CA2102904A1

CA2102904A1 - Novel 2h-benzo[b]pyrane derivatives substituted in the 4 position by aryl or n-heteroaryl, process for producing them and preparations containing the compounds

Info

Publication number: CA2102904A1
Application number: CA002102904A
Authority: CA
Inventors: Benjamin Armah; Dieter Muster; Gerd Ruhter; Theo Schotten; Wolfgang Stenzel
Original assignee: Individual
Current assignee: Beiersdorf Lilly GmbH
Priority date: 1991-05-11
Filing date: 1992-05-06
Publication date: 1992-11-12
Also published as: ATE157974T1; EP0586405B1; EP0586405A1; DE4115465A1; JPH06508109A; PL297368A1; ES2106866T3; DE59208898D1; AU1659192A; DK0586405T3; WO1992020671A1; GR3025290T3

Abstract

ABSTRACT OF THE DISCLOSURE

Substituted benzopyrane derivatives of general formula (1) in which the substituents have the meanings given in the description, and their salts and acid addition salts, tautomers and optical isomers, are thereapeutic agents.

Description

Wo 92~'20671 ~ ~ ~ /DB92/00356 Novel 2H-benzotb~vran derivatives subatitutod ~n the 4 ~osition bY arvl or N-heteroarYl, proce~ses for their ~reParation and their use, and preDarations compr~sina the com~ounds Description The invention relates to novel sub~tituted benzopyran derivatives of the general formula I

R

~~ Z

in which Rl and R" which may be identical or different, denote hydrogen, Clc-alkyl, branched C36-alkyl, C37-cyoloalkyl or phenyl or denote, together with the carbon atom enclosed by them, C37-spiroalkyl, either R3 or R~ is hydrogen, hydroxyl, Cl,-alkoxy, formyl-oxy, Cl~-alkylcarbonyloxy, Cla-alkoxycarbonyloxy, Cl,-monoalkylaminocarbonyloxyorCl~-dialkylaminocarbonyloxy, where the Cl,-alkyl- or -alkoxy groups may be either linear or branched, and the other substituent of the two in each case is hydrogen, or R3 and R~ together form a bond, R5 denotes a monocyclic six-membered aryl or N-heteroaryl group, a bicyclic aryl or N-heteroaryl group which is composed of two fused six-membered rings, in which the heterocycle contains one or two nitrogen atoms which 21~?~;3 . belongs to one of the following three subgroup~ A), B) or C), in which context in A) the aryl or N-heteroaryl group R, carries a hydroxyl group in the 2 position and is optionally urther sub~ti-tuted one or two times by halogen, cyano, Cl,-alkyl or Cl8-alkoxy, in B) R5 is an N-heteroaryl group containing one or two N
atoms, which carries an N-oxide group in the 2 position and is optionally substituted one or two times by halo-gen, C~8-alkyl, Cl~-alkoxy, Cl~-mono- or Cl,-dialkylAm~no, hydroxyl, amino, cyano, Cl~-alkoxycarbonyl, Cl~-mono- or Cl8-dialkylaminocarbonyl, hydroxycarbonyl, aminocarbonyl or phenyl, and in C) Rs is an N-heteroaryl group or an N-heteroaryl N-oxide whose basic structure derives from the group 3-pyridyl, 4-pyridyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-quinolyl and 4-isoquinolyl and is option-ally substituted one or two times by halogen, Cl~-alkyl, Cl~-alkoxy, Cl~-monoalkylamino, Cl~-dialkylamino, cyano, hydroxyl, amino or phenyl, the hydroxyl group or the N-oxide group in this subgroup not being located in the 2 position, and Rc is difluoromethoxy, trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, difluoromethylthio, difluoromethyl-sulfinyl, difluoromethylsulfonyl, trifluoromethylthio,trifluoromethylsulfinyl, trifluoromethylsulfonyl, tri-fluoroethylthio, trifluoroethylsulfinyl, trifluoroethyl-sulfonyl, phosphono or Cl~-dialkoxyphosphoryl, in which abovementioned alkyl can be straight-chain or branched, and to their salts and acid addition salts, tautomers and optical isomer~, to processes for their preparation, to their use and to preparations which comprise these compounds.
For the sake of simplicity, the compounds accord-ing to the invention are defined in only one tautomeric form, which is reproduced by formula 1. The invention, however, extends to all tautomeric forms of the compounds.

` ~ 3 ~ 21~?~9~4 Compound~ of the general formula I and their salts and acid addition salts contain asymmetrlc carbon and sulfur atoms. Consequently, the invent~on al~o relates to the various optical isomers and dla~tereomers.
The racemates can ~e resolved by methods ~nown per se to give their optical isomers.
The invention also relates to the novel compound~
of the formulae II, IV, V and XI:

RS

0 ~ 2 0~ 2 having the abov~mentioned meanings for Rl, ~2~ R~ and R~, -` and to the processes for their preparation. They are u~od as precursors or intermediates in the preparation of the end products according to the invention.
Compounds which are related in structural term~
to the compounds of the present invention are described in ~uropean Patent Application 298 452. The compounds of the pre~ent invention, however, are neither specifically disclosed nor suggested.
Unless otherwise specified, the alkyl groupe and alkyl moietie~ or al~ylene moieties of groups according to the invention can be straight-chain or branched, and they possess in each case preferably from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms and parti-cularly l or 2 carbon atoms. The branched alkyl groups possQss at least 3 carbon atoms. Preferred alkyl or alkylene moieties are methyl, ethyl, n-propyl, isopropyl and butyl and, accordingly, methylene, ethylene, n- or isopropylene and butylene.
Cycloalkyl groups according to the invention preferably posses~ from 3 to 7 carbon atoms, particularly 3 to 6 carbon atoms. Cyclopropyl, cyclopentyl and cyclo-hexyl are particularly preferred.
Formyl 18 HCO-, formyloxy is HCOO-, C1,-alkyl-carbonyloxy is Cl~-alkyl-CO-O-, Cl~-alkoxycarbonyloxy is C1~-alkyl-O-CO-O-, C~-monoalkylaminocarbonyloxy is Cl,-alkyl-NH-CO-O-, C1,-dialkylaminocarbonyloxy is (Cl~-alkyl)~N-CO-O-, Cl~-alkylcarbonyl is Cl,-alkyl-CO-, Cl~-alkoxycarbonyl is Cl,-alkoxy-CO-, C~,-monoal~ylamino-carbonyl is Cl,-alkyl-NH-CO-, Cl,-dialkylamlnocarbonyl is (Cl,-alkyl),N-CO-, Cl,-dialkylamino is (Cl,-alkyl),N-, Cl~-monoalkylamino is Cl,-alkyl-NH-, halogen is fluorine, chlorine, bromine or iodine, phosphono denotes -PO(OH) 2 and Cl,-dialkoxyphosphoryl is (Cl~-alkyl-O)~PO-.
Tho trifluoroethyl group, or trifluoroethyl as part of other radicals according to the invention, such as trifluoroethoxy, is preferably 2,2,2-trifluoroethyl.
The tetrafluoroethyl group, or tetrafluoroethyl as part of other radicals according to the invention, such as tetrafluoroethoxy, is proferably 1,1,2,2-totra-fluoroethyl.
Halogen i8 preferably fluorine or chlorino.
R1 and R~ are preferably hydrogen, methyl or ethyl, of which methyl is particularly preferrod.
R1 and R2 are very particularly preferably both simultaneously methyl.
If R1 and R2, together with the carbon atom which they enclose, form a spiroalkyl ring, spirocyclopentyl and spirocyclohexyl are preferred.
R3 represents preferably hydrogen or hydroxyl if R~ is hydrogen, and R~ represents preferably hydrogen or hydroxyl if R3 i~ hydrogen. Preferably, R3 and R~ also form a bond, 80 that there i8 a double bond between the C-3 and the C-4 of the benzopyran structure.
If R3 is not hydrogen but has the meaning given above, and does not form a bond together with R~, then tho substituents R3 and R5 in compounds of the general formula I are preferably trans with respect to one a 0 another.
If R3 or R~ represent allcoxy, ethoxy and, in particular, methoxy are preferrod.
If R3 or R, represent allcylcarbonyloxy, propionyl-oxy and, in particular, acetoxy and formyloxy are preferred.
R3 and R,, very particularly proferably form a bond between the C-3 and the C-4 of the benzopyran structure.
Monocyclic or bicyclic aryl or N-heteroaryl groups which form the basis for the subgroups A), B) and C) are, in particular, phenyl, naphthyl, pyridyl, pyr-imidinyl, pyridazinyl, pyrazinyl, quinolyl, isoguinolyl, but particularly preferably are pyridyl and pyrimidinyl.
Preferred mono- or bicyclic aryl or N-heteroaryl groups Rs of ~ubgroup A) are 2-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 2-hydroxy-4-methylphenyl, 4-cyano-2-hydroxyphenyl, 2-hydroxy-1-naphthyl, 1-hydroxy-2-naph-thyl, 3-hydroxy-2-naphthyl, 2-hydroxy-3-pyridyl, 4-hydroxy-3-pyridyl, 3-hydroxy-4-pyridyl, 3-hydroxy-4-pyridazinyl, 3-hydroxy-2-pyrazinyl and 2-hydroxy-3-Qquinolyl .
Preferred mono- or bicycllc N-heteroaryl groupe Rs of subgroup B) are 2-pyridyl N-oxide, 3-chloro-2-pyridyl N-oxide, 4-chloro-2-pyridyl N-oxide, 5-chloro-2-pyridyl N-oxide, 6-chloro-2-pyridyl N-oxide, 3-methyl-2-pyridyl N-oxide, 4-methyl-2-pyridyl N-oxlde, 5-methyl-2-pyridyl N-oxide, 6-methyl-2-pyridyl N-oxide, 5-phenyl-2-pyridyl N-oxide, 4-hydroxy-2-pyridyl N-oxide, 5-hydroxy-2-pyridyl N-oxide, 6-hydroxy-2-pyridyl N-oxide, 4-methoxy-2-pyridyl N-oxide, 5-methoxy-2-pyridyl N-oxide, 6-methoxy-2-pyridyl N-oxide, 5-methoxycarbonyl-2-pyridyl N-oxide, 5-cyano-2-pyridyl N-oxide, 2-pyrimidinyl 1-oxide, 6-pyrimidinyl l-oxide, 2-pyrazinyl 1-oxide, 2-quinolyl N-oxide and 3-isoguinolyl N-oxide.
lS Preferred mono- or bicyclic N-heteroaryl groups Rs Of subgroup C) are 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, 4-pyridyl N-oxide, 2-methyl-3-pyridyl, 4-meth-yl-3-pyridyl, 5-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 5-methoxy-3-pyridyl, 6-methoxy-3-pyridyl, 2-fluoro-3-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-cyano-3-pyridyl, 6-cyano-3-pyridyl, 6-methoxycarbonyl-3-pyridyl, 6-dimethylamino-3-pyridyl, 6-hydroxy-3-pyridyl, 3-pyrid-azinyl, 6-methyl-3-pyridazinyl, 2-pyrazinyl, 2-pyrazinyl 4-oxido, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl, 5,6-dimethyl-2-pyrazinyl, 4-pyrimidinyl, 5-pyrimidinyl, 5-pyrimldinyl 1-oxide, 3-quinolyl, 3-quinolyl N-oxide, 4-isoquinolyl and 4-ieoquinolyl N-oxide.
Compounds according to tho invention containing substituents of subgroups B) and C) aro preferred;
particular preference is given, however, to those containing the following eubstituents:
2-pyridyl N-oxide, 2-pyrimidinyl N-oxide, 2-pyrazinyl l-oxide, 6-pyrimidinyl 1-oxide, 2-quinolyl N-oxide, 3-isoquinolyl N-oxide, 3-pyridyl, 3-pyridyl N-oxide, 2-fluoro-3-pyridyl, 5-pyrimidinyl, 3-pyridazinyl, 3-quin-olyl and 4-ieoquinolyl.
Very particularly preferred subetituente R5 are 2-pyridyl N-oxide and 3-pyridyl.

