U.S. patent application number 12/483429 was filed with the patent office on 2009-10-01 for bissulfonamide compounds as agonists of galr1, compositions, and methods of use.
Invention is credited to Robert C. Andrews, Muralidhar Bondlela, Stephen Davis, Bapu Gaddam, Ramesh Gopalaswamy, Adnan M.M. Mjalli, Mohan Rao, Tan Ren, Suvi Simila.
Application Number | 20090247536 12/483429 |
Document ID | / |
Family ID | 36002808 |
Filed Date | 2009-10-01 |
United States Patent
Application |
20090247536 |
Kind Code |
A1 |
Mjalli; Adnan M.M. ; et
al. |
October 1, 2009 |
Bissulfonamide Compounds As Agonists Of GalR1, Compositions, And
Methods Of Use
Abstract
Embodiments of the present invention provide bissulfonamide
compounds that are agonists of GalR1. The present invention further
provides compositions comprising bissulfonamide compounds that are
agonists of GalR1, and methods of use of such compounds and
compositions.
Inventors: |
Mjalli; Adnan M.M.; (Oak
Ridge, NC) ; Gaddam; Bapu; (Greensboro, NC) ;
Rao; Mohan; (Greensboro, NC) ; Bondlela;
Muralidhar; (Greensboro, NC) ; Gopalaswamy;
Ramesh; (Jamestown, NC) ; Andrews; Robert C.;
(Jamestown, NC) ; Davis; Stephen; (Durham, NC)
; Simila; Suvi; (Austin, TX) ; Ren; Tan;
(High Point, NC) |
Correspondence
Address: |
KILPATRICK STOCKTON LLP - 41305;CHARLES CALKINS
1001 WEST FOURTH STREET
WINSTON-SALEM
NC
27101
US
|
Family ID: |
36002808 |
Appl. No.: |
12/483429 |
Filed: |
June 12, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11255000 |
Oct 20, 2005 |
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12483429 |
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60620699 |
Oct 21, 2004 |
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60670752 |
Apr 13, 2005 |
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Current U.S.
Class: |
514/252.13 ;
514/399; 514/443 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 3/04 20180101; A61P 9/12 20180101; A61P 25/02 20180101; A61P
25/24 20180101; A61P 19/00 20180101; A61P 25/08 20180101; C07D
333/62 20130101; A61P 43/00 20180101; A61P 1/12 20180101; A61P 3/10
20180101; C07C 311/29 20130101; A61P 25/04 20180101; C07D 409/12
20130101; A61P 25/00 20180101; C07D 413/04 20130101; C07D 213/42
20130101; C07D 307/82 20130101; C07D 495/04 20130101; C07D 233/54
20130101; C07D 333/34 20130101; A61P 3/06 20180101; A61P 25/36
20180101; A61P 29/00 20180101; A61P 25/20 20180101; A61P 25/18
20180101; C07D 413/12 20130101; A61P 1/00 20180101; A61P 25/22
20180101 |
Class at
Publication: |
514/252.13 ;
514/443; 514/399 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61K 31/381 20060101 A61K031/381; A61K 31/4164
20060101 A61K031/4164; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method comprising administering to a subject a pharmaceutical
composition comprising a compound of Formula (I)
Ar.sub.2--SO.sub.2NH--Ar.sub.1--NHSO.sub.2--Ar.sub.3 (I) wherein
Ar.sub.1 is selected from the group consisting of an arylene,
heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene,
fused cycloalkylheteroarylene and fused heterocyclylheteroarylene
group optionally substituted 1 to 4 times, wherein the substituents
of Ar.sub.1 are selected from the group consisting of: a)
-hydrogen; b) -halo; c) -cyano; d) -nitro; e) -perhaloalkyl; f)
-alkyl; g) -aryl; h) -heteroaryl; i) -cycloalkyl; j) -L-aryl; k)
-L-arylene-aryl; l) -L-arylene-alkyl; m) -Q-alkyl; n) -Q-aryl; o)
-Q-alkylene-aryl; p) -Q-arylene-alkyl; q) -L-Q-alkylene-aryl; r)
-arylene-Q-alkyl; s) -L-Q-alkyl; t) -L-Q-aryl; u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl; w) -L-Q-arylene-alkyl; x)
-D.sub.4-alkylene-NR.sub.1R.sub.2; y) -D.sub.4-NR.sub.1R.sub.2; z)
-D.sub.4-alkyl; and aa) -D.sub.4-H; wherein D.sub.4 is selected
from the group consisting of a direct bond, --CH.sub.2--, --O--,
--N(R.sub.4)--, --C(O)--, --CON(R.sub.4)--, --N(R.sub.4)C(O)--,
--N(R.sub.4)CON(R.sub.4')--, --N(R.sub.4)C(O)O--,
--OC(O)N(R.sub.4)--, --N(R.sub.4)SO.sub.2--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.4)SO.sub.2N(R.sub.4)-- and --N.dbd.N--;
wherein R.sub.4 and R.sub.4' are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and
-alkylene-aryl; R.sub.1 and R.sub.2 are independently selected from
the group consisting of hydrogen, alkyl and aryl, wherein R.sub.1
and R.sub.2 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the sum of the values
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.31)--,
--N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)-- and --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 are independently selected from the group consisting
of -hydrogen, -alkyl, -aryl and -alkylene-aryl; L is selected from
the group consisting of a direct bond, -alkylene, -alkenylene and
-alkynylene; and Q is selected from the group consisting of a
direct bond, --CH.sub.2--, --O-- and --S--; Ar.sub.2 and Ar.sub.3
are independently selected from the group consisting of an aryl,
heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at
least one of Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or
sulfur atom vicinal or geminal to the point of attachment to the
--NHSO.sub.2-group, and Ar.sub.2 and Ar.sub.3 may be optionally
substituted 1 to 5 times with a substituent selected from the group
consisting of: a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-alkyl; f) -aryl; g) -cycloalkyl; h) -heterocyclyl; i)
-alkylene-cycloalkyl; j) -perhaloalkyl; k) heteroaryl; l)
-alkylene-aryl; m) -D.sub.1-H; n) -D.sub.1-R.sub.3; o)
-D.sub.1-alkyl; p) -D.sub.1-aryl; q) -D.sub.1-perhaloalkyl; r)
-D.sub.1-alkylene-R.sub.3; s) -D.sub.1-alkylene-aryl; t)
-D.sub.1-alkylene-D.sub.2-R.sub.3; u) -D.sub.1-cycloalkyl; v)
-D.sub.1-heterocyclyl; w) -D.sub.1-aryl; x) -D.sub.1-heteroaryl; y)
-D.sub.1-arylene-D.sub.2-R.sub.3; z)
-D.sub.1-heteroarylene-D.sub.2-R.sub.3; aa)
-D.sub.1-alkylene-heteroaryl; bb) -D.sub.1-alkylene-heterocyclyl;
cc) -D.sub.1-alkylene-aryl; aa)
-D.sub.1-alkylene-arylene-D.sub.2-R.sub.3; bb)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.3; ff)
-D.sub.1-alkylene-NR.sub.5R.sub.6; gg)
-D.sub.1-arylene-NR.sub.5R.sub.6; and hh) -acid isostere; wherein
D.sub.1 is selected from the group consisting of a direct bond,
--CH.sub.2--, --O--, --N(R.sub.7)--, --C(O)--, --CON(R.sub.7)--,
--N(R.sub.7)C(O)--, --N(R.sub.7)CON(R.sub.8)--,
--N(R.sub.7)C(O)O--, --OC(O)N(R.sub.7)--, --N(R.sub.7)SO.sub.2--,
--SO.sub.2N(R.sub.7)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.7)SO.sub.2N(R.sub.8)-- and --N.dbd.N--;
wherein R.sub.7 and R.sub.8 are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl and -alkylene-arylene-alkyl; R.sub.3 is selected
from the group consisting of -hydrogen, -alkyl, -aryl,
-heterocyclyl and -heteroaryl; and R.sub.5 and R.sub.6 are
independently selected from the group consisting of hydrogen, alkyl
and aryl, wherein R.sub.5 and R.sub.6 may be taken together to form
a ring having the formula
--(CH.sub.2).sub.o-Z.sub.1-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.5 and R.sub.6 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the value of the sum of
o and p is less than or equal to 6, Z.sub.1 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.9)--, --N(C(O)R.sub.9)--,
--N(C(O)NHR.sub.9)--, --N(C(O)NR.sub.9R.sub.10)--,
--N(S(O).sub.2NHR.sub.9)--, --N(SO.sub.2R.sub.9)-- and
--N(C(O)OR.sub.9)--; wherein R.sub.9 and R.sub.10 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl and
-alkylene-aryl; D.sub.2 is selected from the group consisting of
-alkylene-, -alkenylene-, -alkylene-S--, --S-alkylene-,
-alkylene-O--, --O-alkylene-, -alkylene-S(O).sub.2--,
--S(O).sub.2-alkylene, --O--, --N(R.sub.11)--, --C(O)--,
--CON(R.sub.11)--, --N(R.sub.11)C(O)--,
--N(R.sub.11)CON(R.sub.12)--, --N(R.sub.1)C(O)O--,
--OC(O)N(R.sub.11)--, --N(R.sub.11)SO.sub.2--,
--SO.sub.2N(R.sub.11)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2-- and --N(R.sub.11)SO.sub.2N(R.sub.12)--, wherein
R.sub.11 and R.sub.12 are independently selected from the group
consisting of -hydrogen, -alkyl and -aryl; and wherein the alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene,
cycloalkylene, heterocyclylene, arylene, and heteroaryl in
Ar.sub.2, Ar.sub.3, R.sub.1 through R.sub.32 may be optionally
substituted 1 to 4 times with a substituent selected from the group
consisting of a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-perhaloalkyl; f) -A-perhaloalkyl g) -A-R.sub.40; h) -A-alkyl; i)
-A-aryl; j) -A-alkylene-aryl; k) -A-alkylene-NR.sub.41R.sub.42; and
l) -A-alkyl-E-R.sub.43; wherein A and E are independently selected
from the group consisting of --CH.sub.2--, --O--, --N(R.sub.44)--,
--C(O)--, --CON(R.sub.44)--, --N(R.sub.44)C(O)--,
--N(R.sub.44)CON(R.sub.45)--, --N(R.sub.44)C(O)O--,
--OC(O)N(R.sub.44)--, --N(R.sub.44)SO.sub.2--,
--SO.sub.2N(R.sub.44)--, --C(O)--O--, --O--C(O)-- and
--N(R.sub.44)SO.sub.2N(R.sub.45)--, wherein R.sub.44 and R.sub.45
are independently selected from the group consisting of -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and
-alkylene-arylene-alkyl; R.sub.40 and R.sub.43 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and
R.sub.41 and R.sub.42 are independently selected from the group
consisting of hydrogen, aryl and alkyl, wherein R.sub.41 and
R.sub.42 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.41 and R.sub.42 are attached, wherein
o and p are, independently, 1, 2, 3, or 4 and the value of the sum
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.46)--, --N(C(O)R.sub.46)--, --N(C(O)NHR.sub.46)--,
--N(C(O)NR.sub.46R.sub.47)--, --N(S(O).sub.2NHR.sub.46)--,
--N(SO.sub.2R.sub.46)-- and --N(C(O)OR.sub.46)--; wherein R.sub.46
and R.sub.47 are independently selected from the group consisting
of hydrogen, aryl, alkyl and -alkylene-aryl; or a pharmaceutically
acceptable salt thereof, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered at a dose
for which an analgesic effect is observed in a subject.
2. The method of claim 1, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, binds to at least one
peripheral GalR1 while substantially unable to cross the
blood-brain barrier in the subject.
3. The method of claim 1, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered at a
dosage level at about or below 1000 mg/kg of the body weight of the
subject.
4. The method of claim 1, wherein the dose is an amount sufficient
to increase activity of GalR1 receptors in the subject.
5. The method of claim 1, wherein the dose is in an amount
sufficient to stimulate peripheral GalR1 receptors in the subject,
wherein the compound is partially or completely excluded from the
brain of the subject.
6. A method comprising administering a pharmaceutical composition
to a subject having a disorder ameliorated by the activation of a
GalR1 receptor, wherein the pharmaceutical composition comprises a
compound of Formula (I)
Ar.sub.2--SO.sub.2NH--Ar.sub.1--NHSO.sub.2--Ar.sub.3 (I) wherein
Ar.sub.1 is selected from the group consisting of an arylene,
heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene,
fused cycloalkylheteroarylene and fused heterocyclylheteroarylene
group optionally substituted 1 to 4 times, wherein the substituents
of Ar.sub.1 are selected from the group consisting of: a)
-hydrogen; b) -halo; c) -cyano; d) -nitro; e) -perhaloalkyl; f)
-alkyl; g) -aryl; h) -heteroaryl; i) -cycloalkyl; j) -L-aryl; k)
-L-arylene-aryl; l) -L-arylene-alkyl; m) -Q-alkyl; n) -Q-aryl; o)
-Q-alkylene-aryl; p) -Q-arylene-alkyl; q) -L-Q-alkylene-aryl; r)
-arylene-Q-alkyl; s) -L-Q-alkyl; t) -L-Q-aryl; u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl; w) -L-Q-arylene-alkyl; x)
-D.sub.4-alkylene-NR.sub.1R.sub.2; y) -D.sub.4-NR.sub.1R.sub.2; z)
-D.sub.4-alkyl; and aa) -D.sub.4-H; wherein D.sub.4 is selected
from the group consisting of a direct bond, --CH.sub.2--, --O--,
--N(R.sub.4)--, --C(O)--, --CON(R.sub.4)--, --N(R.sub.4)C(O)--,
--N(R.sub.4)CON(R.sub.4)--, --N(R.sub.4)C(O)O--,
--OC(O)N(R.sub.4)--, --N(R.sub.4)SO.sub.2--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.4)SO.sub.2N(R.sub.4)-- and --N.dbd.N--;
wherein R.sub.4 and R.sub.4' are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and
-alkylene-aryl; R.sub.1 and R.sub.2 are independently selected from
the group consisting of hydrogen, alkyl and aryl, wherein R.sub.1
and R.sub.2 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the sum of the values
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.31)--,
--N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)-- and --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 are independently selected from the group consisting
of -hydrogen, -alkyl, -aryl and -alkylene-aryl; L is selected from
the group consisting of a direct bond, -alkylene, -alkenylene and
-alkynylene; and Q is selected from the group consisting of a
direct bond, --CH.sub.2--, --O-- and --S--; Ar.sub.2 and Ar.sub.3
are independently selected from the group consisting of an aryl,
heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at
least one of Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or
sulfur atom vicinal or geminal to the point of attachment to the
--NHSO.sub.2-group, and Ar.sub.2 and Ar.sub.3 may be optionally
substituted 1 to 5 times with a substituent selected from the group
consisting of: a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-alkyl; f) -aryl; g) -cycloalkyl; h) -heterocyclyl; i)
-alkylene-cycloalkyl; j) -perhaloalkyl; k) heteroaryl; l)
-alkylene-aryl; m) -D.sub.1-H; n) -D.sub.1-R.sub.3; o)
-D.sub.1-alkyl; p) -D.sub.1-aryl; q) -D.sub.1-perhaloalkyl; r)
-D.sub.1-alkylene-R.sub.3; s) -D.sub.1-alkylene-aryl; t)
-D.sub.1-alkylene-D.sub.2-R.sub.3; u) -D.sub.1-cycloalkyl; v)
-D.sub.1-heterocyclyl; w) -D.sub.1-aryl; x) -D.sub.1-heteroaryl; y)
-D.sub.1-arylene-D.sub.2-R.sub.3; z)
-D.sub.1-heteroarylene-D.sub.2-R.sub.3; aa)
-D.sub.1-alkylene-heteroaryl; bb) -D.sub.1-alkylene-heterocyclyl;
cc) -D.sub.1-alkylene-aryl; aa)
-D.sub.1-alkylene-arylene-D.sub.2-R.sub.3; bb)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.3; ff)
-D.sub.1-alkylene-NR.sub.5R.sub.6; gg)
-D.sub.1-arylene-NR.sub.5R.sub.6; and hh) -acid isostere; wherein
D.sub.1 is selected from the group consisting of a direct bond,
--CH.sub.2--, --O--, --N(R.sub.7)--, --C(O)--, --CON(R.sub.7)--,
--N(R.sub.7)C(O)--, --N(R.sub.7)CON(R.sub.8)--,
--N(R.sub.7)C(O)O--, --OC(O)N(R.sub.7)--, --N(R.sub.7)SO.sub.2--,
--SO.sub.2N(R.sub.7)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.7)SO.sub.2N(R.sub.8)-- and --N.dbd.N--;
wherein R.sub.7 and R.sub.8 are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl and -alkylene-arylene-alkyl; R.sub.3 is selected
from the group consisting of -hydrogen, -alkyl, -aryl,
-heterocyclyl and -heteroaryl; and R.sub.5 and R.sub.6 are
independently selected from the group consisting of hydrogen, alkyl
and aryl, wherein R.sub.5 and R.sub.6 may be taken together to form
a ring having the formula
--(CH.sub.2).sub.o-Z.sub.1-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.5 and R.sub.6 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the value of the sum of
o and p is less than or equal to 6, Z.sub.1 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)-20,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.9)--, --N(C(O)R.sub.9)--,
--N(C(O)NHR.sub.9)--, --N(C(O)NR.sub.9R.sub.10)--,
--N(S(O).sub.2NHR.sub.9)--, --N(SO.sub.2R.sub.9)-- and
--N(C(O)OR.sub.9)--; wherein R.sub.9 and R.sub.10 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl and
-alkylene-aryl; D.sub.2 is selected from the group consisting of
-alkylene-, -alkenylene-, -alkylene-S--, --S-alkylene-,
-alkylene-O--, --O-alkylene-, -alkylene-S(O).sub.2--,
--S(O).sub.2-alkylene, --O--, --N(R.sub.11)--, --C(O)--,
--CON(R.sub.11)--, --N(R.sub.11)C(O)--,
--N(R.sub.11)CON(R.sub.12)--, --N(R.sub.11)C(O)O--,
--OC(O)N(R.sub.11)--, --N(R.sub.11)SO.sub.2--,
--SO.sub.2N(R.sub.11)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2-- and --N(R.sub.11)SO.sub.2N(R.sub.12)--, wherein
R.sub.11 and R.sub.12 are independently selected from the group
consisting of -hydrogen, -alkyl and -aryl; and wherein the alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene,
cycloalkylene, heterocyclylene, arylene, and heteroaryl in
Ar.sub.2, Ar.sub.3, R.sub.1 through R.sub.32 may be optionally
substituted 1 to 4 times with a substituent selected from the group
consisting of a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-perhaloalkyl; f) -A-perhaloalkyl g) -A-R.sub.40; h) -A-alkyl; i)
-A-aryl; j) -A-alkylene-aryl; k) -A-alkylene-NR.sub.41R.sub.42; and
l) -A-alkyl-E-R.sub.43; wherein A and E are independently selected
from the group consisting of --CH.sub.2--, --O--, --N(R.sub.44)--,
--C(O)--, --CON(R.sub.44)--, --N(R.sub.44)C(O)--,
--N(R.sub.44)CON(R.sub.45)--, --N(R.sub.44)C(O)O--,
--OC(O)N(R.sub.44)--, --N(R.sub.44)SO.sub.2--,
--SO.sub.2N(R.sub.44)--, --C(O)--O--, --O--C(O)-- and
--N(R.sub.44)SO.sub.2N(R.sub.45)--, wherein R.sub.44 and R.sub.45
are independently selected from the group consisting of -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and
-alkylene-arylene-alkyl; R.sub.40 and R.sub.43 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and
R.sub.41 and R.sub.42 are independently selected from the group
consisting of hydrogen, aryl and alkyl, wherein R.sub.41 and
R.sub.42 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.41 and R.sub.42 are attached, wherein
o and p are, independently, 1, 2, 3, or 4 and the value of the sum
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.46)--, --N(C(O)R.sub.46)--, --N(C(O)NHR.sub.46)--,
--N(C(O)NR.sub.46R.sub.47)--, --N(S(O).sub.2NHR.sub.46)--,
--N(SO.sub.2R.sub.46)-- and --N(C(O)OR.sub.46)--; wherein R.sub.46
and R.sub.47 are independently selected from the group consisting
of hydrogen, aryl, alkyl and -alkylene-aryl; or a pharmaceutically
acceptable salt thereof, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in an
amount sufficient to increase activity of GalR1 receptors in a
subject.
7. The method of claim 6, wherein the disorder is selected from the
group consisting of seizure disorders, neuroendocrine disorders,
gastrointestinal disorders, musculoskeletal disorders, psychotic
behavior, schizophrenia, migraine, morphine tolerance, drug
addition, opiate addiction, pain, neuropathic pain, inflammatory
pain, chronic pain, sleep disorders, eating/body weight disorders,
bulimia, bulimia nervosa, anorexia nervosa, metabolic wasting
disorders, cachexia, neuropathological disorders, diabetes,
dyslipidemia, hypertension, memory loss, depression, anxiety,
cerebral hemorrhage, and diarrhea.
8. The method of claim 6, wherein the disorder is selected from the
group consisting of neuropathic pain, inflammatory pain, chronic
pain and allodynia.
9. The method of claim 6, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered at a
dosage level at about or below 1000 mg/kg of the body weight of the
subject.
10. The method of claim 1, wherein the dose is in an amount
sufficient to stimulate peripheral GalR1 receptors in the subject,
wherein the compound is partially or completely excluded from the
brain of the subject.
11. A method comprising: administering to a subject suffering from
pain a GalR1 agonist in an amount sufficient to stimulate
peripheral GalR1 receptors, wherein the GalR1 agonist is partially
or completely excluded from the brain.
12. The method of claim 11, wherein the GalR1 agonist comprises a
compound of Formula (I)
Ar.sub.2--SO.sub.2NH--Ar.sub.1--NHSO.sub.2--Ar.sub.3 (I) wherein
Ar.sub.1 is selected from the group consisting of an arylene,
heteroarylene, fused cycloalkylarylene, fused heterocyclylarylene,
fused cycloalkylheteroarylene and fused heterocyclylheteroarylene
group optionally substituted 1 to 4 times, wherein the substituents
of Ar.sub.1 are selected from the group consisting of: a)
-hydrogen; b) -halo; c) -cyano; d) -nitro; e) -perhaloalkyl; f)
-alkyl; g) -aryl; h) -heteroaryl; i) -cycloalkyl; j) -L-aryl; k)
-L-arylene-aryl; l) -L-arylene-alkyl; m) -Q-alkyl; n) -Q-aryl; o)
-Q-alkylene-aryl; p) -Q-arylene-alkyl; q) -L-Q-alkylene-aryl; r)
-arylene-Q-alkyl; s) -L-Q-alkyl; t) -L-Q-aryl; u) -L-Q-heteroaryl;
v) -L-Q-cycloalkyl; w) -L-Q-arylene-alkyl; x)
-D.sub.4-alkylene-NR.sub.1R.sub.2; y) -D.sub.4-NR.sub.1R.sub.2; z)
-D.sub.4-alkyl; and aa) -D.sub.4-H; wherein D.sub.4 is selected
from the group consisting of a direct bond, --CH.sub.2--, --O--,
--N(R.sub.4)--, --C(O)--, --CON(R.sub.4)--, --N(R.sub.4)C(O)--,
--N(R.sub.4)CON(R.sub.4')--, --N(R.sub.4)C(O)O--,
--OC(O)N(R.sub.4)--, --N(R.sub.4)SO.sub.2--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.4)SO.sub.2N(R.sub.4)-- and --N.dbd.N--;
wherein R.sub.4 and R.sub.4' are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl and
-alkylene-aryl; R.sub.1 and R.sub.2 are independently selected from
the group consisting of hydrogen, alkyl and aryl, wherein R.sub.1
and R.sub.2 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein
and p are, independently, 1, 2, 3, or 4 and the sum of the values
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)-20,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.31)--,
--N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)-- and --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 are independently selected from the group consisting
of -hydrogen, -alkyl, -aryl and -alkylene-aryl; L is selected from
the group consisting of a direct bond, -alkylene, -alkenylene and
-alkynylene; and Q is selected from the group consisting of a
direct bond, --CH.sub.2--, --O-- and --S--; Ar.sub.2 and Ar.sub.3
are independently selected from the group consisting of an aryl,
heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl and fused heterocyclylheteroaryl group, wherein at
least one of Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or
sulfur atom vicinal or geminal to the point of attachment to the
--NHSO.sub.2-group, and Ar.sub.2 and Ar.sub.3 may be optionally
substituted 1 to 5 times with a substituent selected from the group
consisting of: a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-alkyl; f) -aryl; g) -cycloalkyl; h) -heterocyclyl; i)
-alkylene-cycloalkyl; j) -perhaloalkyl; k) heteroaryl; l)
-alkylene-aryl; m) -D.sub.1-H; n) -D.sub.1-R.sub.3; o)
-D.sub.1-alkyl; p) -D.sub.1-aryl; q) -D.sub.1-perhaloalkyl; r)
-D.sub.1-alkylene-R.sub.3; s) -D.sub.1-alkylene-aryl; t)
-D.sub.1-alkylene-D.sub.2-R.sub.3; u) -D.sub.1-cycloalkyl; v)
-D.sub.1-heterocyclyl; w) -D.sub.1-aryl; x) -D.sub.1-heteroaryl; y)
-D.sub.1-arylene-D.sub.2-R.sub.3; z)
-D.sub.1-heteroarylene-D.sub.2-R.sub.3; aa)
-D.sub.1-alkylene-heteroaryl; bb) -D.sub.1-alkylene-heterocyclyl;
cc) -D.sub.1-alkylene-aryl; aa)
-D.sub.1-alkylene-arylene-D.sub.2-R.sub.3; bb)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.3; ff)
-D.sub.1-alkylene-NR.sub.5R.sub.6; gg)
-D.sub.1-arylene-NR.sub.5R.sub.6; and hh) -acid isostere; wherein
D.sub.1 is selected from the group consisting of a direct bond,
--CH.sub.2--, --O--, --N(R.sub.7)--, --C(O)--, --CON(R.sub.7)--,
--N(R.sub.7)C(O)--, --N(R.sub.7)CON(R.sub.8)--,
--N(R.sub.7)C(O)O--, --OC(O)N(R.sub.7)--, --N(R.sub.7)SO.sub.2--,
--SO.sub.2N(R.sub.7)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.7)SO.sub.2N(R.sub.8)-- and --N.dbd.N--;
wherein R.sub.7 and R.sub.8 are independently selected from the
group consisting of -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl and -alkylene-arylene-alkyl; R.sub.3 is selected
from the group consisting of -hydrogen, -alkyl, -aryl,
-heterocyclyl and -heteroaryl; and R.sub.5 and R.sub.6 are
independently selected from the group consisting of hydrogen, alkyl
and aryl, wherein R.sub.5 and R.sub.6 may be taken together to form
a ring having the formula
--(CH.sub.2).sub.o-Z.sub.1-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.5 and R.sub.6 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the value of the sum of
o and p is less than or equal to 6, Z.sub.1 is selected from the
group consisting of a direct bond, --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O).sub.2--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.9)--, --N(C(O)R.sub.9)--,
--N(C(O)NHR.sub.9)--, --N(C(O)NR.sub.9R.sub.10)--,
--N(S(O).sub.2NHR.sub.9)--, --N(SO.sub.2R.sub.9)-- and
--N(C(O)OR.sub.9)--; wherein R.sub.9 and R.sub.10 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl and
-alkylene-aryl; D.sub.2 is selected from the group consisting of
-alkylene-, -alkenylene-, -alkylene-S--, --S-alkylene-,
-alkylene-O--, --O-alkylene-, -alkylene-S(O).sub.2--,
--S(O).sub.2-alkylene, --O--, --N(R.sub.1)--, --C(O)--,
--CON(R.sub.11)--, --N(R.sub.11)C(O)--,
--N(R.sub.11)CON(R.sub.12)--, --N(R.sub.11)C(O)O--,
--OC(O)N(R.sub.11)--, --N(R.sub.11)SO.sub.2--,
--SO.sub.2N(R.sub.11)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2-- and --N(R.sub.11)SO.sub.2N(R.sub.12)--, wherein
R.sub.11 and R.sub.12 are independently selected from the group
consisting of -hydrogen, -alkyl and -aryl; and wherein the alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene,
cycloalkylene, heterocyclylene, arylene, and heteroaryl in
Ar.sub.2, Ar.sub.3, R.sub.1 through R.sub.32 may be optionally
substituted 1 to 4 times with a substituent selected from the group
consisting of a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e)
-perhaloalkyl; f) -A-perhaloalkyl g) -A-R.sub.40; h) -A-alkyl; i)
-A-aryl; j) -A-alkylene-aryl; k) -A-alkylene-NR.sub.41R.sub.42; and
l) -A-alkyl-E-R.sub.43; wherein A and E are independently selected
from the group consisting of --CH.sub.2--, --O--, --N(R.sub.44)--,
--C(O)--, --CON(R.sub.44)--, --N(R.sub.4)C(O)--,
--N(R.sub.44)CON(R.sub.45)--, --N(R.sub.44)C(O)O--,
--OC(O)N(R.sub.44)--, --N(R.sub.44)SO.sub.2--,
--SO.sub.2N(R.sub.44)--, --C(O)--O--, --O--C(O)-- and
--N(R.sub.44)SO.sub.2N(R.sub.45)--, wherein R.sub.44 and R.sub.45
are independently selected from the group consisting of -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl and
-alkylene-arylene-alkyl; R.sub.40 and R.sub.43 are independently
selected from the group consisting of -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl and -alkylene-arylene-alkyl; and
R.sub.41 and R.sub.42 are independently selected from the group
consisting of hydrogen, aryl and alkyl, wherein R.sub.41 and
R.sub.42 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.41 and R.sub.42 are attached, wherein
o and p are, independently, 1, 2, 3, or 4 and the value of the sum
of o and p is less than or equal to 6, Z.sub.4 is selected from the
group consisting of a direct bond a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.46)--, --N(C(O)R.sub.46)--, --N(C(O)NHR.sub.46)--,
--N(C(O)NR.sub.46R.sub.47)--, --N(S(O).sub.2NHR.sub.46)--,
--N(SO.sub.2R.sub.46)-- and --N(C(O)OR.sub.46)--; wherein R.sub.46
and R.sub.47 are independently selected from the group consisting
of hydrogen, aryl, alkyl and -alkylene-aryl; or a pharmaceutically
acceptable salt thereof.
13. The method of claim 11, wherein the pain is inflammatory
pain.
14. The method of claim 11, wherein the pain is allodynia.
15. The method of claim 11, wherein the pain is neuropathic
pain.
16. The method of claim 11, further comprising modulating
peripheral GalR1 receptors in the subject at the level of the
dorsal root ganglia (DRG), wherein the GalR1 agonist is
substantially unable to cross the blood-brain barrier in the
subject at doses for which an analgesic effect is observed in the
subject.
Description
STATEMENT OF RELATED APPLICATIONS
[0001] The present application is a divisional application and
claims priority under 35 USC .sctn..sctn. 120 and 121 to U.S.
application Ser. No. 11/255,000 filed Oct. 20, 2005, and claims the
benefit of priority to U.S. Provisional Application Ser. No.
60/620,699, filed Oct. 21, 2004, and U.S. Provisional Application
Ser. No. 60/670,752, filed Apr. 13, 2005 all of which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to bissulfonamide compounds as
agonists of GalR1, and compositions, and methods of use of such
compounds and compositions.
BACKGROUND
[0003] Galanin is a 30 amino acid neuropeptide in humans (29 amino
acids in rodents) that is widely distributed in tissues including
brain, spinal cord, and gut (1). Galanin regulates numerous
processes including nociception, nerve regeneration, feeding,
memory, neuroendocrine release, gut secretion and contractility
(2,3). Three galanin receptor subtypes (GalR1, GalR2, and GalR3)
have been cloned and belong to the superfamily of G protein-coupled
7-transmembrane receptors (4,5). These receptors have been shown to
couple to various G-protein systems that modulate second messenger
activity. Galanin stimulation of GalR1 is sensitive to pertussis
toxin, consistent with coupling to Gi/o-type G proteins (6).
[0004] All three galanin receptor subtypes are expressed in the
dorsal root ganglia (DRG) and the spinal cord (7). The anatomical
location of both galanin and its receptors, and the upregulation of
galanin in response to nerve damage suggests that the galanin-GalR
pathway may play a key role in the regulation of spinal nociceptive
transmission (8-10). Intrathecal dosing of galanin enhanced the
spinal anti-nociceptive response to morphine and reduced the
physical signs of opiate withdrawal (11, 12). GalR1 may be a key
galanin receptor for anti-nociceptive transmission. Intrathecal
administration of a galanin peptide analog with GalR1 selectivity
improved pain threshold in a neuropathic pain model (13, 14).
[0005] In recent studies, the expression, mitogenic function, and
signaling mechanism of GalR1 were investigated in normal and
malignant oral epithelial cells. Upon competitive inhibition of
GalR1, proliferation was upregulated in immortalized and malignant
keratinocytes. Studies also demonstrated that GalR1 inhibits
proliferation in immortalized and malignant keratinocytes by
inactivating the MAPK pathway. (15)
SUMMARY OF INVENTION
[0006] The present invention provides compounds of Formula (I) as
described herein, wherein the compounds of Formula (I) are GalR1
agonists. In another embodiment, the present invention also
provides methods for the preparation of compounds of Formula
(I).
[0007] The present invention also provides pharmaceutical
compositions comprising compounds of Formula (I). In another
embodiment, the present invention provides methods for the
preparation of pharmaceutical compositions comprising the compounds
of Formula (I). The pharmaceutical compositions may comprise
pharmaceutically acceptable carriers, excipients, and/or
diluents.
[0008] In another embodiment, the present invention provides
methods for the use of compounds of Formula (I) and for the use of
pharmaceutical compositions comprising compounds of Formula (I).
The compounds and pharmaceutical compositions of the present
invention may be used for the treatment of human or animal
disorders.
[0009] The compounds of Formula (I) and pharmaceutical compositions
comprising a compound of Formula (I) may provide a number of
advantages when used for treating human or animal disorders. In one
embodiment, the compounds and pharmaceutical compositions of the
present invention may provide a variety of treatment options. As
small molecule therapeutics, example embodiments of the compounds
and pharmaceutical compositions of the present invention may be
administered orally, topically, or parentally. Also, the compounds
and pharmaceutical compositions of the present invention may
comprise a primary therapeutic or may be used as an adjunct to
other therapeutics.
[0010] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein the compound of Formula (I) is a GalR1 agonist and the
compound of Formula (I) is present in an amount sufficient to
increase activity of a GalR1 receptor. In another embodiment, the
pharmaceutical composition comprises a compound of Formula (I),
wherein the compound of Formula (I) is a GalR1 agonist and the
compound of Formula (I) is present in an amount sufficient to
stimulate GalR1 in a subject.
[0011] In another embodiment, the present invention provides a
method comprising: administering to a subject having a disorder
ameliorated by the activation of a GalR1 receptor, a pharmaceutical
composition comprising a compound of Formula (I) in an amount
sufficient to increase activity of GalR1 in a subject. For example,
the compounds and pharmaceutical compositions of the present
invention may be useful in treating neuropathic pain or cancer.
Further, at doses for which an analgesic effect may be observed,
the compounds of the present invention may be capable of binding to
at least one peripheral GalR1 while substantially unable to cross
the blood-brain barrier. Partial or complete exclusion of the
compounds of the present invention from the brain may reduce the
risk or severity of one or more centrally mediated side effects
associated with the compounds or pharmaceutical compositions.
[0012] Additional features of the present invention will be
described hereinafter. It is to be understood that the invention is
not limited in its application to the details set forth in the
foregoing or following description but is capable of other
embodiments and of being practiced or carried out in various
ways.
DETAILED DESCRIPTION
[0013] Throughout this application, various publications are
referenced. Full citations for these publications may be found
immediately preceding the claims.
[0014] Pain is a sensation and a perception that is comprised of a
complex series of mechanisms. In its most simple construction, pain
is a signal from the firing of nociception, touch and pressure
receptors in the periphery that is transmitted to the spinal cord
and finally to lower and higher centers of the brain. However, this
signal can be modified in a multitude of ways at each level of the
pain pathway. (16).
[0015] Physiological pain is an important protective mechanism
designed to warn of danger from potentially injurious stimuli from
the external environment. The system operates through a specific
set of primary sensory neurons and is exclusively activated by
noxious stimuli via peripherally transducing mechanisms (16). These
sensory fibres are known as nociceptors and are characterized by
smaller diameter axons with slow conduction velocities. Nociceptors
encode the intensity, duration, and quality of noxious stimulus.
Nociceptors also encode the location of the stimulus by virtue of
their topographically organized projection to the spinal cord. The
nociceptors are found on nociceptive nerve fibres of which there
are two main types, A-delta fibres (myelinated) and C fibres
(non-myelinated). The activity generated by nociceptor input is
transferred after complex processing in the dorsal horn, either
directly or via brain stem relay nuclei to the ventrobasal thalamus
and then on to the cortex where the sensation of pain is
generated.
[0016] There are primarily three types of pain. Acute pain, termed
nociception, is the instantaneous onset of a painful sensation in
response to a noxious stimulus. It is considered to be adaptive
because it can prevent an organism from damaging itself. For
example, removing a hand from a hot stove as soon as pain is felt
will prevent serious burns.
[0017] The second type of pain is persistent pain. Unlike acute
pain, it usually has a delayed onset but can last for hours to
days. It is predominately considered adaptive because the
occurrence of persistent pain following injury can prevent further
damage to the tissue. For example, the pain associated with a
sprained ankle will prevent the patient from using the foot thereby
preventing further trauma and aiding healing.
[0018] The final category of pain is chronic pain. It has a delayed
onset and can last for months to years. In contrast to acute and
persistent pain, chronic pain is considered maladaptive and is
associated with conditions such as arthritis, nerve injury, AIDS
and diabetes.
[0019] Chronic or neuropathic pain occurs in a variety of forms
including spontaneous pain (painful sensation without an external
stimulus), allodynia (painful sensation in response to a normally
innocuous stimulus) and hyperalgesia (strong painful sensation to a
mildly painful stimulus). It may be this diversity of symptoms that
has made this condition difficult to treat clinically. In fact,
current treatments are predominately off label use of
antidepressants and anticonvulsants. Both antidepressants and
anticonvulsants may present problems for a patient.
[0020] Tricyclic antidepressants have the longest history of use in
the treatment of neuropathic pain. Such drugs typically target the
serotonergic and noradrenergic systems and increase the available
extracellular levels of both serotonin and norepinephrine. It has
been proposed that the postsynaptic activation of
alpha.sub.2-adrenoceptors by norepinephrine may be the mechanism
through which these compounds alleviate neuropathic pain. Since
antidepressants may readily cross the blood-brain barrier, their
ability to increase the levels of serotonin and norepinephrine may
cause the undesired activation of other receptors leading to the
high risk of centrally mediated side effects. Side effects of
antidepressants may range from mild but irritating symptoms such as
dry mouth and sedation to severe life threatening side effects such
as postural hypotension and cardiac arrythmias. The elderly, who
represent a large number of neuropathic patients, can be
particularly vulnerable to the more serious side effects of
antidepressants.
[0021] The effectiveness of anticonvulsants in the treatment of
various pain states, including neuropathic pain, has recently been
evaluated (17). Similar to antidepressants, side effects may
frequently occur with these medications.
[0022] Due to the common occurrence of side effects with
antidepressants and anticonvulsants and the limitations these side
effects may place on the use of these compounds, there is a need
for a treatment for neuropathic pain that may avoid centrally
mediated side effects.
[0023] In one aspect, the present invention provides compounds of
Formula (I): Ar.sub.2-SO.sub.2NH--Ar.sub.1--NHSO.sub.2--Ar.sub.3
(I), pharmaceutically acceptable salts, or prodrugs thereof,
wherein the compound of Formula (I) is a GalR1 agonist.
[0024] Ar.sub.1 comprises an arylene, heteroarylene, fused
cycloalkylarylene, fused heterocyclylarylene, fused
cycloalkylheteroarylene, or fused heterocyclylheteroarylene group
optionally independently substituted 1 to 4 times. In an
embodiment, Ar.sub.1 comprises an arylene group optionally
independently substituted 1 to 4 times. In various embodiments, the
substituents of Ar.sub.1 may comprise:
hydrogen; -halo; -cyano; -nitro; -perhaloalkyl; -alkyl; -aryl;
-heteroaryl; -cycloalkyl;
-L-aryl;
-L-arylene-aryl;
-L-arylene-alkyl;
-Q-alkyl;
-Q-aryl;
-Q-alkylene-aryl;
-Q-arylene-alkyl;
-L-Q-alkylene-aryl;
[0025] -arylene-Q-alkyl;
-L-Q-alkyl;
-L-Q-aryl;
-L-Q-heteroaryl;
-L-Q-cycloalkyl;
-L-Q-arylene-alkyl;
[0026] -D.sub.4-alkylene-NR.sub.1R.sub.2;
-D.sub.4-NR.sub.1R.sub.2;
[0027] -D.sub.4-alkyl; or
-D.sub.4-H;
[0028] wherein D.sub.4 comprises a direct bond, --CH.sub.2--,
--O--, --N(R.sub.4)--, --C(O)--, --CON(R.sub.4)--,
--N(R.sub.4)C(O)--, --N(R.sub.4)CON(R.sub.4)--,
--N(R.sub.4)C(O)O--, --OC(O)N(R.sub.4)--, --N(R.sub.4)SO.sub.2--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.4)SO.sub.2N(R.sub.4')--, or --N.dbd.N--;
wherein R.sub.4 and R.sub.4' independently comprise -hydrogen,
-alkyl, -aryl, -arylene-alkyl, or -alkylene-aryl; R.sub.1 and
R.sub.2 independently comprise hydrogen, alkyl, or aryl, wherein
R.sub.1 and R.sub.2 may be taken together to form a ring having the
formula --(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the o+p is less than or
equal to 6, Z.sub.4 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.31)--, --N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)--, or --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 independently comprise -hydrogen, -alkyl, -aryl, or
-alkylene-aryl; L comprises a direct bond, -alkylene, -alkenylene ,
or -alkynylene; and Q comprises a direct bond, --CH.sub.2--, --O--,
or --S--.
[0029] In another embodiment, the --NHSO.sub.2--Ar.sub.2 and the
--NHSO.sub.2--Ar.sub.3 groups are located on adjacent atoms in the
Ar.sub.1 ring. In a further embodiment, Ar.sub.1 is
##STR00001##
wherein J and K independently comprise hydrogen; -halo; -cyano;
-nitro; -perhaloalkyl; -alkyl; -aryl; -heteroaryl; -cycloalkyl;
-L-aryl;
-L-arylene-aryl;
-L-arylene-alkyl;
-Q-alkyl;
-Q-aryl;
-Q-alkylene-aryl;
-Q-arylene-alkyl;
-L-Q-alkylene-aryl;
[0030] -arylene-Q-alkyl;
-L-Q-alkyl;
-L-Q-aryl;
-L-Q-heteroaryl;
-L-Q-cycloalkyl;
-L-Q-arylene-alkyl;
[0031] -D.sub.4-alkylene-NR.sub.1R.sub.2;
-D.sub.4-NR.sub.1R.sub.2;
[0032] -D.sub.4-alkyl; or
-D.sub.4-H;
[0033] wherein D.sub.4 comprises a direct bond, --CH.sub.2--,
--O--, --N(R.sub.4)--, --C(O)--, --CON(R.sub.4)--,
--N(R.sub.4)C(O)--, --N(R.sub.4)CON(R.sub.4')--,
--N(R.sub.4)C(O)O--, --OC(O)N(R.sub.4)--, --N(R.sub.4)SO.sub.2--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.4)SO.sub.2N(R.sub.4)--, or --N.dbd.N--;
wherein R.sub.4 and R.sub.4' independently comprise -hydrogen,
-alkyl, -aryl, -arylene-alkyl, or -alkylene-aryl; R.sub.1 and
R.sub.2 independently comprise hydrogen, alkyl, or aryl, wherein
R.sub.1 and R.sub.2 may be taken together to form a ring having the
formula --(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the o+p is less than or
equal to 6, Z.sub.4 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.31)--, --N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)--, or --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 independently comprise -hydrogen, -alkyl, -aryl, or
-alkylene-aryl; L comprises a direct bond, -alkylene, -alkenylene ,
or -alkynylene; and Q comprises a direct bond, --CH.sub.2--, --O--,
or --S--. In a further embodiment, J and K independently comprise
hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, cyano, carboxy,
amide, -D.sub.4-alkyl, -D.sub.4-alkylene-NR.sub.1R.sub.2,
-D.sub.4-NR.sub.1R.sub.2, -D.sub.4-alkyl; -D.sub.4-H, wherein
D.sub.4 comprises a --C(O)--, --CON(R.sub.4)--,
--SO.sub.2N(R.sub.4)--, --C(O)--O--, wherein R.sub.4 comprises
-hydrogen, -alkyl, -aryl, -arylene-alkyl, or -alkylene-aryl;
wherein R.sub.1 and R.sub.2 independently comprise hydrogen, alkyl,
or aryl, wherein R.sub.1 and R.sub.2 may be taken together to form
a ring having the formula
--(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.1 and R.sub.2 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the o+p is less than or
equal to 6, Z.sub.4 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.31)--, --N(C(O)R.sub.31)--, --N(C(O)NHR.sub.31)--,
--N(C(O)NR.sub.31R.sub.32)--, --N(S(O).sub.2NHR.sub.31)--,
--N(SO.sub.2R.sub.31)--, or --N(C(O)OR.sub.31)--; wherein R.sub.31
and R.sub.32 independently comprise -hydrogen, -alkyl, -aryl, or
-alkylene-aryl, wherein at least one of J and K is a group other
than hydrogen.
[0034] In a further embodiment, Ar.sub.1 is
##STR00002##
wherein J and K are defined as above, and wherein Ar.sub.2 and
Ar.sub.3 are unsubstituted benzothiophene group.
[0035] In another embodiment, Ar.sub.1 comprises an unsubstituted
phenylene group. In another embodiment, Ar.sub.1 comprises an
unsubstituted phenylene group and the --NHSO.sub.2--Ar.sub.2 and
the --NHSO.sub.2--Ar.sub.3 substituent groups are located on
adjacent carbon atoms in the Ar.sub.1 ring.
[0036] In another embodiment, the compound of Formula (I) is not C2
symmetric about a plane dividing Ar.sub.1 with Ar.sub.2 and
Ar.sub.3 on opposites sides of the plane.
[0037] Ar.sub.2 and Ar.sub.3 independently comprise an aryl,
heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl, or fused heterocyclylheteroaryl group optionally
independently substituted 1 to 5 times, wherein at least one of
Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or sulfur atom
vicinal or geminal to the point of attachment to the --NHSO.sub.2--
group. In various embodiments, the substituents of Ar.sub.2 and
Ar.sub.3 may independently comprise:
-hydrogen; -halo; -cyano; -nitro; -alkyl; -aryl; -cycloalkyl;
-heterocyclyl; -alkylene-cycloalkyl; -perhaloalkyl; heteroaryl;
-alkylene-aryl;
-D.sub.1-H;
-D.sub.1-R.sub.3;
[0038] -D.sub.1-alkyl; -D.sub.1-aryl; -D.sub.1-perhaloalkyl;
-D.sub.1-alkylene-R.sub.3; -D.sub.1-alkylene-aryl;
-D.sub.1-alkylene-D.sub.2-R.sub.3; -D.sub.1-cycloalkyl;
-D.sub.1-heterocyclyl; -D.sub.1-aryl; -D.sub.1-heteroaryl;
-D.sub.1-arylene-D.sub.2-R.sub.3;
-D.sub.1-heteroarylene-D.sub.2-R.sub.3;
-D.sub.1-alkylene-heteroaryl; -D.sub.1-alkylene-heterocyclyl;
-D.sub.1-alkylene-aryl; -D.sub.1-alkylene-arylene-D.sub.2-R.sub.3;
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.3;
-D.sub.1-alkylene-NR.sub.5R.sub.6;
-D.sub.1-arylene-NR.sub.5R.sub.6; or -acid isostere; wherein
D.sub.1 comprises a direct bond, --CH.sub.2--, --O--,
--N(R.sub.7)--, --C(O)--, --CON(R.sub.7)--, --N(R.sub.7)C(O)--,
--N(R.sub.7)CON(R.sub.8)--, --N(R.sub.7)C(O)O--,
--OC(O)N(R.sub.7)--, --N(R.sub.7)SO.sub.2--,
--SO.sub.2N(R.sub.7)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, --N(R.sub.7)SO.sub.2N(R.sub.8)--, or --N.dbd.N--;
wherein R.sub.7 and R.sub.8 independently comprise -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl; R.sub.3 comprises: -hydrogen, -alkyl,
-aryl, -heterocyclyl, or -heteroaryl; and R.sub.5 and R.sub.6
independently comprise hydrogen, alkyl, or aryl, wherein R.sub.5
and R.sub.6 may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.1-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.5 and R.sub.6 are attached, wherein o
and p are, independently, 1, 2, 3, or 4 and the o+p is less than or
equal to 6, Z.sub.1 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.9)--, --N(C(O)R.sub.9)--, --N(C(O)NHR.sub.9)--,
--N(C(O)NR.sub.9R.sub.10)--, --N(S(O).sub.2NHR.sub.9)--,
--N(SO.sub.2R.sub.9)--, or --N(C(O)OR.sub.9)--; wherein R.sub.9 and
R.sub.10 independently comprise -hydrogen, -alkyl, -aryl, or
-alkylene-aryl; D.sub.2 comprises -alkylene-, -alkenylene-,
-alkylene-S--, --S-alkylene-, -alkylene-O--, --O-alkylene-,
-alkylene-S(O).sub.2--, --S(O).sub.2-alkylene, --O--,
--N(R.sub.11)--, --C(O)--, --CON(R.sub.11)--, --N(R.sub.11)C(O)--,
--N(R.sub.11)CON(R.sub.12)--, --N(R.sub.11)C(O)O--,
--OC(O)N(R.sub.1)--, --N(R.sub.11)SO.sub.2--,
--SO.sub.2N(R.sub.11)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, or --N(R.sub.11)SO.sub.2N(R.sub.12)--, wherein
R.sub.11 and R.sub.12 independently comprise: -hydrogen, -alkyl, or
-aryl.
[0039] In an embodiment, Ar.sub.2 and Ar.sub.3 independently
comprise an aryl, heteroaryl, fused cycloalkylaryl, fused
cycloalkylheteroaryl, fused heterocyclylaryl, or fused
heterocyclylheteroaryl group optionally independently substituted 1
to 5 times, wherein at least one of Ar.sub.2 and Ar.sub.3 comprise
an oxygen atom or sulfur atom vicinal or geminal to the point of
attachment to the --NHSO.sub.2-- group and Ar.sub.2 and Ar.sub.3
are different.
[0040] In another embodiment, Ar.sub.2 and Ar.sub.3 independently
comprise an aryl, heteroaryl, or fused heterocyclylheteroaryl group
optionally independently substituted 1 to 5 times, wherein at least
one of Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or sulfur atom
vicinal or geminal to the point of attachment to the --NHSO.sub.2--
group.
[0041] In another embodiment, Ar.sub.2 and Ar.sub.3 independently
comprise an aryl, heteroaryl, or fused heterocyclylheteroaryl group
optionally independently substituted 1 to 5 times, wherein at least
one of Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or sulfur atom
vicinal or geminal to the point of attachment to the --NHSO.sub.2--
group and wherein Ar.sub.2 and Ar.sub.3 are different.
[0042] In another embodiment, Ar.sub.2 and Ar.sub.3 independently
comprise an optionally substituted or unsubstituted phenyl,
benzothiophenyl, benzofuranyl, or
4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, wherein at least one of
Ar.sub.2 and Ar.sub.3 comprise an oxygen atom or sulfur atom
vicinal or geminal to the point of attachment to the --NHSO.sub.2--
group.
[0043] In another embodiment, Ar.sub.2 and Ar.sub.3 independently
comprise an aryl, heteroaryl, fused cycloalkylaryl, fused
cycloalkylheteroaryl, fused heterocyclylaryl, or fused
heterocyclylheteroaryl group optionally independently substituted 1
to 5 times, wherein at least one of Ar.sub.2 and Ar.sub.3 comprise
either
##STR00003##
wherein R.sub.13 comprises alkyl, alkylene-cycloalkyl, haloalkyl,
perhaloalkyl, or cycloalkyl; R.sub.14 comprises a) -halo; b)
-cyano; c) -nitro; d) -perhaloalkyl;
e) -D.sub.1-R.sub.17;
[0044] f) -D.sub.1-alkyl; g) -D.sub.1-alkylene-R.sub.17; h)
-D.sub.1-alkylene-D.sub.2-R.sub.17; i) -D.sub.1-aryl; j)
-D.sub.1-heteroaryl; k) -D.sub.1-arylene-D.sub.2-R.sub.17; l)
-D.sub.1-heteroarylene-D.sub.2-R.sub.17; m)
-D.sub.1-alkylene-heteroaryl; n) -D.sub.1-alkylene-heterocyclyl; o)
-D.sub.1-alkylene-aryl; p)
-D.sub.1-alkylene-arylene-D.sub.2-R.sub.17; q)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.17; r)
-D.sub.1-alkylene-NR.sub.18R.sub.19; s)
-D.sub.1-arylene-NR.sub.18R.sub.19; or t) -acid isostere; wherein
D.sub.1 comprises direct bond, --S(O).sub.2--, --CON(R.sub.20)--,
--SO.sub.2N(R.sub.20)--, --C(O)--O--, --S--, --S(O)--; wherein
R.sub.20 comprises -hydrogen, -alkyl, -aryl, -heterocyclyl, or
-heteroaryl; R.sub.17 comprises: -hydrogen, -alkyl, -aryl,
-heterocyclyl, or -heteroaryl; R.sub.18 and R.sub.19 independently
comprise hydrogen, aryl, or alkyl, wherein R.sub.18 and R.sub.19
may be taken together to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.2-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.18 and R.sub.19 are attached, wherein
o and p are, independently, 1, 2, 3, or 4 and the o+p is less than
or equal to 6, Z.sub.2 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.20)--, --N(C(O)R.sub.20)--, --N(C(O)NHR.sub.20)--,
--N(C(O)NR.sub.2OR.sub.21)--, --N(S(O).sub.2NHR.sub.20)--,
--N(SO.sub.2R.sub.20)--, or --N(C(O)OR.sub.20)--; wherein R.sub.20
and R.sub.21 independently comprise -hydrogen, -alkyl, -aryl, or
-alkylene-aryl; D.sub.2 comprises -alkylene-, -alkenylene-,
-alkylene-S--, --S-alkylene-, -alkylene-O--, --O-alkylene-,
-alkylene-S(O).sub.2--, --S(O).sub.2-alkylene, --O--,
--N(R.sub.22)--, --C(O)--, --CON(R.sub.22)--, --N(R.sub.22)C(O)--,
--N(R.sub.22)CON(R.sub.23)--, --N(R.sub.22)C(O)O--,
--OC(O)N(R.sub.22)--, --N(R.sub.22)SO.sub.2--,
--SO.sub.2N(R.sub.22)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, or --N(R.sub.22)SO.sub.2N(R.sub.23)--, wherein
R.sub.22 and R.sub.23 independently comprise: -hydrogen, -alkyl, or
-aryl; R.sub.15 and R.sub.16 independently comprise -hydrogen;
-halogen; -cyano; -alkyl; -aryl; -alkylene-aryl;
-D.sub.3-H;
[0045] -D.sub.3-alkyl; -D.sub.3-aryl; -D.sub.3-alkylenearyl;
--Y-alkyl;
--Y-aryl;
--Y-alkylene-aryl;
--Y-alkylene-NR.sub.24R.sub.25; or
--Y-alkylene-W--R.sub.26;
[0046] wherein D.sub.3 comprises --O--, --C(O)--O--, --C(O)--NH--,
--SO.sub.2--, --SO.sub.2--NH--, or --C(O)--; Y and W independently
comprise, --CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--, or --O--CO--,
R.sub.26 comprises aryl, alkyl, alkylene-aryl, alkoxy, and
alkoxyaryl; R.sub.24 and R.sub.25 independently comprise hydrogen,
aryl, or alkyl, wherein R.sub.24 and R.sub.25 may be taken together
to form a ring having the formula
--(CH.sub.2).sub.o-Z.sub.3-(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.24 and R.sub.25 are attached, wherein
o and p are, independently, 1, 2, 3, or 4 and the o+p is less than
or equal to 6, Z.sub.3 comprises a direct bond, --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, S(O).sub.2--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O).sub.2N(H)--, --(O)CO--, --NHS(O).sub.2NH--, --OC(O)--,
--N(R.sub.29)--, --N(C(O)R.sub.29)--, --N(C(O)NHR.sub.29)--,
--N(C(O)NR.sub.29R.sub.30)--, --N(S(O).sub.2NHR.sub.29)--,
--N(SO.sub.2R.sub.29)--, or --N(C(O)OR.sub.29)--; wherein R.sub.29
and R.sub.30 independently comprise hydrogen, aryl, alkyl, or
-alkylaryl; R.sub.26 comprises hydrogen, alkyl, aryl, and
alkylene-aryl; X comprises sulfur or oxygen; and m and n are
independently 0, 1, or 2.
[0047] In another embodiment, Ar.sub.2 comprises
##STR00004##
wherein R.sub.14 comprises -D.sub.1-perhalo-C.sub.2-C.sub.6 alkyl;
-D.sub.1-alkylene-heteroaryl; -D.sub.1-alkylene-heterocyclyl;
-D.sub.1-alkylene-NR.sub.18R.sub.19; or -acid isostere; wherein
R.sub.13, R.sub.15, R.sub.18, R.sub.19, and D.sub.1 are defined as
above.
[0048] In another embodiment, Ar.sub.2 comprises
##STR00005##
and Ar.sub.3 comprises
##STR00006##
wherein R.sub.13, R.sub.14, R.sub.15, R.sub.16, X, m and n are
defined as above.
[0049] In another embodiment, Ar.sub.2 comprises
##STR00007##
and Ar.sub.3 comprises a phenyl group independently substituted 1
to 5 times, wherein Ar.sub.2 and Ar.sub.3 are different, and
R.sub.13, R.sub.14, R.sub.15, and m are defined as above. In a
further embodiment, Ar.sub.3 comprises a phenyl group substituted
with at least one halo group.
[0050] In another embodiment, Ar.sub.2 comprises
##STR00008##
and Ar.sub.3 comprises a phenyl, a benzothiopheneyl, or
benzofuranyl group optionally independently substituted 1 to 5
times, wherein Ar.sub.2 and Ar.sub.3 are the same or different and
R.sub.16 and n are defined as above.
[0051] In another embodiment, Ar.sub.2 comprises an unsubstituted
benzothiophene group.
[0052] In another embodiment, Ar.sub.2 and Ar.sub.3 are
different.
[0053] The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
alkylene, cycloalkylene, heterocyclylene, arylene, and heteroaryl
groups in J, K, Ar.sub.2, Ar.sub.3, and R.sub.1 through R.sub.32
may be optionally independently substituted 1 to 4 times with a
substituent group comprising:
a) -hydrogen; b) -halo; c) -cyano; d) -nitro; e) -perhaloalkyl;
f) -A-perhaloalkyl
g) -A-R.sub.40;
h) -A-alkyl;
i) -A-aryl;
j) -A-alkylene-aryl;
k) -A-alkylene-NR.sub.41R.sub.42; or
l) -A-alkyl-E-R.sub.43;
[0054] wherein A and E independently comprise: --CH.sub.2--, --O--,
--N(R.sub.44)--, --C(O)--, --CON(R.sub.44)--, --N(R.sub.44)C(O)--,
--N(R.sub.44)CON(R.sub.45)--, --N(R.sub.44)C(O)O--,
--OC(O)N(R.sub.44)--, --N(R.sub.44)SO.sub.2--,
--SO.sub.2N(R.sub.44)--, --C(O)--O--, --O--C(O)--, or
--N(R.sub.44)SO.sub.2N(R.sub.45)--, wherein R.sub.44 and R.sub.45
independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl, or -alkylene-arylene-alkyl; R.sub.40 and R.sub.43
independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl, or -alkylene-arylene-alkyl; and R.sub.41 and
R.sub.42 independently comprise hydrogen, aryl, or alkyl, wherein
R.sub.41 and R.sub.42 may be taken together to form a ring having
the formula --(CH.sub.2).sub.o-Z.sub.4-(CH.sub.2).sub.p-- bonded to
the nitrogen atom to which R.sub.41 and R.sub.42 are attached,
wherein o and p are, independently, 1, 2, 3, or 4 and the o+p is
less than or equal to 6, Z.sub.4 comprises a direct bond a direct
bond, --CH.sub.2--, --C(O)--, --O--, --N(H)--, --S--, --S(O)--,
--S(O).sub.2--, --CON(H)--, --NHC(O)--, --NHC(O)N(H)--,
--NH(SO.sub.2)--, --S(O).sub.2N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.46)--,
--N(C(O)R.sub.46)--, --N(C(O)NHR.sub.46)--,
--N(C(O)NR.sub.46R.sub.47)--, --N(S(O).sub.2NHR.sub.46)--,
--N(SO.sub.2R.sub.46)--, or --N(C(O)OR.sub.46)--; wherein R.sub.46
and R.sub.47 independently comprise hydrogen, aryl, alkyl, or
-alkylene-aryl.
[0055] Examples of compounds of Formula (I) of the present
invention are shown in Table 1 and in the Examples section.
TABLE-US-00001 TABLE 1 Ex. Structure Name 1 ##STR00009##
Benzo[b]thiophene-2-sulfonic acid [2-(2-chloro-
5-trifluoromethylbenzenesulfonyl-amino)phenyl] amide 2 ##STR00010##
Benzo[b]thiophene-2-sulfonic acid {2-[2- methoxy-5-(propane-2
sulfonyl) benzenesulfonylamino]phenyl} amide 3 ##STR00011##
3-[2-(Benzo[b]thiophene-2-sulfonylamino)-
phenylsulfamoyl]-4-methoxy-benzoic acid methylester 4 ##STR00012##
3-[2-(Benzo[b]thiophene-2-sulfonylamino)-
phenylsulfamoyl]-4-methoxy-benzoic acid 5 ##STR00013##
N-[2-(3-Imidazol-1-yl-benzenesulfonylamino)-
phenyl]-2-methoxy-5-trifluoromethanesulfonyl- benzenesulfonamide 6
##STR00014## N-[2-(4-Imidazol-1-yl-benzenesulfonylamino)-
phenyl]-2-methoxy-5-trifluoromethanesulfonyl- benzenesulfonamide 7
##STR00015## 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-5-trifluoromethane sulfonyl-
benzenesulfonyl-amino)phenyl]-amide 8 ##STR00016##
Benzo[b]thiophene-2-sulfonic acid [2-(5-bromo- 2-methoxy-benzene
sulfonylamino)-phenyl]-amide 9 ##STR00017##
4,5-Dichlorothiophene-2-sulfonic acid [2-(5-
bromo-2-methoxy-benzenesulfonylamino)- phenyl]-amide 10
##STR00018## 5-Isoxazol-3-yl-thiophene-2-sulfonic acid [2-(5-
bromo-2-methoxy-benzenesulfonylamino)- phenyl]-amide 11
##STR00019## N-[2-(4-Chloro-benzenesulfonylamino)phenyl]-2-
methoxy-5-nitrobenzenesulfonamide 12 ##STR00020##
Benzofuran-2-sulfonic acid [2-(4-chloro-
benzenesulfonylamino)phenyl] amide 13 ##STR00021##
Benzo[b]thiophene-2-sulfonic acid [2-(4-chloro-
benzenesulfonylamino)phenyl] amide 14 ##STR00022##
N-[2-(4-Chlorobenzenesulfonylamino)phenyl]-5-
methanesulfonyl-2-methoxybenzenesulfonamide 15 ##STR00023##
Benzo[b]thiophene-2-sulfonic acid [2-(4- methoxy-2-nitro-
benzenesulfonylamino)phenyl]amide 16 ##STR00024##
Benzo[b]thiophene-2-sulfonic acid [2-(4- methanesulfonyl-2-methoxy-
benzenesulfonylamino)-phenyl] amide 17 ##STR00025##
Benzo[b]thiophene-2-sulfonic acid [2-(2-
methoxy-5-methylbenzenesulfonylamino)phenyl]amide 18 ##STR00026##
Benzo[b]thiophene-2-sulfonic acid [2-(2- methoxy-5-trifluoromethyl-
benzenesulfonylamino)phenyl] amide 19 ##STR00027##
Benzo[b]thiophene-2-sulfonic acid {2-[5-(2-
dimethylaminoethanesulfonyl)-2-methoxy-
benzenesulfonylamino]phenyl} amide 20 ##STR00028##
Benzo[b]thiophene-2-sulfonic acid {2-[2-
methoxy-5-(2-tetrazol-2-yl-ethanesulfonyl)-
benzenesulfonylamino]-phenyl}-amide 21 ##STR00029##
Benzo[b]thiophene-2-sulfonic acid {2-[2-
methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-
benzenesulfonylamino]-phenyl}-amide 22 ##STR00030##
Benzo[b]thiophene-2-sulfonic acid {2-[2-
methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-
benzenesulfonylamino]-phenyl}-amide 23 ##STR00031##
Benzo[b]thiophene-2-sulfonic acid [2-(5-(1,1-
Dichloro-2,2,2-trifluoroethyl)-2-methoxy-
benzenesulfonylamino)phenyl]amide 24 ##STR00032##
N-[2-(4-Chlorobenzenesulfonylamino)phenyl]-2-
methoxy-5-trifluoromethylbenzenesulfonamide 25 ##STR00033##
Benzo[b]thiophene-2-sulfonic acid [2-(4- imidazol-1-yl-2-
methoxybenzenesulfonylamino)phenyl]amide 26 ##STR00034##
N-[2-(Benzothiophene-2-sulfonyl)amino]phenyl-
benzothiophene-2-sulfonamide 27 ##STR00035##
N-[2-(Benzothiophene-2-sulfonyl)amino]phenyl-
benzothiophene-2-sulfonamide 28 ##STR00036##
N-[2-(3,4-Dichlorobenzenesulfonylamino)-
phenyl]-5-fluoro-2-methoxybenzenesulfonamide 29 ##STR00037##
5-Bromo-N-[2-(4-chlorobenzenesulfonylamino)-
5-pyridin-4-ylphenyl]-2- methoxybenzenesulfonamide 30 ##STR00038##
5-Bromo-N-[2-(4-chlorobenzenesulfonylamino)-
4-fluorophenyl]-2-methoxybenzenesulfonamide 31 ##STR00039##
N,N'-(4-fluoro-1,2-phenylene)bis(1- benzothiophene-2-sulfonamide)
32 ##STR00040## N,N'-(4-cyano-1,2-phenylene)bis(1-
benzothiophene-2-sulfonamide) 33 ##STR00041## N,N'-(4-chloro-
1,2-phenylene)bis(1- benzothiophene-2-sulfonamide) 34 ##STR00042##
N,N'-(4-bromo-1,2-phenylene)bis(1- benzothiophene-2-sulfonamide) 35
##STR00043## N,N'-(4-methoxy-1,2-phenylene)bis(1-
benzothiophene-2-sulfonamide) 36 ##STR00044##
Benzo[b]thiophene-2-sulfonic acid [2-(5-cyano-2-
methoxy-benzenesulfonylamino)-phenyl]-amide 37 ##STR00045##
Benzo[b]thiophene-2-sulfonic acid {2-[2-
methoxy-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-
benzenesulfonylamino]-phenyl}-amide 38 ##STR00046##
2-[2-(Benzo[b]thiophene-2-sulfonylamino)-
phenylsulfamoyl]-6,7-dihydro-4H-thieno[3,2- c]pyridine-5-carboxylic
acid tert-butyl ester 39 ##STR00047##
N,N'-(4,5-dichloro-1,2-phenylene)bis(1
benzothiophene-2-sulfonamide) 40 ##STR00048##
N,N'-(4-trifluoromethy1-1,2-phenylene)bis(1-
benzothiophene-2-sulfonamide) 41 ##STR00049##
N,N'-(4-chloro-5-fluoro-1,2-phenylene)bis(1-
benzothiophene-2-sulfonamide) 42 ##STR00050##
N,N'-(4,5-fluoro-1,2-phenylene)bis(1-
benzothiophene-2-sulfonamide)
[0056] Unless indicated otherwise, the structures of the Examples
of compounds of Formula (I) having vacant connectivity for
heteroatoms, such as oxygen and nitrogen, are assumed to have a
hydrogen atom attached thereto.
[0057] As used herein, the term "lower" refers to a group having
between one and six carbons.
[0058] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to ten carbon atoms,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkyl" group may containing
one or more O, S, S(O), or S(O).sub.2 atoms. Examples of "alkyl" as
used herein include, but are not limited to, methyl, n-butyl,
t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
[0059] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkylene" as used herein include, but are not limited to,
methylene, ethylene, and the like.
[0060] As used herein, the term "alkenyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon double bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkenyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0061] As used herein, the term "alkenylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon double bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkenylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkenylene" as used herein include, but are not limited to,
ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the
like.
[0062] As used herein, the term "alkynyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon triple bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkynyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0063] As used herein, the term "alkynylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon triple bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkynylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkynylene" as used herein include, but are not limited to,
ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
[0064] As used herein, "cycloalkyl" refers to a alicyclic
hydrocarbon group optionally possessing one or more degrees of
unsaturation, having from three to twelve carbon atoms, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. "Cycloalkyl" includes by way
of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl, and the like.
[0065] As used herein, the term "cycloalkylene" refers to an
non-aromatic alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms and optionally possessing one or more
degrees of unsaturation, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "cycloalkylene" as used herein include, but are not
limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0066] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring optionally possessing one or more degrees of unsaturation,
containing one or more heteroatomic substitutions selected from S,
SO, SO.sub.2, O, or N, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Such a ring may be optionally fused to one or more of another
"heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" include, but are not limited to, tetrahydrofuran,
1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,
piperazine, and the like.
[0067] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical optionally having
one or more degrees of unsaturation containing one or more
heteroatoms selected from S, SO, SO.sub.2, O, or N, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such a ring may be
optionally fused to one or more benzene rings or to one or more of
another "heterocyclic" rings or cycloalkyl rings. Examples of
"heterocyclylene" include, but are not limited to,
tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,
1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,
piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl,
piperazine-1,4-diyl, and the like.
[0068] As used herein, the term "aryl" refers to a benzene ring or
to an optionally substituted benzene ring system fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of aryl include, but are not
limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the
like.
[0069] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of "arylene" include, but are
not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the
like.
[0070] As used herein, the term "heteroaryl" refers to a five- to
seven-membered aromatic ring, or to a polycyclic heterocyclic
aromatic ring, containing one or more nitrogen, oxygen, or sulfur
heteroatoms, where N-oxides and sulfur monoxides and sulfur
dioxides are permissible heteroaromatic substitutions, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by
alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy,
alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring systems, one or more of the rings may contain one or
more heteroatoms. Examples of "heteroaryl" used herein are furan,
thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,
thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,
pyridine, pyridazine, pyrazine, pyrimidine, quinoline,
isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and
indazole, and the like.
[0071] As used herein, the term "heteroarylene" refers to a five-
to seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl
optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. For polycyclic aromatic ring system diradicals, one
or more of the rings may contain one or more heteroatoms. Examples
of "heteroarylene" used herein are furan-2,5-diyl,
thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,
1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,
1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,
pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the
like.
[0072] As used herein, the term "fused cycloalkylaryl" refers to a
cycloalkyl group fused to an aryl group, the two having two atoms
in common, and wherein the aryl group is the point of substitution.
Examples of "fused cycloalkylaryl" used herein include 5-indanyl,
5,6,7,8-tetrahydro-2-naphthyl,
##STR00051##
and the like.
[0073] As used herein, the term "fused cycloalkylarylene" refers to
a fused cycloalkylaryl, wherein the aryl group is divalent.
Examples include
##STR00052##
and the like.
[0074] As used herein, the term "fused arylcycloalkyl" refers to an
aryl group fused to a cycloalkyl group, the two having two atoms in
common, and wherein the cycloalkyl group is the point of
substitution. Examples of "fused arylcycloalkyl" used herein
include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),
##STR00053##
and the like.
[0075] As used herein, the term "fused arylcycloalkylene" refers to
a fused arylcycloalkyl, wherein the cycloalkyl group is divalent.
Examples include
##STR00054##
and the like.
[0076] As used herein, the term "fused heterocyclylaryl" refers to
a heterocyclyl group fused to an aryl group, the two having two
atoms in common, and wherein the aryl group is the point of
substitution. Examples of "fused heterocyclylaryl" used herein
include 3,4-methylenedioxy-1-phenyl,
##STR00055##
and the like
[0077] As used herein, the term "fused heterocyclylarylene" refers
to a fused heterocyclylaryl, wherein the aryl group is divalent.
Examples include
##STR00056##
and the like.
[0078] As used herein, the term "fused arylheterocyclyl" refers to
an aryl group fused to a heterocyclyl group, the two having two
atoms in common, and wherein the heterocyclyl group is the point of
substitution. Examples of "fused arylheterocyclyl" used herein
include 2-(1,3-benzodioxolyl),
##STR00057##
and the like.
[0079] As used herein, the term "fused arylheterocyclylene" refers
to a fused arylheterocyclyl, wherein the heterocyclyl group is
divalent. Examples include
##STR00058##
and the like.
[0080] As used herein, the term "fused cycloalkylheteroaryl" refers
to a cycloalkyl group fused to a heteroaryl group, the two having
two atoms in common, and wherein the heteroaryl group is the point
of substitution. Examples of "fused cycloalkylheteroaryl" used
herein include 5-aza-6-indanyl,
##STR00059##
and the like.
[0081] As used herein, the term "fused cycloalkylheteroarylene"
refers to a fused cycloalkylheteroaryl, wherein the heteroaryl
group is divalent. Examples include
##STR00060##
and the like.
[0082] As used herein, the term "fused heteroarylcycloalkyl" refers
to a heteroaryl group fused to a cycloalkyl group, the two having
two atoms in common, and wherein the cycloalkyl group is the point
of substitution. Examples of "fused heteroarylcycloalkyl" used
herein include 5-aza-1-indanyl,
##STR00061##
and the like.
[0083] As used herein, the term "fused heteroarylcycloalkylene"
refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl
group is divalent. Examples include
##STR00062##
and the like.
[0084] As used herein, the term "fused heterocyclylheteroaryl"
refers to a heterocyclyl group fused to a heteroaryl group, the two
having two atoms in common, and wherein the heteroaryl group is the
point of substitution. Examples of "fused heterocyclylheteroaryl"
used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
6,7-dihydro-4H-thieno[3,2-c]pyridine,
##STR00063##
and the like.
[0085] As used herein, the term "fused heterocyclylheteroarylene"
refers to a fused heterocyclylheteroaryl, wherein the heteroaryl
group is divalent. Examples include
##STR00064##
and the like.
[0086] As used herein, the term "fused heteroarylheterocyclyl"
refers to a heteroaryl group fused to a heterocyclyl group, the two
having two atoms in common, and wherein the heterocyclyl group is
the point of substitution. Examples of "fused
heteroarylheterocyclyl" used herein include
-5-aza-2,3-dihydrobenzofuran-2-yl,
##STR00065##
and the like.
[0087] As used herein, the term "fused heteroarylheterocyclylene"
refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl
group is divalent. Examples include
##STR00066##
and the like.
[0088] As used herein, the term "acid isostere" refers to a
substituent group, which will ionize at physiological pH to bear a
net negative charge. Examples of such "acid isosteres" include but
are not limited to heteroaryl groups such as but not limited to
isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such
acid isosteres include but are not limited to heterocyclyl groups
such as but not limited to imidazolidine-2,4-dione-5-yl,
imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or
5-hydroxy-4H-pyran-4-on-2-yl.
[0089] As used herein, the term "direct bond", where part of a
structural variable specification, refers to the direct joining of
the substituents flanking (preceding and succeeding) the variable
taken as a "direct bond".
[0090] As used herein, the term "perhaloalkyl" refers to a straight
or branched chain hydrocarbon having from one to ten carbon atoms,
where each position for substitution is substituted with a halogen
atom. A perhaloalkyl group may be substituted with one or more
types of halogen atoms. Examples of "perhaloalkyl" as used herein
include, but are not limited to, a trifluoromethyl group and a
1,1-dichloro-2,2,2-trifluoroethyl group, and the like.
[0091] As used herein, the term "geminal" refers to two individual
atoms, chemical groups or substituents, either the same or
different, which are connected to the same atom. Such a "geminal"
relationship may occur in a chain of atoms or in a ring system. By
way of example, in 2-methoxypyridine, the nitrogen atom and the
methoxy group are in a "geminal" relationship.
[0092] As used herein, the term "vicinal" refers to two individual
atoms, chemical groups or substituents, either the same or
different, which are connected to adjacent atoms. Two such
"vicinal" atoms, substituents, or chemical groups may substitute
consecutive, adjacent atoms in a chain of atoms or in a ring
system. By way of example, in catechol, the two phenolic hydroxy
groups are said to be in a "vicinal" relationship.
[0093] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is alkyl.
[0094] As used herein, the term "alkenyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkenyl.
[0095] As used herein, the term "alkynyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkynyl.
[0096] As used herein, the term "alkylsulfanyl" refers to the group
R.sub.aS--, where R.sub.a is alkyl.
[0097] As used herein, the term "alkenylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkenyl.
[0098] As used herein, the term "alkynylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkynyl.
[0099] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.a is alkyl.
[0100] As used herein, the term "alkenylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkenyl.
[0101] As used herein, the term "alkynylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkynyl.
[0102] As used herein, the term "alkylsulfonyl" refers to the group
R.sub.aSO.sub.2--, where R.sub.a is alkyl.
[0103] As used herein, the term "alkenylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkenyl.
[0104] As used herein, the term "alkynylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkynyl.
[0105] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0106] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aryl.
[0107] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is heteroaryl.
[0108] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.a is alkyl.
[0109] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0110] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl.
[0111] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl.
[0112] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s), which occur, and events that do not occur.
[0113] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0114] As used herein, the terms "contain" or "containing" can
refer to in-line substitutions at any position along the above
defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one
or more of any of O, S, SO, SO.sub.2, N, or N-alkyl, including, for
example, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--SO.sub.2--CH.sub.2--, --CH.sub.2--NH--CH.sub.3 and so
forth.
[0115] Whenever the terms "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g.
arylalkoxyaryloxy) they shall be interpreted as including those
limitations given above for "alkyl" and "aryl". Designated numbers
of carbon atoms (e.g. C.sub.1-10) shall refer independently to the
number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic
alkyl moiety or to the alkyl portion of a larger substituent in
which the term "alkyl" appears as its prefix root.
[0116] As used herein, the term "oxo" shall refer to the
substituent .dbd.O.
[0117] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0118] As used herein, the term "mercapto" shall refer to the
substituent --SH.
[0119] As used herein, the term "carboxy" shall refer to the
substituent --COOH.
[0120] As used herein, the term "cyano" shall refer to the
substituent --CN.
[0121] As used herein, the term "aminosulfonyl" shall refer to the
substituent --SO.sub.2NH.sub.2.
[0122] As used herein, the term "carbamoyl" shall refer to the
substituent --C(O)NH.sub.2.
[0123] As used herein, the term "sulfanyl" shall refer to the
substituent --S--.
[0124] As used herein, the term "sulfenyl" shall refer to the
substituent --S(O)--.
[0125] As used herein, the term "sulfonyl" shall refer to the
substituent --S(O).sub.2--.
[0126] The compounds of Formula (I) may be prepared according to
the following reaction Schemes (in which variables are as defined
before or are defined in the Schemes and Examples). In these
reactions, it is also possible to make use of variants that are
themselves known to those of ordinary skill in this art, but are
not mentioned in greater detail.
[0127] Scheme 1 describes the preparation of a compound of formula
(2). In this scheme Ar.sub.1 and Ar.sub.3 have the same meaning as
for formula (I). R.sub.51 represents a substituent such as but not
limited to alkyl, aryl, heteroaryl, alkoxy or halogen.
##STR00067##
[0128] Bissulfonamides (2) may be prepared by treatment of a
phenylenediamine (1) with an aryl or heteroaryl sulfonyl chloride
in presence of a base such as pyridine or triethylamine in an
aprotic solvent such as dichloromethane or DMF at a temperature of
from 0.degree. C. to 100.degree. C.
[0129] Scheme 2 describes a synthesis of a compound of formula
(4).
##STR00068##
[0130] Phenylenediamine (1) may be monosulfonated with an aryl or
heteroaryl sulfonyl chloride in presence of a base such as pyridine
or triethylamine in an aprotic solvent such as but not limited to
dichloromethane or DMF at a temperature of from 0.degree. C. to
100.degree. C. to afford sulfonamidoanilines (3). Such a
monosulfonylation may take place preferentially when 0.5 to 1.5
molar equivalents of the sulfonyl chloride are employed. The
sulfonamidoaniline (3) obtained may be further sulfonated with an
aryl or heteroaryl sulfonyl chloride in the presence of a base such
as pyridine or triethylamine in an aprotic solvent such as
dichloromethane or DMF at a temperature of from 0.degree. C. to
100.degree. C. to provide the bissulfonamide (4).
[0131] Scheme 3 describes an alternative synthesis of a compound of
formula (4).
##STR00069##
[0132] 2-Nitroanilines (5), either unsubstituted or substituted
with a substituent R.sub.51, may be sulfonylated with an aryl or
heteroaryl sulfonyl chloride in pyridine as solvent, optionally in
a aprotic cosolvent like DMF or acetonitrile in the presence of a
base such as pyridine or triethylamine, at a temperature of from
0.degree. C. to 100.degree. C., to afford a 2-sulfonamidonitroaryl
intermediate. The 2-sulfonamidonitroarene thus obtained may be
reduced using methods such as but not limited to hydrogenation with
a noble metal catalyst such as palladium on carbon, or reduction
with SnCl.sub.2 in EtOH (alternatively with LiAlH.sub.4) to provide
2-sulfonamidoanilines (6). The aniline (6) may be sulfonylated as
described previously to afford (4).
[0133] Scheme 4 describes the preparation of a sulfonyl chloride
(8). R.sub.52 is a substituent such as but not limited to alkyl,
aryl, alkoxy, or -alklylaryl.
##STR00070##
[0134] The sulfonyl chloride (8) may be prepared by reacting an
arene or heteroarene (7) with chlorosulfonic acid in a solvent such
as DCM or DCE at a temperature of from 0.degree. C. to 100.degree.
C., to afford the desired sulfonyl chloride (8).
[0135] Scheme 5 describes an alternate synthesis of a sulfonyl
chloride (8). X is Br or I. M is --MgX or Li.
##STR00071##
[0136] An arene or heteroarene with a halogen substituent (9) may
be metallated by treatment with magnesium metal in a solvent such
as ether or THF, at a temperature of from -20.degree. C. to
100.degree. C., to afford the organometallic reagent (10) where M
is --MgX. Alternately, treatment of (9) with n-butyllithium under
inert atmosphere in a solvent such as ether or THF, at a
temperature of from -78.degree. C. to 0.degree. C. affords (10)
where M is Li. Alternately, treatment of (9) with 2 equivalents of
tert-butyllithium under inert atmosphere in a solvent such as ether
or THF, at a temperature of from -78.degree. C. to 0.degree. C.,
affords (10) where M is Li. The metalloarene or metalloheteroarene
intermediate (10) thus formed may be treated with sulfur dioxide in
an ethereal solvent such as THF to afford a sulfinate salt that is
subsequently treated with N-chlorosuccinimide or sulfuryl chloride
to provide the desired sulfonyl chloride (8).
[0137] The present invention also provides a method for the
synthesis of compounds useful as intermediates in the preparation
of compounds of Formula (I) along with methods for the preparation
of compounds of Formula (I).
Procedure A
[0138] To a solution of o-phenylenediamine (1 mmol) in and DCM (4
mL) pyridine (1 mL) at 0.degree. C., arylsulfonyl chloride (2.2
mmol) was added at 0.degree. C. in small portions at 0.degree. C.
The reaction mixture was then gradually warmed to RT with stirring
continued until the reaction is complete as determined by TLC or
LC-MS. In some cases, the reaction is allowed to proceed overnight
to ensure completion and/or may be aided by adding catalytic amount
of DMAP. The reaction mixture was then diluted with DCM (5 mL). The
organic phase was washed with 10% HCl aqueous solution (5 mL),
water (5 mL) and 5 mL of brine. The organic phase was dried over
anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc system to obtain the requisite
bissulfonamide.
Procedure B
[0139] To a solution of o-phenylenediamine (1 mmol) in and DCM (4
mL) pyridine (1 mL) at 0.degree. C., arylsulfonyl chloride (1.1
mmol) is added at 0.degree. C. in small portions at 0.degree. C.
The reaction mixture is then gradually warmed to RT with stirring
continued until the reaction is complete as determined by TLC or
LC-MS. The reaction mixture is then diluted with DCM (5 mL). The
organic phase is washed with water (2.times.5 mL) and 5 mL of
brine. The organic phase is dried over anhydrous sodium sulfate,
and concentrated under vacuum. The residue obtained is purified by
flash column chromatography eluting with DCM/EtOAc system to obtain
the sulfonamide.
[0140] The monosulfonamide (1 mmol) obtained as above is dissolved
in DCM (2 mL) and pyridine (2 mL). Arylsulfonyl chloride (1.1 mmol)
is then added at RT and the reaction mixture is then allowed to
stir at RT overnight or until the reaction is complete as
determined by TLC or LC-MS. In some cases, the reaction is allowed
to proceed overnight to ensure completion and/or may be aided by
adding catalytic amount of DMAP. The reaction mixture is then
diluted with DCM (5 mL). The organic phase is washed with 10% HCl
aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The
organic phase is dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained is purified by
flash column chromatography eluting with DCM/EtOAc system to obtain
the requisite bissulfonamide.
Procedure C
[0141] To a stirred solution of nitroaniline (2 mmol) in pyridine
(4 mL) at RT, sulfonyl chloride (2.2 mmol) is added and the
resulting reaction mixture is then heated at 100.degree. C. until
the reaction is complete as determined by TLC or LC-MS. The
reaction mixture is diluted with EtOAc (20 mL) and washed with 10%
aq. HCl (2.times.10 mL), H2O (2.times.10 mL) and brine (10 mL). The
product may be used without further purification or may be purified
on a silica gel column chromatography using EtOAc/hexane as
eluant.
[0142] Hydrogenation is carried out in MeOH using 10% Pd/C (wet)
under 1 atm. Alternatively, when hydrogenation is not compatible,
reduction is performed using Fe/AcOH as follows: Sulfonamide from
above (2 mmol) in AcOH (2 mL) is added with Fe powder (20 mmol).
The reaction mixture is then heated at 100.degree. C. until the
reaction is complete as determined by TLC or LC-MS. The reaction
mixture is then cooled to RT and diluted with EtOAc (20 mL) with
vigorous stirring. The suspension is then filtered on a Celite pad
and the filtrate is then concentrated in vacuo to remove most of
the acetic acid. The residue obtained is redissolved in EtOAc (20
mL), washed with saturated aqueous bicarbonate solution (20 mL),
followed by water (20 mL) and brine (20 mL). The product may be
used for further transformation without any purification.
[0143] The monosulfonamide (1 mmol) obtained as above is dissolved
in DCM (2 mL) and pyridine (2 mL). Arylsulfonyl chloride (1.1 mmol)
is then added at RT and the reaction mixture is then allowed to
stir at RT overnight or until the reaction is complete as
determined by TLC or LC-MS. In some cases, the reaction is allowed
to proceed overnight to ensure completion and/or may be aided by
adding catalytic amount of DMAP. The reaction mixture was then
diluted with DCM (5 mL). The organic phase was washed with 10% HCl
aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The
organic phase is dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained is purified by
flash column chromatography eluting with DCM/EtOAc system to obtain
the requisite bissulfonamide.
[0144] The term "pharmaceutical composition" is used herein to
denote a composition that may be administered to a mammalian host,
e.g., orally, topically, parenterally, by inhalation spray, or
rectally, in unit dosage formulations containing conventional
non-toxic carriers, diluents, adjuvants, vehicles and the like.
[0145] The term "parenteral" as used herein, includes subcutaneous
injections, intravenous, intramuscular, intracisternal injection,
or by infusion techniques.
[0146] The pharmaceutical compositions containing a compound of the
invention may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous, or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any known method, and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with non-toxic pharmaceutically-acceptable excipients,
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. The tablets may also be coated by the techniques
described in U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, to
form osmotic therapeutic tablets for controlled release.
[0147] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or a soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0148] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more coloring agents, one or more flavoring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0149] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0150] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring, and coloring agents may also be present.
[0151] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example a liquid paraffin, or a mixture thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
[0152] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[0153] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient, which is solid at ordinary temperatures
but liquid at the rectal temperature and will thus melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols, for example.
[0154] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the invention are
contemplated. For the purpose of this application, topical
applications shall include mouth washes and gargles.
[0155] The compounds of the present invention may also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes may be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[0156] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
Formula (I)) and a solvent. Such solvents for the purpose of the
invention may not substantially interfere with the biological
activity of the solute. Solvents may be, by way of example, water,
ethanol, or acetic acid.
[0157] As used herein, the term "biohydrolyzable ester" is an ester
of a drug substance (in this invention, a compound of Formula (I))
which either a) does not interfere with the biological activity of
the parent substance but confers on that substance advantageous
properties in vivo such as duration of action, onset of action, and
the like, or b) is biologically inactive but is readily converted
in vivo by the subject to the biologically active principle. The
advantage is that, for example, the biohydrolyzable ester is orally
absorbed from the gut and is transformed to Formula (I) in plasma.
Many examples of such are known in the art and include by way of
example lower alkyl esters (e.g., C1-C4), lower acyloxyalkyl
esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters,
alkyl acylamino alkyl esters, and choline esters.
[0158] As used herein, the term "biohydrolyzable amide" is an amide
of a drug substance (in this invention, a compound of general
Formula (I)) which either a) does not interfere with the biological
activity of the parent substance but confers on that substance
advantageous properties in vivo such as duration of action, onset
of action, and the like, or b) is biologically inactive but is
readily converted in vivo by the subject to the biologically active
principle. A biohydrolyzable amide may be orally absorbed from the
gut and transformed to Formula (I) in plasma. Many examples of such
are known in the art and include by way of example lower alkyl
amides, alpha-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides.
[0159] Prodrugs of the compounds of the present invention are also
included within the scope of the invention. As used herein, the
term "prodrug" includes biohydrolyzable amides and biohydrolyzable
esters and encompasses a) compounds in which the biohydrolyzable
functionality in such a prodrug is encompassed in the compound of
Formula (I), and b) compounds that may be oxidized or reduced
biologically at a given functional group to yield drug substances
of Formula (I). Examples of these functional groups include, but
are not limited to, 1,4-dihydropyridine,
N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene,
tert-butyl, and the like.
[0160] The term "pharmacologically effective amount" shall mean
that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, animal or human that is
being sought by a researcher or clinician. This amount can be a
therapeutically effective amount.
[0161] The term "therapeutically effective amount" is used herein
to denote that amount of a drug or pharmaceutical agent that will
elicit the therapeutic response of an animal or human that is being
sought.
[0162] The term "treatment" as used herein, refers to the full
spectrum of treatments for a given disorder from which the patient
is suffering, including alleviation of one, most of all symptoms
resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[0163] Pharmaceutically acceptable salts of the compounds of the
present invention, where a basic or acidic group is present in the
structure, are also included within the scope of the invention. The
term "pharmaceutically acceptable salts" refers to non-toxic salts
of the compounds of this invention which are generally prepared by
reacting the free base with a suitable organic or inorganic acid or
by reacting the acid with a suitable organic or inorganic base.
Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,
Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate,
Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate,
Monopotassium Maleate, Mucate, Napsylate, Nitrate,
N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,
Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate,
Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and
Valerate. When an acidic substituent is present, such as --COOH,
there can be formed the ammonium, morpholinium, sodium, potassium,
barium, calcium salt, and the like, for use as the dosage form.
When a basic group is present, such as amino or a basic heteroaryl
radical, such as pyridyl, an acidic salt, such as hydrochloride,
hydrobromide, phosphate, sulfate, trifluoroacetate,
trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,
succinate, citrate, tartarate, fumarate, mandelate, benzoate,
cinnamate, methanesulfonate, ethanesulfonate, picrate and the like,
and include acids related to the pharmaceutically-acceptable salts
listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p.
1-19.
[0164] Other salts that are not pharmaceutically acceptable may be
useful in the preparation of compounds of the invention and these
form a further aspect of the invention.
[0165] In addition, some of the compounds of Formula (I) may form
solvates with water or common organic solvents. Such solvates are
also encompassed within the scope of the invention.
[0166] The terms "analgesia", "antinociception", and
"anti-allodynia" are used to describe pain reduction and the
reduction of pain associated with neuropathic pain, as well as
allodynia often associated with neuropathic pain.
[0167] As used herein, a compound that is "substantially unable to
cross the blood-brain barrier" or "partially or completely excluded
from the brain" is a compound that diffuses across the blood-brain
barrier at a lower rate than the rate of diffusion in the periphery
of a subject.
[0168] In an embodiment, at dose levels that are able to stimulate
GalR1 receptors in the periphery of a subject, a compound that is
"substantially unable to cross the blood-barrier" or "partially or
completely excluded form the brain" may be present in the brain of
a subject at about or below the limit of detection.
[0169] In another embodiment, at dose levels in which an analgesic
effect is observed in a subject, a compound that is "substantially
unable to cross the blood-brain barrier" or "partially or
completely excluded from the brain" may be present in the brain of
a subject at about or below the limit of detection.
[0170] As used herein, the term "subject" includes mammalian
subjects such as, but not limited to, humans, dogs, cats, cows,
horses, and other agricultural live stock. In an embodiment, a
subject may include one that either suffers from one or more
aforesaid diseases, disease states, or one that is at risk for
contracting one or more aforesaid diseases, or disease states.
[0171] As used herein, a GalR1 agonist comprises compounds: 1) that
are capable of binding to a GalR1 receptor and inhibiting forskolin
induced cAMP production in Bowes cells that express the human GalR1
receptor; and 2) that do not inhibit forskolin induced cAMP
production in cell lines that do not express the GalR1 receptor. In
an embodiment, a GalR1 agonist is a compound that exhibits greater
efficacy in a functional assay in comparison to no ligand.
[0172] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I)
Ar.sub.2--SO.sub.2NH--Ar.sub.1--NHSO.sub.2--Ar.sub.3 (I)
wherein Ar.sub.1, Ar.sub.2 and Ar.sub.3 are as defined above, and
the compound of Formula (I) is a GalR1 agonist.
[0173] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I) and
a pharmaceutically suitable carrier, excipient, diluent, or a
mixture thereof.
[0174] In another embodiment, the present invention also provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein the compound of Formula (I) is a GalR1 agonist and the
compound of Formula (I) is present in an amount sufficient to
increase activity of a GalR1 receptor. In another embodiment, the
pharmaceutical composition comprises a compound of Formula (I),
wherein the compound of Formula (I) is a GalR1 agonist and the
compound of Formula (I) is present in an amount sufficient to
stimulate GalR1 in a subject.
[0175] In another embodiment, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of Formula (I), wherein said therapeutically
effective amount comprises an amount of the compound of Formula (I)
capable of at least partially activating the GalR1 receptor in a
subject, or an amount of the compound of Formula (I) capable of at
least partial amelioration of at least one GalR1 mediated
disease.
[0176] Diseases or disorders that may be ameliorated by a GalR1
agonist may include a seizure disorder, a neuroendocrine disorder,
a gastrointestinal disorder, a musculoskeletal disorder, psychotic
behavior such as schizophrenia, migraine, morphine tolerance, drug
addition, particularly opiate addiction, pain, particularly
neuropathic pain, inflammatory pain, chronic pain, a sleep
disorder, eating/body weight disorders such as bulimia, bulimia
nervosa, and anorexia nervosa metabolic wasting disorders such as
cachexia, neuropathological disorders, diabetes, dyslipidemia,
hypertension, memory loss, depression, anxiety, cerebral
hemorrhage, diarrhea, and one or more cancers such as, but not
limited to, squamous cell carcinoma. Accordingly, treatment of such
disorders may be affected by the administration of a GalR1 agonist.
It is contemplated within the scope of the invention that compounds
of Formula (I) and pharmaceutical compositions comprising a
compound of Formula (I) may be formulated to treat disorders that
are not associated with binding of galanin (or lack thereof) to the
GalR1 receptor but where the symptoms of the disorder may be
mediated by a GalR1 agonist.
[0177] In another embodiment, the pharmaceutical composition is in
the form of an oral dosage. In another embodiment, the
pharmaceutical composition is in the form of a parenteral dosage
unit.
[0178] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
and one or more additional therapeutic agents. In another
embodiment, the pharmaceutical composition may further comprise one
or more therapeutic agents selected from the group consisting of
biologic response modifiers, analgesics, NSAIDs, DMARDs,
glucocorticoids, sulfonylureas, biguanides, acarbose, PPAR
agonists, DPP-IV inhibitors, GK activators, insulin, insulin
mimetics, insulin secretagogues, insulin sensitizers, GLP-1, GLP-1
mimetics, cholinesterase inhibitors, antipsychotics,
antidepressants, anticonvulsants, HMG CoA reductase inhibitors,
cholestyramine, and fibrates. In another embodiment, the
pharmaceutical composition may further comprise one or more
therapeutic agents such as anticancer agents: such as, but not
limited to, cyclophosphamide, nitrosoureas, carboplatin, cisplatin,
procarbazine, Bleomycin, Daunorubicin, Doxorubiciri, Methotrexate,
Cytarabine, Fluorouracil, Vinblastine, Vincristine, Etoposide,
Paclitaxel, Tamoxifen, Octreotide acetate, Finasteride, Flutamide,
Interferons, Interleukins, and anti-tumor antibodies and
antiangiogenic compounds and proteins.
[0179] In another embodiment, the present invention provides a
method comprising: administering to a subject a pharmaceutical
composition comprising a compound of Formula (I), wherein the
compound of Formula (I) is a GalR1 agonist.
[0180] In another embodiment, the present invention provides a
method comprising: administering a pharmaceutical composition to a
subject having a disorder ameliorated by the activation of a GalR1
receptor, wherein the pharmaceutical composition comprises a
compound of Formula (I) in an amount sufficient to increase
activity of GalR1 in a subject. Diseases or disorders that may be
treated with a GalR1 agonist include seizure disorders,
neuroendocrine disorders, gastrointestinal disorders,
musculoskeletal disorders, psychotic behavior such as
schizophrenia, migraine, morphine tolerance, drug addition,
particularly opiate addiction, pain, particularly neuropathic pain,
inflammatory pain, chronic pain, sleep disorders, eating/body
weight disorders such as bulimia, bulimia nervosa, and anorexia
nervosa, metabolic wasting disorders such as cachexia,
neuropathological disorders, diabetes, dyslipidemia, hypertension,
memory loss, depression, anxiety, cerebral hemorrhage, diarrhea,
and one or more cancers such as, but not limited to, squamous cell
carcinoma.
[0181] For example, the compounds and pharmaceutical compositions
of the present invention comprising a GalR1 agonist may be useful
in treating neuropathic pain. Further, at doses for which an
analgesic effect may be observed, the compounds of the present
invention may be capable of binding to at least one peripheral
GalR1 while being substantially unable to cross the blood-brain
barrier. Partial or complete exclusion of a GalR1 agonist from the
brain may reduce the risk or severity of one or more
centrally-mediated side effect associated with the administration
of a GalR1 agonist to a subject.
[0182] It is contemplated within the scope of the invention that
compounds of Formula (I) and that pharmaceutical compositions
comprising a compound of Formula (I) may be formulated to treat
disorders that are not associated with binding of galanin (or lack
thereof) to the GalR1 receptor but where the symptoms of the
disorder may be mediated by a GalR1 agonist.
[0183] The compounds of the present invention may be administered
at a dosage level at about or below 1000 mg/kg of the body weight
of the subject being treated. In another embodiment, the compounds
of the present invention may be administered at a dosage level at
about or below 100 mg/kg. In another embodiment, the compounds of
the present invention may be administered at a dosage level at
about or below 10 mg/kg of body weight per day. In another
embodiment, the compounds of the present invention may be
administered at a dosage level at about or above 0.01 mg/kg of body
weight per day. In another embodiment, the compounds of the present
invention may be administered at a dosage level at about or above
0.5 mg/kg of body weight per day.
[0184] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for oral
administration to humans may contain 1 mg to 2 grams of a compound
of Formula (I) with an appropriate and convenient amount of carrier
material that may vary from about 5 to 95 percent of the total
composition. Dosage unit forms will generally contain between from
about 5 mg to about 500 mg of active ingredient. The dosage may be
individualized by the clinician based on the specific clinical
condition of the subject being treated. Thus, it will be understood
that the specific dosage level for any particular patient will
depend upon a variety of factors including the activity of the
specific compound employed, the age, body weight, general health,
sex, diet, time of administration, route of administration, rate of
excretion, drug combination and the severity of the particular
disease undergoing therapy.
[0185] In another embodiment, the pharmaceutical composition
comprising a compound of Formula (I) may be administered to a
subject in combination with one or more therapeutic agents selected
from the group consisting of biologic response modifiers,
analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas,
biguanides, acarbose, PPAR agonists, DPP-IV inhibitors, GK
activators, insulin, insulin mimetics, insulin secretagogues,
insulin sensitizers, GLP-1, GLP-1 mimetics, cholinesterase
inhibitors, antipsychotics, antidepressants, anticonvulsants, HMG
CoA reductase inhibitors, cholestyramine, and fibrates. In another
embodiment, the pharmaceutical composition comprising a compound of
Formula (I) may be administered in a subject in combination with
one or more therapeutic agents selected from the group consisting
of anticancer agents such as, but not limited to, Cyclophosphamide,
nitrosoureas, carboplatin, cisplatin, procarbazine, Bleomycin,
Daunorubicin, Doxorubicin; Methotrexate, Cytarabine, Fluorouracil;
Vinblastine, Vincristine, Etoposide, Paclitaxel; Tamoxifen,
Octreotide acetate, Finasteride, Flutamide, Interferons,
Interleukins, and anti-tumor antibodies and antiangiogenic
compounds and proteins.
[0186] Neuropathic pain may be ameliorated, at least in part, by a
GalR1 agonist binding to the peripheral GalR1 receptors in a
subject. Where the GalR1 agonist is partially or completely
prevented from passing through the blood-brain barrier, the risk of
inducing centrally mediated central nervous system (CNS) side
effects may be reduced or avoided. In an embodiment, the present
invention provides a method of treating neuropathic pain in a
subject that may avoid or reduce the risk of centrally mediated
side effects in the subject. This method may be practiced with any
GalR1 agonist that is substantially unable to cross the blood-brain
barrier. Because peripheral GalR1 receptors in neuropathic pain may
be associated with allodynia, this discovery provides a novel
method of treating a subject in need of relief from allodynia by
administering to the subject a GalR1 agonist of Formula (I) that is
substantially unable to cross the blood-brain barrier. This method
of treating allodynia may reduce or eliminate the risk of one or
more centrally mediated CNS side effects.
[0187] In another embodiment, the present invention provides a
method comprising: administering to a subject suffering from
neuropathic pain a GalR1 agonist wherein the amount of GalR1
agonist is capable of stimulating peripheral GalR1 receptors in the
subject and the GalR1 agonist is partially or completely excluded
from the brain. In a further embodiment of the method, the GalR1
agonist comprises a compound of Formula (I).
[0188] In another embodiment, the present invention provides a
method comprising: administering to a subject suffering from
allodynia a GalR1 agonist in an amount capable of stimulating
peripheral GalR1 receptors to induce an analgesic effect in the
subject and wherein the GalR1 agonist is substantially unable to
cross the blood-brain barrier at doses for which an analgesic
effect is observed in the subject. In a further embodiment of the
method, the GalR1 agonist comprises a compound of Formula (I).
[0189] In another embodiment, the present invention provides a
method comprising: administering a GalR1 agonist to a subject
suffering from neuropathic pain and modulating peripheral GalR1
receptors in the subject at the level of the dorsal root ganglia
(DRG), wherein the GalR1 agonist is substantially unable to cross
the blood-brain barrier in the subject at doses for which an
analgesic effect is observed in the subject. In a further
embodiment of the method, the GalR1 agonist comprises a compound of
Formula (I).
[0190] In another embodiment, the present invention provides a
method of treatment comprising: administering a compound of Formula
(I) to a subject suffering from cancer.
[0191] In another embodiment of the method of treatment, the cancer
is squamous cell carcinoma. In another embodiment of the method of
treatment, the compound of Formula (I) is administered in an amount
effective to inhibit cancer cell proliferation in a subject. In
another embodiment of the treatment, the compound of Formula (I) is
administered in an amount effective to inhibit or inactivate the
MAPK pathway in cancer cells in the subject.
EXAMPLES
[0192] LC-MS data was obtained using gradient elution on a parallel
MUX.TM. system, running four Waters 1525 binary HPLC pumps,
equipped with a Mux-UV 2488 multichannel UV-Vis detector (recording
at 215 and 254 nM) and a Leap Technologies HTS PAL Auto sampler
using a Waters Xterra MS C18 4.6.times.50 mm column. A three minute
gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05%
TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100%
B. The system is interfaced with a Waters Micromass ZQ mass
spectrometer using electrospray ionization. All MS data was
obtained in the positive mode unless otherwise noted. .sup.1H NMR
data was obtained on a Varian 400 MHz spectrometer.
[0193] Abbreviations used in the Examples are as follows:
APCI=atmospheric pressure chemical ionization
BOC=tert-butoxycarbonyl
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate d=day DIAD=diisopropyl azodicarboxylate
DCC=dicyclohexylcarbodiimide DCM=dichloromethane
DIC=diisopropylcarbodiimide DIEA=diisopropylethylamine
DMA=N,N-dimethylacetamide
[0194] DMAP=dimethylaminopyridine DME=1,2 dimethoxyethane
DMF=N,N-dimethylformamide
[0195] DMPU=1,3-dimethypropylene urea DMSO=dimethylsulfoxide
EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
EDTA=ethylenediamine tetraacetic acid ELISA=enzyme-linked
immunosorbent assay ESI=electrospray ionization ether=diethyl ether
EtOAc=ethyl acetate FBS=fetal bovine serum g=gram h, hr=hour
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate HMPA=hexamethylphosphoric triamide
HOBt=1-hydroxybenzotriazole Hz=hertz i.v.=intravenous kD=kiloDalton
L=liter LAH=lithium aluminum hydride LDA=lithium diisopropylamide
LPS=lipopolysaccharide M=molar m/z=mass to charge ratio
mbar=millibar MeOH=methanol mg=milligram min=minute mL=milliliter
mM=millimolar mmol=millimole mol=mole mp=melting point MS=mass
spectrometry N=normal NMM=N-methylmorpholine, 4-methylmorpholine
NMR=nuclear magnetic resonance spectroscopy p.o.=per oral
PBS=phosphate buffered saline solution PMA=phorbol myristate
acetate ppm=parts per million psi=pounds per square inch
R.sub.f=relative TLC mobility rt, RT=room temperature
s.c.=subcutaneous SPA=scintillation proximity assay
TEA=triethylamine TFA=trifluoroacetic acid THF=tetrahydrofuran
THP=tetrahydropyranyl TLC=thin layer chromatography
TMSBr=bromotrimethylsilane, trimethylsilylbromide T.sub.r=retention
time
Example A
N-(2-Aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide
[0196] To a solution of
2-methoxy-5-trifluoromethanesulfonyl-1-benzenesulfonyl chloride (5
g) in dry dichloromethane (10 mL), benzene-1,2-diamine (5 g) was
added followed by addition of dry pyridine (10 mL) at 0.degree. C.
