U.S. patent application number 10/141208 was filed with the patent office on 2003-05-29 for positive allosteric ampa receptor modulators (paarm), processes for preparing them, and their use as pharmaceutical compositions.
This patent application is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Ceci, Angelo, Klinder, Klaus, Weiser, Thomas, Winter, Karin.
Application Number | 20030100552 10/141208 |
Document ID | / |
Family ID | 27214430 |
Filed Date | 2003-05-29 |
United States Patent
Application |
20030100552 |
Kind Code |
A1 |
Ceci, Angelo ; et
al. |
May 29, 2003 |
Positive allosteric AMPA receptor modulators (PAARM), processes for
preparing them, and their use as pharmaceutical compositions
Abstract
Compounds of formula (I) 1 wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, n, and m, are as defined herein, or an enantiomer
or diastereomer thereof, or a pharmacologically acceptable salt
thereof; processes for preparing these compounds, and their use in
pharmaceutical compositions.
Inventors: |
Ceci, Angelo; (Biberach,
DE) ; Klinder, Klaus; (Oggelshausen, DE) ;
Weiser, Thomas; (Nieder-Olm, DE) ; Winter, Karin;
(Gau-Algesheim, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma
KG
Ingelheim
DE
|
Family ID: |
27214430 |
Appl. No.: |
10/141208 |
Filed: |
May 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60303292 |
Jul 6, 2001 |
|
|
|
Current U.S.
Class: |
514/224.5 ;
544/14 |
Current CPC
Class: |
A61P 25/18 20180101;
C07D 279/02 20130101 |
Class at
Publication: |
514/224.5 ;
544/14 |
International
Class: |
A61K 031/542; C07D
279/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2001 |
DE |
101 23 952.1 |
Claims
We claim:
1. A compound of formula (I) 6wherein: R.sup.1 is a group selected
from hydrogen, a C.sub.1-C.sub.6-alkyl group optionally substituted
by one or more halogen atoms, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--CO--C.sub.1-C.sub.6-alkyl, --O, phenyl-C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, R.sup.2 and R.sup.3, which are
identical or different, are each a group selected from hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --NO.sub.2, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alky- l, --SO--C.sub.1-C.sub.6-alkyl,
--CO--C.sub.1-C.sub.6-alkyl, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C- .sub.1-C.sub.4-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, or R.sup.1 and R.sup.2 together are a
C.sub.4-C.sub.6-alkylene bridge; R.sup.6 and R.sup.7, which are
identical or different, are each hydrogen, C.sub.1-C.sub.4-alkyl,
or --CO--C.sub.1-C.sub.4-alkyl; R.sup.4, each of which are
identical or different, are each a group selected from a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN,
--NO.sub.2, --SO.sub.2H, --SO.sub.3H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--SO.sub.2--NR.sup.6R.sup.7, --COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl,
--NR.sup.6R.sup.7 and an aryl group optionally mono or
polysubstituted by halogen atoms, --NO.sub.2, --SO.sub.2H, or
C.sub.1-C.sub.4-alkyl; R.sup.5, each of which are identical or
different, are each a group selected from a C.sub.1-C.sub.6-alkyl
group optionally substituted by one or more halogen atoms,
phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN, --NO.sub.2,
--SO.sub.2H, --SO.sub.3H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --SO.sub.2--NR.sup.6R.sup.7, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, --NR.sup.6R.sup.7, and an aryl group
optionally mono or polysubstituted by halogen atoms, --NO.sub.2,
--SO.sub.2H, or C.sub.1-C.sub.4-alkyl; and n and m, which are
identical or different, are each 0, 1, 2, or 3, with the proviso
that naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is
excluded, or an enantiomer or diastereomer thereof, or a
pharmacologically acceptable salt thereof.
2. The compound of formula (I) according to claim 1, wherein:
R.sup.1 is a group selected from hydrogen, a C.sub.1-C.sub.6-alkyl
group optionally substituted by one or more halogen atoms,
--SO.sub.2H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --CO--C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.4-alkyl-NR.sup.7R.sup.8, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, benzyl, R.sup.2
and R.sup.3, which are identical or different, are each a group
selected from hydrogen, a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --NO.sub.2,
--SO.sub.2H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --CO--C.sub.1-C.sub.6-alkyl, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, or R.sup.1 and
R.sup.2 together are a C.sub.4-C.sub.6-alkylene bridge; R.sup.6 and
R.sup.7, which are identical or different, are each hydrogen,
C.sub.1-C.sub.4-alkyl, or --CO--C.sub.1-C.sub.2-alkyl, and R.sup.4,
which are identical or different, are each a group selected from a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --CN, --NO.sub.2, --SO.sub.2H, --SO.sub.3H,
--COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl, and
--NR.sup.6R.sup.7; R.sup.5, which are identical or different, are
each a group selected from a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --SO.sub.2H, --SO.sub.3H, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, and --NR.sup.6R.sup.7; and n and m,
which are identical or different, are each 0, 1, or 2, or an
enantiomer or diastereomer thereof, or a pharmacologically
acceptable salt thereof.
3. The compound of formula (I) according to claim 1, wherein:
R.sup.1 is hydrogen, C.sub.1-C.sub.4-alkyl, or benzyl, R.sup.2 and
R.sup.3, which are identical or different, are each hydrogen or
C.sub.1-C.sub.4-alkyl, or R.sup.1 and R.sup.2 together are a
butylene bridge; R.sup.4, which are identical or different, are
each a group selected from a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, -CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl, and
--NR.sup.6R.sup.7; R.sup.5, which are identical or different, are
each a group selected from a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl, and
--NR.sup.6R.sup.7; and n and m, which are identical or different,
are each 0, 1, or 2, or an enantiomer or diastereomer thereof, or a
pharmacologically acceptable salt thereof.
4. The compound of formula (I) according to claim 1, wherein:
R.sup.1, R.sup.2, R.sup.3, which are identical or different, are
each hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.4, which are
identical or different, are each a group selected from a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --NO.sub.2, --O--CO--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.6-alkyl, and
--NR.sup.6R.sup.7; R.sup.5, which are identical or different, are
each a group selected from a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --NO.sub.2,
--O--CO--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.6-alkyl, and --NR.sup.6R.sup.7; and n and m,
which are identical or different, are each 0, 1, or 2, or an
enantiomer or diastereomer thereof, or a pharmacologically
acceptable salt thereof.
