U.S. patent application number 10/401842 was filed with the patent office on 2003-10-09 for substituted and unsubstituted benzooxathiazoles and compounds derived therefrom.
Invention is credited to Baringhaus, Karl-Heinz, Hoelder, Swen, Mueller, Guenter, Petry, Stefan.
Application Number | 20030191161 10/401842 |
Document ID | / |
Family ID | 7651742 |
Filed Date | 2003-10-09 |
United States Patent
Application |
20030191161 |
Kind Code |
A1 |
Petry, Stefan ; et
al. |
October 9, 2003 |
Substituted and unsubstituted benzooxathiazoles and compounds
derived therefrom
Abstract
The invention relates to substituted and unsubstituted
3H-benzo[1,2,3]oxathiazole 2,2-dioxides,
1,3-dihydrobenzo[1,2,5]thiadiazo- le 2,2-dioxides and
1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation
and to their use in medicaments.
Inventors: |
Petry, Stefan; (Frankfurt,
DE) ; Baringhaus, Karl-Heinz; (Woelfersheim, DE)
; Hoelder, Swen; (Frankfurt am Main, DE) ;
Mueller, Guenter; (Sulzbach, DE) |
Correspondence
Address: |
HELLER EHRMAN WHITE & MCAULIFFE LLP
1666 K STREET,NW
SUITE 300
WASHINGTON
DC
20006
US
|
Family ID: |
7651742 |
Appl. No.: |
10/401842 |
Filed: |
March 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10401842 |
Mar 31, 2003 |
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09925019 |
Aug 9, 2001 |
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6566390 |
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Current U.S.
Class: |
514/362 ;
514/338; 514/373; 514/394; 514/439; 546/268.7; 546/271.7;
546/281.1; 548/121; 548/207; 548/305.1; 549/33; 549/49 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
3/04 20180101; A61P 43/00 20180101; C07D 285/14 20130101; C07D
291/08 20130101 |
Class at
Publication: |
514/362 ;
514/373; 514/439; 548/121; 548/207; 549/33; 549/49; 548/305.1;
514/394; 514/338; 546/268.7; 546/271.7; 546/281.1 |
International
Class: |
A61K 031/4439; A61K
031/4436; A61K 031/433; A61K 031/4178; A61K 031/4184; A61K 031/381;
C07D 417/02; C07D 49/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 9, 2000 |
DE |
100 38 709.8 |
Claims
We claim:
1. A compound of the formula I 21in which X is CH.sub.2, O, N; Y is
CH.sub.2, O, N; R1, R2, R3 are each independently of one another H,
F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl- -phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl- , COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or 4-pyridyl,
2- or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; or in each case two of the radicals R1 and R2 or R2 and R3
or R1 and R3 together form a fused aryl radical, where aryl may be
phenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety
may in each case be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; or its physiologically
acceptable salts or prodrugs.
2. A compound of the formula I as claimed in claim 1, wherein X is
O, N; Y is O, N; R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2,
COOH; COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; R2 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; R3 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; or its physiologically acceptable salts or prodrugs.
3. A compound of the formula I as claimed in claim 1, wherein X is
O, N; Y is N; R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-CO.sub.0)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; R2 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
--COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; R3 is COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl- -phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl- , COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; or its physiologically acceptable salts or prodrugs.
4. A compound of the formula I as claimed in claim 1, wherein X is
O; Y is N; R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO,
NSO.sub.3--(C.sub.1-C.sub.10)alkyl- ; R2 is F, Cl, Br, I, NH.sub.2,
OH, NO.sub.2, COOH; COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where the phenyl may be mono- to
trisubstituted by O--(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimid- azole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replace by OH, (C.sub.1-C.sub.6)alkyl-phe- nyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO,
NSO.sub.3--(C.sub.1-C.sub.10- )alkyl; R3 is
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.16)alkyl,
CONH(C.sub.1-C.sub.16)alkenyl, CONH(C.sub.1-C.sub.6)alkyl-phenyl,
where phenyl may be mono- to trisubstituted by
O-(C.sub.1-C.sub.10)alkyl or O--(C.sub.1-C.sub.10)alkyl- -phenyl,
CON H(C.sub.1-C.sub.6)alkyl-benzimidazole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2; O--(C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl
radicals one or more hydrogens may be replaced by fluorine or one
hydrogen may be replaced by OH, (C.sub.1-C.sub.6)alkyl-ph- enyl or
O--(C.sub.1-C.sub.6)alkyl-phenyl, NCO, NSO.sub.3--(C.sub.1-C.sub.1-
0)alkyl; or its physiologically acceptable salts or prodrugs.
5. A pharmaceutical composition comprising an effective amount of
at least one compound as claimed in claim 1 and a pharmaceutically
acceptable excipient.
6. A method of inhibiting a PTPase comprising administering to a
subject in need thereof an effective amount of one or more
compounds of claim 1.
7. The method of claim 6, wherein the PTPase is PTP1B, CD45, LAR,
SHP-1, SHP-2, PTPa or HePTP.
8. A method of treating type 1 diabetes comprising administering to
a subject in need thereof an effective amount of one or more
compounds of claim 1.
9. A method of treating type 2 diabetes comprising administering to
a subject in need thereof an effective amount of one or more
compounds of claim 1.
10. A method of treating insulin resistance comprising
administering to a subject in need thereof an effective amount of
one or more compounds of claim 1.
11. A method of treating pathological obesity comprising
administering to a subject in need thereof an effective amount of
one or more compounds of claim 1.
12. A method of preparing a pharmaceutical composition comprising
the steps of mixing one or more compounds of claim 1 with one or
more pharmaceutically acceptable excipients and bringing this
mixture into a form suitable for administration.
