IE921187A1 - Quinoxalines, processes for their preparation, and their use - Google Patents

Quinoxalines, processes for their preparation, and their use

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Publication number
IE921187A1
IE921187A1 IE118792A IE921187A IE921187A1 IE 921187 A1 IE921187 A1 IE 921187A1 IE 118792 A IE118792 A IE 118792A IE 921187 A IE921187 A IE 921187A IE 921187 A1 IE921187 A1 IE 921187A1
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IE
Ireland
Prior art keywords
alkoxy
chlorine
hydroxyl
fluorine
optionally substituted
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IE118792A
Other versions
IE83508B1 (en
Inventor
Uta-Maria Billhardt
Manfred Rosner
Gunther Rieb
Irvin Winkler
Rudolf Bender
Original Assignee
Hoechst Ag
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Publication of IE83508B1 publication Critical patent/IE83508B1/en
Priority claimed from DE19914142322 external-priority patent/DE4142322A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE921187A1 publication Critical patent/IE921187A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Compounds of the formula I or Ia <IMAGE> in which n and the substituents R<1> - R<5> and also X have the same meaning, have antiviral activity.

Description

Description Quinoxalines, processes for their preparation, and their use The present invention relates to quinoxalines, to processes for their preparation, and to their use.
Quinoxalines are a well-known class of compound (0. Hinsberg, J. Liebigs Ann.
Chem. 237, 327 (1986)).
Quinoxaline derivatives have been described in the patent literature for use in various applications in medicine.
Austrian Patent 284,848 (19.12.67) mentions 1-N-dialkylaminoalkyl3.4- dihydroquinoxalin-2(1H)-ones as spasmolytic agents. A series of patent applications by the Japanese company Sumitomo Chem. Co. Ltd. describe 4-N-aroyl-, arylacyl- and arylsulfonyl-3,4-dihydroquinoxalin-2(1 H)-ones which have an antiinflammatory action (JA 17,137/69 (11.4.66), JA 17,136/69 (8.4.66), JA 7,008/422 (9.8.66), BE 706,623 (16.11.66)). 3,4-Dihydroquinoxalin-2(1H)-one-3-carboxamides are contained in US Patent US 3,654,275 (4.4.72). They, too, have an antiinflammatory action. In US Applications US 4,203,987 (21.5.79) and 4,032,639 (22.3.76), pyridinylalkyltetrahydropyrazino[1,2-a]quinoxalinone derivatives are described by American Home Prod. Corp, as antihypertensive and antisecretory reagents. A European Patent Application by Pfizer Inc. (EP 266,102 A (30.10.86)) includes 4-N-benzenesulfonyl3.4- dihydroquinoxaIin-2(1H)-one-1-alkylcarboxylic acids as aldose reductase inhibitors.
However, an antiviral activity has not been demonstrated to date.
Surprisingly, it has now been found that quinoxalines of the formulae I and la R2 and their tautomeric forms of the formula ia and physiologically acceptable salts or prodrugs thereof have an antiviral action, in particular against retroviruses, for example against the human immunodeficiency virus (HIV).
In the compounds of the formula I or la according to the invention, 1) n is zero, one, two, three or four, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-Ce-alkyl, C5-Ce-cycloalkyl, C,-C6-alkoxy, (C^Cg-alkoxyMC^-alkoxy), C^Cg-alkylthio, C^Cg-alkylsulfinyl, C^Cg-alkylsulfonyl, nitro, amino, azido, C,-C6-alkylamino, di(C,-C6-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methytpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C,-Ce-acyl, C,-C6-acyloxy, C^Cg-acyiamino, cyano, carbamoyl, carboxyl, (C^Cg-alkylJoxycarbonyl, hydroxysulfonyl, sulfamoyl a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, 10 phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyI or 4-pyridyl radical which is substituted by up to five radicals R6 which are independent of one another, where R6 can be 15 fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C^Cg-alkyl, C3-C8-cycloalkyl, C,-C6-alkoxy, C^Cg-alkylthio, C^Cg-alkylsulfinyl, C,-C6-alkylsulfonyl, C^Ce-alkylamino, di(C,-C6-alkyl)amino, (C^Cg-alkyQoxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R2 is hydrogen, C^Cg-alkoxy, hydroxyl, picolyl, cyclopropyl or isopropenyloxycarbonyl and R5 is hydrogen, hydroxyl, C^Cg-alkoxy, aryloxy, C^Cg-acyloxy, cyano, amino, Cj-Cg-alkylamino, di(C,-C6-alkyI)amino, arylamino, C^Cg-acylamino, C^Ce-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di(C,-C6-alkyI)amino, C^Cg-alkylthio, C,-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C2-Ce-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C^Cg-alkylamino, di(C,-C6-aIkyl)amino, C,-Ce-alkyfthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl and carbamoyl; C3-C8-allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo, phenyl; C3-C8-alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di^-Cg-alkyOamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloatkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C,-Ce-alkylamino, diCC^Cg-alkyQamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Cg-alkyQamino, C^Cg-alkylthio, C,-C6-aIkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkyl)-(C,-C4-alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C^Cg-alkylamino, diiC^Cg-alkyljamino, C^Cg-alkylthio, C,-C6-aIkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (Ca-Ce-cycloalkenylJ-CC^C^alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^-Cg-alkylamino, diCC^Ce-alkylJamino, C,-Ce-alkylthio, Ci-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C,-C6-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C^Cg-alkylamino, diTC^Cg-alkylJamino, C^Cg-alkylthio, C,-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C2-Cg-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C3-C8-cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; (C5-Ce-cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; e (C3-C8-cycloalkyl)-(C,-C3-alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-aIkoxy, oxo, phenyl; (C5-C6-cycIoalkenyl)-(C,-C3-alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; C,-C8-aikyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio; C2-C8-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; C2-C8-alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Ce-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-aikoxy, oxo, phenyl; C2-C8-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-aikylamino- and diiC^Cg-alkylJaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl, in each case optionally substituted by C,-C4-alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo, carboxyl, or phenyl; C2-C8-alkenylamino- and di(C,-Ce-alkenyl)aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; IE 187 C^Cg-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4alkoxy, oxo, phenyl; C^Cg-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, 0,-0« 5 alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl10 carbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl, each of which is substituted by up to five radicals Re which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 5 carbon atoms, and Re being as defined above, or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl or heteroarylalkylaminocarbonyl, each of which is substituted by up to three radicals R® which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, R3 and R4 are identical or different and, independently of one another, are hydrogen, C^Cg-alky! which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C4-acyIoxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, CrC4alkylthio, C,-C4-alkylsulfonyl, C^C^alkylsulfinyl, carboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C48 IE I ; 187 alkylamino, difC^C^alkylJamino, C^C^alkylthio, C^C^alkylsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-Ce-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4alkylamino, diiC^C^alkylJamino, C^C^alkylthio, alky (sulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-CB-cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C^C^alkylamino, di(C,-C4-alkyl)amino, C^C^alkylthio, C,-C4-alkyIsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to 15 five radicals R6 which are independent of one another, it being possible for the alkyl radical to contain 1 to 3 carbon atoms in each case, and R6 being as defined above, R3 and R4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 8 carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C6-alkyl, C2-Ce-alkenyl, C2-C6-alkynyl, C^Cg-acyloxy, benzoyloxy, C,-C6-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X is oxygen, sulfur, selenium or substituted nitrogen N-R2, it being possible for R2 to have the abovementioned meanings, with the exception of those compounds in which R3 and R4 are both hydrogen, and compounds in which R2 and R5 are hydrogen and R3 and/or R4 are/is arylalkyl, and compounds in which X is oxygen and R2 and R5 are hydrogen.
IE £21187 In a preferred group of compounds of the formula I or la, 2) n is zero, one, two or three, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C4alkyl, C5-C6-cycloalkyl, C,-C4-aIkoxy, (C^C^alkoxyHC^C^-alkoxy), 0,-C^alkylthio, C1-C4-alkylsulfinyl, C5-C4-alkylsulfonyl, nitro, amino, C^C^alkylamino, di^-C^-alkylJamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, C^C^acyl, C,-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl, carboxyl, (C,-C4-alkyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two radicals R6 which are independent of one another, where R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, 0,-C^alkyl, C3-C7-cycloalkyl, C^C^alkoxy, C,-C4-aikylthio, C,-C4-alkylsulfinyl, C,-^alkylsulfonyl, C,-C4-alkylamino, di(C,-C4-alkyl)amino, (C,-C4-alkyl)oxycarbonyl, phenyl or phenoxy, IE * 187 R2 is hydrogen and R5 is hydrogen, hydroxyl, cyano, amino, CrCe-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C1-C4-aIkylamino, di(C,-C4-alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C^C^alkylamino, di(C1-C4-alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-CB-allenyl, C3-C8-alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 20 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C.,-C4-alkylamino, dKC^C^alkylJamino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-Ce-cycloalkenyl, optionally substituted by ΙΕ ί 187 fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C4acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C^C^alkylamino, difC^C^alkyQamino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3-Ce-cycloalkyl)-(C,-C2-alkyl) optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C4acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C5-C4-alkyiamino, ditCj-C^alkyQamino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; (Qj-Cg-cycloalkenylHCt-Cji-alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C4acyloxy, benzoyloxy, benzyloxy, phenoxy, C^-C^-alkoxy, C^C^alkylamino, diiC^C^alkylJamino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C,-C6-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, 0,-C^ 20 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C^C^alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2-C6-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; (C3-C6-cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or 30 hydroxyl, C,-C4-alkoxy, oxo, phenyl; !E! . 187 (C3-C6-cycloalkyl)-(C,-C2-all (Cs-Cg-cycloalkenyO-iC^Cj-alkylJcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; C^Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^C^alkoxy, C,-C4-alky!amino, difCrC^alkyOamino, C^C^alkylthio; C2-C6-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; C2-C6-alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl; C2-C6-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, 20 C,-C4-alkoxy, oxo, phenyl; C^Cg-alkylamino- and diiC^Cg-alkyOaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl; C2-C6-alkenylamino- and diiC^Ce-alkenylJaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; £1187 C^C^alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4alkoxy, oxo, phenyl; C1-C4-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4 5 alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl10 carbonyl, arylalkenylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl, each of which is substituted by up to three radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 5 carbon atoms and R6 being as defined above, or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3- furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4- picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R® which are independent of one another, R3 and R4 are identical or different and independently of 25 one another are hydrogen, C,-C6-alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C430 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C^C^alkylamino, IE d 187 diCC^C^alkyOamino, C,-C4-alkylthio, C^C^alkylsulfonyl, C,-C4-alkylsuIfinyl, carboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4alkylamino, di^-C^-alkylJamino, C,-C4-aIkylthio, CrC4-alky I sulfonyl, C4-C4alkylsulfinyl, carboxyl or carbamoyl; C3-Ce-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, Cj-C^ alkylamino, di (C,-C4-alkyl) amino, CfC^alkylthio, C^C^alkylsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^^-alkoxy, C^C^alkylamino, di/C^C^alkylJamino, C^C^alkylthio, C^C^alkylsuffonyl, C,-^alkylsulfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to three radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and R6 being as defined above, R3 and R4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 7 25 carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, 0,-C^acyloxy, benzoyloxy, C,-C4-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, and X is oxygen, sulfur or selenium. ΙΕ ί21187 In a yet more preferred group of compounds of the formula I or la, 3) n is zero, one or two, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C,-C4-alkyl, C,-C4-alkoxy, (C^C^alkoxyHC^-C^alkoxy), C^C^alkylthio, nitro, amino, C^C^alkylamino, di^-C^alkyQamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, CrC^acyl, C^C^acyloxy, C^^-acylamino, cyano, carbamoyl, carboxyl, (C,-C4alkyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl, or a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two radicals R6 which are independent of one another, where R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, C^C^alkoxy, (C1-C4-alkyl)oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is CrCe-alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, IE ! '187 C,-C4-alkoxy, C,-C4-alkylamino. di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^^-alkoxy, C^C^alkylamino, di(C,-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-allenyl, C3-C8-alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C^C^alkylamino, di(C,-C4-alky!)amino, C.,-C4-aIkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C^C^aikylamino, di(C,-C4-alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4-alkylamino, diCC^C^alkylJamino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; IE ( 187 (C3-C6-cycloalkyl)-(Ci-C2-alkyI), optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3-C6-cycloalkenyl)-(C,-C2-alkyl), optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-aIkyl, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4-alkylamino, difC^C^alkylJamino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, C,-C4-alkenylamino, di(C,-C4alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl, C,-C4alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2-C6-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl; (C3-C6-cycloalkyl)carbonyl, (C5-C6-cycloalkenyl)carbonyl, (C3-C6-cycioalkyl)-(C2-alkyl)carbonyl, (Cs-C6-cycloalkenyl)-(C,-C2-alkyl)carbonyl, C^Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^C^alkoxy, C^C^alkylamino, di (C,-^-alky I) amino or C,-C4-alkylthio; IE c 1187 C2-C6-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy; C2-C6-alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy; C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy; C2-C6-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy; C^Cg-alkylamino- and diiC^Cg-alkylJaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl; C2-C6-alkenylamino- and di^-Cg-alkenylJaminocarbonyl, in each case optionally 20 substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy; C,-C4-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, alkoxy; C1-C4-alkenylsulfonyl; or aryl, arylcarbonyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl, each of which is substituted by up to two radicals R® which are independent of one IE 187 another, it being possible for the alky! radical to contain in each case 1 to 3 carbon atoms, and R® being as defined above, or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 5 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2- , 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3- thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl or 2- or 3-thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R® which are independent of one another, and R3 and R4 are identical or different and independently of one another are hydrogen, C^C^alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, phenoxy, C1-C4-alkoxy, C^C^alkylamino, diiC^C^alkylJamino, C.,-C4-alkylthio, C,-C4alkylsulfonyl, C.,-C4-alkylsulfinyl, carboxyl or carbamoyl; C2-C6-alkenyl, optionally substituted by fluorine or chlorine; C3-C6-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^-alkoxy, C,-C4 alkylamino, di^-CvalkyQamino, C,-C4-alkylthio, C^C^alkylsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl, each of which is substituted by up to two radicals R® which are independent of one another, IE ‘187 R3 and R4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 6 carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C^C^acyloxy, benzoyloxy, C^C^alkoxy, oxo, thioxo, carboxyl or carbamoyl, and X is oxygen or sulfur.
In a yet again preferred group of compounds of the formula I or la, 4) n is zero, one or two, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, Ct-C4-alkyl, C^-alkoxy, (C1-C4-alkoxy)-(C,-C2-alkoxy), C,-C4-aIkylthio, nitro, amino, C,-C4-alkylamino, dKC^C^alkyQamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C,-C4-acyl, C^C^acyloxy, C,-C4-acylamino, cyano, carbamoyl, carboxyl, (C,-C4alkyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl or a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical, each of which is substituted by up to two radicals R6 which are independent of one another, where R6 can be IE 187 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, C,-C4-alkoxy, (C^-C^alkyljoxycarbonyl, phenyl or phenoxy, Rz is hydrogen and Rs is 5 CrC6-alkyl, optionally substituted by C,-C4-alkoxy or C,-C4-alkylthio; C2-C6-alkenyl, optionally substituted by oxo; C3-C6-allenyl; C3-C8-alkynyl, in particular 2-butynyl; C3-C6-cycloalkyl; C5-C6-cycloalkenyl; (C3-C6-cycloalkyl)-(C1-C2-alkyl), in particular cyclopropylmethyl, optionally substituted by C^C^alkyl; (C-j-Cg-cycloalkenylHC^Ca-alkyl), In particular cyclohexenylmethyl; C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C4-alkoxy, C^C^alkylamino, C^C^alkenylamino, di(C,-C4-alkyl)amino, 1 -pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl or C^C^alkylthio; IE r. 187 C2-C6-alkenylcarbonyl; C^Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^C^alkoxy, C,-C4-alkylamino, difCrC^alkyOamino or C^C^alkylthio; C2-C6-alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2-C6-alkynyloxycarbonyl, in particular propynyloxycarbonyl or 10 butynyloxycarbonyl; C, -C6-alkylthiocarbonyI; C2-C6-alkenylthiocarbonyl, in particular allylthiocarbonyl; C^Cg-alkylamino- and diiC^Cg-alkyl)aminocarbonyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl; C2-C6-alkenylamino- and diCC^Cg-alkenylJaminocarbonyl; C^C^alkylsulfonyl; C,-C4-alkenylsulfonyl; or aryl which is substituted by up to two radicals Re which are independent of one another, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, in particular benzyl, phenylethyl, IE £1187 arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl (alkylthio)carbonyl, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and R6 being as defined above, or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3- furyIcarbonyl, 2- or 3-thienylcarbonyI, 2- or 3-thienylacetyl, 2-, 3- or 4- picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, or 2- or 3-thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R® which are independent of one another, and R3 and R4 are identical or different and independently of 15 one another are hydrogen, C^C^alkyl, optionally substituted by hydroxyl, mercapto, C^C^alkoxy, C^C^alkylthio, C1-C4-alkylsulfonyl, CrC^alkylsulfinyl, carboxyl or carbamoyl; C2-C6-alkenyl, aryl, benzyl, thienyl or thienylmethyl, each of which is substituted by up to two 25 radicals R® which are independent of one another, R® being as defined above, R3 and R4 can also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 6 30 carbon atoms and can optionally be substituted by oxo or thioxo, and IE 1/1187 X is oxygen or sulfur.
Compounds of the formula I or la as defined above wherein the substituents mentioned have the following meanings are very particularly important: n is zero or one, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, C^C^alkyl, C,-C2-alkoxy, C2-C4-acyl or cyano, R2 is hydrogen and R5 is C2-C6-alkenyl, C3-C8-aikynyl, in particular 2-butynyl; (C-j-Ce-cycloalkylHC^Cg-alkyl), in particular cyclopropylmethyl, optionally 20 substituted by C^C^alkyl; (C-j-Ce-cycloalkenylHC^-alkyl), in particular cyclohexenylmethyl; C2-C6-alkylcarbonyl, C2-C6-alkeny Icarbonyl; C^Cg-alkyloxycarbonyl; C2-C6-alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2-C6-alkynyloxycarbonyl, in particular propynyloxycarbonyl or 5 butynyloxycarbonyl; C2-C6-alkenylthiocarbonyl, in particular allylthiocarbonyl; C^-C^alkylsulfonyl; C1-C4-aIkenylsulfonyl; or arylalkyl, in particular benzyl or arylalkenyl, which is substituted by up to two radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and for the alkenyl radical to contain 2-3 carbon atoms, or 1-naphthylmethyl, 2- or 3-picolyl, 2-furylmethyl or 2- or 3-thienylmethyl, each of which is substituted by up to two radicals R6 which are independent of one another, where R6 is fluorine, chlorine, bromine, cyano, C^-Cj-alkyi or C^Cj-alkoxy, and R3 and R4 are identical or different and independently of one another are hydrogen, C^C^alkyl, optionally substituted by hydroxyl, mercapto, C^C^alkoxy, C,-C2-alkylthio, and X is oxygen or sulfur.
The alkyl groups in the above definitions can be straight-chain or branched. Unless otherwise defined, they preferably contain 1-8, particularly preferably 1-6, in particular 1-4, carbon atoms. Examples are the methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl group, and similar groups.
The alkenyl groups mentioned in the above definitions can be straight-chain or branched and contain 1 to 3 double bonds. Unless otherwise defined, these groups preferably contain 2-8, in particular 2-6, carbon atoms. Examples are the 2-propenyl, 1 -methylethenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 3,3-dichloro-2-propenyl and pentadienyl groups and similar groups.
The alkynyl groups mentioned in the above definitions can be straight-chain or branched and contain 1 to 3 triple bonds. Unless otherwise defined, they contain preferably 2-8, particularly preferably 3-6, carbon atoms. Examples are the 2-propynyl and 3-butynyl group and similar groups.
Unless otherwise defined, the cycloalkyl and cycloalkenyl groups mentioned in the above definitions contain preferably 3-8, particularly preferably 4-6, carbon atoms. Examples are the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.
The acyl groups mentioned in the above definitions can be aliphatic, cycloaliphatic or aromatic. Unless otherwise defined, they preferably contain 1-8, particularly preferably 2-7, carbon atoms. Examples of acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl group.
The aryl groups mentioned in the above definitions are preferably aromatic groups having 6-14 carbon atoms, in particular 6-10 carbon atoms, for example phenyl or naphthyl.
Suitable hetero atoms in the abovementioned heterocyclic rings or heteroaryl groups are, in particular, oxygen, sulfur and nitrogen, where, in the case of a nitrogencontaining ring which is saturated in this position, a structure N-Z is present in which Z is H or R5 with the individual above-described definitions.
Unless otherwise defined, the heterocyclic rings preferably have 1-13 carbon atoms and 1-6 hetero atoms, in particular 3-9 carbon atoms and 1-4 hetero atoms.
Suitable radicals for the heteroaryl groups mentioned in the above definitions are, for example, heteroaromatic radicals such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.
Examples of the aralkyl groups mentioned in the above definitions are benzyl, phenylethyl, naphthylmethyl or styryl.
The abovementioned substituents R1 to R5 are preferably trisubstituted, particularly preferably disubstituted, in particular monosubstituted, by the particular substituents mentioned.
In the case of the particular definitions of composite substituents (such as, for example, arylalkoxycarbonyl), the ranges which have been described above as being preferred for the individual substituents are also preferred.
Depending on the various substituents, compounds of the formulae I and la can have several asymmetric carbon atoms. The invention therefore relates both to the pure stereoisomers and to mixtures thereof such as, for example, the corresponding racemate.
The pure stereoisomers of the compounds of the formulae I and la can be prepared directly by known methods or analogously to known methods, or they can be resolved later.
The compounds of the formulae I and la can be prepared by known methods or 10 modifications thereof (see, for example, Rodd’s Chemistry of Carbon Compounds, S.
Coffey, M. F. Ansell (Editor); Elsevier, Amsterdam, 1989; Vol. IV Part IJ, p. 301-311. Heterocyclic Compounds. R. C. Elderfield (Editor); Wiley, New York, 1957; Vol. 6, p. 491-495).
The present invention furthermore includes a process for the preparation of 15 compounds of the formulae I and la as explained in 1) - 4) above, which comprises A) for preparing compounds of the formula I where X is oxygen and the radicals R1, Rz, R3, R4 and R5 are as defined under 1)-4), reacting a compound of the formula II H H with the definitions mentioned under 1) - 4) applying to R1, R3 and R4, with a compound of the formula III R-Z (III) where Ft has the meanings for R5 and R2 which have been mentioned above under 1) 4) with the exception of hydrogen, hydroxyl, C,-C6-alkoxy, aryloxy, C,-C6-acyloxy, amino, C^Cg-alkylamino, di^-Cg-alkyQamino, arylamino and C^Cg-acylamino, and Z is a leaving group, or B) preparing compounds of the formula I where X is sulfur and R1, R2, R3, R4 and Rs are as defined under 1) - 4) by reacting a compound of the formula I where X is oxygen and the definitions mentioned under 1) - 4) apply to R1, R2, R3, R4 and R5, with a sulfurizing reagent, or C) preparing compounds of the formula la where X and the radicals R1 to R5 are as defined under 1)-4), by reacting a compound of the formula IV H where the definitions mentioned under 1)-4) apply to R1, R3, R4 and R5, with a compound of the formula III R2-Z (Hi) where the definitions described under 1)-4) for formula I and la apply to R2, with the exception of hydrogen, hydroxyl, C,-C6-alkoxy, aryloxy, C^Cg-acyloxy, amino, C^Ce-alkylamino, diCC^Ce-alkylJamino, arylamino or C,-C6-acylamino, and Z is a leaving group, or D) preparing compounds of the formula I where X is oxygen and the radicals R1 to R5 are as defined under 1) - 4) by cyclizing a compound of the formula V where R1 to R5 are as defined under 1) - 4) and Y is hydroxyl, C^C^alkoxy, optionally halogenated C,-C4-acyloxy, chlorine, bromine or iodine, or E) preparing compounds of the formula I where X is oxygen, R4 and R5 are hydrogen and the definitions mentioned under 1) - 4) apply to R1 to R3, from the quinoxalinones of the formula XI where R1 to R3 are as defined under 1) - 4), by addition of hydrogen on the C=N 30 bond, or F) preparing compounds of the formula I where X is oxygen and R1 to R5 are as defined under 1)-4), from compounds of the formula VI R2 where R1, R2 and R5 are as defined under 1)-4), by reacting them with chloroform or bromoform and a carbonyl compound of the formula XIII R3-CO-R4 (XIII) where R3 and R4 are as defined under 1)-4), or with σ-(tri halomethyl)alkanols of the formula XIV Hal3C-C(OH)-R3R4 (XIV) where Hal is Cl, Br or I, in which R3 and R4 are as defined under 1)-4), or G) preparing compounds of the formula I where X is oxygen and R1, R2, R3, R4 and R5 are as defined under 1) - 4), by reacting a compound of the formula I where X is oxygen and the definitions mentioned under 1) - 4) apply to R1, R2, Rs and to R3 and R4, with the exception that at least one of the radicals R3 or R4 is hydrogen, with an alkylating reagent of the formula XV R’-Z (XV) where R’ has the meanings mentioned above for R3 and R4 with the exception of hydrogen and Z is a leaving group, or H) preparing compounds of the formula I where X is oxygen, R1, R2, R3 and R4 are as defined under 1)-4) and R5 is C^Cg-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Cg-alkyOamino, C,-C6-alkylthio, cyano, carboxyl, carbamoyl, C3-C8-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C,-Cg-alkoxy, C,-Cg-alkylamino, diiC^Cg-alkyQamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C3-C8-alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Cg-alkylJamino, C,-C6-alkyl thio, cyano, carboxyl or carbamoyl, C4-C8-cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyI)amino, C,-Ce-alkylthio, cyano, carboxyl or carbamoyl, Cs-CB-cydoalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, C^Cg-dialkylamino, C,-C6-alkylthio, cyano, carboxyl or carbamoyl, (C^Cg-alkoxy)(C,-Cg-alkyl), di(C1-C6-alkylamino)-(C1-C6-alkyl) or (C3-C6-cycloalkyl)alkyl, (C6-C8-cycloalkenyl)alkyl, or arylalkyl, naphthylalkyl or heteroarylalkyl, each of which is substituted by up to five radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, by reductive alkylation of a compound of the formula I where R5 is hydrogen and X is oxygen and the definitions mentioned under 1) - 4) apply to R\ R2, R3 and R4, with a carbonyl compound of the formula XVI, R-C(=O)-R’ (XVI) where R" and R'" are identical or different and independently of one another are hydrogen, C^Cy-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C,-C8-alkoxy, C^Cg-alkylamino, diiC^Ce-alkylJamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C3-C7-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di^-Cg-alkylJamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C3-C7-alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, cyano, carboxyl or carbamoyl, C4-C8-cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C6-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, cyano, carboxyl or carbamoyl, C6-cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C,-C6-alkylamino, diiC^Cg-alkylJamino, C,-Cg-alkylthio, cyano, carboxyl or carbamoyl, (C,-C8-alkoxy)-(C1-C6-alkyl), [d/C^-Cg-alkylJaminoHC^-Cg-alkyl) or (C4-C6-cycloalkyl)alkyl, (C6-cycloalkenyl)alkyl, or arylalkyl, naphthylalkyl or heteroarylalkyl, each of which is substituted by up to five radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 0 to 2 carbon atoms, and where R and R’ can be linked to each other to form a 4- to 8-membered ring, or I) preparing compounds of the formula I where X is oxygen and R1, R2, R3 and R4 are as defined under 1)-4) and R5 is C,-Ce-alkyloxycarbonyl, C^Cg-alkylthiocarbonyl, C2-C8-alkenyloxycarbonyl, C2-C8-aikenylthiocarbonyl, C2-C8-alkynyloxycarbonyl, C^Cg-alkylaminocarbonyl, C3-C6-alkenylaminocarbonyl, di(C^Cg-alkyl)aminocarbonyl, pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, 4-methylpiperazin-1-ylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Ce-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Ce-alkoxy, C^Cg-alkylamino, di(C6-alkyl)amino, C^Cg-alkylthio, C,-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; or aryloxycarbonyl, aryIthio(carbonyl), arylaminocarbonyl, heteroaryloxycarbonyl, heteroarylthiocarbonyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, (aryl5 alkylthio)carbonyl, arylalkylaminocarbonyl, heteroalkyloxycarbonyl, (heteroalkylthio)carbonyl or heteroalkylaminocarbonyl, each of which is substituted by up to five radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, by reacting a compound of the formula XVII U where the definitions mentioned under 1) - 4) apply to R1, R2, R3 and R*. n is 0, 1, 2 or 20 3, X is oxygen and U is a leaving group, with a compound of the formula XVIII Nu-H (XVIII) where Nu is C^Cg-alkoxy, C2-C8-alkenyloxy, C2-C8-alkynyloxy, C,-C8-alkylthio, C2-C8-alkenylthio, C^Cg-alkylamino- and dKCrCe-alkylJamino, C2-C8-alkenylamino- and dKCvCe-alkylJamino, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^C^alkoxy, C^C^alkylamino, difC^C^-alkyOamino, C,-C4-alkylthio, pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1 -ylcarbonyl, optionally substituted by C^C^alkyl, C2-C8-alkenyl, C^C^acyl, oxo, thioxo, carboxyl or phenyl, or aryloxy, arylthio, arylamino, arylalkyloxy, arylalkylthio, arylalkylamino, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyloxy, heteroarylalkylthio or heteroarylalkylamino, each of which is substituted by up to five radicals R6 (R6 is as defined at the outset) which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms.
The abovementioned method A preferably proceeds under the following conditions: The substituent Z in formula III is a suitable leaving group such as, for example, chlorine, bromine or iodine, a suitable radical of sulfuric acid, an aliphatic or aromatic sulfonate, or optionally halogenated acyloxy.
The reaction is expediently carried out in an inert solvent. Suitable solvents are, for example, aromatic hydrocarbons such as toluene or xylene, lower alcohols such as methanol, ethanol or 1-butanol, ethers such as tetrahydrofuran or glycol dimethyl ether, dipolar aprotic solvents such as Ν,Ν-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, nitrobenzene, dimethyl sulfoxide, or mixtures of these solvents. Two-phase systems with aqueous solutions of bases in the presence of a phase transfer catalyst such as, for example, benzyltriethylammonium chloride, are also possible.
The presence of a suitable base, for example of an alkali metal carbonate, alkali metal hydrogen carbonate, alkaline earth metal carbonate or alkaline earth metal hydrogen carbonate such as sodium carbonate, calcium carbonate or sodium bicarbonate, of an alkali metal hydroxide or alkaline earth metal hydroxide such as potassium hydroxide or barium hydroxide, an alcoholate such as sodium ethanolate or potassium tert.butylate, an organolithium compound such as butyliithium or lithiumdiisopropylamine, an alkali metal hydride or alkaline earth metal hydride such as sodium hydride or calcium hydride, an alkali metal fluoride such as potassium fluoride, or an organic base such as triethylamine or pyridine for scavenging the acid which is liberated during the reaction, may be expedient.
In some cases, the addition of an iodide, for example potassium iodide, is expedient. The reaction is generally carried out at temperatures between -10 and 160°C, preferably at room temperature.
To carry out this reaction, any nucleophilic substituents such as, for example, hydroxyl, mercapto or amino groups, with the exception of the 1- and/or 4-position in compounds of the formula II or III, must, before the reaction is carried out, be derivatized in a suitable manner or provided with conventional protective groups such as, for example, acetyl or benzyl, which can then be eliminated.
The sulfurizing reagent which is preferably used for the reaction as described above under B) is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson’s reagent), bis(tricyclohexyltin) sulfide, bis(tri-n-butyltin) sulfide, bis(triphenyltin) sulfide, bis(trimethylsilyl) sulfide or phosphorus pentasulfide. The reaction is carried out expediently in an organic solvent or in a solvent mixture, at room temperature or above, preferably at the boiling point of the reaction mixture, and if possible, under anhydrous conditions. Suitable substances are, for example, carbon disulfide, toluene, xylene, pyridine and 1,2-dichloroethane. If the tin sulfides or silyl sulfides which have been mentioned are used, it is advisable to carry out the sulfurization reaction in the presence of a Lewis acid, such as boron trichloride.
In the presence of other carbonyl groups in a compound of the formula I, for example in a compound where X is oxygen and one or more radicals R1 to R6 are acyl, the carbonyl is to be protected by known methods prior to the sulfurization reaction by a suitable protective group, for example by acetaiization; subsequent elimination of the protective groups results in the desired compound.
For the reaction described above under C, the substituent Z is a suitable leaving group, preferably chlorine, bromine or iodine, a suitable radical of sulfuric acid, an aliphatic or aromatic sulfonate, or optionally halogenated acyloxy.
The reaction conditions for this reaction correspond to those of method A.
The cyclization described under D) is effected in a suitable solvent such as methanol, ethanol, Ν,Ν-dimethylformamide or N-methylpyrrolidone, in the presence of a base; suitable bases are alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal carbonates or alkaline earth metal hydrogen carbonates such as sodium carbonate, calcium carbonate or sodium bicarbonate, alkali metal hydroxides or alkaline earth metal hydroxides such as potassium hydroxide or barium hydroxide, alcoholates such as sodium ethanolate or potassium tert.-butylate, organolithium compounds such as butyllithium or lithium diisopropylamine, alkali metal hydrides or alkaline earth metal hydrides such as sodium hydride or calcium hydride, or an organic base such as triethylamine or pyridine - the latter substances can also be used as solvents, or organic or mineral acids such as glacial acetic acid, trifluoroacetic acid, hydrochloric acid or phosphoric acid. The reaction is preferably carried out at temperatures between 20 and 120°C, particularly preferably at room temperature.
The compounds of the formula V, where R1 to R5 and Y are as defined under 1) - 5), can be obtained from compounds of the formula VI where R1, R2 and R5 are as defined under 1) - 4), by alkylation with a compound of the formula VII CO-Y where R3, R4 and Y are as defined under 1)-5) and Z is as defined under A). The reaction conditions for this alkylation correspond to those given in method A. Simultaneous cyclization to give the dihydroquinoxaline of the formula I takes place under suitable conditions.
Compounds of the formula V in which R1, R3 to R5 and Y are as defined under 1)-5) and R2 is hydrogen can also be prepared from compounds of the formula VIII where R1, R3 to R5 and Y are as defined under 1) - 5) by reducing the nitro group by known processes to the amino group.
Simultaneous cyclization to give the dihydroquinoxaline of the formula I takes place under suitable conditions, for example by carrying out the reduction in the presence of an acid.
The reduction is carried out by standard methods (see, for example, Methoden der Organischen Chemie [Methods in Organic Chemistry] (Houben-Weyl), E. Muller (Editor); G. Thieme Verlag, Stuttgart, 1957; Vol. XI/1, p. 360-490), for example using tin (I I) chloride in glacial acetic acid, TiCI3 in hydrochloric acid, or by catalytic hydrogenation, the choice of reagent being determined by the chemical stability of the various substituents R1 and R3 to R5; if, for example, one of the radicals is alkenyl, the first method will be selected to obtain the double bond.
The phenylenediamines of the formula VI which are required as starting materials for the syntheses described are known from the literature or commercially available or can be synthesized by methods known from the literature.
N-ortho-nitrophenylamino acid derivatives of the formula VIII, where R1n and R3 to R5 are as defined under 1)-4) and Y is OR7, where R7 is hydrogen, C^Cg-alkyl, optionally in each case for example halogen-substituted phenyl, benzyl or 9-fluorenylmethyl, can be obtained for example by amination of ortho-halonitro aromatic substances of the formula IX where R1 is as defined under 1)-4) and W is fluorine, chlorine, bromine or iodine, with 15 amino acids or their esters of the formula X COOR7 where R3, R4, R5 and R7 are as defined under 1)-5). The reaction can be carried out in the presence of an inorganic or organic auxiliary base such as, for example, sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine. It is advantageous to use an inert solvent at temperatures between 0 and 150 °C, preferably at reflux temperature. Suitable solvents are open-chain or cyclic ethers, for example tetrahydrofuran or glycol dimethyl ether, aromatic hydrocarbons, for example toluene or chlorobenzene, alcohols, for example ethanol, isopropanol or glycol monomethyl ether, dipolar aprotic solvents, for example N.N-dimethylformamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-tetrahydro-2(1 H)-pyrimidinone.
The N-ortho-nitrophenylamino acids of the formula VIII where Y is hydroxyl can, if desired or necessary, be converted by well-known standard methods into the acid derivatives of the formula VIII where Y is hydroxyl, C^C^alkoxy, optionally halogenated C^C^acyloxy, chlorine, bromine or iodine.
Ortho-halonitroaromatic compounds of the formula IX and amino acids of the formula X are known from the literature and commercially available or can be prepared by methods known from the literature.
The reaction described above under E) is preferably effected by means of catalytic hydrogenation (using hydrogen) or hydrosilylation (using alkylsilanes, for example diphenylsilane) in the presence of a hydrogenation catalyst, for example Raney nickel or palladium-on-charcoal, at a hydrogen pressure of 1 to 5 bar, or by means of a reducing agent from the class of the complex metal hydrides such as sodium borohydride or sodium cyanoborohydride, or using metals, or metal salts, and acid such as, for example, zinc/glacial acetic acid or SnCI2/HCI. It is advantageous to carry out the reaction in an inert solvent such as lower alcohols, for example methanol or isopropanol, ethers such as tetrahydrofuran or glycol dimethyl ether, dipolar aprotic solvents such as Ν,Ν-dimethylformamide, aromatic hydrocarbons such as toluene or xylene, or mixtures of these solvents, at temperatures between -20 and 100°C, preferably at room temperature.
If a chiral hydrogenation catalyst, for example di-//-chloro-bis[(cycloocta-1c,5c-diene)rhodium(l)]/(+) or (-)-4,5-bis-(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane, or a chiral complex metal hydride, for example sodium tris-(N-benzyloxycarbonylL-prolinoyloxy)-borohydride, are used in the above-described reaction, the individual enantiomers can be prepared selectively.
If, in compounds of the formula XI, substituents are present which can be hydrogenated or reduced under the above-described conditions, for example oxo, it is necessary to use an intermediate of the formula XI with substituents which are not attacked, but which can be derivatized to give the group required, for example hydroxyl. The substituents can also be provided with a customary protective group, for example an acetal protective group, which can then be removed after the above-des5 cribed reaction.
Quinoxalinones of the formula XI where R1 to R3 are as defined under 1)-4) can be obtained by known processes by condensing a phenylenediamine of the formula VI, where R1 and R2 are as defined under 1)-4) and R5 is hydrogen, with an alpha10 ketocarboxylic acid of the formula XII R3-CO-COOH (XII) where R3 is as defined under 1)-4).
The reaction is expediently carried out in an inert solvent in a temperature range of between 0 and 150°C; examples of suitable solvents are alcohols, for example ethanol or isopropanol, open-chain or cyclic ethers, for example glycol dimethyl ether or tetrahydrofuran, or dipolar aprotic solvents, for example Ν,Ν-dimethylformamide or acetonitrile.
The reaction described above under F) is expediently carried out in a two-phase system composed of an organic solvent or solvent mixture which is not miscible with water, composed of, for example, halogenated hydrocarbons, for example dichloromethane or 1,2-dichloroethane, or aromatic hydrocarbons, for example toluene or xylene, and a concentrated aqueous solution of an alkali metal hydroxide or alkaline earth metal hydroxide, for example sodium hydroxide or barium hydroxide. The presence of a phase transfer catalyst such as, for example, benzyltriethylammonium chloride or tetrabutylammonium bromide, is advantageous.
The reaction is usually carried out at temperatures between 0 and 50°C, preferably at room temperature.
Substituents in compounds of the formulae VI and XIII, or XIV, which are not stable under the reaction conditions must be replaced by those which can be derivatized to the required group. The substituents can also be provided with a customary protective group which can then be removed after the above-described reaction.
In the reaction described above under G), Z in formula XV is a suitable leaving group such as, for example, chlorine, bromine or iodine, a suitable sulfuric acid radical, an aliphatic or aromatic sulfonate, or optionally halogenated acyloxy.
The reaction conditions for this reaction correspond to those in method A.
The reaction described under H) is preferably effected by catalytic hydrogenation (using hydrogen) in the presence of a hydrogenation catalyst, for example palladiumon-charcoal, at a hydrogen pressure of 1 to 5 bar, or by means of a reducing agent from the class of the complex metal hydrides, such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
The reaction is expediently carried out in an inert solvent, such as lower alcohols, for example methanol or isopropanol, ethers, for example tetrahydrofuran or glycol dimethyl ether, halogenated hydrocarbons, for example dichloromethane or dichloroethane, at temperatures between -20 and 100°C, preferably at room temperature. The presence of an acid such as, for example, acetic acid or trifluoroacetic acid, or of a Lewis acid such as, for example, titanium tetrachloride, is advantageous. If, in compounds of the formulae I and XVI, substituents are present which can be hydrogenated or reduced under the above-described conditions, for example oxo, the use of an intermediate of the formulae I and XVI with substituents which are not attacked but which can be derivatized to the required group, for example hydroxyl, is necessary. Acid-labile groups such as, for example, acetals, or groups which react under the reaction conditions, such as, for example, primary amines, are also to be avoided or to be provided with a customary protective group.
The reaction described under I) is expediently carried out in an inert solvent. Examples of suitable solvents are aromatic hydrocarbons such as toluene or xylene, lower alcohols such as methanol, ethanol or 1-butanol, ethers such as tetrahydrofuran or glycol dimethyl ether, dipolar aprotic solvents such as N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, nitrobenzene, dimethyl sulfoxide, or mixtures of these solvents. Two-phase systems with aqueous solutions of bases in the presence of a phase transfer catalyst such as, for example, benzyltriethylammonium chloride, are also possible.
The presence of a suitable base, for example an alkali metal hydroxide or alkaline earth metal hydroxide such as potassium hydroxide or barium hydroxide, of an alcoholate such as sodium ethanolate or potassium tert.-butylate, an organolithium compound such as butyllithium or lithium diisopropylamide, an alkali metal hydride or alkaline earth metal hydride such as sodium hydride or calcium hydride, an alkali metal fluoride such as potassium fluoride, or an organic base such as triethylamine or pyridine, may be useful. The reaction is usually carried out at temperatures between -10 and 160°C, preferably at room temperature.
To carry out this reaction, any nucleophilic substituents in compounds XVII and XVIII which do not participate in the reaction, such as, for example, hydroxyl, mercapto or amino groups, are to be derivatized in a suitable manner or to be provided with customary protective groups such as, for example, acetyl or benzyl, which can then be eliminated.
The compounds XVII which are required for the abovementioned reaction and in which the definitions described under 1) - 4) apply to R1, R2, R3 and R4, n is 0, 1, 2 or 3, X is oxygen and U is a suitable leaving group, halogen such as, for example, chlorine, bromine, iodine, a halogenated aliphatic or aromatic alcoholate such as, for example, 2,2,2-trichloroethoxy, chlorophenoxy, or a heterocycle which is linked via nitrogen such as, for example, imidazolyl, triazoly, or benzotriazolyl, are prepared by reacting a compound of the formula I where R5 is hydrogen and X is oxygen, and the definitions described under 1)-4) apply to R1, R2, R3 and R4, with a suitable carbonic acid derivative, for example phosgene, diphosgene, triphosgene, trichloroethyl chloroformate or carbonyldiimidazole, or with a suitable halo carbonyl halide, for example bromoacetyl chloride.
The reaction is expediently carried out in an inert solvent. Examples of suitable solvents are aromatic hydrocarbons such as toluene or xylene, ethers such as tetrahydrofuran or glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane or dichloroethane.
The presence of a suitable base, for example of an alkali metal hydroxide or alkaline earth metal hydroxide, such as potassium hydroxide or barium hydroxide, or an organic base such as triethylamine or pyridine, may be useful.
The reaction is usually carried out at temperatures between -30 and 160°C, preferably at room temperature.
The present invention furthermore relates to the compounds as described under 1) to 4) as pharmaceuticals, preferably for treating viral diseases, in particular diseases caused by HIV.
The invention furthermore relates to pharmaceuticals comprising at least one compound according to the invention, and to the use of the abovementioned compounds for the preparation of pharmaceuticals, preferably for the treatment of viral diseases, in particular for the treatment of diseases caused by HIV.
The present invention furthermore relates to the use of compounds of the abovementioned formula I or IA in which n is zero, one, two, three or four, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, Cj-Cg-alkyl, C5-CB-cycloalkyl, C^Cg-alkoxy, (C^Cg-alkoxyJ-^-C^alkoxy), C^Cg-alkylthio, C^Ce-alkylsulfinyl, C,-Ce-alkylsulfonyl, nitro, amino, azido, C^Cg-alkylamino, di(C,-C6-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C^Ce-acyl, C^Cg-acyloxy, C^Cg-acylamino, cyano, carbamoyl, carboxyl, (C^Cg-alkyQoxycarbonyl, hydroxysulfonyl, sulfamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five radicals R6 which are independent of one another, where R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C,-C6-alkyl, C3-Ce-cycloalkyl, C,-C6-aIkoxy, C,-C6-alkylthio, C,-C6-alkylsulfinyl, C^Ce-alkylsulfonyt, C^Ce-alkylamino, diiC^Cg-alkylJamino, (C^Cg-alkyQoxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R2 and R5 are identical or different and independently of one another are hydrogen, hydroxyl, C,-Ce-alkoxy, aryloxy, C,-C6-acyloxy, cyano, amino, C^Cg-alkylamino, diiC^Cg-alkylJamino, arylamino, C^Cg-acylamino, C,-Ce-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-Ce-alkoxy, C^Cg-alkylamino, di^-Cg-alkyOamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Cg-alkylJamino, C,-Cg-alkylthio, C,-C6-alkylsu!fonyl, phenylsulfonyl, oxo, thioxo, carboxyl and carbamoyl; C3-Ce-allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; C3-CB-alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di^-Cg-alkylJamino, C,-C6-alkylthio, C^-Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Ce-alkylJamino, C,-Ce-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C8-alkoxy. C^Cg-alkylamino, di(C^Cg-alkyl)amino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkyl)- (C, -C4-al ky I), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diCC^Cg-alkylJamino, CrCg-alkylthio, C,-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkenyl)- (C, -C4-alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C^Cg-alkylamino, diCC^Cg-alkylJamino, C,-Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di(C,-C6-alkyl)amino, C,-C8-alkylthio, C^Ce-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C2-C8-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^-alkoxy, oxo, phenyl; (C3-C8-cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^-alkoxy, oxo, phenyl; (C5-C8-cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; (Ca-Ce-cycloalkylHC^Ca-alkylJcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl)-(C,-C3-alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo, phenyl; C^Ce-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^-alkoxy, C^Cralkylamino, diiC^C^alkyQamino, C,-C4-alkylthio; C2-C8-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl; C2-C8-alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C2-C8-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, Ο,-C^alkoxy, oxo, phenyl; C,-C8-alkylamino- and di^-Ce-alkyQaminocarbonyl, in each case optionally 5 substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl, in each case optionally substituted by C,-C4-alkyl, C2-C6-alkenyl, Ct-C4-acyl, oxo, thioxo, carboxyl, or phenyl; C2-C8-alkenylamino- and di(C,-C6-alkenyl)aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo, phenyl; C^Cg-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-^15 alkoxy, oxo, phenyl; C^Cg-alkeny I sulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C4alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl, each of which is substituted by up to five radicals R® which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 5 carbon atoms, and R® being as defined above, or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroaryialkyloxycarbonyl, heteroaryl(alkylthio)carbonyl or heteroarylalkylaminocarbonyl, each of which is substituted by up to three radicals R6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, R3 and R4 are identical or different and, independently of one another, are hydrogen, C,-Ce-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy. C,-C4-aIkylamino, di(C,-C4-alkyI)amino, C,-C4alkylthio, C^C^alkylsulfonyl, C^C^alkylsulfinyl, earboxyl or carbamoyl; C2-C8-alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4alkylamino, di(C1-C4-alkyl)amino, C^C^alkylthio, C^C^alkylsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-C8-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4alkylamino, di^-C^alkyQamino, C^C^alkylthio, C^C^alkylsulfonyl, C,-C4alkylsulfinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C4-alkylamino, diCC^C^-alkylJamino, C^C^alkylthio, C1-C4-alkylsuffonyl, C,-^alkylsulfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to five radicals R6 which are independent of one another, it being possible for the alkyl radical to contain 1 to 3 carbon atoms in each case, and Re being as defined above, R3 and R4 or R3 and R5 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 8 carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C6-alkyl, C2-C6-alkenyl, C2-Ce-alkynyl, C^Cg-acyloxy, benzoyloxy, C^C^alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X is oxygen, sulfur, selenium or substituted nitrogen N-R2, it being possible for R2 to have the abovementioned meanings, for the preparation of pharmaceuticals for the treatment of viral diseases.
The compounds mentioned and elucidated above under 1)-4) are preferred for this use.
The pharmaceuticals according to the invention can be administered enterally (orally), parenterally (intravenously), rectally, subcutaneously, intramuscularly or locally (topically).
They can be administered in the form of solutions, powders, (tablets, capsules including microcapsules), ointments (creams or gels) or suppositories. Suitable adjuvants for such formulations are the liquid or solid fillers and extenders, solvents, emulsifiers, glidants, flavorings, colorings and/or buffer substances which are customary in pharmacology. 0.1 -10, preferably 0.2 - 8 mg/kg of body weight are administered once or several times daily as an expedient dosage. The dosage units used depend expediently on the specific pharmacokinetics of the substance used, or on the pharmaceutical formulation used.
For example, the dosage unit of the compounds according to the invention is 1 - 1500 mg, preferably 50 - 500 mg.
The compounds according to the invention can also be administered as a combination with other antiviral agents such as, for example, nucleoside analogs, protease inhibitors or adsorption inhibitors, immunostimulants, interferons, interleukins and colony-stimulating factors (for example GM-CSF, G-CSF, M-CSF).
Activity tests Test of preparations against HIV in cell culture Description of method Medium: RMPI pH 6.8 Complete medium additionally contains 20% fetal calf serum and 40 lU/ml recombinant interleukin 2.
Cells: Lymphocytes which have been isolated from fresh donor blood by means of Ficoll' gradient centrifugation are cultured for 36 hours in complete medium with an addition of 2 pg/ml phytohemagglutinin (Wellcome) at 37°C under 5% of CO2. After 10% of DM SO has been added, the cells are frozen at a density of 5 10® and stored in liquid nitrogen. For the test, the cells are defrosted, washed in RPMI medium and cultured for 3 - 4 days in the complete medium.
Mixture: The test preparations were dissolved in DMSO at a concentration of 16.7 mg/ml and diluted in complete medium to 1 mg/ml. 0.4 ml of medium was introduced into 24-multiwell dishes. 0.1 ml of the dissolved preparation was added to the upper row of the dish, and, by transferring 0.1 ml portions, a geometric dilution series was established. Controls without preparation always contained 0.4 ml of complete medium containing 0.5% of DMSO. Lymphocyte cultures with a cell density of 5 105 cells/ml were infected by adding 1/50 volume supernatant from HIV-infected lymphocyte cultures. The titer of these culture supernatants was determined by end-point titration as 1 - 5 106 infectious units/ml. After 30 minutes’ incubation at 37°C, the infected lymphocytes were removed by centrifugation and taken up in an equal volume of medium. From this cell suspension, 0.6 ml aliquots were transferred into all wells of the test plate. The mixtures were incubated for 3 days at 37°C. _ Evaluation: The infected cell cultures were examined under the microscope for the presence of giant cells, which indicate active virus multiplication in the culture. The lowest concentration of preparation where no giant cells were observed was determined as inhibitory concentration against HIV. As a control, the supernatants from the culture plates were tested for the presence of HIV antigen with the aid of an HIV antigen test following the manufacturer’s instructions (Organon).
Results: The results from this test are shown in Table 1.
Compound of Example No. T-cell culture assay MIC Gvg/ml) Ill 0,8 IV > 0,8 Vl-A 0,16 Compound of Example No. T-cell culture assay MIC Ovg/ml) Vl-B 20 Vl-C < 0,8 VII < 0,16 X 0,8 XII < 0,8 XIII < 0,16 XIV < 0,16 3-7 0,08 3-21 0,16 3-23 0,08 3-24 0,08 3-25 0,4 3-26 0,4 3-29 < 0,4 3-30 < 0,01 3-32 < 0,4 3-33 0,4 3-36 < 2,0 3-44 < 0,8 Compound of Example No. T-cell culture assay MIC Ovg/ml) 3-48 < 0,8 3-49 < 0,8 3-52 > 0,8 3-53 > 0,8 3-57 < 0,8 3-62 < 4,0 3-64 > 0,8 3-66 > 0,08 3-67 < 0,8 3-73 > 0,4 3-75 < 0,8 3-76 < 0,08 3-80 0,4 3-81 0,08 3-87 > 0,8 3-88 0,8 XX < 4,0 6-1 0,4 6-16 < 0,8 Compound of Example No. T-cell culture assay MIC fr/g/ml) 6-17 < 0,8 6-19 < 0,8 6-20 < 0,8 6-22 > 0,8 6-27 < 0,4 6-32 < 0,08 6-33 > 0,8 6-34 < 0,4 6-35 < 0,08 6-36 < 0,8 6-39 0,4 6-41 < 20 6-50 < 0,01 XXIII < 0,01 7-1 < 0,16 7-2 < 0,01 7-3 < 0,01 7-7 0,04 7-10 < 0,04 Compound of Example No. T-cell culture assay MIC (i/g/ml) 7-11 < 0,01 7-12 < 0,8 7-13 < 0,08 7-14 < 0,08 7-16 0,4 7-21 < 0,01 7-22 < 0,01 7-23 < 0,01 10-4 0,4 10-5 < 0,8 10-9 < 0,8 10-10 0,08 10-13 0,08 10-14 < 0,8 10-17 0,8 10-18 < 0,8 10-20 < 0,8 10-21 < 0,8 10-27 0,8 5Θ Compound of Example No. T-cell culture assay MIC G/g/ml) 10-28 < 0,8 11-1 < 0,8 11-2 > 0,8 11-3 < 0,8 11-4 0,8 11-11 0,01 Assay of the substances for HIV reverse transcriptase inhibition The activity of reverse transcriptase (RT) was determined with the aid of a scintillation proximity assay (SPA).
The reagent kit for the RT-SPA was obtained from Amersham/Buchler (Braunschweig) The enzyme RT (from HIV cloned in E. coli) originated from HT-Biotechnology Ltd, Cambridge, UK.
Mixture The assay was carried out using the manufacturer’s (Amersham) protocol manual, with the following modifications: bovine serum albumin was added to the assay buffer to give an end concentration of 0.5 mg/ml the assay was carried out in Eppendorf reaction vessels, using 100 pi volume per batch the manufacturer’s RT concentrate (5000 U/ml) was diluted in Tris-HCl buffer 5 20 mM; pH 7.2; 30% of glycerol, to an activity of 15 U per ml the incubation time for the mixtures was 60 minutes (37°C) after stopping the reaction and developing with the bead suspension, 130 pi of 10 mixture were transferred to 4.5 ml of Tris-HCl buffer, 10 mM; pH 7.4; 0.15 M NaCl, and the tritium activity was measured by means of a e-counter.
Assay For a pre-assay for inhibitory activity, the substances were dissolved in DMSO (stock solution c = 1 mg/ml), and tested as a 10Ί, 10‘2, 10'3, etc., dilution in DMSO.
To determine IC50 values, the inhibitor stock solutions were diluted further in Tris-HCl buffer, 50 mM, pH 8, and tested in suitable concentrations.
The concentration corresponding to a 50% enzyme inhibition was determined from a plot of RT activity versus log C,nh.
The test results are shown in Table 1a.
Table 1a Compound of Example No. Reverse Transcriptase Assay IC50 G/0/ml) V 7,5 Vl-A 0,08 Vl-C 0,8 VII 0,1 XIII 0,04 XIV 0,16 3-23 0,1-1 3-24 0,1 - 1 3-25 0,1-1 3-29 0,1 - 1 3-30 0,025 3-32 approx. 0,1 3-36 0,1-1 3-49 approx. 1 3-57 approx. 1 3-75 0,1-1 3-76 0,018 3-81 approx. 1 Compound of Example No. Reverse Transcriptase Assay ICgo 0/g/ml) 6-1 approx. 1 6-8 0,1-1 6-9 approx. 1 6-16 approx. 1 6-17 0,1 -1 6-27 approx. 1 6-35 0,1-1 6-50 0,01-0,1 XXIII 0,025 7-1 0,08 7-2 0,07 7-3 0,07 7-7 0,1 7-10 0,11 7-11 0,01 7-12 approx. 1 7-13 0,1-1 7-16 approx. 1 10-9 approx. 1 Compound of Example No. Reverse Transcriptase Assay ICM (pg/ml) 10-10 approx. 1 10-13 approx. 1 10-17 approx. 1 10-18 0,1 -1 10-20 0,1 -1 10-21 0,1 -1 10-27 0,1 - 1 10-28 0,1-1 11-11 0,1 - 1 10-34 0,1 - 1 11-6 0,1 - 1 11-5 0,1 - 1 11-7 approx. 1 11-13 approx. 1 7-20 0,1 - 1 7-14 0,01 -0,1 7-15 0,01 - 0,1 7-17 0,01 - 0,1 7-18 0,01 - 0,1 Compound of Example No. Reverse Transcriptase Assay ICM fc/g/ml) 7-19 0,01 - 0,1 7-21 0,01 - 0,1 7-22 0,01 - 0,1 7-23 0,01 - 0,1 3-34 0,1-1 3-35 0,1 - 1 3-37 0,1 - 1 3-7 0,08 3-127 0,01 - 0,1 3-128 0,01 - 0,1 3-129 0,01 - 0,1 7-24 < 0,01 7-25 < 0,01 7-26 0,01 - 0,1 7-27 0,1 - 1 7-28 < 0,01 7-29 0,01 - 0,1 7-30 < 0,01 7-31 < 0,01 IC50 = 0.08pg/ml The examples which follow and the content of the patent claims illustrate the present invention in greater detail.
Example I (3S)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one A) (S)-N-(3-Chloro-6-nitrophenyl)alanine 2,4-Dichloronitrobenzene (21.0 g, 0.109 mol) and 23.0 g (0.258 mol) of L-alanine were refluxed for 48 hours in 400 ml of 2-methoxyethanol with an addition of 120 ml of 2N sodium hydroxide solution. The mixture was subsequently concentrated in vacuo, and the residue was taken up in aqueous sodium hydrogen carbonate solution, the mixture was extracted three times using ethyl acetate, the extract was then acidified with 6N hydrochloric acid, and the yellow product was extracted using ethyl acetate. The organic phase was washed once with saturated aqueous sodium chloride solution and dried (magnesium sulfate), and the solvent was removed under reduced pressure. 14.7 g (55%) of a yellow solid of melting point 167-169°C remained (after crystallization from ethyl acetate). 1H NMR (270 MHz, d6-DMSO): δ = 1.47 (d, J = 7 Hz, 3 H), 4.57 (quintet, J = 7 Hz, H), 6.77 (dd, J = 9, 2 Hz, 1 H), 7.11 (d, J = 2 Hz, 1 H), 8.12 (d, J = 9 Hz, 2 H), 8.41 (br. d, J = 7 Hz, 1 H), 13.2 ppm (br., 1 H).
MS: (M + H)+ = 245 B) (3S)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(1 H)-one The product of Example IA (14.0 g, 0.057 mol) was dissolved in 400 ml of methanol and hydrogenated with Raney nickel catalysis at room temperature, using 1 atm hydrogen. After the calculated amount of hydrogen had been taken up, the catalyst was removed by filtration with suction, and the reaction solution was concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/heptane = 1:2 and 1:1 as the eluent. The yield was 6.0 g (53%) of a brownish solid of melting point 122-123°C (after recrystallization from isopropanol/heptane). 1H NMR (60 MHz, d6-DMSO): δ = 1.23 (d, J = 11 Hz, 3 H), 3.81 (dq, J = 11, 4 Hz, 1 H), 6.27 (br., 1 H), 6.3 - 6.9 (m, 3 H), 10.3 ppm (br., 1 H).
MS: (M + H)+ = 197 [σ]023 = +77.3° (c = 1, MeOH) C) (3R)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(1 H)-one The compound was prepared from D-alanine by the methods described under Example IA and IB. Melting point 123-124°C (after recrystallization from isopropanol/heptane) The NMR data agree with those of the compound described in Example IB. [σ]023 = -81.0° (c = 1, MeOH) D) (3RS)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(1 H)-one The compound was prepared starting from D.L-alanine by the methods described in 20 Examples IA and IB. Melting point 110°C (after recrystallization from isopropanol/heptane) The NMR data agree with those of the compound described in Example IB.
The following compounds of the formula I were synthesized analogously using the 25 corresponding haloaromatic compounds and amino acid derivatives: Example II (3S)-3-Benzyl-7-chloro-3,4-dihydroquinoxalin-2(1H)-one A) (S)-N-(4-chloro-2-nitrophenyl)-phenylalanine 5 L-Phenylalanine (8.3 g, 0.05 mol) and 4.8 g (0.025 mol) of 2,5-dichloronitrobenzene were dissolved in 40 ml of anhydrous dimethyl sulfoxide (DMSO), and the stirred solution was heated to 80 °C under an argon atmosphere. Potassium tert.-butylate (4.2 g, 0.025 mol), dissolved in 30 ml of DMSO, was added dropwise in the course of 40 minutes. Stirring was continued for 3 hours at 80 to 90°C, the mixture was allowed to cool, and unreacted phenylalanine was removed by filtration with suction and washed with water. The collected alkaline filtrates were extracted twice using diethyl ether to remove unreacted dichloronitrobenzene. The mixture was then acidified using glacial acetic acid and extracted several times using ethyl acetate, and the extracts were dried over magnesium sulfate and evaporated.
The product was obtained in the form of a red oil (6.7 g, 84%), which was further reacted without purification.
B) (3S)-3-Benzyl-7-chloro-3,4-dihydroquinoxaIin-2(1H)-one The product of Example IIA (12 g) was dissolved in 300 ml of anhydrous methanol and hydrogenated at room temperature with paliadium/charcoal catalysis, using 1 atm hydrogen. When the reaction had ended, solids were filtered off with suction, the liquid was concentrated, and the concentrate was chromatographed on silica gel using diisopropyl ether as the eluent. This gave 1.32 g of the desired product which crystallized from isopropanol, melting point 185°. 1H NMR (270 MHz, d6-DMSO): δ = 2.9 (m, 2 H), 4.08 (m, 1 H), 6.09 (d, 1 H), 6.7 (m, 2 H), 6.78 (m, 1 H), 7.2 (m, 5 H), 10.34 ppm (br. s, 1 H).
MS: (M + H)+ = 273, (M - 92)+ = 181.
The compounds in Table 2 were prepared as described in the above examples.