5. The compound of formula (I) according to claim 1, wherein:
R.sup.1 is methyl, ethyl, isopropyl, n-butyl, or benzyl, or an
enantiomer or diastereomer thereof, or a pharmacologically
acceptable salt thereof.
6. The compound of formula (I) according to claim 1, wherein:
R.sup.1 is methyl, or a pharmacologically acceptable salt
thereof.
7. The compound of formula (I) according to claim 1, wherein:
R.sup.1 is methyl; R.sup.2 and R.sup.3 are each hydrogen; R.sup.4
and R.sup.5, which are identical or different, are each halogen;
and n and m, which are identical or different, are each 0, 1, or 2,
or a pharmacologically acceptable salt thereof.
8. A compound of general formula (I) 7wherein: R.sup.1 is a group
selected from hydrogen, a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--CO--C.sub.1-C.sub.6-alkyl, --O, phenyl-C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C- .sub.1-C.sub.4-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, R.sup.2 and R.sup.3, which are
identical or different, are each a group selected from hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --NO.sub.2, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--CO--C.sub.1-C.sub.6-alkyl, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7,
--C.sub.1-C.sub.4-alkyl-O--, C.sub.1-C.sub.4-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, or R.sup.1 and R.sup.2 together are a
C.sub.4-C.sub.6-alkylene bridge; R.sup.6 and R.sup.7, which are
identical or different, are each hydrogen, C.sub.1-C.sub.4-alkyl,
or --CO--C.sub.1-C.sub.4-alkyl; R.sup.4, which are identical or
different, are each a group selected from a C.sub.1-C.sub.6-alkyl
group optionally substituted by one or more halogen atoms,
phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN, --NO.sub.2,
--SO.sub.2H, --SO.sub.3H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --SO.sub.2--NR.sup.6R.sup.7, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, --NR.sup.6R.sup.7, and an aryl group
optionally mono or polysubstituted by halogen atoms, --NO.sub.2,
--SO.sub.2H, or C.sub.1-C.sub.4-alkyl; R.sup.5, which are identical
or different, are each a group selected from a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN,
--NO.sub.2, --SO.sub.2H, --SO.sub.3H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--SO.sub.2--NR.sup.6R.sup.7, --COOH --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl,
--NR.sup.6R.sup.7, and an aryl group optionally mono or
polysubstituted by halogen atoms, --NO.sub.2, --SO.sub.2H, or
C.sub.1-C.sub.4-alkyl; and n and m, which are identical or
different, are each 0, 1, 2, or 3, or an enantiomer or diastereomer
thereof, or a pharmacologically acceptable salt thereof.
9. A pharmaceutical composition comprising: (a) a compound of
general formula (I) according to claim 1; and (b) a
pharmaceutically acceptable excipient or carrier.
10. A pharmaceutical composition comprising: (a) a compound of
general formula (I) according to claim 8; and (b) a
pharmaceutically acceptable excipient or carrier.
11. A method of treating neurodegenerative diseases and/or cerebral
ischaemia of various origins in a patient in need thereof, the
method comprising administering to the patient an effective amount
of a compound of formula (I) according to one of claims 1 to 8.
12. A method of treating schizophrenia in a patient in need
thereof, the method comprising administering to the patient an
effective amount of a compound of formula (I) according to one of
claims 1 to 8.
13. A method of treating memory disorders in a patient in need
thereof, the method comprising administering to the patient an
effective amount of a compound of formula (I) according to one of
claims 1 to 8.
14. A method of treating dementias in a patient in need thereof,
the method comprising administering to the patient an effective
amount of a compound of formula (I) according to one of claims 1 to
8.
Description
RELATED APPLICATIONS
[0001] Benefit under 35 U.S.C. .sctn.119(e) of prior U.S.
provisional application Serial No. 60/303,292, filed Jul. 6, 2001,
is hereby claimed and is hereby incorporated by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to new positive allosteric
AMPA receptor modulators, processes for preparing them, and their
use as pharmaceutical compositions.
[0003] Compounds which are structurally similar to the compounds
according to the invention are disclosed in WO 99/67242 which
describes carbapenem derivatives with an antibacterial activity,
wherein naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is
used as a synthesis component.
SUMMARY OF THE INVENTION
[0004] The compounds according to the invention are compounds of
general formula (I) 2
[0005] wherein:
[0006] R.sup.1 denotes a group selected from among hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, --SO.sub.2H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --CO--C.sub.1-C.sub.6-alkyl, --O,
phenyl-C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, and
C.sub.3--C.sub.6-cycloalkyl,
[0007] R.sup.2 and R.sup.3, which may be identical or different,
denote a group selected from among hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --NO.sub.2, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alk- yl,
--CO--C.sub.1-C.sub.6-alkyl, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, or
[0008] R.sup.1 and R.sup.2 together denote a
C.sub.4-C.sub.6-alkylene bridge;
[0009] R.sup.6 and R.sup.7, which may be identical or different,
denote hydrogen, C.sub.1-C.sub.4-alkyl, or
--CO--C.sub.1-C.sub.4-alkyl;
[0010] R.sup.8 and R.sup.9, which may be identical or different,
denote hydrogen or C.sub.1-C.sub.4-alkyl;
[0011] R.sup.4, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms,
phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN, --NO.sub.2,
--SO.sub.2H, --SO.sub.3H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --SO.sub.2--NR.sup.6R.sup.7, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, --NR.sup.6R.sup.7, and an aryl group
optionally mono or polysubstituted by halogen atoms, --NO.sub.2,
--SO.sub.2H, or C.sub.1-C.sub.4-alkyl;
[0012] R.sup.5, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms,
phenyl-C.sub.1-C.sub.4-alkyl, halogen, --CN, --NO.sub.2,
--SO.sub.2H, --SO.sub.3H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --SO.sub.2--NR.sup.6R.sup.7, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, --NRR.sup.7 and an aryl group
optionally mono or polysubstituted by halogen atoms, --NO.sub.2,
--SO.sub.2H, or C.sub.1-C.sub.4-alkyl; and
[0013] n and m, which may be identical or different, represent 0,
1, 2, or 3,
[0014] with the proviso that
naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-t- hiazine is
excluded,
[0015] optionally in the form of their various enantiomers and
diastereomers, and the pharmacologically acceptable salts
thereof.
