U.S. patent application number 10/784413 was filed with the patent office on 2004-08-26 for methods for anti-tumor therapy.
This patent application is currently assigned to Compass Pharmaceuticals, LLC. Invention is credited to Braude, Irwin.
Application Number | 20040167180 10/784413 |
Document ID | / |
Family ID | 22860134 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040167180 |
Kind Code |
A1 |
Braude, Irwin |
August 26, 2004 |
Methods for anti-tumor therapy
Abstract
Disclosed and claimed is a method for treating tumors using
sulfonylamino-substituted N-aryl- or heteroarylcarboxamide
derivatives.
Inventors: |
Braude, Irwin; (Chapel Hill,
NC) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Compass Pharmaceuticals,
LLC
|
Family ID: |
22860134 |
Appl. No.: |
10/784413 |
Filed: |
February 23, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10784413 |
Feb 23, 2004 |
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09941876 |
Aug 29, 2001 |
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6716879 |
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60229181 |
Aug 30, 2000 |
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Current U.S.
Class: |
514/352 ;
514/426; 514/602 |
Current CPC
Class: |
A61K 31/63 20130101;
A61P 35/00 20180101; A61K 31/18 20130101 |
Class at
Publication: |
514/352 ;
514/426; 514/602 |
International
Class: |
A61K 031/445; A61K
031/40; A61K 031/18 |
Claims
What is claimed is:
1. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 15or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-allyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; A.sub.2
represents a ringed structure consisting of aryl, heteroaryl,
heterocyclyl or (C.sub.3-C.sub.10)-cycloalkyl; R.sub.2 is
--NR.sub.5R.sub.6, or aryl, heteroaryl, heterocyclyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which may be optionally substituted with one, two or three groups
selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(Q-(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.3 is
one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl, --O--(C.sub.1-C.sub.7)-alkyl-R-
.sub.7, --O-aryl, --O-heteroaryl, --SH,
--S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-allyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
2. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 16or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.2 is
--NR.sub.5R.sub.6, or aryl, heteroaryl, heterocyclyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which may be optionally substituted with one, two or three groups
selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.3 is
one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl, --O--(C.sub.1-C.sub.7)-alkyl-R-
.sub.7, --O-aryl, --O-heteroaryl, --SH,
--S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O---(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.s- ub.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-allyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
3. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 17or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.3 is
one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl, --O--(C.sub.1-C.sub.7)-alkyl-R-
.sub.7, --O-aryl, --O-heteroaryl, --SH,
--S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl; or
R.sub.5 and R.sub.6 together with the nitrogen atom to which they
are attached form a 5, 6, 7 or 8-membered carbocyclic ring up to
two of which members are optionally hetero atoms selected from N,
O, and S, the carbocyclic ring being optionally substituted with up
to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
4. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 18or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein R.sub.2 is --NR.sub.5R.sub.6, or aryl, heteroaryl,
heterocyclyl, (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which may be optionally
substituted with one, two or three groups selected from halogen,
--OH, aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R- .sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.3
is one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8NR.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub.10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
5. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 19or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.2 is
--NR.sub.5R.sub.6, or aryl, heteroaryl, heterocyclyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which may be optionally substituted with one, two or three groups
selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.3 is
one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl, --O--(C.sub.1-C.sub.7)-alkyl-R-
.sub.7, --O-aryl, --O-heteroaryl, --SH,
--S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
6. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 20or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)--alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; A.sub.2
represents a ringed structure consisting of aryl, heterocyclyl,
heteroaryl or (C.sub.3-C.sub.10)-cycloalkyl; R.sub.3 is one, two or
three substituents independently selected from hydrogen, halogen,
--CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7- , --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub.10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
7. A method for treating a tumor in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound having the formula: 21or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof
wherein A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.7)-alkyl,
--O-aryl, (C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which is optionally substituted
with up to five groups independently selected from halogen, --OH,
aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; A.sub.2
represents a ringed structure consisting of aryl, heteroaryl,
heterocyclyl or (C.sub.3-C.sub.10)-cycloalkyl; R.sub.2 is
--NR.sub.5R.sub.6, or aryl, heteroaryl, heterocyclyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which may be optionally substituted with one, two or three groups
selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo; R.sub.3 is
one, two or three substituents independently selected from
hydrogen, halogen, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl, --O--(C.sub.1-C.sub.7)-alkyl-R-
.sub.7, --O-aryl, --O-heteroaryl, --SH,
--S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo; R.sub.5
and R.sub.6 independently are hydrogen, or
(C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
--(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the
two alkyl groups are optionally linked by a single bond and then,
together with the nitrogen atom to which they are attached, form a
5, 6, 7 or 8-membered carbocyclic ring in which one member is
optionally selected from O, S or NR.sub.5; R.sub.7 is --OH,
--O--(C.sub.1-C.sub.7)-a- lkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
--N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl groups
are optionally linked by a single bond and then, together with the
nitrogen atom to which they are attached, form a 5, 6, 7 or
8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5; R.sub.8 is hydrogen, or
(C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloa- lkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; R.sub.9 is hydrogen,
--CO--(C.sub.1-C.sub.4)-alkyl, or (C.sub.1-C.sub.7)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.7)-alkenyl or
(C.sub.1-C.sub.7)-alkynyl, each of which is optionally substituted
with one, two or three groups selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2; n is 0, 1, or 2; and m is 2, 3,
or 4.