The resulting deep red reaction mixture was then stirred at room
temperature for 4 h. The reaction mixture was diluted with
dichloromethane (250 mL). The contents were washed with saturated
aqueous sodium chloride solution (50 mL) and saturated aqueous
sodium carbonate solution (50 mL). The organic phase was dried over
sodium sulfate and concentrated under vacuum. The residue obtained
was purified by flash column chromatography eluting with DCM/EtOAc
(7:1 to 4:1) to give
N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide
(6 g). LC: T.sub.r 0.95 min, MS: 411 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 4.18 (bs, 2H), 4.21 (s, 3H), 6.43
(m, 2H), 6.57 (bs, 1H), 6.75 (dd, 1H), 7.02 (t, 1H), 7.35 (d, 1H),
8.22 (dd, 1H), 8.40 (d, 1H) ppm.
Example B
2-Methoxy-5-nitrobenzenesulfonyl chloride
[0197] To a solution of 4-nitroanisole (3.1 g; 20 mmol) in
1,2-dichloroethane (20 mL), 2 mL of chlorosulfonic acid was added
at 0.degree. C. The resulting reaction mixture was gradually warmed
to room temperature and then heated to reflux for 2 h at which time
all the anisole had been consumed. The reaction mixture was then
cooled to room temperature and diluted with chloroform (30 mL). The
contents were then transferred to a separatory funnel, washed with
water (50 mL), and the layers were separated. The aqueous layer was
then extracted with chloroform (30 mL). The combined organic layers
was washed with brine (50 mL) and dried over anhydrous sodium
sulfate. The solvent was removed in vacuo and the residue obtained
was purified by silica gel flash column chromatography using ethyl
acetate/hexanes as eluant (1:5 to 1:1 gradient) to afford
2-methoxy-5-nitrobenzenesulfonyl chloride as a dark brown solid.
.sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.21 (s, 3H), 7.28 (d,
1H), 8.59 (dd, 1H), 8.88 (d, 1H) ppm.
Example 1
[0198] To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL)
and pyridine (5 mL) at 0.degree. C., benzo[b]thiophene-2-sulfonyl
chloride (5.5 mmol) was added in small portions. The reaction
mixture was then gradually warmed to RT with stirring continued
until the reaction was complete as determined by TLC or LC-MS. The
reaction mixture was then diluted with DCM (25 mL). The organic
phase was washed with water (2.times.25 mL) and 25 mL of brine. The
organic phase was dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to give 1.2 g of
benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide. T.sub.r
0.94 min, MS: 305.7 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400
MHz): .delta. 6.40 (t, 1H), 6.60 (d, 1H), 6.78 (d, 1H), 6.89 (t,
1H), 7.45 (t, 1H), 7.50 (t, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.80
(d, 1H) ppm.
[0199] The monosulfonamide (2 mmol) obtained as above was dissolved
in DCM (4 mL) and pyridine (4 mL).
2-Chloro-5-(trifluoromethyl)benzenesulfonyl chloride (2.2 mmol) was
then added at RT and the reaction mixture was then allowed to stir
at RT overnight or until the reaction was complete as determined by
TLC or LC-MS. The reaction mixture was then diluted with DCM (10
mL). The organic phase was washed with 10% HCl aqueous solution (10
mL), water (10 mL) and brine (10 mL). The organic phase was dried
over anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to obtain 710 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl]-amide.
T.sub.r 1.2 min, MS: 547.6 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 7.0-7.2 (m, 4H), 7.48 (dd, 1H), 7.53 (dd, 1H),
7.90 (d, 1H), 7.92 (d, 1H), 7.98 (d, 1H), 8.02-8.06 (m, 3H), 9.74
(bs, 1H), 9.88 (bs, 1H) ppm.
Example 2
[0200] To a solution of 4-methoxybenzenethiol (10 mmol) in dry THF
(50 mL), solid t-BuOK (12 mmol) was added at 0.degree. C. in small
portions. The reaction mixture was stirred for 30 min followed by
dropwise addition of 2-bromopropane (1.6 g) at 0.degree. C. The
reaction mixture was then stirred for 1 h at room temperature and
was heated at 60.degree. C. for 1 h. After cooling to the room
temperature, the reaction was diluted with ethyl acetate (250 mL).
The organic phase was washed with water (50 mL) and then with
saturated sodium chloride aqueous solution (100 mL). The organic
layer was dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude 1-isopropylsulfanyl-4-methoxybenzene (10
mmol) was used for further transformation without any
purification.
[0201] To a solution of the aforementioned crude
1-isopropylsulfanyl-4-methoxybenzene (ca. 10 mmol) in DCM (20 ml),
32% aqueous ethaneperoxoic acid solution (7 mL) was added at
0.degree. C. The reaction mixture was then stirred at room
temperature for 2 h then diluted with ethyl acetate (150 mL). The
organic phase was washed with water (50 mL) and 1% aqueous KOH
solution (75 mL). The organic phase was then dried over anhydrous
sodium carbonate and concentrated under vacuum to furnish 2 g of
crude 1-methoxy-4-(propane-2-sulfonyl)-benzene as a pale yellow
oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 1.28 (d, 6H), 3.16
(m, 1H), 3.89 (s, 3H), 7.02 (d, 2H), 7.80 (d, 2H) ppm.
[0202] To a solution of crude
1-methoxy-4-(propane-2-sulfonyl)benzene (8 mmol) in dry
dichloromethane (20 mL), chlorosulfonic acid (1 mL) was added
dropwise at 0.degree. C. The reaction mixture was warmed to room
temperature followed by the addition of PCl.sub.5 (0.5 g). The
resulting reaction mixture was refluxed for 1 h. After cooling to
room temperature, the reaction mixture was poured into ice water
(50 mL) with vigorous stirring. The aqueous layer was then
extracted with EtOAc (2.times.75 mL). The combined organic extracts
was washed with saturated sodium chloride aqueous solution
(2.times.50 mL), dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue was purified by flash column
chromatography eluting with hexanes/EtOAc (3:1) to give 1.25 g of
2-methoxy-5-(propane-2-sulfonyl)benzenesulfonyl chloride. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 1.31 (d, 1H), 3.23 (m, 1H), 4.18
(s, 3H), 7.30 (d, 1H), 8.18 (dd, 1H), 8.46 (d, H) ppm.
[0203] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)-amide (1 mmol) (prepared as in example 1) in DCM (2
mL) and pyridine (2 mL),
2-methoxy-5-(propane-2-sulfonyl)benzenesulfonyl chloride (1.1 mmol)
was added at RT and the reaction mixture was then allowed to stir
at RT overnight. The reaction mixture was then diluted with DCM (10
mL). The organic phase was washed with 10% aqueous HCl (10 mL),
water (10 mL) and brine (10 mL). The organic phase was dried over
anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to obtain 460 mg of
benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(propane-2
sulfonyl)benzenesulfonylamino]phenyl-amide. T.sub.r 1.09 min; MS:
581.4 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
0.97 (d, 6H), 3.58 (m, 1H), 4.02 (s, 3H), 6.84 (dd, 1H), 7.96 (td,
1H), 7.10 (td, 1H), 7.23 (dd, 1H), 7.44-7.54 (m, 3H), 7.86 (d, 1H),
7.90 (s, 1H), 7.96 (d, 1H), 8.03 (dd, 2H), 9.22 (bs, 1H), 9.79 (s,
1H) ppm.
Example 3
[0204] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)-amide (1 mmol) in DCM (2 mL) and pyridine (2 mL),
methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.1 mmol) was added at
RT and the reaction mixture was then allowed to stir at RT
overnight. The reaction mixture was then diluted with DCM (10 mL).
The organic phase was washed with 10% aqueous HCl (10 mL), water
(10 mL) and brine (10 mL). The organic phase was dried over
anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to obtain 350 mg of
3-[2-(benzo[b]thiophene-2-sulfonylamino)phenylsulfamoyl]-4-methoxybenzoic
acid methyl ester. T.sub.r 1.10 min, MS: 533.7 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 3.84 (s, 3H), 4.18 (s, 3H),
7.0-7.2 (m, 5H), 7.4-7.6 (m, 3H), 7.66 (s, 1H), 7.80 (d, 1H), 7.83
(d, 1H), 8.22 (dd, 1H), 8.34 (d, 1H) ppm.
Example 4
[0205] To a solution of
3-[2-(Benzo[b]thiophene-2-sulfonylamino)-phenyl
sulfamoyl]-4-methoxy-benzoic acid methyl ester (5 mmol, obtained as
in Example 3) in THF (10 mL) and methanol (10 mL), 4 M aq. NaOH (5
mL) was added at RT. The reaction mixture was stirred at room
temperature till the reaction was complete. The reaction mixture
was then concentrated in vacuo and acidified with 10% aq. HCl to pH
.about.3. A white precipitate was formed which was filtered, washed
with ether and dried, affording 2.5 g of
3-[2-(benzo[b]thiophene-2-sulfonylamino)-phenylsulfamoyl]-4-methoxyb-
enzoic acid. MS: 519.8 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6, 400
MHz): .delta. 4.05 (s, 3H), 6.89 (d, 1H), 6.99 (dd, 1H), 7.11 (dd,
1H), 7.25 (d, 1H), 7.38 (d, 1H), 7.48 (dd, 1H), 7.53 (dd, 1H), 7.91
(s, 1H), 7.98 (d, 1H), 8.65 (d, 1H), 8.13 (dd, 1H), 8.16 (dd, 1H)
ppm.
Example 5
[0206] To a solution of
N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide
(2 mmol, prepared as in Example A) in DCM (4 mL) and pyridine (4
mL), 3-nitrobenzenesulfonyl chloride (2.2 mmol) was added at RT and
the reaction mixture was then allowed to stir at RT. The reaction
mixture was then diluted with DCM (20 mL). The organic phase was
washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20
mL). The organic phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to afford 1.04 g
of
2-methoxy-N-[2-(3-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesul-
fonylbenzenesulfonamide. LC: T.sub.r 1.17 min, MS: 596.6
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.27 (s,
3H), 6.76 (d, 1H), 6.78 (bs, 1H), 7.05 (m, 1H), 7.16 (m, 2H), 7.34
(d, 1H), 7.68 (bs, 1H), 7.72 (t, 1H), 8.01 (dd, 1H), 8.20 (dd, 1H),
8.25 (d, 1H), 8.46 (dd, 1H), 8.55 (d, 1H) ppm.
[0207] To a solution of the bissulfonamide (1 mmol) obtained as
above in AcOH (5 mL), iron powder (300 mg) was added and the
resulting reaction mixture was heated at 100.degree. C. for 30 min.
The reaction mixture was filtered through a short pad of Celite and
the pad was washed with methanol (50 mL) and dichloromethane (25
mL). The filtrate was concentrated under vacuum. The residue
obtained was dissolved in EtOAc (50 mL) and washed with of 1%
aqueous KOH solution (25 mL). The organic layer was dried over
anhydrous sodium sulfate and the solvent was removed to dryness in
vacuo to give 155 mg of crude
N-[2-(3-amino-benzenesulfonylamino)-phenyl]-2-methoxy-5-trifluoro
methanesulfonyl-benzenesulfonamide. LC: T.sub.r 1.09 min; MS: 566.4
(M+1).sup.+.
[0208] To a solution of the amino intermediate (0.5 mmol) obtained
as above in AcOH (2 mL) was added NH.sub.4OAc (10 mmol), 37%
aqueous formaldehyde solution (2 mL), and 40% aqueous glyoxal (1
mL). The reaction mixture was heated at 100.degree. C. for 1.5 h.
After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (50 mL). The organic phase was washed with water
(25 mL) and 1% aqueous KOH solution (25 mL). The organic phase was
dried over sodium sulfate and concentrated under vacuum. The
residue was purified by flash column chromatography eluting with
EtOAc then ethyl acetate/methanol (100:2 to 100:10) to afford 155
mg of
N-[2-(3-imidazol-1-yl-benzenesulfonylamino)phenyl]-2-methoxy-5-trifluorom-
ethanesulfonyl-benzenesulfonamide. LC: T.sub.r 0.90 min; MS: 617.7
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.15 (s,
3H), 6.75 (d, 1H), 7.01 (bs, 1H), 7.05 (t, 1H), 7.17 (t, 1H), 7.30
(m, 5H), 7.53 (m, 3H), 7.73 (d, 2H), 8.04 (dd, 1H), 8.25 (d, 1H)
ppm.
Example 6
[0209] To a solution of
N-(2-amino-phenyl)-2-methoxy-5-trifluoromethane
sulfonylbenzenesulfonamide (1 mmol, prepared as in Example 3) in
DCM (2 mL) and pyridine (2 mL), 4-nitrobenzenesulfonyl chloride
(1.1 mmol) was added at RT and the reaction mixture was then
allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (10 mL). The organic phase was washed with 10%
aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic
phase was dried over anhydrous sodium sulfate, and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to afford 446 mg of
2-methoxy-N-[2-(4-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesul-
fonyl benzenesulfonamide. LC: T.sub.r 1.15 min, MS: 596.8
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.27 (s,
3H), 6.79 (d, 1H), 6.83 (bs, 1H), 7.07 (m, 1H), 7.17 (m, 2H), 7.34
(d, 1H), 7.59 (bs, 1H), 7.90 (d, 2H), 8.20 (t, 1H), 8.25 (d, 1H),
8.30 (d, 2H) ppm.
[0210] To a solution of the
2-methoxy-N-[2-(4-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesul-
fonylbenzenesulfonamide (1 mmol) in AcOH (5 mL), iron powder (300
mg) was added and the resulting reaction mixture was heated at
100.degree. C. for 30 min. The reaction mixture was filtered
through a short pad of Celite and the pad was washed with methanol
(50 mL) and dichloromethane (25 mL). The filtrate was concentrated
under vacuum. The residue obtained was dissolved in EtOAc (50 mL)
and washed with 1% aqueous KOH solution (25 mL). The organic layer
was dried over anhydrous sodium sulfate and the solvent was removed
to dryness in vacuo to give 486 mg of crude
N-[2-(4-aminobenzenesulfonylamino)-phenyl]-2-methoxy-5-trifluoro
methanesulfonyl-benzenesulfonamide. LC: T.sub.r 1.09 min; MS: 566.7
(M+1).sup.+.
[0211] To a solution of the amino intermediate (0.5 mmol) obtained
as above in AcOH (2 mL) was added NH.sub.4OAc (10 mmol), 37%
aqueous formaldehyde solution (2 mL), and 40% aqueous glyoxal (1
mL). The reaction mixture was heated at 100.degree. C. for 1.5 h.
After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (50 mL). The organic phase was washed with water
(25 mL) and 1% KOH aqueous solution (25 mL). The organic phase was
dried over sodium sulfate and concentrated under vacuum. The
residue was purified by flash column chromatography eluting with
EtOAc then ethyl acetate/methanol (100:2 to 100:10) to afford 200
mg of
N-[2-(4-imidazol-1-yl-benzenesulfonylamino)phenyl]-2-methoxy-5-trifluorom-
ethanesulfonyl-benzenesulfonamide. LC: T.sub.r 0.90 min; MS: 617.6
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.16 (s,
3H), 6.81 (d, 1H), 7.05 (m, 2H), 7.14 (m, 2H), 7.24 (m, 3H), 7.43
(d, 2H), 7.55 (bs, 1H), 7.75 (d, 2H), 7.83 (s, 1H), 8.06 (dd, 1H),
8.25 (d, 1H) ppm.
Example 7
[0212] To a solution of
N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide
(0.5 mmol, prepared as in Example A) in DCM (1 mL) and pyridine (1
mL), 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (0.55
mmol) was added at RT and the reaction mixture was then allowed to
stir at RT overnight. The reaction mixture was then diluted with
DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5
mL), water (5 mL) and brine (5 mL). The organic phase was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to afford 202 mg of
5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-5-trifluoromethanesulfonyl-benzenesulfonylamino)phenyl]-ami-
de. LC: T.sub.r 1.32 min, MS: 655.4 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 2.14 (s, 3H), 4.29 (s, 3H), 6.33
(bs, 1H), 6.54 (d, 1H), 6.98 (t, 1H), 7.24 (t, 1H), 7.35 (d, 1H),
7.45 (dd, 1H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.75 (d, 1H), 8.14 (bs,
1H), 8.17 (dd, 1H), 8.31 (d, 1H) ppm.
Example 8
[0213] To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL)
and pyridine (5 mL) at 0.degree. C.,
5-bromo-2-methoxybenzenesulfonyl chloride (5.5 mmol) was added in
small portions. The reaction mixture was then gradually warmed to
RT with stirring continued until the reaction was complete as
determined by TLC or LC-MS. The reaction mixture was then diluted
with DCM (25 mL). The organic phase was washed with water
(2.times.25 mL) and 25 mL of brine. The organic phase was dried
over anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to give 1.07 g of
N-(2-aminophenyl)-5-bromo-2-methoxybenzene sulfonamide. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 4.08 (s, 3H), 4.22 (bs, 2H), 6.52
(m, 2H), 6.75 (m, 2H), 7.01 (d, 1H), 7.03 (m, 1H), 7.65 (dd, 1H),
7.88 (d, 1H) ppm.
[0214] The monosulfonamide (1 mmol) obtained as above was dissolved
in DCM (2 mL) and pyridine (2 mL). Benzo[b]thiophene-2-sulfonyl
chloride (1.1 mmol) was then added at RT and the reaction mixture
was then allowed to stir at RT overnight. The reaction mixture was
then diluted with DCM (10 mL). The organic phase was washed with
10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The
organic phase was dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to give 390 mg
of benzo[b]thiophene-2-sulfonic acid [2-(5-bromo-2-methoxybenzene
sulfonylamino)phenyl]-amide. LC: T.sub.r 1.19 min, MS: 553.5
(M+).sup.+. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.11 (s,
3H), 7.00 (d, 1H), 7.1-7.2 (m, 5H), 7.47 (m, 2H), 7.62 (d, 1H),
7.64 (d, 1H), 7.68 (s, 1H), 7.78 (d, 1H), 7.84 (dd, 2H) ppm.
Example 9
[0215] To a solution of N-(2-aminophenyl)-5-bromo-2-methoxybenzene
sulfonamide (0.5 mmol; prepared as in Example 7) in DCM (1 mL) and
pyridine (1 mL), 4,5-dichlorothiophene-2-sulfonyl chloride (0.55
mmol) was added at RT and the reaction mixture was then allowed to
stir at RT overnight. The reaction mixture was then diluted with
DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5
mL), water (5 mL) and brine (5 mL). The organic phase was dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to afford 214 mg of
4,5-dichlorothiophene-2-sulfonic acid
[2-(5-bromo-2-methoxybenzenesulfonylamino)-phenyl]-amide. LC:
T.sub.r 1.30 min, MS: 572.8 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 4.12 (s, 3H), 7.00 (d, 1H), 7.10 (d, 1H), 7.12
(dd, 1H), 7.22 (dd, 1H), 7.23-7.32 (m, 3H), 7.66 (dd, 1H), 7.70 (d,
1H) ppm.
Example 10
[0216] To a solution of
N-(2-aminophenyl)-5-bromo-2-methoxybenzenesulfonamide (0.5 mmol;
prepared as in Example 7) in DCM (1 mL) and pyridine (1 mL),
5-isoxazol-3-yl-thiophene-2-sulfonyl chloride (0.55 mmol) was added
at RT and the reaction mixture was then allowed to stir at RT
overnight. The reaction mixture was then diluted with DCM (5 mL).
The organic phase was washed with 10% aqueous HCl (5 mL), water (5
mL) and brine (5 mL). The organic phase was dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue obtained
was purified by flash column chromatography eluting with DCM/EtOAc
to afford 140 mg of 5-isoxazol-3-yl-thiophene-2-sulfonic acid
[2-(5-bromo-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC:
T.sub.r 1.15 min, MS: 572.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 4.10 (s, 3H), 6.51 (s, 1H), 6.99 (d, 1H), 7.04
(d, 1H), 7.11 (dd, 1H), 7.18 (dd, 12H), 7.25 (dd, 1H), 7.40 (d,
1H), 7.46 (d, 1H), 7.54 (dd, 1H), 7.64 (dd, 1H), 7.75 (dd, 1H),
8.31 (s, 1H) ppm.
Example 11
[0217] To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL)
and pyridine (4 mL) at 0.degree. C., 4-chlorobenzenesulfonyl
chloride (4.4 mmol) was added in small portions. The reaction
mixture was then gradually warmed to RT with stirring continued
until the reaction was complete as determined by TLC or LC-MS. The
reaction mixture was then diluted with DCM (20 mL). The organic
phase was washed with water (2.times.20 mL) and 20 mL of brine. The
organic phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to give 960 mg
of N-(2-aminophenyl)-4-chlorobenzenesulfonamide. LC: T.sub.r 0.92
min, MS: 284.0 (M+1).sup.+.
[0218] The monosulfonamide (1 mmol) obtained as above was dissolved
in DCM (2 mL) and pyridine (2 mL). 2-methoxy-5-nitrobenzenesulfonyl
chloride (1.1 mmol, prepared as in Example B) was then added at RT
and the reaction mixture was then allowed to stir at RT overnight.
The reaction mixture was then diluted with DCM (10 mL). The organic
phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and
brine (10 mL). The organic phase was dried over anhydrous sodium
sulfate, and concentrated under vacuum. The residue obtained was
purified by flash column chromatography eluting with DCM/EtOAc to
give 325 mg of
N-[2-(4-chloro-benzenesulfonylamino)phenyl]-2-methoxy-5-nitrobenzenesulfo-
namide. LC: T.sub.r 1.2 min, MS: 498.1 (M+1).sup.+.
Example 12
[0219] To a solution of benzofuran (10 mmol) in dry THF (15 mL) at
40.degree. C., n-BuLi (2.5 M in hexanes; 4.4 mL; 11 mmol) was added
dropwise. The reaction mixture was stirred at -40.degree. C. for
30-40 min. Sulfur dioxide gas was passed into the reaction mixture,
keeping the tip of the needle just above the reaction mixture, for
about 5-10 min. A white precipitate was formed. The reaction
mixture was then brought to RT and the stirring was continued for 1
h, then the mixture was diluted with hexane (20 mL) to give
benzofuran-2-sulfinic acid lithium salt as a white precipitate. The
solid was filtered and dried in vacuo to afford the salt.