Table 2 H R5 Nr. R3 R5 M.P.°C 1 5-CI ch3 H Wax 2 6-CI c2h5 H 120 3 6-CI c2h4cooh H 4 6-CI -ch2ch2co- 5 6-CI (CH3)2CH H 6 6-CI (CH3)2CHCH2 H Oil 7 6-CI C2Hs(CH3)CH H Oil 8 6-CI c6h5ch2 H 156-157 Nr. R3 R5 M.P.°C 9 6-CI CH3SCH2CH2 H 97 10 6-CI ch3sch2 H 149 11 6-CI CH2(OH) H 12 6-CI ch3ch2ch2 H 75 - 77 13 7-CI ch3 H 142 14 7-CI (CH3)2CH H Oil 15 7-CI ch3sc2h4 H 98 16 8-CI ch3 H 17 6,7-CL, ch3 H 18 7-F ch3 H 230 19 6-F ch3 H Wax 20 6-F ch3 c3h5 182 21 6-F c6h5ch2 c3h5 22 7-CF3 ch3 H 147 23 6-CH3OC2H4O c2h6 H 107 24 6-CI c2h4oh H 211 25 6-CI CH2-S-Bn H 170 26 6-CI CH2-S-i.-Pr H 190 27 6-CI CH2O-t.-Bu H 128 28 6-CI C4Hb H 115 Bn = benzyl i-Pr = isopropyl t-Bu = tert.-butyl Example III (3S)-4-N-(Benzyloxycarbonyl)-6-chloro-3-methyl-3,4-di-hydroquinoxalin-2(1H)-one The compound of Example IB (1.0 g, 5.1 mmol) was dissolved in 20 ml of dichloromethane. 10 ml of 2N aqueous sodium hydrogen carbonate solution were added, and 0.9 ml (90%; 5.7 mmol) of benzyl chloroformate was added with icecooling and vigorous stirring. The two-phase system was subsequently stirred for 60 hours at room temperature. After 30 hours, another 0.2 ml (1.3 mmol) of benzyl chloroformate was added. When the reaction was complete, the phases were separated, the organic phase was washed once with water and dried (magnesium sulfate), and the solvent was removed in vacuo. The product was purified by silica gel chromatography with methyl tert.-butyl ether/heptane = 1:1 as the eluent. This gave 1.65 g (98%) of a white, foam-like product. 1H NMR (270 MHz, d6-DMSO): δ = 1.15 (d, J = 7 Hz, 3 H), 4.85 (q, J = 7 Hz, H), 5.20 (d, J = 12 Hz, 1 H), 5.27 (d, J = 12 Hz, 1 H), 6.97 (d, J = 7 Hz, 1 H), 7.19 (dd, J = 8.2 Hz, 1 H), 7.3 - 7.45 (m, 5 H), 7.67 (d, J = 2 Hz, 1 H), 10.81 ppm (br. s, 1 H).
MS: (M + H)+ = 381 Example IV (3S)-4-N-(Benzyloxycarbonyl)-6-chloro-3-methyl-8-nitro-3,4-dihydroquinoxalin2(1H)-one The compound of Example III (1.5 g, 4.5 mmo!) was nitrated in glacial acetic acid (15 ml). A total of 5 ml (124.3 mmol) of fuming nitric acid were added dropwise in the course of 4 hours at 0°C to room temperature. The mixture was subsequently poured into 100 ml of ice-water, and the product, which was obtained in the form of a yellow solid, was filtered off, washed thoroughly with water, and dried. Melting point 85°C (subl.). 1H NMR (270 MHz, d6-DMSO): δ = 1.22 (d, J = 8 Hz, 3 H), 4.89 (q, J = 8 Hz, H), 5.24 (d, J = 12 Hz, 1 H), 5.31 (d, J = 12 Hz, 1 H), 7.35 - 7.5 (m, 5 H), 7.69 (s, 1 H), 8.00 (s, 1 H), 11.11 ppm (br. s, 1 H).
MS: (M + H)+ = 376 Example V (3S)-8-Amino-4-N-(benzyloxycarbonyl)-6-chloro-3-methyl-3,4-dihydroquinoxalin2(1H)-one The compound of Example IV (1.5 g, 4.0 mmol) was dissolved in 150 ml of methanol and hydrogenated at room temperature with Raney nickel catalysis, using 1 atm hydrogen. When the calculated amount of hydrogen had been taken up, the catalyst was removed by filtration with suction, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography using ethyl acetate/heptane = 2:1 as eluent. The yield was 0.68 g (49%) of brownish solid of melting point 152-154°C. Ή NMR (270 MHz, d6-DMSO): δ = 1.11 (d, J = 8 Hz, 3 H), 4.79 (q, J = 8 Hz, H), 5.15 (d, J = 12 Hz, 1 H), 5.24 (d, J = 12 Hz, 1 H), 5.38 (br. s, 2 H), 6.42 (s, H), 7.3-7.4 (m, 6 H), 10.59 ppm (br. s, 1 H).
MS: (M + H)+ = 346 Example VI A) (3S)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydroquinoxalin2(1H)-one The compound of Example IB (1.0 g, 5.0 mmol) was dissolved in 20 ml of acetonitrile and alkylated with 3-methyl-2-buten-1-yl bromide (90%; 0.92 ml, 7.0 mmol) at room temperature in the presence of 1.0 g (7.0 mmol) of pulverulent potassium carbonate. After 7 hours, the reaction had ended. The mixture was filtered off with suction, the filtrate was concentrated in vacuo, and the product was purified by silica gel chromatography using ethyl acetate/heptane = 1:2 as eluent. The yield was 0.97 g (72%) of brownish solid of melting point 117-118°C (after crystallization from methyl tert.-butyl ether/heptane). Ή NMR (270 MHz, d6-DMSO): 6 = 1.02 (d, J = 8 Hz, 3 H), 1.74 (s, 6 H), 3.69 (dd, J = 14, 8 Hz, 1 H), 3.85 - 3.9 (m, 2 H), 5.19 (m, 1 H), 6.65 - 6.8 (m, 3 H), .47 ppm (br. s, 1 H).
MS: (M + H)+ = 265 [σ]023 = +168.0° (c = 1, MeOH) B) (3R)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1 -yl)-3,4-dihydroquinoxalin2(1H)-one The compound was prepared by the method described in Example VIA, starting from the compound of Example IC. Melting point 115-117°C (after recrystallization from isopropanol/diethyl ether) The NMR data agreed with those of the compound described in Example VIA. [o]D23 = -172° (c = 1, MeOH) C) (3RS)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydroquinoxalin2(1H)-one The compound was prepared by the method described in Example VIA starting with the compound of Example ID. Melting point 148-149°C (after recrystallization from isopropanol/diethyl ether) The NMR data agreed with those of the compound described in Example VIA.
Example VII (3S)-6-Chloro-3-methyl-4-N-(2-buten-1-yl)-3,4-dihydroquinoxalin-2(1H)-one The substance was prepared analogously to the compound described in Example VIA, but with 2-buten-1-yl bromide as the alkylating agent. Melting point 87-88°C (after crystallization from diethyl ether/heptane) Ή NMR (270 MHz, d6-DMSO): δ = 1.01 (d, J = 8 Hz, 3 H), 1.70 (dd, J = 8, 1 Hz, H), 3.63 (dd, J = 16, 6 Hz, 1 H), 3.85 - 4.0 (m, 2 H), 5.47 (m, 1 H), 5.75 (m, 1 H), 6.65 - 6.8 (m, 3 H), 10.48 ppm (br. s, 1 H).
MS: (M + H)+ = 251 Example VIII 4-N-(lsopropenyloxycarbonyl)-3,3l7-trimethyl-3,4-di-hydroquinoxalin-2(1 H)-one 3,3,7-Trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.4 g, 2.1 mmol) were dissolved in 10 ml of anhydrous pyridine, and the stirred solution was treated at room temperature with 0.24 ml (2.2 mmol) of isopropenyl chloroformate. The mixture was stirred for 6 hours at room temperature and treated with water, the precipitate which formed was filtered off with suction, washed with water and dried. This gave 0.4 g (69%) of colorless crystals of melting point 185°C. 1H NMR (270 MHz, d6-DMSO): δ = 1.5 (s, 6 H), 1.9 (s, 3 H), 2.25 (s, 3 H), 4.7 (m, H), 6.7 - 6.9 (m, 2 H), 7.15 (d, J = 8 Hz, 1 H), 10.6 ppm (br. s, 1 H).
MS: + = 274 Example IX (3S)-6-Chloro-4-N-(4-methoxyphenoxycarbonyl)-3-methyl-3,4-dihydroquinoxalin2(1H)-one The compound of Example IB (0.5 g, 2.55 mmol) was dissolved in 10 ml of anhydrous Ν,Ν-dimethylformamide, and 0.41 ml (2.8 mmol) of triethylamine were added. To the stirred mixture there was first added dropwise 0.42 ml (2.8 mmol) of 4-methoxyphenyl chloroformate and, after 2 hours, another 0.21 ml (1.9 mmol). When the reaction was complete (18 hours), the solvent was stripped off under reduced pressure, the residue was taken up in ethyl acetate, and the mixture was washed with water and dried (sodium sulfate). 0.48 g (54%) of a white solid remained after concentration. Melting point 187-190°C (after recrystallization from isopropanol) 1H NMR (270 MHz, d6-DMSO): δ = 1.24 (d, J = 8 Hz, 3 H), 3.77 (s, 3 H), 4.94 (q, J = 8 Hz, 1 H), 6.97 (dd, J = 8, 2 Hz, 1 H), 7.03 (d, J = 8 Hz, 1 H), 7.2 - 7.3 (m, H), 7.78 (s, 1 H), 10.89 ppm (br. s, 1 H).
MS: (M + H)+ = 347 Example X (3S)-6-Chloro-4-N-(4-fluorophenoxycarbonyl)-3-methyl-3,4-dihydroquinoxalin2(1H)-one The compound was prepared analogously to the compound described in Example VIA, but 4-fluorophenyl chloroformate was used as acylating agent. Melting point 168-170°C (after crystallization from isopropanol) 1H NMR (270 MHz, d6-DMSO): δ = 1.24 (d, J = 8 Hz, 3 H), 4.94 (q, J = 8 Hz, H), 7.03 (d, 8 Hz, 1 H), 7.2 - 7.5 (m, 5 H), 7.83 (d, J = 2 Hz, 1 H), 10.90 ppm (br. s, 1 H).
MS: (M + H)+ = 335 Example XI (3S)-6-Chloro-4-N-(4-chlorophenoxycarbonyl)-3-methyl-3,4-dihydroquinoxalin2(1H)-one The compound was prepared analogously to the compound described in Example VIA, but 4-chlorophenyl chloroformate was used as acylating agent. Melting point 185-188°C (after crystallization from isopropanol/diethyl ether) 1H NMR (270 MHz, d6-DMSO): δ = 1.25 (d, J = 8 Hz, 3 H), 4.94 (q, J = 8 Hz, H), 7.04 (d, 8 Hz, 1 H), 7.25 (dd, J = 8, 2 Hz, 1 H), 7.35 - 7.6 (m, 4 H), 7.80 (s, 1 H), 10.91 ppm (br. s, 1 H).
MS: (M + H)+ = 351 Example XII (3S)-4-N-(2-BromoethyloxycarbonyI)-6-chloro-3-methyl-3,4-dihydroquinoxalin15 2(1H)-one The compound was prepared analogously to the compound described in Example VIA, but 2-bromoethyl chloroformate was used for the acylation. Melting point 133-136°C (after crystallization from isopropanol) 1H NMR (270 MHz, d6-DMSO): δ = 1.16 (d, J = 8 Hz, 3 H), 3.7 - 3.8 (m, 2 H), 4.4 4.6 (m, 2 H), 4.86 (q, J = 8 Hz), 6.99 (d, 8 Hz, 1 H), 7.21 (dd, 8, 2 Hz, 1 H), 7.74 (d, J = 2 Hz, 1 H), 10.84 ppm (br. s, 1 H).
MS: (M + H)+ = 348 Example XIII (3S)-6-Chloro-N-(isopropenyloxycarbonyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one The substance was prepared analogously to the compound described in Example VIA, but isopropenyl chloroformate was used for the acylation. Melting point 158-159°C 1H NMR (270 MHz, CDCI3): δ = 1.33 (d, J = 8 Hz, 3 H), 2.02 (s, 3 H), 4.79 (s, H), 4.83 (s, 1 H), 5.17 (q, J = 8 Hz, 1 H), 6.86 (d, J = 8 Hz, 1 H), 7.12 (dd, J = 8, 2 Hz, 1 H), 7.74 (br. s, 1 H), 9.28 ppm (br. s, 1 H).
MS: (M + H)+ = 281 5 Example XIV (3S)-6-Chloro-3-methyl-4-N-(vinyloxycarbonyl)-3,4-di- hydroquinoxalin-2(1 H)-one The substance was prepared analogously to the compound described in Example VIA, but vinyl chloroformate was used for the acylation. Melting point 177-179°C 1H NMR (270 MHz, CDCI3): δ = 1.33 (d, J = 8 Hz, 3 H), 4.96 (dd, J = 14, 2 Hz, H), 5.20 (q, J = 8 Hz, 1 H), 6.83 (d, J = 8 Hz, 1 H), 7.12 (dd, J = 8, 2 Hz, 1 H), 7.2 - 7.3 (m, 2 H), 7.71 (br. s, 1 H), 9.42 ppm (br. s, 1 H).
MS: (M + H) + = 267 Example XV and Example XVI 6-Chloro-3,4-dihydroquinoxalin-2(1H)-one was reacted with 3-methyl-2-buten-1-yl bromide analogously to the process described in Example VIA. It was possible to isolate two products by silica gel chromatography. 6-Chloro-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydro- quinoxalin-2(1H)-one Melting point 150-151 °C (after recrystallization from ethyl acetate) 1H NMR (270 MHz, d6-DMSO): δ = 1.72 (s, 6 H), 3.67 (s, 2 H), 3.80 (d, J = 7 Hz, H), 5.20 (m, 1 H), 6.7 - 6.8 (m, 3 H), 10.49 ppm (br. s, 1 H).
MS: (M + H)+ = 251 6-Chloro-4-N-(3-methyl-2-buten-1-yl)-3-(1,1-dimethyl-2-propen-1-yl)3,4-dihydroquinoxalin-2(1 H)-one Melting point 110-112°C (after crystallization from heptane) 1H NMR (270 MHz, d6-DMSO): δ = 0.94 (s, 3 H), 0.97 (s, 3 H), 1.65 (s, 3 H), 1.66 (s, 3 H), 3.77 (dd, J = 16, 7 Hz, 1 H), 4.23 (dd, J = 16, 7 Hz, 1 H), 4.8 - 4.9 (m, H), 5.02 (m, 1 H), 5.75 (dd, J = 17, 11 Hz, 1 H), 6.6 - 6.7 (m, 3 H), 10.49 ppm (br. s, 1 H).
MS: (M + H)+ = 319 The following compounds of the formula I were synthesized from the corresponding unsubstituted quinoxalinones in analogous manner and, if appropriate, derivatized further: Table 3 Ο 0 οί Σ CD in 110 100 o 135 180 - 182 124 - 127 I . .. ___ V CO t— 253 259 - 262 > 270 > 270 180 - 182 CC Γ5 X o o V X fM o X o x" IC o in x" co o x co o in O ί < o o < P5 X o CM o ω O) I co o CM o ω w X o < 1 * X co o CM o to O 1 Μ- ι X CD o CM o ω CM o z 1 Tt 1 * X co o CM o ω CM X o II X o CM o co η CC Ci X o n X o C5 X o Pi X o n X o n X o n X o P) X o pi X o X o o X ϋ n X o Pi X o CM CC X X X X X X X X X X X X X c QC ό 1 in o in b 1 (0 b 1 CD b 1 co b 1 co b 1 co b 1 CD b 1 co b J co uJ z C\l co ^J· in CO h- 00 O) o T— - CM T" co Ο 0 CL Σ 202 216 Foam 108 - 109 co co Ύ— Foam 78-79 155-156 , 105 - 107 149-153 113-116 80-82 131 - 132 k.0 cc co I o o c\ X o o o z o 1 1 X <0 o 1 X z ω o ft n X o X o ft X o o o ιΛ X co o o o o o o ft X o II X o ft X q X o o ϋ co X o o «e X ft o co X co o ft X o O co X o 1 o υ 1 CM <0 X o ft X o o o <_> co X o ft *ft X o o o o <0 X o _eo ft X o o o o ft co X o X o ft X o o o o n cc Γ5 X o CO X o co X o CO X o co X o co X υ co X o «0 X o CO X o CO X ϋ co X υ co X o co X o c\i cc X X X X X X X X X X X X X c cc o 1 CD o CD o t CD ΰ 1 CD o 1 CD o 1 co σ co o 1 co o 1 co o 1 co p CD o 1 co ό I co z LD CD v— CO σ> o CM CM CM CM co CM ’Φ CM in CM co CM CO 0 o £L Σ O CO 155 128 175 204 148 - 150 173 149-150 135 126 - 128 144 - 145 , CM X 0 II X 0 Cd X 0 o co X 0 X 0 II X o CM X 0 o 0) X 0 O O X 0 3 8 0 O o 3 Oi X m 0 O 0 o _l O) X in ec 0 0 o Q. 0 < < 0 & < 0 co X co X in X m X U7 X CM X CM in X Cm F* X tO f*. X to CM CO X 0 X CM ***« X 0 X CM to X 0 X X O o 0 < X CM EC 0 0 o 0 0 0 0 0 0 0 0 0 0 CM ec X X X X X X X X X X X X X c 0 o 0 0 0 1 0 O w X CM $ X 0 « 0 1 0 1 0 1 0 1 0 1 0 1 EC ώ co co co co co co co co CD CD co co kJ co 0) o CM 8 Μ- in CO co 0) z CM CM CM co co CO CO co CO CO co co Ο ο CL 5 Tj- co t— 165 δ 135 δ Ό 140 co 150 decomp. l/5 EC 05 I 4/: o σι z in o O O £L 05 z 1/) o O o CL o o CL 05 z uo o 05 z 1/5 o O 3 < O O cl O> z l/l o 05 z l/5 o 05 z 1/5 o CC 05 z o 4/5 z l£ o CM z o 1/5 z (0 o CM z o 05 z o ω z CM o n z o ω z CM ϋ n z o o co z CM o z o CM z o CM Γ5 z o z υ CM z o CM n z o z ϋ Cm z o CM CO z o z ϋ CM z o Γ5 z o Γ5 z o Γ5 z o CM CC z z z z z I I z z z z z z c CC δ 1 to δ 1 to δ 1 to δ 1 to δ 1 to δ 1 to δ 1 CD δ 1 to δ to δ to CM o 1 to δ t co δ 1 in Nr. o CM co 'S’ in to V r* co O) o in in CM in υ 0 CL Σ δ 129 166 T- CM CM in 142 δ 178 CD O 148 CO in h» 155 iT cc O'. I m o o o _) < O O CL σ> X m o O O CL ϋ O _j < σ> X in o O O cl X in o O o CL o O _j < σι X in o O O _J < cc Γ5 X o CO I o n x o CM Γ5 X o X o CM CO X o X o CM ? o X o m X (0 o CM X o m X Φ o CM X o co X o CZ) w· X CM o n X o ω x’ CM o n X o co * X C\J o co X o CO X o CM CC I X X X X X X X X X X X X c cc δ t r- δ rl δ ( δ 1 h- δ 1 δ 1 δ « h- δ 1 δ 1 1^. δ δ rL LL h- LL 1 r- Nr. co in in in in CD in N- in CD in 0) in o co ω CM CO co co V CO in co Ο ο CL Σ 152-154 128-130 i 126-127 CM h- 1 O r^- o m 82-83 Resin 108 δ O o 264 kfi cc I X X X o> X ΙΛ ϋ X X 0» X m ϋ X σ> X m υ I rt X o o w X CM υ co Γ5 X o CM o to rt rt η rt rt rt rt rt rt rt rt X X X X X I X X X X I X X cc o o o □ ο ο o o o o o o o CM CC I u III o CM X o z X m o CM X p CM -C □_ X ϋ CM rt X o X o ΙΛ X CM o rt X ο rt X ϋ rt r5 X o o o o o 0) X in ϋ 0) X m ϋ 0> X in o 0» X m o rt X o o w X CM o X c 0 1 co o ϋ 0 ο ΰ p p p Cm o ω O x: CL CM o co O .c CL δ cc co co co co co co rt rL rL co Nr. CM σ> co 0) 0) in 0> 8 b- 0) co 0) 8 8 V o CM o T- co o o T- ϋ 0 Cl Σ o CM 108 CD CD 190 185 s T" CD h- w214 152 155-156 δ Ό CM X ο II O 1 >t X , CM CM CM w m £ in X o X CM o n X o X CM o CM X ο Cm X o e> £ ζ ΊΤ 3Σ ο "Τ’ ω η X o χ W· CM z z z z z τ’ .έ ιΛ ζ ο X CM CM CM CM CM «Μ Μ ο CM o X X X X X X co 1 X X ο CM o o o o o Ο ο 1 ο ο 9) τ* ο X o o o o o Ο ο. ο ο ο ιη _j cc u o o υ υ o Ο α ο ϋ υ Ο < Ζ5 η ω ω +-* ό ό Γ5 n Γ5 « « Λ « Γ5 CM CM X X X X X X X X X X X cc o o υ o o ο ο ο υ ο ο CM CC X I I χ X X X I X χ X X c o ό o υ o o ο ο 1 υ υ ο 1 ο 1 1 cc CD CD CD CD CD co co CD CD CD CD CD in CD 00 s o CM ω in CD o O o Ο o t· ν- z t— T- τ— τ— Ο ο Cl σ' 154 δ 158 δ ό 160 158 100 156 157 152 165 O σι Ο σ> ο 0) o O o O O ft X o 1 CM 1 ω co X ft X o X o o O ft X o X o o O X Ο X ο X o o Ό j < o O o cc CL ο 0- ο CL ϋ CL CL < o. o CL o □ CO 1 I 1 o ft I L_ 0. 1 ώ ft X k_ X 1 ώ μ X C CD ώ ft X C m 1 GO 'e\j X η X co X 0) X V 0) X co X co X o w ft X CO X o w ft X co X o W ft X cc o ο ο ο ο ο o o o o o o o ft cc X X X X X X X X X X X X X c ΰ δ δ δ δ ft □ hl ft Q I h- δ ( δ 4 δ δ o CO X o O, X o 1 cc cd ώ ώ ω CD «ο cd CD CD CD cd CD CD ω σ> ο CM ν- αι CM CM co CM V CM in CM 8 N- CM Φ CM O) CM z Ί— - ΊΡ" v- C5H9 = 3-methyl-2-buten-1-yl c4h7 = 2-butenyl C5H„ = 3-methyl-1 -butyl c6h„ = 2,2-dimethylcyclopropyl-1 -methyl sC6Hn = 4-methyl-3-penten-2-yl C3H3 = 2-propen-1-yl (CH3)zCCHCO = 3,3-dimethylacryl IPOC = isopropenyloxycarbonyl ALAC = allylaminocarbonyl ALOC = allyloxycarbonyl c4h3o = furanyl c4h3s = thienyl c£h4n = pyridyl Ph = phenyl Example XVII 6,7-Dimethoxy-3-methyl-3,4-dihydroquinoxalin-2(1H)-one 4,5-Dimethoxy-1,2-dinitrobenzene (34.2 g, 0.15 mol) was hydrogenated in 500 ml of 5 methanol with Raney nickel catalysis using 1 atm hydrogen. After the calculated amount of hydrogen had been taken up, the process was stopped, the catalyst was removed by filtration with suction, and the solvent was stripped off in vacuo.
To remove the water completely, the mixture was taken up twice in methanol and reconcentrated. 4,5-Dimethoxy-1,2-phenylenediamine (24.0 g), which remained as a brown oil, was refluxed for 48 hours in 200 ml of ethanol (96%) together with 17.1 ml (0.15 mol) of methyl 2-chloropropionate, with an addition of 21.0 ml (0.15 mol) of triethylamine. The solution, which was very dark, was concentrated, the concentrate was taken up in ethyl acetate, the mixture was washed twice with water and dried (sodium sulfate), and the solvent was stripped off in vacuo.
The crude product was crystallized by stirring with diethyl ether (6.2 g, 19%). A analytically pure sample of melting point 151 °C was obtained by silica gel chromatography using ethyl acetate as the eluent. 1H NMR (60 MHz, d6-DMSO): 6 = 1.22 (d, J = 7 Hz, 3 H), 3.63 (s, 3 H), 3.67 (s, H), 3.6 - 3.7 (m, 1 H), 5.62 (br. s, 1 H), 6.40 (s, 1 H), 6.45 (s, 1H), 9.90 ppm (br. s, 1 H).
MS: M’ = 222 The following compounds of the formula I were synthesized in analogous manner and, if appropriate, derivatized further: Table 4 Nr. R3 R5 X M.P.°C 1 6,7-(CH3O)2 ch3 IPOC O 133 2 6,7-(CH3O)2 ch3 IPOC S 3 6-C6H5S ch3 CsHe O 115 4 7-C6H5S ch3 CSH, O 107 5 6-C6H5S ch3 H O 6 7-C6H5S ch3 H 0 7 6,7(CH3O)2 ch3 H 0 151 Key: C5H9 = 3-methyl-2-buten-1-yl IPOC = isopropenyloxy carbonyl Example XVIII (3RS)-6-Chloro-4-N-(cyclopropyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one A) (2RS)-N-(4-Chloro-2-cyclopropylaminophenyl)-(2-bromopropionamide) 4-Chloro-2-cyclopropylaminonitrobenzene (2.10 g, 0.01 mol) was hydrogenated in 100 ml of methanol with Raney nickel catalysis, using 1 atm hydrogen. After the calculated amount of hydrogen had been taken up, the process was stopped, the catalyst was removed by filtration with suction, and the solvent was stripped off in IE 971187 vacuo. To remove water completely, the mixture was taken up twice in methanol and reconcentrated. 4-Chloro-2-cyclopropylaminoaniline (1.80 g), which remained in the form of a brown oil, was dissolved in 50 ml of anhydrous 1,2-dimethoxyethane and cooled to -60°C, with stirring. A solution of 1.1 ml (0.01 mol) of 2-bromopropionyl chloride in 5 ml of anhydrous 1,2-dimethoxyethane was slowly added dropwise, and stirring of the reaction mixture was continued for 2 hours at -60 - -70°C. The mixture was then allowed to warm to approx. -20°C and poured into 150 ml of ice-cold, saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice using ethyl acetate, and the organic phase was washed once with water, dried (sodium sulfate) and concentrated in vacuo. After crystallization with diethyl ether/pentane, 2.51 g (79%) of the desired product of melting point 130°C remained. 1H NMR (270 MHz, d6-DMSO): <5 = 0.4 - 0.5 (m, 2 H), 0.7 - 0.8 (m, 2 H), 1.75 (d, J = 7 Hz, 3 H), 2.39 (m, 1 H), 4.72 (q, J = 7 Hz, 1 H), 5.6 (br. s, 1 H), 6.66 (dd, J = 8, 2 Hz, 1 H), 6.96 (d, J = 2 Hz, 1 H), 7.21 (d, J = 8 Hz, 1 H), 9.36 ppm (br.
S, 1 H).
MS: (M + H)+ = 319, 317 B) (3RS)-6-Chloro-4-N-(cyclopropyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one The compound of Example XVIIIA (318 mg, 1.0 mmol) was dissolved in 20 ml of ethanol (96%), 0.28 ml (2.0 mmol) of triethylamine were added, and the mixture was refluxed for 18 hours. The solvent was removed under reduced pressure, and the reaction product was purified by silica gel chromatography using ethyl acetate/heptane = 1:2 as eluent. The yield was 200 mg (85%) of white crystals of melting point 167°C (after crystallization from pentane). Ή NMR (270 MHz, d6-DMSO): 6 = 0.40 (m, 1 H), 0.63 (m, 1 H), 0.76 (m, 1 H), 0.98 (m, 1 H), 1.12 (d, J = 7 Hz, 3 H), 2.47 (m, 1 H), 3.87 (q, J = 7 Hz, 1 H), 6.78 (s, 2 H), 7.0 (s, 1 H), 10.46 ppm (br. s, 1 H).
MS: (M + H)+ = 237 IE f21187 The following compounds of the formula I were synthesized analogously to the procedure described in Example XVIII using the correspondingly substituted orthonitroanilines and 2-halo carboxylic acid derivatives and, if appropriate, derivatized further: Table 5 Nr. R3 R4 R5 X M.P.°C 1 6-CI ch3 H c6h5 0 191 2 6-CI ch3 ch3 c3h5 0 3 6-CI ch3 ch3 c3h5 s 4 6-CI ch3 ch3 c3h5 0 5 6-CI ch3 ch3 c3h5 s Key: C3H5 = cyclopropyl C6H5 = phenyl IE 621187 Example XIX 7-Chloro-1-N-(cyclopropyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one 4-Chloro-2-cyclopropylaminonitrobenzene (2.0 g, 9.4 mmol) was hydrogenated as described in Example XVIIIA, The resulting 4-chloro-2-cyclopropylaminoaniline (1.70 g) was taken up in 20 ml of dichloromethane. 1.6 ml (2.01 mmol) of chloroform, 1.8 ml (2.45 mmol) of acetone and 0.10 g (0.4 mmol) of benzyltriethylammonium chloride were added, and the reaction solution was cooled to 10°C. 4 ml of 50% strength sodium hydroxide solution were slowly added dropwise with vigorous stirring, during which process the reaction temperature should not exceed 10°C. After stirring for 5 hours at 10°C, the phases were diluted and separated. The organic phase was washed once with water, dried (magnesium sulfate) and evaporated in vacuo. The crude product was purified by silica gel chromatography using ethyl acetate/heptane = 1:2 as the eluent, the yield was 1.0 g (42%) of white crystals of melting point 132-133°C (after recrystallization from toluene/heptane). Ή NMR (270 MHz, d6-DMSO): δ = 0.45 - 0.55 (m, 2 H), 1.05 - 1.1 (m, 2 H), 1.19 (s, 6 H), 2.71 (m, 1 H), 6.09 (br. s, 1 H), 6.71 (d, J = 8 Hz, 1 H), 6.88 (dd, J = 8, Hz, 1 H), 7.19 ppm (d, J = 2 Hz, 1 H).
MS: (M + H)4 = 251 The following compounds of the formula I were synthesized in analogous manner and, if appropriate, derivatized further: IE m 187 Table 6: Nr.R,n R3 R4 R5 M.P.°C 1 6-CI ch3 ch3 csh9 179 2 7-CI ch3 ch3 c5h9 171 3 6,7-(CH3O)2 ch3 ch3 H 4 6,7-(CH3O)2 ch3 ch3 C5H9 5 ch3 ch3 sC6Hn 113 6 c6h5 ch3 H 7 c6h5 ch3 C5H9 8 6-CI ch3 ch3 IPOC 128 9 7-CI ch3 ch3 IPOC 169 10 7-CH3 ch3 ch3 CsHe 168 11 6-CH3O ch3 ch3 H 200 12 6-CH3O ch3 ch3 c5h9 138 13 6/7-COOH ch3 ch3 H > 240 ΙΕ ί?Ί87 Nr. R1n R3 R4 R5 M.P.°C 14 6/7-COOH ch3 ch3 C5He 180 15 8-CH3 ch3 ch3 H 140 16 8-CH3 ch3 ch3 c5H8 160 17 8-CH3 ch3 ch3 IPOC 127 18 6/7-CH3 c2h5 c2h6 H 160 19 6-CH3 c2h5 C2Hs C5H8 100 20 7-CH3 C2Hs c2h5 C5Hb 110 21 7-F ch3 ch3 H 120 22 7-F ch3 ch3 c5h9 155 23 7-C2H5O ch3 ch3 H 155 24 7-C2H5O ch3 ch3 C5H9 123 25 6-COOH ch3 ch3 c5h8 245 26 7,8-(CH3)2 ch3 ch3 H 196 27 7,8-(CH3)2 ch3 ch3 c5h9 155 28 6,7-(CH3)2 ch3 ch3 H 248 29 6,7-(CH3)2 ch3 ch3 c5h9 200 30 6-CI,7- (2,3-CI2C6H3O) ch3 ch3 H 211 31 6-CI,7- (2,3-CI2C6H3O) ch3 ch3 C5H8 205 32 7-F ch3 ch3 IPOC 175 33 7-C2H5O ch3 ch3 IPOC 150 Nr. R1n R3 R4 R5 M.P.°C 34 6/7-CH, ch3 ch3 IPOC 152 35 7,8-(CH3)2 ch3 ch3 IPOC 147 36 6,7-(CH3)2 ch3 ch3 IPOC 161 37 7-C6H5 ch3 ch3 H 167 38 7-C6HsO ch3 ch3 CsHe 138 39 7-C6H5O ch3 ch3 IPOC 181 40 5-CH3 ch3 ch3 H 182 41 6-CH3O, 7-(4-Pyridyl) ch3 ch3 H > 240 42 6-CI, 7-Piperidino ch3 ch3 H 219 43 6/7-CI.7/6- Morpholino (mixture) ch3 ch3 H 236 44 6/7-(N-Methyl- piperazin-1-yl) ch3 ch3 H > 240 45 6/7-CI.7/6- (N-Methyl- piperazin-1-yl) ch3 ch3 H 147 46 6-CI ch3 ch3 H 152-154 47 7-CI ch3 ch3 H 48 6-CI ch3 ch3 ALOC 128-129 49 7-CI ch3 ch3 ALOC 144 IE £ 187 Nr. R3 R4 R5 M.P.°C 50 6-CI ch3 ch3 COOCH(CH3)2 118 51 7-CI ch3 ch3 COOCH(CH3)2 171 52 7-(4-F-Ph-SO2O) ch3 ch3 H 53 7-(4-F-Ph-SO2O) ch3 ch3 IPOC 204 54 6-CI,7-Piperidino ch3 ch3 IPOC 152 55 6-CI,7- Morpholino ch3 ch3 IPOC 113 56 6-CI,7-(N- Methyl- piperazin-1-yl) ch3 ch3 IPOC 168 57 6-CI,7-NEt2 ch3 ch3 H 141 58 6-CI,7-NEt2 ch3 ch3 IPOC Oil 59 6,7-CI2 ch3 ch3 H 232 60 6,7-CI2 ch3 ch3 IPOC 171 61 7-(N-Methylpiperazinyl-1 -yl) ch3 ch3 H 198 62 7-(N-Methylpiperazinyl-1 -yl) ch3 ch3 IPOC 123 63 6-CH3O ch3 ch3 IPOC 128 64 7-CI -(ch2)3- IPOC 172 65 7-CI -(CH2)4- IPOC 181 66 6-CI •(CH2)3· IPOC 157-158 67 6-CI ’(CH2)4- IPOC 179-180 IE f 1187 Nr. R3 R* R5 M.P. °C 68 6-Clq ch5 ch3 COOC2H5 137 69 6-CI ch3 ch3 cooc3h7 125 Key: C5H9 = 3-methyl-2-buten-1-yl sC6Hn = 4-methyl-3-penten-2-yl IPOC = isopropenyloxycarbonyl Example XX 3,3-Dimethyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydroquinoxalin-2(1H)-one The compound was prepared analogously to the compound described in Example VIA, starting from 3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (J. T. Lai, Synthesis 1982, 71). Melting point 146-147°C (after crystallization from methyl tert.-butyl ether/heptane) 1H NMR (270 MHz, d6-DMSO): δ = 1.27 (s, 3 Η), 1.68 (s, 3 H), 1.72 (S, 3 H), 3.88 (d, J = 7 Hz, 1 H), 5.15 (m, 1 H), 6.60 (d, J = 7 Hz, 1 H), 6.67 (t, J = 7 Hz, 1 H), 6.78 (d, J = 7 Hz, 1 H), 6.87 (t, J = 7 Hz, 1 H), 10.33 ppm (br. s, 1 H).
MS: (M + H)+ = 245 Example XXI 4-N-(3-Methyl-2-buten-1-yl)-3,4-dihydroquinoxalin-2(1H)-one-3-spiro-1’-cyclohexane The compound was prepared analogously to the compound described in Example 25 VIA, starting from spirofcyclohexane-I.S’-^’^’-dihydroquinoxalin-O’HJ-one)] (J. T.
Lai, Synthesis 1982, 71). Melting point 82-83°C (after crystallization from heptane) 1H NMR (270 MHz, d6-DMSO): δ = 1.25 - 1.75 (m, 10 Η), 3.75 (d, J = 6 Hz, 2 H), 5.07 (m, 1 H), 6.7 - 7.0 (m, 4 H), 10.15 ppm (br. s, 1 H).
MS: (M + H)+ = 285 Example XXII 4-N-(3-Methyl-2-buten-1-yl)-3,4-dihydroquinoxaline-2(1H)-thione-3-spiro1 ’-cyclohexane The compound of Example XXI (500 mg, 1.8 mmol) was refluxed for 1.5 hours under argon together with 370 mg (0.9 mmol) of 2,4-bis-(4-methoxyphenyl)1.3- dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) in 10 ml of anhydrous toluene. The mixture was subsequently concentrated in vacuo, and the products were isolated by silica gel chromatography using methyl tert.-butyl ether/heptane = 10:1 as eluent. The yield was 50 mg (9%) of yellow crystals of melting point 125°C. 1H NMR (270 MHz, d6-DMSO): δ = 1.1 - 1.9 (m, 16 H), 3.64 (d, J = 7 Hz, 2 H), 4.99 (m, 1 H), 6.95 - 7.1 (m, 3 H), 7.18 (d, J = 7 Hz, 1 H), 12.2 ppm (br. s, 1 H). MS: (M + H)+ = 301 3.4- Dihydroquinoxaline-2(1H)-thione-3-spiro-T-cyclohexane was isolated as a further product in a yield of 110 mg (26%); yellow crystals of melting point 178°O. Ή NMR (270 MHz, cDCI3 δ = 1.25 - 2.2 (m, 10 H), 4.18 (br. s, 1 H), 6.7 - 6.8 (m, H), 6.97 (m, 1 H), 9.42 ppm (br. s, 1 H).
MS: (M + H)+ = 233.
Example XXIII (3S)-6-Chloro-4-N-(isopropenyloxycarbonyl)-3-methyl-3,4-dihydroquinoxaline2(1H)-thione The compound of Example XIII (0.5 g, 1.78 mmol), dissolved in 10 ml of anhydrous pyridine, was refluxed for 4 hours together with 0.47 g (2.12 mmol) of phosphorus pentasulfide. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel using ethyl acetate/heptane = 1:1 as eluent. This gave 0.25 g (47%) of a yellow crystalline solid of melting point 148-150°C (after recrystallization from ethyl acetate/heptane).
IE £ 187 1H NMR (270 MHz, d6-DMSO): δ = 1.24 (d, J = 7 Hz, 3 H), 1.96 (S, 3 H), 4.8 - 4.9 (m, 2 H), 5.28 (q, J = 7 Hz, 1 H), 7.22 (d, J = 8 Hz, 1 H), 7.30 (dd, J = 8, 2 Hz, H), 7.72 (br. s, 1 H), 12.84 ppm (br. s, 1 H).
MS: (M + H)+ = 297.
The following compounds of the formula I were synthesized in analogous manner from the corresponding 3,4-dihydroquinoxalin-2(1H)-ones: Table 7 Nr. R’n R3 R4 R5 M.P.°C 1 ch3 Η C5Hb 119 2 6-CI ch3 Η c5h9 109 - 110 3 6-CI ch3 Η c6h5ch2 92 4 6-CI Η -ch2ch2cs- 5 6-CI H -ch2ch2ch2cs- 6 c6h5 ch3 c5h8 7 6-CI ch3 ch3 CsH9 157 8 7-CI ch3 ch3 C5H9 160 9 7-CI ch3 ch3 H 170 100 IE r : 1187 6-CI ch3 H ALOC 143 - 145 11 6-CI ch3 ch3 IPOC 153 12 7-CI ch3 ch3 IPOC 174 13 6-CI ch3 ch3 H 175 14 6-CI c2h5 H IPOC 176-177 15 6-CI c2h5 H ALOC 159-161 16 6,7-(CH3)2 ch3 ch3 c5h9 173 17 6-CI c3h7 H IPOC 154-155 18 6-CI C3H7 H ALOC 98-100 19 6-CI ch3 H (2-C5H4N)-CH2 175-178 20 6-CI ch3 H (3-C5H4N)-CH2 77 21 6-CI ch3 ch3 ALOC 153-154 22 6-CI ch3 ch3 COOCH(CH3)2 151 23 6-CI ch2sch3 H IPOC 128 24 6-CI ch3 ch3 COOC2H5 163 25 6-CI ch3 ch3 cooc3h7 164 26 6-CI CzH5 H (2-CsH4N)-CH2 162-164 27 6-CI C4H9 H IPOC 132 28 6-CI ch2sch3 H COOCH(CH3)2 124 29 6-CI ch2sch3 J (2-CsH4N)-CH2 159 30 6-CH3O ch2sch3 H IPOC 154 31 6-CH3O ch2sch3 H COOCH(CH3)2 163 IE '187 101 32 6-CI CH2SCH3 H CH2C6H4-2-CI Oil Key: C5H9 = 3-methyl-2-buten-1-yl IPOC = isopropenyloxycarbonyl ALOC = allyloxycarbonyl C5H4N = pyridyl Example XXIV (3RS)-3-Methyl-4-N-(3-methyl-2-buten-1-yl)-2-methylthio-3,4-dihydroquinoxaline (3RS)-3-Methyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydroquinoxaline-2(1H)-thione (Table 7, No. 1) (0.49 g, 2.0 mmol) was dissolved in 20 ml of ethanol (96%), and the solution was treated with 5.1 ml (2.2 mmol) of a 1% strength sodium ethanolate solution. After the mixture had been stirred for 15 minutes at room temperature, 0.14 ml (2.2 mmol) of methyl iodide was added dropwise, and the mixture was stirred for a further 2 hours at room temperature. The reaction solution was concentrated, and the residue was chromatographed on silica gel. 500 mg (96%) of a yellow oil were isolated using ethyl acetate/heptane = 1:6. Ή NMR d6-DMSO): δ = 0.96 (d, J = 7 Hz, 3 H), 1.72 (s, 6 H), 2.44 (s, 3 H), 3.71 (dd, J = 15, 6 Hz, 1 H), 3.89 (dd, J = 15, 6 Hz, 1 H), 4.00 (q, J = 7 Hz, 1 H), 5.20 (m, 1 H), 6.65 - 6.75 (m, 2 H), 7.02 (t, J = 8 Hz, 1 H), 7.11 ppm (d, J = 8 Hz, 1 H). MS: (M + Hf = 261 The following compound of the formula I was synthesized in the same manner: 4-lsopropenyloxycarbonyl-2-(isopropenyloxycarbonyl)-thio-3,3,7,8-tetramethyl3,4-dihydroquinoxaline.
Melting point: 115°C IE r ' 187 102 Example XXV (3RS)-3-Methyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydroquinoxalin-2(1H)-one (3RS)-3-Methyl-3,4-dihydroquinoxa!in-2(1H)-one (4.86 g, 0.03 mol) dissolved in 5 50 ml of Ν,Ν-dimethylformamide, was alkylated with 4.2 ml (0.033 mol) of 3-methyl2-buten-1-yl bromide (90%) in the presence of 4.60 g (0.033 mol) of pulverulent potassium carbonate. The reaction mixture was stirred at room temperature until reaction of the educt was complete. The solvent was then stripped off in vacuo, the residue was taken up in ethyl acetate and water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were washed twice with water. Drying over sodium sulfate, concentration in vacuo and crystallization from pentane gave 5.80 g (84%) of white crystalline product of melting point 92-93°C. Ή NMR (270 MHz, d6-DMSO): δ = 0.99 (d, J = 7 Hz, 3 H), 1.72 (s, 6 H), 3.67 (dd, J = 15, 7 Hz, 1 H), 3.86 (q, J = 7 Hz, 1 H), 3.88 (dd, J = 15, 7 Hz, 1 H), 5.21 (m, H), 6.65 - 6.9 (m, 4 H), 10.31 ppm (br. s, 1 H).
MS: (M + H)+ = 231 Example XXVI 3,3a-Dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione 2-Fluoronitrobenzene (14.1 g, 0.1 mol) and L-gtutamic acid (45.0 g, 0.3 mol) were heated in 100 ml of 2-methoxyethanol at 95°C, with stirring, and 300 ml of 2N sodium hydroxide solution were added dropwise. Stirring was then continued for another 3 hours at this temperature. After cooling, the solution was treated with 400 ml of methanol and hydrogenated under atmospheric pressure with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was removed by filtration with suction, and the solution was concentrated under reduced pressure.
The residue was acidified with 250 ml of 2N hydrochloric acid and heated in a steam bath for approx. 30 minutes. The precipitate which resulted in this process 103 IE £ 187 was filtered off with suction, washed with water and alcohol and subsequently dried, melting point 255°C, decomposition. 1H NMR (60 MHz, d6-DMSO): δ = 1.9 - 2.7 (m, 4 H), 4.5 (t, J = 8 Hz, 1 H), 6.8 - 7.3 (m, 3 H), 7.8 - 8.2 (m, 1 H), 10.7 ppm (br. s, 1 H).
MS: (M + H)+ = 202 Example XXVII 7-Phenoxysulfonyl-3,3a-dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione The compound was obtained in analogous manner by reacting phenyl 4-chloro3-nitrobenzenesulfonate with L-glutamic acid, melting point 140°C (decomp.). 1H NMR (60 MHz, d6-DMSO): δ = 1.6-2.5 (m, 4 H), 4.07 (t, J = 6 Hz, 1 H), 6.7 - 7.6 (m, 8 H), 10.57 ppm (br. s, 1 H).
MS: (M + H)+ = 358 Example XXVIII 3-Carboxymethyl-3,4-dihydroquinoxalin-2(1H)-one 2-Fluoronitrobenzene (14.1 g, 0.1 mol) and L-aspartic acid (40.0 g, 0.3 mol) were heated to 95°C in 100 ml of 2-methoxyethanol, with stirring, and 300 ml of 2N sodium hydroxide solution were added dropwise. Stirring was then continued for 1 hour at this temperature. After the solution had cooled, it was treated with 500 ml of methanol and hydrogenated under atmospheric pressure with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was removed by filtration with suction, and the solution was concentrated under reduced pressure.
The residue was acidified with 500 ml of 2N hydrochloric acid, the mixture was subsequently concentrated, neutralized with sodium acetate and extracted with ethyl acetate. The mixture was dried with sodium sulfate, the solvent was stripped off, and the residue was then obtained which was first oily and crystallized upon stirring with water, melting point 152-154°C.
IE 9 ’187 104 Ή NMR (60 MHz, d6-DMSO): δ = 2.5 - 2.7 (dd partly concealed, 2 H), 4.1 (td, J = 6, 2 Hz, 1 H), 5.98 (br. s, 1 H), 6.5 - 6.9 (m, 4 H), 10.30 (br. s, 1 H), 12.37 ppm (br. s, 1 H).
MS: M+ = 206 CHN analysis: calculated C 58.2; H 4.8; N 13.6% found C 58.4; H 4.7; N 13.7% Example XXIX 7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one A) Methyl N-[(2-nitro-4-phenoxysulfonyl)phenyl]glycinate Phenyl 4-chloro-3-nitrobenzenesulfonate (62.7 g, 0.2 mol) and methyl glycinate hydrochloride (100.4 g, 0.8 mol), dissolved in 250 ml of methanol, were treated with 200 ml of triethylamine, and the mixture was refluxed for 15 minutes. After cooling, the mixture was treated with 1 I of 2N acetic acid, subjected to filtration with suction and washed with water. The residue was recrystallized from ethyl acetate and washed with methanol and diisopropyl ether, melting point 120-123°C.
B) 7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one Methyl N-[(2-nitro-4-phenoxysulfonyl)phenyl]glycinate (36.6 g, 0.1 mol) was hydrogenated under atmospheric pressure in a mixture of 250 ml of Ν,Ν-dimethylformamide and 250 ml of methanol, with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was removed by filtration with suction, and the solution was freed from solvent in vacuo. The residue was dissolved in 40 ml of 2-methoxyethanol, and the mixture was heated for one hour in a steam bath. The resulting precipitate was filtered off with suction and washed with methanol, melting point 253-254°C. 1H NMR (60 MHz, d6-DMSO): δ = 4.0 (d, J = 4 Hz, 2 H), 6.6 - 7.6 (m, 9 H), .43 ppm (br. s, 1 H).
MS: (M + H)+ = 305 IE t: :1187 105 Example XXX 4-(3-Methyl-2-buten-1-yl)-7-phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one 7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one (1.52 g, 5.0 mmol) in 20 ml of Ν,Ν-dimethylacetamide was stirred for 8 hours at 100°C with 2 ml of 3-methyl2-buten-1-yl bromide. After cooling, the mixture was treated with water and extracted with ethyl acetate. The solution was dried using magnesium sulfate and then concentrated, and the residue was chromatographed over a silica gel column using ethyl acetate/heptane = 1:1. The fractions which contained the substance were evaporated on a rotary evaporator, and the product was subsequently stirred with pentane and filtered off with suction, melting point 132°C. 1H NMR (270 MHz, d6-DMSO): 6 = 1.73 (s, 6 H), 3.90 (s, 2 H), 3.93 (partly concealed d, J = 6 Hz, 2 H), 5.20 (br. t, J = 6 Hz, 1 H), 6.75 - 7.45 (m, 8 H), 10.66 ppm (s, 1 H).
MS: (M + H)+ = 373 The following compounds of the formula I were synthesized in analogous manner using the corresponding haloaromatic substances and amino acid derivatives and, if appropriate, derivatized further on nitrogen atom 4: ΙΕ ί 1187 Table 8 106 Nr. R1n R3 R4 Rs M.P.°C 1 7-C6Hs-O-SO2 H CH2OH H 199 2 7-C6Hs-O-SO2 H ch2oh C5H9 120 3 7-C6H5-O-SO2 H CH2COOH H 230 decomp. 4 7-C6H5-O-SO2 H CH2COOH C5H9 5 7-C6Hs-O-SO2 H ch2conh2 H 272 decomp. 6 7-C6H6-O-SO2 H ch2conh2 C6H9 7 7-C6H5-O-SO2 H CH2-4-lmi H 216 decomp. 8 7-C6Hs-O-SO2 H CH2-4-lmi C5H9 9 7-C6Hs-CO H H H 280 decomp. 10 7-C6H5-CO H H c6h5-co 277 decomp. 11 7-C6H5-O-SO2 H ch3 H 148 107 IE S '187 Nr. R’„ R3 R* R5 M.P.°C 12 7-C6H5-O-SO2 H ch3 c5h9 Oil 13 7-C6H5-SO2 H ch3 H 198 14 7-C6Hs-SO2 H ch3 C5H9 Oil 15 7-C6Hs-SO2 H ch3 IPOC 108 16 7-C6HsO-SO2 H H H 17 7-C6HsSO2 H H coch3 270 18 7-C6Hs-OSO2 H ch3 IPOC Resin Key: C5H9 = 3-methyl-2-buten-1-yl 4-lmi = 4-imidazolyl IPOC = isopropenyloxycarbonyl Example XXXI 6-Chloro-7-phenoxysulfonyl-1,2,3,3a-tetrahydropyrrolo[2,1-c]-quinoxalin-4(5H)-one A) Phenyl 2,4-dichloro-3-nitrobenzenesulfonate 2,6-Dichloronitrobenzene was stirred for 7 hours at 130°C with an excess of chlorosulfonic acid. After cooling, the mixture was poured onto ice, the sulfochloride was filtered off with suction, washed to neutrality and dried over sodium hydroxide, melting point 91 °C. The resulting sulfochloride (29.05 g, 0.1 mol) and phenol (11.5 g, 0.12 mol) were dissolved in 150 ml of acetone and treated with 14 ml of triethylamine at 10°C. The mixture was stirred for 1 hour with cooling, stirring was then continued for a further 4 hours at room temperature, the mixture was then treated with 200 ml of water, the resulting precipitate was filtered off with suction at 10°C, washed with water and dried in vacuo at 80°C, melting point 102°C.
IE 6 187 108 B) N-[(3-Chloro-2-nitro-4-phenoxysulfonyl)phenyl]proline Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (34.8 g, 0.1 mol), 69.0 g (0.6 mol) of L-proline, 200 ml of 2N sodium hydroxide solution and 200 ml of 2-methoxyethanol were stirred for 10 minutes at 80°C. The clear solution was acidified at 50°C using concentrated hydrochloric acid and poured onto ice. The precipitate was filtered off with suction, washed with water to neutrality and dried at 80°C. Melting point 148°C (after recrystallization from methanol) C) 6-Chloro-7-phenoxysulfonyl-1,2,3,3a-tetrahydropyrrolo[2,1-c]-quinoxalin4(5H)-one N-[(3-Chloro-2-nitro-4-phenoxysulfonyl)phenyl]proline (38.0 g, 0.075 mol) in 500 ml of methanol and 25 ml of concentrated ammonia solution was hydrogenated under atmospheric pressure with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was removed by filtration with suction, the solution was concentrated, the residue together with 2N hydrochloric acid was heated for approximately 30 minutes in a steam bath, cooled, subjected to filtration with suction and washed with water to neutrality. Melting point 197°C (after recrystallization from glacial acetic acid) Example XXXII 8-(4-Methyl-1-piperazinyl)-3-(2-methylpropyl)-5-phenoxysulfonyl3,4-dihydroquinoxalin-2(1 H)-one A) Phenyl 2-chloro-4-(4-methyl-1 -piperazinyl)-3-nitrobenzenesulfonate Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (17.4 g, 0.05 mol) and 25 ml of methylpiperazine in 100 ml of isopropanol were refluxed for 10 minutes and subsequently concentrated. The residue was stirred with 50 ml of 50% methanol, filtered off with suction, and washed with 50% methanol and finally with water. Melting point 94-95°C (after recrystallization from cyclohexane) 109 B) N-[(3-(4-Methyl-l-piperazinyl)-2-nitro-6-phenoxysulfonyl)-phenyl]leucine hydrochloride Phenyl 2-chloro-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonate (41.1 g, 0.1 mol) 5 and L-leucine (39.3 g, 0.3 mol) were stirred for 8 hours at 95°C in a mixture of 100 ml of N.N-dimethylformamide, 50 ml of 2-methoxyethanol and 100 ml of 2N sodium hydroxide solution. When cold, the reaction mixture was acidified with concentrated hydrochloric acid. The precipitate was taken up in ethyl acetate, and the mixture was dried using sodium sulfate and freed from solvent in vacuo. This gave an orange oil.
C) 8-(4-Methyl-1-piperazinyl)-3-(2-methyipropyl)-5-phenoxysulfonyl3,4-dihydroquinoxalin-2(1 H)-one hydrochloride N-[(3-(4-Methyl-1-piperazinyl)-2-nitro-6-phenoxysulfonyI)-phenyl]leucine hydrochloride (25.3 g, 0.05 mol) in 250 ml of methanol and 25 ml of glacial acetic acid was hydrogenated under atmospheric pressure using Raney nickel as catalyst. When the uptake of hydrogen had ended, the catalyst was removed by filtration with suction, the solution was concentrated, and the residue together with 2N of hydrochloric acid was heated for approximately 10 minutes in a steam bath and then concentrated in vacuo. The residue was dissolved in water, the mixture was rendered alkaline using ammonia, and this was taken up in ethyl acetate. The oil which remained after concentration was dissolved in 400 ml of diisopropyl ether, and the mixture was rendered neutral using ethanolic hydrochloric acid. The precipitate was filtered off with suction, washed with diisopropyl ether and dried, melting point 90°C and above (decomp.).
MS: M+ = 458 The following compounds of the formula I were synthesized in analogous manner using the corresponding haloaromatic substances and amino acid derivatives and, if appropriate, derivatized further on nitrogen atom 4: 110 Table 9 CH, I J Nr. R3 R4 R5 M.P.°C 1 H (CH3)2CHCH2 c5h9 2 H ch3 H 100 decomp. (HCI) 3 H ch3 c5h9 4 H H H 126 - 127 (base) 5 H H c5h9 Key: CsHg = 3-methyl-2-buten-1-yl Example XXXIII (3RS)-4-N-Cyclohexyl-3-methyl-3,4-dihydroquinoxalin-2(H)-one (3RS)-3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (0.81 g, 0.005 mol) and 1 ml 25 (0.1 mol) of cyclohexanone were introduced into 20 ml of 1,2-dichloroethane.
Trifluoroacetic acid (1.9 ml, 0.025 mol) was added dropwise, during which process a clear solution formed with gentle heating. 2.1 g (0.01 mol) of sodium triacetoxyborohydride were added, the exothermic reaction was then allowed to 111 proceed for 30 minutes with stirring, and quenching was then effected by adding saturated aqueous sodium hydrogen carbonate solution. The phases were separated, the organic phase was washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate) and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/heptane = 1:1. 1.15 g (94%) of the desired product were obtained, melting point 131-132°C (toluene/heptane). 1H NMR (270 MHz, d6-DMSO): 6 = 0.97 (d, J = 7 Hz, 3 H), 1.0 - 2.0 (m, 10 H), 3.39 (m, 1 H), 3.91 (q, J = 7 Hz, 1 H), 6.68 - 6.94 (m, 4 H), 10.27 ppm (br. s, 1 H) MS: (M + H)+ = 245.
The following compounds of the formula I were synthesized in analogous manner.
Table 10 Nr. R1n R3 R4 R5 M.P.°C 1 ch3 H c2h5 106 - 107 2 ch3 H CH2C(CH3)3 162 3 ch3 H c-C6He 120 4 6-CI ch3 H C-C4H7 100 5 6-CI ch3 H c5h„ 94-95 fE 921187 112 Nr. R1n R3 R4 R5 M.P.°C 6 6-CI ch3 H CH2C(CH3)3 158 - 160 7 6-CI c2h5 H CH2C(CH3)3 158 - 159 8 6-CI ch3 H CH=CHCHO 140 - 146 9 6-Ci ch3 H CH2CsCH3 166 - 168 10 6-CI ch3 H 2-Picolyl 198 - 199 11 6-CI ch3 H 3-Picolyl 136 12 6-CI ch3 H 4-Picolyl 191 - 193 13 6-CI ch3 H Furanyl-2-methyl 116 - 118 14 6-CI ch3 H CH2C6H4-4-Br 149 - 150 15 6-CI ch3 H CH2C6H4-4-CN 95 - 96 16 6-CI ch3 H CH2C6H4-4-NO2 117 17 6-CI ch3 H CH2C6H4-3-NO2 125 18 6-CI ch3 H CH2C6H4-2-NO2 153 - 154 19 6-CI ch3 H CH2C6H4-4-CI 122 - 123 20 6-CI ch3 H CH2C6H4-3-CI 156 - 157 21 6-CI ch3 H CH2C6H4-2-CI 138 22 6-CI ch3 H CH2CeH4-4-F 147 23 6-CI ch3 H CH2C6H4-4-C6H5 164-165 24 6-CI ch3 H CH2C6H4-4-OC6H5 Oil 25 6-CI ch3 H CH2C6H4-4-CH3 60-62 26 6-CI ch3 H CH2C6H4-4-COOCH3 139 27 6-CI ch3 H CH2C6H3-2,6-CI2 190-191 113 Nr.Rln R3 R4 R5 M.P.°C 28 6-CI ch3 H CH2C6H3-3,5-CI2 139-140 29 6-CI ch3 H Naphthyl-1-methyl 164-166 30 6-CI ch3 H Naphthyl-2-methyl 161-164 31 6-CI ch3 H CH2CH2OCH3 78-79 32 6-CI ch3 H Cyclohex-2-enyl Oil 33 6-CI ch3 H c2h4-c6h5 128 34 6-CI ch3 H Thienyl-3-methyl 141-142 35 6-CI ch3 H (5-Methylthienyl)- 2-methyl 58-60 36 6-CI ch3 H (3-Methylthienyl)-2- methyl 124 37 6-CI ch3 H Thienyl-2-methyl 121-123 38 6-CI ch3 H CH2CH = CH-C6H5 59 39 6-CI ch2sch3 H CH2C6H4-2-CI 128 40 6-CI ch2sch3 H CH2C6H4-2-NO2 134 41 6-CI ch2sch3 H 2-Picolyl Oil 42 6-CI ch2sch3 H CH2C6H3-2,4-CL2 143 43 6-CI CH2S-i.Pr H CH2CeH3-2,4-CI2 Oil 44 6-CI CHZS-Bn H CH2C6H3-2,4-CI2 Oil 45 6-CI CHZ-S-H H CH2C6H3-2,4-CI2 46 6-CI c2h5 H 2-Picolyl 160-162 47 6-CI ch3 H (6-CH3)2-Picolyl 158 114 Key: CgHJ = 3-methyl-1-butyl c-C4H7 = cyclobutyl c-C5H9 = cyclopentyl Example XXXIV (3RS)-3-Methyl-4-N-(3-oxo-1-butyl)-3,4-dihydroquinoxalin-2(1H)-one 3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (0.5 g, 3.1 mmol) together with 0.35 ml (4.3 mmol) of methyl vinyl ketone and a catalytic amount of triethylamine were stirred for 20 hours at room temperature in 20 ml of anhydrous ethanol. Silica gel chromatography with methyl tert.-butyl ether/heptane = 2:1 gave 620 mg (87%) of the desired product, melting point 108-109°C (methyl tert.-butyl ether/heptane). 1H NMR (270 MHz, d6-DMSO): δ = 1.03 (d, J = 7 Hz, 3 H), 2.11 (s, 3H), 2.77 (t, J = 6 Hz, 2 H), 3.30 (m, 1 H), 3.50 (m, 1 H), 3.88 (q, J = 7 Hz, 1 H), 6.68 (m, H), 6.78 (m, 1 H), 6.88 (m, 1 H), 10.31 ppm (br. s, 1 H).
MS: (M + H)+ = 233, M+ = 232 Example XXXV (3S)-6-Chloro-4-N-chlorocarbonyI-3-methyl-3,4-dihydroquinoxalin-2(1H)-one The compound of Example IB (2.0 g, 0.01 mol) in 100 ml of anhydrous toluene was heated with bis-(trichloromethyl) carbonate (triphosgene) (1.5 g, 0.005 mol) for 1 hour at 80°C in the presence of 2 ml (0.014 mol) of triethylamine. After cooling, the mixture was washed with water and saturated aqueous sodium chloride solution and dried (magnesium sulfate), and the solvent was removed under reduced pressure. The residue (2.5 g) crystallized after stirring with heptane, its purity being sufficient for preparative purposes. A sample of analytical purity was obtained by silica gel chromatography using ethyl acetate/heptane = 1:1 as eluent. Melting point 142-144°C. •Ε 921187 115 Ή NMR (270 MHz, d6-DMSO): δ = 1.25 (d, J = 7 Hz, 3 H), 3.83 (q, J = 7 Hz, H), 6.61 (dd, J = 6, 2 Hz, 1 H), 6.70 (s, 2H), 10.3 ppm (br. s, 1 H).
MS: (M + H)+ = 259 Example XXXVI (3S)-6-Chloro-4-N-(2-methoxyethoxycarbonyl)-3-methyl-3,4-dihydroquinoxalin2(1H)-one To a solution of 0.24 ml (3.0 mmol) of 2-methoxyethanol in 10 ml of anhydrous 1,2-dimethoxyethane there was added 0.16 g of a 55% suspension of sodium hydride in mineral oil, and the reaction mixture was stirred for 30 minutes at room temperature. 0.50 g (1.9 mmol) of the compound of Example XXXV was subsequently added, with ice-cooling, and the mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was treated with saturated aqueous sodium chloride solution, extracted several times with ethyl acetate, the organic phase was washed once with saturated aqueous sodium chloride solution and dried (magnesium sulfate), and the solvent was removed in vacuo. After silica gel chromatography (ethyl acetate/heptane = 1:1) and crystallization from ether/heptane, 0.29 g (51%) of the desired product was obtained, melting point 93-94°C. 1H NMR (200 MHz, d6-DMSO): δ = 1.13 (d, J = 7.5 Hz, 3 H), 3.32 (s, 3 H), 3.6 (m, 2H), 4.24 (m, 1 H), 4.35 (m, 1 H), 4.81 (q, J = 7.5 Hz, 1 H), 6.98 (d, J = 9 Hz, H), 7.2 (dd, J = 9, 3 Hz, 1 H), 7.66 (d, J = 3 Hz, 1 H, 10.81 ppm (br. 2, 1 H).
MS: (M + H)+ = 299 Example XXXVII (3S)-6-Chloro-3-methyl-4-N-[(phenylthio)carbonyl)]-3,4-dihydroquinoxalin-2(1H)-one To a solution of 0.31 ml (3.0 mmol) of thiophenol in 10 ml of 1,2-dimethoxyethane there was added 0.17 g of a 55% suspension of sodium hydride in mineral oil, with 116 ice-cooling, and the mixture was stirred for 1 hour at room temperature. 0.5 g (1.9 mmol) of the compound of Example XXXV were introduced, again with icecooling, and stirring was then continued for 2 hours at room temperature. For working-up, the mixture was treated with saturated aqueous sodium chloride solution, extracted twice with ethyl acetate and dried (sodium sulfate), and the solvent was stripped off. The solid residue was recrystallized from heptane/isopropanol, 0.35 g (35%), melting point 194-195°C. Ή NMR (200 MHz, d6-DMSO): δ = 1.10 (d, J = 7 Hz, 3 H), 4.93 (q, J = 7 Hz, H), 7.08 (d, J = 9 Hz, 1 H), 7.33 (dd, J = 9, 3 Hz, 1 H), 7.4 - 78.6 (m, 5 H), 7.78 (d, J = 3 Hz, 1 H), 10.16 ppm (br. s, 1 H).
MS: (M + H)+ = 333, (M - C6H5SH + H)+ 223 The following compounds of the formula I were synthesized in analogous manner.
Table 11 Nr. R1n R3 R4 R5 M.P.°C 1 6-CI ch3 H COOCH2CH = CHCH3 116-117 2 6-CI ch3 H COOCH2=C(CH3)2 87-89 3 6-CI ch3 H cooch2c=ch 147 4 6-CI ch3 H cooch2c=cch3 135 117 Nr. R1n R3 R4 R5 M.P.°C 5 6-CI ch3 H cosch2c6h5 158 6 6-CI ch3 H cosch2ch=chz Oil 7 6-CI ch3 H COOCH2C(CH3) = CH2 125-127 8 6-CI ch3 H COOC(CH3)3 9 6-CI ch3 H COO-Cyclohex-2-en-1 -yl 10 6-CI ch3 H COOCH (CH2OCH (C H3)2)2 Oil 11 6-CI ch3 H COOCH(CH3)2 141-142 12 6-CI ch3 H COOC2H4N(CH3)2 Oil 13 6-CI ch3 H cooc2h4sch3 108-110 14 6-CI ch3 H cosc6h5 194-195 15 6-CI ch3 H COOCH2C6H4-2-NO2 227-231 16 6-CI ch3 H COOCHzC6H4-3-NO2 183-185 17 6-CI ch3 H COOCH2C6H4-4-CI 177-180 18 6-CI ch3 H COOCH2C6H4-2-CI 164 19 6-CI ch3 H COOCH2CH=CHCH2CH3 Oil 20 6-CI ch3 H COO(3-Picolyl) 160-161 21 6-CI ch3 H COO(2-Picolyl) 114-116 22 6-CI ch3 H COOCH2C6H4-4-NO2 230-233 23 6-CI ch3 H COOCH2CH2C(CH3)=CH2 Oil 24 6-CI ch3 H CO-(4-Methylpiperazin-1 -yl) Oil 25 6-CI ch3 H CO-NiCH^g 218-220 26 6-CI ch3 H CO-N(CH2)4 200-203 118 Nr. R1n R3 R4 Rs M.P.°C 27 6-CI ch3 H CO-Morpholin-1-yl 193-195 28 6-CI ch3 H CO-HNCHzPh 94-96 29 6-CI ch3 H Cyclopropyl-methyloxy- carbonyl 119-122

Claims (17)

1. Patent claims:
1. A compound of the formula I or la, HOE91/F 111 K (la) and physiologically acceptable salts and prodrugs thereof, where, in formulae I and la, 20 n is zero, one, two, three or four, the individual substituents R 1 independently of one another are fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C^Cg-alkyl, C 5 -C 8 -cycloalkyl, C,-C 6 -alkoxy, (C^Cg-alkoxyHC^q-alkoxy), C^Cg-alkylthio, C^Cg-alkylsulfinyl, C^Cg-alkylsulfonyl, nitro, amino, azido, 30 C^Cg-alkylamino, diiC^Cg-alkyQamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C,-C 6 -acyl, 120 HOE91/F111K C^Cg-acyloxy, C,-C 6 -acylamino, cyano, carbamoyl, carboxyl, (C^Cg-alkyOoxycarbonyl, hydroxysulfonyl, sulfamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five radicals R 6 which are independent of one another, where R 6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C^Cg-alkyl, C 3 -C 8 -cycloalkyl, C^-Cg-alkoxy, C^Cg-alkylthio, 15 C^Cg-alkylsulfinyl, C^Cg-alkylsulfonyl, C,-C 6 -alkylamino, diiC^Cg-alkylJamino, (C^Cg-alkyljoxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R 2 is hydrogen, C^Cg-alkoxy, hydroxyl, picolyl, cyclo-propyl or isopropenyloxycarbonyl 20 and R 5 is hydrogen, hydroxyl, C^Cg-alkoxy, aryloxy, C^Cg-acyloxy, cyano, amino, C^Cg-alkylamino, di^-Cg-alkyOamino, arylamino, C^Cg-acylamino, C,-C 8 -alkyl, optionally substituted by 25 fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, diiC^Cg-alkylJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; 30 C 2 -C 8 -alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, 121 H0E91/F111K C,-C 6 -acyl oxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C^Cg-alkylamino, diiC^Cg-alkyiJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl and carbamoyl; 5 C 3 -C e -allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; C 3 -C 8 -alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, 10 C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C,-C 6 -alkylamino, di^-Cg-aikylJamino, C r C 8 -alkylthio, C,-C 6 -alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl, 15 optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyl oxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C^Cg-alkylamino, diCC^Cg-alkyQamino, C,-Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, 25 C, -C 6 -alky lam ino, diCC^Ce-alkylJamino, C,-C 8 -alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C 3 -C 8 -cycloalkyl)-(C,-C 4 -alkyl), optionally substituted by 30 fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, 122 H0E91/F111K C^Cg-alkylamino, diCC^Cg-alkylJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C 3 -C 8 -cycloalkenyl)-(C 1 -C 4 -alkyl), 5 optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, dKC^Cg-alkylJamino, C,-C 6 -alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C, -Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, 15 C^Cg-alkylamino, difC^Cg-alkyQamino, C,-C 6 -alkylthio, C^Cg-alkylsuffonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 2 -C B -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; (C 3 -C 8 -cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C 5 -C 8 -cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or 25 hydroxyl, C^C^alkoxy, oxo, phenyl; (Ca-Cg-cycloalkyO-iC^Cg-alkyOcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; (C 5 -C6-cycloalkenyl)-(C,-C 3 -alkyl)carbonyl, optionally substituted by fluorine, 30 chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; 123 H0E91/F111K C^Ce-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C 1 -C 4 -alkoxy, C^C^alkylamino, diiC^^-alkylJamino, C,-C 4 -alkylthio; C 2 -C 8 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, 5 hydroxyl, C^C^alkoxy, oxo, phenyl; C 2 -C 8 -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; 10 C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C 2 -C 8 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkylamino- and di^-Cg-alkyQaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin20 1-ylcarbonyl, in each case optionally substituted by C 5 -C 4 -alkyl, C 2 -C 6 -alkenyl, C^C^acyl, oxo, thioxo, carboxyl, or phenyl; C 2 -C 8 -alkenyiamino- and di^-C^alkenyQaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo, 25 phenyl; C^Cg-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; 30 C^Cg-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; 124 H0E91/F111K or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or 5 arylalkylthiocarbonyl, each of which is substituted by up to 5 radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 5 carbon atoms, and R 6 being as defined above, 10 or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl or heteroarylalkylaminocarbonyl, each of which is substituted by up to three radicals R 6 which are independent of one 15 another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, R 3 and R 4 are identical or different and, independently of one another, are hydrogen, C 5 -C 8 -alkyl which is optionally substituted by 20 fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C^C^alkylamino, di^-C^alkylJamino, C 1 -C 4 -alkylthio, C.,-C 4 -alkyIsuIfonyl, C,-C 4 -alkylsulfinyl, carboxyl or carbamoyl; C 2 -C 8 -alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, 25 mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C 4 -alkylamino, di(C^C^alkyl)amino, C 1 -C 4 -alkylthio, C^C^alkylsulfonyl, C 1 -C 4 -alkylsuIfinyl, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, 30 mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C 1 -C 4 -alkylamino, di^-C^-alkylJamino, C^C^alkylthio, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylsulfinyl, carboxyl or carbamoyl; 125 H0E91/F111K C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 alkoxy, C,-C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, C 3 -C 4 -alkylthio, 0,-0«alkylsulfonyl, C 1 -C 4 -alkylsulfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to five radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain 1 to 3 carbon atoms in each case, and R 6 being as defined above, R 3 and R 4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 8 carbon atoms and which can optionally be substituted by fluorine, chlorine, 15 hydroxyl, amino, C^-Cg-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C,-Cg-acyloxy, benzoyloxy, C^Cg-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X is oxygen, sulfur, selenium or substituted nitrogen N-R 2 , it being possible for R z to have the abovementioned meanings, 20 with the exception of those compounds in which R 3 and R 4 are both hydrogen, and compounds in which R 2 and R 5 are hydrogen and R 3 and/or R 4 are/is arylalkyl, and compounds in which X is oxygen and R 2 and R 5 are hydrogen.
2. A compound of the formula I or la as claimed in claim 1, wherein the 25 substituents in the abovementioned formulae have the following meaning: n is zero, one, two 30 or three, 126 H0E91/F111K the individual substituents R 1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C«alkyl, C 5 -C 6 -cycloalkyl, C,-C 4 -alkoxy, (C,-C 4 -alkoxy)-(C 1 -C 4 -alkoxy), 0,-0«5 alkylthio, C 1 -C 4 -alkylsuifinyl, C,-C 4 -alkylsulfonyl, nitro, amino, C,-C 4 alkylamino, di(C,-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, C 1 -C 4 -acyl, C,-C 4 -acyloxy, C^C^acylamino, cyano, carbamoyl, carboxyl, (C,-C 4 -alkyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, 15 phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two radicals R 6 which are independent of one another, where R 6 can be 20 fluorine, chlorine, bromine, cyano, trifiuoromethyl, nitro, amino, C,-C 4 -alkyl, C 3 -C 7 -cycloalkyl, C,-C 4 -alkoxy, C,-C 4 -alkylthio, C,-C«-alkylsulfinyl, C,-C 4 alkylsulfonyl, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, (C,-C 4 -alkyl)oxycarbonyl, phenyl or phenoxy, 25 R 2 is hydrogen and R 5 is hydrogen, hydroxyl, cyano, amino, C,-C 6 -alkyl, optionally substituted by 30 fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^C^alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 127 HOE 91/F 111 Κ C 2 -C 8 -alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, 5 dKC^C^alkyQamino, C^q-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -allenyl, C 3 -C 8 -alkynyl, 10 optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C^C^alkylamino, difC^C^alkylJamino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; 15 C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^q-alkoxy, C^q-alkylamino, diXC^C^alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^C^alkylamino, 25 di(C 1 -C 4 -alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; (Ca-Ce-cycloalkylHC^-Ca-alkyl) optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 4 30 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^C^alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 128 H0E91/F111K (Ca-Ce-cycloalkenylMC^Cj-alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^-C^alkylamino, 5 di(C 1 -C 4 -alkyl)amino, C^C^-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-^10 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^C^alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 6 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; (C 3 -C 6 -cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C 5 -C 6 -cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or 20 hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; (C^Cg-cycloalkylHC^-Cj-alkylJcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; 25 (Cs-Cg-cycloalkenylHC^Cg-alkyQcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C 4 -alkoxy, C^C^alkylamino, diiC^C^alkylJamino, C 1 -C 4 -alkylthio; C 2 -C 6 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; 129 H0E91/F 111 K C 2 -C 6 -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C 2 -C 6 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^-C^-alkoxy, oxo, phenyl; C^Cg-alkylamino- and di^-Cg-alkyQaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl; C 2 -C 6 -alkenylamino- and di(C,-C 6 -alkenyl)aminocarbonyl, in each case 15 optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; C^C^alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; C^C^alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio)carbonyl, 25 (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, or arylalkoxycarbonyl, or aryl(alkylthio)carbonyl, each of which is substituted by up to three radicals R 6 which are independent of one another, it being possible for the alkyl radical 30 to contain in each case 1 to 5 carbon atoms and R 6 being as defined above, 130 HOE91/F111K or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or
3. - fury Icarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or
4. - picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3-thienylmethyl5 oxycarbonyl, each of which is substituted by up to two radicals R® which are independent of one another, and 10 R 3 and R 4 are identical or different and independently of one another are hydrogen, C,-C 8 -alkyl, 15 optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C,-C 4 -alkylsulfonyl, C,-C 4 -alkylsulfinyl, carboxyl or carbamoyl; 20 C 2 -C 8 -alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C^C^alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C 1 -C 4 -alkylsulfonyl, C,-C 4 -alkylsulfinyl, carboxyl or carbamoyl; 25 C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C«-alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C«-alkylthio, C,-C 4 -alkylsulfonyl, C,-C«-alkylsulfinyl, carboxyl or carbamoyl; 30 C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, 0,-0«-acyloxy, benzoyloxy, benzyloxy, phenoxy, 0,-0«alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C,-C 4 IE 921187 131 H0E91/F111K alkylsulfonyl, C 5 -C 4 -alkylsulfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to three radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms
5. And R 6 being as defined above, R 3 and R 4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 10 7 carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C^C^acyloxy, benzoyloxy, C^C^alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, and X is oxygen, sulfur or selenium. 3. A compound of the formula I or la as claimed in claim 1 or 2, wherein the substituents in the abovementioned formulae have the following meanings: n is zero, one 20 or two, the individual substituents R 1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C^-alkyl, C^-alkoxy, 25 (C^C^-alkoxyHC^C^alkoxy), C,-C 4 -alkylthio, nitro, amino, C^C^alkylamino, di(C,-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C^C^acyl, C^C^acyloxy, C,-C 4 -acylamino, cyano, carbamoyl, carboxyl, (C 5 -C 4 -alkyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl, or 132 H0E91/F111K a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two radicals R 6 which are independent of one another, 5 where R 6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C^C^alkyl, C^C^alkoxy, (C^C^alkyQoxycarbonyl, phenyl or phenoxy, 10 R 2 is hydrogen and R 5 is C,-C 6 -alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, 15 C 1 -C 4 -alkoxy, C,-C 4 -alkylamino, diiC^C^alkylJamino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 6 -alkenyl, optionally substituted by 20 fluorine, chlorine, hydroxyl, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C^C^alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -allenyl, C 3 -C 8 -alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C.-C^-alkylamino, di(Ci-C 4 -alkyl)amino, C,-C 4 -alkyIthio, oxo, 30 thioxo, carboxyl or carbamoyl; 133 H0E91/F111K C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 5 alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkyl, C^C^acyloxy, benzoyloxy, benzyloxy, 10 phenoxy, C^C^alkoxy, C^C^alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C^Cg-cycloalkylMC^Cjj-alkyl), optionally substituted by 15 fluorine, chlorine, hydroxyl, C^-C^alkyl, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 alkylthio, oxo, thioxo, carboxyl or carbamoyl; (Ca-Cg-cycloalkenylHC, -C 2 -alkyl), 20 optionally substituted by fluorine, chlorine, hydroxyl, C r C 4 -alkyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^-alkoxy, C^C^alkylamino, di^-C^alkylJamino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 25 C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkyl C 5 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C^C^alkylamino, C^q-alkenylamino, di(C,-C 4 alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl, 30 C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 134 H0E91/F111K C 2 -C 6 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl; (C 3 -C 6 -cycloalkyl)carbonyl, 5 (C 5 -C 6 -cycloalkenyl)carbonyl, (C 3 -C 6 -cycloalkyl)-(C 5 -C 2 -alkyl)carbonyl, (Cg-Cg-cycloalkenylHC^-Cj-alkylJcarbonyl, 10 C^Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C 1 -C 4 -alkoxy, C^-C^alkylamino, di^-C^-alkyljamino or C^C^alkylthio; C 2 -C 6 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, 15 hydroxyl, C,-C 4 -alkoxy; C 2 -C 6 -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, p-C^-alkoxy; 20 C^Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy; C 2 -C 6 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy; C^Cg-alkylamino- and diiC^Cg-alkylJaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin30 1-ylcarbonyl; 135 HOE 91/F 111 K C 2 -C 6 -alkenylamino- and difC^Ce-alkenylJaminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, 0,-0,-alkoxy; C 1 -C 4 -alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, 5 C 1 -C 4 -alkoxy; C, -C 4 -alkenylsulf onyl; or aryl, arylcarbonyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, 10 (arylamino)thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl, each of which is substituted by up to two radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and R 6 being as defined above, or 1 - or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2- , 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3- thienylacetyl, 2-, 3- Oder 4-picolyloxycarbonyl, 2- or 320 furylmethyloxycarbonyl, 2- or 3-thienylmethyloxycarbonyl each of which is substituted by up to two radicals R 6 which are independent of one another, and 25 R 3 and R 4 are identical or different and independently of one another are hydrogen, Ο,-C^alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, Ο,-C^acyloxy, benzoyloxy, phenoxy, Ο,-C^alkoxy, Ο,-C^alkylamino, di^-CVaikylJamino, Ο,-Ο,-alkylthio, 0,-C,alkylsulfonyl, Ο,-Ο,-alkylsulfinyl, carboxyl or carbamoyl; C 2 -C 6 -alkenyl, optionally substituted by fluorine or chlorine; 136 HOE91/F111K C 3 -C 6 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C.,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfonyl, C^-C^alkylsulfinyl, carboxyl or carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroaryimethyl, each of which is substituted by up to two radicals R e which are independent of one another, R 3 and R 4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to
6. Carbon atoms and which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C^-C,-acyloxy, benzoyloxy, C 1 -C 4 -alkoxy, oxo, thioxo, carboxyl or carbamoyl, and X is oxygen or sulfur. 4. A compound of the formula I or la as claimed in claims 1-3, wherein the abovementioned substituents have the following meanings: n is zero, one or two, the individual substituents R 1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C,-C 4 -alkyl, 0,-C^alkoxy, (C l -C 4 -alkoxy)-(C 1 -C 2 -alkoxy), C^C^alkylthio, nitro, amino, C^C^alkylamino, diCC^C^alkylJamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C,-C 4 -acyl, C,-C 4 -acyloxy, C^C^acylamino, cyano, carbamoyl, carboxyl, (C^Cg-alkylJoxycarbonyl, hydroxy sulfonyl or sulfamoyl 137 H0E91/F111K or a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two 5 radicals R 6 which are independent of one another, where R 6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C^C^alkyl, 10 C,-C 4 -alkoxy, (C,-C 4 -alkyI)oxycarbonyl, phenyl or phenoxy, R 2 is hydrogen and R 5 is C,-C 6 -alkyl, 15 optionally substituted by C,-C 4 -alkoxy or C 5 -C 4 -alkylthio; C 2 -C 6 -alkenyl, optionally substituted by oxo; 20 C 3 -C 6 -allenyl; C 3 -C 8 -alkynyl, in particular 2-butynyl; C 3 -C 6 -cycloalkyl; C 5 -C 6 -cycloalkenyl; (C 3 -C 6 -cycloalkyl)-(C 1 -C 2 -alkyl), in particular cyclopropylmethyl, optionally substituted by C,-C 4 -alkyl; (Ca-Ce-cycloalkenylXC^-Cjj-alkyl), in particular cyclohexenylmethyi; 138 HOE91/F111K C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 alkylamino, C^C^alkenylamino, dKC^C^alkylJamino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl or C^-C^-alkylthio; C 2 -C 6 -alkenylcarbonyl; C^Cg-alky I oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C 1 -C 4 -alkoxy, C^C^alkylamino, di(C,-C 4 -alkyl)amino or C,-C 4 -alkylthio; C 2 -C 6 -alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C 2 -C 6 -alkynyloxycarbonyl, in particular propynyloxycarbonyl or butynyloxycarbonyl; C,-C 6 -alkylthiocarbonyl; C 2 -C 6 -alkenylthiocarbonyl, in particular allylthiocarbonyl; C^Cg-alkylamino- and diiC^Cg-alkyQaminocarbonyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl; C 2 -C 6 -alkenylamino- and diiC^Cg-alkenylJaminocarbonyl; C^C^alkylsulfonyl; C 1 -C 4 -alkenylsulfonyl; 139 HOE 91/F 111 K or aryl which is substituted by up to two radicals R® which are independent of one another, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, in 5 particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl (alky It hio) carbony I, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and R® being as defined above, 10 or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3- furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4- picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, or 2- or 3-thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R® 15 which are independent of one another, and R 3 and R 4 are identical or different and independently of 20 one another are hydrogen, C^C^alkyl, optionally substituted by hydroxyl, mercapto, C^C^alkoxy, C^C^alkylthio, 25 C.,-C 4 -alkylsulfonyl, C^C^alkylsulfinyl, carboxyl or carbamoyl; C 2 -C 6 -alkenyl, aryl, benzyl, thienyl or thienylmethyl, each of which is substituted by up to two radicals R® which are independent of one another, r 6 having the 30 meaning as defined above 140 HOE91/F111K R 3 and R 4 can also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 6 carbon atoms and can optionally be substituted by oxo or thioxo, and X is oxygen or sulfur. 5. A process for the preparation of compounds of the formula I as claimed in claim 1, which comprises 10 A) for preparing compounds of the formula I where X is oxygen and the radicals R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1, reacting a compound of the formula II H R4 H 20 with the definitions mentioned in claim 1 applying to R 1 , R 3 and R 4 , with a compound of the formula III R-Z (III) 25 where R has the meanings for R 5 and R 2 which have been mentioned in claim 1 with the exception of hydrogen, hydroxyl, C,-C 6 -alkoxy, aryloxy, C,-C 6 -acyloxy, amino, C^Cg-alkylamino, diiC^Cg-alkylJamino, arylamino and C^Cg-acylamino, and Z is a leaving group, or 30 B) preparing compounds of the formula I where X is sulfur and R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 by reacting a compound of the formula I where X is 141 HOE91/F111K oxygen and the definitions mentioned in claim 1 apply to R 1 , R 2 , R 3 , R 4 and R 5 , with a sulfurizing reagent, or C) preparing compounds of the formula ia where X and the radicals R 1 to R 5 are as defined in claim 1, by reacting a compound of the formula IV H where the definitions mentioned in claim 1 apply to R 1 , R 3 , R 4 and R 5 , with a compound of the formula III R 2 -Z (III) where the definitions described in claim 1 for formula I and la apply to R 2 with the exception of hydrogen, hydroxy, C,-C 6 -alkoxy, aryloxy, C^Cg-acyloxy, amino, C< Cg-alkylamino, DiiC^Cg-allylJamino, arylamino, C^Cg-acylamino and Z is a leaving group, or D) preparing compounds of the formula I where X is oxygen and the radicals R 1 to R 5 are as defined in claim 1 by cyclizing a compound of the formula V 142 HOE 91/F 111 K R R4 where R 1 to R 5 are as defined in claim 1 and Y is hydroxyl, C,-C 4 -alkoxy, optionally halogenated C 1 -C 4 -acyloxy, chlorine, bromine or iodine, or E) preparing compounds of the formula I where X is oxygen, R* and R 5 are hydrogen and the definitions mentioned in claim 1 apply to R 1 to R 3 , from the quinoxalinones of the formula XI 20 where R 1 to R 3 are as defined at the outset, by addition of hydrogen on the C = N bond, or F) preparing compounds of the formula I where X is oxygen and R 1 to R 5 are as defined in claim 1, from compounds of the formula VI 143 HOE 91/F 111 K NH NH where R 1 , R 2 and R 5 are as defined in claim 1, by reacting them with chloroform or bromoform and a carbonyl compound of the formula XIII R 3 -CO-R‘ (XIII) where R 3 and R 4 are as defined in claim 1, or with c-(trihalomethyl)alkanols of the formula XIV Hal 3 C-C(OH)-R 3 R 4 (XIV) where Hal is Cl, Br or I, in which R 3 and R 4 are as defined at the outset, or G) preparing compounds of the formula I where X is oxygen and R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1, by reacting a compound of the formula I where X is oxygen and the definitions mentioned in claim 1 apply to R 1 , R 2 , R 5 and to R 3 and R 4 , with the exception that at least one of the radicals R 3 or R 4 is hydrogen, with an alkylating reagent of the formula XV R’-Z (XV) where R’ has the meanings mentioned above for R 3 and R 4 with the exception of hydrogen and Z is a leaving group, 144 H0E91/F111K or H) preparing compounds of the formula i where X is oxygen, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 and R 5 is C^Cg-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, 5 C^Cg-alkoxy, C^Cg-alkylamino, dKC^Ce-alkyQamino, C^Cg-alkylthio, cyano, carboxyl, carbamoyl, C 3 -C 8 -alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di(C^Cg-alkyl)amino, C,-C 8 -alkylthio, cyano, carboxyl or carbamoyl, C 3 -C 8 -alkynyl, optionally substituted by fluorine, chlorine, bromine, 10 iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Ce-alkoxy, Ο,-Οβalkylamino, diiC^Cg-alkyQamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C 4 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, phenoxy, C,-C 8 -alkoxy, C^Cg-alkylamino, di^-Cg-alkyOamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C 5 -C 8 -cyclo15 alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, phenoxy, C,-C 6 -alkoxy, C^Cg-alkylamino, d^C^Cg-alkyljamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, (C^Cg-alkoxy)(C,-C 6 -alkyl), diiCT-Cg-alkylaminoJ-CC^Cg-alkyl) or (C 3 -C 6 -cycloalkyl)alkyl, (C 6 -C 8 'Cycloalkenyl)alkyl, or arylalkyl, naphthylalkyl or heteroarylalkyl, each of which 20 is substituted by up to five radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, by reductive alkylation of a compound of the formula I where R 5 is hydrogen and X is oxygen and the definitions mentioned in claim 1 apply to R 1 , R 2 , R 3 and R 4 , with a carbonyl compound of the formula XVI, R-C( = O)-R“’ (XVI) where R and R”’ are identical or different and independently of one another are hydrogen, C,-C 7 -alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, 30 hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Ce-alkoxy, C^Cg-alkylamino, di/C^Cg-alkyOamino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C 3 -C 7 -alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^C^acyloxy, 145 H0E91/F111K benzoyloxy, phenoxy, C,-C 6 -alkoxy, C^Cg-alkylamino, di(C,-C 6 -alkyl)amino, C^Cg-alkylthio, cyano, carboxyl or carbamoyl, C 3 -C 7 -alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, phenoxy, C,-Cg-alkoxy, C^Cg-alkylamino, di(C,-C 6 -alkyl)amino, C,-C e -alkylthio, 5 cyano, carboxyl or carbamoyl, C 4 -C e -cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C^Ce-alkoxy, C^Cg-alkylamino, di(C,-C 6 -alkyl)amino, C^Cj-alkylthio, cyano, carboxyl or carbamoyl, C 6 -cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, hydroxyl, C^Cg-acyloxy, benzoyloxy, phenoxy, C,-C 6 -alkoxy, 10 C^Cg-alkylamino, di(C,-C 6 -alkyl)amino, C,-C 6 -alkylthio, cyano, carboxyl or carbamoyl, (C^Ce-alkoxyHC^Cs-alkyl), (diiC^Ce-alkylJaminoHCcCs-alkyl) or (C 4 -C 6 -cycloalkyl)alkyl, (C 6 -cycloalkenyl)alkyl, or arylalkyl, naphthylalkyl or heteroarylalkyl, each of which is substituted by up to five radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each 15 case 0 to 2 carbon atoms, and where R and R’ can be linked to each other to form a 4- to 8-membered ring, or I) preparing compounds of the formula I where X is oxygen and R 1 , R 2 , R 3 and R 4 are as defined in claim 1 and R 5 is C^Cg-alkyloxycarbonyl, C^Ce-alkylthiocarbonyl, 20 C 2 -C 8 -alkenyloxycarbonyl, C 2 -C 8 -alkenylthiocarbonyl, C 2 -C B -alkynyloxycarbonyl, C,-C 6 -alkylaminocarbonyl, C 3 -C 6 -alkenylaminocarbonyl, diiC^Cg-alkylJaminocarbonyl, pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, 4-methylpiperazin-l-ylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, 25 phenoxy, C^Cg-alkoxy, C^Cg-alky I amino, difC^Cg-alkylJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; or aryloxycarbonyl aryIthio(carbonyl), arylaminocarbonyl, heteroaryloxycarbonyl, heteroarylthiocarbonyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, (arylalkylthio)carbonyl, arylalkylaminocarbonyl, heteroalkyloxycarbonyl, 30 (heteroalkylthio)carbonyl or heteroalkylaminocarbonyl, each of which is substituted by up to five radicals R 6 which are independent of one another, it being possible for 146 HOE91/F111K the alkyl radical to contain in each case 1 to 3 carbon atoms, by reacting a compound of the formula XVII XV where the definitions mentioned in claim 1 apply to R 1 , R 2 , R 3 and R 4 , n is 0, 1, 2 or 3, X is oxygen and U is a leaving group, with a compound of the formula XVIII Nu-H (XVIII) where Nu is C^Cg-alkoxy, C 2 -C 8 -alkenyloxy, C 2 -C 8 -alkynyloxy, C,-C 8 -alkylthio, C 2 -C 8 -alkenylthio, C^Cg-alkylamino- and difC^Cg-alkylJamino, C 2 -C 8 -alkenylaminoand di^-Ce-alkylJamino, optionally substituted by fluorine, chlorine, bromine, 20 hydroxyl, C 1 -C 4 -alkoxy, C^-C^-alkylamino, di(C,-C 4 -alkyl)amino, C^C^alkylthio, pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin1-ylcarbonyl, optionally substituted by C,-C 4 -alkyl, C 2 -C 6 -alkenyl, C,-C 4 -acyl, oxo, thioxo, carboxyl or phenyl, or aryloxy, arylthio, arylamino, arylalkyloxy, arylalkylthio, arylalkylamino, heteroaryloxy, heteroarylthio, heteroarylamino, 25 heteroarylalkyloxy, heteroarylalkylthio or heteroarylalkylamino, each of which is substituted by up to five radicals R e (R 6 is as defined at the outset) which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms. 30 6. The use of a compound of the formula I or la as claimed in one or more of claims 1-4 as a pharmaceutical. 147 HOE91/F111K
7. A pharmaceutical comprising an effective amount of at least one compound of the formula la as claimed in one or more of claims 1-4.
8. A process for the preparation of a pharmaceutical as claimed in claim 7, which comprises formulating an effective amount of a compound of the formula I or la together with customary pharmaceutical auxiliaries to give a suitable dosage form.
9. The use of a compound of the formula I or la in which n is zero, one, two, three or four, the individual substituents R 1 independently of one another are fluorine, chlorine, bromine, iodine, trifiuoromethyl, trifluoromethoxy, hydroxyl, C^Ce-alkyl, C 5 -C 8 -cycloalkyl, C,-C 6 -alkoxy, (C 1 -C 6 -alkoxy)-(C 1 -C 4 -alkoxy), 148 HOE91/F111K C^Cg-alkylthio, C^Cg-alkylsulfinyl, C^Cg-alkylsulfonyl, nitro, amino, azido, C^Cg-alkylamino, diiC^Cg-alkylJamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C,-C 6 -acyl, C^Cg-acyloxy, C^Cg-acylamino, cyano, carbamoyl, carboxyl, (C^Cg-alkyQoxycarbonyl, hydroxysulfonyl, sulfamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five radicals R 6 which are independent of one another, where R 6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C^Cg-alkyl, C 3 -C 8 -cycloalkyI, C^Cg-alkoxy, C^Cg-alkylthio, C^Cg-alkylsulfinyl, C^Cg-alkylsulfonyl, C,-C 6 -alkylamino, diiC^Cg-alkyQamino, (C,-C 6 -alky I) oxy carbony I, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R 2 and R 5 are identical or different and independently of one another are hydrogen, hydroxyl, CrCg-alkoxy, aryloxy, Ci-C 6 -acyloxy, cyano, amino, C^Cg-alkylamino, di^-Cg-alkylJamino, arylamino, C,-C 6 -acylamino, C,-C e -alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg- acyl oxy, benzoyloxy, benzyloxy, phenoxy, C^-Cg-alkoxy, Cj-Cg-alkylamino, di^-Cg-alkylJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 8 -alkenyl, optionally substituted by 149 HOE91/F111K fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 8 -alkoxy, CT-Cg-alkylamino, diiCrCg-alkylJamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl and carbamoyl; C 3 -C 8 -allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; C 3 -C e -alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di^-Cg-alkylJamino, C,-C 8 -alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C^Cg-alkylamino, di^-Cg-alkyQamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^Cg-alkoxy, C,-C 6 -alkylamino, ditC^Cg-alkylJamino, C,-C 6 -alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (C 3 -C 8 -cycloalkyl)-(C,-C 4 -alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, 150 HOE 91/F 111 Κ C^Cg-alkylamino, di(C,-C 6 -alkyl)amino, C,-C 6 -alkylthio, C^Ce-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; (Ca-Cg-cycloalkenylHC^C^alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C^Cg-alkylamino, diCC^-Ce-alkylJamino, C^Cg-alkylthio, C^Ce-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C^Cg-alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C^Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 -alkylamino, diiC^Cg-alkyQamino, C^Cg-alkylthio, C^Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 6 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C 3 -C 8 -cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; (C 5 -C 8 -cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; (C 3 -C 8 -cycloalkyl)-(C,-C 3 -alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; (C 5 -C 6 -cycloalkenyl)-(C r C 3 -alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C^C^alkoxy, oxo, phenyl; 151 HOE91/F111K C^Cg-alky I oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C^C^-alkoxy, C^C^alkylamino, di^-C^-alkylJamino, C,-C 4 -alkylthio; C 2 -C 8 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; C 2 -C 8 -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Ca-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; C 2 -C 8 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; C^Cg-alkylamino- and di(C^Cg-alkyl)aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin1-ylcarbonyl, in each case optionally substituted by C^C^alkyl, C 2 -C 8 -alkenyl, C^C^acyl, oxo, thioxo, carboxyl, or phenyl; C 2 -C 8 -alkenylamino- and di(C,-Cg-alkenyl) ami nocar bony I, in each case optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C^C^alkoxy, oxo, phenyl; C^Cg-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio)carbonyl, 152 HOE91/F111K (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl, each of which is substituted by up to five radicals R 6 which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 5 carbon atoms, and R 6 being as defined above, or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroaryialkyloxycarbonyl, heteroaryl (alkylthio)carbonyl or heteroarylalkylaminocarbonyl, each of which is substituted by up to three radicals R® which are independent of one another, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms, R 3 and R 4 are identical or different and, independently of one another, are hydrogen, C^Cg-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C.,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C^C^alkoxy, C^C^alkylamino, difC^C^alkyQamino, C 1 -C 4 -aIkylthio, C^C^-alkylsulfonyl, C^C^alkylsulfinyl, carboxyl or carbamoyl; C 2 -C 8 -alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C^C^-acyloxy, benzoyloxy, benzyloxy, phenoxy, 0,-C^alkoxy, C^-C^-alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C 1 -C 4 -alkylsulfonyl, C,-C 4 -alkylsulfinyl, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C^C^acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C 1 -C 4 -alkylamino, diCC^C^alkylJamino, C,-C 4 -alkylthio, C^C^alkylsulfonyl, C 1 -C 4 -alkylsulfinyl, carboxyl or carbamoyl; 153 HOE 91/F 111 Κ C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, Ο,-C^-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 alkoxy, C^C^alkylamino, di(C,-C 4 -aIkyl)amino, C^C^alkylthio, C,-C 4 alkylsulfonyl, C^C^alkylsylfinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is substituted by up to five radicals R® which are independent of one another, it being possible for the alkyl radical to contain 1 to 3 carbon atoms in each case, and R® being as defined above, R 3 and R 4 or R 3 and R 5 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring which has 3 to 8 carbon atoms and which can optionally be substituted by fluorine, chlorine, 15 hydroxyl, amino, C,-C«-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C^Cg-acyloxy, benzoyloxy, C^Cg-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X is oxygen, sulfur, selenium or substituted nitrogen N-R 2 , it being possible for R 2 to have the abovementioned meanings, for the preparation of pharmaceuticals for the treatment of diseases caused by viruses, in particular diseases caused by HIV. 154
10. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
11. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
12. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 5 or 11.
13. Use according to claim 6, substantially as hereinbefore described.
14. A pharmaceutical according to claim 7, substantially as hereinbefore described.
15. A process for the preparation of a pharmaceutical according to claim 7, substantially as hereinbefore described.
16. A pharmaceutical according to claim 7, whenever prepared by a process claimed in claim 8 or 15.
17. Use according to claim 9, substantially as hereinbefore described.
IE118792A 1991-04-15 1992-04-14 Quinoxalines, processes for their preparation, and their use IE921187A1 (en)

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Families Citing this family (23)

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WO1993022309A1 (en) * 1992-04-23 1993-11-11 Merrell Dow Pharmaceuticals Inc. 4-imidomethyl-1-[2'phenyl-2'oxoethyl-] piperidines as serotonin 5ht2-antagonists, their preparation and use in therapy
TW304945B (en) * 1992-06-27 1997-05-11 Hoechst Ag
TW274550B (en) * 1992-09-26 1996-04-21 Hoechst Ag
DE4335438A1 (en) * 1993-10-18 1995-04-20 Bayer Ag 4-cyanophenylimino heterocycles
DE4342024A1 (en) * 1993-12-09 1995-06-14 Hoechst Ag Combination preparations containing a quinoxaline and a nucleoside
DE4344452A1 (en) * 1993-12-24 1995-06-29 Hoechst Ag Aza-4-iminoquinolines, process for their preparation and their use
DE4437406A1 (en) * 1994-10-19 1996-04-25 Hoechst Ag Quinoxalines, process for their preparation and their use
DE19506742A1 (en) * 1995-02-27 1996-08-29 Bayer Ag Use of quinoxalines in combination with protease inhibitors as medicaments for the treatment of AIDS and / or HIV infections
DE19613591A1 (en) * 1996-04-04 1997-10-09 Hoechst Ag Substituted quinoline derivatives, process for their preparation and their use
DE19703131A1 (en) * 1997-01-29 1998-07-30 Bayer Ag Use of quinoxaline in a combination of three with protease inhibitors and reverse transcriptase inhibitors as medicaments for the treatment of AIDS and / or HIV infections
US6288075B1 (en) 1998-02-26 2001-09-11 Rhone-Poulenc Rorer S.A. Thiazolo[5,4,3-ij]quinolines, preparation and medicines containing the same
FR2760237B1 (en) * 1997-02-28 1999-04-16 Rhone Poulenc Rorer Sa THIAZOLOBENZOHETEROCYCLES, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM
AP2000001924A0 (en) 1998-12-23 2000-09-30 Aventis Pharma Ltd Dihydro-benzo(1,4)oxazines and tetrahydroquinoxalines.
DE10134721A1 (en) * 2001-07-17 2003-02-06 Bayer Ag tetrahydroquinoxalines
WO2005018531A2 (en) * 2003-08-26 2005-03-03 'chemical Diversity Research Institute', Ltd. Pharmaceutical compositions, azo-heterocyclic compounds and method for the production and use thereof
US7351709B2 (en) 2004-06-09 2008-04-01 Wyeth Estrogen receptor ligands
DK1995242T3 (en) 2006-03-14 2012-12-17 Santen Pharmaceutical Co Ltd Newly known 1,2,3,4-tetrahydroquinoxaline derivative with glucocorticoid receptor binding activity.
JP5054996B2 (en) * 2006-03-14 2012-10-24 参天製薬株式会社 Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity
MX2009012885A (en) 2007-05-29 2009-12-10 Santen Pharmaceutical Co Ltd Novel 1,2,3,4-tetrahydroquinoxaline derivative which has, as substituent, phenyl group having sulfonic acid ester structure or sulfonic acid amide structure introduced therein and has glucocorticoid receptor-binding activity.
CN103242238B (en) * 2013-05-10 2016-04-20 常州齐晖药业有限公司 A kind of preparation method of fenbendazole
US9802956B2 (en) 2013-07-15 2017-10-31 Helmholtz Zentrum Munchen-Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death
EP3031802A4 (en) 2013-08-09 2017-07-12 Santen Pharmaceutical Co., Ltd Production method for 3, 3-dimethyl-3, 4-dihydro-1h-quinoxaline-2-one derivative and intermediate for said production method
US10647687B2 (en) 2014-11-10 2020-05-12 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE706623A (en) * 1967-11-16 1968-04-01
US4032639A (en) * 1976-03-22 1977-06-28 American Home Products Corporation 2,3,4,4A-Tetrahydro-1H-pyrazino[1,2-a,]quinoxalin-5(6H)-ones and derivatives thereof for relieving hypertension
EP0190105A3 (en) * 1985-01-31 1988-10-26 Ciba-Geigy Ag Herbicidal agent
WO1992005160A1 (en) * 1986-10-30 1992-04-02 Reinhard Sarges 4-arylsulfonyl-3,4-dihydro-2(1h)-quinoxalinone-1-alkanoic acids, esters, and salts
US5318946A (en) * 1991-11-27 1994-06-07 American Cyanamid Company 2-(heteroaryloxyphenoxy)alkylsulfonates useful as herbicidal agents

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