
Example 62
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
##STR00085##
[0938] Step 1: In an analogous manner to Example 6, step 1, 4.6 g
of N-(4-fluoro-2-methylphenyl)-N-(2-nitrophenyl)amine was prepared
from 4-fluoro-2-methyl aniline (4.8 g, 30.9 mmol) and
2-Fluoronitrobenzene (4.3 g, 30.9 mmol). MS (ES) m/z 266.8
[0939] Step 2: In an analogous manner to Example 60, step 2,
N-(4-fluoro-2-methylphenyl)-N-(2-nitrophenyl)amine (4.6 g, 18.7
mmol) was subjected to hydrogenation to give
N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (4.1 g) that was
carried on directly to the next step.
[0940] Step 3: In an analogous manner to general procedure A, step
1, N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (3.5 g, 15.1
mmol) was treated with sulfamide (1.9 g, 19.6 mmol) to provide
1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (1.5 g).
[0941] Step 4: In an analogous manner to general procedure A, step
2, 1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.31 g, 1.1 mmol) was treated with triphenylphosphine
(0.46 g, 1.7 mmol), 3-bromopropanol (0.24 g, 1.7 mmol), and
diisopropylazodicarboxylate (0.35 g, 1.4 mmol) to provide
1-(3-bromopropyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.25 g).
[0942] Step 5: In an analogous manner to general procedure A, step
3,
1-(3-bromopropyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.20 g, 0.46 mmol) was treated with
methylamine to provide
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]-N-methylpropan-1-amine (0.15 g). HPLC purity 96.3% at
210-370 nm, 7.6 minutes; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes HRMS: calculated for
C.sub.17H.sub.20FN.sub.3O.sub.2S+H+, 350.13330; found (ESI,
[M+H].sup.+), 350.1336.
Example 63
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine
##STR00086##
[0944] Step 1: In an analogous manner to general procedure A, step
2, 1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.25 g, 0.90 mmol) was treated with triphenylphosphine
(0.36 g, 1.4 mmol), 3-boc amino propanol (0.25 g, 1.4 mmol), and
diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 0.23 g of
product used as is in the next step.
[0945] Step 2 The residue isolated from Step 1 was dissolved in
ether:methanol (10:1) and 2 mL of 2N HCl in ether added. The
solution was allowed to stand for 16 hours whereupon the solid was
collected by filtration to provide 0.16 g of
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine hydrochloride.
[0946] HPLC purity 89.8% at 210-370 nm, 7.5 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0947] HRMS: calculated for C.sub.16H.sub.18FN.sub.3O.sub.2S+H+,
336.11765; found (ESI, [M+H].sup.+), 336.118.
Example 64
3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine
##STR00087##
[0949] Step 1: In an analogous manner to Example 6, step 1, 4.1 g
of N-(4-fluoro-2-methoxyphenyl)-N-(2-nitrophenyl)amine was prepared
from 4-fluoro-2-methoxy aniline (4.3 g, 30.9 mmol) and
2-Fluoronitrobenzene (4.3 g, 30.9 mmol).
[0950] Step 2: In an analogous manner to Example 60, step 2,
N-(4-fluoro-2-methoxyphenyl)-N-(2-nitrophenyl)amine (4.2 g, 18.7
mmol) was subjected to hydrogenation to give
N-(4-fluoro-2-methoxyphenyl)benzene-1,2-diamine (3.5 g) that was
carried on directly to the next step.
[0951] Step 3: In an analogous manner to general procedure A, step
1, N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (3.2 g, 10.8
mmol) was treated with sulfamide (1.5 g, 16.3 mmol) to provide
1-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (1.3 g).
[0952] MS (ES) m/z 294.8;
[0953] HRMS: calculated for C.sub.13H.sub.11FN.sub.2O.sub.3S-H+,
293.04017; found (ESI, [M-H]-), 293.0392
[0954] Step 4: In an analogous manner to general procedure A, step
2, 1-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.41 g, 1.4 mmol) was treated with triphenylphosphine
(0.46 g, 1.7 mmol), 3-bromopropanol (0.24 g, 1.7 mmol), and
diisopropylazodicarboxylate (0.35 g, 1.4 mmol) to provide
1-(3-bromopropyl)-3-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothi-
adiazole 2,2-dioxide (0.35 g).
[0955] Step 5: In an analogous manner to general procedure A, step
3,
1-(3-bromopropyl)-3-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothi-
adiazole 2,2-dioxide (0.20 g, 0.48 mmol) was treated with
methylamine to provide
3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1 (3H)-yl]-N-methylpropan-1-amine hydrochloride (0.15 g).
[0956] HPLC purity 96.8% at 210-370 nm, 7.0 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes HRMS:
calculated for C.sub.17H.sub.20FN.sub.3O.sub.3S+H+, 366.12822;
found (ESI, [M+H].sup.+), 366.1283.
Example 65
Preparation of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-
-amine
[0957] Step 1: In an analogous manner to general procedure A, step
1, N-(2-fluorophenyl)benzene-1,2-diamine (1.0 g, 5.0 mmol) was
treated with sulfamide (0.58 g, 6.0 mmol) to provide 0.52 g (40%)
of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. HRMS: calculated for
C.sub.2H.sub.9FN.sub.2O.sub.2S+Na.sup.+, 287.02609; found (ESI,
[M+Na].sup.+), 287.0263; HPLC purity 100.0% at 210-370 nm, 8.4
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes
hold 4 minutes
[0958] Step 2: In an analogous manner to Example 18, step
1,1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.30 g, 1.1 mmol) was treated with cesium carbonate (0.37 g, 1.1
mmol) and 1,5-dibromopentane (0.62 mL, 4.5 mmol) to prepare 0.32 g
(69%) of
1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. HRMS: calculated for
C.sub.17H.sub.8BrFN.sub.2O.sub.2S+H.sup.+, 413.03291; found (ESI,
[M+H].sup.+), 413.0: HPLC purity 100.0% at 210-370 nm, 10.9
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes
hold 4 minutes
[0959] Step 3: In an analogous manner to Example
2,1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.19 mmol) was treated with ammonia (10 mL) to
provide 0.06 g (98%) of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-
-amine. MS (ES) m/z 350.0; HRMS: calculated for
C.sub.17H.sub.20FN.sub.3O.sub.2S+H.sup.+, 350.13330; found (ESI,
[M+H].sup.+), 350.1338; HPLC purity 96.3% at 210-370 nm, 8.6
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes
hold 4 minutes
##STR00088##
Example 66
Preparation of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpentan-1-amine
[0960] In an analogous manner to general procedure A, step 3,
1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.19 mmol) was treated with methylamine (10
mL) to provide 0.06 g (94%) of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lpentan-1-amine. MS (ES) m/z 364.0; HRMS: calculated for
C.sub.8H.sub.22FN.sub.3O.sub.2S+H.sup.+, 364.14895; found (ESI,
[M+H].sup.+), 364.1494; HPLC purity 100.0% at 210-370 nm, 8.7
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85115-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes
hold 4 minutes
##STR00089##
Example 67
Preparation of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylpentan-1-amine
[0961] In an analogous manner to general procedure A, step 3,
1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.19 mmol) was treated with dimethylamine (10
mL) to provide 0.06 g (94%) of
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylpentan-1-amine. MS (ES) m/z 377.5; HRMS: calculated for
C.sub.19H.sub.24FN.sub.3O.sub.2S+H.sup.+, 378.16460; found (ESI,
[M+H].sup.+), 378.1649; HPLC purity 96.8% at 210-370 nm, 9.7
minutes; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/minutes
85115-5195 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes
hold 4 minutes
Example 68
3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
propan-1-amine hydrochloride
##STR00090##
[0963] In an analogous manner to General procedure D, step 1,
N-(3-chlorophenyl)-2-nitroaniline was prepared from 3-chloroaniline
and 1-fluoro-2-nitrobenzene as orange solid. MS (ESI) m/z 248.8
([M+H].sup.+).
[0964] In an analogous manner to General procedure D, step 2,
N-(3-chlorophenyl)benzene-1,2-diamine was prepared from
N-(3-chlorophenyl)-2-nitroaniline as an off-white solid. HRMS:
calculated for C.sub.12H.sub.11ClN.sub.2+H.sup.+, 219.0684; found
(ESI, [M+H].sup.+), 219.0662.
[0965] In an analogous manner to General procedure D, step 3,
1-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
was prepared from N-(3-chlorophenyl)benzene-1,2-diamine as white
crystals. MS (ESI) m/z 278.8 ([M-H].sup.-).
[0966] In an analogous manner to General procedure D, step
4,1-(3-bromopropyl)-3-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 3-bromo-1-propanol as a viscous, colorless liquid. MS (ESI) m/z
337.0 ([M+H-SO.sub.2].sup.+).
[0967] In an analogous manner to General procedure D, step
5,3-[3-(3-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-met-
hylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as white crystals. MS (ESI) m/z 352.1 ([M+H].sup.+).
HRMS: calculated for C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+,
352.0881; found (ESI, [M+H].sup.+), 352.0877.
Example 69
3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propa-
n-1-amine hydrochloride
##STR00091##
[0969] In an analogous manner to General Procedure C, step 4,
tert-butyl
{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pyl}carbamate was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Example 45, step 3) and tert-butyl
N-(3-hydroxypropyl)carbamate as a viscous, colorless liquid.
[0970] In an analogous manner to General Procedure C, step 5,
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
an-1-amine hydrochloride was prepared from tert-butyl
{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pro-
pyl}carbamate as a white solid. MS (ESI) m/z 340.2 ([M+H].sup.+).
HRMS: calculated for
C.sub.15H.sub.15F.sub.2N.sub.3O.sub.2S+H.sup.+, 340.0926; found
(ESI, [M+H].sup.+), 340.0927.
Example 70
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opan-1-amine hydrochloride
##STR00092##
[0972] In an analogous manner to General Procedure C, step 4,
tert-butyl
{3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
propyl}carbamate was prepared from
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl N-(3-hydroxypropyl)carbamate as a
viscous, colorless liquid. MS (ESI) m/z 357.8
([M+H-Boc].sup.+).
[0973] In an analogous manner to General Procedure C, step 5,
3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropan-1-amine hydrochloride was prepared from tert-butyl
{3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
propyl}carbamate as a white solid. MS (ES I) m/z 358.3
([M+H].sup.+).
Example 71
3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine hydrochloride
##STR00093##
[0975] In an analogous manner to General procedure D, step
4,1-(3-bromopropyl)-3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide was prepared from
3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a white solid. MS (ES) m/z
461.3.
[0976] In an analogous manner to General procedure D, step 5,
3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide and methyl amine as an off-white solid. MS (ES)
m/z 412.2.
Example 72
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propa-
n-1-amine hydrochloride
##STR00094##
[0978] In an analogous manner to General procedure D, step
4,1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide was prepared from
11-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a brown oil. MS (ES) m/z
[M+H-SO.sub.2].sup.+ 338.7.
[0979] In an analogous manner to General procedure D, step
5,3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opan-1'-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide and ammonia in methanol as an off-white solid. MS
(ES) m/z 340.1; HRMS: calculated for
C.sub.15H.sub.15F.sub.2N.sub.3O.sub.2S+H+, 340.09258; found (ESI,
[M+H].sup.+), 340.0941.
Example 73
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine hydrochloride
##STR00095##
[0981] In an analogous manner to General procedure D, step 1,
2-fluoro-N-(2-fluorophenyl)-6-nitroaniline was prepared from
2,3-difluoronitroaniline and 2-fluoroaniline as a yellow solid. MS
(ES) m/z 250.9
[0982] In an analogous manner to General procedure D, steps 2-4,
1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide was prepared from
2-fluoro-N-(2-fluorophenyl)-6-nitroaniline as a white solid. MS
(ES) m/z 400.9
[0983] In an analogous manner to General procedure D, step 5,
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide and 33% methanolic methylamine as a light pink
solid. MS (ES) m/z 354.1; HRMS: calculated for
C.sub.16H.sub.17F.sub.2N.sub.3O.sub.2S+H+, 354.10823; found (ESI,
[M+H]+), 354.1085.
Example 74
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
propan-1-amine hydrochloride
##STR00096##
[0985] In an analogous manner to General procedure D, step 5,
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide and 7 N methanolic ammonia as a white amorphous
solid. HRMS: calculated for
C.sub.15H.sub.15F.sub.2N.sub.3O.sub.2S+H+, 340.09258; found (ESI,
[M+H]+), 340.0931
Example 75
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00097##
[0987] In an analogous manner to General procedure D, step 5,
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide and 33% methanolic methyl amine as a light blue
solid. MS (ES) m/z 354.3; HRMS: calculated for
C.sub.16H.sub.17F.sub.2N.sub.3O.sub.2S+H+, 354.10823; found (ESI,
[M+H]+), 354.1073.
Example 76
3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
[0988] Step 1: In an analogous manner to General Procedure D, Step
1, 2-fluoroaniline (4.8 mL, 50 mmol) was treated with
n-butyllithium (2.5 M in hexane, 20 mL, 50 mmol) followed by
2,6-difluoronitrobenzene (7.8 g, 49 mmol) to give
3-fluoro-N-(2-fluorophenyl)-2-nitroaniline (11.1 g).
[0989] HPLC purity 100.0% at 210-370 nm, 10.2 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0990] HRMS: calculated for
C.sub.12H.sub.8F.sub.2N.sub.2O.sub.2+H.sup.+, 251.06266; found
(ESI, [M+H].sup.+), 251.0629;
[0991] Step 2: In an analogous manner to Example 11, Step 2,
3-fluoro-N-(2-fluorophenyl)-2-nitroaniline (8.0 g, 32 mmol) was
dissolved in ethyl acetate (30 mL), treated with 10% palladium on
carbon (250 mg), and shaken under hydrogen to give
3-fluoro-N-1-(2-fluorophenyl)benzene-1,2-diamine (3.4 g).
[0992] HPLC purity 100.0% at 210-370 nm, 9.4 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0993] HRMS: calculated for C.sub.12H.sub.10F.sub.2N.sub.2+H.sup.+,
221.08848; found (ESI, [M+H].sup.+), 221.0888
[0994] Step 3: In an analogous manner to General Procedure A, Step
1, 3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine (0.55 g, 2.5
mmol) was treated with sulfamide (0.31 g, 3.25 mmol) and sulfonyl
diimidazole (48 mg, 0.25 mmol) to give
4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.36 g).
[0995] HPLC purity 99.0% at 210-370 nm, 7.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0996] HRMS: calculated for
C.sub.12H.sub.8F.sub.2N.sub.2O.sub.2S-H.sup.+, 281.02018; found
(ESI, [M-H].sup.-), 281.0202;
[0997] Step 4: In an analogous manner to General Procedure A, Step
2, 4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.4 g, 1.42 mmol), was treated with triphenylphosphine
(0.44 g, 1.7 mmol), 3-bromopropanol (0.12 mL, 1.42 mmol), and
diisopropylazodicarboxylate (0.33 mL, 1.7 mmol) to provide 0.54 g
3-(3-bromopropyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide.
[0998] HPLC purity 92.1% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85115-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0999] Step 5: In an analogous manner to General Procedure A, Step
3,
3-(3-bromopropyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.54 g, 1.34 mmol) was treated with
methylamine to provide
3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]-N-methylpropan-1-amine hydrochloride (0.36 g) after
treatment with HCl.
[1000] HPLC purity 99.5% at 210-370 nm, 6.8 minutes; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[1001] HRMS: calculated for
C.sub.16H.sub.17F.sub.2N.sub.3O.sub.2S+H.sup.+, 354.10823; found
(ESI, [M+H].sup.+), 354.1086;
Example 77
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylpropan-1-amine hydrochloride
##STR00098##
[1003] Step 1: To a solution of 3-(methylamino)-1-propanol (8.91 g,
100 mmol) in ethyl acetate (50 mL) at 0.degree. C. was added
dropwise a solution of di-tert-butyl dicarbonate (21.83 g, 100
mmol, 1 equiv.) in ethyl acetate (20 mL) via an addition funnel.
The resulting solution was stirred for 2 h while warming to room
temperature. More ethyl acetate (80 mL) was added and the mixture
was washed with water, brine, dried (anhydrous sodium sulfate),
filtered, and concentrated. The crude liquid was purified by Isco
CombiFlash Companion column chromatography to give pure tert-butyl
(3-hydroxypropyl)methylcarbamate as a colorless liquid. Yield:
17.80 g (94%). MS (ESI) m/z 190.2 ([M+H].sup.+). HRMS: calcd for
C.sub.9H.sub.19NO.sub.3+H.sup.+, 190.1438; found (ESI,
[M+H].sup.+), 190.1437.
[1004] Step 2: In an analogous manner to General Procedure C, step
4, tert-butyl
{3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
propyl}methylcarbamate was prepared from
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl (3-hydroxypropyl)methylcarbamate as a
viscous, colorless liquid. MS (ESI) m/z 471.7 ([M+H].sup.+). HRMS:
calcd for C.sub.21H.sub.24F.sub.3N.sub.3O.sub.4S+H.sup.+, 472.1512;
found (ESI, [M+H].sup.+), 472.1515. HPLC purity 99.3% at 210-370
nm, 10.5 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1005] Step 3: In an analogous manner to General Procedure C, step
5,
3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine hydrochloride was prepared from tert-butyl
{3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
propyl}methylcarbamate as a white powder. MS (ESI) m/z 371.8
([M+H].sup.+). HRMS: calcd for
C.sub.16H.sub.16F.sub.3N.sub.3O.sub.2S+H.sup.+, 372.0988; found
(ESI, [M+H].sup.+), 372.0990. HPLC purity 99.2% at 210-370 nm, 6.7
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 78
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-N-methylpropan-1-amine hydrochloride
##STR00099##
[1007] Step 1: In an analogous manner to General procedure D
(Example 45), step 4,
3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide was prepared from
1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
HRMS: calcd for C.sub.15H.sub.12BrF.sub.3N.sub.2O.sub.2S.sup.+,
419.9755; found (EI, M.sup.+), 419.9757.
[1008] Step 2: In an analogous manner to General procedure D
(Example 45), step 5,
3-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared
from
3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide as a white powder. MS (ESI) m/z 371.8
([M+H].sup.+). HRMS: calcd for
C.sub.16H.sub.16F.sub.3N.sub.3O.sub.2S+H.sup.+, 372.0988; found
(ESI, [M+H].sup.+), 372.0990.
Example 79
3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-N-methylpropan-1-amine hydrochloride
##STR00100##
[1010] In an analogous manner to General Procedure C, step 4,
tert-butyl
{3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1
(3H)-yl]propyl}methylcarbamate was prepared from
1-(2,4-difluorophenyl)-7-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl (3-hydroxypropyl)methylcarbamate as a
viscous, colorless liquid, MS (ESI) m/z 371.7 ([M+H-Boc].sup.+).
HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1011] In an analogous manner to General Procedure C, step
5,3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from
tert-butyl
{3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]propyl}methylcarbamate as white crystals. MS (ESI) m/z 371.8
([M+H].sup.+). HRMS: calcd for
C.sub.16H.sub.16F.sub.3N.sub.3O.sub.2S+H.sup.+, 372.0988; found
(ESI, [M+H].sup.+), 372.0989. HPLC purity 99.2% at 210-370 nm, 7.4
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 80
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-N,N-dimethylpropan-1-amine hydrochloride
##STR00101##
[1013] In an analogous manner to General procedure D (Example 45),
step 5,
3-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N,N-dimethylpropan-1-amine hydrochloride was prepared from
3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (Example 78, Step 1) using excess
dimethylamine as a white powder. MS (ESI) m/z 386.1 ([M+H].sup.+).