8. The method according to claim 1 wherein the compound is selected
from
5-chloro-2-{[(4-chlorophenyl)sulfonyl]amino}-N-(4-chlorophenyl)benzamide;
5-bromo-2-{[(4-chlorophenyl)sulfonyl]amino}-N-(4-chlorophenyl)benzamide;
(5-bromo-2-{[(4-chloro-3-nitrophenyl)sulfonyl]amino}phenyl)-N-(4-chloroph-
enyl) carboxamide;
N-(3,4-dichlorophenyl)(5-chloro-2-{[(4-chlorophenyl)sul-
fonyl]amino}phenyl) carboxamide; and
N-(4-chlorophenyl)(3-{[(4-chloropheny-
l)sulfonyl]amino}(2-naphthyl))carboxamide.
9. The method of claim 1 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
10. The method of claim 2 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
11. The method of claim 3 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
12. The method of claim 4 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
13. The method of claim 5 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
14. The method of claim 6 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
15. The method of claim 7 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
16. The method of claim 8 wherein the tumor is selected from
sarcoma, carcinoma, and mesothelioma.
Description
BACKGROUND OF THE INVENTION
[0001] Approximately twenty percent of deaths from all causes in
the United States are cancer-related. Although chemotherapy is a
principal means of cancer treatment, the rate at which effective
new drugs have become available for use in cancer chemotherapy has
not increased (Horowitz et al., Journal of Clinical Oncology, Vol.
6, No. 2, pp. 308-314 (1988)). Despite many years of promising new
therapies, cancer remains a major cause of morbidity and mortality
(Bailar et al., N. Engl. J. Med. 336:1569-1574, 1997). Accordingly,
there is a substantial need for new drugs that are effective in
inhibiting the growth of tumors.
[0002] The compounds of the general class sulfonylamino carboxylic
acid N-arylamides are known in the art as useful agents for soluble
guanylate cyclase activation (Schindler, et al., WO 00/02850).
Several other pharmacological uses have been described including,
for example, anti-parasitic, antimicrobial, and fungicidal effects
(EP-A-420 805 and Chemical Abstracts 122, 136 749; 120, 560; 119,
116 978; 116, 228 237; 116, 207 806; 115, 158 666, and 106, 152
850), an anthelminitic effect (DE-A-35 23 705), psychotropic
effects (Chemical Abstracts 104, 33 896), and use in the treatment
of atherosclerosis or arthritis (EP-A-347 168). The use of these
compounds for anti-tumor treatment has not been disclosed or
suggested.
SUMMARY OF THE INVENTION
[0003] The present invention is based on the entirely unexpected
finding that sulfonylamino-substituted N-aryl- or
heteroarylcarboxamide derivatives are an effective class of
anti-tumor agent. In one aspect, the present invention provides
novel methods for treating tumors that involve administering an
effective amount of sulfonylamino-substituted N-aryl- or
heteroarylcarboxamide derivatives, or pharmaceutically acceptable
salts, esters, amides, or prodrugs thereof, to a patient in need of
treatment. In a preferred embodiment, the compounds administered in
the method of the present invention are
N-phenyl{2-[(phenylsulfonyl)am- ino]phenyl}carboxamide derivatives.
In an even more preferred embodiment, the compounds are
{5-substituted-2-[(phenylsulfonyl)amino]phenyl}-N-benza- mide
derivatives.
[0004] In further aspects, the present invention provides a
pharmaceutical composition comprising an effective amount for
treating tumors of a compound according to the general formula or
specific compound hereinafter disclosed, or a pharmaceutical salt
thereof, in a suitable carrier. In yet a further aspect, the
present invention discloses articles of manufacture comprising
packaging material and the above pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The instant invention discloses the use of
sulfonylamino-substitute- d N-aryl- or heteroarylcarboxamides, and
their pharmaceutically acceptable salts, esters, amides, and
prodrugs thereof as anti-tumor agents.
[0006] The present compounds, or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, are useful in treating tumors
from any tissue type. Examples of specific tumor types that the
compounds may be used to treat include, but are not limited to,
sarcomas, carcinomas, and mesotheliomas.
[0007] As used herein the term "mesothelioma" is used to refer to a
neoplasm derived from the cells lining the pleura, pericardium, or
peritoneum, including but not limited to lung mesotheliomas.
[0008] As used herein the term "sarcoma" refers to tumors of
mesenchymal origin, including but not limited to stromal cell
sarcomas, leiomyosarcomas, malignant fibrous histiocytoma, Ewing
sarcoma, fibrosarcomas, chondrosarcomas, osteosarcomas,
liposarcomas, rhabdomyo-sarcomas, hemangiocytomas, and
myxosarcomas.
[0009] As used herein the term "carcinoma" is used to refer to a
neoplasm derived from epithelial cells.
[0010] As used herein the term "ovarian carcinoma" refers to
neoplasms derived from ovarian cells of epithelial origin,
including but not limited to ovarian papillary serous cystadenoma,
ovarian endometroid carcinoma, mucinous, clear cell and Brenner
epithelial tumors.