[0016] Preferred compounds are the compounds of general formula
(I), wherein:
[0017] R.sup.1 denotes a group selected from among hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, --SO.sub.2H, --SO.sub.2--C.sub.1-C.sub.6-alkyl,
--SO--C.sub.1-C.sub.6-alkyl, --CO--C.sub.1-C.sub.6-alkyl, --O,
--C.sub.1-C.sub.4-alkyl-NR.sup.7R.sup.8, and
--C.sub.1-C.sub.4-alkyl-O--C- .sub.1-C.sub.4-alkyl, or benzyl,
[0018] R.sup.2 and R.sup.3, which may be identical or different,
denote a group selected from among hydrogen, a
C.sub.1-C.sub.6-alkyl group optionally substituted by one or more
halogen atoms, halogen, --NO.sub.2, --SO.sub.2H,
--SO.sub.2--C.sub.1-C.sub.6-alkyl, --SO--C.sub.1-C.sub.6-alk- yl,
--CO--C.sub.1-C.sub.6-alkyl, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7, and
--C.sub.1-C.sub.4-alkyl-O--C.sub.1-C.sub.4-alkyl, or
[0019] R.sup.1 and R.sup.2 together denote a
C.sub.4-C.sub.6-alkylene bridge;
[0020] R.sup.6 and R.sup.7, which may be identical or different,
denote hydrogen, C.sub.1-C.sub.4-alkyl, or
--CO--C.sub.1-C.sub.2-alkyl; and
[0021] R.sup.4, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --SO.sub.2H, --SO.sub.3H, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, and --NR.sup.6R.sup.7;
[0022] R.sup.5, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --SO.sub.2H, --SO.sub.3H, --COOH,
--CO--C.sub.1-C.sub.6-alkyl, --O--CO--C.sub.1-C.sub.4-alkyl,
--CO--O--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--CO--NR.sup.6R.sup.7, --OH, --O--C.sub.1-C.sub.6-alkyl,
--S--C.sub.1-C.sub.6-alkyl, and --NR.sup.6R.sup.7; and
[0023] n and m, which may be identical or different, represent 0,
1, or 2,
[0024] optionally in the form of the various enantiomers and
diastereomers thereof, as well as the pharmacologically acceptable
salts thereof.
[0025] Particularly preferred are compounds of general formula (I),
wherein:
[0026] R.sup.1 denotes hydrogen, C.sub.1-C.sub.4-alkyl, or
benzyl,
[0027] R.sup.2 and R.sup.3, which may be identical or different,
denote hydrogen or C.sub.1-C.sub.4-alkyl, or
[0028] R.sup.1 and R.sup.2 together denote a butylene bridge;
[0029] R.sup.4, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.1-alkyl, and
--NR.sup.6R.sup.7;
[0030] R.sup.5, each of which may be identical or different,
denotes a group selected from among a C.sub.1-C.sub.6-alkyl group
optionally substituted by one or more halogen atoms, halogen, --CN,
--NO.sub.2, --COOH, --CO--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl,
--O--CO--O--C.sub.1-C.sub.4-alkyl, --CO--NR.sup.6R.sup.7, --OH,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl, and
--NR.sup.6R.sup.7; and
[0031] n and m, which may be identical or different, represent 0,
1, or 2,
[0032] optionally in the form of the various enantiomers and
diastereomers thereof, as well as the pharmacologically acceptable
salts thereof.
[0033] Also particularly preferred are compounds of general formula
(I), wherein:
[0034] R.sup.1, R.sup.2, and R.sup.3, which may be identical or
different, denote hydrogen or C.sub.1-C.sub.4-alkyl;
[0035] R.sup.4, which may be identical or different, denotes a
group selected from among a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --NO.sub.2,
--O--CO--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--O--C --C.sub.6-alkyl, and --NR.sup.6R.sup.7;
[0036] R.sup.5, which may be identical or different, denotes a
group selected from among a C.sub.1-C.sub.6-alkyl group optionally
substituted by one or more halogen atoms, halogen, --NO.sub.2,
--O--CO--C.sub.1-C.sub.4-alkyl, --O--CO--O--C.sub.1-C.sub.4-alkyl,
--O--Cl--C.sub.6-alkyl, and --NR.sup.6R.sup.7; and
[0037] n and m, which may be identical or different, represent 0,
1, or 2,
[0038] optionally in the form of the various enantiomers and
diastereomers thereof, as well as the pharmacologically acceptable
salts thereof.
[0039] Of particular importance according to the invention are the
compounds of general formula (I), wherein R.sup.1 denotes methyl,
ethyl, isopropyl, n-butyl, or benzyl, optionally in the form of the
various enantiomers and diastereomers thereof, as well as the
pharmacologically acceptable salts thereof.
[0040] Particularly preferred are compounds of general formula (I)
wherein R.sup.1 denotes methyl, optionally in the form of the
pharmacologically acceptable salts thereof.
[0041] Also particularly preferred are compounds of general formula
(I), wherein:
[0042] R.sup.1 denotes methyl;
[0043] R.sup.2 and R.sup.3 denote hydrogen;
[0044] R.sup.4 and R.sup.5, which may be identical or different,
denote halogen, preferably fluorine, chlorine, or bromine, most
preferably fluorine or chlorine; and
[0045] n and m, which may be identical or different, represent 0,
1, or 2, preferably 0 or 1,
[0046] optionally in the form of the pharmacologically acceptable
salts thereof.
[0047] The alkyl groups used, unless otherwise stated, are branched
and unbranched alkyl groups having 1 to 6 carbon atoms, preferably
1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl,
butyl, pentyl, and hexyl. The groups methyl, ethyl, propyl, or
butyl may optionally also be referred to by the abbreviations Me,
Et, Pr, or Bu. Unless otherwise stated, the definitions propyl,
butyl, pentyl, and hexyl also include all possible isomeric forms
of the groups in question. Thus, for example, propyl includes
n-propyl and isopropyl, butyl includes isobutyl, sec-butyl, and
tert-butyl, etc.