~ 7 ~ 2~
If Rc is C1,-dial~oxyphosphoryl, then the alkoxy radicals may be identical or different. Preferably they are both simultaneously methoxy or ethoxy.
Preferred substituents R6 are difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethyl-sulfonyl and diethoxyphosphoryl.
Preferred compounds of the general formula I are compounds of the general formula VI. Particularly pre-ferred compounds of the general formula VI are those in which Rl and R2 are both simultaneou~ly methyl and R5 represents 2-pyridyl N-oxide or 3-pyridyl.
The following compounds according to the in~en-tion, their salt~ and acid addition salts, tautomers and optical isomers, are preferred:
1. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo~b]pyran l'-oxide 2. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran l'-oxide 3. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo~b]pyran l'-oxide 4. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyr-idyl)-2H-benzo[b]pyran l'-oxide 5. 6-Trifluoromethylsulfinyl-2,2-dimethyl-4-(2'-pyridyl)-2~-benzo[b]pyran 1'-oxide 6. 6-Difluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[blpyran l'-oxide 7. 6-Difluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran l'-oxide 8. 6-Difluoromethylsulfinyl-2,2-dimethyl-4-(2'-pyr-idyl)-2H-benzo[b]pyran l'-oxide 9. 6-(2',2',2'-Trifluoroethoxy)-2,2-dimethyl-4-(2'-pyr-idyl)-2H-benzo[b]pyran l'-oxide 10. 6-(2',2',2'-Trifluoroethylthio)-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran l'-oxide 11. 6-(2',2',2'-Trifluoroethylsulfonyl)-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran l'-oxide 12. 6-(2',2',2'-Trifluoroethyl~ulfinyl)-2,2-dimethyl-4-(2'-pyridyl)-2~-benzo[b]pyran 1'-oxide 13. 6-(1',1',2',2'-Tetrafluoroethoxy)-2,2-dimethyl-4-_ 8 - ~ ~ ~2~
(2~-pyridyl)-2H-benzolb]pyran l'-ox~de 14. 6-Diethoxyphosphoryl-2,2-dimethyl-4-(2'-pyridyl)-2R-benzotb~pyran l~-oxide 15. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 16. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzolb]pyran l'-oxide 17. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 18. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyr-idyl)-3,4-dihydro-2R-benzotb]pyran l'-oxide 19. 6-Trifluoromethylsulfinyl-2,2-dimethyl-4-(2'-pyr-idyl)-3,4-dihydro-2H-benzotb]pyran l'-oxide 20. 6-Difluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 21. 6-Difluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyr-idyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 22. 6-Diethoxyphosphoryl-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 23. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran-4-ol l'-oxide 24. 6-Dlfluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran-4-ol l'-oxide 2S. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-2S 3,4-dihydro-2H-benzo[b]pyran-4-ol l'-oxide 26. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyr-idyl)-3,4-dihydro-2H-benzo[b]pyran-4-ol l'-oxide 27. 6-Trifluoromethylsulfinyl-2,2-dimethyl-4-(2'-pyr-idyl)-3,4-dihydro-2H-benzotb]pyran-4-ol l'-oxide 28. 6-Trifluoromethylthio-2,2-dimethyl-4-methoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 29. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-methoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzotb]pyran l'-oxide 30. 6-Trifluoromethyl~ulfinyl-2,2-dimethyl-4-methoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzotb]pyran l'-oxide 31. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-trans-3,4-dihydro-2H-benzo[b]pyran-3-ol l'-oxide 32. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-trans-3,4-dihydro-2H-benzo[b]pyran-3-ol l'-oxide - 9 - 2 ~ s 33. 6-Trifluoromethylthlo-2,2-dimethyl-4-(2'-pyridyl)-trans-3,4-dihydro-2~-benzolb]pyran-3-ol 1'-oxlde 34. 6-Trifluoromethylsulfonyl-2,2-d~methyl-4-(2'-pyridyl)-trans-3,4-dihydro-2H-benzo[b~pyran-3-ol l'-oxide 35. 6-Trifluoromethylth~o-2,2-d$methyl-4-(3'-chloro-2'-pyridyl)-2H-benzo[b]pyran 1'-oxide 36. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3'-chloro-2'-pyridyl)-2H-benzotb]pyran l'-oxide 37. 6-Difluoromethoxy-2,2-dimethyl-4-(4'-chloro-2'-pyridyl)-2H-benzo[blpyran 1'-oxide 38. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-chloro-2'-pyridyl)-2H-benzo[b~pyran 1'-oxide 39. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(4'-chloro-2'-pyridyl)-2H-benzolb]pyran 1'-oxide 40. 6-Difluoromethoxy-2,2-dimethyl-4-(5'-chloro-2'-pyridyl)-2H-benzotb]pyran 1'-oxide 41. 6-Trifluoromethylthio-2,2-dimethyl-4-(5'-chloro-2'-pyridyl)-2H-benzo[blpyran 1'-oxide 42. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-chloro-2'-pyridyl)-2H-benzolb]pyran 1'-oxide 43. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(6'-chloro-2'-pyridyl)-2H-benzo[b]pyran 1'-oxide 44. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-methyl-2'-pyridyl)-2H-benzolb~pyran l'-oxide 45. 6-Difluoromethoxy-2,2-dimethyl-4-(4'-methyl-2'-pyridyl)-2H-benzolb]pyran l'-oxide 46. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(4'-methyl-2'-pyridyl)-2H-benzolb]pyran l'-oxide 47. 6-Difluoromethoxy-2,2-dimethyl-4-(5'-methyl-2'-pyridyl)-2H-benzolb]pyran l'-oxide 48. 6-Trifluoromethylthio-2,2-dimethyl-4-(5'-methyl-2'-pyridyl)-2H-benzolb~pyran l'-oxide 49. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-methyl-2'-pyridyl)-2H-benzo[b]pyran l'-oxide 50. 6-Trifluoromethoxy-2,2-dimethyl-4-(5'-methyl-2'-pyridyl)-2H-benzo[b]pyran l'-oxide 51. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(6'-methyl-2'-pyridyl)-2H-benzolb]pyran l'-oxide - lo 2 ~ ~2;~ Jil 52. 6-Trifluoromethylthio-2,2-dimethyl-4-(S'-phenyl-2'-pyridyl)-2~-benzo[b]pyran 1'-oxide 53. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-phenyl-2'-pyridyl)-2H-benzotb]pyran 1'-oxide S 54. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-hydroxy-2'-pyridyl)-2H-benzotb]pyran 1'-oxide SS. 6-Trifluoromethylthio-2,2-dimethyl-4-(S'-hydroxy-2'-pyridyl)-2~-benzo[b~pyran 1'-oxide 56. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-hydroxy-2'-pyridyl)-2H-benzolb]pyran 1'-oxide 57. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-methoxy-2'-pyridyl)-2H-benzolb]pyran 1'-oxide 58. 6-Trifluoromethylthio-2,2-dimethyl-4-(S'-methoxy-2'-pyridyl)-2H-benzotb~pyran 1'-oxide 59. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-methoxy-2~-pyridyl)-2H-benzotb]pyran 1'-oxide 60. 6-Difluoromethoxy-2,2-dimethyl-4-(5'-methoxy-carbonyl-2'-pyridyl)-2H-benzotblpyran l'-oxide 61. 6-Difluoromethoxy-2,2-dimethyl-4-(5'-cyano-2'-pyridyl)-2H-benzotb]pyran 1'-oxide 62. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyrimidinyl)-2H-benzotb]pyran l'-oxide 63. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyrimidinyl)-3,4-dihydro-2H-benzotb~pyran 1'-oxide 64. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyrimidinyl)-2H-benzotb~pyran l'-oxide 65. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyrimidinyl)-3,4-dihydro-2H-benzotb~pyran 1'-oxide 66. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(2'-pyrim-idinyl)-2~-benzotb~pyran 1'-oxide 67. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(2'-pyrim-idinyl)-3,4-dihydro-2H-benzolb~pyran 1'-oxide 68. 6-Difluoromethoxy-2,2-dimothyl-4-(6'-pyrimidinyl)-3,4-dihydro-2H-benzotb~pyran 1'-oxide 69. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-pyrimidinyl)-3,4-dihydro-2H-benzo[b~pyran 1'-oxide 70. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(6'-pyrim-idinyl)-3,4-dihydro-2H-benzo[b]pyran l'-oxide 71. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyrazinyl)-3,4-dihydro-2H-benzolblpyran l'-oxide 72. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyrazinyl)-3,4-dihydro-2H-benzo[b]pyran l'-ox~de 73. 6-Trifluoromethylsulfonyl-2,2-dlmethyl-4-(2'-pyr-azinyl)-3,4-dihydro-2H-benzolb~pyran l'-oxide 74. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-gulnolyl)-2H-benzo[blpyran l'-oxide 75. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-quinolyl)-2H-benzo[b]pyran l'-oxide 76. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-qu~nolyl)-2H-benzolb]pyran l'-oxide 77. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-quin-olyl)-2H-benzolblpyran l'-oxide 78. 6-Trifluoromethylsulfinyl-2,2-dimethyl-4-t2'-quin-olyl)-2H-benzolb]pyran l'-oxide 79. 6-Trifluoromethoxy-2,2-dimethyl-4-(3'-isoquinolyl)-2H-benzolb]pyran l'-oxide 80. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-isoquin-olyl)-2H-benzolb]pyran l'-oxide 81. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-~3'-iso-quinolyl)-2H-benzo[blpyran l'-oxide 82. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-hydroxy-phenyl)-2H-benzolb]pyran 83. 6-Trifluoromethylsulfonyl-2,2-dimothyl-4-(2~-hydroxyphenyl)-2H-benzotb]pyran 84. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2~-hydroxy-4'-chlorophenyl)-2~-benzolblpyran 85. 6-Trlfluoromethylsulfonyl-2,2-dimethyl-4-(2~-hydroxy-4'-methylphenyl)-2H-benzolblpyran 86. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-hydroxy-4'-cyanophenyl)-2H-benzolb]pyran 87. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-hydroxy-1~-naphthyl)-2H-benzolblpyran 88. 6-Trifluoromethylthio-2,2-dimethyl-4-(1'-hydroxy-2~-naphthyl)-2H-benzolblpyran 89. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-hydroxy-2~-naphthyl)-2H-benzolb]pyran 90. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-hydroxy-3'-pyridyl)-2H-benzolblpyran ' - " ' "

:' - 12 _ 2 ~ G.~
91. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-hydroxy-3'-pyridyl)-2H-benzotb~pyran 92. 6-Trifluoromethylthio-2,2-dimothyl-4-(4'-hydroxy-3'-pyridyl)-2H-benzolb~pyran 93. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-hydroxy-4'-pyridyl)-2H-benzo[b~pyran 94. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-hydroxy-4'-pyridazinyl)-2~-benzo[b]pyran 9S. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-hydroxy-2'-pyrazinyl)-2H-benzo[blpyran 96. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-hydroxy-3'-quinolyl)-2H-benzo[b]pyran 97. 6-Difluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-2H-benzolb]pyran 98. 6-Difluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-2H-benzolb]pyran l'-oxide 99. 6-Difluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-3,4-dihydro-2H-benzo[b~pyran 100. 6-Trifluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-2H-benzolb]pyran 101. 6-Trifluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-2~-benzo[b]pyran l'-oxide 102. 6-Trifluoromethoxy-2,2-dimethyl-4-(3'-pyridyl)-3,4-dihydro-2H-benzolb~pyran 103. 6-Trifluoromothylthio-2,2-dimothyl-4-(3'-pyridyl)-2~-benzolb~pyran 104. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-pyridyl)-2H-benzotb]pyran l'-oxido 105. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-pyridyl)-3,4-dihydro-2H-benzolb]pyran 106. 6-Trifluoromothylthio-2,2-dimethyl-4-(3'-pyridyl)-3,~4-dihydro-2H-benzotb]pyran-4-ol 107. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3~-pyridyl)-2H-benzolb~pyran 108. 6-Trifluoromethyleulfonyl-2,2-dimethyl-4-(3~-pyridyl)-2H-benzolb~pyran 1'-oxide 109. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3-pyridyl)-3,4-dihydro-2~-benzo[b]pyran 110. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(3'-pyridyl)-3,4-dihydro-2H-benzolb]pyran-4-ol 111. 6-Diethoxypho~phoryl-2,2-dimethyl-4-(3'-pyrldyl)-2H-benzo[b]pyran 112. 6-Diethoxypho~phoryl-2,2-dimethyl-4-(3'-pyridyl)-2H-benzo[b]pyran l'-oxide 113. 6-Diethoxyphosphoryl-2,2-dimethyl-4-(3'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran 114. 6-Difluoromethoxy-2,2-dimethyl-4-(4'-pyridyl~-2~-benzo[b]pyran 115. 6-Trifluoromethoxy-2,2-dimethyl-4-(4'-pyridyl)-2H-benzo[blpyran 116. 6-Trifluoromethoxy-2,2-dimethyl-4-(4'-pyridyl)-2~-benzo[b]pyran l'-oxide 117. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-pyridyl)-2H-benzo[b]pyran 118. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(4'-pyridyl)-2H-benzo[b]pyran 119. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(4~-pyridyl)-2H-benzotb]pyran l'-oxide 120. 6-Trifluoromethyl~ulfonyl-2,2-dimethyl-4-(2'-methyl-3'-pyridyl)-2H-benzo[b]pyran 121. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(4'-methyl-3'-pyridyl)-2H-benzolb]pyran 122. 6-Trifluoromethylsulfonyl-2,2-d~methyl-4-(5'-methyl-3'-pyridyl)-2H-benzotb]pyran 123. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(6'-methyl-3'-pyridyl)-2H-benzolb]pyran 124. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-methoxy-3'-pyridyl)-2H-benzo[b]pyran 125. 6-Trifluoromothylthio-2,2-dimethyl-4-(2'-methoxy-3'-pyridyl)-2H-benzotb]pyran-4-ol 126. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-methoxy-3~-pyridyl)-2H-benzotb]pyran 127. 6-Trifluoromethylthio-2,2-dimethyl-4-(4'-methoxy-3'-pyridyl)-2H-benzotb]pyran-4-ol 128. 6-Trifluoromethylthio-2,2-dimethyl-4-(5'-methoxy-3'-pyridyl)-2H-benzo[b]pyran 129. 6-Trifluoromethylthio-2,2-dimethyl-4-(5~-methoxy-3~-pyridyl)-2H-benzotb]pyran-4-ol , 130. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-met~oxy-3'-pyridyl)-2H-benzolb]pyran 131. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-methoxy-3'-pyridyl)-2~-benzo[blpyran-4-ol 5132. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-fluoro-3'-pyridyl)-2~-benzo[blpyran 133. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-fluoro-3'-pyridyl)-2H-benzo[b]pyran-4-ol 134. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-chloro-3'-10pyridyl)-2H-benzo[b]pyran 135. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-chloro-3'-pyridyl)-2H-benzo[b]pyran 136. 6-Trifluoromethoxy-2,2-dimethyl-4-~2'-cyano-3'-pyridyl)-2H-benzo[b]pyran 15137. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-cyano-3'-pyridyl)-2H-benzo[b]pyran 138. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-methoxy-carbonyl-3'-pyridyl)-2H-benzo[b]pyran 139. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-dimethylA~;no-203'-pyridyl)-2H-benzo[b]pyran 140. 6-Trifluoromethoxy-2,2-dimethyl-4-(6'-hydroxy-3'-pyridyl)-2H-benzolb]pyran 141. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-pyrid-azinyl)-2H-benzolb]pyran 25142. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-methyl-3'-pyridazinyl)-2H-benzo[b]pyran 143. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyrazinyl)-2H-benzo[b]pyran 144. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyrazinyl)-302H-benzotblpyran-4-ol 145. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyrazinyl)-2H-benzo[blpyran 4'-oxide 146. 6-Trifluoromethylthio-2,2-dimethyl-4-(5'-methyl-pyrazinyl)-2H-benzolb]pyran 35147. 6-Trifluoromethylthio-2,2-dimethyl-4-(6'-methyl-2'-pyrazinyl)-2H-benzo[b]pyran 148. 6-Trifluoromethylthio-2,2-dimethyl-4-(5',6'-dime-thyl-2'-pyrazinyl)-2H-benzo[b]pyran 149. 6-Trifluoromethoxy-2,2-dimethyl-4-~4'-pyrimidinyl)-3,4-dihydro-2H-benzolb]pyran 150. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-pyrim-idinyl)-2H-benzolb]pyran 151. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-pyrim-idinyl)-2H-benzo[b]pyran-4-ol 152. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(5'-pyr~m-idinyl)-2~-benzo[b~pyran 1'-oxlde 153. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3'-quin-olyl)-2H-benzo[b]pyran 154. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3'-guin-olyl)-2H-benzo[b]pyran 1'-oxide 155. 6-Trifluoromsthylsulfonyl-2,2-dimethyl-4-(4'-iso-quinolyl)-2~-benzo[b]pyran 156. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(4'-iso-quinolyl)-2H-benzolb]pyran 1'-oxide.
The compounds 1-19, 22-27, 44-50, 62-70, 74-77, 82, 83, 90, 91, 97-113, 132, 133, 141, 150 and 151 are particularly preferred, in particular 1-19 and 97-113, and very particular preference is given to 1-4, 103 and 107.
The compounds of the formula I and thoir salts and acid addition salts can be prepared by a) preferably, for the preparation o$ a compound of the formula I in which R5 is an N-heteroaryl group which carriee an N-oxide group in the 2, 3 or 4 position, oxidizing a compound of tho general formula I in which R~, R2, R3, R~ and R6 have the abovementioned meaning and Rs i8 a corresponding N-heteroaryl group having an N atom in 2, 3 or 4 position, or b) for the preparation of a compound of the formula I
corresponding to the formula VI

Vl in which R1, R2, Rs and R6 have the meaning given above and .

.
, ,, . , , ~ ., .

~"` `` - 16 - ~ al~
R3 and R~ together form a bond, heating a compound of the general formula II

R~ t ~ 2 having the meaning given above of Rl, R2, R5 and R6, or eliminating water from a compound of the formula I which S corresponds to the formula III and in which R3 denotes hydrogen and R~ denotes hydroxyl R~ 5 ~H

ttl having the given meaning of Rl, R2, Rs and R6, or c) for the preparation of a compound of the formula I
which corresponds to the general formula III and has the meaning given abovo o$ Rl, R" Rs and R6, reacting a compound of the general formula IV

o R 1 t~
in which Rl, R, and R6 have the meaning given above with an organometallic compound RsM in which Rs has the above-mentioned meaning and M represents a metal or metal halide, preferably Li- or Mg~al, where Hal is chlorine, bromine or iodine, or d) for the preparation of those compounds of the - 17 - ~ 9~
general formula I in which Rl and R~ denote hydrogen and which come under the formula X of reaction schemes 1 and 2, in which Rl, R2, Rs and R~ have the meaning g$ven above, cyclizing a compound of the general formula V

in which R1, R2, Rs and R6 have the meaning given above, or hydrogenating a compound of the general formula VI

1~ R 2 in which R~, R~, Rs and Rc have the given meaning in the presence of a catalyst, or e) preferably, for the preparation o$ a compound of the general formula I in which R6 denotes difluoromethyl-8ul finyl, difluoromethylsulfonyl, trifluoromethyl-sulfinyl,tr$fluoromethylsulfonyl,trifluoroethylsulfinyl or trifluoroethylsulfonyl and R1, R~, R3, R~ and R5 have the abovementioned meaning, oxidizing a compound of the general formula I in which R, is difluoromethylthio, trifluoromethylthio or trifluoroethylthio, or f) preferably, for the preparation of a compound of the general formula I in which R5 denotes an N-heteroaromatic radical which is substituted in the o or p position relative to the N atom by chloro or cyano, and R3 and R~
in each case denote hydrogen or together denote a bond and Rl, R~ and R6 have the meaning given above, reacting a compound of the general formula I in which R5 is an N-heteroaryl N-oxide group and Rl, R2, R3, R~ and R6 have .

the appropriate meaning with a nonmetal chloride or a 8ilyl cyanide, or g) for the preparation of a compound of tho formula XII
according to scheme 1, corresponding to the formula I in which R3 is hydroxyl and R~ is hydrogen, and Rl, R~, R5 and R6 have the meaning given above, epoxidizing a compound of the general formula VI in which R~, R2~ Rs and R, have the meaning given above to give the compound XI
(scheme 1) and then reducing the epoxide to the compound of the formula XII (~cheme 1), or h) for the preparation of compounds of the formula I in which Rl, R2, ~5 and R~ have the meaning given above and R3 or R, denote ClR-alkoxy, formyloxy, Cl~-alkylcarbonyloxy, C~-alkoxycarbonyloxy, C~-monoalkylaminocarbonyloxy or Cl8-dialkylaminocarbonyloxy, reacting the corresponding compounds of the formula I in which R3 or R~ denotes hydroxyl, i.e. the compounds corresponding to formulae III and XII (scheme 1), with corresponding alkylating agents or acylating agents, and optionally converting compounds obtained by the above processes into their salts or acid addition salts or N-oxides.
For the oxidation of an N-heteroaromatic radical Rs according to process a), reagents can be used which are known per se. For instance, the oxidation can be carried out using hydrogen peroxide, organic per-acids, for example peracetic acid, perbenzoic acid, m-chloro-perbenzoic acid, perphthalic acid, salts thereof such as magnesium perphthalate, or using sodium metaperiodate, sodium perborato and the like. The reaction is expedi-ently carried out in acetic acid, in an alcohol of lowchain length, preferably in ethanol or methanol, with or without the addition of water, in an inert organic sol~ent, for example dichloromethane, dichloroethane and trichloromethane, and at temperatures between 0C and the boiling temperature of the solvent, preferably at room temperature.
The conversion of a compound of the general ``` 21 a.~d11 formula II in accordance with process b) is carrled out at the boiling temperature of a high-bolllng lnert organic solvent, for example chlorobsnzene, 1,2-dlchloro-benzene, N,N-diethylaniline, ethylene glycol and diphenyl S ether, i.e. at temperatures of between approxlmately 120C and approxlmately 300C, or else ~ithout eolvent~
in this temperature range. If at least one of the substl-tuents Rl and R2 is hydrogen, higher temperatures are preferably necessary. Increased pre~sure may be of advantage in this reaction.
The dehydration of the compounds of the general formula III is carried out by methods which are known from the literature. Examples which may be mentioned are:
sodium hydride in tetrahydrofuran or another inert organlc solvent, preferably at the reflux temperature of the reaction mixture; p-toluenesulfonic acid in toluene at reflux temperature with water separation; reaction with excess methanesulfonyl chlorlde/triethylamine in dichloromethane or chloroform with subsequent heating at reflux temperature; heating with anhydrous copper(II) sulfate or potassium hydrogen sulfate at temperatures of between 50C and 200C, preferably 100-120C.
The addition of metalated aromatic or N-hetero-aromatic compounds RsM to chromanones of the general formula IV in accordance with process c) is carried out at tomperatures of between -120C and room temperature, proferably at, initlally, approx~Ptely -78C with subsoguent heating. Tho reaction 18 preferably carried out in an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyothane or dioxano. Polar solvents such as hexamothylphosphoric triamide or 1,3-dimethyl-2-oxohexa-hydropyrimldino may be added.
The processes for the generation of the anions of the aromatlc compounds R5H are known from the literature.
They can be obtained either from RsH by regiospecific deprotonation using strong bases, for exa~ple metal alkyl or aryl compounds, preferably compounds of lithium, for example methyllithium, isomers of butyllithium, phenyl-lithium or mesityllithium, or secondary metal amides, for - 20 2 1 i3 ~ 3 -~
example lithium diisopropylamidQ (LDA) or llthium 2,2,6,6-tetramethylpiperidide (LiTMP), with the optional addition of complexing, chelatlng or otherwise reactlon-promoting amine compounds, for example tetramethylethy-lenediamine (TMEDA), ethylenedlamine, hexamethylphos-phoric triamide (HMPT), or polyamines (DMEU, DMPU, DABCO) (for examples see, inter alia, Tetrahedron 39, (1983), 2009, Organic Reactions 26, (1979), 1, Tetrahedron Letters 29, (1988), 773, and Synthesis 1988, 881 and the literature cited therein), or are accessible by halogen-metal exchange with the corresponding haloheterocycles Rs-Hal, in which Hal preferably represents bromine or iodine, by means of metals, metal al~yls or halo-metal al~yls, for example lithium alkyls or Grignard reagents by processe~ known from the literature.
The cyclization of u com~ound of the general formula V in accordance with process d) can be effected by reaction with an acid, preferably with an inorganic acid, for example sulfuric acid, and in an inert organic solvent such as a halogenated hydrocarbon, preferably dichloromethane, dichloroethane or chloroform. The reaction is preferably carried out at room temperature and, advantageously, in situ.
The hydrogenation of the compounds of the general formula VI can be effected in a known manner in the presencQ of a noble metal catalyst, in particular a catalyst containing metals from subgroup VIII of the Periodic Table, especially containing palladium or platinum, a~ the metals themselves or their oxides or hydroxides on suitable supports, such as activated charcoal, under hydrogen pressures from 1-250 bar and at temperature~ of from 20C to 200C in suitable inert organic solvents, for example methanol, ethanol, iso-propanol, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate or hexane, with the optional addition of acids such as hydrochloric acid or acetic acid.
The oxidation of the thioether substituents R6 in compounds of the general formula I in accordance with process e) can be carried out in a known manner. The - 21 - 21~2'~
oxidizing agents used can be hydrogen peroxide, organlc per-acids, for example peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, their salts, for example magnesium perphthalate or inorganic ealts, for example sodium metaperiodate, ~odium perborate, potassium permanganate or Oxone~. The solvents u~ed are halogenated hydrocarbons such as dichloromethane, chloro-form and dichloroethane, or acetic acid in the case of hydrogen peroxide, or, in the case of metal salts, alcohols of low chain length or water or mixtures of the two. The reaction can also be carried out in a two-phase solvent system with phase-transfer catalysis in accor-dance with conventional literature methods. For the oxidation of thioether substituents R6 to sulfinyl sub-stituents R~, it is per-acids, especially peracetic acid and m-chloroperbenzoic acid, which are preferred: for the oxidation to sulfone substituents R6, it is Oxone~ in methanol/water mixtures at temperatures of between 0C
and the reflux temperature of the mixture, in particular at room temperature. Mixtures of the sulfinyl and the sulfonyl compound may also be obtained, which can be separated by conventional methods such as crystallization or chromatography. In this process, it is also posssible to oxidize compounds of the formula I in which Rs is an N-heteroaryl group to compounds containing R5 as the sub-stituent which carries a corresponding N-oxide group, or to oxidize compound~ of the formula I in which R, and R~
together form a bond to a benzopyran 3,4-epoxide. It may thorefore, if appropriate, be of advantage to undertake the conversion of R, into one of the precursors listed in reaction scheme 1 or 2.
The conversion of N-oxides of N-heteroaryl substituents R5 of the formula I in accordance with process f) to give compounds of the general formula I
having N-heteroaryl substituents Rs~ which are ~ubsti-tuted in the o or p position relative to the N atom by chlorine or cyano, is carried out by methods known from the literature. Those compounds which are used in particular for the introduction of chlorine are chlorides ... ... ........ .

2'~''3~

of phosphorus, preferably phosphorus oxychlorido (Chem.
Pharm. Bull. 31, (1983), 4533; Chem. Pharm. Bull. 36, (1988), 2244). The solvents used may be chlorinated hydrocarbons such a~ dichloromethane, chloroform and 1,2-dichloroethane, or ethers such a~ tetrahydrofuran,dioxane or 1,2-dimethoxyethane, preferably at the boillng temperature of the reaction mixture. The reaction can also be carried out without a solvent, i.e. with an excess of chlorinating agent, at temperatures between 50C and 150C, preferably at approximately 110C, and the mixture of o- and p-chloro compounds which is generally formed can be resolved by chromatography. The preferred compound for the introduction of cyano is trimethylsilyl cyanide (J. Org. Chem. 48 (1983), 1375;
Synthesis 1983, 316; Synthesis 1984, 681: Chem. Pharm.
Bull. 33 (1985), 565; Chem. Pharm. Bull. 35 (1987), 3119), which can also be generated during the reaction in situ from trimethylchlorosilane and sodium cyanide or potassium cyanide, with the addition of a tertiary amine, for example triethylamine, as base. The solvents used are chlorinated hydrocarbons, for example dichloromethane, dichloroethane or chloroform, or dimethylformamide or preferably acetonitrile at reaction temperatures of between 0C and the boiling temperature of the reaction mixture.
The reduction of a benzopyran 3,4-epoxide in accordance with process g) can be carried out using various reducing agents, for example by hydrogenation, which is preferably carried out with the same noble metal catalysts and under similar reaction conditions as already describod for process variant d). Another possibility is reaction with phenyl selenide, which is generated from diphenyl diselenide by reduction in an alcohol of low chain length, for example ethanol, and reacted in situ (Tetrahedron Letters 28 (1987), 4293).
Further suitable reagents are: an excess of alkali metal iodide in a buffered solution containing acetic acid and acetone, preferably at room temperature (Chem. Ber. 109 (1976), 3907); transition metai compounds in low - 23 ~ 2~
oxidation states, preferably samarium(II) lodide ln tetrahydrofuran (J. Org. Chem. Sl (1986), 2596;
Tetrahedron Letters 28 (1987), 4437) and of low selectivity, especially when groups which are capable of being reduced further, for example an N-oxide group, are present in the molecule, or else with complex metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or sodium bi~(2-methoxyethoxy)aluminum hydride.
The compounds of the general formula I in which R3 or R~ is hydroxyl, and which are conse~uently obtain-able by processes g) or c), respectively, can be reacted according to process h), by conversion of the free hydroxyl group, to give further compounds of the formula I, specifically by alkylation to give ethers, or by acylation to give carboxylates, carbonates or carbamates.
Tho methods used for this purpose are standard methods of organic synthesis.
Alkylation can be carried out, for example, by ao using a Cl6-alkyl iodide in an inert solvent such as toluene or dimethylformamide in the presence of a base such as potassium hydroxide or barium oxide.
Esterification can be aarried out by u~ing a Cl~-acyl chloride or acyl anhydride or another activated dorivativo of the relevant alkanoic acid, optionally with the presence of an organic base such as pyridine or triethylamine or of an inorganic base such as potassium carbonato, accompanied optionally by the action of catalycts such as 4-(N,N-dimethylamino)pyridine, or with the Cl~-carboxylic acid with the accompanying action of condensation reagents such as dicyclohexylcarbodiimide in an inert solvent, if desired at elevated temperature.
Reaction to give carbonates is carried out analogously, by reaction with Cl~-alkyl chloroformate~
under the conditions given above.
Reaction to give carbamates is carried out either in analogy to processes described above, by reaction with mono- or dialkylaminocarbamoyl chlorides, or by reaction with C,~-alkyl isocyanates in an inert solvent, for - 24 - 21~9~'~
example toluene, at temperaturee of between 0C and the boiling temperature of the reaction mixture.
Formyloxy can be introduced by reaction with pho~gene and subsequent hydrolysis of the corresponding chloroformate or reaction with formic acid ln pyridine.
Compounds of the general formula I in which Rs is a substituent of subgroup A), i.e. an aryl or N-hetero-aryl group having a hydroxyl group in the 2 position, can be obtained from compounds in which these groups are protected by protective groups which are customary for phenolic hydroxyl groups. Preferred such groups are Cl~-alkoxy groups, particularly preferably methoxy, or formaldehyde acatals, for example methoxymethyl.
The elimination of an ether group is carried out in a manner known per se. The reaction can be effected, for example, using an alkali metal al~anethiolate of low chain length, preferably sodium methanethiolate, expe-diently in an inert organic solvent, for example dimethylformamide, at elevated temperature, for example at about 100C, or el~e using other reagents, for example lithium iodide, a silyl halide or a boron halide.
The elimination of a formaldehyde acetal can be carried out by customary literature methods, for example under acidic reaction conditions, using, in particular, mineral acids such as hydrochloric acid.
The precursors which are suitable for these described hydrolysea are obtainable by the procees variants given above, in particular b), c) and d), particularly preferably c). For the metalation of alkoxy N-heteroaromatic compounds, many examples are ~nown from the literature tcf. discussion of process variant c)).
Ortho metalations of anisole derivative~ (J. Org. Chem.
41 (1976), 3653) and of methoxymethoxybenzene derivatives (Tetrahedron Lett. 22 ~1981), 3923; J. Org. Chem. 47 (1982), 2101 are li~ewise known.
If Rs~ specifically, is an N-heteroaromatic radical having an N atom in the 3 position and a hydroxyl group in the 2 position, then such a compound i~ obtain-able from a compound of the general formula I in which R5 - 25 - 21~2~
is a heteroaromatic N-oxide with tho nitrogen in tho samo position. ~he conversion is carried out uslng a Cl~-carboxylic acid anhydride, preferably acetic anhydrido, with ~ubsequent hydrolysis. It is carried out at elevated temperature, preferably at the boiling temperature of tho reaction mixture. The hydrolysis of the product obtained, namely a compound of the formula I in which R5 denotes an N-heteroaryl group having an N atom in the 3 position and an alkanoyloxy group in the 2 position with the al~anoyl radical of the C1~-carboxyl$c acid anhydride, can be carried out under acidic or basic conditions by known processes. For the acid hydrolysis, aqueous mineral acids are used, for example hydrochloric acid, hydrobromic acid, sulfuric acid or organic acids, for example p-toluenesulfonic acid, expediently in an inert organic solvent, for example dioxane or tetrahydrofuran. The reaction preferably takes place at room temperature. The basic hydrolysis can be carried out using an al~ali metal hydroxide, for example sodium hydroxide, or an al~ali metal Cl~-alkoxide, for example sodium methoxide or sodium ethoxide, preferably in an $nert organic solvent such as methanol or ethanol at room temperature. The synthesis of the abovementioned 2-hydroxy-N-hetero-aromatic compounds from N-oxides of 3-N-heteroaromatic compounds can also be carried out via the 2-halo-3-N-heteroaromatic compounds described by process f), the hydrolysis of which in an acidic or in a basic reaction medium can be carried out li~ewise as described above.
Some substituents of the aromatic and N-hetero-aromatic radicals Rs can be converted into other func-` tional groups by conventional, known processes. Forexample, a nitro group can be rsduced to an ~;no group.
The preferred reducing agent used is iron powder/acetic acid. An amino group can be converted by conventional processes, in a Sandmeyer reaction, to a cyano group, a halogen or a hydroxyl group. Furthermore, a cyano group can be hydrolyzed to give a carboxyl group, which can be converted, for example, using a diazoal~ane into a carboxylic acid ester, preferably with diazomethane to a - 26 - 2 1 ~ 2 ~
methyl carboxylate. Other carboxylic acid derivatives can also be obtained from the cyano group by k~own procos~es.
A halogen atom, preferably a chlorine atom, can be converted in~o a C,~-alkoxy, Cl,-monoalkylamino or C1~-dialkylamino group. ~he exchange can be offected in amanner known per se using an alkali metal alkoxide of the corresponding chain length, for example using sodium methoxide or sodium ethoxide. The reaction is preferably carried out in an inert organic solvent, such as the alcohol corresponding to the alkali metal al~oxide, and preferably at the reflux temperature of the reaction mixture.
The exchange with an alkali metal ~m~ de is carried out in similar manner, but the inert organic solvent used is expodiently an ether, for example tetra-hydrofuran, dioxane or l,2-dimethoxyethane. The alkali metal amides are preferably produced from the correspond-ing amines using al~ali metal al~yls, for example butyl-lithium, in the same solvent, and reacted in situ.
The resolution of diastereomers and cis/trans mixtures can be carried out by conventional methods, for example by chromatography or crystallization.
Compounds of the general formula I which are obtained as racemates, or certain racemic precursors thereof, can be resolved by known methods to give their optical isomer~, for example by recrystallization in optically active solvents, by microorganisms, or by reaction with an optically active acid or base which forms a salt or another compound with the racemic com-pound, separation of the diastereoisomers by fractional crystallization, and liberation of the enantiomers using suitable agents. Examples of particularly suitable optically active acids are the d and 1 forms of tartaric acid, ditolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or pyrrolidonecarboxylic acid.
Suitable optically active bases are alpha-phenylethyl-amine, menthylamine, ephedrine, brucine and quinine.
Preferably, a chiral compound of the general formula I in which R5 is a basic N-heteroaromatic radical - 27 _ 21~29~
is reacted with one of the chiral acid~ llsted above, or a chiral compound of the general formula I which contaln~
a free hydroxyl group, especially if R3 or R~ i8 hydroxyl, is esterified with a chiral acid.
Advantageously, the more active of tho isomers ~
isolated. According to the invention, however, it is also pos~ible to obtain the pure enantiomers by asymmetric synthesis.
Compounds of the general formula I in which Rs is an N-heteroaromatic radical or contains an amino group are basic and can therefore be converted into their acid addition salts. Compounds of the general formula I in which R5 is a phenolic hydroxyl group or contains a carboxyl group aro acidic, and can therefore be converted into their salts.
Physiologically tolerated salts or aaid addition salts are preferred. Examples of suitable such acids are, as regards inorganic acids, sulfuric acid or hydrohalic acids, for example hydrochloric acid, and, as regards ao organic acids, examples are fumaric acid, maleic acid, citric acid and tartaric acid. In the preparation, the alcoholic solution of a suitable acid is added to the hot alcoholic solution of the base, and the salt is obtained after adding ether. Preferred salts are the alkali metal, alkaline earth metal and ammonium salts of compounds of the formula I, which are obtained using the corresponding bases, in particular sodium hydroxide or potassium hydroxide.
The precursors and intermediates which are required for the preparation of compounds of tho general formula I and which, to the extent that they are novel, are a further sub~ect of the present invention, are li~ted in reaction schemes 1 and 2. In every case, the starting compounds are phenols VII in which R6 has the meaning given above. They are known or can be prepared by known processes, for example by reduction of the corres-ponding 4-substituted nitroaromatic compounds, for example using hydrogen with Raney nickel a~ catalyst, or using nascent hydrogen, to give the corresponding 2~ ~7~4 Reaction cchemo 1 R~o ~ VII
2 ~oill 2 Iv ~ ~/VIII

I x 5 5 o a ~0~1 2 tl~

2 ~ ~ ~2 Xt 1~ ~ x~ X' - 2 9 - 2 ~ u ~
React~ on ~cheme 2 ~OH 6~ O~OQ
VII X~tI

~o~ 2 ~o~ 2 XIV XV

~ 3~ $ ~

X~'l X`'t ~

4-substituted anilinen, which are diazotized and boiled to give the said 4-substituted phenols~
In cases where R~ has the meaning difluoromethyl-thio, difluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylthio, trifluoromethyl~ulfinyl, trlfluoro-methylsulfonyl, 2,2,2-trifluoroothylthio, 2,2,2-tr$-fluoroethylsulfinyl and 2,2,2-trifluoroethylsulfonyl, the radicals mentioned can often be introduced more advan-tageously by chemical transformations of intermediates in which R6 has a meaning other than is mentioned above. For example, 2H-benzo[b~pyrans of the general formula VI in which Rc has the meaning difluoromethylsulfonyl, trifluo-romethylsulfonyl and 2,2,2-trifluoroethylsulfonyl, are obtained by reacting the corresponding fluoroalkyl-sulfonyl fluorides with 2H-benzo[b]pyrans of the general formula VI in which R6 has the meaning MgHal, where Hal has the meaning chlorine, iodine and in particular bromine, a~ long as Rs contains no substituents which interfere with this reaction: i.e. R5 is unsubstituted or is substituted, for example, by Cl~-alkyl, phenyl or Cl~-al~oxy. It i~ also po~sible to react the Grignard compounds of the 2H-benzo[b]pyrans described above with disulfides of the general formula R7-S-S-R7, in which R7 has the meaning trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, to give 2~-benzo[b]pyrans in which R~ has the meaning difluoromethylthio, trifluoromethylthio and 2,2,2-trifluoroethylthio.
Starting from intermediates or end products in which R6 contains a sulfur atom, it is also possible, in conventional methods, by reduction and in particular oxidation, to obtain intermediates and end products in which the sulfur atom referred to has a different oxida-tion state. Possible oxidizing agents have already been listed in the description of proce~s variant e). ~or example, 4-difluoromethylsulfonylphenol, 4-trifluoro-methylsulfonylphenolor4-(2,2,2-trifluoroethyl~ulfonyl)-phenol can be obtained more favorably than by known processes by oxidizing the corresponding fluoroal~yl-thiophenol~ with Oxone~ in methanol/water mixtures at temperatures of between -10C and the reflux temperature of the reaction mixture, preferably at temperatures between 0C and 25C.
~pecially in cases where R, has the moaning difluoromethylsulfinyl, trifluoromethylsulfinyl or 2,2,2-trifluoroethylsulfinyl, it is more favorable, ~tarting from the corre~ponding 4-fluoroal~ylthiophenols in accordance with reaction scheme 1, first to prepare the corresponding 6-fluoroal~ylthio-2H-benzo[b~pyrans VI in which Rl, R, and R5 have the meaning given above, and then to carry out the desired oxidation to give the respective 6-fluoroal~ylsulfinyl-2~-benzolb]pyrans of the general formula VI.
In some cases it is possible to introduce Cl,-dialkoxyphosphoryl as the substituents R~ in inter-mediates and end products of the present invention, by reacting corresponding compounds in which R6 is bromine with a Cl~-trialkyl phosphite in the presence of a nickel(II) halide, preferably nic~el(II) chloride, at elevated temperature, preferably at approximately 180C.
Intermediates and end products in which R6 denotes phos-phono can be obtained by conventional methods for the elimination of phosphonic acid esters from the corres-ponding Cl~-dialkoxypho~phoryl compounds. Li~ewise, the converse transformation to give phosphonic acid esters can also be carried out.
Compounds of the general formula YIII can be obtained from the phenols VII by reaction with compounds of the general formula Y-CRlR~-C~CH, in which Y is chlor-ine, bromine or hydroxyl. If Y is chlorine or bromine, ` the reaction is carried out by known methods which havebeen described in many references (e.g. J. Org. Chem. 38 (1973), 3832; J. Org. Chem. 39 (1974), 881; J. Org. Chem.
37 (1972), 841; J. Ned. Chem. 26 (1983), 1582) in an inert organic solvent in the presence of a base. Pre-ferred reaction conditions are, for example, potassium carbonate as base in dimethylformamide at approximately 90C or, preferably, in acetone or butanone under reflux, or sodium hydroxide or potassium hydroxide with a phase-3 ,~J';~

transfer catalyst such as trimethylbenzylamoonium hydroxide in methanol at room temperaturo. If Y i~
hydroxyl, the reaction can be carried out in the pre~ence of a condensation agent, for example diethyl azo-dicarboxylate/triphenylphosphine (see Synthesis 1981, 1)in an inert organ$c solvent, for example dichloromethane.
A compound of the general formula II can be obtained from a compound of the general formula VIII by reacting the latter with a halogenated aromatic or N-heteroaromatic compound R5~al, in which Hal denotes bromine or iodine, preferably iodine. The reaction is carried out in the prese~ce of copper(I) iodide and a palladium compound as catalyst, preferably bis(triphenyl-phosphine)palladium dichloride or diacetate, and a triarylphosphine, preferably triphenylphosphine, in an aliphatic amine of low chain length, preferably in triethylamine or diethylamine, as solvent, at tempera-tures between room temperature and the boiling point of the reaction mixture, preferably at approximately 80C.
It may be advantageous to conduct the reaction in a sealed reaction vessel, i.e. at somewhat greater than atmospheric pressure. Such reactions are known from the literature in large number (e.g. Heterocycles 9 (1978), 271t Synthesis I980, 627: Synthesis 1981, 364: Chem.
Pharm. Bull. 28 (1980), 3488; Synthesis 1983, 313; and J.
Org. Chem. 53 (1988), 386).
The benzo[b]pyran-4-ones of the general formula IV can be prepared by methods known from the literature (Angew. Chem. 94 (1982), 254), preferably by the conden-sation of ~etones or aldehydes of the general formula R~R~C=O with phenols of the general formula VII, which are additionally substituted in the 2 position by an acetyl group, or by hydrolysis of 4-bromobenzo[b~pyrans IX. This reaction is carried out using strong inorganic acids, for example concentrated sulfuric acid, preferably at room temperature, or using heavy metal salts in organic acids, preferably using mercury salts, for example mercury(II) acetate or mercury(II) trifluoroacetate in glacial acetic acid or trlfluoroacetic acid, or else in other inert ,," . ~ , . ,~ -- , .
' _ 33 _ organic solvents, for example acetonitrile, nitromethano or dichloromethane, and t~mperatures between 0C and the reflux temperature of the reaction mixture. ~he ~ddition of a Lewis acid, for example boron trifluorido, may be 5advantageous (Tetrahedron Letters 1978, 1943; ibid. 1979, 3489).
4-Bromobenzo[b]pyrans IX can be obtained by first cyclizing the propargyl ethers of the general formula VIII under the reaction conditions described for proces~
b) to give benzo[b]pyrans which carry hydrogen in posi-tions 3 and 4 and the substituents Rl, R, and Rc, having the meaning given above, in positions 2 and 6, and then adding bromine to the C-C double bond between the C-3 and the C-4 of the benzopyran, preferably in an inert organic solvent such as tetrachloromethane or chloroform at temperatures between 0C and room temperature. ~sing bases, the bromine in the 3 position, exclusively or preferentially, is eliminated from the trans-3,4-dibromo-benzo[b]pyrans which are obtained to give the compounds of the general formula IX. The bases preferably used are alkali metal alkoxides, for example sodium methoxide, sodium ethoxide or potassium tert-butoxide in the corres-ponding alcohol as solvent, tertiary amines, for example triethylamine, diisopropylethylamine or diazabicyclo-undecane (DBU), or alkali metal hydrides, for example sodium hydride, in inert organic solvents such as diethyl ether, tetrahydrouran, 1,2-dimethoxyethane, dichloro-methane and the like. The reaction temperature is prefer-ably room temperature or a slightly elevated temperature.
30Benzo[b~pyran-3,4-epoxides of the general formula XI can be prepared from the benzo[b~pyrans VI by oxida-tion in accordance with known proce~ses. If R5 is an N-heteroaromatic radical and/or R~ is difluoromethylthio, difluoromethylsulfinyl, trifluoromethylthio, trifluoro-methylsulfinyl, trifluoroethylthio or trifluoroethyl-sulfinyl, a possible secondary reaction is for oxidation to take place additionally at the nitrogen or at the sulfur. Reagents which can be used are per-acids, for example peracetic acid, perbenzoic acid, perphthalic acid or m-chloroperbenzoic acid in inert anhydrou~ organic solvents such as dichloromethane, chloroform, dichloro-ethane, diethyl ether, tetrahydrofuran or acetonitrlle, or magnesium perphthalate in an alcohol of low chaln length with or without the additlon of water or hydrogen peroxide in the presence of a tungstate, preferably sodium tungstate, in the same solvent at temperatures between room temperature and the reflux temperature of the reaction mixture.
The synthesis route to compounds of the general formula V by cyclization according to process d) is represented in reaction scheme 2. Phenols of the general formula VII are reacted with a-halocarboxylic acid esters HalRlR2CCOOR~, in which halogen preferably ropresents bromine or chlorine, and R, represents an alkyl radical of low chain length, preferably methyl or ethyl, by known processes to givo compounds of the general formula XIII.
The base used in this reaction is an alkali metal alkoxide of the alcohol R~OH in this latter compound as solvent, an alkali metal hydride, for example sodium hydride, in an ether, for example tetrahydrofuran, or in dimethylformamide, or an alkali metal carbonate, for example potassium carbonate in acetone or butanone as solvent. The reaction is carried out at temperatures between 0C and the boiling temperature of the reaction mixture, preferably at room temperature.
The reaction of the compounds of the general formula XIII to give the ketones of the general formula XIV is carried out with anions of methyl heterocycles MeR5 in which R, i~ preferably an N-heterocycle having an N atom or an N-oxide group in the 2 position, for example 4-methylpyrimidine or 2-picoline N-oxide. The anions are produced from the heterocycles MeR5 with strong bases, for example with alkali metal dialkylamides of low chain length, for example lithium diisopropylamide, or with alkali metal al~yls ~uch as butyllithium, in inert organic solvents such as diethyl ether or tetrahydro-furan. The reaction is preferably carried out in the same solvent at temperatures of between -78C and the reflux _ 35 i~

temperature of the reaction mixture, preferably at reduced temperature with subse~uent heating to room temperature.
The reduction of the ketones XIV to give the alcohols of the general formula XV can be carrlod out ln a known manner, preferably uslng complex hydrldes, for example sodium borohydride, in an alcohol such as methanol or ethanol, or using lithium aluminum hydride in diethyl ether or tetrahydrofuran as solvent, preferably at room temperature. If it is desired to convert an N-heterocycle Rs into its N-oxide, this is preferably carried out at this stage of the synthesis seguence by methods and under reaction conditions which have been described under process a).
The conversion of the alcohols XV into compounds of the general formula XVI in which Rg is a leaving group is carried out by known processes. Rg is preferably iodine, an alkanesulfonate, e.g. methanesulfonate, or an arylsulfonate, e.g. phenylsulfonate or p-tolylsulfonate.
The sulfonates are obtained with the corresponding sulfonyl chlorides in the presence of an acid-binding agent, for example a tertiary am~ne such as trlethyl-amine, diisopropylethylamine or pyridine, which can also be used as the solvent. The reaction is otherwise carried out in a conventional inert organic solvent, preferably at room temperature. Compounds of the general formula XVI
in which Rg is iodine can be obtained from the above-described sulfonatee of the general formula XVI by known processes using an alkali metal iodide, for example sodium iodide. The reaction is carried out in an inert organic solvent, preferably acetone or butanone, at elevated temperature, preferably at the reflux tempera-ture of the reaction mixture.
The compounds of the general formula XVI are converted into compounds of the general formula V, passing through the stage of the olefins XVII. These can be isolated if the elimination of HRg is carried out at room temperature or ~lightly elevated temperature. The reaction employs strong bases, for example sodium r.~ ~ vi L,~L
~ 36 ~
hydride, sodium methoxide, sodium ethoxido, potassium tert-butoxide or tertiary amine~ ~uch as dlisopropyl-ethylamine, triethylamine or diazabicycloundecane (DB~
in inert organic solvents such as tetrahydrofuran, diethyl ether, methanol, ethanol and tho like. The reaction of the compounds XVII is then carried out by heating in high-boiling aromatic hydrocarbons ~uch as chlorobanzene or 1,2-dichlorobenzene. The direct conver-sion of compounds XVI into compounds of the formula V is preferably carried out at the reflux temperature of the above reaction mixture using tertiary amines as the base.
Compounds of the formula XVII can also be obtained, as by-products from the alcohols XV, as early as during the preparation of the compounds of the general formula XVI.
The compounds of the formula I according to the invention, their physiologically tolerated salts and acid addition salts and their tautomeric and optical isomers are therapeutic active substances; they possess a high pharmacological activity and are valuable pharma-ceutical~. In particular, they exhibit vasodilatory, vasospasmolytic and, especially, broncholytic activity, the vasospasmolytic activity being expressed tbroughout the vascular system or else, in a more or less isolated mannor, in defined vascular regions such as the cerebral, coronary or peripheral vessels.
The compound~ according to the invention have, in particular, a hypotensive activity, and can therefore be used as antihypertensives.
Tho substances according to the invention are notable for a considerable reduction in the arterial blood pressure. Oral doses of from 0.01 - 10 mg/kg led to a reduction in the blood pressure of hypertensive rats by at least 20 %.
The substances according to the invention are notable for their particular influence on the flow of potassium ions in the cells. They are, in particular, potassium-channel activators. They are suitable for the prophylaxi~ and for the treatment of the following diseases in warm-blooded animals, e~pecially in humans:

~ 3i~

1. high blood pressure, especially high artorlal blood pressure, 2. cardiac insufficiency, coronary insufflciency and angina pectoris, 3. occlusive arterial disease and peripheral circùl-atory disorders, 4. cerebral insufficiency, migraine, vertigo, diseases of the inner ear and of the auditory system, 5. increased intraocular tension, glaucoma, weak-sightedness, 6. renal insufficiency, organic diseases of the urinarytract and of the accessory glands of the urinary tract, impaired potency, 7. organic diseases of the gastrointestinal tract and of the pancreas and liver, 8. deficient circulation in the scalp, hair 1088, 9. disoases of tho respiratory tract, including bronchial asthma, 10. metabolic disease~, 11. spasmogenic diseases of the uterus, and 12. incontinenco.

Furthermore, the compounds according to the invention promote circulation in the scalp and promote hair growth. They also have an inhibitory action on uterine contractions.
The compounds according to the invention exhibit a long period of action with only a low toxicity. They ~ ~ ~ " ~ ~ ~ L~

are therefore particularly euitable for the treatment of acute and chronic heart diseaee, for the therapy of high blood pressure and cardiac in~ufficiency, and for the treatment of asthma and of cerebral and peripheral circulatory disorders.
The compounds of the present invention can be administered to humans orally or parenterally in a dose of from 0.001 to 100 mg, preferably from 0.01 to 50 mg and particularly preferably from O.OS to 10 mg per day, and, in particular, in subdivided doses, for example from two to four times daily. These dosages are advantageous for the treatment of the abovementioned diseases, in particular heart disease, hypertension, asthma and circulatory disorders.
In general it has proven advantageous, in the case of intravenous human application to administer amounts of from approximately 0.001 to 10 mg, preferably from approximately 0.05 to 5 mg per day in order to achieve e~fective results. In the case of oral adminis-ao tration to humans, the dosage is from approximately O.OS
to 30 mg, preferably from 0.1 to 10 mg per day.
The dosages stated above are particularly preferred for the treatment of hypertension.
In spite of thie, it may be necessary to depart from the stated quantities, specifically in dependence on body weight and/or on the nature of administration, but also on account of the individual response to the medica-ment and/or of the nature of its formulation and the time, or time interval, at which administration i8 made.
For example, it may in some instancee be sufficient to employ lese than the abovementioned minimum amount, whereas in other cases the upper limit mentioned may be exceeded. In the case where greater quantities are administered, it may be advisable to divide these into a number of individual doeee over the day.
The invention also relates to the compounde according to the invention for treating the above-mentioned diseases, and to methods for the treatment of these dieeaees in which these compounde are ueed, and to - 39 _ '~ ?J~ ~L~
their use in processes for the preparation of compo~i-tions which comprise these compounds, for the treatment of said diseases, and to processes for the proparation of the compounds.
In accordance with the inventlon, pharmaceut~cal preparations or compositions are provided which compr~se a compound according to the invention or a pharma-ceutically acceptable salt or acid addition salt thereof, together if desired with a pharmaceutically acceptable diluent or excipient.
The compounds according to the invention can be mixed with conventional pharmaceutically acceptable diluents or excipients and, if desired, with other auxiliaries and can be administered, for example, orally or parenterally. They can be administered, preferably orally, in the form of granules, capsules, pills, tablets, coated tablets - including film-coated tablets -syrups, emulsions, suspensions, dispersions, aerosols and solutions, and as liquids, or parenterally in the form of ao solutions, emulsions or suspensions. Preparations for oral administration may contain one or more additives such as sweeteners, flavors, colorants and preservatives.
Tablets may contain the active substance mixed with conventional pharmaceutically acceptable auxiliaries, for example inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating agents and agents which promote the decomposition of the tablets on oral administration, such as starch or alginic acid, binders such as starch or gelatine, and lubricants such as magnesium stearate, stearic acid and talc. Examples of suitable excipients are lactose, gelatine, corn starch, stearic acid, ethanol, propylene glycol, ethers of tetrahydrofurfuryl alcohol and water.
Examples of auxiliaries which may be listed are:
water, nontoxic organic solvents such as paraffins (e.g.
petrolaum fractions), vegetable oils (e.g. groundnut/
sesame oil), alcohols (e.g. ethyl alcohol, glycerol), glycols (e.g. propylene glycol, polyethylene glycol), solid excipients such as natural ground minerals (e.g.

- 40 - ~ J ~
~aolins, clays, talc, chalk) and synthetic ground minerals (e.g. highly disperse silica, silicates), sugar~
(e.g. cane sugar, lactose and dextrose), emulsifier~
(e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, al~ylsulfonates and aryl-sulfonates), dispersants ~e.g. lignin-sulflte wasto liquors, methylcellulose, starch and polyvinyl-pyrrolidone), and lubricants ~e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
The formulations are prepared, for example, by extending the active substances with solvents and/or exc~pients, using if desired emulsifiers and/or disper-sants; in the case, for example, where water is used as a diluent, organic solvents may if desired be used as auxiliary solvents.
Administration is carried out in a conventional manner, preferably orally or parenterally, and in particular perlingually or intravenously. In the case of oral administration, tablets may also of course contain, in addition to the excipients mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. It is also possible to use in addition lubricants such as magnesium stearate, sodium lauryl sulfate and talc for tableting. In the case of aqueous suspensions and/or elixirs which are meant for oral administration, the active substances can be mixed not only with the abovementioned auxiliaries but with various taste improvers or colorants.
In the case of parenteral administration, solu-tions of the active substances may be employed with the use of suitable liquid carrier materials.
Using ~nown procedures, the tablets can be coated in order to delay their decomposition and absorption in the gastrointestinal tract, whereby the activity of the active substance may extend over a prolonged time period.
Likewise, the suspension may contain the active substance mixed with auxiliaries which are conventional for the , - 41 ^
preparation of such compositions, for example ~usponding agents such as methylcellulose, tragacanth or ~odlum alginate, wetting agents such a~ lecithin, polyoxyethyl-ene stearate and polyoxyethylenesorbltan monooleate and preservatives such as ethyl parahydroxybenzoate. Capsulss can contain the active substance as the ~ole component or mixed with a solid diluent such as calcium carbonate, calcium phosphate or kaolin. The injectable preparations are likewise formulated in a manner ~nown per se.
The pharmaceutical preparations may contain the active substance in an amount of from 0.1 to 90 percent by weight, in particular from 1 to 90 percent by weight, i.e. in quantities which are sufficient to achieve the stated scope of dosage, the remaining percentage compris-ing excipient or additive. With regard to the preparation and administration, solid preparations such as tablets and capsules are preferred. The preparations preferably contain the active substance in an amount of from 0.05 to 10 mg.
The invention also relates to a process for the preparation of pharmaceutical preparations, which comprises mixing one or more compounds as claimed in claim 1 or their physiologically tolerated salts and, if desired, conventional excipients and/or diluents.
The examples which follow are intended to eluci-dato the invention:

Example 1 2,2-Dimethyl-6-trifluoromethylthio-4-(2'-pyridyl)-2H-benzolb]pyran l'-oxide 1.5 g (4.4 mmol) of 2,2-dimethyl-6-trifluoromethylthio-4-(2'-pyridyl)-2H-benzolb~pyran and 1.4 g (2.4 mmol) of 85%
magnesium monoperoxyphthalate hexahydrate are dissolved in a mixture of 10 ml of ethanol and 5 ml of water and stirred for 1 h at 80C. The solution is cooled, diluted with water and extracted twice with ether, and the combined organic pha~es are dried over magnesium sulfate and concentrated. Chromatography on silica gel using ' ' ',~ , ' 21~2~

dichloromethane/ethanol, 98:2, gave 100 mg (6.4~) of tho pyridine N-oxide, m.p. 144-145C.

ExamDle 2 2,2-Dimethyl-6-trifluoromethoxy-4-(2'-pyridyl)-2~-benzo-lb]pyran 1'-oxide From 2.0 g (6.2 mmol) of 2,2-dimethyl-6-tri-fluoromethoxy-4-(2'-pyridyl)-2H-benzo[blpyran, by a procedure analogous to that de~cribed in Example 1, 200 mg (9.6%) of the pyridine N-oxide, m.p. 168-170C, were obtained.

ExamDle 3 a, a -Dimethyl-6-difluoromethoxy-4-(2'-pyridyl)-2~-benzo-tb]pyran 1'-oxido 1.9 g (6.3 mmol) of 2,2-dimethyl-6-difluorometh-oxy-4-(2'-pyridyl)-2H-benzolb]pyran and 1.9 g (3.2 mmol) of 85% strength magnesium monoperoxyphthalate hexahydrate are dissolved in 10 ml of glacial acetic acid and heated at 80C for 1 h. Tho solution is cooled, neutralized with sodium hydrogen carbonate solution and extracted with dichloromethane, and the organic phase i~ dried over magnesium sulfate and concentrated. After chromatography on silica gol using dichloromethane/ethanol, 98:2, 330 mg (16%) of the pyridine N-oxide, m.p. 147-148C (from ethyl acetate/petroleum ether) are obtained.

a s Example 4 2,2-Dimethyl-6-trifluoromethyl~ulfonyl-4-(2'-pyridyl)-2H-benzolb]pyran l'-oxide From 350 mg (0.95 mmol) of 2,2-dimethyl-6-tri-fluoromethylsulfonyl-4-(2'-pyridyl)-2H-benzo[b]pyran l'-oxide, by a procedure as described in Example 3, 100 mg (27~) of the pyridine N-oxide were obtained as colorless crystals, m.p. 174-179C.

Example 5 2,2-Dimethyl-6-trifluoromethoxy-4-(3'-pyridyl)-2H-benzo-lblpyran l'-oxide 7.0 g (21.8 mmol) of 2,2-dimethyl-6-trlfluoro-methoxy-4-(3'-pyridyl)-2H-benzo[b~pyran and 7 7 g (13.2 mmol) of 85% magnesium monoperoxyphthalate hexa-hydrate are diseolved in a mixture of 100 ml of water and 30 ml of glacial acetic acid and stirred at room tempera-ture for 2 h. The solution is diluted with ether and extracted with 2 N eodium hydroxide eolution, and the organic phase is dried over magnesium sulfate and concen-trated. After chromatography on silica gel using dichloromethane/ethanol, 95:5, 4.8 g (65%) of the pyri-dine N-oxide are obtained as an oil.

Exam~le 6 2,2-Dimethyl-6-trifluoromethylsulfonyl-4-(2'-quinolyl)-28-benzo~b]pyran l'-oxide From 750 mg (1.8 mmol) of 2,2-dimethyl-6-tri-fluoromethylsulfonyl-4-(2'-quinolyl)-2H-benzo[b]pyran by a procedure analogous to that of Example 3, 110 mg (14~) of the quinoline N-oxide (colorless crystals, m.p. 138-140C) were obtained.

Exam~le 7 2,2-Dimethyl-6-trifluoromethoxy-4-(3'-pyridyl)-2H-benzo-~b]pyran 3.0 g (9.3 mmol) of 1-(3'-pyridyl)-3-methyl-3-(4'-trifluoromothoxyphenoxy)butyne are dissolved in 20 ml of 1,2-dichlorobenzene and heated at 175C for 4 h. After dilution with ether, the solution i8 washed with water and the organic phase is dried over magnesium sulfate and concentrated. After chromatography on silica gel using chloroform as eluent, the benzopyran is isolated as an o~l. Yield: 2.1 g (70~).

Example 8 2,2-Dimethyl-6-trifluoromethylthio-4-(3'-pyridyl)-2H-benzo~b]pyran From 800 mg (2.4 mmol) of 1-(3'-pyridyl)-3-methyl-3-(4'-trifluoromethylthiophenoxy)butyne, by a procedure ae described in the preceding examplé, 250 mg (31%) of the benzo[b]pyran are obtained as an oil.

Example 9 2,2-Dimethyl-6-trifluoromethylsulfonyl-4-(3'-pyrldyl)-2~-benzo[b~pyran In analogy to Example 7, from 2.7 g (7.3 mmol) of 1-(3'-pyridyl)-3-methyl-3-(4'-trifluoromethylsulfonyl-phenoxy)butyne, 1.14 g (42%) of the benzopyran were obtained as colorless crystals, m.p. 121-122C (ethyl acetate/petroleum ether).

Exam~le 10 2,2-Dimethyl-6-diethoxyphosphoryl-4-(3'-pyridyl)-2H-benzo[b]pyran In analogy to Example 7, from 600 mg (1.61 mmol) of 3-mQthyl-1-(3'-pyridyl)-3-(4'-diethoxyphosphoryl-phenoxy)butyne after chromatography on silica gel usingdichloromethane/ethanol, 95:5, 360 mg (60~) of the benzopyran are obtained as an oil.

Exam~le ll 2,2-Dimethyl-6-trifluoromethylsulfonyl-4-(4'-pyridyl)-2H-benzolb~pyran By a procedure analogous to that described inExample 7, from 2.7 g (7.3 mmol) of 1-(4'-pyridyl)-3-methyl-3-(4'-trifluoromethylsulfonylphenoxy)butyne, 110 mg (4~) of the substance were obtained as colorless crystal~, m.p. 91-93C.

Example 12 2,2-Dimethyl-6-trifluoromethoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzolb]pyran l'-oxide a) 700 mg (2.2 mmol) of 2,2-dimethyl-6-trifluorometh-oxy-4-(2'-pyridyl)-2H-benzolb]pyran are dissolved in a mixture of 10 ml of ethanol and 1 ml of glacial acetic acid, 100 mg of 10% palladium on activated charcoal are added, and the mixture is hydrogenated overnight in an autoclave at 50C and 50 bar. After filtering off the catalyst, the mixture is concentrated and the re~idue is ... ..

taken up in dichloromethane and extracted by ~ha~lng wlth saturated sodium hydrogen carbonate ~olution. The organlc phase is dried over magnesium sulfate and concentrated ln vacuo. 500 mg of crude 2,2-dimethyl-6-trifluoromothoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzotb~pyran are obtalned, which i8 employed further for the oxidation.

b) The crude 3,4-dihydro-2H-benzo[b~pyran 18 dissolved in 12 ml of dichloromethane, 350 mg (1.7 mmol) of 85%
strength m-chloroperbenzoic acid are added, and the mixture is stirred overnight. After extraction by sha~ing with saturated sodium hydrogen carbonate solution, the organic pha~e is dried over magnesium sulfate and concen-trated. After chromatography on silica gel using dichloromethane/ethanol, 95:5, 275 mg (37% based on both reaction steps) of the pyridine N-oxide are obtained as an oil.

ExamDle 13 2,2-Dimethyl-6-trifluoromethoxy-4-(2'-cyano-3'-pyridyl)-2H-benzo[b~pyran 1.5 g (4.4 mmol) of 2,2-dimethyl-6-trifluorometh-oxy-4-(3'-pyridyl)-2H-benzo[b~pyran l'-oxide are dissolved in 10 ml of acetonitrile, 900 mg (8.9 mmol) of triethylamine and 1.34 g (13.5 mmol) of trimethylsilyl cyanide are added, and the mixture is boiled at reflux overnight. ~he mixture is concentrated in vacuo, the residue is taken up in chloroform and extracted by sha~ing with water, and the organic phase is dried over magnesium sul$ate. Chromatography on silica gel using dichloromethane/ethanol, 98:2, gives 320 mg (21~) of the substance as colorles~ crystals (m.p. 88-90C).

Example 14 2,2-Dimethyl-6-trifluoromethoxy-4-(4'-cyano-3'-pyridyl)-2H-benzo[b]pyran 120 mg (7.8%) of the nitrile are obtained from the batch described above, after chromatography, a~
colorless crystals (m.p. 126-127C, ethyl acetate/

- 46 - ~ & ~ ~t~3 petroleum ether).

Example 15 2,2-Dimethyl-6-trifluoromethoxy-4-(4'-chloro-3'-pyrldyl)-2H-benzo[b]pyran 1.5 g (4.4 mmol) of 2,2-dimethyl-6-trifluoro-methoxy-4-(3'-pyridyl)-2H-benzo[blpyran l'-oxide in 7.5 ml of phosphorus oxychloride are heated at 110C for 2 h. The mixture is cooled and concentrated in vacuo, the re~idue is taken up in chloroform and extracted by ~haking with sodium hydrogen carbonate solution, and the organic phase is dried over magnesium sulfate and concen-trated. After chromatography on silica gel using dichloromethane, 400 mg (25%) of the substance are isolatQd as an oil.

Exam~le 16 2,2~Dimethyl-6-trifluoromethoxy-4-(2'-chloro-3'-pyridyl)-2H-benzolb~pyran 140 mg (9~) of the substance are obtained from the reaction mixture described above, after chromato-ao graphy, as an oil.

Example 17 2,2-Dlmethyl-6-trifluoromethylsulfonyl-trans-3,4-dihydro-3-hydroxy-4-(2'-pyridyl)-2H-benzolblpyran l'-oxide a) 600 mg (1.6 mmol) of 2,2-dimethyl-6-trifluoromethyl-sulfonyl-4-(2'-pyridyl)-2H-benzo[b]pyran and 1.3 g (6.4 mmol) of m-chloroporbenzoic acid are dissolved in 10 ml of dichloromethane and stirred at room temperature for 60 h. The product is extracted by sha~ing with saturated sodium hydrogen carbonate solution, the organic phase is dried over magnesium sulfate, concentrated, and chromatographed on silica gel using dichloromethane/
sthanol, 98:2, and in this procedure 500 mg (77%) of 2,2-dimethyl-6-trifluoromethylsulfonyl-3,4-epoxy-4-(2~-pyridyl)-3,4-dihydro-2H-benzolblpyran l'-oxide are isolated as an oil.

- 47 _ b) Under an argon atmosphere, 530 mg (1.7 mmol) of diphenyl diselenide are dissolved in 6 ml of ethanol~
130 mg (3.4 mmol) of sodium borohydride are added, whereupon foaming occurs, and the mixture is stlrred for a further 10 min. After neutralization of this solution using glacial acetic acid, a solution of 500 mg (1.25 mmol) of the above-described epoxide in 4 ml of ethanol is added, and the mixture is boiled at reflux for 8 h. The mixture is cooled, diluted with water and extracted twice with ethyl acetate, the organic phase i8 washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated, and then chromatographed on silica gel using dichloromethane/
ethanol, 98:2, with a rising ethanol content, affording 100 mg of the title substance.

Exam~le 18 2,2-Dimethyl-6-trifluoromethoxy-4-(4'-pyridyl)-3,4-dihydro-2H-benzo[b]pyran 3'-oxide a) 26.7 g (150 mmol) of 4-trifluoromethoxyphenyl and 38.0 g (195 mmol) of ethyl 2-bromo-2-methylpropionate are dissolved in 300 ml of butanone, 30.4 g (0.22 mol) of potassium carbonate and 1 g of potassium iodide are added, and the mixture is boiled at reflux for 26 h.
After the addition of a further 13.1 g (67 mmol) of the ester and 10 g (72 mmol) of potassium carbonate the mixture is heated for a further 17 h and is cooled; the inorganic salts are filtered off, the filtrate is concen-trated, and the residue is chromatographed on silica gel using dichloromethane. 31.1 g (71%) of ethyl 2-methyl-2-(4'-trifluoromethoxyphenoxy)propionate are isolated as an oil by this procedure.

b) 10.1 ml of diisopropylamine are dis~olved in 300 ml of absolute tetrahydrofuran; the solution is cooled to -78C, 45 ml (72 mmol) of a 1.6 M solution of 3S butyllithium in hexane are added dropwise under an argon atmosphere, and the mixture is stirred for 15 min.
Subsequently, a solution of 5.64 g (60 mmol~ of 4-methylpyrimidine in 120 ml of TH~ is added dropwlso, the mixture is heated to room temperature and stirrod for 2 h at this temperature before being cooled agaln to -78C, and 17.5 g (60 mmol) of the above-descrlbed estor in 180 ml of THF are added dropwise. The mixture i~ heated overnight to room temperature, water is added, the mixture is extracted with ethyl acetate, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
Chromatography of the residue on silica gel using ether gives 9.8 g (48%) of 3-methyl-1-(4'-pyrimidinyl)-3-(4~-trifluoromethoxyphenoxy)-2-butanone as an oil.

c) 9.8 g (28.8 mmol) of the above-doscribed ~etone are dissolved in 250 ml of ethanol, 1.1 g (29.1 mmol) of sodium borohydride are added, and the mixture is stirred at room temperature overnight. The solvent is removed by distillation, saturated sodium chloride solution is added, the mixture is extracted with ethyl acetate, the organ$c phaso is dried over magnesium sulfate and concen-trated, and the residue is chromatographed on silica gel using dichloromethane/ethanol, 98:2. Yield: 8.2 g (83%) of 3-methyl-1-(4'-pyrimidinyl)-3-(4'-trifluorometh-oxyphenoxy)-2-butanol.

d) 8.2 g (24.0 mmol) of the alcohol described in the aforogoing proceduro and 8.0 g (39.4 mmol) of 85%
strength m-chloroperbenzoic acid are dissolved in 150 ml of dichloromethane, and the solution is stirred at room temperature for 24 h. The reaction mixture is washed thoroughly with saturated sodium hydrogen carbonate solution and twico with sodium chloride solution, and the organic phase is dried over magnesium sulfate, concen-trated, and chromatographed on silica gel using dichloro-methane/ethanol, 96:4.
Yield: 4.3 g (50%) of 4-(3'-methyl-3'-(4n-trifluorometh-oxyphenoxy)-2'-hydroxy)butylpyrimidine 3-oxide.

``` 21~2~

e) 4.2 g (11.7 mmol) of the above-de~cr~bod alcohol are dissolved in 20 ml of dry triethylamlne, 2.6 g (23.3 mmol) of methanesulfonyl chloride are addod, and the mixture is heated at 60C for 30 min. The mlxture 1~
cooled, water is added, and after extractlon with dichloromethane the organlc phase is dr$ed over magneslum sulfate, concentrated and chromatographed on sllica ge~1 using chloroform.
Yield: 300 mg (7.5%) of 3-methyl-3-(4'-trifluoromethoxy-phenoxy)-1-(4n-pyrimidinyl)-trans-1-butene 3~-oxide.

f) 300 mg (0.88 mmol) of the trans-butene from the above-described reaction step in 30 ml of toluene are heated at reflux for 28 h. The solvent is removed by distillation in vacuo, and the residue is chromatographed on silica gel using chloroform.
Yield: 100 mg (33%) of 1-(4'-pyrimidinyl)-1-(2n-hydroxy-5n-trifluoromethoxyphenyl)-3-methyl-2-butene 3'-oxide.

g) 100 mg (0.29 mmol) of the phenol from the preceding reaction step are dissolved in 10 ml of chloroform, 6 drops of concentrated sulfuric acid are added, and the mixture is heated at 50C for 40 h. It is cooled and extracted by shaking with sodium carbonate solution, and tho extract is dried over magnesium sulfate and chromato-graphed on silica gel using chloroform, affording 45 mg (45%) of the title benzo[b~pyran as an oil.

ExamDle 19 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-methoxy-4-(2'-`pyridyl)-3,4-dlhydro-2H-benzolb]pyran 1'-oxide a) 1.1 g (7.0 mmol) of 2-bromopyridine are dissolved in 20 ml of dry tetrahydrofuran under an argon atmosphere and cooled to -78C, and 4.4 ml (7.0 mmol) of a 1.6 molar solution of butyllithium in hexane are added over 20 min.
After 30 min, the mixture is heated to -60C, a solution of 2.2 g (8.0 mmol) of 6-trifluoromethylthio-2,2-dimethyl-3,4-dihydro-2H-benzolb~pyran-4-one in 10 ml of T~F is in~ected rapidly, and the mixture is stirred at so - -this temperature for 2 h, cooled to -78C and heated to room temperature overnight. Saturated ammonlum chlor~do solution is added, the mixture i8 extracted wlth ether, and the organic phase is dried over mngnesium sulfate and concentrated. After chromatography on silica gel uslng dichloromethane, 330 mg ~13%) of 6-trifluoromethylthio-2,2-dimethyl-4-(2'-pyridyl)-3,4-dihydro-2~-benzotb]pyran-4-ol are obtained.

b) 300 mg (0.84 mmol) of the above-described alcohol are dissolved in 10 ml of dry tetrahydrofuran under an argon atmosphere, 30 mg (1.0 mmol) of 80% sodium hydride are added, and the mixture i8 stirred at room temperature for 40 min. After the addit~on of 240 mg (1.7 mmol) of iodomethane, the mixture is stirred for a further 2 h and wor~ed up as in a).
Yield: 300 mg (96%) of 6-trifluoromethylthio-2,2-dime-thyl-4-methoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzotb]-pyran.

c) 300 mg (0.81 mmol) of the above-described ether are stirred overnight with 200 mg (1.0 mmol) of 85% strength m-chloroperbenzoic acid in 10 ml of dichloromethane, then the same quantity of the oxidizing agent is again added, and the mixture is stirred for a further 24 h. Saturated sodium hydrogen carbonate solution iB added, the mixture is extracted by shaking with dichloromethane, the organic phase ie dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel using dichloromothane/ethanol, 98:2.
Yield: 130 mg (38%) of the title sulfone as colorless crystals, m.p. 157-158C.

Exam~le 20 6-Trifluoromethylsulfinyl-2,2-dimethyl-4-methoxy-4-(2'-pyridyl)-3,4-dihydro-2H-benzotb]pyran 1'-oxide In the oxidation described in the preceding example, 90 mg (28%) of the sulfoxide are obtained as colorless crystals, m.p. 62-64C.

Example 21 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-methoxy-3'-pyridyl)-3,4-dihydro-2H-benzotb]pyran-4-ol 1.2 g (5.1 mmol) of 3-iodo-2-methoxypyridino are dissolved under an argon atmocphere in 15 ml of dry tetrahydrofuran and cooled to -90C, 3.1 ml (5.0 mmol) of a 1.6 molar solution of butyllithium in hexane are added dropwise, and the mixture is stirred at this temperature for 2.5 h. The mixture is warmed to -50C, 1,5 g (5.4 mmol) of 6-trifluoromethylthio-2,2-dimethyl-3,4-dihydro-2H-benzo[b~pyran-4-one in 10 ml of THF are rapidly added dropwise, the mixture ie again cooled to -80C, and is heated to -40C over a period of 2 h.
Working up i8 carried out as in reaction a) of Example 19, and by this procedure 400 mg (20%) of the substance are isolated as an oil.

Exam~le 22 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-methoxy-3'-pyridyl)-2H-benzolb~pyran 400 mg (1.0 mmol) of the above-described alcohol are boiled with 490 mg (2.6 mmol) of p-toluene~ulfonic acid monohydrate in 15 ml of toluene in a water separator for 3 h. The mixture is cooled and worked up as in reaction c) of Example 19, and chromatography is carried as out using dichloromethane.
Yield: 270 mg (71%) of colorless needles, m.p. approxi-matoly 25C.
The precursors needed for the example~ listed above are prepared as follows:
Examplos 1'-6' were obtained by a procedure analogous to that described in Example 7, and in some cases were reacted further without intensive purification operations.

Example 1' 2,2-Dimethyl-6-trifluoromethylthio-4-(2'-pyridyl)-2H-benzolb]pyran 1.8 g (50%) of semi-crystalline substance from - 52 ~ 2~ ~2~ ~4 3.6 g (10.7 mmol) of 1-(2'-pyridyl)-3-mothyl-3-(4'-trifluoromethylthiophenoxy)-butyne.

ExamPle 2' 2,2-Dimethyl-6-trifluoromethoxy-4-(2'-pyridyl)-2H-benzo-lb]pyran 2.0 g (69%) of crystals, m.p. 57-59C, from 2.9 g (9.0 mmol) of 1-(2'-pyridyl)-3-methyl-3-(4'-trifluoro-methoxyphenoxy)butyne.

Example 3' 2,2-Dimethyl-6-trifluoromethylsulfonyl-4-(2'-pyridyl)-2H-benzo[b]pyran 350 mg (17%) of an oil from 2.0 g (5.4 mmol) of 1-(2'-pyridyl-3-methyl-3-(4'-trifluoromethylsulfonyl-phenoxy)butyne.

Exam~le 4' 2,2-Dimethyl-6-difluoromethoxy-4-(2'-pyridyl)-2H-benzo-lb]pyran 1.9 g (46%) of an oil from 4.1 g (13.5 mmol) of 1-(2'-pyridyl)-3-methyl-3-(4'-difluoromethoxyphenoxy)-butyne.

Example 5' 2,2-Dimethyl-6-trifluoromethylsulfonyl-4-(2'-quinolyl)-2H-benzotb]pyran After chromatography on silica gel using dichloromethane, 700 mg (19%) of crystals, m.p. 140-142C
(from ether/petroleum ether) were obtained, in addition to 600 mg (16%) of 2-isopropyl-3-(2'-guinolyl)-5-tri-fluoromethylsulfonylbenzofuran, m.p. 133-134C
(ether/petroleum ether), from 3.7 g (8.8 mmol) of 1-(2'-quinolyl)-3-methyl-3-(4'-trifluoromethylsulfonylphenoxy)-butyne.

ExamDle 6' 1-(2'-Pyridyl)-3-methyl-3-(4'-trifluoromethylthio-phenoxy)butyne 3.9 g (15 mmol) of 3-methyl-3-(4'-trlfluoro-methylthiophenoxy)butyne and 3.1 g (15 mmol) of 2-iodo-pyridine are dis~olved in 30 ml of triethylamine, 240 mg of bis~triphenylphosphine)pallad~um dichlorlde and 140 mg of copper(I) iodide are added, and the mixture 1~ stirred at 80C for 2.5 h in a screw-top test-tube. The mlxture is cooled, diluted with ether and extracted by shaking with water, and the organic phase is washed a number of times with dilute hydrochloric acid and dried over magnesium sulfate. After chromatography on silica gel using dichloromethane/ethanol, 98:2, 3.6 g (71~) of the propargyl ether are isolated as an oil.

Example 7' 1-(2'-Pyridyl)-3-methyl-3-(4'-trifluoromethoxyphenoxy)-butyno 7.4 g (30 mmol) of 3-methyl-3-(4'-trifluorometh-oxyphenoxy)butyne, 6.0 g (29.3 mmol) of 2-iodopyridine, 480 mg of bi~(triphenylphosphine)palladium dichloride and 280 mg of copper(I) iodide are dissolved in 50 ml of triethylamine, and the solution is stirred at room temperature for 2 h. After being worked up as described above, 9.6 g (98%) of the propargyl ether are obtained as an oil.

E~ample 8' 1-(2'-Pyridyl)-3-methyl-3-(4'-trifluoromethylsulfonyl-phenoxy)butyne From 5.0 g (17.1 mmol) of 3-methyl-3-(4~-trifluoromethylsulfonylphenoxy)butyne and 3.8 g (18.5 mmol) of 2-iodopyridine, by a procedure analogous to that of Example 7' after 12 h at room temperature, 2.0 g (32%) of the substance were obtained as an oil.

Exam~le 9' 1-(2'-Pyridyl)-3-methyl-3-(4'-difluoromethoxyphenoxy)-butyne From 3.4 g (15 mmol) of 3-methyl-3-(4'-difluoro-9 ~ ~L

methoxyphenoxy)butyne and 3.1 g (15 mmol) of 2-lodo-pyridine, by a procedure analogous to that of Example 6', 4.1 g (90%) of the propargyl ether were obtainod a~ an oil.

ExamDle 10' 1-(3'-Pyridyl)-3-methyl-3-(4'-trifluoromethylthiophen-oxy)butyne 500 mg (1.9 mmol) of 3-methyl-3-(4'-trifluoro-methylthiophenoxy)butyne and 390 mg (1.9 mmol) 3-iodo-pyridine give, by a procedure analogous to that ofExample 6', 500 mg (77%) of the substance as an oil.

Examplo 11' 1-(3'-Pyridyl)-3-methyl-3-(4'-trifluoromethoxyphenoxy)-butyne 12.2 g (50 mmol) of 3-methyl-3-(4'-trifluorometh-oxyphenoxy)butyne, 9.4 g (46 mmol) of 3-iodopyridine, 700 mg of bis(triphenylphosphine)palladium dichloride and 500 ml of copper(I) iodide are dissolved in 70 ml of triethylamine, and the solution is stirred at room temperature for 3 h. The solution is wor~ed up as described in Example 6' and 14.2 g (96%) of the substance are isolated as an oil.

Example 12' 1-(3'-Pyridyl)-3-methyl-3-~4'-trifluoromethylsulfonyl-phenoxy)butyne From 2.7 g (9.2 mmol) of 3-methyl-3-(4'-tri-fluorosulfonylphenoxy)butyne, 2.1 g (10.2 mmol) of 3-iodopyridine, 200 mg of bis(triphenylphosphine)-palladium dichloride and 100 mg of copper(I) iodide in 30 ml of triethylamine, after 3 h at 50C and after being worked up in a manner analogous to that of Example 6', 2.7 g (79%) of the substance are obtained as an oil.

Example 13' 3-Methyl-1-(3'-pyridyl)-3-(4'-diethoxyphosphorylphenoxy)-butyne From 1.0 g (3.37 mmol) of 3-methyl-3-(4'-dieth-oxyphosphorylphenoxy)butyne and 640 mg (3.12 mmol) of 3-iodopyridine, in a manner analogous to that of Example 6' after chromatography on silica gel uoing ether, 620 mg (54%) of the substance are obtained.

ExamDle 14' 1-(4'-Pyridyl)-3-methyl-3-(4'-trifluoromethylsulfonyl-phenoxy)butyne From 2.9 g (9.9 mmol) of 3-methyl-3-(4'-tri-fluoromethylsulfonylphenoxy)butyne, 2.0 g (9.9 mmol) of4-iodopyridine, 100 mg of copper(I) iodide and 150 mg of bis(triphenylphosphine)palladium dichloride in 20 ml of triethylamine, after 2 h at 80C and wor~ing up the mixture as already described, 2.7 g (74%) of the pro-pargyl ether are obtained as an oil.

Example 15' 1-(2'-Quinolyl)-3-methyl-3-(4'-trifluoromethylsulfonyl-phenoxy)butyno 3.2 g (10.9 mmol) of 3-methyl-3-(4'-trifluoro-methylsulfonylphenoxy)butyne, 2.6 g (10.2 mmol) of 2-iodoquinoline, 140 mg of bis(triphenylphosphine)-palladium dichloride and 100 mg of copper(I) iodide are dissolved in 20 ml of triethylamine, and the mixture is heated at 50C for 10 min. Wor~ing up the mixture in a as mannor analogous to that of ~xample 6', and chromato-graphy on silica gel using dichloromethane, give 3.8 g (89~) of the substance as an oil.

gxample 16' 3-Methyl-3-(4'-trifluoromethylthiophenoxy)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 at reflux with stirring for ~' ~ , .

' ' , , , , - 56 _ 2 ~ 3~
20 hours. 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g of potas~ium carbonate are aga~n added, and the m~xture is aga~n heated at reflux, for 40 hour~. Inorgan~c constituents are removed by filtrat~on, tho solut~on i8 concentrated, and the residue is ta~en up in 200 ml of methylene chloride and extracted with 1 N NaOH ~olution.
The organ~c phase is washed with water, dr~ed and concen-trated, and the residue is filtered over silica gel.
Yield: 22 g (85~).

Exam~le 17' 3-Methyl-3-(4'-trifluoromethoxyphenoxy)butyne 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. The mixture is stirred at reflux temperature for 36 hours, after which a further 35 g (0.34 mol) of 3-chloro-3-methyl-1-butyne are added, and the mixture is stirred at reflux tempera-ture for a further 36 hours. The suspension is cooled, filtered and washed with acetone. The filtrate is concen-trated, and the residue is taken up in methylene chloride and extracted with 1 N NaOH solution. The organic phase is washed until neutral, dried and concentrated by evaporation.
Yield: 67 g (55~).

Example 18' 3-Methyl-3-(4'-trifluoromethylsulfonylphenoxy)butyne A) 1 g (4.4 mmol) of 4-trifluoromethylsulfonylphenol 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 are stirred at 80-90C under argon for 20 hours. The mixture is allowed to cool and is filtered, and the filtrate is concentrated by evapor-ation. The residue is taken up in 20 ml of methylene chloride and washed with water (2 x 20 ml), and is dried and concentrated by evaporation. 1.2 g (93%) of the ~ ~ ~ 2 ~ ~ ~

butyne remain as an oil.

B) 20 g (76.8 mmol) of 3-methyl-3-(4'-trlfluoromethyl-thiophenoxy)butyne are dissolved in a mixture of 700 21 of water and 700 ml of methanol, and 141.8 g oS Oxone~
are added. The mixture i8 stirred for 4 day~ at room temperature, a further 500 ml of water are added, and extraction i8 carried out three times with chloroform.
The combined organic phases are dried over magnesium sulfate and concentrated, and the residue is chromato-graphed on silica gel using dichloromethane.Yield: 14.0 g (62%).

Example 19' 3-Methyl-3-(4'-difluoromethoxyphenoxy)butyne is prepared in a manner analogous to that of Example 16'.
Yield: 70%; b.p. 56-58C/0.035 mbar.

Example 20' 3-Methyl-3-(4'-diethoxyphosphorylphenoxy)butyne is prepared, in a manner analogous to that of Example 16', from 4-diethoxyphosphorylphenol.
Yield: 78%; colorless oil after chromatography on silica gel using ethyl acetate/hexane, 40:5.

Example 21' 4-Trifluoromethylsulfonylphenol A) 1 g ~5.2 mmol) of 4-trifluoromethylthiophenol is dissolved in 20 ml of methanol, and a suspension of 9.6 g of Oxono~ in 20 ml of water is added at 0C with stirring. After stirring for 5 days at room temperature, the mixture is diluted with 50 ml of water and extracted with chloroform (3 x 50 ml). After being dried and concentrated by evaporation, 1.1 g (94%) of colorless crystals remain, m.p. 123C (lit.: 119-120C).

B) 1 g (5.2 mmol) of 4-tr$fluoromethylthiophenol together with 4 ml of glacial acetic acid and 4 ml of 30%
strength hydrogen peroxide are stirred at 50C for .

20 hours. Subsequently, a further 2 ml of 30% ~trength hydrogen peroxide are added, and after a further 2 hour~
at 50C the mixture i8 worked up as de~cribod above.
After chromatography on silica gel, 230 mg ~20%) of tho phenol are obtained.

Example 22' 2,2-Dimethyl-6-trifluoromethylthio-3,4-dihydro-2H-benzo-tb]pyran-4-one a) 22.0 g (84.5 mmol) of 3-methyl-3-(4'-trifluoro-methylthiophenoxybutyne are dissolved in 50 ml of 1,2-dichlorobenzene, and the solution is heated at 180C for 2 h under an argon atmosphere and then fractionated in vacuo, affording 13.0 g (59%) of 2,2-dimethyl-6-tri-fluoromethylthio-2H-benzo~b~pyran (b.p. 55C/0.02 mbar).

b) 6.5 g (25.0 mmol) of 2,2-dimethyl-6-trifluoromethyl-thio-2H-benzolb]pyran are dissolved in 25 ml of dry chloroform and cooled to -5C. At this temperature a solution of 4.0 g (1.27 ml; 25.0 mmol) of bromine in 20 ml of chloroform is added dropwise, and the mixture is stirred for a further 5 min and concentrated. 2,2-Dime-thyl-trans-3,4-dibromo-6-trifluoromethylthio-3,4-dihydro-2H-benzotb~pyran crystallizes in colorless crystals from cold petroleum ether.
Yield: 10.1 g (96~), m.p.: 66-67C.

c) 1.25 g (54.4 mmol) of sodium are dissolved in 20 ml of absolute methanol and the solution is concentrated to drynes~, the residue is ta~en up in 1,2-dimethoxyethane (DME), and 22.5 g (53.6 mmol) of the above-dQscribed dibromide in 60 ml of DME are added. The mixture i8 then boiled at reflux for 40 min, water is added, the mixture is extracted by sha~ing with ether, and the organic phase is washed with saturated sodium chloride ~olution, dried over magnesium sulfate and concentrated. 2,2-Dimethyl-4-bromo-6-trifluoromethylthio-2H-benzo[b]pyran is obtained as an oil which, on the ba~i~ of it~ lH-NMR spectrum, is sufficiently pure for further reaction.

59 ~29~
Yield: 16.5 g (91%).

d) 4.5 g (13.3 mmol) of the above-de~cribed benzopyran are dissolved in 10 ml of concentrated sulfuric acid, and the solution is stirred at room temperature overn~ght.
The mixture i~ then carefully poured into sodium hydrogen carbonate ~olution and extracted with ether, and the organic phase is dried over magnesium sulfate and concen-trated. After chromatography on silica gel uslng dichloromethane, 2.0 g (55%) of the chromanone are obtained a~ colorless crystals, m.p. 45-47C.

Exam~le 23 Production of tablets and capsules Tablets and capsules containing the constituents indicated below are produced by known procedures. These tablets and capsules are suitable for the treatment of the abovementioned diseases, in particular hypertension, in dosage~ of in each case one tablet or capsule once daily.

Components Weight (mg) Tablet Capsule 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyridyl)-2H-benzotb]pyran l'-oxide 0.2 0.1 Tragacanth 10 Lactose 247.5 300 Corn starch 25 Tal¢ 15 Magnesium stearate 2.5 Exam~le 24 Production of ampules Ampules which contain the components stated below can be produced in a ~nown manner. Glass ampules are filled under nitrogen with a solution of the active substance in water and 1,2-propanediol.

`` 2 1 ~

6-Trlfluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyrldyl)-2H-benzo-[b]pyran 1'-oxlde 0.02 mg 1,2-Propanediol 0.8 ml 5 Dlstilled water to 2.0 ml

Claims

Patent Claims

1. A substituted benzopyran derivative of the general formula I

(I) in which R1 and R2, which may be identical or different, denote hydrogen, C1-6-alkyl, branched C3-6 alkyl, C3-7-cycloalkyl or phenyl or denote, together with the carbon atom enclosed by them, C3-7-spiroalkyl, either R3 or R4 is hydrogen, hydroxyl, C1-3-alkoxy, formyl-oxy, C1-?-alkylcarbonyloxy, C1-8-alkoxycarbonyloxy, C1-8-monoalkylaminocarbonyloxy or C1-8-dialkylaminocarbonyloxy, where the C1-8-alkyl- or -alkoxy groups may be either linear or branched, and tho other substituent of the two in each case is hydrogen, or R3 and R4 together form a bond, R5 denotes a monocyclic six-membered aryl or N-heteroaryl group, a bicyclic aryl or N-heteroaryl group which is composed of two fused six-membered rings, in which the heterocycle contains one or two nitrogen atoms which belongs to one of the following three subgroups A), B) or C), in which context in A) the aryl or N-heteroaryl group R5 carries a hydroxyl group in the 2 position and is optionally further substi-tuted one or two times by halogen, cyano, C1-8-alkyl or C1-8-alkoxy, in B) R5 is an N-heteroaryl group containing one or two N
atoms, which carries an N-oxide group in the 2 position and is optionally substituted one or two times by halo-gen, C1-8-alkyl, C1-8-alkoxy, C1-8-mono- or C1-8-dialkylamino, hydroxyl, amino, cyano, C1-8-alkoxycarbonyl, C1-8-mono- or C1-8-dialkylaminocarbonyl, hydroxycarbonyl, aminocarbonyl or phenyl, and in C) R5 is an N-heteroaryl group or an N-heteroaryl N-oxide whose basic structure derives from the group 3-pyridyl, 4-pyridyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-quinolyl and 4-isoquinolyl and is option-ally substituted one or two times by halogen, C1-8-alkyl, C1-8-alkoxy, C1-8-monoalkylamino, C1-8-dialkylamino, cyano, hydroxyl, amino or phenyl, the hydroxyl group or the N-oxide group in this subgroup not being located in the 2 position, and R6 is difluoromethoxy, trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, difluoromethylthio, difluoromethyl-sulfinyl, difluoromethylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, tri-fluoroethylthio, trifluoroethylsulfinyl, trifluoroethyl-sulfonyl, phosphono or C1-8-dialkoxyphosphoryl, in which abovementioned alkyl can be straight-chain or branched, and to its salts and acid addition salts, tautomers and optical isomers.

2. 6-Difluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran 1'-oxide as claimed in claim 1.

3. 6-Trifluoromethoxy-2,2-dimethyl-4-(2'-pyridyl)-2H-benzotblpyran 1'-oxide as claimed in claim 1.

4. 6-Trifluoromethylthio-2,2-dimethyl-4-(2'-pyri-dyl)-2H-benzolb]pyran 1'-oxide as claimed in claim 1.

5. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(2'-pyridyl)-2H-benzo[b]pyran 1'-oxide as claimed in claim 1.

6. 6-Trifluoromethylthio-2,2-dimethyl-4-(3'-pyr-idyl)-2H-benzo[b]pyran as claimed in claim 1.

7. 6-Trifluoromethylsulfonyl-2,2-dimethyl-4-(3'-pyridyl)-2H-benzotb]pyran as claimed in claim 1.

8. A process for the preparation of a compound of the formula I or of a salt or acid addition salt thereof, which comprises a) for the preparation of a compound of the formula I
in which R5 is an N-heteroaryl group which carries an N-oxide group in the 2, 3 or 4 position, oxidizing a compound of the general formula I in which R1, R2, R3, R4 and R6 have the abovementioned meaning and R5 is a corres-ponding N-heteroaryl group having an N atom in 2, 3 or 4 position, or b) for the preparation of a compound of the formula I
corresponding to the formula VI

in which R1, R2, R5 and R6 have the meaning given above and R3 and R4 together form a bond, heating a compound of the general formula II

II

having the meaning given above of R1, R2, R5 and R6, or eliminating water from a compound of the formula I which corresponds to the formula III and in which R3 denotes hydrogen and R4 denotes hydroxyl III
having the given meaning of R1, R2, R5 and R6, or c) for the preparation of a compound of the formula I
which corresponds to the general formula III and has the meaning given above of R1, R2, R5 and R6, reacting a compound of the general formula IV
in which R1, R2 and R6 have the meaning given above with an organometallic compound R5M in which R5 has the above-mentioned meaning and M represents a metal or metal halide, preferably Li- or MgHal, where Hal is chlorine, bromine or iodine, or d) for the preparation of those compounds of the general formula I in which R3 and R4 denote hydrogen and which come under the formula X of reaction schemes 1 and 2, in which R1, R2, R5 and R6 have the meaning given above, cyclizing a compound of the general formula V

in which R1, R2, R5 and R6 have the meaning given above, or hydrogenating a compound of the general formula VI
VI

in which R1, R2, R5 and R6 have the given meaning in the presence of a catalyst, or e) for the preparation of a compound of the general formula I in which R6 denotes difluoromethylsulfinyl, difluoromethylsulfonyl,trifluoromethylsulfinyl,trifluo-romethylsulfonyl, trifluoroethylsulfinyl or trifluoroe-thylsulfonyl and R1, R2, R3, R4 and R5 have the abovementioned meaning, oxidizing a compound of tho general formula I in which R6 is difluoromethylthio, trifluoromethylthio or trifluoroethylthio, or f) the preparation of a compound of the general formula I in which R5 denotes an N-heteroaromatic radical which is substituted in the o or p position relative to the N
atom by chloro or cyano, and R3 and R4 in each case denote hydrogen or together denote a bond and R1, R2 and R6 have the meaning given above, reacting a compound of the general formula I in which R5 is an N-heteroaryl N-oxide group and R1, R2, R3, R4 and R6 have the appropriate meaning with a nonmetal chloride or a silyl cyanide, or g) for the preparation of a compound of the formula XII
according to scheme 1, corresponding to the formula I in which R3 is hydroxyl and R4 is hydrogen, and R1 R2, R5 and R6 have the meaning given above, epoxidizing a compound of the general formula VI in which R1, R2, R5 and R6 have the meaning given above to give the compound XI
(scheme 1) and then reducing the epoxide to the compound of the formula XII (scheme 1), or h) for the preparation of compounds of the formula I in which R1, R2 R5 and R6 have the meaning given above and R3 or R4 denote C1-8-alkoxy, formyloxy, C1-8-alkylcarbonyloxy, C1-8-alkoxycarbonyloxy, C1-8-monoalkylaminocarbonyloxy or C1-8-dialkylaminocarbonyloxy, reacting a corresponding compound of the formula I in which R3 or R4 denotes hydroxyl, i.e. a compound corresponding to formulae III
and XII (scheme 1), with corresponding alkylating agents or acylating agents, and optionally converting a compound obtained by the above processes into its salts or acid addition salts or N-oxides.

9. A pharmaceutical preparation which comprises one or more compounds as claimed in claim 1 or their physiologically tolerated salts and, if appropriate, conventional excipients and/or diluents.

10. A compound of the formula II, IV, V or XI having the meaning as given in claim 1 for the substituents:

II

IV

V

XI

11. A method of using one or more compounds as claimed in claim 1 or their physiologically tolerated salts for the preparation of an agent for the prophylaxis and treatment of high blood pressure, cardiac insufficiency, angina pectoris, peripheral circulatory disorders, cerebral insufficiency, asthma, and acute and chronic heart disease.