[0011] In one embodiment, the sulfonylamino-substituted N-aryl- or
heteroarylcarboxamides compounds comprise the general formula I, in
all their stereoisomeric forms and mixtures thereof, in all
proportions (see Schindler, et al., WO 00/02850). 1
[0012] wherein
[0013] A.sub.1 is aryl or heteroaryl, each of which may be
optionally substituted with one, two or three groups independently
selected from halogen, aryl, --CF.sub.3, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.7)-alkyl- ,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.sub.7)-alkyl, --O-aryl,
(C.sub.1-C.sub.2)-alkylenedioxy, --NR.sub.5R.sub.6, --CN,
--CO--NR.sub.5R.sub.6, --COOH, --CO--O--(C.sub.1-C.sub.5)-alkyl,
heterocyclyl, --CHO, --CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl,
--CO-heteroaryl, or
[0014] (C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-allyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo;
[0015] A.sub.2 represents a ringed structure consisting of aryl,
heteroaryl, heterocyclyl or (C.sub.3-C.sub.10)-cycloalkyl;
[0016] R.sub.2 is --NR.sub.5R.sub.6, or
[0017] aryl, heteroaryl, heterocyclyl, (C.sub.1-C.sub.10)-alkyl,
(C.sub.3-C.sub.10)-cycloalkyl, (C.sub.1-C.sub.10)-alkenyl or
(C.sub.1-C.sub.10)-alkynyl, each of which may be optionally
substituted with one, two or three groups selected from halogen,
--OH, aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R- .sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, heterocyclyl, and oxo;
[0018] R.sub.3 is one, two or three substituents independently
selected from hydrogen, halogen, --CF.sub.3, --OH,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
(C.sub.1-C.sub.3)-alkylene dioxy, --CN, --NO.sub.2,
--NR.sub.8R.sub.9, --CONR.sub.5R.sub.6, --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl,
--S(O).sub.n--(C.sub.1-C.- sub.7)-alkyl, --S(O).sub.n-aryl,
--S(O).sub.n-heteroaryl, --S(O).sub.n--NR.sub.5R.sub.6, or
[0019] (C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with up to five groups
independently selected from halogen, --OH, aryl, heteroaryl,
--O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, and oxo;
[0020] R.sub.5 and R.sub.6 independently are hydrogen, or
[0021] (C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkenyl or (C.sub.1-C.sub.10)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from aryl, heteroaryl, heterocyclyl,
--CO--(C.sub.1-C.sub.10)-alkyl, --CO-aryl, --CO-heteroaryl,
--CO-heterocyclyl, --SO.sub.2--(C.sub.1-C.sub- .10)-alkyl,
--SO.sub.2-aryl --SO.sub.2-heteroaryl, or --SO.sub.2-heterocyclyl;
or
[0022] R.sub.5 and R.sub.6 together with the nitrogen atom to which
they are attached form a 5, 6, 7 or 8-membered carbocyclic ring up
to two of which members are optionally hetero atoms selected from
N, O, and S, the carbocyclic ring being optionally substituted with
up to five groups selected from halogen, (C.sub.1-C.sub.5)-alkyl,
(C.sub.3-C.sub.6)-cycloal- kyl, (C.sub.1-C.sub.5)-alkenyl,
(C.sub.1-C.sub.5)-alkynyl, (C.sub.1-C.sub.3)-hydroxyalkyl,
(C.sub.1-C.sub.3)-alkyl-O--(C.sub.1-C.sub- .4)-alkyl, aryl,
heteroaryl, --CF.sub.3, --OH, --O--(C.sub.1-C.sub.7)-alky- l,
--O-aryl, --O-heteroaryl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.su- b.7)-alkyl,
(C.sub.2-C.sub.3)-alkylenedioxy, --NR.sub.8R.sub.9, --CN,
--CO--NH.sub.2, --CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH,
--CO--O--(C.sub.1-C.sub.5- )-alkyl, --CHO,
CO--(C.sub.1-C.sub.5)-alkyl, --S(O).sub.n--(C.sub.1-C.sub.-
4)-alkyl, --S(O).sub.n--NH.sub.2,
--S(O).sub.n--NH--(C.sub.1-C.sub.3)-alky- l,
--S(O).sub.n--N((C.sub.1-C.sub.3)-alkyl).sub.2, oxo,
--(CH.sub.2).sub.m--NH.sub.2,
--(CH.sub.2).sub.m--NH--(C.sub.1-C.sub.4)-a- lkyl or
[0023] --(CH.sub.2).sub.m--N((C.sub.1-C.sub.4)-alkyl).sub.2,
wherein the two alkyl groups are optionally linked by a single bond
and then, together with the nitrogen atom to which they are
attached; form a 5, 6, 7 or 8-membered carbocyclic ring in which
one member is optionally selected from O, S or NR.sub.5;
[0024] R.sub.7 is --OH, --O--(C.sub.1-C.sub.7)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl, or
[0025] --N((C.sub.1-C.sub.4)-alkyl).sub.2, wherein the two alkyl
groups are optionally linked by a single bond and then, together
with the nitrogen atom to which they are attached, form a 5, 6, 7
or 8-membered carbocyclic ring in which one member is optionally
selected from O, S or NR.sub.5;
[0026] R.sub.8 is hydrogen, or
[0027] (C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2;
[0028] R.sub.9 is hydrogen, --CO--(C.sub.1-C.sub.4)-alkyl, or
[0029] (C.sub.1-C.sub.7)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.7)-alkenyl or (C.sub.1-C.sub.7)-alkynyl, each of
which is optionally substituted with one, two or three groups
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, --NH.sub.2,
--NH--(C.sub.1-C.sub.4)-alkyl and
--N((C.sub.1-C.sub.4)-alkyl).sub.2;
[0030] n is 0, 1, or 2; and
[0031] m is 2, 3, or 4.
[0032] As used herein, "aryl" is an aromatic carbocyclic group
having a single ring (e.g., phenyl), multiple rings (e.g.,
biphenyl), or multiple condensed rings in which at least one is
aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or
phenanthryl), all of which may be substituted by one or several
identical or different substituents from the group consisting of
halogen, (C.sub.1-C.sub.5)-alkyl, phenyl, tolyl, --CF.sub.3,
--NO.sub.2, --OH, --O--(C.sub.1-C.sub.5)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.- sub.3)-alkyl,
(C.sub.1-C.sub.2)-alkylenedioxy, --NH.sub.2,
--NH--(C.sub.1-C.sub.3)-alkyl, --N((C.sub.1-C.sub.3)-alkyl).sub.2,
--NH--CHO, --NH--CO--(C.sub.1-C.sub.5)-alkyl, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, --CHO,
--CO--(C.sub.1-C.sub.5)-alkyl,
--S(O).sub.n--(C.sub.1-C.sub.4)-alkyl, --S(O).sub.n-phenyl,
--S(O).sub.n-tolyl, --S(O).sub.2--NH.sub.2,
--S(O).sub.2--NH--(C.sub.1-C.sub.3)-alkyl and
--S(O).sub.2--N((C.sub.1-C.- sub.3)-alkyl).sub.2.
[0033] As used herein, "heteroaryl" is one or more aromatic ring
systems of 5-, 6-, 7-, 8-, 9- or 10-membered rings containing at
least one and up to four heteroatoms selected from nitrogen,
oxygen, or sulfur. Such heteroaryl groups include, for example,
thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,
pyrimidinyl, (iso)quinolinyl, napthyridinyl, benzimidazolyl,
benzoxazolyl.
[0034] A "carbocyclic group" "carbocycle" or "cycloalkyl" is a
saturated or partially unsaturated cyclic ring or fused rings.
Examples include cyclopropyl, cyclobutyl, and cycloheptyl. These
rings may be substituted with one or more of the substituent groups
mentioned above for aryl. The carbocyclic group may contain one or
two heteroatoms selected from oxygen, sulfur, and nitrogen, and
such ring systems may be referred to as "heterocyclyl" or
"heterocyclic".
[0035] As used herein, "heterocyclyl" or "heterocyclic" includes
monocyclic or polycyclic 5-membered to 11-membered saturated or
partially unsaturated heterocycles that contain one or more ring
heteroatoms selected from N, O, and S, and which may be substituted
by one or more identical or different substituents selected from
the group consisting of fluorine, (C.sub.1-C.sub.5)-alkyl, --OH,
--O--(C.sub.1-C.sub.5)-alkyl,
--O--(C.sub.2-C.sub.4)-alkyl-O--(C.sub.1-C.sub.3)-alkyl,
--NH.sub.2, --NH--(C.sub.1-C.sub.3)-alkyl,
--N((C.sub.1-C.sub.3)-alkyl).sub.2, --CN, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2, --COOH and
--CO--O--(C.sub.1-C.sub.5)-alkyl.
[0036] As used herein, "alkyl" includes straight-chain or branched
hydrocarbon groups that may be optionally substituted with one or
more of the substituents listed above for aryl, or from the group
consisting of alkoxycarbonyl, alkoxy, or amino. Examples of alkyl
groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl, the n-isomers of these groups, isopropyl,
isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl,
3,3-dimethylbutyl.
[0037] "Alkenyl" means straight and branched hydrocarbon radicals
having at least one double bond and includes ethenyl, propenyl,
1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. Examples of
such groups include the vinyl group, 2-propylene (allyl),
2-butenyl, 2-methyl-2-propylene, ethinyl, 2-propinyl (propargyl),
and 3-butinyl.
[0038] "Alkynyl" means straight and branched hydrocarbon radicals
having one triple bond and includes ethynyl, propynyl, butynyl,
pentyn-2-yl and the like.
[0039] By "alkoxy" in the present invention is meant straight or
branched chain alkyl groups having 1-10 carbon atoms, attached
through a divalent oxygen atom, and includes such as, for example,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,
tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy,
2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
[0040] By "halogen" in the present invention is meant fluorine,
bromine, chlorine, and iodine.
[0041] In another embodiment of the invention, compounds of the
formula Ia are employed: 2
[0042] wherein R.sub.2, R.sub.3, and A.sub.1 are as defined above
for formula I.
[0043] In yet another embodiment of the invention, compounds of the
formula Ib are used: 3
[0044] wherein A.sub.1 and R.sub.3 are as defined above for formula
I, and
[0045] R.sub.10, R.sub.11 and R.sub.12 independently represent from
halogen, --OH, aryl, heteroaryl, --O--(C.sub.1-C.sub.10)-alkyl,
--O--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --O-aryl, --O-heteroaryl,
--SH, --S--(C.sub.1-C.sub.10)-alkyl,
--S--(C.sub.1-C.sub.7)-alkyl-R.sub.7, --S-aryl, --S-heteroaryl,
--P(O)(O--(C.sub.1-C.sub.5)-alkyl).sub.2, --P(O)(OH).sub.2, --CN,
--NR.sub.8R.sub.9, --CO--NH.sub.2,
--CO--NH--(C.sub.1-C.sub.3)-alkyl,
--CO--N((C.sub.1-C.sub.3)-alkyl).sub.2- , --COOH,
--CO--O--(C.sub.1-C.sub.5)-alkyl, heterocyclyl, or oxo. R.sub.7,
R.sub.8 and R.sub.9 are all as defined above for formula I.
[0046] In still another embodiment of the invention, compounds of
the formula Ic are employed: 4
[0047] wherein R.sub.2 and R.sub.3 are as defined above for formula
I and R.sub.10, R.sub.11 and R.sub.12 are as defined for formula
Ib.
[0048] In another embodiment of the invention, compounds of the
formula Id are employed: 5
[0049] wherein A.sub.1, R.sub.2 and R.sub.3 are as defined above
for formula I.
[0050] In yet another embodiment of the invention, compounds of the
formula Ie are employed: 6
[0051] wherein A.sub.1, A.sub.2 and R.sub.3 are as defined above
for formula I and R.sub.10, R.sub.11 and R.sub.12 are as defined
for formula Ib.
[0052] In still another embodiment of the invention, compounds of
the formula If are used: 7
[0053] wherein A.sub.2, R.sub.2 and R.sub.3 are as defined above
for formula I and R.sub.10, R.sub.11 and R.sub.12 are as defined
for formula Ib.
[0054] Preferred compounds according to this invention are
compounds of the formula I, in which one or more of the groups
contained therein have preferable meanings, wherein all
combinations of preferable substituent definitions are the object
of this invention. This invention also applies to all of the
stereoisomer forms and mixtures, in all ratios, of all preferable
compounds of the formula I, as well as their physiologically
compatible salts.
[0055] Representative compounds of the invention are shown below in
Table 1.
1TABLE 1 8 5-chloro-2-{[(4-chlorophenyl)sulfonyl]amino}-
N-(4-chlorophenyl)benzamide 9
5-bromo-2-{[(4-chlorophenyl)sulfonyl]amino}-
N-(4-chlorophenyl)benzamide 10
(5-bromo-2-{[(4-chloro-3-nitrophenyl)sulfonyl]amino}phenyl)-
N-(4-chlorophenyl)carboxamide 11
N-(3,4-dichlorophenyl)(5-chloro-2-{[(4- chlorophenyl)sulfonyl]amin-
o}phenyl)carboxamide 12 N-(4-chlorophenyl)(3-{[(4-
chlorophenyl)sulfonyl]amino}(2-naphthyl- ))carboxamide
[0056] Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table I and their pharmaceutically acceptable
salts.
[0057] The compounds disclosed herein can be prepared by any of the
methods known in the art. Non-limiting examples of these methods
include those disclosed in DE-A-35 23 705 and its equivalents. An
example of a synthetic route for these compounds is described below
(see Schindler, et. al., WO 00/02850).
[0058] According to Scheme 1 an aminocarboxylic acid of formula II
can first be reacted with a sulfonyl chloride of the formula
R.sub.2--SO.sub.2--Cl or a sulfonic acid anhydride, in a solvent
such as water, pyridine, or an ether, in the presence of a base.
The bases used may be common inorganic bases such as, for example,
sodium carbonate or organic bases such as, for example, pyridine or
triethylamine. The resulting sulfonylaminocarboxylic acid of
formula III can then be converted to an acid chloride of formula
IV, through reaction with a chlorinating agent as, for example,
phosphorus pentachloride, phosphorus oxychloride, or thionyl
chloride in an inert solution, and can then be reacted with an
arylamine. The activation of the carboxylic acid group of the
compounds of formula III can also follow a different reaction
pathway, such as by means of one of the many methods known to a
person skilled in the art that are used in peptide chemistry to
establish amide bonds, such as through the use of a mixed
anhydride, an activated ester, or by use of carbodiimides, such as
dicyclohexylcarbodiimide.
[0059] The reaction of the activated sulfonylaminocarboxylic acid
with an arylamine is completed preferably in an inert solution such
as, for example, pyridine, tetrahydrofuran, or toluol with or
without the addition of an inert auxiliary base, such as a tertiary
amine or pyridine. If the arylamine used in the reaction with the
activated carboxylic acid already contains the desired substituent
or substituents R.sub.1 in its A.sub.1 group, (the arylamine is of
the formula A.sub.1-NH.sub.2, wherein the A.sub.1 group can
contain, as specified above, one or more substituents R.sub.1), the
reaction scheme proceeds directly to the end product of formula I.
13
[0060] However, the activated carboxylic acid can also be converted
initially with an arylamine of the formula
R.sub.1a-A.sub.1-NH.sub.2, in which R.sub.1a represents hydrogen or
one or more of the groups R.sub.1, which can be contained in
A.sub.1 as substituents, or R.sub.1a represents one or more groups
that can be converted into groups R.sub.1 according to the above
definition. For example, R.sub.1a can represent a hydrogen atom
that is replaced in an electrophilic reaction with another group,
such as a halogen atom or an aldehyde group. The conversion of the
reaction product of formula V into a compound of formula I can take
place according to standard procedures known in the art.
[0061] Compounds of formula I can also be obtained, for example, by
initial activation of a substituted nitrocarboxylic acid of formula
VI, such as by conversion into the corresponding acid chloride of
formula VII or by other means, which is then, for example, reacted
with a substituted arylamine of the formula A.sub.1-NH.sub.2, by
methods analogous to those described above (see Scheme 2;
Schindler, et al. WO 00/02850).
[0062] Before the nitro group is reduced to the amino group in the
resulting nitro intermediate products of formula VIII, the
activating effect of the nitro group on ring A.sub.2 can be
utilized, and a suitable group R.sub.3, such as a halogen atom, can
be replaced by another group R.sub.3, such as an amine, by
conversion with a nucleophile. The reduction of the nitro group to
an amino group may take place, for example, by catalytic hydration
in the presence of a precious metal catalyst or, preferably, in the
presence of Raney nickel in a solvent such as ethanol, glacial
acetic acid, or ethanolic hydrochloric acid, or by reduction with a
non-precious metal such as tin, zinc, or iron in the presence of
acid. The reduction can also be completed, for example, with
tin(II)-chloride or by reduction with sodium dithionite,
preferably, for example, in a mixture of methanol, tetrahydrofuran,
and water as a solvent. 14
[0063] The sulfonylation of the amino group in the reduction
product of formula IX with an activated sulfonic acid derivative by
analogy to the reactions described above, such as with a sulfonic
acid chloride in the presence of pyridine, ultimately produces the
compound of formula I. Instead of an arylamine of the formula
A.sub.1-NH.sub.2, an arylamine of the formula
R.sub.1a-A.sub.1NH.sub.2 can be used, in which R.sub.1a has the
meaning specified above, and the group or groups R.sub.1a can then
be converted into the group or groups R.sub.1.
[0064] A person of ordinary skill in the art is familiar with all
the reactions for synthesis of compounds of formula I, which can be
performed under standard conditions. Further details on this
subject can be found, for example, in Houben-Weyl, Methods of
Organic Chemistry, Thieme-Verlag, Stuttgart, or Organic Reactions,
John Wiley & Sons, New York. Depending on the circumstances of
each case, it may be advantageous or even necessary to block
certain functional groups by introducing protective groups, and
subsequently release these groups at a later step in the synthesis
scheme, in order to avoid secondary reactions during the synthesis
of compounds of formula I. One of skill in the art may also begin
synthesis with functional groups in the form of precursor stages
from which the desired functional group is generated in a later
stage. These synthesis strategies are well known to a person of
skill in the art. If necessary, the compounds of formula I can be
isolated and purified using conventional methods, such as through
the use of recrystallization or chromatography. The starting
compounds used in the synthesis of the compounds of formula I are
commercially available, or can be made according to the methods
described in the literature, or by analogous methods.
[0065] The present compounds, or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, are useful in treating tumors
from any tissue type. Examples of specific tumor types that the
compounds may be used to treat include, but are not limited to,
sarcomas, carcinomas, and mesotheliomas. The instant compounds can
be administered individually or in combination, usually in the form
of a pharmaceutical composition. Such compositions are prepared in
a manner well known in the pharmaceutical art and comprise at least
one active compound. Accordingly, a further aspect of the present
invention also includes pharmaceutical compositions comprising as
active ingredient compounds of the general formula I, associated
with a pharmaceutically acceptable carrier. The invention further
comprises the method of treating susceptible neoplasms using the
compositions containing as an active ingredient one or more of the
disclosed compounds.
[0066] The term "pharmaceutically acceptable salts, esters, amides,
and prodrugs" as used herein refers to those carboxylate salts,
amino acid addition salts, esters, amides, and prodrugs of the
compounds of the present invention which are, within the scope of
sound medical judgment, suitable for use in contact with the
tissues of patients without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the
invention. The term "salts" refers to the relatively non-toxic,
inorganic and organic acid addition salts of compounds of the
present invention. These salts can be prepared in situ during the
final isolation and purification of the compounds or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts, and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium, and the like, as
well as non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. (See, for example, Berge
S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19
which is incorporated herein by reference.)
[0067] Examples of pharmaceutically acceptable, non-toxic esters of
the compounds of this invention include C.sub.1-C.sub.6 alkyl
esters, wherein the alkyl group is a straight or branched,
substituted or unsubstituted, C.sub.5-C.sub.7 cycloalkyl esters, as
well as arylalkyl esters such as benzyl and triphenylmethyl.
C.sub.1-C.sub.4 alkyl esters are preferred, such as methyl, ethyl,
2,2,2-trichloroethyl, and tert-butyl. Esters of the compounds of
the present invention may be prepared according to conventional
methods.
[0068] Examples of pharmaceutically acceptable, non-toxic amides of
the compounds of this invention include amides derived from
ammonia, primary C.sub.1-C.sub.6 alkyl amines and secondary
C.sub.1-C.sub.6 dialkyl amines, wherein the alkyl groups are
straight or branched. In the case of secondary amines, the amine
may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-C.sub.3 alkyl primary amines and C.sub.1-C.sub.2 dialkyl
secondary amines are preferred. Amides of the compounds of the
invention may be prepared according to conventional methods.
[0069] The term "prodrug" refers to compounds that are rapidly
transformed in vivo to yield the parent compound of the above
formulae, for example, by hydrolysis in blood. A thorough
discussion of prodrugs is provided in T. Higuchi and V. Stella,
"Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon
Press, 1987, both of which are hereby incorporated by
reference.
[0070] As used herein, the term "effective amount" means a dosage
sufficient to produce a desired result. The desired result can be
subjective or objective improvement in the recipient of the dosage,
a decrease in tumor size, time to progression of disease, and/or
survival.
[0071] The compounds of the invention can be administered as the
sole active pharmaceutical agent, or they can be used in
combination with one or more other anti-tumor agents. When
administered as a combination, the therapeutic agents can be
formulated as separate compositions that are given at the same time
or different times, or the therapeutic agents can be given as a
single composition.
[0072] The compounds may be made up in a solid form (including
granules, powders or suppositories) or in a liquid form (e.g.,
solutions, suspensions, or emulsions). The compounds of the
invention may be applied in a variety of solutions and may be
subjected to conventional pharmaceutical operations such as
sterilization and/or may contain conventional adjuvants, such as
preservatives, stabilizers, wetting agents, emulsifiers, buffers
etc.
[0073] For administration, the compounds are ordinarily combined
with one or more adjuvants appropriate for the indicated route of
administration. The compounds may be admixed with lactose, sucrose,
starch powder, cellulose esters of alkanoic acids, stearic acid,
talc, magnesium stearate, magnesium oxide, sodium and calcium salts
of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate,
polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or
encapsulated for conventional administration. Alternatively, the
compounds of this invention may be dissolved in saline, water,
polyethylene glycol, propylene glycol, carboxymethyl cellulose
colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil,
sesame oil, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well known in the pharmaceutical
art. The carrier or diluent may include time delay material, such
as glyceryl monostearate or glyceryl distearate alone or with a
wax, or other materials well known in the art.
[0074] Pharmaceutical compositions containing the compounds
described herein are administered to an individual having a tumor.
In therapeutic applications, compositions are administered to a
human patient in an amount sufficient to cause regression of the
tumor, or at least partially arrest tumorigenesis and metastasis.
Amounts effective for this use depend on factors including, but not
limited to, the nature of the compound (specific activity, etc.),
the manner of administration, the stage and severity of the cancer,
the weight and general state of health of the patient, and the
judgment of the prescribing physician. The active compounds are
effective over a wide dosage range. For example, dosages per day
will normally fall within the range of about 1 .mu.g/kg body weight
to about 100 mg/kg of body weight. It will be understood that the
amount of the compound actually administered will be determined by
a physician, in the light of the relevant circumstances including
the condition to be treated, the choice of compound to be
administered, the chosen route of administration, the age, weight,
and response of the individual patient, disorders affecting the
heart, and other specific organ dysfunction, and therefore the
above dosage ranges are not intended to limit the scope of the
invention in any way.
[0075] The compounds of the invention may be administered by any
suitable route, including orally, parentally, by inhalation or
rectally in dosage unit formulations containing conventional
pharmaceutically acceptable carriers, adjuvants, and vehicles,
including liposomes. The term parenteral as used herein includes,
subcutaneous, intravenous, intraarterial, intramuscular,
intrasternal, intratendinous, intraspinal, intracranial,
intrathoracic, infusion techniques, intracavity, or
intraperitoneally.
[0076] In a preferred embodiment, the compounds of formula I are
used for treating tumors from any tissue type. Examples of specific
tumor types that the compounds may be used to treat include, but
are not limited to, sarcomas, carcinomas, and mesotheliomas.
[0077] In yet further aspects, the invention provides an article of
manufacture comprising packaging material and the above
pharmaceutical compositions.
[0078] The instant invention may be embodied in other forms or
carried out in other ways without departing from the spirit or
essential characteristics thereof. The present disclosure and
enumerated examples are therefore to be considered as in all
respects illustrative and not restrictive, and all equivalency are
intended to be embraced therein. One of ordinary skill in the art
would be able to recognize equivalent embodiments of the instant
invention, and be able to practice such embodiments using the
teaching of the instant disclosure and only routine
experimentation.
[0079] The disclosures in this application of all articles and
references, including patents, are incorporated herein by
reference.
[0080] The invention is illustrated further by the following
examples which are not to be construed as limiting the invention in
scope or spirit to the specific procedures described in them.
EXAMPLES
Example 1
Tissue Processing
[0081] Excess tissue specimens obtained from patients undergoing
therapeutic surgical resections were freshly obtained at the time
of surgery and a small portion of the specimen was sent for
pathological testing. For diagnosis and grading of tissue samples
(ie: prior to processing), hematoxylin and eosin stained tissue
sections were examined by a pathologist. If the diagnosis and
grading of the tissue concurred with the determination made by the
surgical pathologist that provided the tissue, then the tissue was
used in the screen. If there was no agreement, then two additional
pathologists served as referees. If no consensus was reached, then
the tissue was not used.
[0082] The remaining tissue was used to prepare cell suspensions.
The tissue was initially treated enzymatically via standard methods
until only undigested material remained. The digested cell
suspension was filtered through one or more screens of between 40
micron and 100 micron porosity. The resulting cell suspension was
further purified via isokinetic density centrifugation.
[0083] Additional normal cells were removed from the cell
suspension by negative immunoselection with a combination of
monoclonal antibodies linked to magnetic beads (Dynal) that were
used according to the manufacturers' instructions. The remaining
cells were placed into appropriate medium, frozen down in 1.0 mL
aliquots, and stored until use.
Example 2
General Screen/Bioassay Procedures
[0084] After tissue processing, the relative purity of the
resulting cell suspension was determined by cytological examination
after fixation and Papanicolaou staining. Only those cell
preparations greater than 80% tumor cells were used for testing of
candidate compounds. If there was any doubt about the percentage of
tumor cells in the cell preparation, additional pathologists served
as referees to make a determination.
[0085] Cell preparations that passed histological and cytological
examination for diagnosis, grading, and cell purity were thawed at
37.degree. C. and resuspended in tissue culture medium designed to
maintain the cells during the incubation period. The live and dead
cells were counted and the cells were diluted in culture medium to
1.0.times.10.sup.3 live cells/test well for tumor cells and
3.3.times.10.sup.3 live cells/test well for normal cells.
[0086] The cells were added to microtiter plates and incubated at
37.degree. C. overnight with 10 .mu.M of the candidate compounds
that were added at {fraction (1/10)}th the volume of the cell
suspension. Alamar Blue (Accumed International, Westlake Ohio) was
then added to the cells at {fraction (1/10)} the volume of the
well, and the cells were further incubated at 37.degree. C. for
various times. Alamar Blue dye measures cellular re-dox reactions
(ie: cellular respiration) whereby a spectral shift occurs upon
reduction of the dye. (Excitation 530 nm; emission 590 nm)
[0087] The kinetics of cellular re-dox reactions were subsequently
measured at various times, for example at 3 hours, 3 days, and 5
days post-dye addition. These measurements, in comparison with
control cells (untreated with compound) and media controls (test
wells without cells) provide the percent inhibition of cellular
mitochondrial respiration as a result of candidate compound
treatment, as well as IC.sub.50 determinations.
[0088] The Alamar Blue data were subsequently confirmed by
microscopic observation, and by the use of calcein AM (Molecular
Probes, Eugene Oreg.), a cell permeant esterase substrate that
measures both esterase activity and cell membrane activity. If the
cell is alive, the dye is converted into a fluorogenic substrate by
intracellular esterases and is retained by the cell (excitation 485
nm; emission 530 nm). If the cells are dead, the calcein AM rapidly
leaks from the cells and is not converted into a fluorogenic
substrate. Thus, the assay is useful for cytotoxicity testing.
Example 3
Anti-Tumor Screen
[0089] In a blinded fashion, approximately 10,000 compounds were
tested at a rate of 1,000-4,000 compounds per run set against
various tumor types. The anti-tumor screen utilized was composed of
three tiers as follows. In screen 1, patient tumor cells were
tested in singles, with candidate compounds at a concentration of
10 .mu.M. Samples that showed at least 80% inhibition (compared to
cell and media controls) and/or two standard deviations from the
mean of the plate samples were advanced. In the first part of the
second test (screen 2a), the compounds were re-tested, in
duplicate, at 10 .mu.M concentrations on patient tumors. Compounds
that re-confirmed were then tested, in duplicate, at 10 .mu.M
concentration on patient normal cells. Samples that exhibited at
least 80% inhibition on tumor cells and no more than 20% inhibition
of normal cells were tested in the second part (screen 2b).
[0090] Compound 1,
(5-chloro-2-{[(4-chlorophenyl)sulfonyl]amino}-N-(4-chlo-
rophenyl)benzamide), was shown to have selectivity against tumor
cells in the above screen, and was further tested against other
tumor types. The anti-tumor screen utilized was composed of three
tiers as discussed above. In screen 1, patient tumor cells were
tested, with compound 1 at a concentration of 10 .mu.M. Compound 1
showed at least 80% inhibition (compared to cell and media
controls) and/or two standard deviations from the mean of the plate
samples, and was advanced. In the second test (screen 2), compound
1 was re-tested, in duplicate, at 10 .mu.M concentrations on
patient tumors. Compound 1 re-confirmed and was then tested, in
duplicate, at 10 .mu.M concentration on patient normal cells, on
which it exhibited at least 80% inhibition on tumor cells and no
more than 20% inhibition of normal cells. Compound 1 was then
tested for IC.sub.50, in triplicate, on both patient tumor and
patient normal cells for the concentration at which tumor cell
processes were inhibited 50% vs. untreated tumor cells.
[0091] A summary of the results from this screen is shown below in
Table 2:
2TABLE 2 Tumor # Tumor Type/Location IC50 (nM) 1
Leiomyosarcoma/abdominal 170 1 Leiomyosarcoma/abdominal 150 2
Fibrohistiocytic Sarcoma/lung 30 3 Myxofibrosarcoma/thigh 49 3
Myxofibrosarcoma/thigh 49 4 Leiomyosarcoma/pelvic 339 4
Leiomyosarcoma/pelvic 339 4 Leiomyosarcoma/pelvic 410 5
Gastrointestinal stromal tumor (sarcoma) 2400 6 Gastrointestinal
stromal tumor (sarcoma) 531 7 Ovarian 35
[0092] Taken together, the data shows that compound 1 exhibits good
anti-tumor activity potency against a variety of tumor types.
Example 4
Identification of Additional Anti-Tumor Compounds
[0093] In an effort to identify further compounds structurally
related to compound 1 that exhibited similar or improved anti-tumor
efficacy, a series of structurally related
sulfonylamino-substituted N-aryl- or heteroarylcarboxamide
derivatives were tested as in Example 3, on tumor #4 in Table 2.
Results are depicted below in Table 3.
3 TABLE 3 COMPOUND IC50 (nM) TUMOR TYPE 2 44.7
Leiomyosarcoma/pelvic 3 118 Leiomyosarcoma/pelvic 4 12.4; 74.3
Leiomyosarcoma/pelvic 5 209 Leiomyosarcoma/pelvic
[0094] Based on the above data, the present invention unexpectedly
provides needed methods, compounds, and pharmaceutical compositions
for treating tumors.
[0095] The invention and manner and process of making and using it,
are now described in such full, clear, concise and exact terms as
to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *