Note: Descriptions are shown in the official language in which they were submitted.
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NAPHTOTHIAZINE POSITIVE ALLOSTERIC AMPA RECEPTOR MODULATORS (PAARM)
The present invention relates to new positive allosteric AMPA receptor
modulators,
processes for preparing them and their use as pharmaceutical compositions.
As compounds which are structurally similar to the compounds according to the
invention, WO 9967242 describes carbapenem derivatives with an antibacterial
~o activity, wherein naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is
used as a
synthesis component.
The compounds according to the invention are compounds of general formula (I)
5
R (n)
/ O-0
R4(m) I
/ N..R~
~s R3 R2
wherein
2o R' denotes a group selected from among hydrogen, a C,-Cs-alkyl group
optionally substituted by one or more halogen atoms, -SOZH, -SOZ-C1-Cs-alkyl,
-SO-C,-Cs-alkyl, -CO-C~-C6-alkyl, -O, phenyl-C,-C4-alkyl, -C,-C~-alkyl-NR6R'
and -C,-C4-alkyl-O- C,-C4-alkyl, and C3-C6-cycloalkyl,
R2, R3 , which may be identical or different, denote a group selected from
2s among hydrogen, a C~-Cs-alkyl group optionally substituted by one or more
halogen atoms, halogen, -NOz, -SOZH, -S02-C,-Cs-alkyl, -SO-C,-Cs-alkyl, -CO-
C~-Cs-alkyl, -OH, -0-C,-Cs-alkyl, -S-C~-Cs-alkyl, -C,-Ca-alkyl-NR6R' and -C,-
C4
-alkyl-O- C,-C4-alkyl and C3-Cs-cycloalkyl, or
R' and RZ together denote a C4-Cs-alkylene bridge,
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Rs, R' , which may be identical or different, denote hydrogen, C,-Ca-alkyl or
-CO-C,-C4-alkyl ,
R$ , R9 , which may be identical or different, denote hydrogen or C,-C4-alkyl,
R4 , which may be identical or different, denotes a group selected from among
a C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
phenyl-C,-C4-alkyl, halogen, -CN, -N02, -SOZH, -S03H, -S02-C,-Cs-alkyl, -SO-
C,-Cs-alkyl, -SOZ-NRsR', -COOH, -CO-C,-Cs-alkyl, -0-CO-C,-C4-alkyl, -CO-0-
C,-C4-alkyl, -O-CO-0-C,-Ca-alkyl, -CO-NR6R', -OH, -O-C,-Cs-alkyl, -S-C,-Cs-
alkyl, -NR6R' and an aryl group optionally mono or polysubstituted by halogen
atoms, -N02, -S02H or C,-C4-alkyl,
R5 , which may be identical or different, denotes a group selected from among
a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
phenyl-C,-C4-alkyl, halogen, -CN, -NO2, -S02H, -SOsH, -S02-C,-Cs-alkyl, -SO-
C,-Cs-alkyl, -S02-NRsR', -COOH, -CO-C,-Cs-alkyl, -0-CO-C~-C4-alkyl, -CO-O-
C,-Ca-alkyl, -0-CO-0-C~-C4-alkyl, -CO-NRsR', -OH, -O-C,-Cs-alkyl, -S-C,-Cs-
alkyl, -NR6R' and an aryl group optionally mono or polysubstituted by halogen
atoms, -N02, -SOZH or C,-C4-alkyl, and
n, m which may be identical or different represent 0, 1, 2 or 3,
with the proviso that naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is
2o excluded,
optionally in the form of their various enantiomers and diastereomers, and the
pharmacologically acceptable salts thereof.
Preferred compounds are the compounds of general formula (I), wherein
R' denotes a group selected from among hydrogen, a C,-Cs-alkyl group
optionally substituted by one or more halogen atoms, -SOzH, -SOz-C,-Cs-alkyl,
-SO-C,-Cs-alkyl, -CO-C,-Cs-alkyl, -O, -C,-Ca-alkyl-NR'R8 and -C,-C4-alkyl-0-
C,-C4-alkyl, benzyl,
R2, R3 , which may be identical or different, denote a group selected from
so among hydrogen, a C,-Cs-alkyl group optionally substituted by one or more
halogen atoms, halogen, -NO2, -S02H, -SOz-C,-Cs-alkyl, -SO-C,-Cs-alkyl, -CO-
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C,-Cs-alkyl, -OH, -O-C,-Cs-alkyl, -S-C,-Cs-alkyl, -C,-C4-alkyl-NR6R' and -C,-
C4
-alkyl-O- C,-C4-alkyl, or
R' and Rz together denote a C4-Cs-alkylene bridge,
Rs, R' , which may be identical or different, denote hydrogen, C~-C4-alkyl or
-CO-C,-Cz-alkyl,
and
R4 , which may be identical or different, denotes a group selected from among
a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
halogen, -CN, -NOz, -SOzH, -S03H, -COOH, -CO-C,-Cs-alkyl, -O-CO-C,-C4-
alkyl, -CO-O-C,-C4-alkyl, -O-CO-0-C,-Ca-alkyl, -CO-NRsR', -OH, -O-C,-Cs-
alkyl, -S-C,-Cs-alkyl and -NRsR',
R5 , which may be identical or different, denotes a group selected from among
a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
halogen, -CN, -NOz, -SOZH, -SOsH, -COOH, -CO-C,-Cs-alkyl, -O-CO-C,-C4-
~5 alkyl, -CO-0-C,-C4-alkyl, -O-CO-0-C,-C4-alkyl, -CO-NR6R', -OH, -O-C,-Cs-
alkyl, -S-C,-Cs-alkyl and -NR6R', and
n, m which may be identical or different represent 0,1 or 2,
optionally in the form of the various enantiomers and diastereomers thereof,
as
2o well as the pharmacologically acceptable salts thereof.
Particularly preferred are compounds of general formula (I), wherein
R' denotes hydrogen, C,-C4-alkyl or benzyl,
Rz, R3 which may be identical or different, denote hydrogen or C,-C4-alkyl, or
25 R' and Rz together denote a butylene bridge, and
R° , which may be identical or different, denotes a group selected from
among a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
halogen, -CN, -NOz, -COOH, -CO-C,-Cs-alkyl, -O-CO-C,-C4-alkyl, -CO-0-C,-
C4-alkyl, -O-CO-O-C,-Ca-alkyl, -CO-NRsR', -OH, -O-C,-Cs-alkyl, -S-C,-Cs-alkyl
3o and -NR6R',
R5, which may be identical or different, denotes a group selected from among a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
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halogen, -CN, -NOz, -COOH, -CO-C1-Cs-alkyl, -O-CO-C,-C4-alkyl, -CO-O-C,-
C4-alkyl, -0-CO-0-C,-C4-alkyl, -CO-NR6R', -OH, -O-C,-Cs-alkyl, -S-C~-Cs-alkyl
and -NR6R', and
n, m which may be identical or different represent 0,1 or 2,
optionally in the form of the various enantiomers and diastereomers thereof,
as
well as the pharmacologically acceptable salts thereof.
Also particularly preferred are compounds of general formula (I), wherein
90 R', Rz , R3, which may be identical or different, denote hydrogen or C,-Ca-
alkyl,
R° , which may be identical or different, denotes a group selected from
among a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
halogen, -NOz, -0-CO-C,-C4-alkyl, -O-CO-0-C,-C4-alkyl, -O-C~-Cs-alkyl, and
-NRsR',
~5 R5, which may be identical or different, denotes a group selected from
among a
C,-Cs-alkyl group optionally substituted by one or more halogen atoms,
halogen, -NOz, -O-CO-C,-C4-alkyl, -0-CO-O-C,-C4-alkyl, -O-C,-Cs-alkyl, and
-NRsR', and
n, m which may be identical or different represent 0,1 or 2,
optionally in the form of the various enantiomers and diastereomers thereof,
as
well as the pharmacologically acceptable salts thereof.
Of particular importance according to the invention are the compounds of
general formula (I), wherein R' denotes methyl, ethyl, i-propyl, n-butyl or
benzyl,
optionally in the form of the various enantiomers and diastereomers thereof,
as
well as the pharmacologically acceptable salts thereof.
3o Particularly preferred are compounds of general formula (I) wherein
R' denotes methyl,
optionally in the form of the pharmacologically acceptable salts thereof.
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Also particularly preferred are compounds of general formula (I), wherein
R' denotes methyl,
R2 , R3 denote hydrogen,
5 R4, R5, which may be identical or different, denote halogen, preferably
fluorine,
chlorine, bromine, most preferably fluorine or chlorine,
and
n, m which may be identical or different represent 0,1 or 2, preferably 0 or
1,
optionally in the form of the pharmacologically acceptable salts thereof.
~o
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 hexyf. The groups methyl,
ethyl,
propyl or butyl may optionally also be referred to by the abbreviations Me,
Et, Pr or
~5 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 iso-propyl, butyl includes iso-butyl, sec. butyl
and tert.-
butyl, etc.
2o 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.
The alkyl group mentioned in the group phenyl-C,-Ca-alkyl may be in branched
or
unbranched form. Unless otherwise stated benzyl and phenylethyl are preferred
phenyl-C,-C4-alkyl groups. Benzyl is particularly preferred.
3o The alkyl groups mentioned in the groups -S02-C,-C6-alkyl, -SO-C~-C6-alkyl,
-CO-
C,-Cs-alkyl, -CO-C,-C4-alkyl, -C,-C4-alkyl-NR6R', -C,-Ca-alkyl-O- C~-C4-alkyl,
-O-
C,-Cs-alkyl, -S-C~-Cs-alkyl, -0-CO-C,-C4-alkyl, -CO-0-C,-C4-alkyl or -0-CO-O-
C,-C4-
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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.
The C4-Cs-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.
1o The aryl group is an aromatic ring system having 6 to 10 carbon atoms,
preferably
phenyl.
In the abovementioned aryl groups, one or more hydrogen atoms may optionally
be
substituted by halogen atoms, -NOz, -SOzH or -C,-C4-alkyl, preferably
fluorine,
chlorine , -NOz, ethyl or methyl, most preferably fluorine or methyl.
The term C3-Cs-cycloalkyl denotes saturated cyclic hydrocarbon groups having 3
- 6
carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term halogen, unless otherwise stated, refers to fluorine, chlorine,
bromine and
2o iodine, preferably fluorine, chlorine and bromine, most preferably fluorine
and
chlorine, most preferably fluorine.
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' is hydrogen may be converted by reaction with inorganic bases into
3o 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, sulphuric acid, phosphoric acid,
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methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric
acid, tartaric acid or malefic 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' denotes hydrogen, it is preferable to use the alkali
and
s 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.
The compounds according to the invention may be prepared in a manner known per
1o 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.
Method 1
Diagram 1
s R
R (n)~~
/
\SOZH / SO CI
R (m) / ~ R4(m) ~ 2 --
Rs Rs
(n) (n)
Ra / SOZ R4 ~ SOZ
(m) I / N w ~ -~ (m) ~ / N w 1
3
R 3~ 2 R
R z' CO H R R
R O
(IV)
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Starting from a compound of formula (II) a compound of formula (III) is
prepared by
sulphonation and subsequent chlorination. The compound of formula (IV)
obtained
after condensation with aminoacetic acid derivatives is cyclised by adding
polyphosphoric acid to the target compound (I).
The general preparation of the compounds according to the invention in
accordance
with Diagram 1 is described in detail hereinafter.
to Sulphonation of the naphthalenes (II):
About 10 mmol of the naphthalene derivative (II) are taken up in 2 - 100 ml,
preferably 3 - 80 ml, most preferably about 4 ml, of acetic anhydride and 10 -
100
mmol, preferably 11 - 80 mmol, particularly preferably 11 mmol or conc.
sulphuric
acid are added at 0 - 50°C, preferably 5 - 20°C, particularly
preferably about 18 °C.
~5 After 2 - 16 h, preferably about 5 h, stirring at 20 - 100°C,
preferably about 25 C°,
the mixture is poured onto a saturated NaCI solution. The crystals formed are
isolated.
Methylene chloride, diisopropylether, ethyl acetate, trichloromethane,
toluene,
benzene or 1,4-dioxin may be used instead of acetic acid anhydride, while
fuming
2o sulphuric acid, sulphur trioxide, chlorine sulphates or combinations
thereof may be
used as an alternative to conc. sulphuric acid.
Synthesis of the naphthalene-1-sulphonic acid chlorides (III
About 10 mmol of the naphthalene-1-sulphonic acids are combined successively
25 with 10 - 500 mmol, preferably about 90 mmol, of phosphorus oxytrichloride
and 8 -
50 mmol, preferably about 10 mmol, of phosphorus pentachloride and heated for
2 -
16 h, preferably about 5 h, at 20 - 100°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
3o product obtained is used in the subsequent steps without being purified.
Instead of the phosphorus oxytrichloride/phosphorus pentachloride mixture,
thionyl
chloride, phosphorus pentachloride, a phosphoric acid/chlorine mixture or
phosgene
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may be used. The reaction may alternatively be carried out in the diluents
ethyl
acetate, water, acetonitrile, N,N-dimethylacetamide, sulpholane, DMF, hexane
or
dichloroethane.
Synthesis of the naphthalene-1-su~~honyl-amino-acetic acids
About 10 mmol of the chlorosulphonyl-naphthalenes, 10 - 100 mmol, preferably
11 -
30 mmol, most preferably about 12 mmol, of aminoacetic acid and 10 - 100 mmol,
preferably 11 - 30 mmol, most preferably about 12 mmol, of sodium hydroxide
are
dissolved in water and toluene. The reaction mixture is stirred for 2 - 16 h
at 0 -
~0 110°C, preferably at about 65°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.
Triethylamine, potassium carbonate, sodium hydrogen carbonate or sodium
hydride
may be used instead of sodium hydroxide, while tetrahydrofuran, diethylether,
~5 dichloromethane, trichloromethane, dioxin, acetone, benzene, ethanol,
methanol,
ethyl acetate or acetonitrile may be used instead of toluene.
Cyclisation of the naphthalene-1-sulphonyl-amino-acetic acids (IV):
About 10 mmol of the naphthalene-1-sulphonyl-amino-acetic acids are combined
2o with 10 - 200 g, preferably about 40 g, of polyphosphoric acid and stirred
for 2 - 16
h, preferably about 5 h, at 20 - 110°C, preferably 75 - 95°C,
most preferably at about
80°C . Then the reaction mixture is poured onto water and extracted.
The combined
organic extracts are dried and evaporated down. The residue is purified.
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Method 2
Diagram 2
s Qs
Rs R (n)
(n) \ ~ \
SO
R4 / SOZCI -.~ R4(m) / HN 2 ~ R4("'.
(m) ~ wR1 Z1
5 (III)
M (I)
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
cyclised by the addition of a compound of formula R2R3C=O in the presence of
strong acid to obtain the target compounds (I).
~o In order to prepare the compounds of formula (I) wherein R' and RZ
represent
hydrogen, paraformaldehyde, trioxane or formalin may be used and
methanesulphonic acid, trifluoroacetic acid, sulphuric acid, phosphoric acid
or
polyphosphoric acid may be used as strong acids.
~5 The general preparation of the compounds according to the invention in
accordance
with Diagram 2 is described in detail hereinafter.
Synthesis of the naphthalene-sulphonamides (V):
About 10 mmol of the chlorosulphonyl-naphthalenes (III) are combined with an
2o alcoholic solution of the primary amine (10 - 1000 mmol in 5 - 200 ml, for
example
200 mmol in 50 ml ethanol) and then heated to 0 - 100 °C for 2 - 16 h,
preferably
about 5 h, preferably by refluxing. Then the reaction mixture is evaporated
down
and purified.
Instead of the alcoholic solvent it is also possible to use toluene, benzene,
25 trichloromethane, dichloromethane, diethylether, tetrahydrofuran, water,
acetonitrile,
acetic anhydride, acetone, pyridine, dimethylsulphoxide, dimethylformamide,
dioxin
or hexane.
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Cyclisation of the naphthalene-1-sulphonamides (V) to form the target
compounds
About 10 mmol of the naphthalene-1-sulphonamides are added to 0 - 100 ml,
preferably 20 - 80 ml, most preferably about 40 ml of methanesulphonic acid
and
combined with a solution of 3 - 50 mmol, preferably 4 - 30 mmol, most
preferably 5
mmol of trioxane in 0 - 100 ml, preferably about 12 ml, of trifluoroacetic
acid. The
reaction mixture is stirred for 2 - 16 h, preferably 5 h, at 20 - 100
C°, preferably 30 -
80 °C, most preferably about 35°C and then poured onto ice
water. After extraction
to and drying of the combined organic extracts the solution is evaporated
down. The
crude product is purified.
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 sulphuric acid. Acetic anhydride or
~5 dichloromethane may be used as possible diluents.
The new compounds of general formula (I) may be synthesised 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
2o subject matter thereof.
Synthesis of 2-methyl-2.3-dihydro-naphthof1.8-delt'1.31thiazine-1.1-dioxide
(Example 1 ):
2.21 g of N-methyl-1-naphthalenesulphonic acid amide are dissolved in 25 ml of
25 methanesulphonic acid at 35°C and combined with a solution of 0.30 g
of trioxane in
8 ml of trifluoroacetic acid. After 2 h 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
crystallisation from
methylcyclohexane the product is isolated as a white solid. Yield: 2.20 g.
M.p.:
30 136°C.
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Synthesis of 6-chloro-2-methyl-2,3-dihydro-naphtho~1,8-de1~1.31thiazine-1 1-
dioxide (Example 2):
0.45 g of 5-chloro-naphthalene-1-sulphonic acid-N-methylamide are dissolved in
6.8
ml of methanesulphonic acid at 35°C and combined with a solution of
0.07 g of
trioxane in 2 ml of trifluoroacetic acid. After 2 h stirring at 35°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 sulphate,
evaporated
down in vacuo and then purified by chromatography. Yield: 0.41 g. M.p.:
150°C.
~o
Synthesis of 2,3-dihydro-naphthof1,8-delf1,31thiazine- 1,1-dioxide
(Example 3):
Naphthalene-1-sulphonic acid tent-butylamide:
75 8 ml of tert. butylamine are placed in 50 ml of chloroform, cooled to
0° 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 h 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
sulphate and
2o evaporated down in vacuo. Yield: 5.48 g.
2-tert-butyl-1,1-dioxo-1,2-dihydro-1 ~,s-naphtho[1,8-de][1,3Jthiazin-3-one:
4.36 g of naphthalene-1-sulphonic acid tent-butylamide are placed in 80 ml
tetrahydrofuran, cooled to -10° C and 29 ml of N-butyl lithium (1.6
molar solution in
25 hexane) are cautiously added dropwise. The mixture is first stirred for 0.5
h at -10°
C, then for 3 h at ambient temperature. Then it is cooled to -5° C and
within 0.25 h
COZ obtained from dry ice is piped in. The reaction mixture is stirred for 2.5
h 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
3o dried with sodium sulphate and after evaporation in vacuo purified by
chromatography. Yield: 0.42 g.
2-tert-butyl-2,3-dihydro-naphtho[1,8-de)[1, 3]thiazine-1,1-dioxide:
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0.17 g of 2-tent-butyl-1,1-dioxo-1,2-dihydro-1~,s-naphtho[1,8-de][1,3]thiazin-
3-one
are suspended in 2 ml tetrahydrofuran at ambient temperature, 1.17 ml of
borane-
tetrahydrofuran complex (1 molar Solution) are added. Then the mixture is
refluxed
with stirring for 100 h, with a total of a further 8.2 ml of 1 M borane-
tetrahydrofuran
s 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 h
with stirring. 2 ml of ammonia are added and any crystals formed are filtered
off. The
filtrate is extracted with ethyl acetate, the organic extracts collected are
dried with
sodium sulphate. After evaporation in vacuo the residue obtained is purified
by
to chromatography. Yield: 0.06 g.
2,3-Dihydro-naphtho[1,8-de][1,3]thiazine-1,1-dioxide:
0.06 g of 2-tent-butyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazin-1,1-dioxide are
dissolved in 1 ml of dichloromethane and 0.02 ml of trifluoroacetic acid are
added.
~s Then the mixture is stirred for a total of 22 h at reflux temperature and
for 96 h at
ambient temperature, while during this period a total of 0.07 ml of
trifluoroacetic acid
are added. The reaction mixture is evaporated down in vacuo and purified by
chromatography. Yield: 0.034 g. M.p.: 206°-207° C.
2o Synthesis of f2-(1.1-dioxo-1H-3H-1~,6-naphthof1.8-delthiazine-2-
yl)ethylldimethylamine (Example 41:
0.028 g of sodium hydride are 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
2s dimethylformamide are added. Then 0.053 g of diethylaminoethyl chloride-
hydrochloride are added batchwise. The reaction mixture is stirred for 18 h at
ambient temperature and then poured onto ice water. The mixture is extracted
with
dichloromethane and the organic extracts collected are dried with sodium
sulphate.
After evaporation in vacuo the residue obtained is purified by chromatography.
3o Yield: 0.035 g. M.p.: 97°-98°C.
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Synthesis of N-(2-methyl-1,1-dioxo-2,3-dihydro-1H-1~,6-naphthof1,8-
delft,3lthiazin-6-yl)-acetamide: (Example 51:
5-acetylamino-naphthalene-1-sulphonylchloride:
s 1.40 g of 5-acetylamino-naphthalene-1-sulphonic acid and 2.23 g of
phosphorus
pentachloride are combined and stirred for 4 h at 60° C. Then the
solution is poured
onto ice water and extracted with dichloromethane. The organic extracts
collected
are dried with sodium sulphate and evaporated down in vacuo. Yield: 1.10 g.
N-(5-methylsulphamoyl-naphthalene-1-yl)-acetamide:
1.10 g of 5-acetylamino-naphthalene-1-sulphonyl chloride are 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 h and the solvent
is distilled
off in vacuo. The residue is purified by chromatography. Yield: 0.50 g.
N-(2-methyl-1,1-dioxo-2,3-dihydro-1 H-1 ~,s-naphtho[1,8-de][1,3]thiazin-6-yl)-
acetamide:
0.25 g of N-(5-methylsulphamoyl-naphthalene-1-yl)-acetamide are dissolved in
3.4
2o ml of methanesulphonic acid at 35° C and combined with a solution of
0.027 g of
trioxane in 1 ml of trifluoroacetic acid. After 6 h stirring at 35° 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 sulphate, evaporated down in
vacuo
and purified by chromatography. Yield: 0.136 g. M.p.: 189°-190°
C.
Synthesis of 2-(1,1-Dioxo-1H,3H-1~,s-naphthof1,8-delt1,31thiazin-2-yl)-
acetamide: (Example 6):
8-tent-butylsulphamoyl-naphthalene-1-carboxylic acid:
4.36 g of naphthalene-1-sulphonic acid tent-butylamide are placed in 80 ml
tetrahydrofuran, cooled to -10° 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 h
at -
10°C, then for 3 h at ambient temperature. It is then cooled to -
5°C and COZ
obtained from dry ice is piped in within 0.25 h. The reaction mixture is
stirred for 2.5
h 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 sulphate and after evaporation in vacuo
purified by
chromatography. Yield: 1.19 g.
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1,1-Dioxo-1,1-dihydro-1 ~,6-naphtho[1,8-de][1,3]thiazin-3-one:
0.25 g of polyphosphoric acid are taken and 0.15 g of 8-tent-butylsulphamoyl-
naphthalene-1-carboxylic acid is added. The mixture is stirred for 4 h at
150°C. Then
5 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
sulphate and
evaporated down in vacuo. Yield: 0.07 g.
2,3-Dihydro-naphtho[1,8-de][1, 3]thiazine-1,1-dioxide:
90 0.07 g of 1,1-dioxo-1,1-dihydro-1~,6-naphtho[1,8-de][1,3]thiazin-3-one are
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 h 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 h at reflux temperature. 2 ml of
ammonia are
t5 added and any crystals formed are filtered off. The filtrate is extracted
with ethyl
acetate, the organic extracts collected are dried with sodium sulphate and
evaporated down in vacuo. Yield: 0.06 g.
2-(1,1-Dioxo-1 H,3H-1 ~,s-naphtho[1,8-de][1,3]thiazin-2-yl)-acetamide:
0.011 g of sodium hydride are suspended in 0.5 ml of dimethylformamide, and
0.06 g
of 2,3-dihydro-naphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 ml of
dimethylformamide
are added. The mixture is stirred for 1 h at ambient temperature and then
0.042 g of
2-bromoacetamide are added batchwise. Then the mixture is stirred for 18 h at
ambient temperature. The reaction mixture is poured onto ice water and
extracted
with dichloromethane. The organic extracts collected are dried with sodium
sulphate
and after evaporation in vacuo purified by chromatography. Yield: 0.043 g.
M.p.:
195°-196° C.
3o Synthesis of 7-hydroxy-2-methyl-2,3-dihydro-naphthof1,8-delf1,31thiazine-
1,1-
dioxide (Example 7):
0.6 g of 7-methoxy-2-methyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazine-1,1-
dioxide
are dissolved in 23 ml dichloromethane and the solution is cooled to -
78° C. 2.3 ml
of boron tribromide (1 molar solution in dichloromethane) are added dropwise.
Then
the mixture is stirred for 24 h at ambient temperature. After evaporation in
vacuo the
residue is purified by chromatography. Yield: 0.36 g. M.p.: 245°-
246° C.
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Synthesis of methyl 2-methyl-1,1-dioxo-2,3-dihydro-1H-1~,s-naphthof1,8-
de1~1,31thiazin-7-yl ester carboxylate (Example 8):
0.11 g of 7-hydroxy-2-methyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazine-1,1-
dioxide
and 0.061 ml triethylamine are placed in 2 ml toluene and cooled to
0°C. 0.037 ml of
methyl chloroformate are added dropwise. Then the mixture is stirred for 5 h
at
ambient temperature. The suspension is then poured onto ice water and
extracted
with ethyl acetate. The organic extracts collected are dried with sodium
sulphate
and, after evaporation in vacuo, purified by chromatography.
~o Yield: 0.065g. M.p.: 161 °-162°C.
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The following compounds of formula IA are obtained, inter alia, analogously to
the
procedure described hereinbefore:
Rs
R4 Rs
R3 I / O
~S=0
R2 ~ N~R~
( IA)
Table 1
Example R' RZ R3 R4 Rs Rs Mp.[C]
9 CH3 H H H H Br 226-227
CH3 NOZ H H H H 264-265
11 CH3 H H OCH3 H H 174-175
12 CH3 H H F H H 129-130
13 CH3 H H Br H H 163-164
14 CH3 H H CH3 H H 142-143
CH3 H H I H H 192-193
16 CH3 H I H H H 160-161
17 CH3 H N02 H H H 169-170
18 CH3 H OH H H H 160-161
19 CH3 N(CH3)z H H H H
CH3 H H H H N(CH3)z
21 CH3 i-Pr H H iso-Pr H
22 CH3 H OCOMe H H H
23 CH3 H F H H H
~o
It has been found that the compounds of general formula (I) are characterised
by
their wide range of applications in the therapeutic field. Particular mention
should be
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18
made of those applications in which the positive modulation of AMPA receptors
plays a part.
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.
The test was carried out at concentrations of between 0.3 ~,mol and 300 ~,mol.
9o Table 2: Intensification of the agonist-induced current (+ good, ++ very
good activity)
Example Activity
1 +
++
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.
The compounds of general formula (I) can thus be used in dementias, in
neurodegenerative or psychotic illnesses and in neurodegenerative disorders
and
cerebral ischaemias of various origins, preferably in schizophrenia or
learning and
memory disorders.
The following are also included: epilepsy, hypoglycaemia, hypoxia, anoxia,
cerebral
trauma, brain oedema, amyotropic lateral sclerosis, Huntington's Disease,
Alzheimer's disease, sexual dysfunction, disorders of sensory/motor function,
memory formation, hyperkinetic behavioural changes (particularly in children),
2s hypotension, cardiac infarct, cerebral pressure (increased intracranial
pressure),
ischaemic and haemorrhagic 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.
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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.
The compounds of general formula (I) may be given on their own or in
conjunction
9o 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., i.m.) and infusion - elixirs, emulsions
or dispersible
powders. The content of the pharmaceutically active compounds) should be in
the
~5 range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.-% of the composition as
a whole,
i.e. in amounts which are sufficient to achieve the dosage range specified
below.
Suitable tablets may be obtained, for example, by mixing the active
substances)
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
2o 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.
Coated tablets may be prepared accordingly by coating cores produced
analogously
25 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.
Syrups or elixirs containing the active substances or combinations thereof
according
to the invention may additionally contain a sweetener such as saccharine,
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cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as
vanilline 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
5 preservatives such as p-hydroxybenzoates.
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
stabilisers
such as alkali metal salts of ethylenediamine tetraacetic acid, optionally
using
~o 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.
Capsules containing one or more active substances or combinations of active
95 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.
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.
Excipients which may be used include, for example, water, pharmaceutically
2o 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
sulphite
liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants
(e.g.
magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
The preparations are administered by the usual methods, preferably by oral or
transdermal route, particularly orally. For oral administration the tablets
may of
3o 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
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such as magnesium stearate, sodium lauryl sulphate 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 flavour enhancers or colourings in
addition to the excipients mentioned above.
s For parenteral use, solutions of the active substances with suitable liquid
carriers
may be used.
The dosage for intravenous use is from 1 - 1000 mg per hour, preferably
between 5
and 500 mg per hour.
~o 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.
~s When administering large amounts it may be advisable to divide them up into
a
number of smaller doses spread over the day.
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The following examples of formulations illustrate the present invention
without
restricting its scope:
Examples of Pharmaceutical Formulations
A) Tablets per Tablet
active substance 100 mg
lactose 140 mg
1o maize starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
500 mg
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
2o together. The mixture is compressed to produce tablets of suitable shape
and size.
B) 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
3o magnesium stearate 2 mg
400 mg
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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
s which is dried and screened. The sodiumcarboxymethyl starch and the
magnesium
stearate are added and mixed in and the mixture is compressed to form tablets
of a
suitable size.
C) Amaoule solution
active substance 50 mg
sodium chloride 50 mg
aqua for inj. 5 ml
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 sterilised and sealed by fusion. The ampoules contain
5
mg, 25 mg and 50 mg of active substance.
