CA2053962A1

CA2053962A1 - Benzopyran derivatives, process for their preparation and use thereof and preparations containing the compounds

Info

Publication number: CA2053962A1
Application number: CA 2053962
Authority: CA
Inventors: Theo Schotten; Gerd Ruhter; Dieter Muster; Wolfgang Stenzel; Ben Armah
Original assignee: Beiersdorf AG; Beiersdorf Lilly GmbH
Current assignee: Beiersdorf AG; Beiersdorf Lilly GmbH
Priority date: 1991-10-22
Filing date: 1991-10-22
Publication date: 1993-04-23

Abstract

Abstract The invention relates to novel substituted benzopyran derivatives of the general formula I, (I) in which R1 and R2, which can be identical or different, denote hydrogen, C1-6-alkyl, C3-7-branched alkyl, C3-7-cycloalkyl or together with the carbon atom enclosed by them denote C3-7-spiroalkyl, R3 denotes hydroxyl, C1-6-alkoxy, formyloxy, C1-8-alkyl-carbonyloxy, C6-10-arylcarbonyloxy, C1-8-alkoxycarbonyloxy, C1-6-monoalkylaminocarbonyloxy, C1-5-alkyleneamino-carbonyloxy substituted by C6-10-aryl or C1-8-dialkylamino-carbonyloxy,where the C1-8-alkyl or alkoxy groups can be either linear or branched, and R4 stands for hydrogen or R3 and R4 together form a bond, R5 denotes a 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thiopyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by identical or different C1-6-alkyl, C3-7-branched alkyl, C3,cycloalkyl, fluorine, chlorine, bromine, iodine, C1-5-alkoxy, C3-7-branched alkoxy, C37-cycloalkoxy, hydroxyl, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyloxy, C6-10-aryl-carbonyloxy, nitro, amino, amino mono- or disubstituted by C1-6-alkyl, C1-8-alkylcarbonylamino, C6-10-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, trifluoromethyl-sulphonyl, trifluoroethylthio, trifluoroethylsulphinyl or trifluoroethylsulphonyl, where the heterocycle R5 is in the trans position to the radical R3, if R3 and R4 do not together form a bond but R4 stands for hydrogen, and their salts and acid addition salts, tautomers and optical isomers.
The compounds are therapeutic active compounds.

Description

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, .

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 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-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 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-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 ..

.:
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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 2C533~2 137. 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 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 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~;~

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 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 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.

~.

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

Claims

1. Substituted benzopyran derivatives of the general formula I, (I) in which R1 and R2, which can be identical or different, denote hydrogen, C1-8-alkyl, C3-7-branched alkyl, C3-7-cycloalkyl or together with the carbon atom enclosed by them denote C3-7-spiroalkyl, R3 denotes hydroxyl, C1-8-alkoxy, formyloxy, C1-8-alkyl-carbonyloxy, C6-10-arylcarbonyloxy, C1-8-alkoxycarbonyloxy, C1-6-monoalkylaminocarbonyloxy, C1-6-alkyleneamino-carbonyloxy substituted by C6-10-aryl, or C1-8-dialkylamino-carbonyloxy, where the C1-8-alkyl or alkoxy groups can be either linear or branched, and R4 stands for hydrogen or R3 and R4 together form a bond, R5 denotes a 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thiopyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by identical or different C1-6-alkyl, C3-7-branched alkyl, C3-7-cycloalkyl, fluorine, chlorine, bromine, iodine, C1-6-alkoxy, C3-7-branched alkoxy, C3-7-cycloalkoxy, hydroxyl, C1-8-alkoxycarbonyl, C1-8-alkylcarbonyloxy, C6-10-aryl-carbonyloxy, nitro, amino, amino mono- or disubstituted by C1-6-alkyl, C1-8-alkylcarbonylamino, C6-10-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, trifluoromethyl-sulphonyl, trifluoroethylthio, trifluoroethylsulphinyl or trifluoroethylsulphonyl, where the heterocycle R5 is in the trans position to the radical R3, if R3, and R4 do not together form a bond but R4 stands for hydrogen, and their salts and acid addition salts, tautomers and optical isomers.

2. Compound according to Claim 1, selected from the group comprising 6-trifluoromethoxy-2,2-dimethyl-4-(1H-2-pyridon-1-yl)-2H-benzo[b]pyran, 6-trifluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(1H-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethylthio-2,2-dimethyl-4-(1H-2-pyridon-1-yl)-2H-benzo[b]pyran, 6-trifluoro-methylthio-3,4-dihydro-2,2-dimethyl-trans-4-(1H-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethyl-sulphonyl-2,2-dimethyl-4-(1H-2-pyridon-1-yl)-2H-benzo[b]-pyran, 6-trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-trans-4-(1H-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethylthio-2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]pyran, 6-trifluoromethylthio-

3,4-dihydro-2,2-dimethyl-trans-4-(1H-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethylsulphonyl-2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]-pyran, 6-trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-trans-4-(1H-4-hydroxy-2-pyridon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethylthio-2,2-dimethyl-

4-(1H-2-pyrazinon-1-yl)-2H-benzo[b]pyran, 6-trifluoro-methylthio-3,4-dihydro-2,2-dimethyl-trans-4-(1H-2-pyrazinon-1-yl)-2H-benzo[b]pyran-3-ol, 6-trifluoromethyl-sulphonyl-2,2-dimethyl-4-(1H-2-pyrazinon-1-yl)-2H-benzo[b]pyranand6-trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-trans-4-(1H-2-pyrazinon-1-yl)-2H-benzo[b]-pyran-3-ol.

3. Process for the preparation of the compounds according to Claim 1, characterised in that an oxirane of the formula II

(II) in which R1, R2 and R6 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 H, 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 that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid.

4. 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.

5. Pharmaceutical preparation, characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.

6. Compounds of the formula I for the control of diseases.

7. Use of compounds of the formula I for the produc-tion of a medicament.

8. Use of compounds of the formula I in the control of diseases.

9. Compounds of the formulae II, III and IV

(II) (III) (IV) in which R1, R2 and R5 have the meaning given for formula I, excluding 1a, 7b-dihydro-2,2-dimethyl-6-(trifluoro-methoxy)-2H-oxireno(c)(1)benzopyran.