Note: Descriptions are shown in the official language in which they were submitted.
2C~'``!3~i2
Beiersdorf Aktiengesellschaft
Description
Benzopyran derivatives, process for their preparation and
use thereof and preparations containing the compounds
The invention relates to novel substituted
benzopyran derivatives of the general formula I,
Rs
(I)
o~R2
Rl .
in which
R1 and R2, which can be identical or different, denote
hydrogen, C16-alkyl, C3~-branched alkyl, C3,-cycloalkyl or
together with the carbon atom enclosed by them denote
C3,-spiroalkyl,
R3 denote~ hydroxyl, Cl~-alkoxy, formyloxy, Cl~-alkyl-
carbonyloxy, C6l0-arylcarbonyloxy, Cl8-alkoxycarbonyloxy,
Cl~-monoalkylaminocarbonyloxy, Cl6-alkyleneamino-
carbonyloxy substituted by C6_10-aryl~or Cl 8-dialkylamino-
carbonyloxy, where the Cl~-alkyl or alkoxy groups can be
either linear or branched, and
R~ stands for hydrogen or
R3 and R~ together form a bond,
R5 denotes a lH-2-pyridon-1-yl~ lH-6-pyridazinon-l-yl~
lH-2-pyrimidinon-1-yl, lH-6-pyrimidinon-1-yl, lH-2-
pyrazinon-l-yl or lH-2-thiopyridon-1-yl radical which is
unsubstituted or monosubstituted or disubstituted by
identical or different C16-alkyl, C3~-branched alkyl,
C37-cycloalkyl, fluorine, chlorine, bromine, iodine, C16-
alkoxy, C3,-branched alkoxy, C3,-cycloalkoxy, hydroxyl,
.
- 2 - Z C 53 9S2
Cl8-alkoxycarbonyl, Cl~-alkylcarbonyloxy, C61O-aryl-
carbonyloxy, nitro, amino, amino mono- or disubstituted
by C16-alkyl, C1~-alkylcarbonylamino, C6l0-arylcarbonyl-
amino-, cyano or carboxyl substituents, where these
radicals can also be partially hydrogenated,
R6 denotes difluoromethoxy, trifluoromethoxy, trifluoro-
ethoxy, tetrafluoroethoxy, difluoromethylthio, difluoro-
methylsulphinyl, difluoromethylsulphonyl, trifluoro-
methylthio,trifluoromethylsulphinyl,trifluoromethylsul-
phonyl, trifluoroethylthio, trifluoroethylsulphinyl ortrifluoroethylsulphonyl, where the heterocycle R5 is in
the trans position to the radical R3, if R3 and R~ do not
together form a bond but R4 stands for hydrogen, and their
salts and acid addition salts, tautomers and optical
isomers, a process for their preparation, their use and
preparations which contain these compounds.
For the sake of simplicity, the compounds accord-
ing to the invention are defined in only one tautomeric
form represented by formula I. However, the invention
extends to all tautomeric forms of the compounds.
Although pharmaceutically tolerable salts and
acid addition salts of the novel compounds of the formula
I and their tautomeric forms are preferred, all salts are
within the field of the invention. All salts are useful
for the preparation of the compounds, even if the speci-
fic salt is only desired as an intermediate, such as, for
example, if the salt is formed only for the purposes of
purification or identification, or if it is used as an
intermediate in the preparation of a pharmaceutically
tolerable salt, for example by an ion exchange procedure.
Compounds of the general formula I and their
salts and acid addition salts contain asymmetric carbon
and sulphur atoms. The invention therefore also relates
to the various optical isomers and diastereomers. The
racemates can be separated into their optical antipodes
by methods which are known per se.
The invention also relates to the novel compounds
of the formulae II, III and IV
3 xc539~2
R~`~C ~ R2
R
OH
--~R ;2
(111 ) .
R6~RR2(N)
having the meanings indicated previously for R~, R2 and
Rs~ excluding la, 7b-dihydro-2,2-dimethyl-6-(trifluoro-
methoxy)-2H-oxireno(c)(1)benzopyran (EP 314,446), and to
the processes for their preparation. They are used as
precursors or intermediates for the preparation of the
final products according to the invention.
Compounds structurally related to the compounds
of the present invention are described in US Patent
4,251,537, European Patent Specifications EP A 076,075,
EP A 273,262, EP A 314,446, EP A 296,975, EP A 312,432
and in the Journal of Medicinal Chemistry 26, 1582
(1983), 27, 1127 ~1984) and 29, 2194 (1986). However, the
compounds of the present invention are neither specifi-
cally disclosed nor suggested.
The compounds of the formula I according to the
invention are distinguished in particular by a
4 XC53962
considerably higher intensity of action combined with a
considerably prolonged duration of action compared to the
known compounds.
If not stated otherwise, the alkyl groups and
alkyl moieties or alkylene moieties of groups according
to the invention may be straight-chain or branched and in
each case preferably have 1 to 6 carbon atoms, preferably
1 to 4 carbon atoms, in particular 1 or 2 carbon atoms.
The branched alkyl groups have at least 3 carbon atoms.
Preferred alkyl or alkylene moieties are methyl, ethyl,
n-propyl, isopropyl, or butyl and correspondingly methyl-
ene, ethylene, n- or isopropylene and butylene.
Preferably, cycloalkyl groups and cycloalkyl
moieties according to the invention such as cycloalkyl
radicals of cycloalkylalkyl groups have 3 to 7 carbon
atoms, in particular 3 to 6 carbon atoms. Cyclopropyl and
cyclohexyl are particularly preferred.
Formyl is HCO-, formyloxy is HCOO-,
C~a-alkylcarbonyloxy is Cl8-alkyl-CO-O-,
C18-alkoxycarbonyloxy is Cl8-alkyl-O-CO-O-,
Cl9-monoalkylaminocarbonyloxy is ClB-alkyl-NH-CO-O-,
Cl3-dialkylaminocarbonyloxy is (Cl8-a.lkyl)2-N-CO-O-,
Cl8-alkylcarbonyl is Cl8-alkyl-CO-,
Cl6-alkylcarbonyl is Cl6-alkyl-CO-,
Cl8-alkoxycarbonyl is Cl8-alkoxy-CO-,
C6l0- arylcarbonyloxy is C6l0-aryl-CO-O-,
Cl8-alkylcarbonyIamino is Cl~-alkyl-CO-NH-,
C6l0-arylcarboxylic acid is C6l0-aryl-COOH, and
Cl6-alkyleneaminocarbonyloxy substituted by C6l0-aryl is
preferably
C6-10-aryl \
~CH-NHCO-O-
C1 -alkyl
The C6l0-aryl radicals according to the invention
which may thus also be alkylated and which also occur as
a part of other radicals such as, for example,
~ 5 ~ 2C~39~2
C6l0-arylcarbonyloxy preferably denote phenyl, tolyl and
naphthyl.
The trifluoroethyl group or trifluoroethyl as a
part of other radicals according to the invention such as
trifluoroethoxy is preferably 2,2,2-trifluoroethyl.
The tetrafluoroethyl ~roup or tetrafluoroethyl as
a part of other radicals according to the invention such
as tetrafluoroethoxy is preferably 2,2',1,1'-tetrafluoro-
ethyl.
R1 is preferably hydrogen, methyl or ethyl, of
these particularly preferably methyl.
R2 is preferably hydrogen, methyl or ethyl, of
these particularly preferably methyl.
R~ and R2 together are particularly preferably
lS both methyl.
If R1 and R2 stand for preferred branched alkyl
or cycloalkyl, isopropyl or cyclopropyl are particularly
preferred.
If R1 and R2 together with the carbon atom en-
closed by them form a spiroalkyl ring, spirocyclopentyland spirocyclohexyl are preferred.
R3 and R4 are together preferably a bond, so that
a double bond exists between the C3- and C4-position of
the benzopyran structure. If R4 denotes H, R3 is prefer-
ably OH, O-CHO or O-COCH3.
If R3 stands for alkoxy, ethoxy and particularly
methoxy are preferred.
R5 i8 preferably unsubstituted lH-2-pyridon-1-yl,
lH-2-pyrazinon-1-yl or lH-4-hydroxy-2-pyridon-1-yl,
furthermore preferably unsubstituted lH-6-pyrididazinon-
l-yl, 4,5-dihydro-lH-6-pyrididazinon-1-yl, lH-2-pyrimid-
inon-l-yl, lH-6-pyrimidinon-1-yl or lH-2-thiopyridon-1-
yl. If R5 denotes a substituted pyridone or thiopyridone
ring, this is preferably monosubstituted in the 3-, 4- or
5-position or disubstituted in the 3- and S-position.
Particularly preferred substituents are OH, N02 and NH2,
furthermore Cl6-alkyloxycarbonyl, Cl6-alkoxy, cyano, Cl,
Br and NHCOCH3, particularly preferred substituted
radicals R5 are in particular 4-, furthermore 3-, 5- and
2C539~2
-- 6 --
6-hydroxy-, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-
acetoxy-, 3-, 5- or 6-chloro-, 3- or 5-nitro-, 3- or 5-
amino-, 3- or 5-carboxy-, 3- or 5-methoxycarbonyl-, 3- or
5-ethoxycarbonyl-, 3- or 5-acetamido, 3,S-dichloro-, 3,5-
dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-
5-nitro-, 3-nitro-5-bromo-, 3, 5-dinitro-, 3-chloro-5-
amino-, 3-amino-5-chloro-, 3-bromo-5-amino-, 3-amino-5-
bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-
bromo-5-acetamido- and 3-acetamido-5-bromo-lH-2-pyridon-
l-yl or -lH-2-thiopyridon-1-yl, lH-3-, lH-4- or lH-5-
hydroxy-6-pyrididazinon-1-yl, lH-3-, lH-4- or lH-5-
ethoxycarbonyl-6-pyrididazinon-1-yl, lH-4-, lH-5- or lH-
6-hydroxy-2-pyri~nidinon-1-yl, lH-2- or lH-4-hydroxy-6-
pyrimidinon- 1-yl .