Description
[0001] This application claims priority to German Patent
Application 10038709.8-44, filed Aug. 9, 2000, which is hereby
incorporated by reference, in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1 Field of the Invention
[0003] The present invention relates to substituted and
unsubstituted 3H-benzo-[1,2,3]oxathiazole 2,2-dioxides,
1,3-dihydrobenzo[1,2,5]thiadiaz- ole 2,2-dioxides and
1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation
and to their use in medicaments
[0004] 2. Description of the Related Art
[0005] Aminobenzosultam derivatives acting as lipoxygenase
inhibitors are known (WO 92/05164). Also known is the use of
corresponding bifunctional derivatives as charge transporters in
photoreceptors (JP 95/325942). Andersen et al. described the
synthesis of toluenesulfonyl-protected derivatives and studies of
reactions of these derivatives with nucleophiles (K. Andersen et
al., J. Phys. Org. Chem., 10, 175-181 (1997); K. Andersen et al., J
Org. Chem., 60, 2003-2007 (1995)).
SUMMARY OF THE INVENTION
[0006] It was an object of the present invention to provide novel
substituted and unsubstituted benzooxathiazoles and their
preparation and use as pharmaceutically active compounds. In
particular, it was an object to provide novel substituted and
unsubstituted benzooxathiazoles for treating type 1 and type 2
diabetes, insulin resistance and pathological obesity.
[0007] The present invention relates to compounds of the formula I
1
[0008] in which
[0009] X is CH.sub.2, O, N;
[0010] Y is CH.sub.2, O, N;
[0011] R1, R2, R3 are each independently of one another
[0012] H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0013] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0014] O--(C.sub.1-C.sub.6)alkyl;
[0015] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0016] Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0017] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0018] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl; or in each case two
of the radicals R1 and R2 or R2 and R3 or R1 and R3 together form a
fused aryl radical, where aryl may be phenyl, naphthyl, biphenyl,
thienyl or pyridyl and the aryl moiety may in each case be mono- to
trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0019] or its physiologically acceptable salts or prodrugs.
[0020] The invention preferably relates to compounds of the formula
I wherein
[0021] X is O, N;
[0022] Y is O, N;
[0023] R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0024] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0025] O--(C.sub.1-C.sub.6)alkyl;
[0026] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0027] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0028] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0029] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0030] R2 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0031] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-CO.sub.0)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-CO.sub.6)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0032] O--(C.sub.1-C.sub.6)alkyl;
[0033] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0034] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0035] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0036] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0037] R3 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0038] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0039] O--(C.sub.1-C.sub.6)alkyl;
[0040] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0041] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0042] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl, NCO,
NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0043] or its physiologically acceptable salts or prodrugs.
[0044] The invention furthermore preferably relates to compounds of
the formula I wherein
[0045] X is O, N;
[0046] Y is N;
[0047] R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0048] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0049] O--(C.sub.1-C.sub.6)alkyl;
[0050] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0051] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0052] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0053] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0054] R2 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0055] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0056] O--(C.sub.1-C.sub.6)alkyl;
[0057] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(CG-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0058] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0059] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0060] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0061] R3 is COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl- -phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl- , COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0062] O--(C.sub.1-C.sub.6)alkyl;
[0063] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2--;
[0064] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0065] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl, NCO,
NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0066] or its physiologically acceptable salts or prodrugs.
[0067] The invention furthermore preferably relates to compounds of
the formula I wherein
[0068] X is O;
[0069] Y is N;
[0070] R1 is H, F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0071] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0072] O--(C.sub.1-C.sub.6)alkyl;
[0073] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0074] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0075] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0076] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0077] R2 is F, Cl, Br, I, NH.sub.2, OH, NO.sub.2, COOH;
[0078] COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl-phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazo- le, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0079] O--(C.sub.1-C.sub.6)alkyl;
[0080] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,
biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each
case be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0081] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0082] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0083] R3 is COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.16)alkyl, CONH(C.sub.1-C.sub.16)alkenyl,
CONH(C.sub.1-C.sub.6)alkyl-phenyl, where phenyl may be mono- to
trisubstituted by O-(C.sub.1-C.sub.10)alkyl or
O--(C.sub.1-C.sub.10)alkyl- -phenyl,
CONH(C.sub.1-C.sub.6)alkyl-benzimidazole, where the benzimidazole
ring may be mono- to trisubstituted by S-phenyl, wherein the
S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)alkyl- , COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2;
[0084] O--(C.sub.1-C.sub.6)alkyl;
[0085] (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-COOH,
(C.sub.1-C.sub.6)alkyl-aryl, where aryl may be phenyl, naphthyl,
biphenyl, thienyl or pyridyl and the aryl moiety may in each case
be mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl- , COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0086] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,
naphthyl, pyridyl, furanyl or thienyl rings may in each case be
mono- to trisubstituted by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.10)alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)alkyl, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2;
[0087] (C.sub.3-C.sub.18)cycloalkyl, where in the alkyl radicals
one or more hydrogens may be replaced by fluorine or one hydrogen
may be replaced by OH, (C.sub.1-C.sub.6)alkyl-phenyl or
O--(C.sub.1-C.sub.6)alky- l-phenyl,
[0088] NCO, NSO.sub.3--(C.sub.1-C.sub.10)alkyl;
[0089] or its physiologically acceptable salts or prodrugs.
[0090] The invention further relates to a method of inhibiting a
PTPase, preferentially PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or
HePTP, comprising administering to a subject in need thereof an
effective amount of one or more compounds of formula 1 as described
above.
[0091] The invention further relates to a method of treating type 1
diabetes, type 2 diabetes, insuling resistance, or pathological
obesity comprising administering to a subject in need thereof an
effective amount of one or more compounds of formula 1 as described
above.
[0092] The invention still further relates to a method of preparing
a pharmaceutical composition comprising the steps of mixing one or
more compounds of formula 1 with one or more pharmaceutically
acceptable excipients and bringing this mixture into a form
suitable for administration.
[0093] Other compounds, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0094] In a compound of the formula I, X and Y in preferred
embodiments may in each case independently of one another be
CH.sub.2, O or N.