HRMS: calcd for C.sub.17H.sub.18F.sub.3N.sub.3O.sub.2S+H.sup.+,
386.1145; found (ESI, [M+H].sup.+), 386.1148.
Example 81
4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylbutan-1-amine hydrochloride
##STR00102##
[1015] Step 1: Ethanolic methylamine (33% in ethanol, 80 mL) was
added to a solution of 4-bromo-1-butanol (80% in tetrahydrofuran,
7.00 g, 36.6 mmol). The reaction mixture was sealed tightly and
stirred for 12 h, then concentrated. The residue was dissolved in
dichloromethane (80 mL), triethylamine (16 mL, 115 mmol, 3 equiv.)
was added. To this solution was added dropwise a solution of
di-tert-butyl dicarbonate (10.0 g, 45.8 mmol, 1.25 equiv.) in
dichloromethane (25 mL) via an addition funnel. The reaction
mixture was stirred at room temperature for 5 h, then pour into a
mixture of dichloromethane (200 mL) and water (200 mL). The organic
layer was washed with water, dried (anhydrous sodium sulfate),
filtered, and concentrated. The crude liquid was pre-adsorbed onto
Florisil and purified via Isco flash column chromatography (330-g
redisep silica gel column, 0-65% ethyl acetate/hexane) to give pure
tert-butyl (4-hydroxybutyl)methylcarbamate as a colorless liquid.
Yield: 4.15 g (56%).
[1016] Step 2: In an analogous manner to General Procedure C, step
4, tert-butyl
{4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
butyl}methylcarbamate was prepared from
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl (4-hydroxybutyl)methylcarbamate as a
viscous, colorless liquid. MS (ESI) m/z 486.1 ([M+H].sup.+). HRMS:
calcd for C.sub.22H.sub.26F.sub.3N.sub.3O.sub.4S+H.sup.+, 486.1669;
found (ESI, [M+H].sup.+), 486.1680. HPLC purity 100.0% at 210-370
nm, 10.6 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1017] Step 3: In an analogous manner to General Procedure C, step
5, 4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1
(3H)-yl]-N-methylbutan-1-amine hydrochloride was prepared from
tert-butyl
{4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-
butyl}methylcarbamate as a white powder. MS (ESI) m/z 386.2
([M+H].sup.+). HRMS: calcd for
C.sub.17H.sub.18F.sub.3N.sub.3O.sub.2S+H.sup.+, 386.1145; found
(ESI, [M+H].sup.+), 386.1153. HPLC purity 99.4% at 210-370 nm, 7.0
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85115-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 82
4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-1-amine hydrochloride
##STR00103##
[1019] In an analogous manner to General Procedure C, step 4,
tert-butyl
{4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}m-
ethylcarbamate was prepared from
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(Example 6, step 3) and tert-butyl (4-hydroxybutyl)methylcarbamate
as a viscous, colorless liquid. MS (ESI) m/z 450.1 ([M+H].sup.+).
HRMS: calcd for C.sub.22H.sub.28FN.sub.3O.sub.4S+H.sup.+, 450.1857;
found (ESI, [M+H].sup.+), 450.1865. HPLC purity 100.0% at 210-370
nm, 10.9 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1020] In an analogous manner to General Procedure C, step 5,
4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine hydrochloride was prepared from tert-butyl
{4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}m-
ethylcarbamate as a white powder. MS (ESI) m/z 350.2 ([M+H].sup.+).
HRMS: calcd for C.sub.17H.sub.20FN.sub.3O.sub.2S+H.sup.+, 350.1333;
found (ESI, [M+H].sup.+), 350.1344. HPLC purity 99.7% at 210-370
nm, 7.3 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
Example 83
4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylbutan-1-amine hydrochloride
##STR00104##
[1022] In an analogous manner to General Procedure C, step 4,
tert-butyl
{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-
yl}methylcarbamate was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Example 45, step 3) and tert-butyl
(4-hydroxybutyl)methylcarbamate as a viscous, colorless liquid. MS
(ESI) m/z 468.1 ([M+H].sup.+). HRMS: calcd for
C.sub.22H.sub.27F.sub.2N.sub.3O.sub.4S+H.sup.+, 468.1763; found
(ESI, [M+H].sup.+), 468.1763. HPLC purity 99.5% at 210-370 nm, 10.5
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1023] In an analogous manner to General Procedure C, step 5,
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbutan-1-amine hydrochloride was prepared from tert-butyl
{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-
yl}methylcarbamate as a white powder. MS (ESI) m/z 368.1
([M+H].sup.+). HRMS: calcd for
C.sub.17H.sub.19F.sub.2N.sub.3O.sub.2S+H.sup.+, 368.1239; found
(ESI, [M+H].sup.+), 368.1246. HPLC purity 99.5% at 210-370 nm, 6.8
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 84
N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclopropanamine hydrochloride
##STR00105##
[1025] In an analogous manner to General procedure D (Example 45),
step 5,
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopropanamine hydrochloride was prepared as a white powder
from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) using excess cyclopropylamine
at 60.degree. C. for 6 h. HRMS: calcd for
C.sub.18H.sub.19F.sub.2N.sub.3O.sub.2S+H.sup.+, 380.1239; found
(ESI, [M+H].sup.+), 380.1246. HPLC purity 99.7% at 210-370 nm, 9.4
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min, hold 4
min.
Example 85
N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclopropanamine hydrochloride
##STR00106##
[1027] In an analogous manner to General procedure D (Example 45),
step 5,
N-{3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}cyclopropanamine hydrochloride was prepared as a white powder
from
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide using excess cyclopropylamine at 60.degree. C. for 6
h. HRMS: calcd for C.sub.18H.sub.19F.sub.2N.sub.3O.sub.2S+H.sup.+,
380.1239; found (ESI, [M+H].sup.+), 380.1245. HPLC purity 99.5% at
210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10
min, hold 4 min.
Example 86
N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]bu-
tyl}cyclopropanamine hydrochloride
##STR00107##
[1029] In an analogous manner to General procedure D (Example 45),
step 4,
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Example 45, step 3) and 4-bromo-1-butanol as a
viscous, colorless liquid. MS (EI) m/z 416 [M+.cndot.]. HPLC purity
95.2% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH)
for 10 min, hold 4 min.
[1030] In an analogous manner to General procedure D (Example 45),
step 5,
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utyl}cyclopropanamine hydrochloride was prepared as a white powder
from
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide using excess cyclopropylamine at 60.degree. C. for 6
h. MS (ESI) m/z 393.9 ([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 394.1395; found
(ESI, [M+H].sup.+), 394.1403. HPLC purity 99.7% at 210-370 nm, 9.6
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min, hold 4
min.
Example 87
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylbutan-1-amine hydrochloride
##STR00108##
[1032] Step 1: In an analogous manner to Example 6, step 1,
N-(2-chloro, 4-fluorophenyl)-N-(2-nitrophenyl)amine was prepared
from 2-chloro, 4-fluoroaniline and 2-fluoronitrobenzene.
[1033] Step 2: N-(2-chloro,4-fluorophenyl)-N-(2-nitrophenyl)amine
(6 g, 22.5 mmol) was dissolved in ethanol (30 mL) and 10% palladium
on activated carbon (500 mg) was added. The mixture was shaken
under a hydrogen atmosphere (50 psi) until hydrogen absorption was
complete. The mixture was filtered through a pad of silica and
concentrated to give N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine
(4.8 g) that was carried on directly to the next step.
[1034] Step 3: In an analogous manner to general procedure A, step
1, 2.1 g of 1-(2-chloro,
4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was
prepared from 4.1 g of N-(2-choro,
4-fluorophenyl)benzene-1,2-diamine and 2.5 g of sulfamide.
[1035] MS (ES) m/z 296.8.
[1036] Step 4: In an analogous manner to Example 18, step 1
1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide was prepared from 1-(2-chloro,
4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and
1,4-dibromobutane. MS (ES) m/z 368.6; HPLC purity 94.9% at 210-370
nm, 10.9 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1037] Step 5: In an analogous manner to general procedure A, step
3,
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine hydrochloride was prepared from
1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z
383.8; HPLC purity 99.0% at 210-370 nm, 8.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon.
Bicarb Buff. Ph=9.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd
for C17H19ClFN3O2S+H+, 384.09433; found (ESI, [M+H]+ Obs'd),
384.0943.
Example 88
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N,N-dimethylbutan-1-amine hydrochloride
##STR00109##
[1039] In an analogous manner to Example
214-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]-N,N-dimethylbutan-1-amine hydrochloride was prepared from
1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole and dimethyl amine (.about.5.6 M in ethanol). MS (ES) m/z
397.7; HPLC purity 96.3% at 210-370 nm, 8.3 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for
C18H21ClFN3O2S+H+, 398.10998; found (ESI, [M+H]+ Obs'd),
398.1101.
Example 89
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpentan-1-amine hydrochloride
##STR00110##
[1041] Step 1: In an analogous manner to Example 18, step 1,
1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide was prepared from 1-(2-chloro,
4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and
1,5-dibromopentane. MS (ES) m/z 382.7.
[1042] Step 2: In an analogous manner to general procedure A, step
3,
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpentan-1-amine hydrochloride was prepared from
1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z
397.8; HRMS: calcd for C18H21ClFN3O2S+H+, 398.10998; found (ESI,
[M+H]+Obs'd), 398.1103.
Example 90
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N,N-dimethylpentan-1-amine hydrochloride
##STR00111##
[1044] In an analogous manner to Example 21,
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylpentan-1-amine hydrochloride was prepared from
1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole and dimethyl amine (.about.5.6 M in ethanol). MS (ES) m/z
411.8; HRMS: calcd for C19H23ClFN3O2S+H+, 412.12563; found (ESI,
[M+H]+ Obs'd), 412.1257.
Example 91
3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine hydrochloride
##STR00112##
[1046] Step 1: In an analogous manner to Example 6 step 1,
N-(2-fluoro, 4-methoxyphenyl)-N-(2-nitrophenyl)amine was prepared
from 2-fluoro, 4-methoxy aniline and 2-fluoronitrobenzene.
[1047] Step 2: In an analogous manner to Example 87 step 2,
N-(2-fluoro-4-methoxyphenyl)benzene-1,2-diamine was prepared from
N-(2-fluoro, 4-methoxyphenyl)-N-(2-nitrophenyl)amine and was
carried on directly to the next step.
[1048] Step 3: In an analogous manner to general procedure A, step
1, 2.1 g of 1-(2-fluoro,
4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was
prepared from N-(2-fluoro, 4-methoxyphenyl)benzene-1,2-diamine and
sulfamide.
[1049] Step 4: In an analogous manner general procedure A, step 2,
1-(3-bromopropyl)-3-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothi-
adiazole 2,2-dioxide was prepared from
1-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 3-bromopropanol.
[1050] Step 5: In an analogous manner to general procedure A, step
3,
3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-N-methylpropan-1-amine hydrochloride was prepared from
1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z
365.6; HPLC purity 100.0% at 210-370 nm, 7.2 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for
C17H20FN3O3S+H+, 366.12822; found (ESI, [M+H]+ Obs'd),
366.1283.
Example 92
3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl}phenol hydrochloride
##STR00113##
[1052] Step 1: A solution of 3-fluoro, 4-nitro phenol (5.6 g, 36.6
mmol) in 15 mL of DMF was added dropwise to a suspension of sodium
hydride (1.6 g, 41 mmol) in 10 mL of DMF at 0.degree. C. After 15
minutes added trimethylsilyl ethoxy methyl chloride (7.5 mL, 41
mmol) via syringe. At stirred for 1 hr. The solution was poured
into water and extracted three times with hexane. Drying
(MgSO.sub.4) and concentrating afforded 10.4 g of an orange oil.
This oil was dissolved in ethanol, placed in a Parr bottle and
.about.1.0 g of 10% Pd/C added. The solution was hydrogenated at 50
psi until absorption of hydrogen ceased. The catalyst was removed
by filtration through silica gel and the filtrate concentrated to
afford 9.1 g of 2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)
aniline used in the next step without further purification.
[1053] Step 2: 6.2 g (24 mmol) of
2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy) aniline was
dissolved in 50 mL of THF and cooled to -78.degree. C. A solution
of n-butyllithium (16.5 mL, 26 mmol) was diluted with 20 mL of THF
and added dropwise. After 0.5 hr added a solution of
2-fluoronitrobenzene (3.4 g, 24.1 mmol) in 15 mL of THF. The
cooling was removed after 1.5 hr. After stirring an additional 16 h
the reaction was quenched with saturated ammonium chloride and
extracted twice with ethyl acetate. The solution was dried and
concentrated and the residue purified by column chromatography
(Biotage 10-30% ethyl acetate:hexane). The orange oil was
hydrogenated as in step 1 to yield 3.1 g (33% overall) of
N-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)benzene-1,2-diami-
ne.
[1054] Step 3: In an analogous manner to general procedure A, step
1, 2.1 g of 1-(2-fluoro,
4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide was prepared from
N-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)benzene-1,2-diami-
ne and sulfamide.
[1055] Step 4: In an analogous manner to General Procedure C, Step
4, tert-butyl
3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide propyl carbamate was prepared from
1-(2-fluoro,
4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide and tert-butyl 3-hydroxypropylcarbamate.
[1056] Step 5:
tert-Butyl-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-d-
ihydro-2,1,3-benzothiadiazole-2,2-dioxide propyl(methyl)-carbamate
was prepared from tert-butyl
3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide propyl carbamate by treatment with
methyl iodide and sodium hydride in DMF.
[1057] Step 6: The product from Step 5 was dissolved in 9:1
ether:methanol and 2N HCl in ether added. After allowing to stand
overnight a solid formed which was removed by filtration to afford
3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl}phenol hydrochloride. MS (ES) m/z 352.0; HPLC purity 94.6%
at 210-370 nm, 6.5 min.; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min. HRMS: calcd for C16H18FN3O3S+H+, 352.11257;
found (ESI, [M+H]+ Obs'd), 352.1133.
Example 93
3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl}phenol hydrochloride
##STR00114##
[1059] Step 1: In an analogous manner to Example 18, step 1,
1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-
-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from
1-(2-fluoro,
4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide and 1,4-dibromobutane.
[1060] Step 2: In an analogous manner to general procedure A, step
3,
4-[3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,-
1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine was prepared
from
1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-
-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methyl amine
(33% in ethanol).
[1061] Step 3: In an analogous manner to Example 92, step 6,
3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl}phenol hydrochloride was prepared from
4-[3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,-
1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine. HPLC purity
99.1% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min. HRMS: calcd for C17H20FN3O3S+H+, 366.12822;
found (ESI, [M+H]+ Obs'd), 366.1287.
Example 94
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-1-amine
##STR00115##
[1063] Step 1: To a stirring solution of
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(770 mg, 2.91 mmol) and cesium carbonate (1.42 g, 4.37 mmol) in
anhydrous dimethylformamide was added 1,4-dibromobutane (1.72 mL,
14.6 mmol) and the solution was stirred, under nitrogen, at room
temperature for 18 hr. The reaction was transferred to a separatory
funnel with ethyl acetate and washed with a saturated solution of
ammonium chloride, water, brine and dried (MgSO.sub.4), filtered,
the solvent removed and the material adsorbed onto silica and
purified using column chromatography (Isco: 0-20% ethyl acetate in
hexane) to afford the product as a clear oil (960 mg, 83%
Yield).
[1064] HRMS: calcd for C16H16BrFN2O2S+H+, 398.01. found (EI M+)
398.0104 HPLC purity 99.0% at 210-370 nm, 10.5 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1065] Step 2:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine (275 mg, 0.714 mmol) was stirred in methylamine solution (33%
in absolute ethanol) in a capped vial at room temperature for 18
hr. The reaction mixture was concentrated then loaded directly onto
silica gel and purified via Isco chromatography (Redisep, silica,
gradient 0-10% NH.sub.3-MeOH in dichloromethane to afford 0.250 g
of
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine as a white solid. This material was dissolved in
diethyl ether and methanol and 4N HCl in dioxane was added a
precipitate formed. The mixture was filtered to afford 0.197 g of
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine as a white solid.
[1066] HRMS: calcd for C17H20FN3O2S+H+, 350.13331; found (ESI,
[M+H]1+, 350.13365 HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra
RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195
(ammonium formate buffer pH-3.5, acetonitrile/MeOH) for 10 min,
hold 4 min.
Example 95
3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
##STR00116##
[1068] Example 95 was prepared using
1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide analogous to the conditions used in step 2 of
example 94.
[1069] HRMS: calcd for HPLC purity 95.0% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 96
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cycloprop-
anamine
##STR00117##
[1071] Example 96 was prepared using
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 94.
[1072] HRMS: calcd for C18H21N3O2S+H+, 344.1427; found (ESI,
[M+Na]+, 344.1432
[1073] HPLC purity 92.5% at 210-370 nm, 10.6 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 97
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl-
}cyclopropanamine
##STR00118##
[1075] Example 97 was prepared using
1-(3-bromopropyl)-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 94.
[1076] HRMS: calcd for C18H20FN3O2S+H+, 362.1333; found (ESI,
[M+Na]+, 362.1333 HPLC purity 98.1% at 210-370 nm, 10.6 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 98
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cyclopropa-
namine
##STR00119##
[1078] Example 98 was prepared using
1-(3-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 94.
[1079] HRMS: calcd for C19H23N3O2S+H+, 358.1584; found (ESI,
[M+Na]+, 358.1588 HPLC purity 99.3% at 210-370 nm, 10.6 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 99
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}-
cyclopropanamine
##STR00120##
[1081] 99 was prepared using
1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 94.
[1082] HRMS: calcd for C19H22FN3O2S+H+, 376.1490; found (ESI,
[M+Na]+, 376.1494 HPLC purity 98.7% at 210-370 nm, 10.6 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 100
3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
##STR00121##
[1084] Example 100 was prepared using
1-(3-bromopropyl)-3-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide analogous to the conditions used in step 2 of
example 94.
[1085] HRMS: calcd for C17H20ClN3O2S+H+, 366.1037; found (ESI,
[M+H]+, 366.1038 HPLC purity 97.8% at 210-370 nm, 8.4 min.; Xterra
RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5/95 (Ammon.
Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 101
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
hexan-1-amine
##STR00122##
[1087] Step 1: In an analogous manner to example 18, step
1,1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.40 g, 1.51 mmol) was treated with cesium carbonate (0.50 g, 1.51
mmol) and 1, 6 dibromohexane (0.93 mL, 6.04 mmol) to prepare 0.49 g
(76%) of
1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. HRMS: calcd for C.sub.18H.sub.20BrFN.sub.2O.sub.2S+H+,
427.04856; found (ESI, [M+H]+), 427.0488; HPLC purity 100.0% at
210-370 nm, 11.1 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min.
[1088] Step 2: In an analogous manner to general procedure A, step
3,
1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.18 mmol) was treated with methylamine (10
mL) to provide 0.03 g (46%) of
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lhexan-1-amine. MS (ES) m/z 378;
[1089] HPLC purity 99.1% at 210-370 nm, 7.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 102
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1-a-
mine
##STR00123##
[1091] In an analogous manner to Example
2,1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.18 mmol) was treated with ammonia (10 mL) to
prepare 0.04 g (68%) of
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1--
amine. MS (ES) m/z 364; HPLC purity 98.9% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 103
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dime-
thylhexan-1-amine
##STR00124##
[1093] In an analogous manner to general procedure A, step 3,
1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.08 g, 0.18 mmol) was treated with dimethylamine (10
mL) to provide 0.03 g (49%) of
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylhexan-1-amine. MS (ES) m/z 327.9; HPLC purity 99.5% at 210-370
nm, 7.7 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min,
hold 4 min.