R5 may furthermore preferably denote: -
3, 4-dihydro-lH-2-pyridon-1-yl,
2, 3-dihydro-6H-2-pyridon-1-yl,
5, 6-dihydro-lH-2-pyridon-1-yl,
2, 3 -dihydro- lH- 6 -pyrididaz inon- 1-yl,
1, 2-dihydro-5H-6-pyrididazinon-l-yl,
3, 4 -dihydro- lH- 2 -pyrimidinon- 1 -yl,
1, 6 -dihydro - 3H- 2 -pyrimidinon- 1 -yl,
5, 6 -dihydro - lH- 2 -pyrimidinon- 1 -yl,
2, 3 -dihydro- lH- 6 -pyrimidinon- l-yl,
1, 2-dihydro-SH-6-pyrimidinon-1-yl,
4, 5 -dihydro- lH- 6 -pyrimidinon- 1 -yl,
3, 4-dihydro-lH-2-pyrazinon-l-yl,
1, 6-dihydro-3H-2-pyrazinon-1-yl,
S, 6-dihydro-lH-2-pyrazinon-1-yl,
3, 4-dihydro-lH-2-thiopyridon-1-yl,
2, 3-dihydro- lH-2 -thiopyridon- 1-yl,
5, 6 -dihydro- lH-2 -thiopyridon- 1-yl,
R6 is preferably difluoromethoxy, trifluoro-
methoxy, trif luoromethylthio, dif luoromethylthio,
dif luoromethylsulphonyl, trif luoromethylsulphonyl,
trifluoroethoxy and tetrafluoroethoxy, of these par-
ticularly preferably difluoromethoxy, trifluoromethoxy,
trifluoromethylthio, difluoromethylthio,
~ 7 ~ XC~3~2
difluoromethylsulphonyl, trifluoromethylsulphonyl, in
particular trifluoromethoxy, trifluoromethylthio, di-
fluoromethylsulphonyl, trifluoromethylsulphonyl, di-
fluoromethylthio.
Accordingly, the invention relates in particular
to those compounds of the formula I in which at least one
of the said radicals has one of the abovementioned
preferred meanings. Some preferred groups of compounds
can be expressed by the formulae Ia to Ii below, which
correspond to the formula I and in which the radicals not
designated in greater detail have the meaning given in
formula I, but in which
in Ia R1 and R2 each denote Cl6-alkyl;
in Ib R1 and R2 each denote CH3; .
in Ic R1 and R2, together with the carbon atom enclosed by
them, denote C37-spiroalkyl, in particular spirocyclo--
pentyl and spirocyclohexyl;
in Id R5 denotes lH-2-pyridon-1-yl, lH-2-pyrazinon-1-yl,
lH-6-pyrididazinon-1-yl, 4,5-dihydro-lH-6-pyrididazinon-
1-yl, lH-2-pyrimidinon-1-yl, lH-6-pyrimidinon-1-yl, lH-
2-thiopyridon-1-yl, 3-, 4-, 5- or 6-hydroxy-, 3-, 4-, 5-
or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-
chloro-, 3- or 5-nitro-, 3- or 5-amino-, 3- or 5-
carboxy-, 3- or 5-methoxycarbonyl-, 3-or 5-ethoxycar-
bonyl-, 3- or S-acetamido-, 3,5-dichloro-, 3,5-dibromo,
3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-S-nitro-,
3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-
amino-5-chloro-, 3-bromo-5-amino-, 3-amino-5-bromo-, 3-
chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo-5-
acetamido- or 3-acetamido-5-bromo-lH-2-pyridon-1-yl or
-lH-2-thiopyridon-1-yl, lH-3-, lH-4-or lH-5-hydroxy-6-
pyrididazinon-l-yl, lH-3-, lH-4- or lH-5-ethoxycarbonyl-
6-pyrididazinon-1-yl, lH-4-, lH-5- or lH-6-hydroxy-2-
pyrimidinon-l-yl, lH-2- or lH-4-hydroxy-6-pyrimidinon-1-
yl;
in Ie R5 denotes lH-2-pyridon-1-yl, lH-2-pyrazinon-1-yl
or lH-4-hydroxy-2-pyridon-1-yl;
in If R5 denotes lH-2-pyridon-l yl;
~C~3
8 --
in Ig R~ and R2 each denote CH3 and
R5 denotes lH-2-pyridon-1-yl, lH-2-pyrazinon-1-yl, lH-6-
pyrididazinon-l-yl, 4,5-dihydro-lH-6-pyrididazinon-1-yl,
lH-2-pyrimidinon-1-yl, lH-6-pyrimidinon-1-yl, lH-2-
thiopyridon-l-yl, 3-, 4-, 5- or 6-hydroxy-, 3-, 4-, 5-
or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or
6-chloro-, 3- or 5-nitro-, 3- or 5-amino-, 3- or
5-carboxy-, 3- or 5-methoxycarbonyl-, 3- or 5-ethoxy-
carbonyl-, 3- or 5-acetamido-, 3,5-dichloro-,
3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-,
3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5-dinitro-,
3-chloro-5-amino-, 3-amino-5-chloro-, 3-bromo-5-amino-,
3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-
5-chloro-, 3-bromo-5-acetamido or 3-acetamido-5-bromo-lH-
2-pyridon-1-yl or -lH-2-thiopyridon-1-yl, lH-3-, lH-4-or-
lH-5-hydroxy-6-pyrididazinon-1-yl, lH-3-, lH-4- or lH-5-
ethoxycarbonyl-6-pyrididazinon-1-yl, lH-4-, lH-5- or lH-
6-hydroxy-2-pyrimidinon-1-yl, lH-2- or lH-4-hydroxy-6-
pyrimidinon-l-yl;
in Ih Rl and R2 each denote CH3 and
Rs denotes lH~2-pyridon-1-yl, lH-2-pyrazinon-1-yl
or lH-4-hydroxy-2-pyridon-1-yl;
in Ii Rl and R2 each denote CH3 and
R5 denotes lH-2-pyridon-1-yl.
Compounds of the formulae I' and Ia' to Ii' are
furthermore preferred which correspond to the formulae I
and Ia to Ii, but in which in each case R3 additionally
denotes OH, OCHO or OCOCH3 and R4 denotes H.
Compounds of the formulae I" and Ia" to Ii" are
furthermore preferred which correspond to the formulae I
and Ia to Ii, but in which in each case R3 and R4 addi-
tionally together denote a bond.
Compounds of the formulae I, I', I", Ia to Ii,
Ia' to Ii', and Ia" to Ii" are furthermore preferred, in
which in each case additionally
~a) R6 denotes difluoromethoxy, trifluoromethoxy,
difluoromethylthio, trifluoromethylthio, difluoromethyl-
9 2C~33~2
sulphonyl, trifluoromethylsulphonyl, trifluoroethoxy and
tetrafluoroethoxy;
tb) R~ denotes difluoromethoxy, trifluoromethoxy,
trifluoromethylthio, difluoromethylthio, difluoro-
methylsulphonyl and trifluoromethylsulphonyl;
(c) R6 denotes trifluoromethoxy, trifluoromethylthio and
trifluoromethylsulphonyl;
(d) R6 denotes trifluoromethylthio and trifluoromethyl-
sulphonyl;
(e) R~ denotes trifluoromethylsulphonyl;
Otherwise, the radicals Rl and R6 above and below
have the meaning given in formula I if not expressly
stated otherwise.
The following compounds according to the inven-
tion, their salts and acid addition salts, tautomers and-
optical isomers are preferred:
1. 6-Difluoromethoxy-2,2-dimethyl-4-(lH-2-pyridon-1-
yl)-2H-benzo[b]pyran
2. 6-Difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4-
(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
3. 6-Trifluoromethoxy-2,2-dimethyl-4-(lH-2-pyridon-1-
yl]-2H-benzotb~pyran
4. 6-Trifluoromethoxy 3,4-dihydro-2,2-dimethyl-trans-
4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
5. 6-(2,2,2-Trifluoroethoxy)-2,2-dimethyl-4-(lH-2-
pyridon-l-yl)-2H-benzo[b]pyran
6. 6-(2~2,2-Trifluoroethoxy)-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
7. 6-(2l2,1,1-Tetrafluoroethoxy)-2,2-dimethyl-4-(lH-2-
pyridon-1-yl)-2H-benzo[b]pyran
8. 6-(2,2,1,1-Tetrafluoroethoxy)-3,4-dihydro-2,2-
dimethyl-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
9. 6-Difluoromethylthio-2,2-dimethyl-4-(lH-2-pyridon-
1-yl)-2H-benzo[b]pyran
10. 6-Difluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-
4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
11. 6-3ifluoromethylsulphinyl-2,2-dimethyl-4-(lH-2-
pyridon-1-yl)-2H-benzo[b]pyran
lo 2C533~2
12. 6-Difluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
13. 6-Difluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyridon-1-yl)-2H-benzo[b]pyran
14. 6-Difluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
15. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-pyridon-
l-yl)-2H-benzotb]pyran
16. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
17. 6-Trifluoromethylsulphinyl-2,2-dimethyl-4-(lH-2-
pyridon-l-yl)-2H-benzo~b]pyran
18. 6-Trifluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
19. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyridon-l-yl)-2H-benzo~b]pyran
20. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzotb]pyran-3-ol
21. 6-(2,2,2-Trifluoroethylthio)-2,2-dimethyl-4-(lH-2-
pyridon-1-yl~-2H-benzotb]pyran
22. 6-(2,2,2-Trifluoroethylthio)-3,4-dihydro-2,2-di-
methyl-trans-4-(lH-2-pyridon-1-yl)-2H-benzo~b~pyran-
3-ol
23. 6-(2,2,2-Trifluoroethylsulphinyl-2,2-dimethyl-4-(lH-
2-pyridon-1-yl)-2H-benzotb]pyran
24. 6-(2,2,2-Trifluoroethylsulphinyl-3,4-dihydro-2,2-
dimethyl-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
25. 6-(Trifluoroethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyridon-1-yl)-2H-benzotb]pyran
26. 6-(Trifluoroethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b~pyran-3-ol
27. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-thiopyri-
don-l-yl)-2H-benzo[b]pyran
28. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-thiopyridon-1-yl)-2H-benzo~b]pyran-3-
ol
29. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-chloro-
2-pyridon-1-yl)-2H-benzo [b]pyran
2C~.3~2
30. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-2-pyridon-1-yl)-2H-benzo~b]-
pyran-3-ol
31. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-5-chloro-
2-pyridon-1-yl)-2H-benzotb]pyran
32. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-chloro-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
33. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-6-chloro-
2-pyridon-1-yl)-2H-benzotb]pyran
34. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-chloro-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
35. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-hydroxy-
2-pyridon-1-yl)-2H-benzotb3pyran
36. 6-Tri f luoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
37. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-4-hydroxy-
2-pyridon-1-yl)-2H-benzo[b]pyran
38. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
39. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-5-hydroxy-
25 2-pyridon-1-yl)-2H-benzo[b]pyran
40. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
41. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-methoxy-
2-pyridon-1-yl)-2H-benzo[b]pyran
42. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-methoxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
43. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-acetoxy-
2-pyridon-1-yl)-2H-benzo[b]pyran
44. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetoxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
45. 6-Trifluoromethylthio-2,2-dLmethyl-4-(lH-3-nitro-2-
- 12 - 2CS~3~2
pyridon-1-yl)-2H-benzo~b]pyran
46. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
47. 6-Trifluoromethylthio-2,2-dimethyl-4-~lH-5-nitro-2-
pyridon-l-yl)-2H-benzotb]pyran
48. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-nitro-2-pyridon-1-yl)-2H-benzo~b]-
pyran-3-ol
49. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-amino-2-
pyridon-l-yl)-2H-benzo[b]pyran
50. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-amino-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
lS 51. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-5-amino-2-~
pyridon-1-yl)-2H-benzo~b]pyran
52. 6-Trifluoromethyithio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-amino-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
53. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-acet-
amido-2-pyridon-1-yl)-2H-benzotb]pyran
54. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetamido-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
55. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-5-acet-
amido-2-pyridon-1-yl)-2H-benzotb]pyran
56. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-acetamido-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
57. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-carboxy-
2-pyridon-1-yl)-2H-benzotb]pyran
58. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-carboxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
59. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-5-carboxy-
2-pyridon-1-yl)-2H-benzo[b]pyran
60. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-carboxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
- : ~
- 13 2C~39~2
61. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3,5-di-
chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
62. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dichloro-2-pyridon-1-yl)-2H-benzo-
[b]pyran-3-ol
63. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3,5-di-
bromo-2-pyridon-1-yl)-2H-benzo[b]pyran
64. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dibromo-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
65. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-chloro-
5-nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
66. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl
trans-4-(lH-3-chloro-5-nitro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
67. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-nitro-5-
chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
68. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-5-chloro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
69. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-bromo-5-
nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
70. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-nitro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
71. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-nitro-5-
bromo-2-pyridon-1-yl)-2H-benzo[b]pyran
72. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-5-bromo-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
73. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3,5-di-
nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
74. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dinitro-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
75. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-chloro-
5-amino-2-pyridon-1-yl)-2H-benzo[b]pyran
76. 6-Trifluoromethylthio-3~4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-5-amino-2-pyridon-1-yl)-2H-
- 14 -
2C~ 2
benzo[b]pyran-3-ol
77. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-amino-5-
chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
78. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-amino-5-chloro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
79. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-bromo-5-
amino-2-pyridon-1-yl)-2H-benzotb]pyran
80. ~6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-amino-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
81. 6-Trifiuoromethylthio-2,2-dimethyl-4-(lH-3-amino-5-
bromo-2-pyridon-1-yl)-2H-benzotb]pyran
82. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
lS trans-4-(lH-3-amino-5-bromo-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
83. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-chloro-
5-acetamido-2-pyridon-1-yl)-2H-benzotb]pyran
84. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-~lH-3-chloro-5-acetamido-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
85. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-
acetamido-5-chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
86. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acet~~do-5-chloro-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
87. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-bromo-5-
acetamido-2-pyridon-1-yl)-2H-benzo~b]pyran
88. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-acetamido-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
89. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-
acetamido-5-bromo-2-pyridon-1-yl)-2H-benzo[b]pyran
90. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetamido-5-bromo-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
91. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
thiopyridon-l-yl)-2H-benzo[b]pyran
,
1S ~C~33~2
g2. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-thiopyridon-l-yl)-2H-benzo~b]
pyran-3-ol
93. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
94. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
95. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
chloro-2-pyridon-1-yl)-2H-benzotb]pyran
96. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-chloro-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
97. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-6-
lS chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
98. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-chloro-2-pyridon-1-yl)-2H-benæotb]-
pyran-3-ol
99. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
hydroxy-2-pyridon-1-yl)-2H-benzo[b]pyran
100. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
101. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-4-
hydroxy-2-pyridon-1-yl)-2H-benzo~b]pyran
102. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
103. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
hydroxy-2-pyridon-1-yl)-2H-benzo~b]pyran
104. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
105. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
methoxy-2-pyridon-l~yl)-2H-benzo[b]pyran
106. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-methoxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
- 16 - 2C~
107. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
acetoxy-2-pyridon-1-yl)-2H-benzo[b]pyran
108. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dLmethyl-
trans-4-(lH-3-acetoxy-2-pyridon-1-yl)-2H-benzo[b]-
5pyran-3-ol
109. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
110. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-2-pyridon-1-yl)-2H-benzo[b]-
10pyran-3-ol
111. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
: 112. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-nitro-2-pyridon-1-yl)-2H-benzotb]-
15pyran-3-ol
11~. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
amino-2-pyridon-1-yl)-2H-benzo[b]pyran
114. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-amino-2-pyridon-1-yl)-2H-benzo[b]-
20pyran-3-ol
115. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
amino-2-pyridon-1-yl)-2H-benzo[b]pyran
116. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-amino-2-pyridon-1-yl)-2H-benzo[b]-
25pyran-3-ol
117. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
acetamido-2-pyridon-1-yl)-2H-benzo~b]pyran
118. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetamido-2-pyridon-1-yl)-2H-
30benzo~b]pyran-3-ol
119. 6-Tri~luoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
acetamido-2-pyridon-1-yl)-2H-benzotb]pyran
120. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-acetamido-2-pyridon-1-yl)-2H-
35benzo~b]pyran-3-ol
121. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
carboxy-2-pyridon-1-yl)-2H-benzo[b]pyran
..
.:
: .
2C~ i2
- 17 _
122. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-carboxy-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
123. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
carboxy-2-pyridon-l-yl)-2H-benzotb]pyran
124. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
4-trans-4-(lH-5-carboxy-2-pyridon-1-yl)-2H-
benzolb]pyran-3-ol
125. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3,5-
~0 dichloro-2-pyridon-1-yl)-2H-benzo[b]pyran
126. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dichloro-2,pyridon-1-yl)-2H-
benzo[b~pyran-3-ol
127. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3,5-
dibromo-2-pyridon-1-yl)-2H-benzotb]pyran
128. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dibromo-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
129. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
chloro-5-nitro-2-pyridon-1-yl)-2H-benzo[b]pyran
130. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-5-nitro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
131. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
nitro-S-chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
132. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-5-chloro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
133. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
bromo-5-nitro-2-pyridon-1-yl)-2H-benzo~b]pyran
134. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-nitro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
135. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
nitro-5-bromo-2-pyridon-1-yl)-2H-benzo[b]pyran
136. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-nitro-5-bromo-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
2C533~2
- 18 -
137. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3,5-
dinitro-2-pyridon-1-yl)-2H-benzo[b]pyran
13B. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3,5-dinitro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
139. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
chloro-5-amino-2-pyridon-1-yl)-2H-benzotb]pyran
140. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-5-amino-2-pyridon-1-yl)-2H-
benzo~b]pyran-3-ol
141. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
amino-5-chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
142. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-amino-5-chloro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
143. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
bromo-5-amino-2-pyridon-1-yl)-2H-benzoCb]pyran
144. 6-TrifIuoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-amino-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
145. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
amino-S-bromo-2-pyridon-1-yl)-2H-benzotb]pyran
146. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(1H-3-amino-5-bromo-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
147. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
chloro-5-acetamido-2-pyridon-1-yl)-2H-benzo[b]pyran
148. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-chloro-5-acetamido-2-pyridon-1-yl~-2H-
benzotb]pyran-3-ol
149. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
acetamido-5-chloro-2-pyridon-1-yl)-2H-benzo[b]pyran
150. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetamido-5-chloro-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
151. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
bromo-5-acetamido-2-pyridon-1-yl)-2H-benzo[b]pyran
, ~ .
- 19 - XC533~i2
152. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-bromo-5-acetæmido-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol
153. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
S acetamido-S-bromo-2-pyridon-1-yl)-2H-benzo[b]pyran
154. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-acetamido-5-bromo-2-pyridon-1-yl)-2H-
benzo[b]pyran-3-ol
155. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-pyri-
dazinon-1-yl)-2H-benzo[b]pyran
156. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridazinon-1-yl)-2H-benzo[b]pyran-3-
ol
157. 6-Trifluoromethylthio-2,2-dimethyl-4-(4,5-dihydro-
lS lH-6-pyridazinon-1-yl)-2H-benzotb]pyran
158. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(4,5-dihydro-lH-6-pyridazinon-1-yl)-2H-
benzo[b]pyran-3-ol
159. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-hydroxy-
6-pyridazinon-1-yl)-2H-benzo~b]pyran
160. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-hydroxy-6-pyridazinon-1-yl)-2H-
benzolb]pyran-3-ol
161. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-ethoxy-
carbonyl-6-pyridazinon-1-yl)-2H-benzotb]pyran
162. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-ethoxycarbonyl-6-pyridazinon-1-yl)-2H-
benzo~b]pyran-3-ol
163. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-
pyrimidinon-1-yl)-2H-benzo~b]pyran
164. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyrimidinon-1-yl)-2H-benzotb]pyran-3-
ol
16S. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-4-hydroxy-
3S 2-pyrimidinon-1-yl)-2H-benzotb]pyran
166. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-2-pyrimidon-1-yl)-2H-
benzo[b]pyran-3-ol
- 20 - ~C533~2
167. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-6-
pyrimidinon-l-yl)-2H-benzotb]pyran
168. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-pyrimidinon-1-yl)-2H-benzo[b]pyran-3-
ol
169. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-4-hydroxy-
6-pyrimidinon-1-yl~-2H-benzotb]pyran
170. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-6-pyrimidinon-1-yl)-2H-
10benzotb]pyran-3-ol
171. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-
pyrazinon-l-yl)-2H-benzotb]pyran
172. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyrazinon-1-yl)-2H-benzo[b]pyran-3-ol
15173. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-6-methyl-2-
pyridon-l-yl)-2H-benzotb]pyran
174. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-methyl-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
20175. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyridazinon-l-yl)-2H-benzotb]pyran
176. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridazinon-1-yl)-2H-benzotb]pyran-
3-ol
25177. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(4,5-
dihydro-lH-6-pyridazinon-1-yl)-2H-benzo[b]pyran
178. 6-Trifluoromethylsulphonyl-3,4-dihydko-2,2-dimethyl-
trans-4-(4,5-dihydro-lH-6-pyridazinon-1-yl)-2H-
benzotb]pyran-3-ol
30179. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
hydroxy-6-pyridazinon-1-yl)-2~-benzo[b]pyran
180. 6-Trifluoromethylsulphonyl-3~4-dihydro-2,2-dimethyl-
trans-4-(lH-3-hydroxy-6-pyridazinon-1-yl)-2H-
benzotb]pyran-3-ol
35181. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
ethoxycarbonyl-6-pyridazinon-1-yl)-2H-benzo[b]pyran
182. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-ethoxycarbonyl-6-pyridazinon-1-yl)-2H-
benzo[b]pyran-3-ol
2C53~i2
-- 21 --
183. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyrimidinon-l-yl)-2H-benzo[b]pyran
184. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyrimidinon-1-yl)-2H-benzo[b]-
5pyran-3-ol
185. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-4-
hydroxy-2-pyrimidinon-1-yl)-2H-benzo[b]pyran
186. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-2-pyrimidinon-1-yl)-2H-benzo-
10[b3pyran-3-ol
187. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-6-
pyrimidinon-l-yl)-2H-benzo[b]pyran
188. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-pyrimidinon-1-yl)-2H-benzo[b]-
15pyran-3-ol
189. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-4-
hydroxy-6-pyrimidinon-1-yl)-2H-benzo[b]pyran
l90. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-hydroxy-6-pyrimidinon-1-yl)-2H-benzo-
20[b]pyran-3-ol
191. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-
pyrazinon-l-yl)-2H-benzo[b]pyran
192. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyrazinon-1-yl)-2H-benzo[b]pyran-3-ol
25193. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-6-
methyl-2-pyridon-1-yl)-2H-benzo[b]pyran
194. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-6-methyl-2-pyridon-l-yl)-2H-benzo[b]-
pyran-3-ol
30195. Cyclopentanespiro-2-6-trifluoromethylthio-4-(lH-2-
pyridon-l-yl)-2H-benzo~b]pyran
196. Cyclopentanespiro-2-6-trifluoromethylthio-3,4-
dihydro-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
35197. Cyclohexanespiro-2-6-trifluoromethylthio-4-(lH-2-
pyridon-l-yl)-2H-benzo[b]pyran
198. Cyclohexanespiro-2-6-trifluoromethylthio-3,4-
dihydro-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
` - 22 - 2C~3~2
199. Cyclopentanespiro-2-6-trifluoromethylsulphonyl-4-
~lH-2-pyridon-1-yl)-2H-benzo[b]pyran
200. Cyclopentanespiro-2-6-trifluoromethylsulphonyl-3,4-
dihydro-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
201. Cyclohexanespiro-2-6-trifluoromethylsulphonyl-4-(lH-
2-pyridon-1-yl)-2H-benzo[b]pyran
202. Cyclohexanespiro-2-6-trifluoromethylsulphonyl-3,4-
dihydro-trans-4-(1H-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
203. 6-Trifluoromethylthio-a,2-diethyl-4-(lH-2-pyridon-
l-yl)-2H-benzo[b]pyran
204. 6-Trifluoromethylthio-3,4-dihydro-2,2-diethyl-trans-
4-(lH-2-pyridon-1-yl)-2H-benzotb]pyran-3-ol
205. 6-Trifluoromethylsulphonyl-2,2-diethyl-4-(lH-2-
pyridon-l-yl)-2H-benzotb]pyran
206. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-diethyl-
trans-4-(lH-2-pyridon-1-yl)-2H-benzotb]pyran-3-ol
207. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-3-cyano-2-
pyridon-1-yl)-2H-benzotb]pyran
208. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-3-cyano-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
209. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-3-
cyano-2-pyridon-1-yl)-2H-benzo~b]pyran
210. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dLmethyl-
trans-4-(lH-3-cyano-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
211. 6-Trifluoromethylthio-2,2-dimethyl-4-(lH-4-cyano-2-
pyridon-1-yl)-2H-benzotb]pyran
212. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-cyano-2-pyridon-1-yl)-2H-benzotb]-
pyran-3-ol
213. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-4-
cyano-2-pyridon-1-yl)-2H-benzotb]pyran
214. 6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-4-cyano-2-pyridon-1-yl)-2H-benzo[b]-
pyran-3-ol
- ~3 =
215~ 6-Trifluoromethylthio-2,2-dimethyl-4 ~ 5-cyano~2-
pyridon-1-yl~-2~-benzo[b]pyran
216. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-
trans-4~(1H-5-cyano-2-pyridon-l-yl~-2H-benzo[b]-
pyran-3-ol
217. 6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-5-
cyano-2-pyridon-1-yl)-2H-benzo[b]pyran
218. 6~Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
trans-4-(lH-5-cyano-2-pyridon 1-yl)-2H-benzo[b]-
pyran-3-ol
The compounds of the formula I according to the
invention~ their physiologically tolerable salts and acid
addition salts and their tautomers and optical isomers
are therapeutic active compounds, have a ~ery good
pharmacological action and are useful medicaments. In
particular, they show vasodilating and vascular
spasmolytic, in particular broncholytic action, it being
possible for the vascular spasmolytic action to develop
in the entire vascular system or else more or less
isolated in prescribed vascular areas such as cerebral,
coronary or peripheral vessels.
The compounds according to the invention in
particular have hypotensive action and can thus be used
as antihypertensive agents.
The substances according to the invention are
distinguished by a considerable lowering of the arterial
blood pressure. Dosas of 0.01 - lO mg/kg p.o. lead to a
lowering of the blood pressure by at least 20 % in
hypertensive rats.
The substances according to the invention are
distinguished by a particular influence on the potassium
ion circulation in the cells7 In particular, they are
potassium channel activators~ They are suitable for the
prophylaxis and for the treatment of the following
disorders in mammals, in particular the human:
1. high blood pressure, in particular high ~rterial
blood pressure,
2. cardiac insufficiency, coronary insufficiency,
angina pectoris,
- 24 - X(~ 3~2
3. obstructive arterial disease and peripheral circu-
latory disturbances,
4. cerebral insufficiency, migraine, vertigo, disorders
of the inner ear or the hearing apparatus,
5. elevated internal ocular pressure, glaucoma, weak-
ness of vision,
6. renal insufficiency, organic disorders of the
efferent urinary passages and the accessory glands
of the urinary passages, potency disturbances,
7. organic disturbances of the gastrointestinal tract
and also the pancreas and liver,
8. deficient circulation of the scalp, hair loss,
9. disorders of the airways, including bronchial
asthma,
10. metabolic disorders,
11. spasmogenic disorders of the uterus,
12. incontinence.
Furthermore, the compounds according to the
invention promote the circulation of the scalp and hair
growth. They are also tocolytically active.
The compounds according to the invantion have a
long duration of action accompanied by only minor tox-
icity. They are therefore suitable in particular for the
treatment of acute and chronic cardiac diseases, for the
therapy of high blood pressure, cardiac insufficiency and
also for the treatment of asthma and cerebral and peri-
pheral circulatory disturbances.
The compound~ of the present invention may be
used in the human orally or parenterally in a dosage of
0.001 to 100 mg, preferably 0.01 to 50 mg, particularly
preferably 0.05 to 10 mg per day, particularly also in
subdivided doses, for example twice to four times daily.
These dosages are advantageous for the treatment of the
diseases previously mentioned, in particular cardiac
diseases, hypertension, asthma and circulatory disturban-
ces.
In general, it has proved advantageous on intra-
venous administration to administer amounts of about
0.001 to 10 mg, preferably about 0.05 to 5 mg, to the
, - ~ , .~ . ` .
' ,'; ~. ~ ` ~'
. .
..
- 25 - XC~33~2
human per day to attain effective results. On oral
administration, the dosage is about 0.05 to 30 mg,
preferably 0.1 to 10 mg per day in the human.
The dosages previously mentioned are particularly
preferred for the treatment of hypertonia.
In spite of this it may be necessary to depart
from the amounts mentioned, in particular depending on
the body weight or the type of the administration route,
but also because of the individual behaviour towards the
medicament or the manner of its formulation and the point
in time or interval at which the administration takes
place. Thus, in some cases it may be sufficient to manage
with less than the minimum amount previously mentioned,
whereas in other cases the upper limit mentioned must be
exceeded. In the case of the administration of larger
amounts, it may be advisable to divide these into a
number of individual doses over the day.
The invention also relates to the compounds
according to the invention for the treatment of the
preceding diseases and methods for the treatment of these
diseases in which these compounds are used and also their
use in a method for the production of agents which
contain these compounds, for the treatment of these
diseases and methods for the preparation of the
compounds.
According to the invention, pharmaceutical
preparations or compositions are provided which contain
one compound according to the invention or its pharma-
ceutically tolerable salt or acid addition salts together
with a pharmaceutically tolerable diluent or excipient.
The compounds according to the invention can be
mixed with the customary pharmaceutically tolerable
diluents or excipients, and, if appropriate, with other
auxiliaries and, for example, administered orally or
parenterally. They may preferably be administered orally
in the form of granules, capsules, pills, tablets, film
tablets, coated tablets, syrups, emulsions, suspensions,
dispersions, aerosols and solutions as well as liquids or
parenterally in the form of solutions, emulsions or
- 26 - 2C533~2
suspensions. Preparations to be administered orally may
contain one or more additives such as sweeteners, fla-
vourings, colourants and preservatives. Tablets may
contain the active compound mixed with customary pharma-
ceutically tolerable auxiliaries, for example inertdiluents such as calcium carbonate, sodium carbonate,
lactose and talc, granulating agents and agents which
promote the disintegration of the tablets on oral admini-
stration such as starch or gelatin, lubricants such as
magnesium stearate, stearic acid and talc.
Suitable excipients are, for example, milk sugar
(lactose), gelatin, maize starch, stearic acid! ethanol,
propylene glycol, ethers of tetrahydrofurfuryl alcohol
and water.
Examples of auxiliaries which may be mentioned
are: ~
Water, non-toxic oxganic solvents, such as
paraffins (for example mineral oil fractions), vegetable
oils (for example groundnut/sesame oil), alcohols (for
example ethyl alcohol, glycerol), glycols (for example
propylene glycol, polyethylene glycol), solid excipients,
such as, for example, ground natural minerals (for
example kaolins, aluminas, talc, chalk), ground synthetic
minerals (for example highly disperse silica, silicates~,
sugars (for example sucrose, lactose and dextrose),
emulsifiers (for example polyoxyethylene fatty acid
esters, polyoxyethylene fatty alcohol ethers, alkylsul-
phonates and arylsulphonates), dispersants (for example
methylcellulose, starch and polyvinylpyrrolidone) and
lubricants (for example magnesium stearate, talc, stearic
acid and sodium lauryl sulphate).
The formulations are prepared, for example, by
extending the active compounds with solvents and/or
excipients, if appropriate using emulsifiers and/or
dispersants, it being possible, for example, in the case
of the use of water as a diluent to use, if appropriate,
organic solvents as auxiliary solvents.
Administration is carried cut in a customary
manner, preferably orally or parenterally, in particular
~ C5~3~i2
- 27 -
perlingually or intravenously. In the case of oraladministration, tablets may of course also contain
additives, such as sodium citrate, calcium carbonate and
dicalcium phosphate together with various additives, such
as starch, preferably potato starch, gelatin and the like
in addition to the excipients mentioned. Furthermore,
lubricants such as magnesium stearate, sodium lauryl
sulphate and talc may additionally be used for tableting.
In the case of aqueous suspensions and/or elixirs, which
are intended for oral administration, various flavour
enhancers or colourants may be added to the active
compounds in addition to the abovementioned auxiliaries.
In the case of parenteral administration, solu-
tions of the active compounds using suitable liquid
excipients may be employed.
The tablets can be coated by known procedures in
order to delay disintegration and absorption into the
gastrointestinal tract, as a result of which the activity
of the active compound may be extended over a relatively
long period of time. Similarly, in the suspensions, the
active compound may be mixed with auxiliaries which are
customary for the preparation of such compositions, for
example suspending agents such as methylcellulose,
tragacanth or sodium alginate, wetting agents such as
lecithin, polyoxyethylene stearate and polyoxyethylene
sorbitan monooleate and preservatives such as ethyl
parahydroxybenzoate. Capsules may contain the active
compound as a single constituent or mixed with a solid
diluent such as calcium carbonate, calcium phosphate or
kaolin. The injectable preparations are likewise formu-
lated in a manner known per se.
The pharmaceutical preparations may contain the
active compound in an amount from 0.1 to 90 per cent by
weight, in particular 1 to 90 per cent by weight, i.e. in
amounts which are sufficient in order to achieve the
dosage range indicated, the remainder being an excipient
or additive. In respect of preparation and adminiætra-
tion, solid preparations such as tablets and capsules are
preferred. Preferably, the preparations contain the
~C533~;~
- 28 -
active compound in an amount from 0.05 to 10 mg.
The invention further relates to a process for
the preparation of the compounds of the formula I and
their salts, which is characterised in that a 3,4-oxi-
ranyl-2H-benzo[b]pyran of the formula II
RE ~ R 2 (I~
Rl '
in which
R~, R2 and R5 have the meaning given for formula I, is
reacted with a compound of the formula V
R5-H (V)
in which R5 has the meaning given for formula I, or with
one of its reactive derivatives and/or in that a compound
of the formula I, in which R3 denotes OH and R4 denotes ~,
is dehydrated and/or in that in a compound of the formula
I, one or more of the radicals R3, R5 and/or R6 are con-
verted into other radicals R3, R5 and/or R6 and/or in thata basic compound of the formula I is converted into one
of its acid addition salts by treating with an acid.
The compounds of the formula I are otherwise
prepared by methods known per se, such as are described
in the literature (for example in the standard works such
as ~ouben-Weyl, Methoden der organischen Chemie ~Methods
of Organic Chemistry), Georg-Thieme-~erlag, Stuttgart;
Organic Reactions, John Wiley & Sons, Inc., New York; and
the abovementioned patent applications), and under
reaction conditions which are known and suitable for the
reactions mentioned. Use can also be made in this case of
variants which are known per se but which are not men-
tioned here in greater detail.
If desired, the starting substances can also be
formed in situ by not isolating them from the reaction
,~ , ,. " ,~
.
: , : - -
XC~33~i2
-- 29 --
mixture, but immediately reacting them further to give
the compounds of the formula I.
The compounds of the formula I are preferably
prepared by reaction of compounds of the formula II with
compounds of the formula V, expediently in the presence
of an inert solvent at temperatures between about 0 and
150.
One starting substance of the formula II is
known. The preparation of the starting substances II
according to the invention is described in the following.
The starting substances V are as a rule known. If
they are not known, they can be prepared by methods which
are known per se.
Suitable reactive derivatives of V are the
corresponding salts, for example the Na or K salts, which
can also be formed in situ.
It is expedient to work in the presence of a
base. Suitable bases are, for example, alkali metal or
alkaline earth metal hydroxides, hydrides or alternative-
ly amides such as NaOH, KO~, Ca(OH)z, NaH, KH, CaH2,NaNH2, KNH2, and furthermore organic bases such as tri-
ethylamine or pyridine, which can also be used in an
excess and then simultaneously serve as the solvent.
The reaction is particularly advantageously
carried out in an inert solvent in the presence of
quaternary organic ammonium compounds, such as, for
example, trimethylbenzylammonium hydroxide.
Suitable inert solvents are in particular
alcohols such as methanol, ethanol, isopropanol,
n-butanol or tert-butanol; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran or dioxane; glycol
ethers such as ethylene glycol monomethyl ether or
ethylene glycol monoethyl ether (methyl glycol or ethyl
glycol), ethylene glycol dimethyl ether (diglyme);
ketones such as acetone or butanone; nitriles such as
acetonitrile; nitro compounds such as nitromethane or
nitrobenzene; esters such ac ethyl acetate; amides such
as dimethylformamide (DMF), dimethylacetamide or hexa-
methylphosphoramide; sulphoxides such as dimethyl
, , ,, . . ~ ~ . .: , - . .
2C~3~3~2
sulphoxide (DMS0); chlorinated hydrocarbons such as
dichloromethane, chloroform, trichloroethylene, 1,2-
dichloroethane or carbon tetrachloride; and hydrocarbons
such as benzene, toluene or xylene. Mixtures of these
solvents with one another are furthermore suitable.
The epoxide II can also be prepared in situ, for
example by the action of a base on the corr~sponding
bromohydrin III.
A compound of the formula I in which R3 = OH
and R4 = H can be converted into a compound of the formula
I in which.R3 and R4 together denote a bond by treating
with a dehydrating agent. This is carried.out, for
example, by the action of one of the bases indicated, for
example NaH, in one of the solvents indicated, for
example DMS0, at temperatures between 0 and 150.
Compounds of the formula I in which R3 and R4
together denote a bond.can also be obtained, if desired,
directly, i.e. without isolation of compounds of the
formula I in which R3 denotes hydroxyl and R4 denotes
hydrogen, from oxiranes of the formula II and compounds
of the formula V by means of an excess of one of the
abovementioned bases, such as NaH in one of the solvents
indicated, preferably at elevated temperature. Mixtures
of benzopyran-3-ols and benzopyrans of the formula I
which may be obtained can be separated by customary
purification methods, such as crystallisation or chroma-
tography.
In some cases, it may be advantageous first to
convert the corresponding hydroxy compound by customary
methods into a corresponding alkyl- or arylsulphonate, in
particular a mesylate, brosylate or tosylate, and then to
produce the desired benzopyran of the formula I in wh~ch
R3 and R4 denote a bond by the action of bases, such as,
for example, triethylamine.
Furthermore, in a compound of the formula I it is
possible to convert one or more of the radicals R3, R5
and/or R6 into other radicals R3, Rs and/or R6.
For example, it is possible to replace an H atom
by a halogen atom by means of halogenation or by a nitro
- - 31 - 2C~;3~3~2
group by means of nitration and/or to reduce a nitro
group to an amino group and~or to oxidise a difluoro-
methylthio, trifluoromethylthio, trifluoroethylthio
and/or difluoromethylsulphinyl, trifluoromethylsulphinyl
or trifluoroethylsulphinyl radical and/or to reduce a
difluoromethylsulphonyl, trifluoromethylsulphonyl,
trifluoroethylsulphonyl and/or difluoromethylsulphinyl,
trifluoromethylsulphinyl or trifluoroethylsulphinyl
radical and/or to alkylate or acylate an amino or hydroxy
group and/or to convert a cyano group (for example with
HCL in water/methanol at 20-100C) into a carboxyl group
or (for example with Raney nickel in water/acetic acid/
pyridine in the presence of sodium phosphate) into a
formyl group or (for example with ROH in tert.-butanol)
into a carbamoyl group or (for example with H2S in
pyridine/triethylamine) into a thiocarbamoyl group and/or
to convert a substituted or unsubstituted lH-2-pyridon-
1-yl radical (for example with P2S5 or with Lawesson~s
reagent in toluene) into the corresponding lH-2-thio-
pyridon-l-yl radical.
Nitration i8 carried out under customary condi-
tions, for example using a mixture of concentrated nitric
acid and concentrated sulphuric acid or using copper(II)
nitrate in acetic anhydride at temperatures between 0
2S and 30C.
Owing to the electron-attracting properties of
R6, nitration takes place very predominantly at the
radical R5. Mixtures which may be obtained can be split
up into the pure components by methods known per se such
as crystallisation or chromatography.
The same applie~ to halogenation, which can be
carried out, for example, using elemental chlorine or
bromine in one of the customary inert solvents at temper-
atures between about 0 and 30.
Compounds of the formula I, in which R6 denotes
difluoromethylthio, trifluoromethylthio or 2,2,2-
trifluoroethylthio, can be converted by suitable oxidis-
ing agents such as, for example, hydrogen peroxide in
glacial acetic acid, organic peracids or particularly
- 32 - 2C.,~2
preferably OxoneR in methanol-water mixtures at tempera-
tures between 0C and the reflux temperature of the
reaction mixture, preferably at temperatures between 20
and 60C, into compounds of the formula I, in which R6 has
the meaning difluoromethylsulphinyl, difluoromethyl-
sulphonyl, trifluoromethylsulphinyl, trifluoromethyl-
sulphonyl, 2,2,2-trifluoroethylsulphinyl or 2,2,2-tri-
fluoroethylsulphonyl. Mixtures of sulphinyl and sulphonyl
compound which may be produced can be obtained pure by
customary methods such as crystallisation or chromato-
graphy.
A primary or secondary amino group and/or an OH
group can be converted into the corresponding secondary
or tertiary amino group and/or alkoxy group by treating
lS with alkylating agents. Suitable alkylating agents are,-
for example,
Cl6-alkyl halides or appropriate sulphuric acid or
sulphonic acid esters such as methyl chloride, bromide,
or iodide, dimethylsulphate and methyl-p-toluenesul-
phonate. One or two methyl groups, for example, mayfurthermore be introduced using formaldehyde in the
presence of formic acid. The alkylation is expediently
carried out in the presence or absence of one of the
inert solvents mentioned, for example DMF at temperatures
between about 0C and about 120C, it also being possible
for a catalyst to be present, preferably a base such as
potassium tert.-butoxide or NaH.
Acylating agents suitable for the acylation of
amino or hydroxy groups are expediently the halides (for
example chlorides or bromides) or anhydrides of Cla-
alkylcarboxylic acids or COlO-arylcarboxylic acids, for
example acetic anhydride, propionyl chloride, isobutyryl
bromide, formic acid/acetic anhydride or benzoyl
chloride. The addition of a base such as pyridine or
triethylamine during the acylation is possible. The
acylation is expediently carried out in the presence or
absence of an inert solvent, for example of a hydrocarbon
such as toluene, of a nitrile such as acetonitrile, of an
amide such as DMF or of an excess of a tertiary base such
~(~533~2
-- 33 --
as pyridine or triethylamine, if appropriate using a
catalyst such as, for example, 4-dimethylaminopyridine,
at temperatures between about 0-C and about 160C,
preferably between 20C and 120C. Acylation using the
corresponding free carboxylic acids with the aid of
customary condensation reagents such as dicyclohexyl-
carbodiimide is also possible.
Reaction to give carbonates is carried out
analogously by reaction with chloroformic acid Cl9-alkyl
esters under the abovementioned conditions.
Reaction to give carbamates is either carried out
in analogy to processes described above by reaction with
mono- or dialkylaminocarbamoyl chlorides or by reaction
with C1~-alkyl isocyanates or with C6,0-aryl substituted
Cl6-alkyl isocyanates in an inert solvent, for example-
toluene, at temperatures between 0C and the boiling
temperature of the reaction mixture. Formylation is also
carried out using formic acid in the presence of
pyridine.
An oxirane of the formula II may preferably be
prepared in situ, from compounds of the formula III, by
reaction with a base such as sodium hydride in a solvent
such as DMSO at temperatures between 0 and 80C, prefer-
ably at 20-25C. In these cases, it is advantageous only
to add the compounds of the formula V to the reaction
mixture when the formation of oxirane is complete.
If it is desired to isolate the oxirane II, the
reaction of the bromohydrin III can also be carried out
in a suitable ether such as diethyl ether, dioxane or
tetrahydrofuran using a base such as potassium hydroxide
or sodium hydride or in aqueous mixtures of water-mis-
cible ethers and a base such as potassium hydroxide. In
these cases, the use of sodium hydride in tetrahydrofuran
is preferred.
Compounds of the general formula III in which the
bromine atom and hydroxyl group are arranged trans to one
another can be prepared by processes which are customary
per se. One such process can be represented as follows
and has been described many times, for example
2C533~2
EP 076,075, EP A 314,446, J. Org. Chem. 38, (22), 3832
(1973), ibid. 39 (7), 881 (1974), ibid. 37 (6), 841
(1972):
Scheme I
R6~ ~ i R6
(VI)
. ii
~r ~ , :
R6~3r iv. R6~ ~ .
2 1 11 ~R OV)
~1 ~Rl
\' /
V\ /
R6~ r
o~R2
(III )
The following conditions are preferred:
i) for example K2CO3/acetone; reflux
or K2CO3/butanone; reflux
or K2CO3/dimethylformamide, 90C
or NaOH/40 % triethylbenzylammonium hydroxide in
methanol; room temperature
ii) for example 1,2-dichlorobenzene, 180C
or N,N'-diethylaniline, 200C
~.
2C~33~2
3s --
or without solvent, 200C
iii) N-bromosuccinimide/dimethyl sulphoxide/water
iv) bromine, tetrachloromethane
v) acetone/water
The 4-substituted phenols VI, in which ~ has the
abovementioned meaning, are known or can be prepared by
known methods, for example by reduction of the
corresponding 4-substituted nitroaromatics, for example
using hydrogen and Raney nickel as the catalyst or by
nascent hydrogen to give the corresponding 4-substituted
anilines and diazotization and boiling of the latter to
give the said 4-substituted phenols.
In cases in which R~ has the meaning difluoro-
methylthio, difluoromethylsulphinyl, difluoromethylsul-
phonyl, trifluoromethylthio, trifluoromethylsulphinyl,~
trifluoromethylsulphonyl, 2,2,2-trifluoromethylthio,
2,2,2-trifluoroethylsuiphinyl and 2,2,2-trifluoroethyl-
sulphonyl, the radicals mentioned can frequently be
introduced more advantageously by chemical transforma-
tions of intermediates in which R6 has a meaning other
than the abovementioned meaning, for example 2H-
benzo~b~pyrans of the general formula IV, in which R6 has
: the meaning difluoromethylsulphonyl, trifluoromethyl-
sulphonyl and 2,2,2-trifluoroethylsulphonyl, are obtained
by reaction of the corresponding fluoroalkylsulphonyl
fluorides with 2H-benzo~b]pyrans of the general formula
IV, in which F~ has the meaning MgHal, where Hal has the
meaning chlorine, iodine and in particular, bromine.
Likewise, it is possible to react the Grignard
compounds of 2H-benzo~b]pyrans described above with
disulphides of the general formula R-S-S-R, in which R
has the meaning trifluoromethyl, difluoromethyl and
2,2,2-trifluoroethyl, to give 2H-benzo~b]pyrans in which
Fb has the meaning difluoromethylthio, trifluoromethylthio
or 2,2,2-trifluoroethylthio.
Furthermore, it is possible, starting from
intermediates or final products in which R6 contains a
sulphur atom, to obtain intermediates or final products
by methods which are customary per se by means of
36 XC533~2
reduction and, in particular, oxidation, in which the
designated sulphur atom has another oxidation level.
Possible oxidizing agents which may be mentioned
by way of example are: potassium permanganate, sodium
periodate, chromium trioxide or, preferably, Oxone~
(potassium monopersulphate) or hydrogen peroxide/glacial
acetic acid.
Thus, for example, 4-difluoromethylsulphonyl-
phenol, 4-trifluoromethylsulphonylphenol or 4-(2,2,2-
trifluoroethylsulphonyl)phenol can be obtained moreconveniently than by known methods by oxidation of the
corresponding fluoroalkylthiophenols with Oxonea in
methanol/water mixtures at temperatures between -10C and
the reflux temperature of the reaction mixture, prefer-
ably at temperatures between 0C and 25C.
Particularly in cases in which R~ has the meaningdifluoromethylsulphinyl, trifluoromethylsulphinyl or
2,2,2-trifluoroethylsulphinyl, it i8 more convenient,
starting from the corresponding 4-fluoroalkylthiophenols
(VI) according to scheme I, first to prepare the cor-
responding 6-fluoroalkylthio-2H-benzotb]pyrans IV, in
which R1 and R2 have the abovementioneq meaning, and then
to carry out the desired oxidation to give the respective
6-fluoroalkylsulphinyl-2H-benzo~b]pyrans of the general
formula IV, in which R~ has the abovementioned meaning.
Surprisingly, the selectivity of this reaction is very
high with the classes of compound mentioned.
The starting materials used are known or can be
prepared by processes which are known per se or
analogously to those described here or can be prepared
analogously to processes known per se.
The compounds of the formula I may be either
bases or acids or may be amphoteric and are therefore
isolated from the reaction mixtures in the form of their
salts or acid addition salts. As bases, they can be
converted into salts by known methods using suitable
inorganic or organic acids or, as acids, form salts with
bases.
Suitable acids for this reaction are in
37 2C~3~2
particular acids which yield physiologically acceptable
salts. Inorganic acids can thus be used, for example
sulphuric acid, nitric acid, hydrohalic acids such as
hydrochloric acid or hydrobromic acid, phosphoric acids
such as orthophosphoric acid, sulphamic acid, furthermore
organic acids, in particular aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic mono- or polybasic
carboxylic, sulphonic or sulphuric acids, for example
formic acid, acetic acid, propionic acid, pivalic acid,
diethylacetic acid, malonic acid, succinic acid, pimelic
acid, fumaric acid, maleic acid, lactic acid, tartaric
acid, malic acid, benzoic acid, salicylic acid, 2- or
3-phenylpropionic acid, citric acid, gluconic acid,
ascorbic acid, nicotinic acid, isonicotinic acid,
methane- or ethanesulphonic acid, ethanedisulphonic acid,-
2-hydroxyethanesulphonic acid, benzenesulphonic acid,
p-toluenesulphonic acid, naphthalene mono- and -disul-
phonic acids, and laurylsulphuric acids. For preparation,
the hot alcoholic solution of the base is treated with
the alcoholic solution of a suitable acid, and the salt
is obtained after addition of ether. Preferred salts are
the alkali metal, alkaline earth metal and ammonium salts
of the compounds of the formula I, which are obtained
with the appropriate bases, in particular sodium
hydroxide or potassium hydroxide.
Salts with physiologically unacceptable acids,
for example picrates, can be used for the purification of
the compounds of the formula I.
As a result of asymetric sulphur or carbon atoms,
the compounds of the formula I according to the invention
can have one or more chiral centres. They can therefore
be obtained during their preparation as racemates,
diastereomeric mixtures of racemates, or, if optically
active starting substances are used, also in optically
active form as enantiomers or mixtures of diastereomers.