[0048] In the abovementioned alkyl groups, one or more hydrogen
atoms may optionally be substituted by the halogen atoms fluorine,
chlorine, bromine, or iodine. The substituents fluorine and
chlorine are preferred. The substituent fluorine is particularly
preferred. If desired, all the hydrogen atoms of the alkyl group
may be replaced.
[0049] The alkyl group mentioned in the group
phenyl-C.sub.1-C.sub.1-alkyl may be in branched or unbranched form.
Unless otherwise stated benzyl and phenylethyl are preferred
phenyl-C.sub.1-C.sub.4-alkyl groups. Benzyl is particularly
preferred.
[0050] The alkyl groups mentioned in the groups
--SO.sub.2--C.sub.1-C.sub.- 6-alkyl, --SO--C.sub.1-C.sub.6-alkyl,
--CO--C.sub.1-C.sub.6-alkyl, --CO--C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkyl-NR.sup.6R.sup.7,
--C.sub.1-C.sub.4-alkyl--O--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.6-alkyl, --S--C.sub.1-C.sub.6-alkyl,
--O--CO--C.sub.1-C.sub.4-alkyl, --CO--O--C.sub.1-C.sub.4-alkyl, or
--O--CO--O--C.sub.1-C.sub.4-alkyl may be in branched or unbranched
form with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms,
particularly preferably with 1 to 3 carbon atoms, most preferably
with 1 to 2 carbon atoms.
[0051] The C.sub.4-C.sub.6-alkylene bridge may, unless otherwise
stated, be branched and unbranched alkylene groups having 4 to 6
carbon atoms, for example, n-butylene, 1-methylpropylene,
2-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc.
n-Butylene bridges are particularly preferred.
[0052] The aryl group is an aromatic ring system having 6 to 10
carbon atoms, preferably phenyl.
[0053] In the abovementioned aryl groups, one or more hydrogen
atoms may optionally be substituted by halogen atoms, --NO.sub.2,
--SO.sub.2H, or --C.sub.1-C.sub.4-alkyl, preferably fluorine,
chlorine, --NO.sub.2, ethyl, or methyl, most preferably fluorine or
methyl.
[0054] The term C.sub.3-C.sub.6-cycloalkyl denotes saturated cyclic
hydrocarbon groups having 3 to 6 carbon atoms, for example,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0055] The term halogen, unless otherwise stated, refers to
fluorine, chlorine, bromine, and iodine, preferably fluorine,
chlorine, and bromine, most preferably fluorine and chlorine, most
preferably fluorine.
[0056] As already mentioned, the compounds of formula (I) or the
various enantiomers and diastereomers thereof may be converted into
the salts thereof, particularly, for pharmaceutical use, into the
physiologically and pharmacologically acceptable salts thereof.
These salts may on the one hand take the form of physiologically
and pharmacologically acceptable acid addition salts of the
compounds of formula (I) with inorganic or organic acids. On the
other hand, the compound of formula (I) where R.sup.1 is hydrogen
may be converted by reaction with inorganic bases into
physiologically and pharmacologically acceptable salts with alkali
or alkaline earth metal cations as counter-ions. The acid addition
salts may be prepared, for example, using hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic
acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric
acid, tartaric acid, or maleic acid. It is also possible to use
mixtures of the above acids. For preparing the alkali and alkaline
earth metal salts of the compound of formula (I) wherein R.sup.1
denotes hydrogen, it is preferable to use the alkali and alkaline
earth metal hydroxides and hydrides, the hydroxides and hydrides of
the alkali metals, especially sodium and potassium, being
preferred, while sodium and potassium hydroxide are particularly
preferred.
DETAILED DESCRIPTION OF THE INVENTION
[0057] The compounds according to the invention may be prepared in
a manner known per se. The following general methods of synthesis 1
and 2 shown in Diagrams 1 and 2 below are meant to illustrate the
invention without restricting it to their content. 3
[0058] Starting from a compound of formula (II), a compound of
formula (III) is prepared by sulfonation and subsequent
chlorination. The compound of formula (IV) obtained after
condensation with aminoacetic acid derivatives is cyclized by
adding polyphosphoric acid to the target compound (I).
[0059] The general preparation of the compounds according to the
invention in accordance with Diagram 1 is described in detail
hereinafter.
[0060] Sulfonation of the Naphthalene Derivative (II)
[0061] About 10 mmol of the naphthalene derivative (II) are taken
up in 2 mL to 100 mL, preferably 3 mL to 80 mL, most preferably
about 4 mL, of acetic anhydride and 10 mmol to 100 mmol, preferably
11 mmol to 80 mmol, particularly preferably 11 mmol or concentrated
sulfuric acid is added at 0.degree. C. to 50.degree. C., preferably
5.degree. C. to 20.degree. C., particularly preferably about
18.degree. C. After 2 hours to 16 hours, preferably about 5 hours,
stirring at 20.degree. C. to 100.degree. C., preferably about
25.degree. C., the mixture is poured onto a saturated NaCl
solution. The crystals formed are isolated.
[0062] Methylene chloride, diisopropylether, ethyl acetate,
trichloromethane, toluene, benzene, or 1,4-dioxane may be used
instead of acetic acid anhydride, while fuming sulfuric acid,
sulfur trioxide, chlorine sulfates or combinations thereof may be
used as an alternative to concentrated sulfuric acid.
[0063] Synthesis of the Naphthalene-1-sulfonic Acid Chlorides
(III)
[0064] About 10 mmol of the naphthalene-1-sulfonic acids are
combined successively with 10 mmol to 500 mmol, preferably about 90
mmol, of phosphorus oxytrichloride and 8 mmol to 50 mmol,
preferably about 10 mmol, of phosphorus pentachloride and heated
for 2 hours to 16 hours, preferably about 5 hours, at 20.degree. C.
to 100.degree. C., preferably by refluxing. Then the reaction
mixture is evaporated down and combined with water. After
extraction with organic diluent, the combined organic extracts are
dried and freed from solvent. The crude product obtained is used in
the subsequent steps without being purified.
[0065] Instead of the phosphorus oxytrichloride/phosphorus
pentachloride mixture, thionyl chloride, phosphorus pentachloride,
a phosphoric acid/chlorine mixture, or phosgene may be used. The
reaction may alternatively be carried out in the diluents ethyl
acetate, water, acetonitrile, N,N-dimethylacetamide, sulfolane,
DMF, hexane, or dichloroethane.
[0066] Synthesis of the Naphthalene-1-sulfonylaminoacetic Acids
[0067] About 10 mmol of the chlorosulfonylnaphthalenes, 10 mmol to
100 mmol, preferably 11 mmol to 30 mmol, most preferably about 12
mmol, of aminoacetic acid and 10 mmol to 100 mmol, preferably 11
mmol to 30 mmol, most preferably about 12 mmol, of sodium hydroxide
are dissolved in water and toluene. The reaction mixture is stirred
for 2 hours to 16 hours at 0.degree. C. to 110.degree. C.,
preferably at about 65.degree. C., then the phases are separated.
The aqueous phase is acidified and extracted. The combined organic
extracts are dried and evaporated down. Purification may be carried
out by chromatography.
[0068] Triethylamine, potassium carbonate, sodium hydrogen
carbonate, or sodium hydride may be used instead of sodium
hydroxide, while tetrahydrofuran, diethylether, dichloromethane,
trichloromethane, dioxane, acetone, benzene, ethanol, methanol,
ethyl acetate, or acetonitrile may be used instead of toluene.
[0069] Cyclization of the Naphthalene-1-sulfonylaminoacetic Acids
(IV)
[0070] About 10 mmol of the naphthalene-1-sulfonylaminoacetic acids
are combined with 10 g to 200 g, preferably about 40 g, of
polyphosphoric acid and stirred for 2 hours to 16 hours, preferably
about 5 hours, at 20.degree. C. to 110.degree. C., preferably
75.degree. C. to 95.degree. C., most preferably at about 80.degree.
C. Then the reaction mixture is poured onto water and extracted.
The combined organic extracts are dried and evaporated down. The
residue is purified.
[0071] Method 2 4
[0072] The compounds of formula (III) obtained as intermediate
compounds in Method 1 are reacted with primary amines to obtain the
compounds of formula (V) and then cyclized by the addition of a
compound of formula R.sup.2R.sup.3C.dbd.O in the presence of strong
acid to obtain the target compounds (I).
[0073] In order to prepare the compounds of formula (I) wherein
R.sup.1 and R.sup.2 represent hydrogen, paraformaldehyde, trioxane,
or formalin may be used and methanesulfonic acid, trifluoroacetic
acid, sulfuric acid, phosphoric acid, or polyphosphoric acid may be
used as strong acids.
[0074] The general preparation of the compounds according to the
invention in accordance with Diagram 2 is described in detail
hereinafter.
[0075] Synthesis of the Naphthalenesulfonamides (V)
[0076] About 10 mmol of the chlorosulfonylnaphthalenes (III) are
combined with an alcoholic solution of the primary amine (10 mmol
to 1000 mmol in 5 mL to 200 mL, for example, 200 mmol in 50 mL
ethanol) and then heated to 0.degree. C. to 100.degree. C. for 2
hours to 16 hours, preferably about 5 hours, preferably by
refluxing. Then the reaction mixture is evaporated down and
purified.
[0077] Instead of the alcoholic solvent, it is also possible to use
toluene, benzene, trichloromethane, dichloromethane, diethylether,
tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone,
pyridine, dimethylsulfoxide, dimethylformamide, dioxane, or
hexane.
[0078] Cyclization of the Naphthalene-1-sulfonamides (V) to Form
the Target Compounds (I)
[0079] About 10 mmol of the naphthalene-1-sulfonamides are added to
0 mL to 100 mL, preferably 20 mL to 80 mL, most preferably about 40
mL of methanesulfonic acid and combined with a solution of 3 mmol
to 50 mmol, preferably 4 mmol to 30 mmol, most preferably 5 mmol of
trioxane in 0 mL to 100 mL, preferably about 12 mL, of
trifluoroacetic acid. The reaction mixture is stirred for 2 hours
to 16 hours, preferably 5 hours, at 20.degree. C. to 100.degree.
C., preferably 30.degree. C. to 80.degree. C., most preferably
about 35.degree. C. and then poured onto ice water. After
extraction and drying of the combined organic extracts, the
solution is evaporated down. The crude product is purified.
[0080] Instead of trioxane, it is possible to use paraformaldehyde
or formalin, while instead of trifluoroacetic acid it is possible
to use boron trifluoride-diethylether, acetic acid, polyphosphoric
acid, phosphoric acid, or sulfuric acid. Acetic anhydride or
dichloromethane may be used as possible diluents.
[0081] The new compounds of general formula (I) may be synthesized
analogously to the following Examples of synthesis. These Examples
are, however, intended solely as examples of procedure to
illustrate the invention further without restricting it to the
subject matter thereof.
Synthesis of
2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide
EXAMPLE 1
[0082] 2.21 g of N-methyl-1-naphthalenesulfonic acid amide is
dissolved in 25 mL of methanesulfonic acid at 35.degree. C. and
combined with a solution of 0.30 g of trioxane in 8 mL of
trifluoroacetic acid. After 2 hours stirring at ambient
temperature, the reaction mixture is poured onto 300 mL of ice
water. The solid formed is separated off by filtration, washed with
100 mL of water, and dried overnight. After crystallization from
methylcyclohexane, the product is isolated as a white solid. Yield:
2.20 g; m.p.: 136.degree. C.
Synthesis of 6-chloro-2-methyl-2,3-dihydronaphtho[1,8-de]
[1,3]thiazine-1,1-dioxide
EXAMPLE 2
[0083] 0.45 g of 5-chloro-naphthalene-1-sulfonic acid-N-methylamide
is dissolved in 6.8 mL of methanesulfonic acid at 35.degree. C. and
combined with a solution of 0.07 g of trioxane in 2 mL of
trifluoroacetic acid. After 2 hours stirring at 35.degree. C., the
reaction mixture is poured onto 100 mL of ice water and the aqueous
phase is extracted with ethyl acetate. The organic extracts
collected are dried with sodium sulfate, evaporated down in vacuo,
and then purified by chromatography. Yield: 0.41 g; m.p.:
150.degree. C.