[0095] The invention relates to compounds of the formula I, in the
form of their racemates, racemic mixtures and pure enantiomers, and
to their diastereomers and mixtures thereof.
[0096] The alkyl, alkenyl and alkynyl radicals in the substituents
R1, R2 and R3 can be either straight-chain or branched.
[0097] On account of their higher water solubility,
pharmaceutically acceptable salts are particularly suitable for
medicinal applications compared with the starting materials or base
compounds. These salts must have a pharmaceutically acceptable
anion or cation. Suitable pharmaceutically acceptable acid addition
salts of the compounds according to the invention are salts of
inorganic acids, such as hydrochloric acid, hydrobromic acid,
phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid
and sulfuric acid, and of organic acids, such as, for example,
acetic acid, benzenesulfonic acid, benzoic acid, citric acid,
ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,
isethionic acid, lactic acid, lactobionic acid, maleic acid, malic
acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid,
tartaric acid and trifluoroacetic acid. For medicinal purposes, the
chlorine salt is particularly preferred. Suitable pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such
as sodium salts and potassium salts) and alkaline earth metal salts
(such as magnesium salts and calcium salts).
[0098] Salts having a pharmaceutically acceptable anion are
likewise included in the scope of the invention as useful
intermediates for the production or purification of
pharmaceutically acceptable salts and/or for use in nontherapeutic,
for example in-vitro, applications.
[0099] Salts of chemical compounds of the formula I can be prepared
using customary methods familiar to the person skilled in the art.
A salt can be prepared, for example, by combining a chemical
compound of the formula I with an inorganic or organic acid or base
in a solvent or diluent.
[0100] The term "physiologically functional derivative" used here
relates to any physiologically acceptable derivative of a compound
of the formula I according to the invention, for example an ester,
which on administration to a mammal, such as, for example, man, is
able (directly or indirectly) to form a compound of the formula I
or an active metabolite thereof.
[0101] The physiologically functional derivatives also include
prodrugs of the compounds according to the invention. Such prodrugs
can be metabolized in vivo to a compound according to the
invention. These prodrugs can themselves be active or inactive.
[0102] The compounds according to the invention can also be present
in various polymorphic forms, for example as amorphous and
crystalline polymorphic forms. All polymorphic forms of the
compounds according to the invention are included in the scope of
the invention and are a further aspect of the invention.
[0103] Hereinbelow, all references to "compound(s) according to
formula (I)" refer to a compound/compounds of the formula (I) as
described above, and to their salts, solvates and physiologically
functional derivatives as described herein.
[0104] The amount of a compound according to formula (I) which is
necessary in order to achieve the desired biological effect is
dependent on a number of factors, for example the specific compound
selected, the intended use, the manner of administration and the
clinical condition of the patient. In general, the daily dose is in
the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per
day per kilogram of bodyweight, for example 3-10 mg/kg/day. An
intravenous dose can be, for example, in the range from 0.3 mg to
1.0 mg/kg, which can be suitably administered as an infusion of 10
ng to 100 ng per kilogram per minute. Suitable infusion solutions
for these purposes can contain, for example, from 0.1 ng to 10 mg,
typically from 1 ng to 10 mg per milliliter. Individual doses can
contain, for example, from 1 mg to 10 g of the active compound.
Thus, ampoules for injections can contain, for example, from 1 mg
to 100 mg, and orally administrable individual dose formulations,
such as, for example, tablets or capsules, can contain, for
example, from 1.0 to 1 000 mg, typically from 10 to 600 mg. In the
case of pharmaceutically acceptable salts, the abovementioned
weight details relate to the weight of the dihydrothiazolium ion
derived from the salt. For the prophylaxis or therapy of the
abovementioned conditions, the compounds according to formula (I)
can be used themselves as the compound, but they are preferably
present in the form of a pharmaceutical composition with a
tolerable excipient. The excipient must of course be tolerable, in
the sense that it is compatible with the other constituents of the
composition and is not harmful to the patient's health. The
excipient can be a solid or a liquid or both and is preferably
formulated with the compound as an individual dose, for example as
a tablet which can contain from 0.05% to 95% by weight of the
active compound. Further pharmaceutically active substances can
also be present, including further compounds according to formula
(I). The pharmaceutical compositions according to the invention can
be prepared by one of the known pharmaceutical methods, which
essentially consist in mixing the constituents with
pharmacologically acceptable excipients and/or auxiliaries.
[0105] Pharmaceutical compositions according to the invention are
those which are suitable for oral, rectal, topical, peroral (e.g.
sublingual) and parenteral (e.g. subcutaneous, intramuscular,
intradermal or intravenous) administration, although the most
suitable manner of administration in each individual case is
dependent on the nature and severity of the condition to be treated
and on the nature of the compound according to formula (I) used in
each case. Sugar-coated formulations and sugar-coated delayed
release formulations are also included in the scope of the
invention. Acid-resistant and enteric formulations are preferred.
Suitable enteric coatings include cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate
and anionic polymers of methacrylic acid and methyl
methacrylate.
[0106] Suitable pharmaceutical compounds for oral administration
can be present in separate units, such as, for example, capsules,
cachets, lozenges or tablets which in each case contain a certain
amount of the compound according to formula (I); as powders or
granules; as solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. As already
mentioned, these compositions can be prepared by any suitable
pharmaceutical method which includes a step in which the active
compound and the excipient (which can consist of one or more
additional constituents) are brought into contact. In general, the
compositions are prepared by uniform and homogeneous mixing of the
active compound with a liquid and/or finely divided solid
excipient, after which the product is shaped, if necessary. Thus a
tablet, for example, can be prepared by pressing or shaping a
powder or granules of the compound, if appropriate with one or more
additional constituents. Pressed tablets can be prepared by
tableting the compound in free-flowing form, such as, for example,
in a powder or granules, if appropriate mixed with a binder,
lubricant, inert diluent and/or one (a number of)
surface-active/dispersi- ng agent(s) in a suitable machine. Shaped
tablets can be prepared by shaping the pulverulent compound,
moistened with an inert liquid diluent, in a suitable machine.