If the compounds, for example, have two or more
chiral centres, then they can be obtained during syn-
thesis as mixtures of racemates from which the individual
racemates can be isolated in pure form, for example by
- 38 - ~C~3~2
recrystallising from inert solvents. Thus, for example,
compounds of the formula I in which Rl = R2, R3 = OH and
R~ = H have two chiral centres at C(3) and Ct4) of the
3,4-dihydro-2H-benzopyran structure; however, during
preparation by reaction of II with V very predominantly
only one racemate having the trans position of the
substituents R3 = OH and R5 is formed. Racemates obtained
may, if desired, be separated mechanically or chemically
into their enantiomers by methods known per se. Thus,
diastereomers can be formed from the racemate by reaction
with an optically active resolving agent. Resolving
agents which are suitable for basic compounds of the
formula I are, for example, optically active acids, such
as the D- and L-forms of tartaric acid, dibenzoyltartaric
acid, diacetyltartaric acid, camphorsulphonic acids,
mandelic acid, malic acid or lactic acid. Carbinols (I,-
R3 = OH) can furthermore be esterified with the aid of
chiral acylating reagents, for example D- or L-~-methyl-
benzyl isocyanate, and then resolved (cf. EP-Al-120 428).
The different forms of the diastereomers of the formula
I can be set free from the diastereomers in a manner
known per se. Resolutions of enantiomers are furthermore
carried out by chromatography on optically active support
materials. However, according to the invention it is also
possible to obtain the pure enantiomers by asymmetric
synthesis.
The invention also relates to a process for the
production of pharmaceutical preparations, characterised
in that a compound of the formula I and/or of one of its
physiologically acceptable salts is brought into a
suitable dosage form together with at least one solid,
liquid or semi-liquid excipient or auxiliary and, if
appropriate, in combination with one or more further
active compounds.
The following examples serve to illustrate the
invention:
- 39 ~ 33~Z
Example 1
6-Trifluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(lH-
2-pyridon-1-yl)-2H-benzotb]pyran-3-ol
g (19.2 mmol) of 6-trifluoromethoxy-3,4-
dihydro-3,4-oxiranyl-2,2-dimethyl-2H-benzo[b]pyran are
heated under reflux for 16 hours together with 4 g
(42.1 mmol) of lH-2-pyridone and 0.8 ml of Triton B
solution (35% in methanol) in 40 ml of absolute dioxane.
The mixture is allowed to cool, is poured onto ice and
extracted with ethyl acetate (or diethyl ether or
methylene chloride, 3x50 ml), the combined organic phases
are dried over Na2SO4, filtered and evaporated in vacuo,
and the residue is recrystallised from diisopropyl ether.
4.2 g of colourless crystals of the abovemen-
tioned compound are obtained (62% of theory), m.p. 182C
The preferred 2-H-benzo[b]pyran-3-ols mentioned
in the description are obtained analogously.
Example 2
6-Difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(lH-
2-thiopyridone-1-yl)-2H-benzotb]pyran-3-ol (A) and
6-difluoromethoxy-2,2-dimethyl-4-(lH-2-thiopyridone-1-
yl)-2H-benzotb]pyran (B)
0.9 g (37.5 mmol) of oil-free sodium hydride is
added in portions at room temperature to a solution of
5 g (21 mmol) of 6-difluoromethoxy-3,4-dihydro-3,4-
oxiranyl-2,2-dimethyl-2H-benzotb]pyran and 3.11 g
(28 mmol) of lH-2-thiopyridone in 50 ml of absolute DMSO.
After stirring at room temperature for 20 hours, the
mixture is worked up in the customary manner (see Example
1) and the mixture which remains is separated by prepara-
tive HPLC (silica gel; methylene chloride/ ethanol).
0.67 g (9~ of theory) (oil) of 2H-benzotb]pyran-3-ol (A)
and 1.11 g (15~ of theory), m.p. 103C of 2H-benzo[b]-
pyran (B) are obtained.
_ 40 - 2C533~Z
Example 3
6-Difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(lH-
2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol (A) and
6-difluoromethoxy-2,2-dimethyl-4-(lH-2-pyridon-1-yl)-2H-
benzo[b]pyran (~)
0.67 g (7.1 mmol) of lH-2-pyridone is added with
stirring to 60 ml of a freshly prepared 0.11 M sodium
ethoxide solution in absolute ethanol. After 15 minutes,
2.0 g (8.3 mmol) of 6-difluoromethoxy-3,4-dihydro-3,4-
oxiranyl-2,2-dimethyl-2H-benzo[b]pyran are added and the
mixture is heated under reflux for 2 hours. The mixture
is worked up in the customary manner and separated by
preparative HPLC:
0.80 g (33~ of theory) m.p. 166-167C of (A) and 0.47 g
(18% of theory) (oil) of (B) are obtained.
The preferred compounds mentioned in the descrip-
tion are obtained analogously.
Example 4
6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4-
(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
A mixture of 6.0 g (22 mmol) of 6-trifluoro-
methylthio-3,4-dihydro-3,4-oxiranyl-2,2-dimethyl-2H-
benzotb]pyran and 2.2 g (23 mmol) of lH-2-pyridone is
heated under reflux for 12 hours in 60 ml of absolute
triethylamine.~ After working up (see Example 1), 2.5 g
(32~ of theory) of colourless crystals of the abovemen-
tioned compound are obtained, m.p. 146C
Example 5
6-Trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-
traDs-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol
0.5 g (1.4 mmol) of 6-trifluoromethylthio-3,4-
dihydro-2,2-dimethyl-trans-4-(lH-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol (Example 4) is stirred at room tem-
perature for 120 hours together with 2.5 g (1.8 mmol) of
- 41 - ~C~3~2
Oxone~ in 40 ml of 60% aqueous methanol. After customary
working up (see Example 1), the desired compound is
isolated by preparative HPLC (silica gel, methylene
chloride/ethanol 97:3).
0.18 g (33% of theory) of colourless crystals of the
abovementioned compound is obtained, m.p. 208-210C.
6-Trifluoromethylsulphinyl-3,4-dihydro-2,2-
dimethyl-trans-4-(lH-2-pyridon-1-yl)-2H-benzo[b]pyran-
3-ol can be isolated by rechromatography of eluent frac-
tions (silica gel, methylene chloride/ethanol ~9:1).
m.p. 218-220C.
Example 6
6-Trifluoromethylsulphonyl-2,2-dimethyl-4-(lH-2-pyridon-
1-yl)-2H-benzotb]pyran
1.4 g (3.47 mmol) of 6-trifluoromethylsulphonyl-
3,4-dihydro-2,2-dimethyl-trans-4-(lH-2-pyridon-1-yl)-2H-
benzo[b]pyran are dissolved in 30 ml of absolute
methylene chloride, 3.9 ml (28 mmol) of absolute tri-
ethylamine are added and 1.6 g (14 mmol) of methanesul-
phonyl chloride are added dropwise at 0C with stirring.
After stirring at room temperature for 16 hours and
customary working up, 1.57 g of the corresponding
mesylate are obtained as colourless crystals; these are
dissolved in 40 ml of absolute triethylamine again and
the solution is heated to reflux temperature for 3 days.
After customary working up, the product is recrystallised
from ethanol with the addition of active carbon.
0.5 g (37% of theory) of colourless crystals of the
abovementioned compound is obtained, m.p. 217C
6-Trifluoromethylthio-2,2-dimethyl-4-(lH-2-pyridon-1-yl)-
2H-benzo[b]pyran is obtained analogously starting from
the compound described in Example 4.
~.
- 42 - 2C533
Example 7
6-Trifluoromethoxy-2,2-dimethyl-4-(lH-2-pyridon-1-yl)-2H-
benzo[b]pyran
200 mg (0~56 mmol) of the compound described in
Example 1 are dissolved in 5 ml of absolute ~HF and the
solution is heated under reflux for 3 days with excess
sodium hydride. After customary working up and prepara-
tive HPLC (methylene chloride/ethanol 97:3), 120 mg (63%
of theory) of the abovementioned compound are obtained,
colourless oil.
Example 8
0.35 g (lS mmol) of oil-free sodium hydride is added with
cooling to a solution of 3.75 g (11 mmol) of 6-trifluoro-
methoxy-trans-3-bromo-4-hydroxy-3,4-dihydro-2,2-dimethyl-~
2H-benzo[b]pyran in 50 ml of DMSO. After 2 hours, a
further 0.35 g of oii-free sodium hydride and 2.1 g
~22 mmol) of lH-2-pyridone are added to the solution of
the intermediately formed 6-t~ifluoromethoxy-3,4-dihydro-
3,4-oxiranyl-2,2-dimethyl-2H-benzo[b]pyran. After
stirring at room temperature for 16 hours, the mixture is
worked up in the customary manner. The compound described
in Example 1 and 6-trifluoromethoxy-2,2-dimethyl-4-(lH-
2-pyridon-1-yl)-2H-benzo[b]pyran as a by-product are
obtained.
Example 9
6-Trifluoromethylsulphonyl-3,4-dihydro-trans-3-acetoxy-
4-(lH-2-pyridon-1-yl)-2,2-dimethyl-2H-benzo~b]pyran
0.5 g of the compound described in Example 5 is
heated to 140C for 1 hour in 5 ml of acetic anhydride.
The abovementioned compound is obtained after customary
working up, m.p. 195-198C.
43 ~C533~2
Example 10
6-Trifluoromethylthio-3,4-dihydro-tran~-3-formyloxy-4-
(lH-2-pyridon-l-yl)-2,2-dimethyl-2H-benzotb]pyran
A mixture of l g of the compound described in
S Example 4, 6 ml of formic acid and 1.7 ml of acetic
anhydride is stirred at room temperature for 16 hours and
then warmed to 40C for 2 hours. The abovementioned
compound is obtained after evaporating in vacuo and
customary working up, m.p. 123-129C.
Example 1'
4-Trifluoromethylsulphonylphenol
Method A': -
g (5.2 mmol) of 4-trifluoromethylthiophenol is dis-
solved in 20 ml of methanol and a suspension of 9.6 g of
Oxone~9 in 20 ml of water i8 added at 0C with stirring.
After stirring at room temperature for S days, the
mixture is diluted with 50 ml of water and extracted with
chloroform (3 x 50 ml). After drying and evaporating,
1.1 g of colourless crystals of 4-trifluoromethylsul-
phonylphenol remain (g4% of theory) M~=226 (8)
Method B':
1 g (5.2 mmol) of 4-trifluoromethylthiophenol is stirred
at 50C for 20 hours together with 4 ml of glacial acetic
acid and 4 ml of 30% strength hydrogen peroxide, another
2 ml of 30% strength hydrogen peroxide are then added
and, after a further 2 hours at 50-C, the mixture i8
worked up a8 in A'. After chromatography on silica gel,
230 mg of colourless crystals of 4-trifluoromethylsul-
phonylphenol are obtained (20% of the~ory) m.p. 123C
(Lit.: 119-120-C)
Example 2~
4-Difluoromethylsulphonylphenol
The compound is accessible analogously to the
_ 44 _ 2C~3~2
process described under 1', A' or 1', ~'.
Example 3'
4-(2,2,2-Trifluoroethylsulphonyl)phenol
The compound is obtainable analogously to process
1', A' or 1', B'.
Example 4'
6-Trifluoromethylthio-2,2-dLmethyl-2H-benzo[b]pyran
a) 3-(4-Trifluoromethylthio)phenoxy)-3-methyl-1-butyne
13.8 g (0.1 mol) of dried potassium carbonate and
1.6 g (0.01 mol~ of potassium iodide are suspended in a
solution of 19.4 g (0.1 mol) of 4-(trifluoromethylthio)-
phenol in 250 ml of dry butanone and 15.4 g (0.15 mol) of
3-chloro-3-methyl-1-butyne are added dropwise. The
mixture is then heated under reflux for 20 hours with
stirring, another 15.4 g of 3-chloro-3-methyl-1-butyne
and 13.8 g of potassium carbonate are added and the
mixture is further heated under reflux for 40 hours.
Inorganic constituents are filtered off, the solution is
concentrated, the residue is taken up in 200 ml of
methylene chloride and the solution is extracted with lN
NaOH solution. The organic phase is washed with water,
dried and concentrated, and the residue is filtered
through silica gel.
Yield: 22 g (85% of theory)
b) 6-Trifluoromethylthio-2,2-dimethyl-2H-benzo[b]pyran
22 g (0.085 mol) of the compound described above
(4'a) are heated under argon at 180C for 2 hours in 50
ml of 1,2-dichlorobenzene and the mixture is then frac-
tionated in vacuo.
Yield: 13 g of colourless oil (59.1~ of theory) b.p.
55C/2 Pa
_ 45 _ 2C~3~2
Example 5'
6-Trifluoromethylsulphonyl-2~2-dimethyl-2H-benzo[b]pyran
1 g (4.4 mmol) of 4-trifluoromethylsulphonyl-
phenol is stirred under argon for 20 hours at 80-90C
together with 0.66 g of potassium carbonate, 80 mg of
potassium iodide and 2 g of 3-chloro-3-methyl-1-butyne in
13 ml of dry butanone. Another 0.33 g of potassium
carbonate, 40 mg of potassium iodide and 1 g of 3-chloro-
3-methyl-1-butyne are then added and the mixture is
stirred at 80-90C for a further 20 hours. It is allowed
to cool and is filtered, and the filtrate is evaporated.
The residue is taken up in 20 ml of methylene chloride,
and the solution is washed with water (2 x 20 ml), dried
and evaporated. The oil which remains (1.3 g) is heated
under argon at 180C for 3 hours in o-dichlorobenzene~
(3 ml). After distilling off the solvent, the residue is
chromatographed on silica gel. 0.5 g of colourless oil is
obtained (50% of theory). N1=292 (5).
Example 6'
6-Trifluoromethoxy-2,2-dimethyl-2H-benzo[b]pyran
69.2 g (0.5 mol) of dried potassium carbonate and
8.3 g (0.05 mol) of potassium iodide are suspended in a
solution of 90 g (0.5 mol) of 4-trifluoromethoxyphenol in
900 ml of dry acetone and 70 g (0.68 mol) of 3-chloro-3-
methyl-1-butyne are added dropwise. After stirring at
reflux temperature for 36 hours, another 35 g (0.34 mol)
of 3-chloro-3-methyl-1-butyne are added and the mixture
is stirred at reflux temperature for 8 further 36 hourq.
The cooled suspension is filtered, the filtrate is then
washed with acetone and concentrated, the residue is
taken up in methylene chloride and the solution is
extracted with lN NaOH solution. The methylene chloride
phase is washed until neutral, dried and evaporated.
Yield: 67 g (54.9% of theory)
67 g of the above compound are heated to 180C for 4
hours in 380 ml of 1,2-dichlorobenzene.
- 46 - XC~39~Z
Fractionation in vacuo gives the desired product.
Yield: 45 g (67.2% of theory) b.p. 75-80C/1.3 Pa
Example 7'
6-Trifluoromethylsulphinyl-2,2-dimethyl-2H-benzo[b]pyran
a) 2 g (7.7 mmol) of 6-trifluoromethylthio-2,2-dimethyl-
2H-benzo[b]pyran (Example 4') are dissolved in 40 ml of
methanol and a suspension of 14.2 g (23.1 mmol) of Oxone~
in 40 ml of water is added at 0C. After stirring a~ room
temperature for 2 days, the mixture is diluted with 50 ml
of water, extracted with chloroform (3 x 100 ml) and the
residue which remains after drying and evaporating is
chromatographed on silica gel. 1 g of colourless oil is
obtained (47% of theory) N~=276(9)
b) 6-~rifluoromethylsulphonyl-2,2-dimethyl-2H-benzotb]-
lS pyran
2 g (7.7 mmol) of 6-trifluoromethylthio-2,2-
dimethyl-2H-benzotb]pyran are stirred at room temperature
for 6 days together with 6 ml of glacial acetic acid and
6 ml of 30~ hydrogen peroxide, and the mixture is then
diluted to 100 ml with water and extracted with chloro-
form (3 x 70 ml). After drying and evaporating, 2 g of
colourless oil remain. 0.3 g of colourless oil
6-trifluoromethylsulphinyl-2,2-dimethyl-2H-benzotb]pyran
(14% of theory) and 0.2 g of colourless oil
8-trifluoromethylsulphonyl-2,2-dimethyl-2H-benzo[b]pyran
(9% of theory)
are obtained by means of HPLC (eluent, 98:2 chloroform/
methanol).
Example 8'
6-Difluoromethylsulphinyl-2,2-dimethyl-2H-benzo[b]pyran
and
47 _ 2C~3~2
Example 9~
6-(2,2,2-Trifluoroethylsulphinyl)-2,2-dimethyl-2H-
benzotb]pyran
were obtained analogously.
5Other 6-substituted 2H-benzotb]pyrans of the
general formula IV are prepared analogously.
Example 10'
6-Trifluoromethylthio-3,4-dihydro-3-bromo-2,2-dimethyl-
2H-benzotb]pyran-4-ol
107.7 g (0.043 mol) of N-bromosuccinimide-are added
at 20-25C to a solution of 7 g (0.027 mol) of the
benzopyran described above (Example 4'b) in 60 ml of DMSO
and 1 ml of water. After stirring for 1 hour, the mixture
was poured onto ice and extracted with ethyl acetate
lS(3 x 100 ml). The combined organic phases were washed
with water (3 x 50 ml), dried and concentrated, during
the course of which the product crystallises out. Yield:
8 g (83% of theory) of slightly brownish crystals.
Example 11~
206-Trifluoromethylthio-3,4-dihydro-3,4-oxiranyl-2,2-
; dimethyl-2H-benzotb]pyran
Oil-free sodium hydride (3.5 g, 80%, in paraffin
oil) were added in portions under nitrogen to a solution
of 32 g (0.09 mol) of the bromohydrin described above in
500 ml of dry tetrahydrofuran. After stirring at room
temperature for 1 hour, another 1 g of sodium hydride i8
added. After a further hour, the mixture i8 filtered
through silLca gel and the solution is evaporated.
rield: 26 g (100% of theory)
30Example 12'
6-Trifluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-3-
bromo-2H-benzo[b]pyran-4-ol
51 g (28.6 mmol) of N-bromosuccinimide are added
"
'
.
- 48 - XC539~2
at 20-25C to a solution of 5 g (18 mmol) of 6-trifluoro-
methylsulphinyl-2r2-dimethyl-2H-benzo[b]pyran in 45 ml
of DMSO and 0.7 ml of water. After stirring for one hour,
the mixture is poured onto ice and extracted with ethyl
acetate (3 x 100 ml). The combined organic phases are
washed with water (3 x 50 ml), dried and concentrated,
during the course of which the product crystallises out.
Yield 6.1 g (90% of theory) of light brown crystals.
Example 13'
6-Trifluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-3,4-
oxiranyl-2H-benzotb]pyran
Oil-free sodium hydride (0.58 g, 80%, in paraffin
oil) is added in portions under nitrogen to a solution
of 5.6 g (lS mmol) of the bromohydrin described above in~
80 ml of dry tetrahydrofuran. After stirring at room
temperature for 1 hour, another 0.2 g of sodium hydride
is added. After a further hour, the mixture is filtered
through silica gel and the solution is evaporated.
Yield: 4.3 g (100% of theory)
Example 11
Preparation of tablets and capsules
Tablets and capsules which contain the
constituents indicated below are prepared by known
procedures. These are suitable for the treatment of the
abovementioned diseases, in particular hypertension, in
dosage amounts of in each case one tablet or capsule once
daily.
Constituent~ Weight ~mg)
Tablet Capsule
6-Trifluoromethylthio-
3,4-dihydro-2,2-dimethyl-
trans-4-(lH-2-pyridon-1-yl)-
2H-benzotb]pyran-
;~C~33~i2
3-ol 0.2 0.1
Tragacanth 10
Lactose 247.5 300
Maize starch 25
Talc 15
Magnesium stearate 2.5
Example 12
Preparation of ampoules
~ Ampoules which contain the constituents mentioned
in the following can be prepared in a known manner. The
active compound is dissolved in water and 1,2-propanediol
and poured into glass ampoules under nitrogen.
6-Trifluoromethylsulphonyl-
3,4-dihydro-2,2-dimethyl-trans-
4-(lH-2-pyridon-1-yl)-2H-
benzotb]pyran-3-ol 0.02 mg
1,2-Propanediol 0.8 ml
dist. water to 2.0 ml