[0220] The solid obtained as above was suspended in DCM (50 mL) and
was treated with N-chlorosuccinimide (11 mmol) at 0.degree. C. The
resulting suspension was then brought to RT with stirring
maintained vigorously overnight. The dark brown reaction mixture
was filtered and washed with DCM. The filtrate was concentrated in
vacuo and the residue obtained was purified through silica gel
column chromatography using EtOAc/hexane as eluant to furnish 1.19
g of benzofuran-2-sulfonyl chloride as a pale brown solid.
[0221] To a solution of
N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as
in Example 11) in DCM (1 mL) and pyridine (1 mL),
benzofuran-2-sulfonyl chloride (0.55 mmol), prepared as above, was
added at RT and the reaction mixture was then allowed to stir at RT
overnight or until the reaction was complete as determined by TLC
or LC-MS. The reaction mixture was then diluted with DCM (5 mL).
The organic phase was washed with 10% aqueous HCl (5 mL), water (5
mL) and brine (5 mL). The organic phase was dried over anhydrous
sodium sulfate, and concentrated under vacuum. The residue obtained
was purified by flash column chromatography eluting with DCM/EtOAc
to afford 92 mg benzofuran-2-sulfonic acid
[2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: T.sub.r 1.13
min, MS: 464.0 (M+1).sup.+.
Example 13
[0222] To a solution of
N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as
in Example 11) in DCM (1 mL) and pyridine (1 mL),
benzo[b]thiophene-2-sulfonyl chloride (0.55 mmol), prepared as
above, was added at RT and the reaction mixture was then allowed to
stir at RT overnight or until the reaction was complete as
determined by TLC or LC-MS. The reaction mixture was then diluted
with DCM (5 mL). The organic phase was washed with 10% HCl aqueous
solution (5 mL), water (5 mL) and brine (5 mL). The organic phase
was dried over anhydrous sodium sulfate and concentrated under
vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to afford 180 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: T.sub.r 1.23
min, MS: 479.8 (M+1).sup.+.
Example 14
[0223] To a solution of 1-methoxy-4-methylsulfanylbenzene (10 mmol)
in DCM (20 ml), 32% aqueous ethaneperoxoic acid solution (7 mL) was
added at 0.degree. C. The reaction mixture was then stirred at room
temperature for 2 h then diluted with ethyl acetate (100 mL). The
organic phase was washed with water (50 mL) and 1% aqueous KOH
solution (75 mL). The organic phase was then dried over anhydrous
sodium carbonate and concentrated under vacuum to furnish 1.5 g of
crude 1-methanesulfonyl-4-methoxybenzene as an off-white solid.
[0224] To a solution of crude 1-methanesulfonyl-4-methoxybenzene (8
mmol) in dry dichloromethane (20 mL), chlorosulfonic acid (1 mL)
was added dropwise at 0.degree. C. The reaction mixture was warm to
room temperature followed by the addition of PCl.sub.5 (0.5 g). The
resulting reaction mixture was refluxed for 1 h. After cooling to
room temperature, the reaction mixture was poured into stirring ice
water (50 mL). The water layer was then extracted with EtOAc
(2.times.40 mL.) The combined organic extracts was washed with
saturated sodium chloride aqueous solution (2.times.40 mL), dried
over anhydrous sodium sulfate, and concentrated under vacuum. The
residue was purified by flash column chromatography eluting with
hexanes/EtOAc (3:1) to give 1.6 g of
5-methanesulfonyl-2-methoxybenzenesulfonyl chloride.
[0225] To a solution of
N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as
in Example 11) in DCM (1 mL) and pyridine (1 mL),
5-methanesulfonyl-2-methoxybenzenesulfonyl chloride (0.55 mmol),
prepared as above, was added at RT and the reaction mixture was
then allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (5 mL). The organic phase was washed with 10%
aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic
phase was dried over anhydrous sodium sulfate, and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to afford 160 mg of;
N-[2-(4-chlorobenzenesulfonylamino)phenyl]-5-methanesulfonyl-2-methox-
ybenzenesulfonamide. LC: T.sub.r 1.05 min, MS: 531.9
(M+1).sup.+.
Example 15
[0226] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)amide (1 mmol, prepared as in Example 1) in DCM (2
mL) and pyridine (2 mL), 4-methoxy-2-nitrobenzenesulfonyl chloride
(1.1 mmol) was added at RT and the reaction mixture was then
allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (10 mL). The organic phase was washed with 10%
aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to obtain 348 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(4-methoxy-2-nitro-benzenesulfonylamino)phenyl]-amide. LC:
T.sub.r 1.09 min; MS: 520.7 (M+1).sup.+.
Example 16
[0227] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2
mL) and pyridine (2 mL), 5-methanesulfonyl-2-methoxybenzenesulfonyl
chloride (1.1 mmol) was added at RT and the reaction mixture was
then allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (10 mL). The organic phase was washed with 10%
aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to obtain 330 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(4-methanesulfonyl-2-methoxy-benzenesulfonylamino)phenyl]-amide.
LC: T.sub.r 1.06 min; MS: 553.8 (M+1).sup.+.
Example 17
[0228] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2
mL) and pyridine (2 mL), 2-methoxy-5-methylbenzenesulfonyl chloride
(1.1 mmol) was added at RT and the reaction mixture was then
allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (10 mL). The organic phase was washed with 10%
aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to obtain 390 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-5-methylbenzenesulfonylamino)phenyl]-amide. LC:
T.sub.r 1.25 min; MS: 489.1 (M+1).sup.+.
Example 18
[0229] To a solution of benzo[b]thiophene-2-sulfonic acid
[2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl]-amide
(0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was
added in one portion and the resulting reaction mixture was then
heated to reflux for ca. 4 h. After the completion of the reaction,
the reaction mixture was cooled to RT and concentrated in vacuo.
The residue obtained was redissolved in EtOAc (10 mL) and was
washed with water (10 mL) and brine (10 mL). The organic phase was
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to obtain 204 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-5-trifluoromethyl-benzenesulfonylamino)phenyl]-amide.
LC: T.sub.r 1.20 min; MS: 544.1 (M+1).sup.+.
Example 19
[0230] To a solution of 2-(4-methoxybenzenesulfonyl)ethanol (20
mmol) in dry DCM (20 mL), triethylamine (4 mL) was added. The
reaction mixture was cooled to 0.degree. C. followed by dropwise
addition of methanesulfonyl chloride (3 mL). The reaction mixture
was then stirred at room temperature for 12 h after which it was
diluted with DCM (150 mL). The organic phase was washed with 10%
aqueous HCl (50 mL), dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with hexanes/EtOAc (3:1 to 1:1)
to give 5-ethenesulfonyl-2-methoxybenzene (3 g).
[0231] To a solution of 5-ethenesulfonyl-2-methoxybenzene (3 g),
obtained as above, in dry dichloromethane (30 mL), chlorosulfonic
acid (3 mL) was added dropwise at 0.degree. C. The reaction mixture
was warm to room temperature followed by the addition of PCl.sub.5
(3 g) in three portions. The resulting reaction mixture was
refluxed for 2 h. After cooling to room temperature, the reaction
mixture was poured into ice water (100 mL) with stirring. The
contents were extracted with EtOAc (2.times.150 mL). The combined
organic phase was washed with saturated sodium chloride aqueous
solution (2.times.100 mL), dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue obtained was purified by
column chromatography eluting with ethyl acetate/hexanes (1:4 to
1:1) to give 5-ethenesulfonyl-2-methoxybenzenesulfonyl chloride (3
g).
[0232] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)-amide (10 mmol, prepared as in Example 1) in DCM
(20 mL) and pyridine (20 mL),
5-ethenesulfonyl-2-methoxybenzenesulfonyl chloride (11 mmol) was
added at RT and the reaction mixture was then allowed to stir at RT
overnight. The reaction mixture was then diluted with DCM (100 mL).
The organic phase was washed with 10% aqueous HCl (100 mL), water
(100 mL) and brine (100 mL). The organic phase was dried over
anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with DCM/EtOAc to obtain benzo[b]thiophene-2-sulfonic acid
[2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]amide
(2.8 g). LC: T.sub.r 1.15 min; MS: 565.9 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 4.17 (s, 3H), 6.03 (d, 1H), 6.42 (d,
1H), 6.56 (dd, 1H), 6.81 (dd, 1H), 6.97 (t, 1H), 7.13 (t, 1H), 7.18
(d, 1H), 7.32 (d, 1H), 7.42-7.52 (m, 2H), 7.62 (s, 1H), 7.80 (d,
1H), 7.83 (d, 1H), 8.04 (dd, 1H), 8.19 (d, 1H) ppm.
[0233] To a solution of benzo[b]thiophene-2-sulfonic acid
[2-(5-ethenesulfonyl-2-methoxy-benzenesulfonylamino)-phenyl]-amide
(0.5 mmol), as prepared above, in dry THF (10 mL), Me.sub.2NH-THF
solution (2.5 mL; 2 M Me.sub.2NH in THF solution) was added. The
resulting reaction mixture was stirred at room temperature for 30
min. After removal of the solvent under vacuum, the residue
obtained was purified by flash column chromatography eluting with
EtOAc then DCM/methanol (100:2 to 100:10) to give 290 mg of
benzo[b]thiophene-2-sulfonic acid
{2-[5-(2-dimethylaminoethanesulfonyl)-2-methoxybenzenesulfonylamino]pheny-
l}-amide. LC: T.sub.r 0.99 min; MS: 610.7 (M+1).sup.+.
Example 20
[0234] To a solution of benzo[b]thiophene-2-sulfonic acid
[2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]-amide
(0.2 mmol, prepared as in Example 19) in dry DMF (3 mL),
2H-tetrazole (25 mg) was added. The resulting reaction mixture was
stirred in a sealed tube for 2 hours at 110.degree. C. The reaction
mixture was diluted with DCM (20 mL) and washed with saturated
sodium chloride solution (25 mL). The organic phase was dried over
anhydrous sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by flash column chromatography
eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to
furnish two separable regio-isomers. The less polar was
benzo[b]thiophene-2-sulfonic acid
{2-[2-methoxy-5-(2-tetrazol-2-yl-ethanesulfonyl)-benzenesulfonylamino]-ph-
enyl}-amide (51 mg). LC: T.sub.r 1.08 min; MS: 635.6
(M+1).sup.+.
Example 21
[0235] To a solution of benzo[b]thiophene-2-sulfonic acid
[2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]-amide
(0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added
0.2 mL of pyrrolidine. The resulting reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was diluted with
DCM (10 mL) and was washed with saturated sodium chloride aqueous
solution (25 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue obtained was
purified by flash column chromatography eluting with EtOAc then
DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 121 mg of
benzo[b]thiophene-2-sulfonic acid
{2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]p-
henyl}amide. LC: T.sub.r 0.94 min; MS: 636.8 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 1.68 (m, 4H), 2.38 (m, 4H), 2.78
(t, 2H), 3.28 (t, 2H), 4.20 (s, 3H), 6.76 (d, 1H), 6.96 (d, 1H),
7.14 (t, 1H), 7.21 (d, 1H), 7.36 (d, 1H), 7.41 (t, 1H), 7.49 (t,
1H), 7.60 (s, 1H), 7.79 (d, 1H), 7.83 (d, 1H), 8.07 (d, 1H), 8.26
(d, 1H) ppm.
Example 22
[0236] To a solution of benzo[b]thiophene-2-sulfonic acid
[2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]amide
(0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added
0.2 mL of 1-methylpiperazine. The resulting reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was
diluted with DCM (10 mL) and washed with saturated sodium chloride
aqueous solution (25 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
obtained was purified by flash column chromatography eluting with
EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 118
mg of benzo[b]thiophene-2-sulfonic acid
{2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]--
phenyl}-amide. LC: T.sub.r 0.84 min; MS: 666.0 (M+1).sup.+.
Example 23
[0237] To a solution of 4'-methoxy-2,2,2-trifluoroacetophenone (5
mmol) in 1,2-dichloroethane (10 mL), 0.5 mL of chlorosulfonic acid
was added at 0.degree. C. The resulting reaction mixture was
gradually warmed to room temperature and then heated to reflux for
4 h. The reaction mixture was then cooled to room temperature and
was diluted with chloroform (30 mL). The contents were then
transferred to a separatory funnel, washed with water (50 mL), and
the layers were separated. The aqueous layer was then extracted
with chloroform (30 mL). The combined organic layers were washed
with brine (50 mL) and dried over anhydrous sodium sulfate. The
solvent was removed in vacuo and the residue obtained was purified
by silica gel flash column chromatography using ethyl
acetate/hexanes as eluant (1:10 to 1:2 gradient) to afford 440 mg
of 5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxybenzenesulfonyl
chloride. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 4.14 (s, 3H),
7.14 (d, 1H), 8.14 (dd, 1H), 8.44 (d, 1H) ppm.
[0238] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2
mL) and pyridine (2 mL),
5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxybenzenesulfonyl
chloride (1.1 mmol) was added at RT and the reaction mixture was
then allowed to stir at RT overnight. The reaction mixture was then
diluted with DCM (20 mL). The organic phase was washed with 10%
aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to afford 374 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxy-benzenesulfonylamino)-
phenyl]-amide. LC: T.sub.r 1.40 min; MS: 625.8 (M+1).
Example 24
[0239] To a solution of
N-(2-amino-phenyl)-4-chlorobenzenesulfonamide (1.0 mmol, prepared
as in Example 11) in DCM (2 mL) and pyridine (2 mL),
2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride (1.1 mmol) was
added at RT and the reaction mixture was then allowed to stir at RT
overnight. The reaction mixture was then diluted with DCM (10 mL).
The organic phase was washed with 10% aqueous HCl (10 mL), water
(10 mL), and brine (10 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
obtained was purified by flash column chromatography eluting with
DCM/EtOAc to obtain 419 mg of
2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylben-
zenesulfonamide. LC: T.sub.r 1.25 min; MS: 525.9 (M+1).
[0240] To a solution of
2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylben-
zenesulfonamide (0.5 mmol) in dioxane (5 mL), solid sodium
methoxide (2 mmol) was added in one portion and the resulting
reaction mixture was then heated to reflux for ca. 4 h. After the
completion of the reaction, the reaction mixture was cooled to RT
and concentrated in vacuo. The residue obtained was redissolved in
EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The
organic phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to obtain 160 mg
of N-[2-(4-chlorobenzenesulfonylamino)phenyl]-2-methoxy-5-trifluor-
omethylbenzenesulfonamide. LC: T.sub.r 1.22 min; MS: 521.8
(M+1).sup.+.
Example 25
[0241] To a solution of benzo[b]thiophene-2-sulfonic acid
(2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2
mL) and pyridine (2 mL), 2-methoxy-4-nitrobenzenesulfonyl chloride
(1.1 mmol) was added at RT and the reaction mixture was then
allowed to stir at RT overnight or until the reaction was complete
as determined by TLC or LC-MS. The reaction mixture was then
diluted with DCM (20 mL). The organic phase was washed with 10%
aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic
phase was dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue obtained was purified by flash column
chromatography eluting with DCM/EtOAc to yield 353 mg of
benzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]-amide. LC:
T.sub.r 1.21 min; MS: 520.7.7 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 4.24 (s, 3H), 6.72 (bs, 1H), 6.88 (d, 1H), 7.03
(t, 1H), 7.16 (t, 1H), 7.30 (d, 1H), 7.52 (t, 1H), 7.51 (t, 1H),
7.64 (s, 1H), 7.67-7.88 (m, 5H), 7.92 (s, 1H) ppm.
[0242] To a solution of the aforementioned
benzo[b]thiophene-2-sulfonic acid
[2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]amide (0.5 mmol)
in ethyl acetate (5 mL) and methanol (5 mL) was added palladium on
activated carbon (10%, wet, .about.20 mg). The reaction mixture was
deaerated under vacuum for 5 min and stirred under hydrogen
atmosphere (1 atm) for 20 min. The reaction mixture was filtered
through a short pad of Celite and the pad was washed with methanol
(20 mL) and dichloromethane (20 mL). The combined organic phase was
concentrated under vacuum to afford 238 mg of the amino
intermediate. LC: T.sub.r 1.13 min, MS: 490.9 (M+1).sup.+. .sup.1H
NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.82 (s, 3H), 6.03 (dd, 1H),
6.06 (bs, 2H), 6.21 (d, 1H), 6.90 (m, 2H), 7.05 (td, 1H), 7.20 (dd,
1H), 7.46 (td, 1H), 7.52 (td, 1H), 7.88 (s, 1H), 7.97 (dd, 1H),
8.06 (dd, 1H), 8.66 (bs, 1H), 9.78 (bs, 1H) ppm.
[0243] To a solution of the amino intermediate (0.3 mmol) obtained
as above in AcOH (2 mL) was added NH.sub.4OAc (10 mmol), 37%
aqueous formaldehyde solution (2 mL), and 40% aqueous glyoxal (1
mL). The reaction mixture was heated at 100.degree. C. for 1.5 h.
After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (50 mL). The organic phase was washed with water
(25 mL) and 1% aqueous KOH (25 mL). The organic phase was dried
over sodium sulfate and concentrated under vacuum. The residue
obtained was purified by flash column chromatography eluting with
hexane/EtOAc (1:1) then with DCM/methanol (100:2 to 100:10) to
afford 98 mg of benzo[b]thiophene-2-sulfonic acid
[2-(4-imidazol-1-yl-2-methoxybenzenesulfonylamino)phenyl]-amide.
LC: T.sub.r 0.87 min; MS: 541.6 (M+1).sup.+. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 4.06 (s, 3H), 6.80 (dd, 1H), 6.95
(td, 1H), 7.06 (m, 2H), 7.13 (s, 1H), 7.23 (dd, 1H), 7.29 (d, 1H),
7.52-7.42 (m, 3H), 7.67 (d, 1H), 7.88 (s, 1H), 7.90 (s, 1H), 7.94
(d, 1H), 8.02 (d, 1H), 8.46 (s, 1H), 9.06 (bs, 1H) ppm.
Example 26
[0244] To a solution of benzene-1,2-diamine (1 mmol) in DCM (4 mL)
and pyridine (1 mL) at 0.degree. C., benzo[b]thiophene-2-sulfonyl
chloride (2.2 mmol) was added at 0.degree. C. in small portions
(over 10-15 min) at 0.degree. C. The reaction mixture was then
gradually warmed to RT with stirring continued for 6 h. The
reaction mixture was then diluted with DCM (10 mL). The organic
phase was washed with 10% aqueous HCl (10 mL), water (10 mL), and
brine (10 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue obtained was
purified by flash column chromatography eluting with DCM followed
by EtOAc/DCM (1% to 3%) to give 425 mg of
N-[2-(benzothiophene-2-sulfonyl)amino]phenyl-benzothiophene-2-sulfonamide-
. LC: T.sub.r 1.18 min; MS: 501.7 (M+1).sup.+. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 7.14 (A.sub.2B.sub.2, 4H), 7.48
(dd, 2H), 7.54 (dd, 2H), 7.95 (s, 2H), 7.97 (d, 2H), 8.03 (d, 2H)
ppm.
Example 27
[0245] To a solution of benzene-1,2-diamine (0.5 mmol) in DCM (2
mL) and pyridine (0.5 mL) at 0.degree. C., benzofuran-2-sulfonyl
chloride (1.1 mmol; prepared as in Example 12) was added at
0.degree. C. in small portions over 10-15 min. The reaction mixture
was then gradually warmed to RT with stirring continued for 6 h.
The reaction mixture was then diluted with DCM (5 mL). The organic
phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and
brine (5 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue obtained was
purified by flash column chromatography eluting with DCM followed
by EtOAc/DCM (1% to 3%) to give 117 mg of
N-{2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}-1-benzofuran-2-sulfonamide-
. T.sub.r 1.18 min; MS: 469.7 (M+1).sup.+.
Example 28
[0246] To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL)
and pyridine (4 mL) at 0.degree. C., 3,4-dichlorobenzenesulfonyl
chloride (4.4 mmol) was added in small portions. The reaction
mixture was then gradually warmed to RT with stirring continued
until the reaction was complete as determined by TLC or LC-MS. The
reaction mixture was then diluted with DCM (20 mL). The organic
phase was washed with water (2.times.20 mL) and 20 mL of brine. The
organic phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to give 760 mg
of N-(2-amino-phenyl)-3,4-dichloro-benzenesulfonamide. LC: T.sub.r
0.98 min, MS: 317.0 (M+1).sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta. 4.95 (bs, 2H), 6.45 (t, 1H), 6.11 (d, 1H), 6.72 (d, 1H),
6.92 (t, 1H), 7.59 (dd, 1H), 7.80 (d, 3H) ppm.
[0247] The monosulfonamide (1 mmol) obtained as above was dissolved
in DCM (2 mL) and pyridine (2 mL).
5-fluoro-2-methoxy-benzenesulfonyl chloride (1.1 mmol) was added at
RT and the reaction mixture was then allowed to stir at RT
overnight. The reaction mixture was then diluted with DCM (10 mL).
The organic phase was washed with 10% aqueous HCl (10 mL), water
(10 mL), and brine (10 mL). The organic phase was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
obtained was purified by flash column chromatography eluting with
DCM/EtOAc to give 302 mg of
N-[2-(3,4-dichlorobenzenesulfonylamino)-phenyl]-5-fluoro-2-methoxybenzene-
sulfonamide. LC: T.sub.r 1.19 min; MS: 505.5 (M+1).sup.+; .sup.1H
NMR (DMSO-d6, 400 MHz): .delta. 3.92 (s, 3H), 6.85 (dd, 1H), 7.02
(m, 1H), 7.08 (m, 2H), 7.28 (dd, 1H), 7.40 (dd, 1H), 7.50 (m, 1H),
7.56 (dd, 1H), 7.80 (d, 1H), 7.82 (s, 1H), 9.11 (bs, 1H), 9.56 (bs,
1H) ppm.
Example 29
[0248] To a mixture of pyridine-4-boronic acid (3 mmol),
4-bromo-2-nitrophenylamine (2 mmol), and Pd(PPh.sub.3).sub.4 (20
mg) in DME (10 mL), 2 M aqueous Na.sub.2CO.sub.3 was added. The
suspension was then refluxed under nitrogen for 36 h. After cooling
to the room temperature, the reaction mixture was diluted with
ethyl acetate (150 mL). The organic phase was washed with brine (50
mL), dried over sodium sulfate, and concentrated under vacuum. The
residue obtained was purified by column chromatography eluting with
hexanes/ethyl acetate (1:1) then ethyl acetate/methanol (10:1) to
give 516 mg of 2-nitro-4-pyridin-4-ylphenylamine. .sup.1H NMR
(DMSO-d6, 400 MHz): LC: T.sub.r 0.44 min, MS: 216.1 (M+1).sup.+.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 7.13 (d, 1H), 7.60 (d,
2H), 7.69 (bs, 2H), 7.88 (dd, 1H), 8.37 (d, 1H), 8.55 (d, 2H)
ppm.
[0249] To a solution of 2-nitro-4-pyridin-4-ylphenylamine (1 mmol)
in pyridine (3 mL), 4-chloro-benzenesulfonyl chloride (1.2 mmol)
was added and the resulting mixture was stirred at room temperature
for 24 h. The reaction mixture was diluted with ethyl acetate (20
mL). The contents were washed with brine (25 mL), dried over sodium
sulfate and concentrated under vacuum. The residue obtained was
purified by column chromatography eluting with hexanes/ethyl
acetate (1:1) then ethyl acetate to give 156 mg of
4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide.
[0250] To a solution of
4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide (0.2
mmol) in ethyl acetate (10 mL), palladium on activated carbon (10%,
wet, 10 mg) was added. The reaction mixture was deaerated under
vacuum for 5 min and stirred under hydrogen atmosphere (1 atm) for
30 min. The reaction mixture was filtered through a short pad of
Celite, washing the pad with methanol (10 mL) and ethyl acetate (15
mL). The combined organic phase was concentrated under vacuum to
give 58 mg of N-(2-amino-4-pyridin-4-ylphenyl)-4-chlorobenzene
sulfonamide.
[0251] To a solution of
N-(2-amino-4-pyridin-4-ylphenyl)-4-chlorobenzene sulfonamide (0.1
mmol) in pyridine (0.5 mL), 5-bromo-2-methoxy-benzenesulfonyl
chloride (0.12 mmol) was added. The reaction mixture was stirred at
room temperature for 2 h and then was diluted with ethyl acetate
(10 mL). The contents were washed with brine (10 mL), dried over
sodium sulfate, and concentrated under vacuum. The residue obtained
was purified by column chromatography eluting with hexanes/ethyl
acetate (1:1) followed by ethyl acetate to give 49 mg of
5-bromo-N-[2-(4-chlorobenzenesulfonylamino)-5-pyridin-4-ylphenyl]-2-metho-
xybenzenesulfonamide. LC: T.sub.r 0.94 min, MS: 610.8
(M+1).sup.+.
Example 30
[0252] To a solution of 4-fluoro-2-nitroaniline (1 mmol) in
pyridine (3 mL), 5-bromo-2-methoxybenzenesulfonyl chloride (1.2
mmol) was added and the resulting mixture was stirred at room
temperature for 24 h. The reaction mixture was diluted with ethyl
acetate (20 mL). The contents were washed with 10% aqueous HCl (20
mL) and brine (20 mL), dried over sodium sulfate, and concentrated
under vacuum. The residue obtained was purified by column
chromatography eluting with hexanes/ethyl acetate to give 223 mg of
5-bromo-N-(4-fluoro-2-nitrophenyl)-2-methoxybenzenesulfonamide.
[0253] The nitro intermediate (0.5 mmol) above was dissolved in
EtOH (10 mL) and was treated with tin (II) chloride (2.5 mmol). The
reaction mixture was heated to reflux for 12 h. The contents were
cooled to RT and treated with 1 M aqueous NaOH until the pH of the
reaction mixture was between 8-9 which resulted in formation of a
precipate. The precipitate was then filtered, washed with methanol
(10 mL) and DCM (10 mL). The combined filtrate was concentrated in
vacuo and the residue obtained was purified by column
chromatography eluting with DCM/ethyl acetate as eluant to give 115
mg of
5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulfonamide.
[0254] To a solution of
5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulfonamide (0.1
mmol) in pyridine (0.5 mL) and DCM (2 mL), 4-chlorobenzenesulfonyl
chloride (0.12 mmol) was added. The reaction mixture was stirred at
room temperature for 4 h and then diluted with ethyl acetate (10
mL). The contents were washed with 10% aqueous HCl (10 mL) and
brine (10 mL), dried over sodium sulfate, and concentrated under
vacuum. The residue obtained was purified by column chromatography
eluting with hexanes/ethyl acetate (1:1) followed by ethyl acetate
to give 43 mg of
5-bromo-N-[2-(4-chlorobenzenesulfonylamino)-4-fluorophenyl]-2-methoxybenz-
enesulfonamide. LC: T.sub.r 1.10 min, MS: 551.8 (M+1).sup.+
Example 31
[0255] To a solution of 4-fluorobenzene-1,2-diamine (1 mmol) in DCM
(2 mL) and pyridine (2 mL) at 0.degree. C.,
benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small
portions. The reaction mixture was then stirred at rt until the
reaction was complete as determined by TLC or LC-MS. The reaction
mixture was then diluted with DCM (15 mL). The organic phase was
washed with 10% aqueous HCl (5 mL), water (5 mL), and 5 mL of
brine. The organic phase was dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to obtain 192 mg
of N,N'-(4-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
as a solid.
[0256] .sup.1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 6.8-6.9 (m, 1H),
7.0-7.2 (m, 2H), 7.4-7.6 (m, 4H), 7.83 (s, 1H), 7.9-8.0 (m, 4H),
8.04 (s, 1H), 9.7-10.1 (br s, 2H) ppm.
Example 32
[0257] To a solution of 4-cyanobenzene-1,2-diamine (1 mmol) in
pyridine (4 mL), benzothiophene-2-sulfonyl chloride (2.2 mmol) was
added in small portions. The reaction mixture was then heated at
80.degree. C. with stirring until the reaction was complete as
determined by TLC or LC-MS. The reaction mixture was then diluted
with ethyl acetate (20 mL). The organic phase was washed with 10%
aqueous HCl solution (15 mL), water (15 mL) and brine (5 mL). The
organic phase was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue obtained was purified by
flash column chromatography eluting with DCM/EtOAc to obtain 184 mg
of N,N'-(4-cyano-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
as a solid.
[0258] .sup.1H NMR (CDCl.sub.3; 300 MHz) .delta. 7.31 (s, 1H);
7.4-7.6 (m, 6H), 7.65 (s, 1H), 7.7-7.9 (m, 5H) ppm.
Example 33
[0259]
N,N'-(4-chloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
(310 mg) was prepared as in Example 31 using
4-chlorobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride
as requisite starting materials.
[0260] .sup.1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 7.18 (s, 2H),
7.22 (s, 1H), 7.4-7.6 (m, 4H), 7.9-8.1 (m, 6H), 9.8-10.1 (br s, 2H)
ppm.
Example 34
[0261]
N,N'-(4-bromo-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
(255 mg) was prepared as in Example 31 using
4-bromobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride
as requisite starting materials.
[0262] .sup.1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 7.06 (d, 1H),
7.2-7.4 (m, 2H), 7.4-7.7 (m, 4H), 7.9-8.1 (m, 6H), 9.8-10.2 (br s,
2H) ppm.
Example 35
[0263]
N,N'-(4-methoxy-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
(472 mg) was prepared as in Example 31 using
4-methoxybenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride
as requisite starting materials.
[0264] .sup.1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 3.58 (s, 3H),
6.62 (dd, 1H), 6.81 (d, 1H), 6.88 (d, 1H), 7.4-7.6 (m, 4H), 7.83
(s, 1H), 7.9-8.2 (m, 5H), 9.65 (br s, 2H) ppm.
Example 36
[0265] To a solution of
3-[2-(benzo[b]thiophene-2-sulfonylamino)-phenyl
sulfamoyl]-4-methoxybenzoic acid (1 mmol, see Example 4) in
anhydrous DMF (4 mL), DIEA (1.5 mmol) and HBTU (1.2 mmol) were
added at rt and the mixture was stirred for 30 min. tert-Butylamine
(1.2 mmol) was then added at rt with stirring continued for another
60 min. The reaction mixture was diluted with water (20 mL) and the
precipitate formed was filtered and washed with water. A white
solid (488 mg) was obtained which was used for further
transformation without purification.
[0266] 1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 1.36 (s, 9H), 4.05
(s, 3H), 6.90 (d, 1H), 6.98 (t, 1H), 7.12 (t, 1H), 7.23 (d, 1H),
7.30 (d, 1H), 7.4-7.6 (m, 2H), 7.85-8.05 (m, 3H), 8.05-8.15 (m,
3H), 9.10 (s, 1H), 9.82 (s, 1H) ppm.
[0267] The amide product from above (0.5 mmol) was suspended in dry
benzene (10 mL) and was treated with phosphrous oxychloride (1 mL).
The reaction mixture was refluxed for 3 h after which the reaction
was complete. The solvent and excess POCl.sub.3 was removed in
vacuo and residue obtained was recrystallized from isopropanol to
afford 125 mg of benzo[b]thiophene-2-sulfonic acid
[2-(5-cyano-2-methoxybenzenesulfonylamino)-phenyl]-amide as a light
yellow solid.
[0268] 1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 4.05 (s, 3H), 6.90
(d, 1H), 7.02 (t, 1H), 7.14 (t, 1H), 7.25 (d, 1H), 7.4-7.6 (m, 3H),
7.91 (s, 1H), 7.95-8.05 (m, 2H), 8.06-8.14 (m, 2H), 9.18 (br s,
1H), 9.82 (br s, 1H) ppm.
Example 37
[0269] To a solution of
3-[2-(Benzo[b]thiophene-2-sulfonylamino)-phenyl
sulfamoyl]-4-methoxybenzoic acid (1 mmol, see Example 4) in
anhydrous DMF (4 mL), DIEA (4.5 mmol) and HBTU (1.2 mmol) were
added at RT and the mixture was stirred for 30 min.
N-Hydroxyacetamidine (2.0 mmol) was then added at RT with stirring
continued for another 60 min. The reaction mixture was diluted with
ethyl acetate (30 mL), washed with water (2.times.20 mL), and dried
over anhydrous Na.sub.2SO.sub.4. After removal of the solvent in
vacuo, 385 mg of the oxamate ester was obtained as a white solid,
which was used for further transformation without any
purification.
[0270] The oxamate obtained as above (0.35 mmol) was suspended in
xylene (6 mL) and was treated with powdered 4 .ANG. molecular
sieves (1 g). The reaction mixture was heated to reflux for 6 h
after which the reaction was complete. The contents were then
filtered and the solvent was removed in vacuo to give 29 mg of
benzo[b]thiophene-2-sulfonic acid
{2-[2-methoxy-5-(3-methyl-[1,2,4]oxadiazol-5-yl)benzenesulfonylamino]phen-
yl}-amide as an off-white solid.
[0271] 1H NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.38 (s, 3H), 4.05
(s, 3H), 6.90 (d, 1H), 6.98 (t, 1H), 7.12 (t, 1H), 7.23 (d, 1H),
7.30 (d, 1H), 7.4-7.6 (m, 2H), 7.85-8.05 (m, 3H), 8.05-8.15 (m,
3H), 9.10 (s, 1H), 9.82 (s, 1H) ppm.
Example 38
[0272] To a solution of 2-thiopheneethylamine (1.5 g, 11.8 mmol)
and 37% aqueous formaldehyde (3.9 ml, 47.2 mmol) in ethanol (10
mL), concentrated hydrochloric acid (3.9 mL) was added and the
resulting solution was heated at 50.degree. C. for 6 h. All
volatiles were removed under reduced pressure. The residue was
taken up in dioxane (13 mL) and 2 N aq. NaOH solution (12.8 mL) and
cooled to 0.degree. C. The reaction mixture was treated with
di-t-butyldicarbonate (2.24 g, 10.28 mmol) and stirred for 10 at
room temperature. The reaction mixture was diluted with ethyl
acetate (25 mL) and the aqueous layer was extracted with ethyl
acetate (10 mL). The combined organic phase was washed with water,
brine, and dried over Na.sub.2SO.sub.4. Solvent was removed under
reduced pressure and the product was purified by silica gel column
chromatography eluting with 3% EtOAc/hexanes to obtain 1.7 g of
6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl
ester.
[0273]
2-Chlorosulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic
acid tert-butyl ester (0.25 g) was prepared from
6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl
ester (1.6 g, 6.69 mmol) by using n-BuLi and N-chlorosuccinimide as
described in the Example 12.
[0274]
2-[2-(Benzo[b]thiophene-2-sulfonylamino)-phenylsulfamoyl]-6,7-dihyd-
ro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (280
mg) was prepared by using
2-chlorosulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic
acid tert-butyl ester (0.049 g, 0.148 mmol) and
benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (0.045 g,
0.148 mmol, prepared as in Example 1) using pyridine in DCM
following procedure as in Example 2.
[0275] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 1.48 (s, 9H),
2.76-2.85 (m, 2H), 3.65-3.75 (m, 2H), 4.39 (s, 2H), 7.06-7.24 (m,
5H), 7.36-7.52 (m, 4H), 7.71 (s, 1H), 7.78-7.86 (m, 2H) ppm.
Example 39
[0276]
N,N'-(4,5-Dichloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide-
) (120 mg) was prepared by using 4,5-dichloro-benzene-1,2-diamine
(0.06 g, 0.33 mmol) and Benzo[b]thiophene-2-sulfonyl chloride
(0.157 g, 0.67 mmol), following procedure as in Example 32.
[0277] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.34 (s, 2H),
7.41-7.57 (m, 4H), 7.93-8.20 (m, 6H), 9.60-10.50 (br s, 2H)
ppm.
Example 40
[0278]
N,N'-(4-Trifluoromethyl-1,2-phenylene)bis(1-benzothiophene-2-sulfon-
amide) (100 mg) was prepared by using
4-trifluoromethyl-benzene-1,2-diamine (0.06 g, 0.33 mmol) and
benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol),
following procedure as in Example 32.
[0279] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.48 (s, 1H),
7.42-7.55 (m, 6H), 7.89-8.08 (m, 6H), 9.90-10.40 (m, 2H) ppm.
Example 41
[0280]
N,N'-(4-chloro-5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfon-
amide) (0.108 g) was prepared by using
4-chloro-5-fluoro-benzene-1,2-diamine (0.054 g, 0.33 mmol) and
Benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol),
following the procedure as in Example 32.
[0281] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.15-7.26 (dd,
2H), 7.42-7.56 (m, 4H), 7.90-8.09 (m, 6H), 9.60-10.30 (br s, 2H)
ppm.
Example 42
[0282]
N,N'-(4,5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide)
(0.095 g) was prepared employing 4,5-difluoro-benzene-1,2-diamine
(0.048 g, 0.33 mmol) and benzo[b]thiophene-2-sulfonyl chloride
(0.157 g, 0.67 mmol), following procedure as in Example 32.
[0283] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.16 (t, 2H),
7.44-7.56 (m, 4H), 7.93-8.30 (m, 6H), 9.80-10.02 (br s, 2H)
ppm.
Biological Assays
[0284] GalR1 Binding Assay
[0285] The affinity of compounds for GalR1 were studied in an
[.sup.125I]galanin displacement binding assay. Bowes melanoma cell
membranes were used in the GalR binding assay. Compound was diluted
in 40% DMSO/water. The final assay concentration ranging from 0.1
nM to 10 uM in 4% final DMSO concentration was used. The final
binding assay conditions were 25 mM Tris-HCL, pH 7.4 buffer
containing 10 mM MgCl.sub.2, 1-10 ug membrane, 300 pM
[.sup.125I]galanin (SA=2200 Ci/mmol, (Perkin Elmer part no.
NEX333), and compound in final DMSO concentration of 4% (final
assay volume of 100 uL). Positive control wells (C+) lacked
compound, and negative control wells (C-) lacked compound and
contained cold excess galanin (1 micromolar). The reaction was
carried out at room temp for 60-90 min. Membrane containing bound
[.sup.125I]galanin ligand was isolated following filtration onto
Unifilter-96 GF/C filter plates (PerkinElmer part no. 6005177)
using a cell harvester instrument. Plates were washed 5 times with
cold 25 mM Tris-HCL, pH 7.5 containing 0.05% bovine serum albumin
(BSA). Following filtration, 50 uL of Microscint PS (Packard part
no. 6013631) was added, plates were sealed with TopSeal-A adhesive
seals (Packard part no. 6005185). .sup.125I isotope bound to the
Unifilter-96 GF/C plates was counted using a TopCount instrument
(Packard).
Data Analysis
Raw Data Conversion
[0286] Percent inhibition of [.sup.125I]galanin binding was
calculated according to the equation
[100.times.1-{(Sample.sub.cpm-C-.sub.cpm)/C+.sub.cpm-C-.sub.cpm)}].
Percent inhibition of [.sup.125I]galanin binding (Y) vs compound
concentration (X) data were generated.
Curve Fitting
[0287] The IC.sub.50 values were calculated by fitting the data
using parameters for a sigmoidal dose response, variable slope
nonlinear regression (GraphPAD Prizm, San Diego, Calif.) according
to the equation: Y=Bottom+(Top-Bottom)/(1+10 ((Log
EC50-X)*HillSlope)); X is the logarithm of concentration. Y is the
response; Y starts at Bottom and goes to Top with a sigmoid shape.
This is identical the "four parameter logistic equation."
[0288] The compounds of Formula (I) in Table 1 showed an IC.sub.50
of less than or about 10 micromolar in the binding assay described
above.
Functional Cell-Based Assay
[0289] The agonist functional activity of compounds in Bowes cells
was determined by measuring forskolin-stimulated intracellular
cAMP. cAMP was quantitated using a cAMP detection kit. Bowes cells
were grown minimum essential medium eagle containing Earle's salts,
L-glutamine and sodium bicarbonate, supplemented with 10% fetal
bovine serum. Cells were harvested by incubating cell monolayers in
15 mL PBS (Ca.sup.2+, Mg.sup.2+-free) for 20 min in humidified
37.degree. C. incubator containing 95% O.sub.2, 5% CO.sub.2. Gentle
tapping of flasks dislodged cells, and cell suspensions were
centrifuged 600.times.g for 5 min (4.degree. C.). Cells were
counted using a hemocytometer and diluted in stimulation mix
(containing anti-cAMP antibody and isobutyl methyl xanthine) to a
final cell density of 1- to 5.times.10.sup.6 cell/mL. Typically,
assays used between 10,000 and 50,000 of cells per well. Compound
was diluted in 1% DMSO/PBS to final assay concentration ranging
from 0.1 nM to 10 uM, and 5 uL was dispensed in Costar black
384-well plates. Forskolin was filuted in 1% DMSO/PBS. Galanin was
diluted in PBS containing complete protease inhibitor cocktail
(Complete Mini, EDTA-free, Roche Diagnostics). Cells (10 uL) were
pre-incubated with compound for 15 min, and then forskolin (5 to 20
uM) and galanin (0.1 to 10 nM) were added to a final assay volume
of 20 uL. Following 30 min incubation of cells in a humidified
37.degree. C. incubator with 95% O.sub.2, 5% CO.sub.2, Alexa Fluor
594-cAMP detection mix was added (20 uL), and plates were incubated
at room temp with shaking for 1 hr. The degree of fluorescence
polarization (expressed as mP units) was measured using an Envision
(Perkin Elmer) fluorescence plate reader. Standard curves of cAMP
(1-100 nM) were used to quantitate the amount of cAMP.
[0290] The compounds of Formula (I) in Table 1 showed an EC.sub.50
of less than or about 10 micromolar in the functional cell based
assay described above and were determined to be GalR1 agonists.
Behavioral Assessment
Animals
[0291] Male Sprague Dawley rats (100-150 g for nerve ligation) were
purchased from Charles River (Portage, Mich.). Prior to surgery,
animals were group-housed and maintained in a temperature regulated
environment (lights on between 7:00 a.m. and 8:00 p.m.). Two weeks
after surgery, experimentation began when animals were between
250-350 g. Rats had access to food and water ad libitum.
[0292] For the assessment of neuropathic pain, mechanical allodynia
in the affected paw of animals who had undergone sciatic nerve
ligation was evaluated using von Frey filaments. As described
previously (Chaplan et al, Quantitative assessment of tactile
allodynia in the rat paw. J Neurosci Meth, 1994; 53:55-62), two
weeks following surgery, rats were acclimated to the testing box
which was constructed of plexiglass with a wire mesh floor to allow
access to the planter surface of the hind paws. Using the Dixons
Up-Down method, a baseline level of allodynia was taken with
allodynia defined as a withdrawal threshold of less than 4 g. Test
compounds were then administered and subsequent withdrawal
thresholds determined.
[0293] When dosed in the range between about 15 to 100 mg/kg with
compounds of Examples 1-30 in Table 1, the withdrawal thresholds of
the animals with sciatic nerve injury increased as compared to the
withdrawal threshold of vehicle treated animals with sciatic nerve
injury.
[0294] While the invention has been described and illustrated with
reference to certain embodiments thereof, those skilled in the art
will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the dosages as set forth herein may be applicable as a
consequence of variations in the responsiveness of the mammal being
treated. Likewise, the specific pharmacological responses observed
may vary according to and depending on the particular active
compound selected or whether there are present pharmaceutical
carriers, as well as the type of formulation and mode of
administration employed, and such expected variations or
differences in the results are contemplated in accordance with the
objects and practices of the present invention.
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