[0107] Pharmaceutical compositions which are suitable for peroral
(sublingual) administration include lozenges which contain a
compound according to formula (I) with a flavoring, customarily
sucrose and gum arabic or tragacanth, and pastilles which include
the compound in an inert base such as gelatin and glycerol or
sucrose and gum arabic.
[0108] Suitable pharmaceutical compositions for parenteral
administration preferably include sterile aqueous preparations of a
compound according to formula (I), which are preferably isotonic
with the blood of the intended recipient. These preparations are
preferably administered intravenously, although the administration
can also take place subcutaneously, intramuscularly or
intradermally as an injection. These preparations can preferably be
prepared by mixing the compound with water and rendering the
obtained solution sterile and isotonic with the blood. Injectable
compositions according to the invention in general contain from 0.1
to 5% by weight of the active compound.
[0109] Suitable pharmaceutical compositions for rectal
administration are preferably present as individual dose
suppositories. These can be prepared by mixing a compound according
to formula (I) with one or more conventional solid excipients, for
example cocoa butter, and shaping the resulting mixture.
[0110] Suitable pharmaceutical compositions for topical application
to the skin are preferably present as ointment, cream, lotion,
paste, spray, aerosol or oil. Excipients which can be used are
petroleum jelly, lanolin, polyethylene glycols, alcohols and
combinations of two or more of these substances. The active
compound is in general present in a concentration of from 0.1 to
15%, for example of from 0.5 to 2%, by weight of the
composition.
[0111] Transdermal administration is also possible. Suitable
pharmaceutical compositions for transdermal administration can be
present as individual patches which are suitable for long-term
close contact with the epidermis of the patient. Such patches
suitably contain the active compound in an optionally buffered
aqueous solution, dissolved and/or dispersed in an adhesive or
dispersed in a polymer. A suitable active compound concentration is
from about 1% to 35%, preferably from about 3% to 15%. As a
particular possibility, the active compound can be released by
electrotransport or iontophoresis, as described, for example, in
Pharmaceutical Research, 2(6): 318 (1986).
[0112] The invention furthermore relates to a process for preparing
the compounds of the formula I, which comprises obtaining the
compounds of the formula I in such a way that the procedure is
according to the following reaction scheme:
[0113] A benzylidenediamine of the formula II in which R1, R2 and
R3 are as defined in the sections above is reacted with
sulfonediamine. In particular, it is possible to prepare a chemical
compound of the formula I in which X is N and Y is N in this
manner. 2
[0114] It is also possible to prepare a compound of the present
invention by reacting a 2-aminophenol of the formula III whose N
group is protected and whose substituents R1, R2 and R3 are as
defined under formula I with sulfuryl chloride, followed by removal
of the protective group. The N group of the 2-aminophenol of the
formula III is preferably protected by p-toluenesulfonyl.
[0115] Alternatively, a 2-aminophenol of the formula III in which
the 2-aminophenol is present without protective group is used as
starting material. This 2-aminophenol of the formula III whose N
group is not protected and whose substituents R1, R2 and R3 are
each defined as in claim 1 is treated with sulfonyidiimidazole
under basic conditions. The base used can, for example, be
triethylamine, a Hunig base or DBU
(1,5-diazabicyclo[4.3.0]non-5-ene). 3
[0116] It is also possible to prepare a compound of the present
invention by a process in which initially a
1-bromomethyl-2-nitrobenzene of the formula IV 4
[0117] whose substituents R1, R2 and R3 are as defined under
formula I with Na.sub.2SO.sub.3 (sodium sulfite) to give a compound
of the formula V which is then converted by reduction of the nitro
group into the corresponding aniline. A compound of the formula I
is finally obtained by heating this aniline of the compound of the
formula V.
[0118] The invention also relates to a pharmaceutical composition
or medicament which comprises at least one of the compounds of the
formula I and/or its physiologically acceptable salts and/or their
prodrugs and, if appropriate, additional excipients.
[0119] The compounds of the formula I, and/or their physiologically
acceptable salts and/or their prodrugs can be used for preparing
medicaments.
[0120] Such medicaments are suitable, in particular, for treating
type 1 and 2 diabetes, insulin resistance and pathological obesity.
In addition, they are also suitable for treating elevated blood
lipid levels, hypertension, atherosclerosis, immune system
dysfunctions, autoimmune diseases, allergic diseases such as
asthma, osteoporosis, disturbed proliferation, such as cancer and
psoriasis, diseases where the production of growth factors,
hormones or cytokines which effect the release of growth hormones
is reduced or increased, infectious diseases or disorders of the
nervous system, such as Alzheimer's disease and schizophrenia.
[0121] The compounds of the formula I, and/or their physiologically
acceptable salts and/or their prodrugs can furthermore be used for
preparing a medicament which inhibits a PTPase. Suitable PTPases
are, in particular, PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or
HePTP.
[0122] Finally, compounds of the formula I and/or their
physiologically acceptable salts and/or their prodrugs can be used
for preparing a medicament for the treatment of diseases, in
particular, type 1 and 2 diabetes, insulin resistance, pathological
obesity, elevated blood lipid levels, hypertension,
atherosclerosis, immune system dysfunctions, autoimmune diseases,
allergic diseases such as asthma, osteoporosis, disturbed
proliferation, such as cancer and psoriasis, diseases where the
production of growth factors, hormones or cytokines which effect
the release of growth hormones is reduced or increased, disorders
of the nervous system such as Alzheimer's disease and schizophrenia
and infectious diseases.
[0123] The invention relates to the preparation of a medicament
comprising at least one compound of this invention, which comprises
mixing the active compound with a pharmaceutically acceptable
excipient, and bringing this mixture into a form suitable for
administration.
[0124] List of abbreviations:
1 aa amino acids DBU 1,5-diazabicyclo(4.3.0)non-- 5-ene DMSO
dimethyl sulfoxide DIT dithiotreitol EDTA
ethylenediaminetetraacetic acid EtOAc ethyl EGTA
ethylenebis(oxyethylenenitrilo)tetraacetic acid h hour HPLC high
pressure liquid chromatography MeOH methanol MOI multiplicity of
infection MS mass spectroscopy NMR nuclear magnetic resonance PAGE
polyacrylamide gel electrophoresis RP reversed phase RT room
temperature SDS sodium dodecylsulfate TFA trifluoroacetic acid
[0125] The present invention, thus generally described, will be
understood more readily by reference to the examples listed below,
which serve to illustrate the present invention without limiting
it.
EXAMPLES
[0126] 5
2TABLE 1 Compound R1 R2 R3 X Y 1 7-H 6-H 5-H N N 2 7-H 6-H
5-CH.sub.3 N O 3 7-H 6-H 5-H O N 4 In positions 4 and 5, in each
case two O N radicals R1 and R2 or R2 and R3 or R1 and R3 together
form a fused benzene radical; the respective remaining radical
located in position 7 or 6 is H 5 7-H 6-NO.sub.2 5-H O N 6 7-H
6-NH.sub.2 5-H O N 7 7-H 6-H 5-COO(CH.sub.3) O N 8 7-H 6-H 5-COOH O
N 9 7-H 6-H 5-CON O N (CH.sub.2--CH.sub.2-- phenyl-3,4-O-
CH.sub.2-phenyl) 10 7-H 6-H 5-CON O N (CH.sub.2-phenyl-4-
O--(CH.sub.2).sub.7--CH.sub.3) 11 7-H 6-H 5-CON O N
((CH.sub.2).sub.15--CH.sub.3) 12 7-H 6-H 5-COO(CH.sub.3) N O 13 7-H
6-H 5-COOH N O 14 7-H 6-H 5-CON N O (CH.sub.2--CH.sub.2--
phenyl-3,4-O- CH.sub.2-phenyl) 15 7-H 6-H 5-CON N O (CH.sub.2-
benzimidazolyl -2,5-S-phenyl)
[0127] Inhibitors of phosphatases are described, inter alia, in
WO97/3974 (cinnamic acid derivatives as inhibitors of PTP) which is
hereby incorporated herein by reference. Unspecific phosphatase
inhibition by vanadium oxo complexes and other vanadium complexes
results in improved insulin resistance.
[0128] Enzymatic test systems for detecting phosphatase
inhibition
[0129] In an in vitro assay, the compounds of the formula I were
tested for their phosphatase-inhibiting action. Enzyme preparation
and assay were carried out as follows.
[0130] Obtaining the Enzyme Preparation:
[0131] A) Cell Culture:
[0132] Sf9 cells (=Spodoptera frugiperda cell type; obtainable from
Invitrogen) are cultivated in spinner flasks at 28.degree. C. in
Grace's supplemented medium (Gibco-BRL) with 10% heat-inactivated
fetal calf serum (Gibco-BRL) according to the protocol of Summers
and Smith (A Manual for Methods for Baculovirus Vectors and Insect
Culture Procedures [Bulletin No. 15555]. Texas A & M
University, Texas Agricultural Experiment Station, College Station,
TX, 1987). Construction of recombinant Baculovirus transfer
vectors: cDNA encoding the regulatory and catalytic domains of
human PTP1 B, but without the carboxy-terminal hydrophobic region
(corresponding to 1-299 aa) was obtained via polymerase chain
reaction using primers with added donation sites and suitable cDNA
matrices (obtainable, for example, from Invitrogen) and then cloned
in Baculovirus expression vectors (Amersham Pharmacia Biotech.).
The recombinant Baculoviruses were prepared using the Bac-to-Bac
Baculovirus expression system (obtainable from Gibco-BRL). The gene
was cloned into the pFASTBAC donor plasmid (obtainable from Life
Technologies). The resulting plasmid was transformed into competent
DH10BAC Escherichia coli cells (obtainable from Life Technologies).
Following transposition and antibiotic selection, the recombinant
plasmid DNA of selected E. coli colonies was isolated and then used
for the transfection of Sf9 insect cells. The virus particle in the
supernatant medium was amplified three times, up to a viral stock
volume of 500 ml.
[0133] B) Production of Recombinant Protein:
[0134] Baculovirus infection of a 500 ml spinner culture of Sf9
cells was carried out essentially as described by Summers and Smith
(see above). At a density of 1-3.times.10.sup.6 cells/ml, Sf9 cells
were pelleted by centrifugation at 300 g for 5 min, the supernatant
was removed and the cells were resuspended at a density of
1.times.10.sup.7 cell/ml in a suitable recombinant viral stock (MOI
10). The culture was shaken carefully at room temperature for 1.5 h
and fresh medium was then added to a cell density of
1.times.10.sup.6 cells/ml. The cells were then cultivated in
suspension at 28.degree. C. for suitable periods following
postinfection.
[0135] C) Cellular Fractionation and Total Cell Extracts of
Infected Sf9 Cells:
[0136] Following postinfection, aliquots were subjected to an
analysis of protein expression by SDS-PAGE and Western blot
analysis. Cellular fractionation was carried out as described
(Cromlish, W. and Kennedy, B. Biochem. Pharmacol. 52: 1777-1785,
1996). Total cell extracts were obtained of 1 ml aliquots of the
infected Sf9 cells after certain intervals postinfection. The
pelleted cells (300.times.g, 5 min) were washed once in
phosphate-buffered saline (4.degree. C.), resuspended in 50 .mu.l
of water and broken up by repeated freezing/thawing. Protein
concentrations were determined using the Bradford method, with
bovine serum albumin as standard.
[0137] Assay:
[0138] A) Dephosphorylation of a Phosphopeptide:
[0139] This assay is based on the release of phosphate from a
consensus substrate peptide which is detected in the nanomolar
concentration range by the Malachite Green/ammonium molybdate
method (Lanzetta, P. A., Alvarez, L. J., Reinach, P. S., Candia, O.
A. Anal Biochem. 100: 95-97, 1979) adapted for the microtiter plate
format. The dodecatrisphosphopeptide, TRDIYETDYYRK (Biotrend,
Cologne) corresponds to the amino acids 1142-1153 of the catalytic
domain of the insulin receptor and is (auto)phosphorylated on the
tyrosine residues 1146, 1150, and 1151. The recombinant hPTP1B was
diluted with assay buffer (40 mM Tris/HCl, pH 7.4, 1 mM EDTA, 20 mM
DTT), corresponding to an activity of 1000-1500 nmol/m in/mg of
protein, and then preincubated (a 20 .mu.l portion, 15 min,
30.degree. C.) in the absence or presence of the test substance (5
.mu.l) in the desired concentration (final concentration DMSO 2%
max.) in a total volume of 90 .mu.l (assay buffer). To initiate the
dephosphorylation reaction, the peptide substrate (10 .mu.l,
pre-warmed to 30.degree. C.) was added to the preincubated enzyme
preparation with or without test substance (final concentration
02-200 .mu.M), and the incubation was continued for 1 h. The
reaction was terminated by addition of 100 .mu.l of Malachite Green
hydrochloride (0.45%, 3 parts), ammonium molybdate tetrahydrate
(4.2% in 4 N HCl, 1 part) and 0.5% of Tween 20 as stop solution.
Following 30 min of incubation at 22.degree. C. for color
development, the absorption at 650 nm was determined using a
microtiter plate reader (Molecular Devices). Samples and blank
values were determined in three replications. The PTP1B activity
was calculated as nanomoles of released phosphate per min and mg of
protein using potassium phosphate as standard. The inhibition of
recombinant hPTP1B by test substances was calculated as a
percentage of the phosphatase control. The IC.sub.50 values show
significant correlation with a four-parameter nonlinear logistic
regression curve.
[0140] B) Cleavage of p-nitrophenyl Phosphate:
[0141] This assay is based on the change in absorption of the
non-physiological substrate p-nitrophenyl phosphate during cleavage
to nitrophenol under standard conditions (Tonks, N. K., Diltz, C.
D:, Fischer, E. H. J. Biol. Chem. 263: 6731-6737, 1988; Burke T.
R., Ye, B., Yan, X. J., Wang, S. M., Jia, Z. C., Chen, L., Zhang,
Z. Y., Barford, D. Biochemistry 35: 15989-15996, 1996). The
inhibitors, at a suitable dilution, are pipetted to the reaction
mixtures containing 0.5-5 mM of p-nitrophenyl phosphate. The
following buffers were used (total volume 100 .mu.l): (a) 100 mM
sodium acetate (pH 5.5), 50 mM NaCl, 0.1% (w/v) bovine serum
albumin, 5 mM glutathione, 5 mM DTT, 0.4 mM EGTA and 1 mM EDTA; (b)
50 mM Hepes/KOH (pH 7.4), 100 mM NaCl, 0.1% (w/v) bovine serum
albumin, 5 mM glutathione, 5 mM DTT and 1 mM EDTA. The reaction was
started by addition of enzyme and carried out in microtiter plates
at 25.degree. C. for 1 h. The reaction was terminated by addition
of 100 .mu.l of 0.2 N NaOH. The enzyme activity was determined by
measuring the absorption at 405 nm, with suitable corrections for
the absorption of the test substances and of p-nitrophenyl
phosphate. The results were expressed in percent of the control by
comparing the amount of p-nitrophenol formed in the samples treated
with test substance (nmol/min/mg of protein) with the amount in the
untreated samples. Mean values and standard deviations were
calculated and the IC50 values were determined by regression
analysis of the linear portion of the inhibition curves.
[0142] The test results show that the compounds of the formula I
according to the invention have an inhibitory effect on the
phosphotyrosine phosphatase 1B (PTP1B). It is known that PTP1B
plays an important role in intracellular signal cascades. The
compounds are therefore suitable for treating in particular, type 1
and 2 diabetes, insulin resistance and pathological obesity. Owing
to the fact that they inhibit PTP1B, the compounds are also
suitable for treating hyperglycemia, hypertension, atherosclerosis,
immune system dysfunctions, autoimmune diseases, allergic diseases
such as asthma, osteoporosis, proliferation disturbances, such as
cancer and psoriasis, diseases with reduced or increased production
of growth factors, hormones or cytokines which effect the release
of growth hormones, disorders of the nervous system, such as
Alzheimer's disease and schizophrenia, and infectious diseases.
[0143] Preparation of Exemplary Compounds (Numeration According to
Table 1):
[0144] Below, the preparation of some compounds is described in
detail; the other compounds of the formula I were obtained in a
similar manner:
[0145] Compound 1: 1,3-Dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide
6
[0146] A solution of 1,2-phenylenediamine (91 mg, 0.84 mmol) and
sulfamide (81 mg, 0.84 mmol) in diglyme (2.5 ml) is stirred at
155.degree. C. for 1.5 h. After cooling to RT, the reaction
solution is poured into ice-water (15 ml) and the product is
extracted with ethyl acetate. The solvent is distilled off under
reduced pressure and the red residue is purified by flash
chromatography (1:1 ethyl acetate/toluene).
[0147] Yield: 41 mg (35%).
[0148] .sup.1H-NMR (D.sub.6-DMSO): .delta. 10.8 (s, 2H, NH), 6.88
(m, 2H) aryl, 6.8 (m, 2H) aryl. MS (ESI-MS) 171.1 (M+1).
[0149] Compound 2: 6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
7
[0150] N-(2-Hydroxy-4-methylphenyl)4-methylbenzenesulfonamide
Pyridine (810 .mu.l) and then, a little at a time,
p-toluenesulfonyl chloride (1.91 g, 10 mmol) are added to a
solution of 2-amino-5-methylphenol (1.23 g, 10 mmol) in
CH.sub.2Cl.sub.2 (20 ml). The reaction mixture is stirred at
40.degree. C. for 4 h. The solvent is distilled off under reduced
pressure, ethyl acetate is added to the residue and the solid is
filtered off with suction.
[0151] Yield: 2.32 g (83%)
[0152] 6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole
2,2-dioxide
[0153] At -78.degree. C., a solution of sulfuryl chloride (450
.mu.l, 5.41 mmol) in CH.sub.2Cl.sub.2 (10 ml) is slowly added
dropwise to a solution of
N-(2-hydroxy-4-methylphenyl)-4-methyl-benzenesulfonamide (1.5 g,
5.41 mmol) and triethylamine (1.5 ml), and the mixture is stirred
at -78.degree. C. for one hour. After thawing to RT, the solvent is
distilled off under reduced pressure and the residue is purified by
RP chromatography.
[0154] Yield: 592 mg (32%).
[0155] 6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
[0156] 6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole
2,2-dioxide (100 mg, 0.295 mmol) is dissolved in acetonitrile (5
ml). A solution of sodium azide (of 20 mg, 0.29 mmol of sodium
azide in 1 ml of H.sub.2O) is added to this solution, and the
mixture is stirred at RT overnight. The mixture is then stirred at
60.degree. C. for 1 h, the solvent is distilled off under reduced
pressure and the residue is purified by RP chromatography.
[0157] Yield: 47 mg (85%).
[0158] .sup.1H-NMR (D.sub.6-DMSO): .delta. 6.51 (d, 1H, aryl), 6.45
(d, 1H, aryl), 6.29 (m, 1H, aryl), 2.14 (s, 3H, CH.sub.3).
[0159] MS (ESI-MS, ES-) 184.9 (M-1).
[0160] Compound 3: 5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
8
[0161] 5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide was
synthesized starting with 2-amino-4-methylphenol, according to the
sequence described under example 2.
[0162] .sup.1H-NMR (D.sub.6-DMSO): .delta. 6.53 (d, 1H, aryl), 6.23
(m, 1H, aryl), 6.10 (dd, 1H, aryl), 2.13 (s, 3H, CH.sub.3).
[0163] MS (ESI-MS, ES-) 184.9 (M-1).
[0164] Compound 4: 1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl
2,2-dioxide 9
[0165] 1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl 2,2-dioxide was
synthesized from 1-aminonaphthyl-2-ol, according to the sequence
described under example 2.
[0166] .sup.1H-NMR (D.sub.6-DMSO): .delta. 7.8 (dd, 1H, aryl), 7.66
(dd, 1H, aryl), 7.23 (m, 2H, aryl), 7.1 (d, 1H aryl), 6.9 (d, 1H,
aryl).
[0167] MS (ESI-MS, ES-) 221 (M-1).
[0168] Compound 5: 6-Nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
10
[0169] A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) in
acetonitrile (300 ml) is treated with N-ethyldiisopropylamine (18.7
ml, 11.0 mmol) and N,N'-sulfuryldiimidazole (10.8 g, 55 mmol) and
boiled at reflux for 18 h. After cooling to RT, the solvent is
distilled off under reduced pressure, the residue is taken up in 1
N HCl and the product is extracted with ethyl acetate. The product
is then purified by flash chromatography (17:2:1,
EtOAc/MeOH/H.sub.2O).
[0170] Yield: 8.3 g (76.9%).
[0171] .sup.1H-NMR (D.sub.6-DMSO): .delta. 7.6 (dd, 1H, aryl), 7.58
(s, 1H, aryl), 6.55 (d, 1H, aryl).
[0172] MS (ESI-MS, ES-) 214.9 (M-1).
[0173] Compound 6: 6-Amino-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
11
[0174] A solution of 6-nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide
(example 5) (8.1 g, 37 mmol) in methanol (250 ml) is hydrogenated
at atmospheric pressure in the presence of Pd--C. The catalyst is
then filtered off, the clear solution is treated with methanolic
HCl (1 N) and the solvent is distilled off under reduced pressure.
The residue is dissolved in ethanol and the product crystallizes
after addition of diethyl ether.
[0175] Yield: 3.95 g (57.3%)
[0176] Compound 7: Methyl
2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazol- e-5-carboxylate
12
[0177] 3 g of methyl 3-amino-4-hydroxybenzoate (0.018 mol), 3.9 g
of sulfonyidiimidazole (0.02 mol) and 3 g of DBU (0.02 mol) are
dissolved in 50 ml of acetonitrile and the solution is degassed and
then heated at boiling point for 3 h.
[0178] For work-up, the solution is diluted with 120 ml of ethyl
acetate and extracted with 50 ml of 1 N HCl. The organic phase is
dried over magnesium sulfate and the solvent is distilled off under
reduced pressure.
[0179] The crude product is used without purification for the next
step.
[0180] Yield: 3.6 g (88%)
[0181] .sup.1H-NMR (D6-DMSO): .delta. 7.55 (dd, 1H, aromat.), 7.45
(d, 1H, aromat.), 7.23 (d, 1H, aromat.), 3.85 (s, 3H, OMe). MS
(ESI-MS) 230.1 (M+1).
[0182] Compound 8:
2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-car- boxylic
Acid 13
[0183] 3.3 g of compound 1 (21 mmol) are dissolved in a solution of
1.25 g of NaOH in 70 ml of water. The reaction mixture is stirred
at 25.degree. C. for 4 h.
[0184] The mixture is then acidified to pH 2 using 2N HCl and
evaporated to dryness. To remove the NaCl, the residue is taken up
in 150 ml of acetone and filtered, and the solvent is distilled
off. The crude product is used without purification for the next
step.
[0185] Yield: 2.3 g (75%)
[0186] .sup.1H-NMR (D6-DMSO): .delta. 7.54 (dd, 1H, aromat.), 7.40
(d, 1H, aromat.), 7.27 (d, 1H, aromat.). MS (ESI-MS) 216.1
(M+1).
[0187] Compound 9:
N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihyd-
ro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide 14
[0188] A solution of 100 mg of compound 3 (0.46 mmol), 160 mg of
2-(3,4-bisbenzyloxyphenyl)ethylamine hydrochloride (0.6 mmol), 115
mg of EDC (0.6 mmol), 81 mg of HOBT and 260 mg of
ethyldiisopropylamine in 2 ml of DMF is stirred at 25.degree. C.
for 5 h.
[0189] The mixture is then diluted with 20 ml of ethyl acetate and
extracted with 10 ml of 2N HCl. The organic phase is dried over
magnesium sulfate and the solvent is distilled off. The crude
product is purified by HPLC (RP18, acetonitrile/water 0.1%
TFA).
[0190] Yield: 66 mg (40%).
[0191] .sup.1H-NMR (D6-DMSO): .delta. 8.49 (t, 1H, NH), 7.46-7.23
(m, 13H, aromat.), 6.97 (d, 2H, aromat.), 6.74 (dd, 1H, aromat.),
5.08 (s, 4H, OCH.sub.2), 3.43 (dt, 2H, NCH.sub.2), 2.74 (2H, t,
CH.sub.2). MS (ESI-MS) 531.2 (M+1).
[0192] Compound 10:
N-(4-Octyloxybenzyl)-2,2-dioxo-2,3-dihydro-2,6-benzo[1-
,2,3]oxathiazole-5-carboxamide 4 15
[0193] Compound 4 is prepared as described for compound 3.
[0194] Yield: 63 mg (52%)
[0195] .sup.1H-NMR (D6-DMSO): .delta. 8.95 (t, 1H, NH), 7.52 (dd,
1H, aromat.), 7.45 (d, 1H, aromat.), 7.3 (d, 1H, aromat.), 7.22 (d,
2H, aromat.), 6.86 (d, 2H, aromat.), 4.37 (d, 2H, NCH.sub.2), 3.91
(t, 2H, OCH.sub.2), 1.65 (m, 2H, CH.sub.2), 1.45-1.2 (m, 10H,
CH.sub.2), 0.86 (t, 3H, CH.sub.3). MS (ESI-MS) 433.2 (M+1).
[0196] Compound 11:
N-Hexadecyl-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxat-
hiazole-5-carboxamide 5 16
[0197] Compound 5 is prepared as described for compound 3.
[0198] Yield: 51 mg (26%)
[0199] .sup.1H-NMR (D6-DMSO): .delta. 8.35 (t, 1H, NH), 7.38 (d,
1H, aromat.), 734 (s, 1H, aromat.), 7.2 (d, 1H, aromat.), 3.21 (dt,
2H, NCH.sub.2), 1.5 (m, 2H, CH.sub.2), 1.4 (m, 26H, CH.sub.2), 0.85
(t, 3H, CH.sub.3). MS (ESI-MS) 439.3 (M+1).
[0200] Compound 12: Methyl
2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazo- le-6-carboxylate 6
17
[0201] Compound 6 is prepared as described for compound 1.
[0202] Yield: 3.35 g (82%)
[0203] .sup.1H-NMR (D6-DMSO): .delta. 7.43 (dd, 1H, aromat.), 7.19
(d, 1H, aromat.), 6.53 (d, 1H, aromat.). MS (ESI-MS) 227.9
(M-1).
[0204] Compound 13:
2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-ca- rboxylic
acid 7 18
[0205] Compound 7 is prepared from 6 as described for compound
2.
[0206] Yield: 2.2 g (71%)
[0207] .sup.1H-NMR (D6-DMSO): .delta. 7.46 (dd, 1H, aromat.), 7.25
(d, 1H, aromat.), 6.46 (d, 1H, aromat.) 3.73 (s, 3H, Ome). MS
(ESI-MS) 213.9 (M-1).
[0208] Compound 14:
N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihy-
dro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide 8 19
[0209] Compound 8 is prepared from 7 as described for compound
3.
[0210] Yield: 4,1 g (25%)
[0211] .sup.1H-NMR (D6-DMSO): .delta. 8.33 (t, 1H, NH), 7.55 (m,
2H, aromat.), 7.45-7.3 (m, 10H, aromat.), 6.96 (d, 2H, aromat.),
6.86 (d, 1H, aromat.), 6.74 (dd, 1H, aromat.), 5.08 (s, 4H,
OCH.sub.2), 3.41 (dt, 2H, NCH.sub.2), 2.73 (2H, t, CH.sub.2). MS
(ESI-MS) 531.3 (M+1).
[0212] Compound 15:
N-(5-Phenylsulfanyl-1H-benzoimidazol-2-ylmethyl)-2,2-d-
ioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide 9 20
[0213] Compound 9 is prepared from 7 as described for compound
3.
[0214] Yield: 6,9 g (34%)
[0215] .sup.1H-NMR (D6-DMSO): .delta. 8.96 (t, 1H, NH), 7.75 (d,
1H, aromat.), 7.61 (d, 1H, aromat.), 7.46, (m, 2H, aromat.)
7.41-7.3 (m, 6H, aromat.), 6.55 (d, 1H, aromat.), 4.81 (d, 2H,
NCH.sub.2). MS (ESI-MS) 453.2 (M+1).
[0216] Additional advantages, features and modifications will
readily occur to those skilled in the art. Therefore, the invention
in its broader aspects is not limited to the specific details, and
representative devices, shown and described herein. Accordingly,
various modifications may be made without departing from the spirit
or scope of the general inventive concept as defined by the
appended claims and their equivalents.
[0217] As used herein and in the following claims, articles such as
"the", "a" and "an" can connote the singular or the plural.
[0218] All documents referred to herein are specifically
incorporated herein by reference in their entireties.
* * * * *