Synthesis of
2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide
EXAMPLE 3
[0084] Naphthalene-1-sulfonic acid tert-butylamide
[0085] 8 mL of tert-butylamine is placed in 50 mL of chloroform,
cooled to 0.degree. C., and 5.75 g of 1-naphthalenic acid chloride
in 45 mL of chloroform are added dropwise. Then the mixture is
stirred for 24 hours at ambient temperature. After concentration by
evaporation in vacuo, the residue obtained is dissolved in
dichloromethane and washed with 2 N hydrochloric acid. The organic
extracts collected are dried with sodium sulfate and evaporated
down in vacuo. Yield: 5.48 g.
[0086]
2-tert-butyl-1,1-dioxo-1,2-dihydro-1.lambda..sup.6-naphtho[1,8-de][-
1,3]thiazin-3-one
[0087] 4.36 g of naphthalene-1-sulfonic acid tert-butylamide is
placed in 80 mL tetrahydrofuran, cooled to -10.degree. C., and 29
mL of N-butyl lithium (1.6 molar solution in hexane) are cautiously
added dropwise. The mixture is first stirred for 0.5 hour at
-10.degree. C., then for 3 hours at ambient temperature. Then it is
cooled to -5.degree. C. and within 0.25 hour, CO.sub.2 obtained
from dry ice is piped in. The reaction mixture is stirred for 2.5
hours at ambient temperature, then combined with water. The
solution is poured onto 4 N hydrochloric acid and extracted with
ethyl acetate. The organic extracts collected are dried with sodium
sulfate and, after evaporation in vacuo, purified by
chromatography. Yield: 0.42 g.
[0088]
2-tert-butyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide
[0089] 0.17 g of
2-tert-butyl-1,1-dioxo-1,2-dihydro-1.lambda..sup.6-naphth-
o[1,8-de][1,3]thiazin-3-one is suspended in 2 mL tetrahydrofuran at
ambient temperature and 1.17 mL of borane-tetrahydrofuran complex
(1 molar solution) is added. Then the mixture is refluxed with
stirring for 100 hours, with a total of a further 8.2 mL of 1M
borane-tetrahydrofuran complex solution being added in several
batches. The reaction mixture is combined with 2 mL of 2 N
hydrochloric acid and with 2 mL of methanol, then refluxed for 12
hours with stirring. 2 mL of ammonia is added and any crystals
formed are filtered off. The filtrate is extracted with ethyl
acetate and the organic extracts collected are dried with sodium
sulfate. After evaporation in vacuo, the residue obtained is
purified by chromatography. Yield: 0.06 g.
[0090] 2,3-Dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide
[0091] 0.06 g of
2-tert-butyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazin-1,1-- dioxide
is dissolved in 1 mL of dichloromethane and 0.02 mL of
trifluoroacetic acid is added. Then the mixture is stirred for a
total of 22 hours at reflux temperature and for 96 hours at ambient
temperature, while during this period a total of 0.07 mL of
trifluoroacetic acid is added. The reaction mixture is evaporated
down in vacuo and purified by chromatography. Yield: 0.034 g; m.p.:
206.degree. C.-207.degree. C.
Synthesis of
[2-(1,1-dioxo-1H-3H-1.lambda..sup.6-naphtho[1,8-de]thiazine-2-
-yl)ethyl]dimethylamine
EXAMPLE 4
[0092] 0.028 g of sodium hydride is suspended in 0.5 mL of
dimethylformamide and 0.073 g of
2,3-dihydro-naphtho[1,8-de][1,3]thiazine- -1,1-dioxide in 1 mL of
dimethylformamide is added. Then 0.053 g of diethylaminoethyl
chloride-hydrochloride are added batchwise. The reaction mixture is
stirred for 18 hours at ambient temperature and then poured onto
ice water. The mixture is extracted with dichloromethane and the
organic extracts collected are dried with sodium sulfate. After
evaporation in vacuo, the residue obtained is purified by
chromatography. Yield: 0.035 g; m.p.: 97.degree. C.-98.degree.
C.
Synthesis of
N-(2-methyl-1,1-dioxo-2,3-dihydro-1H-1-naphtho[1,8-de][1,3]th-
iazin-6-yl)-acetamide
EXAMPLE 5
[0093] 5-acetylaminonaphthalene-1-sulfonylchloride
[0094] 1.40 g of 5-acetylaminonaphthalene-1-sulfonic acid and 2.23
g of phosphorus pentachloride are combined and stirred for 4 hours
at 60.degree. C. Then the solution is poured onto ice water and
extracted with dichloromethane. The organic extracts collected are
dried with sodium sulfate and evaporated down in vacuo. Yield: 1.10
g.
[0095] N-(5-methylsulfamoylnaphthalene-1-yl)-acetamide
[0096] 1.10 g of 5-acetylaminonaphthalene-1-sulfonyl chloride is
dissolved in 8 mL of ethanol and 8 mL of methylamine solution in
ethanol are added dropwise. Then the resulting mixture is stirred
at reflux temperature for 3.5 hours and the solvent is distilled
off in vacuo. The residue is purified by chromatography. Yield:
0.50 g.
[0097]
N-(2-methyl-1,1-dioxo-2,3-dihydro-1H-1.lambda..sup.6-naphtho[1,8-de-
][1,3]thiazin-6-yl)-acetamide
[0098] 0.25 g of N-(5-methylsulfamoylnaphthalene-1-yl)-acetamide is
dissolved in 3.4 mL of methanesulfonic acid at 35.degree. C. and
combined with a solution of 0.027 g of trioxane in 1 mL of
trifluoroacetic acid. After 6 hours stirring at 35.degree. C., the
reaction mixture is poured onto ice water and the aqueous phase
extracted with ethyl acetate. The organic extracts collected are
dried with sodium sulfate, evaporated down in vacuo, and purified
by chromatography. Yield: 0.136 g; m.p.: 189.degree. C.-190.degree.
C.
Synthesis of
2-(1,1-Dioxo-1H,3H-1.lambda..sup.6-naphtho[1,8-de][1,3]thiazi-
n-2-yl)-acetamide
EXAMPLE 6
[0099] 8-tert-butylsulfamoylnaphthalene-1-carboxylic acid
[0100] 4.36 g of naphthalene-1-sulfonic acid tert-butylamide are
placed in 80 mL tetrahydrofuran, cooled to -10.degree. C., and 29
mL of N-butyl lithium (1.6 molar solution in hexane) are cautiously
added dropwise. The mixture is stirred first for 0.5 hour at
-10.degree. C., then for 3 hours at ambient temperature. It is then
cooled to -5.degree. C. and CO.sub.2 obtained from dry ice is piped
in within 0.25 hour. The reaction mixture is stirred for 2.5 hours
at ambient temperature and then combined with water. The solution
is poured onto 4 N hydrochloric acid and extracted with ethyl
acetate. The organic extracts collected are dried with sodium
sulfate and, after evaporation in vacuo, purified by
chromatography. Yield: 1.19 g.
[0101]
1,1-Dioxo-1,1-dihydro-1.lambda..sup.6-naphtho[1,8-de][1,3]thiazin-3-
-one
[0102] 0.25 g of polyphosphoric acid and 0.15 g of
8-tert-butylsulfamoylna- phthalene-1-carboxylic acid are combined.
The mixture is stirred for 4 hours at 150.degree. C. Then the
reaction mixture is poured onto ice water and the aqueous phase is
extracted with ethyl acetate. The organic extracts collected are
dried with sodium sulfate and evaporated down in vacuo. Yield: 0.07
g.
[0103] 2,3-Dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide
[0104] 0.07 g of
1,1-dioxo-1,1-dihydro-1.lambda..sup.6-naphtho[1,8-de][1,3-
]thiazin-3-one is dissolved in 2 mL of tetrahydrofuran and then 1.2
mL of 1 molar borane-tetrahydrofuran complex solution is carefully
added dropwise. The mixture is stirred for 18 hours at reflux
temperature. The reaction mixture is combined with 1.5 mL of 2 N
hydrochloric acid and 2 mL of methanol, then stirred for 2 hours at
reflux temperature. 2 mL of ammonia is added and any crystals
formed are filtered off. The filtrate is extracted with ethyl
acetate, the organic extracts collected are dried with sodium
sulfate and evaporated down in vacuo. Yield: 0.06 g.
[0105]
2-(1,1-Dioxo-1H,3H-1.lambda..sup.6-naphtho[1,8-de][1,3]thiazin-2-yl-
)-acetamide
[0106] 0.011 g of sodium hydride is suspended in 0.5 mL of
dimethylformamide, and 0.06 g of
2,3-dihydronaphtho[1,8-de][1,3]thiazine-- 1,1-dioxide in 1 mL of
dimethylformamide is added. The mixture is stirred for 1 hour at
ambient temperature and then 0.042 g of 2-bromoacetamide are added
batchwise. Then the mixture is stirred for 18 hours at ambient
temperature. The reaction mixture is poured onto ice water and
extracted with dichloromethane. The organic extracts collected are
dried with sodium sulfate and, after evaporation in vacuo, purified
by chromatography. Yield: 0.043 g; m.p.: 195.degree. C.-196.degree.
C.
Synthesis of
7-hydroxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,-
1-dioxide
EXAMPLE 7
[0107] 0.6 g of
7-methoxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-
-1,1-dioxide is dissolved in 23 mL dichloromethane and the solution
is cooled to -78.degree. C. 2.3 mL of boron tribromide (1 molar
solution in dichloromethane) is added dropwise. Then the mixture is
stirred for 24 hours at ambient temperature. After evaporation in
vacuo, the residue is purified by chromatography. Yield: 0.36 g;
m.p.: 245.degree. C.-246.degree. C.
Synthesis of methyl
2-methyl-1,1-dioxo-2,3-dihydro-1H-1.lambda..sup.6-naph-
tho[1,8-de][1,3]thiazin-7-yl ester carboxylate
EXAMPLE 8
[0108] 0.11 g of
7-hydroxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazin-
e-1,1-dioxide and 0.061 mL triethylamine are placed in 2 mL toluene
and cooled to 0.degree. C. 0.037 mL of methyl chloroformate are
added dropwise. Then the mixture is stirred for 5 hours at ambient
temperature. The suspension is then poured onto ice water and
extracted with ethyl acetate. The organic extracts collected are
dried with sodium sulfate and, after evaporation in vacuo, purified
by chromatography. Yield: 0.065 g; m.p.: 161.degree. C.-162.degree.
C.
[0109] The following compounds of formula (IA) are obtained, inter
alia, analogously to the procedure described hereinbefore:
1TABLE 1 (IA) 5 Example R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5
R.sup.6 m.p. (.degree. C.) 9 CH.sub.3 H H H H Br 226--227 10
CH.sub.3 NO.sub.2 H H H H 264--265 11 CH.sub.3 H H OCH.sub.3 H H
174--175 12 CH.sub.3 H H F H H 129--130 13 CH.sub.3 H H Br H H
163--164 14 CH.sub.3 H H CH.sub.3 H H 142--143 15 CH.sub.3 H H I H
H 192--193 16 CH.sub.3 H I H H H 160--161 17 CH.sub.3 H NO.sub.2 H
H H 169--170 18 CH.sub.3 H OH H H H 160--161 19 CH.sub.3
N(CH.sub.3).sub.2 H H H H 20 CH.sub.3 H H H H N(CH.sub.3).sub.2 21
CH.sub.3 i-Pr H H i-Pr H 22 CH.sub.3 H OCOMe H H H 23 CH.sub.3 H F
H H H
[0110] It has been found that the compounds of general formula (I)
are characterized by their wide range of applications in the
therapeutic field. Particular mention should be made of those
applications in which the positive modulation of AMPA receptors
plays a part.
[0111] The effect of the compounds according to the invention as
AMPA receptor modulators was measured electrophysiologically on
cells which express functional AMPA receptors. Investigations were
carried out to see whether the test substances have a positive
allosteric influence on the agonist-induced current.
[0112] The test was carried out at concentrations of between 0.3
.mu.mol and 300 .mu.mol.
2TABLE 2 Intensification of the Agonist-Induced Current Example
Activity 1 + 2 ++ Legend: + good; ++ very good
[0113] The new compounds can also be used to treat illnesses or
conditions in which neuronal networks which require AMPA receptors
in order to function are damaged or limited in their function.
[0114] The compounds of general formula (I) can thus be used in
dementias, in neurodegenerative or psychotic illnesses and in
neurodegenerative disorders and cerebral ischemias of various
origins, preferably in schizophrenia or learning and memory
disorders.
[0115] The following are also included: epilepsy, hypoglycemia,
hypoxia, anoxia, cerebral trauma, brain edema, amyotrophic lateral
sclerosis, Huntington's Disease, Alzheimer's disease, sexual
dysfunction, disorders of sensory/motor function, memory formation,
hyperkinetic behavioral changes (particularly in children),
hypotension, cardiac infarct, cerebral pressure (increased
intracranial pressure), ischemic and hemorrhagic stroke, global
cerebral ischaemia on stoppage of the heart, acute and chronic
neuropathic pain, diabetic polyneuropathy, tinnitus, perinatal
asphyxia, psychosis, Parkinson's disease and depression, and
related anxiety states.
[0116] The new compounds may also be given in conjunction with
other active substances, such as those used for the same
indications or, for example, with neuroleptics, nootropics,
psychostimulants, etc. They may be administered topically, orally,
transdermally, nasally, parenterally, or by inhalation. Moreover,
the compounds of general formula (I) or the salts thereof may also
be combined with active substances of other kinds.
[0117] The compounds of general formula (I) may be given on their
own or in conjunction with other active substances according to the
invention, and possibly also in conjunction with other
pharmacologically active substances. Suitable preparations include,
for example, tablets, capsules, suppositories, solutions
(particularly solutions for injection (s.c., i.v., and i.m.) and
infusion), elixirs, emulsions, or dispersible powders. The content
of the pharmaceutically active compound(s) should be in the range
from 0.1 wt. % to 90 wt. %, preferably 0.5 wt. % to 50 wt. % of the
composition as a whole, i.e., in amounts which are sufficient to
achieve the dosage range specified below.
[0118] Suitable tablets may be obtained, for example, by mixing the
active substance(s) with known excipients, for example, inert
diluents such as calcium carbonate, calcium phosphate, or lactose,
disintegrants such as corn starch or alginic acid, binders such as
starch or gelatine, lubricants such as magnesium stearate or talc,
and/or agents for delaying release, such as carboxymethyl
cellulose, cellulose acetate phthalate, or polyvinyl acetate. The
tablets may also comprise several layers.
[0119] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example, collidone or shellac, gum arabic,
talc, titanium dioxide, or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0120] Syrups or elixirs containing the active substances or
combinations thereof according to the invention may additionally
contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavor enhancer, e.g., a flavoring such as vanillin or
orange extract. They may also contain suspension adjuvants or
thickeners such as sodium carboxymethyl cellulose, wetting agents
such as, for example, condensation products of fatty alcohols with
ethylene oxide, or preservatives such as p-hydroxybenzoates.
[0121] Solutions for injection and infusion are prepared in the
usual way, e.g., with the addition of isotonic agents,
preservatives such as p-hydroxybenzoates, or stabilizers such as
alkali metal salts of ethylenediamine tetraacetic acid, optionally
using emulsifiers and/or dispersants, whilst if water is used as
the diluent, for example, organic solvents may optionally be used
as solvating agents or dissolving aids, and transferred into
injection vials or ampoules or infusion bottles.
[0122] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0123] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0124] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g., petroleum fractions), vegetable oils (e.g., groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or
glycerol), carriers such as e.g., natural mineral powders (e.g.,
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.,
highly dispersed silicic acid and silicates), sugars (e.g., cane
sugar, lactose, and glucose) emulsifiers (e.g., lignin, spent
sulfate liquors, methylcellulose, starch, and polyvinylpyrrolidone)
and lubricants (e.g., magnesium stearate, talc, stearic acid, and
sodium lauryl sulfate).
[0125] The preparations are administered by the usual methods,
preferably by oral or transdermal route, particularly orally. For
oral administration, the tablets may of course contain, apart from
the abovementioned carriers, additives such as sodium citrate,
calcium carbonate, and dicalcium phosphate together with various
additives such as starch, preferably potato starch, gelatine, and
the like. Moreover, lubricants such as magnesium stearate, sodium
lauryl sulfate, and talc may be used at the same time for the
tabletting process. In the case of aqueous suspensions, the active
substances may be combined with various flavor enhancers or
colorings in addition to the excipients mentioned above.
[0126] For parenteral use, solutions of the active substances with
suitable liquid carriers may be used.
[0127] The dosage for intravenous use is from 1 mg to 1000 mg per
hour, preferably between 5 mg and 500 mg per hour.
[0128] However, it may sometimes be necessary to depart from the
amounts specified, depending on the body weight, the route of
administration, the individual response to the drug, the nature of
its formulation, and the time or interval over which the drug is
administered. Thus, in some cases, it may be sufficient to use less
than the minimum dose given above, whereas in other cases, the
upper limit may have to be exceeded. When administering large
amounts, it may be advisable to divide them up into a number of
smaller doses spread over the day.
[0129] The following examples of formulations illustrate the
present invention without restricting its scope:
Examples of Pharmaceutical Formulations
[0130]
3 A. Tablets per Tablet active substance 100 mg lactose 140 mg
maize starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5
mg 500 mg
[0131] The finely-ground active substance, lactose and some of the
maize starch are mixed together. The mixture is screened, then
moistened with a solution of polyvinylpyrrolidone in water,
kneaded, wet-granulated and dried. The granules, the remaining
maize starch and the magnesium stearate are screened and mixed
together. The mixture is compressed to produce tablets of suitable
shape and size.
4 Tablets per Tablet active substance 80 mg lactose 55 mg maize
starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone
15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400
mg
[0132] The finely ground active substance, some of the corn starch,
lactose, microcrystalline cellulose, and polyvinylpyrrolidone are
mixed together, the mixture is screened and worked with the
remaining corn starch and water to form a granulate which is dried
and screened. The sodium carboxymethyl starch and the magnesium
stearate are added and mixed in and the mixture is compressed to
form tablets of a suitable size.
5 C. Ampoule Soultion active substance 50 mg sodium chloride 50 mg
aqua for inj. 5 mL
[0133] The active substance is dissolved in water at its own pH or
optionally at pH 5.5 to 6.5 and sodium chloride is added to make it
isotonic. The solution obtained is filtered free from pyrogens and
the filtrate is transferred under aseptic conditions into ampoules
which are then sterilized and sealed by fusion. The ampoules
contain 5 mg, 25 mg, and 50 mg of active substance.
* * * * *