Example 104
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylbutan-1-amine
##STR00125##
[1095] A solution of
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N-methylbut-2-en-1-amine hydrochloride (0.1 g) in methanol
(3 mL) was hydrogenated using a Thales Nanotechnology H-cube
apparatus (palladium-charcoal, 0 bar, 1 mL/minute flow rate) to
provide
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbutan-1-amine hydrochloride (80 mg) as a white solid:
[1096] HPLC purity 95.1% at 210-370 nm, 7.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1097] HRMS: calcd for C18H22FN3O2S+H+, 364.14895; found (ESI,
[M+H]+ Obs'd), 364.1493.
Example 105
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
butan-1-amine
##STR00126##
[1099] In an analogous manner to example 104 1
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]but-2-en-1-amine hydrochloride was hydrogenated to provide
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]butan-1-amine hydrochloride: HPLC purity 87.5% at 210-370 nm, 8.5
min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1100] HRMS: calcd for C17H20FN3O2S+H+, 350.13330; found (ESI,
[M+H]+ Obs'd), 350.1336.
Example 106
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N,N-dimethylbutan-1-amine
##STR00127##
[1102] In an analogous manner to example 104,
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N,N-dimethylbut-2-en-1-amine hydrochloride was hydrogenated
to provide
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]-N,N-dimethylbutan-1-amine hydrochloride:
[1103] HPLC purity 97.4% at 210-370 nm, 7.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1104] HRMS: calcd for C19H24FN3O2S+H+, 378.16460; found (ESI,
[M+H]+ Obs'd), 378.1651.
Example 107
N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]butan-1-amine
##STR00128##
[1106] In an analogous manner to example 104,
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]but-2-en-1-amine hydrochloride was hydrogenated to
provide
N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol--
1(3H)-yl]butan-1-amineydrochloride:
[1107] HPLC purity 94.6% at 210-370 nm, 8.0 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1108] HRMS: calcd for C19H24FN3O2S+H+, 378.16460; found (ESI,
[M+H]+ Obs'd), 378.1651.
Example 108
3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylpropan-1-amine
##STR00129##
[1110] Step 1: A solution of
1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.56 g, 2 mmol) in tetrahydrofuran (10 mL) was cooled
to 0.degree. C. and treated with triphenylphosphine (0.78 g, 3
mmol), 3-bromopropanol (0.28 mL, 4 mmol), and diisopropyl
azodicarboxylate (0.6 mL, 3 mmol), warmed to 22.degree. C. and
stirred for 2 h. The reaction mixture was concentrated and the
residue purified by flash chromatography (5-50% ethyl
acetate/hexanes) provided
1-(3-bromopropyl)-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.55 g) as a tan powder:
[1111] HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1112] HRMS: calcd for C16H16BrFN2O2S+Na+, 420.99920; found (ESI,
[M+Na]+), 420.9995.
[1113] Step 2: A solution of
1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.15 g) in an 8 M methylamine-ethanol solution was
heated to 70.degree. C. for 16 h. The reaction mixture was
concentrated, and flash chromatography (0-10% 8 M
NH-methanol/dichloromethane) provided the free purified free base,
which was dissolved in methanol (10 mL) and treated with 2 M
HCl-ether and concentrated to provide
3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylpropan-1-amine (0.16 g) as a white solid: HPLC purity
97.5% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85115-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min.
[1114] HRMS: calcd for C17H20FN3O2S+H+, 350.13330; found (ESI,
[M+H]+ Obs'd), 350.1341
Example 109
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine
##STR00130##
[1116] Step 1: In an analogous manner to General Procedure A, step
2, a solution of
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.65 g, 2.2 mmol) in tetrahydrofuran (10 mL) was
cooled to 0.degree. C., treated with triphenylphosphine (0.87 g,
3.3 mmol), 3-bromo-1-propanol (0.39 mL, 4.5 mmol) were added
followed by diisopropylazodicarboxylate (0.65 mL, 3.3 mmol) to
provide
1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.82 g, 92%) as a brown oil:
[1117] HPLC purity 98.2% at 210-370 nm, 10.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1118] HRMS: calcd for C15H13BrF2N2O2S, 401.98491; found (EI, M+),
401.9842;
[1119] Step 2:
1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.2, 0.5 mmol) was dissolved in an 8 M solution of
methylamine in ethanol (8 mL, 64 mmol) and was stirred in a capped
vial at room temperature for 2 h. The reaction mixture was
evaporated and the residue purified by flash chromatography
(SiO.sub.2, 0-5% 7 M NH.sub.3-methanol/dichloromethane). The
purified free-base was dissolved in dichloromethane (3 mL) and
treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl
ether), resulting in a white precipitate that was evaporated and
dried under vacuum to provide
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine (0.177 g, 78%) as a white solid:
[1120] HPLC purity 98.6% at 210-370 nm, 7.4 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1121] HRMS: calcd for C16H17F2N3O2S+H+, 354.10823; found (ESI,
[M+H]+ Obs'd), 354.1086;
[1122] HRMS: calcd for C16H17F2N3O2S+H+, 354.10823; found (ESI,
[M+H]+ Calc'd), 354.1082;
Example 110
4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylbutan-1-amine
##STR00131##
[1124] Step 1: A solution of
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.45 g, 1.6 mmol) in dimethylformamide (10 mL) was
treated with 1,4-dibromobutane (1 mL, 8.4 mmol) and cesium
carbonate (0.52 g, 1.6 mmol). The reaction mixture stirred at
ambient for 72 h. The reaction mixture was diluted with ethyl ether
(50 mL) and washed with H.sub.2O (2.times.20 mL), the organic layer
was isolated, dried with MgSO.sub.4 and evaporated. The crude
reaction product was purified by flash chromatography (SiO.sub.2,
3-50% ethyl acetate/hexane) to provided
1-(4-bromobutyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (0.64 g, 95%) as a brown oil:
[1125] HPLC purity 87.0% at 210-370 nm, 10.9 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1126] Step 2: In an analogous manner as Example 109, step 2,
1-(4-bromobutyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (0.21 g, 0.5 mmol) was dissolved in an 8 M solution
of methylamine in ethanol (5 mL, 40 mmol) to provide
4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbutan-1-amine (0.16 g, 83%) as a white solid:
[1127] HPLC purity 93.5% at 210-370 nm, 7.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1128] HRMS: calcd for C17H19F2N3O2S+H+, 368.12388; found (ESI,
[M+H]+ Obs'd), 368.1239;
Example 111
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(2-
,2,2-trifluoroethyl)propan-1-amine
##STR00132##
[1130] A solution of
1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.12 g, 0.3 mmol) in 2,2,2-trifluoroethylamine (0.5
mL, 6.4 mmol) was heated to 130.degree. C. for 2 h. in a microwave.
The crude reaction product was purified by flash chromatography
(SiO.sub.2, 370% ethyl acetate/hexane) to provide the intended
free-base that was taken up in dichloromethane (5 mL) was treated
with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether),
resulting in a white precipitate that was evaporated and dried
under vacuum to provided
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(-
2,2,2-trifluoroethyl)propan-1-amine (0.11 g, 85%) as a white
solid:
[1131] HPLC purity 96.7% at 210-370 nm, 10.2 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1132] HRMS: calcd for C17H16F5N3O2S+H+, 422.09561; found (ESI,
[M+H]+ Obs'd), 422.0959;
Example 112
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-ethylpropan-1-amine
##STR00133##
[1134] Step 1: In an analogous manner to General Procedure A, step
2, a solution of
1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.74 g, 2.5 mmol) in tetrahydrofuran (10 mL) was
cooled to 0.degree. C., treated with triphenylphosphine (0.97 g,
3.7 mmol), 3-bromo-1-propanol (0.42 mL, 4.9 mmol) were added
followed by diisopropylazodicarboxylate (0.72 mL, 3.7 mmol) to
provide
1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide (0.71 g, 69%) as a brown oil:
[1135] HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1136] Step 2: In an analogous manner as Example 109, step 2,
1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide (0.2 g, 0.48 mmol) was dissolved in an 2 M
solution of ethylamine in methanol (10 mL, 20 mmol) to provide
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-ethylpropan-1-amine (0.13 g 73%) as a white solid:
[1137] HPLC purity 88.2% at 210-370 nm, 7.6 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1138] HRMS: calcd for C17H18F3N3O2S+H+, 386.11446; found (ESI,
[M+H]+ Obs'd), 386.1153;
Example 113
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylpropan-1-amine
##STR00134##
[1140] In an analogous manner as Example 109, step 2,
1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide (0.2 g, 0.48 mmol) was dissolved in an 8 M
solution of methylamine in ethanol (5 mL, 40 mmol) to provide
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]--
N-methylpropan-1-amine (0.13 g, 88%) as a white solid:
[1141] HPLC purity 97.5% at 210-370 nm, 7.4 min.; Xterra RP18,
3.5u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1142] HRMS: calcd for C16H16F3N3O2S+H+, 372.09881; found (ESI,
[M+H]+ Obs'd), 372.0991;
Example 114
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpropan-1-amine hydrochloride
##STR00135##
[1144] Step 1: A.) 2,4-Difluoroaniline (72 mL, 710 mmol) was
dissolved in tetrahydrofuran (500 mL), cooled to -78.degree. C.,
and 2.5 M n-butyl lithium in hexanes (185 mL, 462 mmol) was added.
The mixture was warmed to -20.degree. C. and stirred for 30
minutes. The mixture was cooled down to -78.degree. C. and
2-fluoronitrobenzene (37.4 mL, 355 mmol) in tetrahydrofuran (50 mL)
was added dropwise. After stored in a freezer for 16 hours, the
mixture was quenched with saturated ammonium chloride (100 mL) and
diluted with ethyl acetate (100 mL). 1N hydrochloric acid (100 mL)
was added to break up the emulsion. The organic layer was
separated, washed with sodium bicarbonate (100 mL), dried over
anhydrous magnesium sulfate, and concentrated to give
2,4-difluoro-N-(2-nitrophenyl)aniline (52.5 g, 59%) as an orange
solid. 2,4-Difluoro-N-(2-nitrophenyl)aniline (10 g, 40 mmol) in
methanol (130 mL) was subjected to hydrogenation (30 psi) in the
presence of 5% Pd/C (200 mg) to give
N-(2,4-difluorophenyl)benzene-1,2-diamine (8.15 g, 93%) as a brown
oil.
