DE3923839A1 - New benzopyran derivs. (I) as vasodilators and spasmolytic agents - for treatment of hypertension, angina, migrating, asthma etc. - Google Patents

Abstract

Cpds. of formula (I), their salts, acid addn. salts, tautomers and optical isomers are new, where R1 and R2 are independently H, 1-6C alkyl or 3-7C branched alkyl, cycloalkyl or spiroalkyl. R3 is OH, 1-8C alkoxy(carbonyloxy), formyloxy, 1-8C alkylcarbonyloxy, 6-10C arylcarbonyloxy, 1-8C monoalkylaminocarbonyloxy, 1-6C alkyleneaminocarbonyloxy or 1-8C dialkylaminocar bonyloxy substd. by 6-10C aryl. R4 is H, or R3 and R4 form an extra bond. R5 is 1H-2-pyridone-1-yl, 1H-6-pyridazinone-1-yl, 1H-2-pyrimidone-1yl, 1H-6-pyrimidinone-1-yl, 1H-2-pyrazinone-1-yl or 1H-2-thiopyridone-1-yl. (These gps. may be partially hydrogenated). All the R5 gps. may be mono-or disubstd. by 1-6C alkyl, 3-7C branched alkyl or cycloalkyl, F, Cl, Br, L, 1-6C alkoxy, 3-7C branched alkoxy or cycloalkoxy, OH, 1-8C alkoxy-carbonyl, 3-7C alkylcarbonyloxy, 6-10C arylcarbony-loxy, NO2, NH2, 1-6C alkyl-substituted NH2, 1-8C alkylcarbonylamino, 6-10C arylcarbonylamino, CN- or COOH-. R6 is di- or trifluoromethoxy; tri- or tetrafluoroethoxy; difluoromethylthio; -sulphinyl, or -sulphonyl; trifluoromethylthio, -sulphinyl or -sulphonyl; or trifluoroethylthio, -sulphinyl or -sulphonyl. R5 is in the trans position to R3 when R3 and R4 do not form a double bond. The pref. daily oral dose is 0.1-10 mg. USE/ADVANTAGE - In the prevention and treatment of high blood pressure, coronary insufficiency, and angina pectoris. Examples of other conditions treated by (I) include migraine, glaucoma, impotence, liver disorders, hair loss, bronchial asthma, incontinence and spasmogenic conditions of the uterus. (I) is more potent and its effect is of a longer duration than known cpds..

Description

The invention relates to new substituted Benzopyran derivatives of the general formula I,

in which R₁ and R₂, which may be identical or different, are hydrogen, C _1-6 -alkyl, C _3-7- branched-alkyl, C _3-7 -cycloalkyl or together with the carbon atom C _3-7 thereof enclosed by them R 6 is hydroxy, C _1-8 -alkoxy, formyloxy, C _1-8 -alkylcarbonyloxy, C _6-10 -arylcarbonyloxy, C _1-8 -alkoxycarbonyloxy, C _1-8 -mono-alkylaminocarbonyloxy by C _6-10 - Aryl substituted C _1-6 -Alkylenaminocarbonyloxy or C _1-8 -Dialkylamino-carbonyloxy, wherein the C _1-8 alkyl or alkoxy groups can be both linear and branched, and R₄ is hydrogen or R₃ and R₄ together form a bond R, represents an unsubstituted or mono- or di-ore, identical or different, C _1-6 alkyl, C _3-7 branched alkyl, C _3-7 cycloalkyl, fluoro, chloro, bromo, iodo, C _1-6 Alkoxy, C _3-7 branched alkoxy, C _3-7 cycloalkoxy, hydroxy, C _1-8 alkoxycarbonyl, C _3-7 alkylcarbonyloxy, C _6-10 arylcarbonyloxy, nitro, amino, once or twice C _1-6 alkyl substituted amino, C _1-8 alkylcarbonylamino, C _6-10 arylcarbonylamino, cyano or carboxy substituted 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-thiopyridone-1-yl radical, these radicals also being partial can be hydrogenated, means
R₆ difluoromethoxy, trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, difluoromethylthio, difluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, trifluoroethylthio, trifluoroethylsulfinyl or trifluoroethylsulfonyl, wherein the heterocycle R₅ is trans to the radical R₃, when R₃ and R₄ are not together Binding, but R₄ is hydrogen, and their salts and acid addition salts, tautomers and optical isomers, processes for their preparation, their use and preparations containing these compounds.

For the sake of simplicity, the invention Compounds in only one by formula I defined tautomeric form. The However, invention extends to all tautomers Forms of connections.

Although pharmaceutically acceptable salts and Acid addition salts of the new compounds of the formula I and their tautomeric forms are preferred lie all salts within the scope of the invention. All Salts are valuable for preparing the compounds, even if the special salt only as an intermediate is desired, such as when the salt is only for Purposes of cleaning or identification formed or if it is considered an intermediate in the Preparation of a pharmaceutically acceptable salt, for example by ion exchange procedure, is used.

Compounds of general formula I and their salts and acid addition salts contain asymmetric Carbon and sulfur atoms. Therefore, also the various optical isomers and diastereomers Subject of the invention. The racemates can after known methods in their optical antipodes be separated.

The invention also relates to the new Compounds of the formulas II, III and IV  

with the meanings given above for R₁, R₂ and R₆ except 1a, 7b-dihydro-2,2-dimethyl-6- (trifluoromethoxy) -2H-oxireno (c) (1) benzopyr-an (EP 3 14 446), and the processes for their preparation. you serve as precursors or intermediates for Production of the end products according to the invention.

With the compounds of the present invention structurally related compounds are in the US Patent 42 51 537, the European patents EP-A 0 76 075, EP-A 2 73 262, EP-A 3 14 446, EP-A 2 96 975, EP-A 3 12 432 and in the Journal of Medicinal Chemistry 26, 1582 (1983), 27, 1127 (1984) and 29, 2194 (1986) described. The compounds of the present  However, the invention is neither specifically disclosed nor suggested.

The compounds of the formula I according to the invention are characterized in particular by a significantly higher Strength with significantly extended duration of action compared to the known compounds.

Unless otherwise stated, the alkyl groups and alkyl moieties according to the invention or alkylene groups of groups straight-chain or branched and they are each preferred 1 to 6 carbon atoms, preferably 1 to 4 Carbon atoms, in particular 1 or 2 Carbon atoms. Have the branched alkyl groups at least 3 carbon atoms. Preferred alkyl or Alkyl parts are methyl, ethyl, n-propyl, isopropyl, Butyl or according to methylene, ethylene, n- or isopropylene and butylene.

Preferably have inventive Cycloalkyl groups and cycloalkyl parts such as Cycloalkyl radicals of cycloalkylalkyl groups 3 to 7 Carbon atoms, in particular 3 to 6 Carbon atoms. Particularly preferred are cyclopropyl and cyclohexyl.

Formyl is HCO-, formyloxy is HCOO-, C _1-8 -alkylcarbonyloxy is C _1-8 -alkyl-CO-O-, C _1-8 -alkoxycarbonyloxy is C _1-8 -alkyl-O-CO-O-, C _1-8 -monoalkylaminocarbonyloxy is C _1-8 -alkyl-NH-CO-O-, C _1-8 -dialkylaminocarbonyloxy is (C _1-8 -alkyl) ₂-N-CO-O-, C _1-8 - Alkylcarbonyl is C _1-8 alkyl CO, C _1-6 alkylcarbonyl is C _1-6 alkyl CO, C _1-8 alkoxycarbonyl is C _1-8 alkoxy CO, C _6-10 -Arylcarbonyloxy is C _6-10 aryl-CO-O-, C _1-8 -arylcarbonylamino is C _1-8 -aryl-CO-NH-, C _6-10 -arylcarboxylic acid is C _6-10 -aryl-COOH, C _6-10 aryl-substituted C _1-6 alkyleneaminocarbonyloxy is preferred

The C _6-10 aryl radicals according to the invention, which may therefore also be alkylated, and which also occur as part of other radicals, such as. For example, C _6-10 arylcarbonyloxy is preferably phenyl, tolyl and naphthyl.

The trifluoroethyl group or trifluoroethyl as part other radicals of the invention such as trifluoroethoxy preferably 2,2,2-trifluoroethyl.

The tetrafluoroethyl group or tetrafluoroethyl as part other radicals according to the invention, such as tetrafluoroethoxy is preferably 2,2 ', 1,1'-tetrafluoroethyl.

R 1 is preferably hydrogen, methyl or ethyl thereof particularly preferably methyl.

R₂ is preferably hydrogen, methyl or ethyl thereof particularly preferably methyl.

R₁ and R₂ are particularly preferably both at the same time Methyl.  

If R₁ and R₂ are preferred branched-alkyl or Cycloalkyl is isopropyl or cyclopropyl particularly preferred.

If R₁ and R₂ together with that of them included carbon atom, a spiroalkyl ring are spirocyclopentyl and spirocyclohexyl prefers.

R₃ and R₄ are preferably together a bond, so that between C₃ and C₄ position of the benzopyran skeleton a double bond exists. If R₄ is H, R₃ is preferably OH, O-CHO or O-COCH₃.

If R₃ is alkoxy, ethoxy and especially Methoxy preferred.

R₅ is preferably unsubstituted 1H-2-pyridon-1-yl, 1H-2-pyrazinon-1-yl or 1H-4-hydroxy-2-pyridon-1-yl, furthermore preferably unsubstituted 1H-6-pyridazinon-1-yl , 4,5-dihydro-1H-6-pyridazinone-1-yl, 1H-2-pyrimidinone-1-yl, 1H-6-pyrimidinone-1-yl or 1H-2-thiopyridone-1-yl. If R₅ is a substituted pyridone or thiopyridone ring, this ring is preferably monosubstituted in the 3-, 4- or 5-position or in the 3- and 5-position. Particularly preferred substituents are OH, NO₂ and NH₂, further C _1-6 alkyloxycarbonyl, C _1-6 alkoxy, cyano, Cl, Br and NHCOCH₃, particularly preferred substituted radicals R₅ in the individual 4-, further 3-, 5- and 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, 3,5-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 and 3-acetamido-5-bromo-1H-2-pyridone-1-yl and -1H-2-thiopyridone-1-yl, 1H-3-, 1H-4, respectively - or 1H-5-hydroxy-6-pyridazinon-1-yl, 1H-3, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy-2-pyrimidinon-1-yl, 1H-2- or 1H-4-hydroxy-6-pyrimidinon-1-yl.

R₅ may further preferably mean:
3,4-dihydro-1H-2-pyridone-1-yl,
2,3-dihydro-6H-2-pyridone-1-yl,
5,6-dihydro-1H-2-pyridone-1-yl,
2,3-dihydro-1H-6-pyridazinon-1-yl,
1,2-dihydro-5H-6-pyridazinon-1-yl,
3,4-dihydro-1H-2-pyrimidinone-1-yl,
1,6-dihydro-3H-2-pyrimidinone-1-yl,
5,6-dihydro-1H-2-pyrimidinone-1-yl,
2,3-dihydro-1H-6-pyrimidinone-1-yl,
1,2-dihydro-5H-6-pyrimidinone-1-yl,
4,5-dihydro-1H-6-pyrimidinone-1-yl,
3,4-dihydro-1H-2-pyrazinone-1-yl,
1,6-dihydro-3H-2-pyrazinone-1-yl,
5,6-dihydro-1H-2-pyrazinone-1-yl,
3,4-dihydro-1H-2-thiopyridone-1-yl,
2,3-dihydro-1H-2-thiopyridone-1-yl,
5,6-dihydro-1H-2-thiopyridone-1-yl.

R₆ is preferably difluoromethoxy, trifluoromethoxy, Trifluoromethylthio, difluoromethylthio, Difluoromethylsulfonyl, trifluoromethylsulfonyl,  Trifluoroethoxy and tetrafluoroethoxy, especially preferably difluoromethoxy, trifluoromethoxy, Trifluoromethylthio, difluoromethylthio, Difluoromethylsulfonyl, trifluoromethylsulfonyl, in particular trifluoromethoxy, trifluoromethylthio, Difluoromethylsulfonyl, trifluoromethylsulfonyl, Difluoromethylthio.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following formulas Ia to Ii, which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I, wherein, however
in Ia R₁ and R₂ are each C _1-6 -alkyl;
in Ib R₁ and R₂ are each CH₃;
in Ic R₁ and R₂ together with the carbon atom enclosed by them C _3-7 -Spiroalkyl, in particular spirocyclopentyl and spirocyclohexyl;
in Id R₅ 1H-2-pyridone-1-yl, 1H-2-pyrazinone-1-yl, 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H 2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-thiopyridone-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-ethoxycarbonyl, 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-1H-2-pyridone-1-yl or -1H-2-thiopyridone-1-yl, 1H-3-, 1H-4- or 1H-5-hydroxy-6-pyridazinone-1 -yl, 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy-2-pyrimidinon-1-yl , 1H-2- or 1H-4-hydroxy-6-pyrimidinon-1-yl;
in Ie R₅ is 1H-2-pyridone-1-yl, 1H-2-pyrazinone-1-yl or 1H-4-hydroxy-2-pyridon-1-yl;
in If R₅ is 1H-2-pyridone-1-yl;
in Ig R₁ and R₂ each CH₃ and
R₅ 1H-2-pyridone-1-yl, 1H-2-pyrazinone-1-yl, 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2 Pyrimidinone-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-thiopyridone-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-ethoxycarbonyl, 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-1H-2-pyridon-1-yl or -1H-2-thiopyridone-1-yl, 1H-3-, 1H-4- or 1H-5-hydroxy-6-pyridazinon-1-yl , 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy-2-pyrimidinon-1-yl, 1H -2- or 1H-4-hydroxy-6-pyrimidinon-1-yl;
in Ih R₁ and R₂ each CH₃ and
R₅ is 1H-2-pyridon-1-yl, 1H-2-pyrazinon-1-yl or 1H-4-hydroxy-2-pyridon-1-yl;
in Ii R₁ and R₂ each CH₃ and
R₅ is 1H-2-pyridone-1-yl.

Furthermore, preference is given to compounds of the formula I ' and Ia 'to Ii', which are the formulas I and Ia to Ii in which, however, in each case additionally R₃ is OH, OCHO or OCOCH₃ and R₄ H mean.

Furthermore, preference is given to compounds of the formulas I " and Ia "to Ii", which correspond to the formulas I and Ia to Ii in which, however, in each case additionally R₃ and R₄ together mean a bond.

Furthermore, preference is given to compounds of the formulas I, I ', I '', Ia to Ii, Ia 'to Ii' and Ia '' to Ii '', wherein each in addition

• (a) R₆ difluoromethoxy, trifluoromethoxy, Difluoromethylthio, trifluoromethylthio, Difluoromethylsulfonyl, trifluoromethylsulfonyl, Trifluoroethoxy and tetrafluoroethoxy;
• (b) R₆ difluoromethoxy, trifluoromethoxy, Trifluoromethylthio, difluoromethylthio, Difluoromethylsulfonyl and trifluoromethylsulfonyl means;
• (c) R₆ trifluoromethoxy, trifluoromethylthio and Trifluoromethylsulfonyl;
• (d) R₆ trifluoromethylthio and trifluoromethylsulfonyl means;
• (e) R₆ is trifluoromethylsulfonyl.

Incidentally, the radicals R₁ and R₆ is the meaning given for formula I, if not expressly stated otherwise.

The following compounds according to the invention, their Salts and acid addition salts, tautomers and optical Isomers are preferred:

1. 6-Difluoromethoxy-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
2. 6-Difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
3. 6-Trifluoromethoxy-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
4. 6-Trifluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
5. 6- (2,2,2-Trifluoroethoxy) -2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
6. 6- (2,2,2-Trifluoroethoxy) -3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridone-1-yl) -2H-benzo [b] pyran 3-ol
7. 6- (2,2,1,1-Tetrafluoroethoxy) -2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
8. 6- (2,2,1,1-tetrafluoroethoxy) -3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
9. 6-Difluoromethylthio-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
10. 6-Difluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
11. 6-Difluoromethylsulfinyl-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
12. 6-Difluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
13. 6-Difluoromethylsulfonyl-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
14. 6-Difluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
15. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
16. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
17. 6-Trifluoromethylsulfinyl-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
18. 6-Trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
19. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
20. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
21. 6- (2,2,2-Trifluoroethylthio) -2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
22. 6- (2,2,2-trifluoroethylthio) -3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
23. 6- (2,2,2-Trifluoroethylsulfinyl-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
24. 6- (2,2,2-Trifluoroethylsulfinyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3 -oil
25. 6- (trifluoroethylsulfonyl-2,2-dimethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
26. 6- (trifluoroethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
27. 6-Trifluoroethylthio-2,2-dimethyl-4- (1H-2-thiopyridone-1-yl) -2H-benzo [b] pyran
28. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-thiopyridone-1-yl) -2H-benzo [b] pyran-3-ol
29. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
30. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
31. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-chloro-pyridon-1-yl) -2H-benzo [b] pyran
32. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
33. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-6-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
34. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
35. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
36. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
37. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-4-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
38. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
39. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
40. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
41. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-methoxy-2-pyridon-1-yl) -2H-benzo [b] pyran
42. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-methoxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
43. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-acetoxy-2-pyridon-1-yl) -2H-benzo [b] pyran
44. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetoxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
45. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
46. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
47. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
48. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
49. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
50. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-amino-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
51. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
52. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
53. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
54. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
55. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
56. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
57. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran
58. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
59. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran
60. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
61. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3,5-dichloro-2-pyridon-1-yl) -2H-benzo [b] pyran
62. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dichloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
63. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3,5-dibromo-2-pyridon-1-yl) -2H-benzo [b] pyran
64. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dibromo-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
65. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-chloro-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
66. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
67. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-nitro-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
68. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
69. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-bromo-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
70. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
71. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-nitro-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
72. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
73. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3,5-dinitro-2-pyridon-1-yl) -2H-benzo [b] pyran
74. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dinitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
75. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-chloro-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
76. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
77. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-amino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
78. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-amino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
79. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-bromo-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
80. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
81. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-amino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
82. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-amino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
83. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-chloro-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
84. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
85. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-acetamino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
86. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
87. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-bromo-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
88. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
89. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-acetamino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
90. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
91. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-2-thiopyridone-1-yl) -2H-benzo [b] pyran
92. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-thiopyridone-1-yl) -2H-benzo [b] pyran-3-ol
93. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
94. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
95. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
96. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
97. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-6-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
98. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
99. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
100. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
101. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-4-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
102. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
103. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran
104. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-hydroxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
105. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-methoxy-2-pyridon-1-yl) -2H-benzo [b] pyran
106. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-methoxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
107. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-acetoxy-2-pyridon-1-yl) -2H-benzo [b] pyran
108. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetoxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
109. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
110. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
111. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
112. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
113. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
114. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
115. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
116. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
117. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
118. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
119. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
120. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
121. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran
122. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
123. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran
124. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-carboxy-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
125. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3,5-dichloro-2-pyridon-1-yl) -2H-benzo [b] pyran
126. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dichloro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
127. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3,5-dibromo-2-pyridon-1-yl) -2H-benzo [b] pyran
128. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dibromo-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
129. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-chloro-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
130. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
131. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-nitro-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
132. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
133. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-bromo-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran
134. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-nitro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
135. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-nitro-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
136. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-nitro-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
137. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3,5-dinitro-2-pyridon-1-yl) -2H-benzo [b] pyran
138. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3,5-dinitro-2-pyridon-1-yl) -2H-benzo [b] pyran-3-one oil
139. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-chloro-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
140. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
141. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-amino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
142. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-amino-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
143. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-bromo-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran
144. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-amino-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
145. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-amino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
146. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-amino-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
147. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-chloro-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
148. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-chloro-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
149. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-acetamido-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran
150. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamido-5-chloro-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
151. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-bromo-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran
152. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-bromo-5-acetamido-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
153. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-acetamido-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran
154. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-acetamido-5-bromo-2-pyridon-1-yl) -2H-benzo [b] pyran 3-ol
155. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyridazinon-1-yl) -2H-benzo [b] pyran
156. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
157. 6-Trifluoromethylthio-2,2-dimethyl-4- (4,5-dihydro-1H-6-pyridazinon-1-yl) -2H-benzo [b] pyran
158. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (4,5-dihydro-1H-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3 oil
159. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-hydroxy-6-pyridazinon-1-yl) -2H-benzo [b] pyran
160. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-hydroxy-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
161. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-ethoxycarbonyl-6-pyridazinon-1-yl) -2H-benzo [b] pyran
162. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-ethoxycarbonyl-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
163. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyrimidinon-1-yl) -2H-benzo [b] pyran
164. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
165. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-4-hydroxy-2-pyrimidinon-1-yl) -2H-benzo [b] pyran
166. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-2-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
167. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-6-pyrimidinon-1-yl) -2H-benzo [b] pyran
168. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
169. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-4-hydroxy-6-pyrimidinon-1-yl) -2H-benzo [b] pyran
170. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-6-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
171. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyrazinon-1-yl) -2H-benzo [b] pyran
172. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyrazinon-1-yl) -2H-benzo [b] pyran-3-ol
173. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-6-methyl-2-pyridon-1-yl) -2H-benzo [b] pyran
174. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-methyl-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
175. 6-Trifluoromethylsulfone-2,2-dimethyl-4- (1H-2-pyridazinon-1-yl) -2H-benzo [b] pyran
176. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
177. 6-Trifluoromethylsulfone-2,2-dimethyl-4- (4,5-dihydro-1H-6-pyridazinon-1-yl) -2H-benzo [b] pyran
178. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (4,5-dihydro-1H-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3 oil
179. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-hydroxy-6-pyridazinon-1-yl) -2H-benzo [b] pyran
180. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-hydroxy-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
181. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-ethoxycarbonyl-6-pyridazinon-1-yl) -2H-benzo [b] pyran
182. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-ethoxycarbonyl-6-pyridazinon-1-yl) -2H-benzo [b] pyran-3-ol
183. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-2-pyrimidinon-1-yl) -2H-benzo [b] pyran
184. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
185. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-4-hydroxy-2-pyrimidinon-1-yl) -2H-benzo [b] pyran
186. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-2-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
187. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-6-pyrimidinon-1-yl) -2H-benzo [b] pyran
188. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
189. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-4-hydroxy-6-pyrimidinon-1-yl) -2H-benzo [b] pyran
190. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-hydroxy-6-pyrimidinon-1-yl) -2H-benzo [b] pyran-3-ol
191. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-2-pyrazinon-1-yl) -2H-benzo [b] pyran
192. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyrazinon-1-yl) -2H-benzo [b] pyran-3-ol
193. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-6-methyl-2-pyridon-1-yl) -2H-benzo [b] pyran
194. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-6-methyl-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
195. Cyclopentanspiro-2-6-trifluoromethylthio-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
196. Cyclopentanspiro-2-6-trifluoromethylthio-3,4-dihydro-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
197. Cyclohexanspiro-2-6-trifluoromethylthio-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
198. Cyclohexane-spiro-2-6-trifluoromethylthio-3,4-dihydro-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
199. Cyclopentanspiro-2-6-trifluoromethylsulfone-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
200. Cyclopentanspiro-2-6-trifluoromethylsulfone-3,4-dihydro-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
201. Cyclohexanspiro-2-6-trifluoromethylsulfonyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
202. Cyclohexanspiro-2-6-trifluoromethylsulfonyl-3,4-dihydro-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
203. 6-Trifluoromethylthio-2,2-diethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
204. 6-Trifluoromethylthio-3,4-dihydro-2,2-diethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
205. 6-Trifluoromethylsulfonyl-2,2-diethyl-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran
206. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-diethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
207. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-3-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
208. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
209. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-3-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
210. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-3-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
211. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-4-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
212. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
213. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-4-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
214. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-4-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
215. 6-Trifluoromethylthio-2,2-dimethyl-4- (1H-5-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
216. 6-Trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol
217. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-5-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran
218. 6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-5-cyano-2-pyridon-1-yl) -2H-benzo [b] pyran-3-ol

The compounds of the formula I, their physiologically acceptable salts and Acid addition salts and their tautomers and optical Isomers are therapeutic agents, have high levels pharmacological action and are valuable Drug. In particular, they show vasodilating, Vascular spasmolytic, especially broncholytic Effect, wherein the vascular spasmolytic effect in entire vascular system or more or less isolated in circumscribed vascular areas such as brain, Coronar or peripheral vessels can unfold.

The compounds according to the invention have in particular hypotensive effect and can thus be considered antihypertensive agents are used.

The substances according to the invention are characterized a considerable lowering of the arterial blood pressure out. Doses of 0.01-10 mg / kg p. o. lead to a Lowering blood pressure by at least 20% hypertensive rats.

The substances according to the invention are characterized a special influence on the potassium ion flow in out of the cells. In particular, they are Potassium channel activators. They are suitable for prophylaxis and for the treatment of the following diseases Warm-blooded animals, especially humans:

• 1. hypertension, especially arterial High blood pressure,
• 2. Heart failure, coronary insufficiency, angina pectoris,  
• 3. arterial occlusive disease and peripheral Circulatory disorders,
• 4. cerebral insufficiency, migraine, dizziness, Diseases of the inner ear or the Auditory apparatus,
• 5. increased intraocular pressure, glaucoma, poor eyesight,
• 6. Renal insufficiency. organic diseases of the urinary tract as well as the accessory Glands of the urinary tract, potency disorders,
• 7. orangic disorders of the gastrointestinal tract and the Pancreas and liver,
• 8. lack of blood circulation to the scalp, hair loss,
• 9. Respiratory diseases including Bronchial asthma,
• 10. metabolic diseases,
• 11. spasmogenic diseases of the uterus,
• 12. Incontinence.

Furthermore, the compounds according to the invention promote the circulation of the scalp and hair growth. you are also tocolytically active.

The compounds of the invention show a long Duration of action with only low toxicity. Therefore they show especially for the treatment of acute and chronic Heart disease, for the treatment of hypertension, the  Heart failure and for the treatment of asthma and cerebral and peripheral circulatory disorders.

The compounds of the present invention can be used in the People orally or parenterally in a dosage of 0.001 to 100 mg, preferably 0.01 to 50 mg, more preferably 0.05 to 10 mg per day be, especially in divided doses, the Example twice to four times a day. These dosages are advantageous for the treatment of the above said diseases, in particular of Heart disease, hypertension, and asthma Circulatory disorders.

In general, it has proven to be advantageous with intravenous administration amounts of about 0.001 to 10 mg, preferably about 0.05 to 5 mg per person Day to achieve effective results. For oral administration, the dosage is about 0.05 to 30 mg, preferably 0.1 to 10 mg per day at People.

The above dosages are for the Treatment of hypertension particularly preferred.

Nevertheless, this may be necessary from to deviate from the said quantities, in Dependence on body weight or type the application route, but also due to the individual behavior towards the drug or the nature of its formulation and the Time or interval to which the Administration takes place. So it can in some cases be sufficient, with less than the aforementioned Minimum amount to get along, while in other cases the  said upper limit must be exceeded. in the If the application of larger quantities it can be recommended to translate these into several single doses to distribute the day.

The invention also relates to Compounds of the invention for the treatment of above diseases and methods of treatment of these diseases in which these compounds be used as well as their use in the process for Production of funds containing these compounds included, for the treatment of these diseases as well Process for the preparation of the compounds.

According to the invention, pharmaceutical preparations or compositions that provide a Compound of the invention or pharmaceutically compatible salt or acid addition salts together with a pharmaceutically acceptable Diluent or carrier included.

The compounds according to the invention can with customary pharmaceutically acceptable Diluents or carriers and optionally with other adjuvants and, for example, orally or parenterally. You can preferably orally in the form of granules, capsules, Pills, tablets, film-coated tablets, dragees, syrups, Emulsions, suspensions, dispersions, aerosols and Solutions as well as liquids or parenteral in form of solutions, emulsions or suspensions become. Orally administered preparations may have a or several additives, such as sweeteners, Flavoring agents, dyes and Preservative included. Tablets can do that  Active substance with conventional pharmaceutically acceptable Auxiliaries mixed, for example, inert Diluents such as calcium carbonate, Sodium carbonate, lactose and talc, granulating agents and agents that inhibit the disintegration of the tablets in the case of oral Promote administration such as starch or gelatin, Lubricants such as magnesium stearate, stearic acid and Talk.

Suitable carriers are, for example, lactose (Lactose), gelatin, corn starch, stearic acid, ethanol, Propylene glycol, ethers of tetrahydrofurfuryl alcohol and water.

Examples of adjuvants are:

Water, non-toxic organic solvents, such as Paraffins (eg petroleum fractions), vegetable oils (eg. Peanut / sesame oil), alcohols (eg ethyl alcohol, Glycerol, glycols (eg, propylene glycol, Polyethylene glycol), solid carriers, such as. B. ground natural minerals (eg kaolins, clays, Talc, chalk), ground synthetic minerals (eg highly disperse silica, silicates), sugars (eg. Pipe, milk and dextrose), emulsifying agents (eg. Polyoxyethylene fatty acid esters, Polyoxyethylene fatty alcohol ethers, alkyl sulfonates and Arylsulfonates), dispersants (eg, methylcellulose, Starch and polyvinylpyrrolidone) and lubricants (e.g. Magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).

The formulations are prepared, for example by stretching the active ingredients with solvents and / or carriers, optionally using  of emulsifiers and / or dispersants, wherein z. B. in the case of using water as Diluent optionally organic Solvent can be used as auxiliary solvent can.

The application is carried out in the usual way, preferably oral or parenteral, especially perlingual or intravenously. In the case of oral use can Tablets of course except those mentioned Excipients, such as sodium citrate, Calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably Potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, Sodium lauryl sulfate and talc for tableting be used. In the case of aqueous suspensions and / or elixirs intended for oral use are, the active ingredients except with the above Excipients with different flavor enhancers or dyes are added.

In the case of parenteral use, solutions the active ingredients using suitable liquid Carrier materials are used.

The tablets can be prepared by known methods be coated to decay and absorption in the Delay the gastrointestinal tract, reducing the activity of the Drug extend over a longer period of time can. Likewise, in the suspensions of the active substance with Auxiliaries may be mixed for the production such compositions are common, 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 ingredient as the only ingredient or mixed with a solid diluent such as Calcium carbonate, calcium phosphate or kaolin. The injectable preparations are also in themselves formulated in a known manner.

The pharmaceutical preparations can be the active ingredient in in an amount of 0.1 to 90% by weight, especially 1 to 90 weight percent, d. H. in amounts sufficient to the specified Dosage scope to achieve, with the rest a Carrier or additive is. In terms of Production and administration become solid preparations like tablets and capsules preferred. Preferably the preparations contain the active substance in an amount from 0.05 to 10 mg.

The invention further provides a method for Preparation of the compounds of formula I and their Salts, characterized in that one 3,4-oxiranyl-2H-benzo (b) pyran of the formula II

wherein R₁, R₂ and R₆ are as defined for formula I.  have, with one of a compound of formula V

R₅-H (V)

wherein R₅ has the meaning given in formula I or reacted with one of their reactive derivatives and / or that a compound of formula I, wherein R₃ OH and R₄ H means dehydrated and / or that one in a compound of formula I one or more of Radicals R₃, R₅ and / or R₆ into other radicals R₃, R₅, and / or R₆ converts and / or that one is a basic Compound of formula I by treatment with an acid converted into one of their acid addition salts.

The compounds of the formula I are, moreover, according to produced by known methods, as described in the Literature (eg in the standard works such as Houben-Weyl, Methods of organic chemistry. Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York; and the above-mentioned patent applications) are described, under reaction conditions, known and suitable for the reactions mentioned are. You can also of known, here unspecified variants make use.

If desired, the starting materials may also be in situ be formed, so that they can be removed from the Reaction mixture not isolated, but immediately further to the compounds of formula I.

Preferably, the compounds of formula I are Reaction of compounds of formula II with Compounds of formula V prepared, useful in Presence of an inert solvent at temperatures between about 0 and 150 °.  

A starting material of the formula II is known. The Preparation of the Starting Materials II According to the Invention will be described below.

The starting materials V are generally known. Provided they are not known, they can be be prepared known methods.

Suitable reactive derivatives of V are the corresponding salts, for. As the Na or K salts, the can also arise in situ.

It is convenient to work in the presence of a base. Suitable bases are z. B. alkali metal or Alkaline earth metal hydroxides, hydrides or amides such as NaOH, KOH, Ca (OH) ₂, NaH, KH, CaH₂, NaNH₂, KNH₂, furthermore organic bases such as triethylamine or pyridine, which can also be applied in excess and then simultaneously serve as a solvent.

Particularly advantageous is the reaction in the presence quaternary organic ammonium compounds, such as. B. Trimethylbenzylammonium hydroxide in an inert Solvens performed.

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 or monoethyl ether (methyl glycol or ethyl glycol), Ethylene glycol dimethyl ether (diglyme); Ketones like acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene;  Esters, such as ethyl acetate; Amides such as dimethylformamide (DMF), dimethylacetamide or triamide; Sulfoxides like Dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride; Hydrocarbons such as benzene, toluene or xylene. Furthermore, mixtures of these solvents are suitable among themselves.

The epoxide II can also be prepared in situ, z. B. by the action of a base on the corresponding Bromohydrin III.

A compound of formula I, wherein R₃ = OH and R₄ = H can, by treating with a Dehydrating agent in a compound of the formula I, wherein R₃ and R₄ together signify a bond, being transformed. This succeeds z. B. by exposure one of the specified bases, z. B. NaH, in one of specified solvent, eg. B. DMSO, at temperatures between 0 and 150 °.

Compounds of formula I, wherein R₃ and R₄ together If desired, they can also be a bond directly, d. H. without isolation of compounds of Formula I, wherein R₃ is hydroxy and R₄ is hydrogen from oxiranes of the formula II and compounds of the formula V by an excess of one of the above Bases, such as NaH in one of the specified solvents preferably obtained at elevated temperature. Possibly resulting mixtures of benzopyran-3-ols and Benzopyrans of the formula I can be by customary Cleaning methods, such as crystallization or Separate chromatography.  

In some cases, it may be beneficial to the corresponding hydroxy compound first according to customary Methods in a corresponding alkyl or Arylsulfonate, in particular mesylate, brosylate or Transfer tosylate and then by action of bases, such as B. triethylamine the desired Benzopyran of the formula I, wherein R₃ and R₄ is a bond mean to produce.  

Furthermore, in a compound of formula I one or more of R₃, R₅ and / or R₆ in other radicals R₃, R₅ and / or R₆ convert.

For example, it is possible to be an H atom by halogenation by a halogen atom or replaced by a nitration by a nitro group and / or a nitro group to an amino group reduced and / or a difluoromethylthio, Trifluoromethylthio, trifluoroethylthio, or Difluoromethylsulfinyl, trifluoromethylsulfinyl or Trifluorethylsulfinylrest oxidized and / or a Difluoromethylsulfonyl, trifluoromethylsulfonyl, Trifluoroethylsulfonyl or difluoromethylsulfinyl, Trifluoromethylsulfinyl or Trifluorethylsulfinylrest reduced and / or an amino or hydroxy group alkylated or acylated and / or a cyano group (eg. with HCL in water / methanol at 20-100 °) in a Carboxyl group or (eg with Raney nickel in Water / acetic acid / pyridine in the presence of Sodium phosphate) into a formyl group or (e.g. KOH in tert-butanol) into a carbamoyl group or (Eg, with H₂S in pyridine / triethylamine) in a Thiocarbamoyl group converts and / or one substituted or unsubstituted 1H-2-pyridone-1-yl-rest (eg with P₂S₅ or with Lawesson reagent in toluene) in the corresponding 1H-2-thiopyridone-1-yl residue converts.

Nitration succeeds under usual conditions, z. B. with a mixture of concentrated nitric acid and concentrated sulfuric acid or with Copper (II) nitrate in acetic anhydride at temperatures between 0 ° and 30 ° C.  

Due to the electron-attracting properties of R₆ the nitration takes place predominantly at the radical R₅. Possibly resulting mixtures can by itself known methods such as crystallization or Chromatography decomposed into pure components become.

The same applies to the halogenation z. B. with elemental chlorine or bromine in one of the usual inert solvents at temperatures between about 0 and 30 ° can be performed.

Compounds of the formula I in which R₆ is difluoromethylthio, trifluoromethylthio or 2,2,2-trifluoroethylthio can be prepared by suitable oxidizing agents, such as, for example, As hydrogen peroxide in glacial acetic acid, organic peracids or particularly preferably Oxone ^R in methanol-water mixtures at temperatures between 0 ° C and the reflux temperature of the reaction mixture, preferably at temperatures between 20 and 60 ° C, are converted into compounds of formula I, in where R₆ is difluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfinyl or 2,2,2-trifluoroethylsulfonyl. Any resulting mixtures of sulfinyl and sulfonyl compound can be kept pure by conventional methods such as crystallization or chromatography.

A primary or secondary amino group and / or an OH group can be converted to the corresponding secondary or tertiary amino group and / or alkoxy group by treatment with alkylating agents. As alkylating agents are z. B. C _1-6 alkyl halides or corresponding sulfuric acid or sulfonic acid esters such as methyl chloride, bromide, iodide, dimethyl sulfate, methyl p-toluenesulfonate. Furthermore, you can z. B introduce one or two methyl groups with formaldehyde in the presence of formic acid. The alkylation is conveniently carried out in the presence or absence of one of said inert solvents, e.g. B. DMF at temperatures between about 0 ° C, and about 120 ° C, wherein a catalyst may be present, preferably a base such as potassium tert-butoxide or NaH.

Suitable acylating agents for the acylation of amino or hydroxy groups are suitably the halides (for example chlorides or bromides) or anhydrides of C _1-8 -alkylcarboxylic acids or C _6-10 -arylcarboxylic acids, for example. For example, acetic anhydride, propionyl chloride, isobutyryl bromide, formic acid / acetic acid hydride, benzoyl chloride. The addition of a base such as pyridine or triethylamine in the acylation is possible. It is advisable to acylate in the presence or absence of an inert solvent, e.g. Example, a hydrocarbon such as toluene, a nitrile such as acetonitrile, an amide such as DMF or an excess of a tertiary base such as pyridine or triethylamine, optionally using a catalyst such as. For example, 4-dimethylamino-pyridine at temperatures between about 0 ° C and about 160 ° C, preferably between 20 ° C and 120 ° C. Acylation with the corresponding free carboxylic acids with the aid of conventional condensation reagents such as dicyclohexylcarbodiimide is also possible.

A conversion to carbonates is carried out analogously by reaction with chloroformic acid C _1-8 -alkyl esters under the conditions given above.

The conversion to carbamates is carried out either analogously to the above-described process by reaction with mono- or dialkylaminocarbamoyl chlorides or by reaction with C _1-8 -alkyl isocyanates or with C _6-10 -aryl-substituted C _1-6 -alkyl isocyanates in an inert Solvency, z. As toluene, at temperatures between 0 ° C and the boiling temperature of the reaction mixture. Formylation is also possible with formic acid in the presence of pyridine.

An oxirane of the formula II can preferably in situ, from Compounds of formula III by reaction with a Base such as sodium hydride in a solvent such as DMSO at temperatures between 0 and 80 ° C, preferably at 20-25 ° C are produced. In these cases it is advantageous, the compounds of formula V only then add to the reaction mixture when the Oxiran formation is complete.

If isolation of oxirane II is desired, The reaction of the bromohydrin III can also take place in one suitable ethers such as diethyl ether, dioxane or Tetrahydrofuran with a base such as potassium hydroxide or Sodium hydride or in aqueous mixtures water-miscible ether and a base such as Potassium hydroxide take place. In these cases, the Use of sodium hydride in tetrahydrofuran prefers.

Compounds of general formula III in which Bromatom and hydroxy group arranged trans to each other can, according to usual procedures getting produced. Such a procedure can be like  follows and is described several times been, z. EP-A 0 76 075, EP-A 3 14 446, J. Org. Chem. 38, (22), 3822 (1973), ibid, 39 (7), 881 (1974), ibid. 37 (6), 841 (1972):

Scheme I

The following conditions are preferred:

• I) z. B K₂CO₃ / acetone; reflux or K₂CO₃ / butanone; reflux or K₂CO₃ / dimethylformamide, 90 ° C. or NaOH / 40% triethylbenzylammonium hydroxide in methanol; room temperature
• II) z. For example, 1,2-dichlorobenzene, 180 ° C. or N, N'-diethylaniline, 200 ° C or without solvent, 200 ° C
• III) N-bromosuccinimide / dimethyl sulfoxide / water
• IV) bromine, carbon tetrachloride
• V) acetone / water

The 4-substituted phenols VI, in which R₆ is the one above has meaning, are known or can after known methods are prepared, for. B. by Reduction of the corresponding 4-substituted Nitroaromatics, for example with hydrogen and Raneynickel as a catalyst or by nascent Hydrogen to the corresponding 4-substituted Anilines and diazotization and boiling the same too the said 4-substituted phenols.

In cases where R₆ is difluoromethylthio, Difluoromethylsulfinyl, difluoromethylsulfonyl, Trifluoromethylthio, trifluoromethylsulfinyl, Trifluoromethylsulfonyl, 2,2,2-trifluoromethylthio, 2,2,2-trifluoroethylsulfinyl and 2,2,2-trifluoroethylsulfonyl, may be mentioned Remains often more advantageous by chemical  Transformations of intermediates in which R₆ has a meaning other than the above, be introduced, for. For example, 2H-benzo (b) pyrans become the general formula IV, in which R₆ is the meaning Difluoromethylsulfonyl, trifluoromethylsulfonyl and 2,2,2-trifluoroethylsulfonyl has, by reaction of corresponding Fluoralkylsulfonylfluoride with 2H-Benzo (b) pyrans of the general formula IV in which R₆ has the meaning MgHal, where Hal is the meaning Chlorine, iodine and especially bromine has received.

It is also possible to use the one described above Grignard compounds of 2H-benzo (b) pyrans with Disulfides of the general formula R-S-S-R in which R the meaning trifluoromethyl, difluoromethyl and 2,2,2-trifluoroethyl has, to 2H-benzo (b) pyrans, in R₆ meaning difluoromethylthio, Trifluoromethylthio and 2,2,2-trifluoroethylthio, implement.

Furthermore, it is possible, starting from intermediate or End products in which R₆ contains a sulfur atom, according to conventional methods by reduction and in particular oxidation to intermediates or end products, in which the designated sulfur atom is another Oxidation stage has to arrive.

Examples of possible oxidizing agents are potassium permanganate, sodium periodate, chromium trioxide or preferably oxone ^R (potassium monopersulfate) or hydrogen peroxide / glacial acetic acid.

So z. B. 4-difluoromethylsulfonyl-phenol, 4-trifluoromethylsulfonyl-phenol or 4- (2,2,2-trifluoroethylsulfonyl) phenol cheaper than by known methods by oxidation of the corresponding Fluoroalkylthiophenole with Oxone ^R in methanol-water mixtures at temperatures between - 10 ° C and the reflux temperature of the reaction mixture, preferably at temperatures between 0 ° C and 25 ° C are obtained.

Especially in cases where R₆ is the meaning Difluoromethylsulfinyl, trifluoromethylsulfinyl or 2,2,2-trifluoroethylsulfinyl, it is more convenient starting from the corresponding 4-Fluoroalkylthiophenols (VI) according to Scheme I first the corresponding 6-fluoroalkylthio-2H-benzo (b) pyrans IV, in the R₁ and R₂ the meaning given above have, manufacture and then the desired Oxidation to the respective 6-Fluoroalkylsulfinyl-2H-benzo (b) pyrans of the general Formula IV, in which R₆ has the abovementioned meaning, make. Surprisingly, the selectivity this reaction in the mentioned classes of compounds very high.

The starting materials used are known or can be prepared by methods known per se or analogously to the one described here or analogously to known per se Process are produced.

The compounds of the formula I can be both bases also be acids or amphoteric and therefore in the form of their salts or acid addition salts from the Reaction mixtures are isolated. They let themselves as Bases with suitable inorganic or organic Turn acids into salts by known methods or form salts as acids with bases.  

In particular, acids are used for this reaction Question that provide physiologically acceptable salts. Thus, inorganic acids can be used, for. B. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric or hydrobromic acid, Phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. 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 ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulphonic acids, laurylsulphuric acids. For the production becomes the hot alcoholic solution of the base with the alcoholic solution of a suitable acid, and the ether is added to the salt. preferred Salts are the alkali, alkaline earth and ammonium salts the compounds of the formula I which are compatible with the corresponding bases, especially sodium, or Potassium hydroxide are obtained.

Salts with physiologically unacceptable acids, z. As picrates, can be used to purify the compounds of formula I can be used.

The compounds of the formula I according to the invention can due to asymmetric sulfur or carbon atoms own one or more chiral centers. You can  therefore, in their preparation as racemates, diastereomers Mixtures of racemates, or, if optically active Starting materials are used, also in optical active form as enantiomers or mixtures of Diastereomers are obtained.

Do the compounds z. B. two or more chiral Centers on, then you can use in the synthesis as Mixtures of racemates accumulate, from which the individual racemates, for example by Recrystallization from inert solvents, in pure Can isolate form. So z. B. compounds of Formula I, wherein R₁ = R₂, R₃ = OH and R₄ = H, two chiral centers at C (3) and C (4) of the 3,4-dihydro-2H-benzopyrangerüsts; in the preparation of however, reaction of II with V produces all predominantly only a racemate with trans position of Substituents R³ = OH and R⁵. Preserved racemates can, if desired, according to known Methods mechanically or chemically into their enantiomers be separated. So can from the racemate by Reaction with an optically active release agent Diastereomers are formed. As a release agent for Basic compounds of the formula I are suitable for. B. optically active acids, such as the D and L forms of Tartaric acid, dibenzoyltartaric acid, diacetyl-acid, Camphorsulfonic acids, mandelic acid, malic acid or Lactic acid. Carbinols (I. R³ = OH) can also with Aid of chiral acylating reagents, e.g. B. D or L-a-methylbenzyl isocyanate, esterified and then separated be (see EP-A1 1 20 428). The different forms The diastereomers of the formula I can in per se known manner from the diastereomers in freedom be set. Enantiomer separations succeed further by chromatography on optically active  Support materials. However, according to the invention it is also possible, the pure enantiomers by to obtain asymmetric synthesis.

The invention also provides a method for Preparation of pharmaceutical preparations, characterized characterized in that a compound of the formula I and / or one of their physiologically acceptable salts together with at least one solid, one liquid or one semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients in a suitable dosage form brings.

The following examples serve to illustrate the Invention:  

example 1 6-trifluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4- (1H- 2-pyridone-1-yl) -2H-benzo (b) pyran-3-ol

5 g (19.2 mmol) 6-trifluoromethoxy-3,4-dihydro-3,4-oxiranyl-2,2-dimethyl- 2H-benzo (b) pyran is added together with 4 g (42.1 mmol) 1H-2-pyridone and 0.8 ml Triton B solution (35% in Methanol) in 40 ml of absolute dioxane for 16 hours Reflux heated. Allow to cool, pour on ice and extracted with ethyl acetate (or diethyl ether or Methylene chloride, 3 x 50 ml), the combined dried organic phases over Na₂SO₄, filtered, evaporated in Vacuum and crystallized from the residue Diisopropyl ether around. This gives 4.2 g of colorless crystals of the above Compound (62% of theory), mp 182 ° C

Analog you get the listed in the description preferred 2-H-benzo (b) pyran-3-ols.

Example 2 6-difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2 thiopyridone-1-yl) -2H-benzo (b) pyran-3-ol (A) and 6-difluoromethoxy-2,2-dimethyl-4- (1H-2-thiopyridone-1-yl) - 2H-benzo (b) pyran-3-ol (B)

In a solution of 5 g (21 mmol) 6-difluoromethoxy-3,4- dihydro-3,4-oxiranyl-2,2-dimethyl-2H-benzo (b) pyran and 3.11 g (28 mmol) of 1H-2-thiopyridone in 50 ml absolute DMSO is added in portions at room temperature 0.9 g (37.5 mmol) de-oiled sodium hydride. After 20 hours  Stirring at room temperature is worked up as usual (see Example 1) and separates the remaining mixture by preparative HPLC (silica gel; Methylene chloride / ethanol). This gives 0.67 g (9% of theory) (oil) 2H-Benzo (b) pyran-3-ol (A) and 1.11 g (15% of th.), M.p. 103 ° C 2H-benzo (b) pyran (B).

Example 3 6-difluoromethoxy-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2 pyridon-1-yl) -2H-benzo (b) pyran-3-ol (A) and 6-difluoromethoxy-2,2-dimethyl-4- (1H-2-pyridone-1-yl) -2H-benzo (b) pyran-3-ol (B)

To 60 ml of a fresh prepared 0.11 M Sodium ethylate solution in absolute ethanol is added with stirring, 0.67 (7.1 mmol) of 1H-2-pyridone. After 15 Minutes, 2.0 g (8.3 mmol) 6-difluoromethoxy-3,4-dihydro-3,4-oxiranyl-2,2-dimethyl- 2H-benzo (b) pyran added and refluxed for 2 hours heated. You work up as usual and separate that Mixture by preparative HPLC: 0.80 g (33% of theory) of mp 166-167 ° C. (A) and 0.47 g (18% of theory) (oil) (B)

Analog you get the listed in the description preferred compounds.  

Example 4 6-trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridone-1-yl) -2H-benzo (b) pyran-3-ol

A mixture of 6.0 g (22 mmol) 6-trifluoromethylthio 3,4-dihydro-3,4-oxiranyl-2,2-dimethyl-2H-benzo (b) pyran and 2.2 g (23 mmol) of 1H-2-pyridone in 60 ml absolute triethylamine for 12 hours under reflux heated. After work-up (see Example 1) is obtained 2.5 g (32% of theory) of colorless crystals of the abovementioned Compound, mp. 146 ° C

Example 5 6-trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans- 4- (1H-2-pyridone-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- (1H-2-pyridon-1-yl) -2H-benzo (b) pyran 3-ol (Example 4) are stirred together with 2.5 g (1.8 mmol) of Oxone ^R in 40 ml of 60% aqueous methanol for 120 hours at room temperature. After customary work-up (see Example 1), the desired compound is isolated by preparative HPLC (silica gel, methylene chloride / ethanol 97: 3). This gives 0.18 g (33% of theory) of colorless crystals of the abovementioned compound, mp 208-210 ° C.

By rechromatography of eluent fractions (Silica gel, methylene chloride / ethanol 99: 1) can be 6-trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-trans- 4-1H-2-pyridon-1-yl) -2H-benzo (b) pyran-3-ol. Mp. 218-220 ° C.  

Example 6 6-trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-2-pyridone-1 yl) -2H-benzo (b) pyran

1.4 g (3.47 mmol) 6-trifluoromethylsulfonyl-3,4- dihydro-2,2-dimethyl-trans-4- (1H-2-pyridone-1-yl) -2H- benzo (b) pyran are dissolved in 30 ml of absolute methylene chloride dissolved, 3.9 ml (28 mmol) of absolute triethylamine added and at 0 ° C with stirring 1.6 g (14 mmol) Methanesulfonyl chloride added dropwise. After 16 hours Stir at room temperature and usual work-up 1.57 g of the corresponding mesylate are obtained colorless crystals; these are again in 40 ml heated to absolute triethylamine. After usual work-up is made from ethanol with the addition of activated carbon recrystallized. 0.5 g (37% of theory) of colorless crystals of the above compound, m.p. 217 ° C

The procedure is analogous to that in Example 4 described compound 6-trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyridone-1-yl) - 2H-benzo (b) pyran.

Example 7 6-trifluoromethoxy-2,2-dimethyl-4- (1H-2-pyridone-1-yl) -2H- benzo (b) pyran

200 g (0.56 mmol) of that described in Example 1 Compound are dissolved in 5 ml of absolute THF and washed with  Excess sodium hydride for 3 days under reflux cooked. After usual work-up and preparative HPLC (methylene chloride / ethanol 97: 3) gives 120 mg (63% of theory) of the abovementioned compound, colorless oil.

Example 8

To a solution of 3.75 g (11 mmol) 6-trifluoromethoxy-trans-3-bromo-4-hydroxy-3,4-dihydro- 2,2-dimethyl-2H-benzo (b) pyran in 50 ml of DMSO with cooling, 0.35 g (15 mmol) of deoiled sodium hydride added. After 2 hours, the solution of the formed intermediately 6-trifluoromethoxy-3,4-dihydro-3,4-oxiranyl-2,2-dimethyl- 2H-benzo (b) pyran, further 0.35 g of deoiled sodium hydride and 2.1 g (22 mmol) of 1H-2-pyridone. After 16 Stirring at room temperature for hours is as usual worked up. The obtained in Example 1 described connection or 6-trifluoromethoxy-2,2-dimethyl-4- (1H-2-pyridone-1-yl) -2H- benzo (b) pyran as a by-product.

Example 9 6-trifluoromethylsulfonyl-3,4-dihydro-trans-3-acetoxy-4- (1H-2-pyridone-1-yl) -2,2-dimethyl-2H-benzo (b) pyran

0.5 g of that described in Example 5 is heated Compound in 5 ml of acetic anhydride for 1 hour at 140 ° C. After usual work-up, the above-mentioned Compound, mp 195-198 ° C.  

Example 10 6-trifluoromethylthio-3,4-dihydro-trans-3-formyloxy-4- (1H-2-pyridone-1-yl) -2,2-dimethyl-2H-benzo (b) pyran

A mixture of 1 g of that described in Example 4 Compound, 6 ml of formic acid and 1.7 ml of acetic anhydride is stirred for 16 hours at room temperature and then heated to 40 ° C for 2 hours. To Evaporation in vacuo and usual workup receives the abovementioned compound, mp. 123-129 ° C.  

Example 1' 4-trifluoromethylsulfonyl-phenol Method A '

1 g (5.2 mmol) of 4-trifluoromethylthiophenol are dissolved in 20 ml of methanol and, at 0 ° C., a suspension of 9.6 Oxone ^R in 20 ml of water is added with stirring. After 5 days of stirring at room temperature, it is diluted with 50 ml of water and extracted with chloroform (3 × 50 ml). After drying and evaporation, 1.1 g of colorless crystals of 4-trifluoromethylsulfonyl-phenol (94% of theory) remain M⁺ = 226 (8)

Method B '

1 g (5.2 mmol) of 4-trifluoromethylthiophenol together with 4 ml glacial acetic acid and 4 ml 30% Hydrogen peroxide stirred for 20 hours at 50 ° C, then another 2 ml 30% Hydrogen peroxide added and after further 2 Hours at 50 ° C is worked up at A '. To Chromatography on silica gel gives 230 g of colorless Crystals 4-trifluoromethylsulfonyl-phenol (20% of theory) Mp 123 ° C (Lit .: 119-120 ° C)

Example 2 ' 4-difluoromethylsulfonyl-phenol

The connection is analogous to that under 1 ', A' or 1 ', B' accessible methods described.  

Example 3 ' 4- (2,2,2-trifluoroethylsulfonyl) -phenol

The compound is analogous to method 1 ', A' or 1 ', B' available.

Example 4 ' 6-trifluoromethylthio-2,2-dimethyl-2H-benzo (b) pyran a) 3- (4- (Trifluoromethylthio) -phenoxy) -3-methyl-1-butyne

In a solution of 19.4 g (0.1 mol) 4- (trifluoromethylthio) -phenol in 250 ml of dry Butanone 13.8 g (0.1 mol) of dried Potassium carbonate and 1.6 g (0.01 mol) of potassium iodide suspended and 15.4 g (0.15 mol) 3-chloro-3-methyl-1-butyne was added dropwise. Then it will be under Stirred for 20 hours under reflux, again 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g Potassium carbonate is added and continues for 40 hours heated to reflux. Inorganic ingredients are filtered off, the solution concentrated, the residue taken up in 200 ml of methylene chloride and with 1N NaOH solution extracted. The organic phase is with Washed water, dried and concentrated, the 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 above (4'a) described Compound are in 50 ml of 1,2-dichlorobenzene under  Heated argon for 2 hours at 180 ° C and then in Vacuum fractionated. Yield: 13 g of colorless oil (59.1% of theory) bp 55 ° C / 2 Pa

Example 5 ' 6-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran

1 g (4.4 mmol) of 4-trifluoromethylsulfonyl-phenol 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 was stirred under argon at 80-90 ° C for 20 hours. Then again 0.33 g of potassium carbonate, 40 mg Added potassium iodide and 1 g of 3-chloro-3-methyl-1-butyne and it is stirred for a further 20 hours at 80-90 ° C. It is allowed to cool, filtered and the filtrate is evaporated on. The residue is dissolved in 20 ml of methylene chloride taken up, washed with water (2 × 20 ml), dried and evaporated. The remaining oil (1.3 g) is dissolved in o-dichlorobenzene (3 ml) under argon for 3 hours heated to 180 ° C. After distilling off the Solvent is chromatographed on silica gel. you receives 0.5 g of colorless oil (50% of theory). M⁺ = 292 (5).

Example 6 ' 6-trifluoromethoxy-2,2-dimethyl-2H-benzo (b) -pyran

In a solution of 90 g (0.5 mol) 4-trifluoromethoxyphenol in 900 ml of dry acetone 69.2 g (0.5 mol of dried potassium carbonate and Suspended 8.3 g (0.05 mol) of potassium iodide and it will be 70 g (0.68 mol) of 3-chloro-3-methyl-1-butyne was added dropwise.  

After stirring for 36 hours at reflux temperature another 35 g (0.34 mol) of 3-chloro-3-methyl-1-butyne It will be added for another 36 hours Reflux temperature stirred. The cooled suspension is filtered, washed with acetone, the filtrate is concentrated, the residue in methylene chloride taken up and extracted with 1N NaOH solution. The Methylene chloride phase is washed neutral, dried and evaporated. Yield: 67 g (54.9% of theory) 67 g of the above compound are in 380 ml 1,2-dichlorobenzene heated to 180 ° C for 4 hours. Fractionation in vacuo gives the desired product. Yield: 45 g (67.2% of theory) bp: 75-80 ° C./1.3 Pa

Example 7 ' 6-trifluoromethylsulfinyl-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 at 0 ° C, a suspension of 14.2 g (23.1 mmol) of Oxone ^R in 40 ml of water. After 2 days of stirring at room temperature, it is diluted with 50 ml of water, extracted with chloroform (3 × 100 ml) and the residue remaining after drying and evaporation is chromatographed on silica gel. This gives 1 g of colorless oil (47% of theory) M⁺ = 276 (9)

b) 6-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran

2 g (7.7 mmol) of 6-trifluoromethylthio-2,2-dimethyl-2H-benzo (b) pyran are taken together with 6 ml of glacial acetic acid and 6 ml  30% hydrogen peroxide for 6 days at room temperature stirred, then diluted to 100 ml with water and extracted with chloroform (3 x 70 ml). To Dry and evaporate leave 2 g of colorless oil. By HPLC (mobile phase 98: 2 chloroform: methanol) 0.3 g of colorless oil is obtained, 6-trifluoromethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran (14% of theory) and 0.2 g of colorless oil, 8-trifluoromethylsulfonyl-2,2-dimethyl-2H-benzo (b) pyran (9% of theory).

Analog were:

Example 8 ' 6-Difluormethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran

and

Example 9 ' 6- (2,2,2-trifluoroethylsulfinyl) -2,2-dimethyl-2H-benzo (b) pyran

receive.

Other 6-substituted 2H-benzo (b) pyrans of the general formula IV are prepared analogously.

Example 10 ' 6-trifluoromethylthio-3,4-dihydro-3-bromo-2,2-dimethyl-2H-benzo (b) pyr an-4-ol

To a solution of 7 g (0.027 mol) of the above benzopyrans (Example 4'b) in 60 ml of DMSO and 1 ml of water at 7.7 g (0.043 mol) at 20-25 ° C Added N-bromosuccinimide. After stirring for an hour was added to ice and extracted with ethyl acetate (3 x 100 ml). The combined organic phases were washed with water (3 × 30 ml), dried and concentrated, the product crystallized out. Yield: 8 g (83% of theory) of slightly brownish crystals.

Example 11 ' 6-trifluoromethylthio-3,4-dihydro-3,4-oxiranyl-2,2-dimethyl-2H-benzo (b) pyran

To a solution of 32 g (0.09 mol) of the above bromohydrin described in 500 ml of dry Tetrahydrofuran was de-oiled under nitrogen Sodium hydride (3.5 g, 80%, in paraffin oil) in portions added. After stirring for one hour at room temperature another 1 g of sodium hydride is added. After a Another hour is filtered through silica gel and the Solution evaporated. Yield: 26 g (100% of theory)

Example 12 ' 6-trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-3-bromo-2H-benzo (b) pyran-4-ol

To a solution of 5 g (18 mmol) 6-trifluoromethylsulfinyl-2,2-dimethyl-2H-benzo (b) pyran in 45 ml of DMSO and 0.7 ml of water at 20-25 ° C  51 g (28.6 mmol) of N-bromosuccinimide were added. After a Stirring was performed on ice and with ethyl acetate extracted (3 × 100 ml). The combined organic Phases are washed with water (3 × 50 ml), dried and concentrated, the product crystallized. Yield 6.1 g (90% of theory) of light brown crystals.

Example 13 ' 6-trifluoromethylsulfinyl-3,4-dihydro-2,2-dimethyl-3,4-oxiranyl-2H-be-nzo (b) pyran

To a solution of 5.6 g (15 mmol) of the above bromohydrin described in 80 ml of dry Tetrahydrofuran is de-oiled under nitrogen Sodium hydride (0.58 g, 80%, in paraffin oil) added in portions. After stirring for one hour Room temperature is again 0.2 g of sodium hydride added. After another hour is over Silica gel filtered off and the solution was evaporated. Yield: 4.3 g (100% of theory)

Example 11 Production of tablets and capsules

Tablets and capsules containing the following contained ingredients are, after manufactured known ways of working. These are for the Treatment of the aforementioned diseases, in particular hypertension in dosage amounts of one tablet or capsule once a day  suitable.

Example 12 Production of ampoules

Ampoules containing the ingredients listed below contained, can be prepared in a known manner. The active ingredient is dissolved in water and 1,2-propanediol and bottled under nitrogen in glass ampoules.

6-Trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl-trans-4- (1H-2-pyridon-1-yl) -2H-benzo (b) pyran-3-ol | 0.02 mg 1,2-propanediol 0.8 ml least. Water ad 2.0

Claims (9)

1. Substituted benzopyran derivatives of the general formula I, in the
R₁ and R₂, which may be the same or different, are hydrogen, C _1-6 alkyl, C _3-7 branched alkyl, C _3-7 cycloalkyl or together with the carbon atom enclosed by them C _3-7 spiroalkyl , R₃ is hydroxy, C _1-8 alkoxy, formyloxy, C _1-8 alkylcarbonyloxy, C _6-10 arylcarbonyloxy, C _1-8 alkoxycarbonyloxy, C _1-8 monoalkylaminocarbonyloxy substituted by C _6-10 aryl C _1-6 -alkyleneaminocarbonyloxy or C _1-8 -dialkylamino-carbonyloxy, where the C _1-8 -alkyl or alkoxy groups may be both linear and branched, and R₄ is hydrogen or R₃ and R₄ together form a bond, R₅ is an unsubstituted or mono- or disubstituted by identical or different, C _1-6 alkyl, C _3-7 branched alkyl, C _3-7 cycloalkyl, fluorine, chlorine, bromine, iodine, C _1-6 alkoxy , C _3-7 branched alkoxy, C _3-7 cycloalkoxy, hydroxy, C _1-8 alkoxycarbonyl, C _3-7 alkylcarbonyloxy, C _6-10 arylcarbonyloxy, nitro, amino, one or two times C _1-6 alkyl substituted amino, C _1-8 alkylcarbonylamino, C _6-10 arylcarbonylamino, cyano or carboxy substituted 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-thiopyridone-1-yl radical, these radicals also being partially hydrogenated R₆ is difluoromethoxy, trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, difluoromethylthio, difluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, trifluoroethylthio, trifluoroethylsulfinyl or trifluoroethylsulfonyl, wherein the heterocycle R₅ is trans to the radical R₃ when R₃ and R₄ does not together represent a bond, but R₄ is hydrogen, and their salts and acid addition salts, tautomers and optical isomers. 2. A compound according to claim 1, selected from the Group 6-trifluoromethoxy-2,2-dimethyl-4- (1H-2-pyridone-1-yl) -2H-benzo (b) pyran, 6-trifluoromethoxy-3,4-dihydro-2,2-dimethyl- trans-4- (1H-2-pyridone-1-yl) -2H-benzo (b) pyran-3-ol, 6-trifluoromethylthio-2,2-dimethyl-4- (1H-2-pyridone-1 yl) -2H-benzo (b) pyran, 6-trifluoromethylthio-3,4- dihydro-2,2-dimethyl-trans-4- (1H-2-pyridone-1-yl) -2H- benzo (b) pyran-3-ol, 6-trifluoromethylsulfonyl-2,2- dimethyl-4- (1H-2-pyridone-1-yl) -2H-benzo (b) pyran, 6-trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl- trans-4- (1H-2-pyridone-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-pyridone-1-yl) -2H-benzo (b) pyran-3- ol, 6-trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-4-) hydroxy-2-pyridone-1-yl) -2H-benzo (b) pyran, 6-trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl- trans-4- (1H-4-hydroxy-2-pyridone-1-yl) -2H- benzo (b) pyran-3-ol, 6-trifluoromethylthio-2,2-dimethyl 4- (1H-2-pyrazinone-1-yl) -2H-benzo (b) pyran, 6-trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans- 4-1H-2-pyrazinone-1-yl) -2H-benzo (b) pyran-3-ol, 6-trifluoromethylsulfonyl-2,2-dimethyl-4- (1H-2 -pyrazinone-1-yl) -2H-benzo (b) pyran, 6-trifluoromethylsulfonyl-3,4-dihydro-2,2-dimethyl- trans-4- (1H-2-pyrazinone-1-yl) -2H-benzo (b) pyran-3-ol. 3. A process for the preparation of the compounds according to claim 1, characterized in that an oxirane of the formula II wherein R₁, R₂ and R₆ have the meaning given in formula I, with a compound of the formula VR₅-H (V) wherein R₅ has the meaning given in formula I or reacting with one of its reactive derivatives and / or that a compound of Formula I, wherein R₃ is OH and R₄ is H, dehydrated and / or that in a compound of formula I, one or more of the radicals R₃, R₅ and / or R₆ converts to other radicals R₃, R₅, and / or R₆ and / or by converting a basic compound of the formula I into one of its acid addition salts by treatment with an acid. 4. Process for the preparation of pharmaceutical Preparations, characterized in that a Compound of formula I and / or one of its physiologically acceptable salts together with at least one solid, one liquid or one semi-liquid carrier or excipient and optionally in combination with one or several other active ingredients in a suitable Dosage form brings. 5. Pharmaceutical preparation, characterized by a content of at least one compound of Formula I and / or one of its physiological harmless salts.   6. Compounds of the formula I for combating Diseases. 7. Use of compounds of the formula I for Production of a drug. 8. Compound of compounds of formula I in the Fight against diseases. 9. Compounds of the formulas II, III and IV wherein R₁, R₂ and R₆ have the meaning given for formula I, except 1a, 7b-dihydro-2,2-dimethyl-6- (trifluoromethoxy) -2H-oxireno (c) (1) benzopyran.