[1145] B.) A mixture of N-(2,4-difluorophenyl)benzene-1,2-diamine
(8.15 g, 37 mmol) and sulfamide (4.3 g, 44.4 mmol) in diglyme (20
mL) was added to a solution of sulfamic acid (0.9 g, 9.3 mmol) in
diglyme (20 mL) that had been heated to 190.degree. C. After 20
minutes, the mixture was cooled to room temperature, diluted with
ethyl ether (100 mL) and washed with 2N hydrochloric acid (100 mL).
The organic layer was extracted with 2N sodium hydroxide (100 mL).
The aqueous layer was then washed with ethyl ether (2.times.100
mL), acidified with 6N hydrochloric acid, and extracted with ethyl
ether (2.times.100 mL). The combined ethereal extracts were washed
with brine (100 mL), dried over anhydrous sodium sulfate, and
concentrated. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 0-100% ethyl
acetate/hexane) to afford
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as a white solid (4.6 g, 41%). MS (ES) m/z 280.8
[1146] Step 2: In an analogous manner to general procedure A of
Example 1, step 2,
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.34 g, 1.2 mmol) was treated with triphenylphosphine
(0.37 g, 1.4 mmol), 3-bromopropanol (0.12 mL, 1.4 mmol), and
diisopropylazodicarboxylate (0.27 mL, 1.4 mmol) to provide
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.2 g, 41%) as a brown oil. MS (ES) m/z 338.7.
[1147] Step 3: In an analogous manner to general procedure A of
Example 1, step 3,
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.2 g, 0.5 mmol) was treated with 8N
methylamine in methanol to give
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpropan-1-amine. The free base was converted to the title
compounds as hydrochloride salt as a light blue solid (0.087 g,
46%). MS (ES) m/z 354.3 ([M+H].sup.+). HRMS: calcd for
C.sub.16H.sub.17F.sub.2N.sub.3O.sub.2S+H.sup.+, 354.10823; found
(ESI, [M+H].sup.+), 354.1073. HPLC retention time: 6.9 min.
Example 115
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thylpentan-1-amine hydrochloride
##STR00136##
[1149] Step 1: In an analogous manner to example 18, step 1,
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (1.3 g, 4.6 mmol) was treated with 1,5-dibromopentane
(2.2 mL, 16.1 mmol) and cesium carbonate (1.5 g, 4.6 mmol) to give
1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (1.2 g, 60%) as a white amorphous solid. MS (ES) m/z
366.7 [M+H-SO.sub.2].sup.+.
[1150] Step 2: In an analogous manner to example 18, step 2,
1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.5 g, 1.2 mmol) was treated with 8N methylamine in
methanol to give
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylpentan-1-amine which was treated with 1N hydrochloric acid in
ether to afford its hydrochloride salt as a white solid (0.31 g,
64%). MS (ES) m/z 382.4 ([M+H].sup.+). HRMS: calcd for
C.sub.18H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 382.13953; found
(ESI, [M+H].sup.+), 382.1412. HPLC retention time: 7.5 min.
Example 116
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]penta-
n-1-amine hydrochloride
##STR00137##
[1152] Step 1: In an analogous manner to example 18, step 2,
1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.29 g, 0.67 mmol) was treated with 7N ammonium in
methanol to give
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pent-
an-1-amine which was treated with 1N hydrochloric acid in ether to
give its hydrochloride salt as a white solid (0.06 g, 20%). MS (ES)
m/z 367.9 ([M+H].sup.+). HPLC retention time: 7.6 min.
Example 117
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N--
dimethylpentan-1-amine hydrochloride
##STR00138##
[1154] Step 1: In an analogous manner to example 18, step 2,
1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.29 g, 0.67 mmol) was treated with 33%
dimethylamine in ethanol to give
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpentan-1-amine which was treated with 1N hydrochloric acid
in ether to give its hydrochloride salt as a white solid (0.09 g,
31%). MS (ES) m/z 395.9 ([M+H].sup.+). HPLC retention time: 7.6
min.
Example 118
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N--
dimethylpropan-1-amine hydrochloride
##STR00139##
[1156] Step 1: In an analogous manner to general procedure A, step
3,
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.45 g, 1.1 mmol) was treated with 33%
dimethylamine in ethanol to give
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylpropan-1-amine which was treated with 1N hydrochloric acid
in ether to give its hydrochloride salt as a white solid (0.309 g,
69%). MS (ES) m/z 367.8 ([M+H].sup.+). HPLC retention time: 7.0
min.
Example 119
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-et-
hylpropan-1-amine hydrochloride
##STR00140##
[1158] Step 1: In an analogous manner to general procedure A, step
3,
1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.45 g, 1.1 mmol) was treated with 2M ethylamine in
ethanol to give
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-e-
thylpropan-1-amine which was treated with 1N hydrochloric acid in
ether to give its hydrochloride salt as a white solid (0.332 g,
81%). MS (ES) m/z 367.9;
[1159] HPLC retention time: 7.2 min.
Example 120
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N--
dimethylbutan-1-amine hydrochloride
##STR00141##
[1161] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (example NNN) and dimethyl amine and was converted to
its HCl salt as a white solid. MS (ES) m/z 382.3; HRMS: calcd for
C.sub.18H.sub.21F.sub.2N.sub.3O.sub.2S+H+, 382.13953; found (ESI,
[M+H]+ Obs'd), 382.1395. HPLC retention time: 7.2 min.
Example 121
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-et-
hylbutan-1-amine hydrochloride
##STR00142##
[1163] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (example NNN) and ethyl amine and was converted to
its HCl salt as a white solid. MS (ES) m/z 381.8; HRMS: calcd for
C.sub.18H.sub.21F.sub.2N.sub.3O.sub.2S+H+, 382.13953; found (ESI,
[M+H]+ Obs'd), 382.1402. HPLC retention time: 7.5 min.
Example 122
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-et-
hylbutan-1-amine hydrochloride
##STR00143##
[1165] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide and ethyl amine and was converted to its HCl salt as
a white solid. MS (ES) m/z 381.9; HPLC retention time: 7.1 min.
Example 123
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-is-
opropylbutan-1-amine hydrochloride
##STR00144##
[1167] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide and isopropyl amine and was converted to its HCl salt
as a white solid. MS (ES) m/z 395.9. HPLC retention time: 7.4
min.
Example 124
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]bu-
tyl}cyclobutanamine hydrochloride
##STR00145##
[1169] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide and cyclobutyl amine and was converted its HCl salt
as a white solid. MS (ES) m/z 407.9. HPLC retention time: 7.6
min.
Example 125
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-yl]buty-
l}cyclohexanamine hydrochloride
##STR00146##
[1171] In an analogous manner to Example 45, step 5, the title
compound was prepared from
1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide and cyclohexanyl amine and was converted to its HCl
salt as a white solid. MS (ES) m/z 436.0. HPLC retention time: 8.3
min.
Example 126
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-et-
hylpropan-1-amine hydrochloride
##STR00147##
[1173] In an analogous manner to Example 45, Step 5, the title
compound was prepared from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) and ethyl amine and converted
to its HCl salt as a white solid. MS (ES) m/z 367.9. HPLC retention
time: 6.8 min.
Example 127
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-is-
opropylpropan-1-amine hydrochloride
##STR00148##
[1175] In an analogous manner to Example 45, Step 5, the title
compound was prepared from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) and isopropyl amine and
converted to its HCl salt as a white solid. (ES) m/z 382.1. HPLC
retention time: 7.1 min.
Example 128
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclobutanamine hydrochloride
##STR00149##
[1177] In an analogous manner to Example 45, Step 5, the title
compound was prepared from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) and cyclobutyl amine and
converted to its HCl salt as a white solid. (ES) m/z 394.1. HPLC
retention time: 7.3 min.
Example 129
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclopentanamine hydrochloride
##STR00150##
[1179] In an analogous manner to Example 45, Step 5, the title
compound was prepared from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) and cyclopentyl amine and
converted to its HCl salt as a white solid. (ES) m/z 408.2. HPLC
retention time: 7.6 min.
Example 130
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pr-
opyl}cyclohexanamine hydrochloride
##STR00151##
[1181] In an analogous manner to Example 45, Step 5, the title
compound was prepared from
1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (Example 45, step 4) and cyclohexanyl amine and
converted to its HCl salt as a white solid. (ES) m/z 422.2. HPLC
retention time: 8.1 min.
Example 131
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl-
}piperidin-4-amine dihydrochloride
##STR00152##
[1183] Step 1: In an analogous manner to General Procedure A, step
3,
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.61 g, 1.56 mmol) was treated with 430 mg (3.1 mmol)
of potassium carbonate and 0.32 g (1.56 mol) tert-butyl
4-aminopiperidine-1-carboxylate to provide tert butyl
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine carbonate (0.16 g).
[1184] Step 2: In an analogous manner to General Procedure C, step
5,
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine dihydrochloride was prepared from tert butyl
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine carbonate (0.12 g). HPLC purity 97.4% at
210-370 nm, 5.5 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min. HRMS: calcd for
C.sub.20H.sub.25FN.sub.4O.sub.2S+H+, 405.17550; found (ESI, [M+H]+
Obs'd), 405.1768.
Example 132
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-
-4-amine dihydrochloride
##STR00153##
[1186] Step 1: In an analogous manner to General Procedure A, step
3, 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.34 g, 0.92 mmol) was treated with 255 mg (1.85 mmol)
of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl
4-aminopiperidine-1-carboxylate to afford tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperid-
in-4-amine)carbamate (0.18 g).
[1187] Step 2: In an analogous manner to General Procedure C, step
5,
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine dihydrochloride was prepared from tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperid-
in-4-amine)carbamate (0.12 g). MS (ES) m/z 386.8; HPLC purity
100.0% at 210-370 nm, 5.7 min.; Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min. HRMS: calcd for C20H26N4O2S+H+, 387.18492;
found (ESI, [M+H]+ Obs'd), 387.1849.
Example 133
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-
piperidin-4-amine dihydrochloride
##STR00154##
[1189] Step 1: In an analogous manner to General Procedure A, step
3, tert butyl
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethyl}piperidin-4-amine carbonate was prepared from
1-(3-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl 4-aminopiperidine-1-carboxylate.
[1190] Step 2: In an analogous manner to General Procedure C, step
5,
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine dihydrochloride was prepared from tert butyl
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine carbonate. MS (ES) m/z 390.8; HPLC purity 64.0%
at 210-370 nm, 5.3 min., Xterra RP18, 3.5u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min. HRMS: calcd for C19H23FN4O2S+H+, 391.15985;
found (ESI, [M+H]+ Obs'd), 391.1598.
Example 134
N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin--
4-amine dihydrochloride
##STR00155##
[1192] Step 1: In an analogous manner to General Procedure A, step
3, tert butyl
N-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}pip-
eridin-4-amine carbonate was prepared from
1-(3-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl 4-aminopiperidine-1-carboxylate.
[1193] Step 2: In an analogous manner to General Procedure C, step
5,
N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-
-4-amine dihydrochloride was prepared from tert butyl
N-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-
-4-amine carbonate. MS (ES) m/z 372.8; HPLC purity 93.4% at 210-370
nm, 5.3 min.; Xterra RP18, 3.5u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min,
hold 4 min. HRMS: calcd for C19H24N4O2S+H+, 373.16927; found (ESI,
[M+H]+ Obs'd), 373.1696.
Example 135
2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}amino)ethanol
##STR00156##
[1195]
1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide (100 mg, 0.260 mmol) was stirred in neat
ethanolamine (25 mL) at room temperature in a sealed vial for 18
hr. The reaction was transferred to a separatory funnel with
diethyl ether and washed with water, brine, dried (MgSO.sub.4),
filtered, and the solvent removed in vacuo. The material was
purified by Gilson RP-HPLC (YMC CombiPrep ProC18 50.times.20 mm
I.D. column, S-5 .mu.m, 12 nm. Flow rate 20 mL/min. Gradient: 10/90
Acetonitrile/Water to 100% acetonitrile over 10 minutes then hold
for three minutes at 100% acetonitrile and ramp back to 10/90
acetonitrile/water over two minutes). This material was dissolved
in diethyl ether and methanol and 4N HCl in dioxane was added to
give a red solid (12 mg, 12% Yield) as the mono-HCl salt.
[1196] HRMS: calcd for
[1197] HPLC purity 100% at 210-370 nm, 6.6 min.; Xterra RP18, 3.5u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1198] hNET Assay Procedure Protocol A: Inhibition of [.sup.3H] NE
Uptake into Cloned Human NE Transporters (MDCK Cells) ("hNET
uptake")
[1199] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
Materials and Methods:
Cell Line and Culture Reagents:
[1200] [.sup.3H] NE uptake studies were performed using MDCK cells
stably expressing human norepinephrine transporter (hNET) (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) cultured in growth medium
containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS
(dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI)
and 500 .mu.g/ml G418 (Gibco, Cat. No. 10131). Cells were seeded at
300,000/T75 flask, and split twice weekly.
Norepinephrine Uptake Assays:
[1201] All uptake experiments were performed in 96-well plates
(Falcon Optilux, cat #353947) in a total volume of 250 .mu.l/well.
MDCK cells were plated at 50,000 cells/well. At the time of the
assay, the media was removed, and 200 .mu.l assay buffer (25 mM
Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl.sub.2, 1.2 mM
MgSO.sub.4.7H.sub.2O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1
.mu.M pargyline, pH 7.4) was added to each well. 25 .mu.l of each
test compound was subsequently added to plates in triplicate and
incubated at 37.degree. C. for 5 minutes. All test compounds were
dissolved in 100% DMSO and diluted in 4% DMSO/H.sub.2O, and assayed
using a 7-point dose response curve (1 nM-10 .mu.M). Next, 25 .mu.l
of [.sup.3H] NE (74.9 Ci/mmol, Perkin Elmer, Boston, Mass.) was
added to all wells and incubated at 37.degree. C. for an additional
5 minutes. Non-specific uptake was defined by 20 .mu.M desipramine.
The final concentrations of [.sup.3H] NE was 16 nM, respectively.
The reaction was terminated by aspiration and washed with ice cold
50 mM Tris (pH 7.4). The plates were left to air dry for roughly 30
min, and MDCK cells were lysed by the addition of 25 .mu.l of 0.25
M NaOH. 100 .mu.l of Microscint-20 were added to each well
(Packard, Perkin Elmer, Boston, Mass.), and the plates were counted
using a TopCount (Perkin Elmer, Downer's Grove, Ill.) liquid
scintillation counter.
Analysis of Results:
[1202] % Inhibition of uptake=((mean cpm control wells-each cpm
drug well)/(mean cpm control wells-non-specific
wells).times.100.
[1203] IC.sub.50 values were calculated using a Prism.RTM.
nonlinear regression program where % inhibition is plotted versus
concentration of inhibitor.
[1204] See: Pacholczyk T, Blakely R D and Amara S G (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature. 350:350-354.
[1205] See also: Ramamoorthy J D, Ramamoorthy S, Papapetropoulos A,
Catravas J D, Leibach F H and Ganaphthy V (1995) Cyclic
AMP-independent up-regulation of the human serotonin transporter by
staurosporine in choriocarcinoma cells. Journal of Biological
Chemistry. 270:17189-17195, the contents of which is hereby
incorporated by reference.
[1206] hNET Assay Procedure Protocol B: Cell Based Norepinephrine
(NE) Reuptake Assay Using the Recombinant Human Norepinephrine
Transporter (hNET) ("hNET Uptake")
[1207] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
Materials and Methods:
Compounds:
[1208] For screening, hydrochloride salts of compounds were
dissolved in solution and 25 .mu.l aliquots of compound solution at
a 1 .mu.M or 10 .mu.M final concentration delivered directly to
cells. For IC.sub.50 determinations, stock compounds were prepared
at 10 mM from powder. The stock solution was diluted according to
compound testing range. Typically, the compound testing range was
from 6 nM to 6 .mu.M by half log dilutions. On the day of assay, 25
.mu.l of compound solution at the specified concentrations was
added to the plates containing cells. A DMSO stock of desipramine
was prepared at 10 mM in DMSO and diluted for a final concentration
of 20 .mu.M to determine the non-specific reuptake. The radioligand
in this assay is .sup.3H-norepinephrine (NE) (PerkinElmer; NET678;
40-80 Ci/mmol) was delivered at approximately 16 nM final
concentration for both single point testing and compound IC.sub.50
determinations.
Tissue Culture Conditions:
[1209] MDCK-Net6 cells, stably transfected with human hNET (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) was maintained in growth media
[high glucose DMEM (Gibco Cat. 11995), 10% FBS (dialyzed,
heat-inactivated, Sigma, dialysed, heat inactivated, Lot# K0922 or
equivalent) 1.times. Pen/Strep, and 500 .mu.g/ml G418 (Gibco Cat.
10131)]. Cells were plated at 300,000/T75 flask and cells were
split twice weekly.
Functional Reuptake Assay:
[1210] Cells were plated at 3,000 cells/well on day 1 in BD Falcon
Microtest 96-well sterile cell culture plates, Optilux White/Clear
Bottom TC plate (VWR; # 62406-466 or equivalent) in growth media
and maintained in a cell incubator (37.degree. C., 5% CO.sub.2). On
Day 2, cells were removed from the cell incubator and the growth
media is replaced by 200 .mu.l of assay buffer (25 mm HEPES 120 mM
NaCL; 5 mM KCl; 2.5 mM CaCl.sub.2; 1.2 mM MgSO.sub.4; 2 mg/ml
glucose (pH 7.4, 37.degree. C.)) containing 0.2 mg/ml ascorbic acid
and 1 .mu.M parglyine. For screening, 25 .mu.l of compound in 4%
DMSO is added directly to each well and the plate is incubated for
5 min (37.degree. C.). To initiate the norepinephrine reuptake, 16
nM (final concentration) of .sup.3H norepinephrine (specific
activity; 40-80 Ci/mmol) in assay buffer was delivered in 25 .mu.l
aliquots to each well, and the plates were incubated for 5 min at
37.degree. C. The reaction was aspirated from the plate and the
cells washed with 250 .mu.l of 50 mM Tris Buffer (4.degree. C.).
The plates were left to dry for 1 hour. The cells were lysed using
0.25 M NaOH solution then placed on a shake table and vigorously
shaken for 10 min. After cell lysis, 100 .mu.l of Microscint 20
(PerkinElmer; #87-051101) was added to the plates and the plates
were sealed with film tape and replaced on the shake table for a
minimum of 10 min. The plates were counted in a TopCount counter
(PerkinElmer).
Analysis of Results:
[1211] For screening single point determinations, each compound
plate contained at least 3 control wells (maximum NE reuptake
determinant) and 3 non-specific wells determined by adding 20 .mu.M
of desipramine (minimum NE reuptake determinant). Determination of
active compounds were calculated using a Microsoft Excel spread
sheet applying the following formula:
% inhibition = [ 1 - ( ( mean cpm test compound wells - mean cpm
non - specific wells ) ( mean cpm control wells - mean cpm non -
specific wells ) ) ] .times. 100 ##EQU00001##
[1212] For IC.sub.50 determination, raw cpm values were generated
in a data file from the TopCount counter. The data was organized
Microsoft Excel and transferred into PRIZM graphing and statistical
program, which calculated the estimated IC.sub.50 value.
Calculation of IC.sub.50 values was made using non-linear
regression analysis with a sigmoidal dose response with variable
slope. The statistical program used wells containing .sup.3H
norepinephrine only as the maximal NE reuptake determinant and
wells containing .sup.3H norepinephrine plus 20 .mu.M desipramine
as the minimal NE reuptake determinant (non-specific determinant).
Estimation of the IC.sub.50 value is completed on a log scale and
the line is fit between the maximal and minimal NE reuptake values.
In the event that the highest test concentration does not exceed
50% reuptake inhibition, data will be reported as percent maximal
NE reuptake at the highest concentration tested.
[1213] See: Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature, 350, 350-354, the contents of
which is hereby incorporated by reference.
[1214] Results are shown in the following table:
TABLE-US-00003 NE uptake (Protocol A) NE uptake (Protocol B)
Example IC.sub.50 (nM) IC.sub.50 (nM) 1 20.5 2 2529 3 4217 4 37%
inh. @ 2 uM 5 2.63 6 6.87 7 1775 8 35.7 9 12.6 10 40.2 11 1.3 12
12.2 13 534 14 2620 15 96.2 16 7.06 17 10.8 18 0.3 19 1130 20 478
21 5889 22 27% inh. @ 2 uM 23 28% inh. @ 2 uM 24 60.9 25 146 26
57.1 27 11.7 28 1899 29 434 30 15.3 31 23.6 32 192 33 282 34 85 35
20.6 36 11.3 37 2364 38 13.9 39 29.3 40 252 41 2.41 42 86.3 43 1320
44 4.26 45 0.116 46 4.84 47 2.73 48 2.78 49 147 50 190 51 3174 52
2.74 53 24.5 54 3% inh. @ 2 uM 55 15% inh. @ 2 uM 56 13.1 57 2.56
58 3273 59 0.4 60 40.2 61 113 62 50.9 63 324 64 295 65 14.1 66 14.2
67 298 68 84.1 69 10.4 70 277 71 206 72 259 73 2.81 74 2.7 75 4.17
76 5.24 77 15 78 45 79 9 80 448 81 19 82 46 83 2 84 21 85 203 86 21
87 82 88 57% inhibition @ 6 uM 89 2109 90 49% inhibition @ 6 uM 91
325 92 3 93 3 94 4 95 30 96 113 97 21 98 36 99 22 100 370 101 1158
102 26 103 1202 104 26 105 125 106 591 107 582 108 4 109 20 110 39
111 0% @ 6 uM 112 2770 113 109 114 11 115 61 116 binding IC50 679.1
nM* 117 7195 118 153 119 77 120 411 121 1503 122 48 123 1173 124
132 125 440 126 15 127 148 128 222 129 195 130 224 131 365 132 267
133 45 134 67 135 43 *For hNET binding performed according to: P.
E. Mahaney et al. Bioorg. Med. Chem. 14 (2006) 8455-8466, the
contents of which is hereby incorporated by reference in its
entirety.
Rat Liver Microsomal Stability Assay:
[1215] DMSO stock solutions of test compounds were prepared at 0.5
mM concentration. Diluted solutions of test compounds were prepared
by adding 50 uL of each DMSO stock solution to 200 uL of
acetonitrile to make 0.1 mM solutions in 20% DMSO/80% acetonitrile.
Rat liver microsomal solution was prepared by adding 1.582 mL of
concentrated rat liver microsomes (20 mg/mL protein concentration)
to 48.291 mL of pre-warmed (to 37.degree. C.) 0.1M potassium
phosphate buffer (pH 7.4) containing 127 uL of 0.5 M EDTA to make a
0.6329 mg/mL (protein) microsomal solution. 11.2 uL of each test
compound diluted solution was each added directly to 885 uL of rat
liver microsomal solution (allowing direct binding of drugs to
microsomal proteins and lipids to minimize precipitation and
non-specific binding to the plasticware). This solution was mixed
and 180 uL was transferred to "Time 0" and "Time 15 min" plates
(each in duplicate wells). For the Time 15 min plate, NADPH
regenerating agent (45 uL) was added to each well to initiate the
reaction, the plate was incubated at 37.degree. C. for 15 min,
followed by quenching of the reaction by adding 450 uL of cold
acetonitrile to each well. For the Time 0 plate, 450 uL of cold
acetonitrile was added to each well, followed by addition of NADPH
regenerating agent (45 uL) and no incubation. All of the plates
were centrifuged at 3000 rpm for 15 min and the supernatants were
transferred to other well plates for analysis by LC-MS.
Dopamine Transporter (hDAT) Membrane Binding Assay
[1216] The method for this radioligand binding assay was modified
from the methods supplied with hDAT membranes (catalog number
RBHDATM; Perkin Elmer Life Analytical Sciences), and those
modifications are listed within this method section. Frozen
membrane samples from a cell line that expresses hDAT were diluted
to 7.5 ml in binding buffer (50 mM Tris-HCl; pH 7.4, 100 mM NaCl),
homogenized with a tissue-tearer (Polytron PT 120.degree. C.,
Kinematica AG) and delivered at a volume of 75 .mu.l to each well
of a polypropylene 96-well plate. The binding reaction was run in
polypropylene 96-well plates (Costar General Assay Plate, Cat. No.
3359; Lid, Cat. No. 3930). A stock solution of mazindol was
prepared in DMSO (10 mM) and delivered to triplicate wells
containing membrane for a final test concentration of 10 uM.
Mazindol is a DA transporter inhibitor with a 50% inhibitory
concentration (IC.sub.50) value of 18.0.+-.6.0 nM in the present
assays. Data from wells containing mazindol (10 uM) were used to
define non-specific (NSB) hDAT binding (minimum hDAT binding).
Total binding is defined by addition of 5 .mu.l of binding buffer
alone in the presence of [.sup.3H] WIN-35,428. Stock solutions of
compounds to be tested were prepared in DMSO at concentrations of
10 mM to 10 uM. On the day of assay, test compounds were diluted in
assay buffer according to test range (100,000 to 10 nM) ensuring a
maximal DMSO concentration of less than 0.5% in the assay reaction
wells. Homogenized membranes were pre-incubated with test compounds
for 20 min at 4.degree. C. before the initiation of the binding
reaction. The binding reaction is initiated by addition of 25 .mu.l
of .sup.3-[H]-WIN 35,428 diluted in binding buffer. The final
concentration of .sup.3-[H]-WIN 35,428 delivered was 10 nM. The
K.sub.D value estimated for .sup.3-[H]-WIN-35,428 in hDAT membranes
(Lot#296-083-A) was 6.9 nM. The radioligand concentration, [L],
used in the competition binding assays is a factor difference of
1.4 compared to the K.sub.D value and was used to calculate the
K.sub.i value. The plate containing the radioligand binding
reactions were incubated for 2 h at 4.degree. C. on a shaking table
(Bellco, Vineland, N.J.) at 3 revolutions per minute. The
MultiScreen-FB opaque 96-well filtration plates contained Millipore
glass fiber filters (Millipore glass fiber B, Cat. No. MAFBN0B)
were used to terminate the binding reactions and to separate bound
from free radioligand. The plates were presoaked with 0.5%
polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a
minimum of two hours at room temperature to reduce nonspecific
binding of .sup.3-[H]-WIN 35,428 during the harvest procedure.
Before harvesting the reaction plates, the PEI solution is
aspirated from the filter plates using a vacuum manifold. Aliquots
of each reaction (90 .mu.l of each 100 .mu.l reaction well) were
transferred from the reaction plates to the filter plates using a
Zymark Rapid Plate-96 automated pipette station. The binding
reaction is terminated by vacuum filtration through the glass fiber
filters. The filter plates were aspirated at 5-10 inches of Hg, and
the wells are washed 9 times with 200 .mu.l wash buffer (50 mM
Tris-HCl, 0.9% NaCl, pH 7.4; 4.degree. C.) using a 12 channel
aspiration/wash system. Plastic bottom supports are removed from
the filter plates and the plates are placed in plastic liners. A
100 .mu.l aliquot of scintillation fluid was added to each well and
the top of each plate is sealed with adhesive film. The plates are
vigorously shaken at 5 rpm for 10-15 minutes to ensure adequate
equilibration of aqueous to solvent partitioning. The collection of
raw counts per minute (cpm) data was done using a Wallac Microbeta
counter (Perkin Elmer).
Evaluation of Results
[1217] For each experiment, a data stream of cpm values collected
from the Wallac Microbeta counter was downloaded to a Microsoft
Excel statistical application program. Calculations of IC.sub.50
values were made using the transformed-both-sides logistic dose
response program that uses mean cpm values from wells representing
maximum binding (total)(assay buffer) and mean cpm values from
wells representing minimum binding (NSB, 10 .mu.M mazindol).
Estimation of the IC.sub.50 values was completed on a log scale and
the line was fit between the maximum and minimum binding values.
The K.sub.i value is a function of the concentration of the
compound required to inhibit 50% of the radioligand (IC.sub.50
value) divided by the free radioligand concentration [L] divided by
the K.sub.D value plus one (K.sub.i=IC.sub.50/(1+[L]/K.sub.D)). The
K.sub.i value for these studies was determined by dividing the
IC.sub.50 value by a factor of 2.4 to account for the concentration
of .sup.3-[H]-WIN 35,428 used in the assay.
[1218] Results are shown in the following table:
TABLE-US-00004 hNET hDAT RLM Function Binding stability Structure
IC50 IC50 t1/2 CHEMISTRY (nM) (nM) (min) ##STR00157## 2.6 598.0 2.0
##STR00158## 0.3 211.0 2.0 ##STR00159## 3.6 686.0 3.0 ##STR00160##
0.7 512.4 1.0 ##STR00161## 9.0 5260.1 2.0 ##STR00162## 2.3 9333 1
##STR00163## 19.8 121.7 18.0 ##STR00164## 2.7 479.0 2.0
##STR00165## 11.3 365.6 10.0 ##STR00166## 8.4 449.0 11.0
##STR00167## 46.1 52.8 19 ##STR00168## 7.06 276.4 <1
##STR00169## 10.8 178 2 ##STR00170## 2.56 665 1
[1219] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[1220] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in its entirety.
[1221] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *