IE83508B1 - Quinoxalines, processes for their preparation, and their use - Google Patents

Description

PATENTS ACT, 1992 PROCESSES FOR THEIR PREPARATION, AND THEIR USE HOECHST AKTIENGESELLSCHAFT Description The present invention relates to quinoxalines, to pro- cesses for their preparation, and to their use. class of compound 327 (1986)). in the in. various applications in well—known Chem. 237, been are a J. Liebigs Ann.

Quinoxalines (O. Hinsberg, have described Quinoxaline derivatives patent literature for use medicine.

Austrian Patent 284,848 (l9.l2.67) mentions 1—N—dialkylaminoalkyl—3,4—dihydroquinoxalin—2(1H)—ones as spasmolytic agents. A series of patent applications by the Japanese company Sumitomo Chem. Co. Ltd. describe 4—N—aroy1—, arylacyl— and ary1sulfonyl— 3,4—dihydroquinoxa1in—2(1H)—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): pyridiny1— alkyltetrahydropyrazino[1,2—a]quinoxalinone derivatives are described by American Home Prod. Corp. as antihypertensive and antisecretory reagents. A European Inc. (EP 266,102 A —N—benzenesu1fonyl- Patent Application by Pfizer (30.l0.86)) ,4—dihydroquinoxa1in-2(lH)—one—1—alkylcarboxy1ic includes acids an antiviral as aldose reductase inhibitors. Howeven activity has not been demonstrated to date. quinoxalines are known in herbicidal Furthermore, certain agriculture, specifically as compositions (cf. EP 0 190 105). with the object of providing novel antivirelly active compounds, it has rmmz been. found, surprisingly, that quinoxalines of the formulae 1 and Ia R I X N 1 KC;\\‘ \\fQ R” \ I ,2: \\ V//V 2 R4 I: Rd (I) and their tautomeric forms of the formula Ia N X\\\ Z V R 52'“ ‘ R3 I R‘ (Ia) and physiologically“ acceptable salts 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 Ia according to the invention, ) n is zero, one or two, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C1—C4—alkyl, C1—C4—alkoxy, (C1-C4- alkoxy)—(Cy4h—alkoxy), C1—C4~aUqdthio, nitro, amino, Cy%M—alkylamino, di(C1—Cyalkyl)amino, l—pyrrolidinyl, 4— piperidino, morpholino, _ 3 _ methylpiperazinyl, C1—C4—acyl, C1—C4—acyloxy, C1- C4—acylamino, cyano, carbamoyl, Carboxyl, (C1- C4—alkyl ) oxycarbonyl, hydroxysul fonyl, sul famoyl 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, C1—C4—alkyl, C1- C4—alkoxy, (C1—C4~alkyl)oxycarbonyl, phenyl, phenoxy, is hydrogen and R5 is C1—C5—alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—aCyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, Cl—C4— alkylamino, di(C1—C4~alkyl)amino, C1—C4— alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2—C6—alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—aCyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1~C4— alkylamino, di(C1—C4—alkyl)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; allenyl, C3—Cg—alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4—acy1oxy, benzoyloxy, _ 4 _ benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4— alkylamino, di(C1—C4—alkyl)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3—Cg—Cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1~C4—alkoxy, C1—C4—alkylamino, di(C1—C4—alkyl)amino, C1-C4- alkylthio, OX0, thioxo, carboxyl or carbamoyl; C3—Cg—cyCloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di(C1—C4—alkyl)amir1o, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3—C5—cycloalkyl) - (C1-C2-alkyl), optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di(C1—C4—alky1)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or Carbamoyl; (C3—C6—cyCloalkenyl) — (C1—C2—alkyl) , optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—aCyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1—C4—alkylamino, di(C1-C4-alkyl)aminO, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C1—C5—alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alky1, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, Cl—C4—alkoxy, C1—C4—alkylamino, C1—C4—alkenylamino, di(C1—C4~ alkyl)amir1o, C1—C4—alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2—C5—alkenyl carbonyl , optional ly substi tuted by fluorine, chlorine or hydroxyl; (C3—C5—cycloalkyl) carbonyl, (C5—C5—cycloalkenyl) carbonyl , (C3—C5—cycloalkyl)—(C1—C2—a1kyl)carbonyl , (C5—C5—cycloalkenyl) — (C1—C2—alkyl) carbonyl , C1—C6—alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C1—C4— alkoxy, C1—C4—alkylamino, di(C1-C4—alkyl)amino, C1—C4—alkylthio; C2—C5—alkeny1oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1- C4—alkoxy; C2—C5—alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1— C4—alkoxy; C1—C5—alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1— C4—alkoxy; C2—C6—alkenylthiocarbonyl, optionally substitu—ted by fluorine, chlorine, hydroxyl, C1—C4—alkoxy; C1—C6—alkylamino— and di (C1—C6—a1kyl)amino— carbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkoXy; pyrrolidin—l—yl, morpholino—, piperidino—, piperazinyl— or 4—methylpiperazin—1—ylcarbonyl; C2-C5-alkenylamino— and di (C1-C5-alkenyl) - aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C1- C4-alkoxy; C1—C4—alkylSulfOnyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-alkoxy; C1-C4 -alkenylsulfonyl; aryl, arylcarbonyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkoxycarbonyl or aryl(alky1thio)carbonyl, each of 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 R6 being as defined above, or l- 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-, 3- or 4—picolyl— oxycarbonyl, 2- or 3-furylmethyloxycarbonyl or 2- or 3—thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R6 which are independent of one another, ~:' and R4 are identical or different and, independently of one another, are hydrogen, C1-C4-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C1-C4- _ 7 _ acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1- C4—alkylamino, di(C1—C4—a1kyl)amino, C1-C4- alkylthio, C1-C4—alkylsulfonyl, C1-C4- alkylsulfinyl, carboxyl or carbamoyl; C2—C5—alkenyl, optionally substituted by fluorine or chlorine; C3—C5—cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4~alkoXy, C1—C4—alkylamino, di(C1—C4— alkyl)amino, C1—C4—alkylthio, C1-C4- alkylsulfonyl, C1—C4—alkylsulfinyl, carboxyl or carbamoyl; C3-C3-cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl, each of which is substituted by up to two radicals R6 which are independent of one another, 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, C1-C4- acyloxy, benzoyloxy, C1—C4—alkoxy, oxo, thioxo, carboxyl or carbamoyl, and the aryl groups mentioned in the preceding definitions are aromatic groups having 6-14 carbon atoms, the heterocyclic rings or heteroaryl groups mentioned in the preceding definitions contain l—l3 carbon atoms and 1-6 heteroatoms selected from the group consisting _ 8 _ of O, S and N, where in the case of an N- containing ring saturated in this position, N—Z is present, in which ring Z is H or R? having the respective definitions described above, x is oxygen or sulfur, with the exception of those compounds in which R3 and R4 are both hydrogen, and compounds in which R5 is COCHCl2, and compounds in which n is 1, R1, R3 and R5 are methyl and R5 is acetyl, and compounds in which n is zero, R3 and R4 are methyl or phenyl and R5 is ethoxycarbonyl. preferred group of compounds of the formula I or n is zero, one Or CWO , the individual substituents R} independently of one another are fluorine, chlorine, bromine, trifluoromethyl, C1—C4—alkyl, C1-C4-alkoxy, (C1-C4- alkoxy)-(C1—C2-alkoxyi, C1-C4-alkylthio, nitro, hydroxyl, amino, Cy%h—alkylamino, di(C1%h—alkyl)amino, piperidino, morpholino, l—pyrrolidinyl, 4- methylpiperazinyl, Ch—C4—acyl, QeC4—acyloxy, C;~ C4—acy1amino, cyano, carbamoyl, carboxyl, (Clw C4—a1kyl)oxycarbonyl, hydroxysulfonyl or sulfamoyl a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2- pyridyl, 3—pyridyl or 4—pyridylradical which _ 9 _ 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, C1—C4—alkyl, C1- C4—alkoXy, (C1-C4—alkyl)oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is C1—C5—alkyl, optionally substituted by C1—C4—alkoxy or C1- l5 C4—alkylthio; C2—C5—alkenyl, optionally substituted by oxo; allenyl; C3—Cg—alkynyl, in particular 2—butynyl; C3—Ce—cycloalkyl; C5—C5—cycloalkenyl; (C3—C5—cycloa1kyl) —(C1—C2—alkyl), in particular cyclopropylmethyl, optionally substituted by C1—C4—alkyl; (C3—C5—cycloalkenyl) — (C1—C2—alkyl) , in particular cyclohexenylmethyl; C1—C5—alkylcarbonyl, 33 optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C1-C4- alkoxy, C1—C4—alkylamino, C1—C4—alkenylamino, di(C1—C4—alkyl)amino or C1-C4-alkylthio; _ 1 Q _ C2—C5—alkenylcarbonyl; C1—C6—alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C1-C4- alkoxy, C1—C4—alkylamino, di(C1—C4—alkyl)amino, C1—C4—alkylthio; C2—C.g—alker1ylox3/carbonyl, in particular vinyloxycarbonyl , allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2~C6—alkynyloxycarbonyl, in particular propynyloxycarbonyl or butynyloxycarbonyl; C1—C5—alkylthiocarbonyl; C2—C5—alkenylthiocarbonyl, in particular allylthiocarbonyl; C1—C5—alkylamino— and di (C1—C5—alkyl) amino~ carbonyl; pyrrolidin—l—yl, morpholino—, piperidino—, piperazinyl— or 4—methylpiperazin—l—ylcarbonyl; C2—C6—alkenylamino— and di (C1—C5—alkenyl)amino~ carbonyl; C1—C4—alkylsulfonyl; C1-Cralkenylsulfonyl; or aryl which is substituted by up to two radicals R6 which are independent of one another, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (aryl— amino) thiocarbonyl, arylalkylamino—carbonyl, _ 11 _ arylsulfonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, it being possible for the alkyl radical in each case to contain 1 to 3 carbon atoms and Rebeing 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-, 3- or 4- picolyloxycarbonyl, 2- or 3- furylmethyloxycarbonyl or 2- or 3- thienylmethyloxycarbonyl, each of which is substituted by up to two radicals Ré which are independent of one another, R? and R5 are identical or different and independently of one another are hydrogen, C1-C4-alkyl, optionally substituted by hydroxyl, mercapto, C1—C4—alkoxy, C1—C4—alkylthio, Cy{Q—alkyl— sulfonyl, C1%h—alkylsulfinyl, carboxyl or carbamoyl; C2—C5—alkenyl, aryl, benzyl, thienyl or thienylmethyl, each of which is substituted by up to two radicals R6 which are independent of one another, R6 being as defined above, and R4can furthermore also be part of a saturated or unsaturated carbo— or _ 12 _ heterocyclic ring which has 3 to 6 carbon atoms and which can optionally be substituted by oxo or thioxo, and x is oxygen or sulfur. of the formula I or Ia as defined above wherein the substituents mentioned have the following Compounds meanings are very particularly important: )n is zero or one, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, Cy{h—alkyl, c1-c2_alkoxy, Cy%h—acyl or cyano, R? is hydrogen and R5 is c2—C6—alkenyl, c3—Cg—alkynyl, in particular 2—butynyl; (C3*C6“CYC1Oa1kY1)—(C1-C2-alkyl), in particular cyclopropylmethyl, optionally substituted. by C1-C4- alkyl; (C3-C5-cycloalkenyl)-(C:-C2—alkyl), in particular cyclohexenylmethyl; C2—C5—alkylcarbonyl, Cy{k—alkenylcarbonyl; Q—Ce—alkyloxycarbonyl; Q;C6—alkenyloxycarbonyJn in particular‘ vinyloxy— _ 13 _ carbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2—C5—alkynyloxycarbonyl, in particular propynyloxycarbonyl or butynyloxycarbonyl; C2-C5—alkenylthiocarbonyl, in particular allylthio— carbonyl; C1—C4—alkylsulfonyl; C1—C4—alkenylsulfonyl; or arylalkyl, in particular benzyl or arylalkenyl, which is substituted by up to two radicals Ré which are independent of one another, it being possible for the alkyl radical to contahi 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, —furylmethyl or 2- or 3—thienylmethyl, each of which is substituted by up to two radicals R? which are independent of one another, . where R is bronune, C1—C2—alkyl or fluorine, chlorine, cyano, C1-Cn—alkoxy, and R9 and R3 are identical or differern: and independently one another are hydrogen, C1—C4—alkyl , optionally substituteci by luydrmwl, mercapto, _ 14 _ C1—C4—alkoxy, C1—C2—alky1thio, and X is oxygen or sulfur.

The alkyl groups in the above definitions can be straight—chain or kmanched. Unless otherwise defined, they preferably contain 1-8, particularly" preferably 1-6, in particular 1-4, carbon atoms. Examples are the methyl, ethyl , propyl, l—methyl ethyl , butyl, Lmethylpropyl. 2-methylpropyl and l,1~dimethylethyl group, and similar groups.

The alkenyl groups mentioned in the above definitions can he straight—chain (mt branched and contain ]_ 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—methy1etheny1, 2—butenyl, 3—butenyl, 2—methyl—2—propeny1, 3—methy1- 2—butenyl, 2,3—dimethyl-2—butenyl, 3,3—dich1oro— —propenyl and pentadienyl groups and similar groups.

The alkynyl groups mentioned in the above definitions can fibe straight—chain or‘ branched. and contain ]_ 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 abmma definitions contain preferably 3~8, particularly preferably 4-6, carbon atoms. Examples are the cycloprqwl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.

The acyl groups mentioned in the abovecmfinitions can Unless 1-8, cycloaliphatic or anmatic. they be aliphatic, defined, particularly preferably 2-7, preferably contain otherwise carbon atmm. Examples; of _ 15 _ 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 rmtrogen—containing ring which is saturated a structure N—Z is present in which Z in this position, is H or R5 with definitions. individual above—described Unless otherwise defined, the heterocyctk: rings pre- ferably have 1-13 carbon atoH$ and 1-6 hetero atoms, in particular 3-9 carbon atoms and 1-4 hetero atoms.

Suitable radicals for the Iheteroaryl grmnos mentioned in the above definitions are, for example, heteroaromatic radicals sucli as 2- or 3—thienyl, 2- or 3—furyl, 2-, 3— or guinolyl or isoquinolyl. —pyridyl, pyrhmdyl, indolyl, Examples of the aralkyl groups mentioned in the above definitions are benzyl, phenylethyl, nqmthylmethyl or styryl.

The abovementioned substituents R1 to R5are preferably trisubstituted, particularly’ preferably disubstituted, T] particular monosubstituted, by the particular substituents mentioned. n the case of the particulxar definitions of composite (such as, for example, substituents arylalkoxycarbonyl), ranges whfim have been _ 16 _ described above as being preferred for the individual substituents are also preferred.

Depending on the various substituents, compounds of the formulae I and Ia 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 Ia 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 Ia can be prepared by known methods or 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 compounds of the formulae I and la as explained in 1) above, which comprises A) for preparing compounds of the formula I where X is oxygen and the radicals R1, R2, R3, R4 and R5 are as defined under 1) — 4), reacting a compound of the formula II T N O , /NY R F‘ H ' \ /R--R3 N \ ‘ Ra.

H (II) with the definitions mentioned under 1) applying to R1, RJ and R4, with a compound of the formula III (III) where R has the meanings for R5 and R2 which have been mentioned above under 1) with the exception of hydrogen, hydroxyl, C1-C5—alkoxy, aryloxy, C1—C5—acyloxy, amino, C1—C5—alkylamino, di(C1-Cs—alkyl)amino, arylamino and C1—C5—acylamino, and Z is a leaving group, or the formula I where X is and R5 B) preparing compounds of sulfur and R1, R2, R3, R4 l) by reacting a compound of the formula I where X is apply to R4 and R5, with a sulfurizing reagent, are as defined under oxygen and the definitions mentioned under 1) R1, R2, R3, or C) preparing compounds of the formula Ia where X and 1 to R5 are as defined under 1), by the radicals R reacting a compound of the formula IV N\ «X ‘ / P n—- l \ , R3 I R4 (IV) or N x\ / ” R‘ H i “ ‘ * R 3 WM’ \\ j RA R5 (IVa) when:-2 the definitions mentioned under 1) apply to R1, Pf, R/’ and R5, with a compound of the formula III (III) where the definitions described under 1) for formula I and la apply to R2, with the exception of hydrogen, C1—C5—alkoxy, aryloxy, C1—Ce—acyloxy, amino, di (C1—C6—alkyl) amino, hydroxyl, C1—C5-alkylamino, arylamino or C1—C5—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) by cyclizing a compound of the formula V C0-Y /L.“ .N \ 1 ‘H R (v) where R1’to R5 are as defined under 1) and Y is hydroxyl, C;—C4—alkoxy, optionally halogenated C1~C4—acyloxy, chlorine, bromine or iodine, or the formula I where X is E) preparing compounds of oxygen, R4 and R5 are hydrogen and the definitions men- tioned under 1) apply to R1 to R3, from the quinoxa— linones of the formula XI (XI) where R1 to R3 are as defined under l), by addition of hydrogen on the C=N bond, .19. :) preparing compounds of the formula I where X is Oxygen and R1 to R5 are as defined under I), from compounds of the formula VI R /. ‘ i,/ R fl ‘\ (VI) where R1, R2 and R5 are as defined under 1), 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, or with Q-(trihalomethyhalkanols 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), the where X is G) preparing compounds of formula I 2 3 oxygen and R1, R, R , R4 and R5 are as defined under 1), by reacting a compound of the formula I where X is oxygen and the definitions mentioned under 1) R‘ R2, R5 and to R3 and R4, apply to 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) (7 - 20 _ where R‘ has the meanings mentioned above for R3 and R4 a leaving with the exception of hydrogen and Z is group , 01’ H) preparing compounds of the formula I where X is oxygen, R1, R2, R5 is C1-C6~alkyl, hydroxyl, R3 and R4 are as defined in claim 1 and optionally substituted by fluorine, chlorine, C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1-C4—alkylamino, (ii (C1—C4—alkyl)amino, C1—C4—alkylthio, carboxyl, carbamoyl, C3-C6—alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di(C1—C4—alkyl)amino, C1-C4—alkylthio, carboxyl or carbamoyl, C3—Cg—alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4— alkylamino, di (C1—C4—alkyl)amino, C1—C4—alkylthio, carboxyl or carbamoyl, C4—Cg—cycloalkyl , optionally substituted by fluorine, chlorine , hydroxyl, C1-C4 —acyloxy, benzoyloxy, C1—C4—alkoxy, C1-Cralkylamino, di(C1—C4—alkyl)amino, C1—C4—alkylthio, carboxyl or carbamoyl, C5—Cg—cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C3—C4—aCyloXy, benzoyloxy, phenoxy, C1—C4—alkoXy, C1-Cralkylamino, di(C1—C4—alkyl)amino, C1—C5—alkylthio, carboxyl or carbamoyl, by reductive alkylation of a compound of the formula I where R5 is hydrogen and X is oxygen and the definitions mentioned under 1) apply to R1, 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, C1—C5—alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C: —C». —acyloxy, benzoyloxy , phenoxy, C1—C4—alkoxy, di (C1—C4—alkyl) amino, C1—C4—alkylthio, C3—C5—alkenyl , C; —C/, —alkylamino, carboxyl or carbamoyl, optionally _21_ substituted by fluorine, chlorine, hydroxyl, c1—c4—acyl0xy, crcralkylamino, C1—C4—alkoXy, C1—C4—alkylthio , benzoyloxy, phenoxy, di (C1—C4—alkyl) amino, carboxyl or carbamoyl, C3—C7—alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, cl_c4_acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, crcralkylamino, di(C1—C4—alkyl)amino, C1-C4-alkylthio, carboxyl or carbamoyl, C4—Cg—cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1_C4_acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1-C4- alkylamino, di (C1—C4—alkyl) amino , C1—C4—alkylthio, carboxyl or carbamoyl, Ce—cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, c1—c4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, crcralkylamino, di(C1—C4—alkyl)amino, C1-C4—alkylthio, or carbOXYl» and where R" to 8—membered ring , and R"' can be linked to each other to form a 4- the formula I where X is R3 and R4 are as defined under 1) ) preparing compounds of Oxygen and R1, R , and R‘ is C2435 —alkenyloxycarbonyl, C1 —C5—alkyloxycarbonyl, C1 —Ce—alkylthiocarbonyl , C2—C5— alkenyl thiocarbonyl , c2_c5 -a1kynyloxycarbonyl, C1 —C5—alkylaminocarbonyl , C3_c, _alkenylaminocarbonyl, di (C1—C6—alky1)aminocarbonyl , pyrro1idin—1—yl, morpholino— , piperidino—, pipera:/;inyl~, 4—methylpiperazin~l—ylcarbonyl, optionally substituted by fluorine or chlorine; or aryloxycarbonyl, arylthio(carbonyl), arylaminoCar~ (arylalkylthio) carbonyl or arylalkylamino— bony 1, carbonyl, each of 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 to 3 carbon atoms, by reacting a compound of the case f. ormu la XVI I (XVII) where the definitions mentioned under 1) apply to R1, R2, R3 and R4, n is 0, l, 2 or 3, X is oxygen and U is a leaving group, with a compound of the formula XVIII Nu—H (XVIII) C2-Cs—alkeny1oxy, C2-C5-alkenylthio , di (C1—C5—alkyl) amino , where Nu is C1—C5—alkyloxy, C2-C6—alkynyloxy, C1—C5—alkylthio, c1—c6—alkylamino— and C3—C6—alkenylamino— and di(C1—Cg—alkyl)amino, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4- alkoxy, pyrrolidin—l—yl, morpholino—, piperidino—, piperazinyl— or 4~methylpiperazin—l—yl , or aryloxy , arylthio , arylamino, arylalkyloxy, arylalkylthio, arylalkylamino, 2-, 3- or 4—pyridyl, 2- or 3—furyl, 2- or 3- thienyl, -, 3- or 4—picolyoxy, 2- or 3—furylmethyloxy or 2- or each of which is substituted by up the outset) —thienylmethyloxy, to two radicals R6 (R6 is as defined at 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 2 ’]‘J"u~,- 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 l—butanol, ethers such as tetrahydrofuran or glycol dimethyl ether, dipolar aprotic solvents such as N,N~dimethylformamide, N—methyl—2—pyrro—lidone, 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 pota ssium tert . —butylate, an organolithium compound such as butyllithium 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 for the organic base such as triethylamine or pyridine scavenging the acid which is liberated during reaction, may be expedient. the addition of an iodide, for example potassium The generally carried out at temperatures between ln some Cases, reaction is -10 and iodide, is expedient. l60“c, preferably at room temperature. it _ 24 _ To carry out this reaction, any nucleophilic substituents such as, mercapto for example, hydroxyl, or amino groups, with the exception of the 1- and/or —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 protec- acetyl or benzyl, such. as, for example, tive groups which can then be eliminated.

The su1furizing' reagent which is preferably ‘used for the reaction as described above under B) is 2,4_bis(4—methoxyphenyl)—l,3—dithia—2,4—diphosphetane (Lawesson's reagent), sulfide, sulfide, pentasulfide. ,4—disulfide bis(tricyclohexyltin) bis(tri—n—butyltin) sulfide, bis(trimethylsilyl) sulfide The carried out expediently in an organic solvent or in a bis(triphenyltin) or phosphorus reaction is room temperature or above, mixture, at solvent preferably at boiling point of reaction mixture, and, if possible, under anhydrous conditions. for example, carbon disulfide, 1,2—dichloroethane. If sulfides which. have been Suitable substances are, toluene, Xylene, pyridine and the mentioned are used, it tin sulfides or silyl 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 grmmm in a compound for example in a cmmwund where X is the of the formula I, oxygen and one or more radicals R9 to R6 are acyl, carbonyl is to be protected far known methods prior to the sulfurization reaction by a suitable protective subsequent example by acetalization; of the group, for elimination protective groups results in desired compound.

Iwn the reaction described above under C, the mflxmjtuent Z is a suitable leavinggnpup, 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 ethanol, the suitable solvent such as methanol , N,N—dimethylformamide or N—methylpyrrolidone, in 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 alkali hydroxides metal hydroxides or or sodium bicarbonate , alkaline earth metal 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 alkaline earth metal hydrides such as sodium hydride or calcium metal hydrides or 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 and 120°C, particularly at temperatures between 20 preferably at room temperature.

The compounds of the formula V, where R3 to R5 and Y are as defined under l), can be obtained from compounds of the 1': ormula VI _26_ R 1 NH R‘ / I H \ NH 1 R5 (VI) where R1, R2 and R5 are as defined under 1), by alkylation with a compound of the formula VII C O - Y I .2, R Z I R 4 (VII) and Y are as defined under 1) and Z is as where R3, R defined Under A). The reaction conditions for this l0 alkylation correspond to those given in method A.

Simultaneous cyclization to give the dihydroquinoxaline of the fOl’mU1a I takes place under suitable conditions.

Compounds of the formula V in which R1, R3 to R5 and Y are as defined Under 1) and R2 is hydrogen can also be prepared from compounds of the formula VIII N02 4\/ co—‘r R \\ ii i R3 N’ \ I R‘ ': (VIII) where R1, R to R5 and Y are as defined under 1) 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/l, p. 360—490), for example using tin(II) chloride in glacial acetic acid, TiCl3 in hydrochloric acid, or by catalytic hydrogenation, the choice of reagent being determined by the chemical stability of the various substituents R? 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 re- quired aS the described are known from the literature or commercially starting materials for syntheses available or can be synthesized by methods known from the literature.

N—ortho—nitrophenylamino acid derivatives of the formula VIII, where Rfl and R? to R? are as defined under 1) and Y is OR7, C1-C6-alkyl, optionally in each case for example halogen—substituted where R7 is hydrogen, phenyl, benzyl or 9—fluorenylmethyl, can be obtained for example by amination of ortho—ha1onitro aromatic substances of the formula IX N02 , // R] (‘I \\ W (Ix) where; R1 is as defined under 1) and W is fluorine, chlorine, bromine or iodine, with amhw acids or their esters of the formula X where R3, R4, R5 and R7 are as defined under 1). The reaction can be carried out in the presence of an inor- ganic or organic auxiliary base such as, for example, potassium carbonate, sodium hydroxide It is sodium carbonate, or triethylamine. 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 , 3-dimethyl—tetrahydro—2 (lH) —pyrimidinone.

The 1\]—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, halogenated C1—C4—aCyloxy, c¢_(j4_alkoxy, optionally Chlorine, bromine or iodine.

Q3-thO—halonitroaromatic compounds of the formula IX and amino acids of the formula X are known from the litera- ture: and commercially available or can be prepared by methods known from the literature. is preferably Thw reaction described above under E) effected by means of catalytic hydrogenation (using hydrogerl) or hydrosilylation (using alkylsilanes, for example diphenylsilane) in the presence of a hydrogena- ’) catalyst, for example Raney nickel or palladium- -29.. 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 S1'1Cl2/HCl. 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 N,N—dimethylformamide, aromatic hydrocarbons such as toluene or xylene, or mixtures of these solvents, at temperatures between -20 and lOO°C, preferably at room temperature.

If a chiral hydrogenation catalyst, for example di-u—chloro—bis [ (cycloocta—lc, 5c—diene) —rhodium(I) ] / (+) or (—) -4, 5—bis— (diphenylphosphinomethyl) -2 , 2—dimethyl— for l,3—dioxOlane, or a chiral complex metal hydride, example sodium tris— (N—benzyloxycarbonyl- L—prolir1oyloxy)-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—desCribed reaction .

Quinoxalinones of the formula XI where R1 to R3 are as defined under 1) can be obtained by known processes by condensing a phenylenediamine of the formula VI, where R; and R2 are as defined under 1) and R5 is hydrogen, with an alpha—ketocarboxylic acid of the formula XII R3~CO—COOH (XII) where R3 is as defined under 1).

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 N,N—dimethyl— formamide 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 l,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. usually carried out at temperatures The reaction is between 0 and 50°C, preferably at room temperature.

Substituents in compounds of the formulae VI and XIII, which stable the must be replaced by those which are not under reaction or XIV, conditions delfjlvatized to the required group. can be The substituents can also be provided with a Customary protective group which can the above—described then be removed after reaction. n the reaction described above under G), Z in formula xv jg a suitable leaving group such as, for example, chlorine, bromine or iodine, a suitable sulfuric acid ';_3dj(;a1, an aliphatic or aromatic sulfonate, or _ 31 _ optionally halogenated acyloxy.

The reaction conditions for this reaction correspond to those in method A. effected the The reaction described under H) is preferably by catalytic hydrogenation (using hydrogen) in example of 1. to presence of a hydrogenation catalyst, for palladium—on—charcoal, at a hydrogen pressure bar, or by neans of a reducing agent from the class of the sodium complex metal hydrides, such as borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. in an inert The reaction is expediently' carried. out solvent, such as lower alcohols, for example methanol or isopropanol, ethers, for example tetrahydrofuran or dimethyl example dichloromethane or‘ dichloroethane, between -20 100°C, The an acid acetic acid or trifluoroacetic acid, glycol ether, halogenated hydrocarbons, for at tempera- tures and preferably at room temperature. presence of such as, for example, 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 substhments which are which the example hydroxyl, is not attacked but can be derivatized to for necessary. required group, 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. Exanples of suitable solvents are aromatic hydrocarbons such as toluene or >qylene, lower alcohols such as methanol, ethanol or l—butanol, ethers such as tetrahydrofuran or glycol dimethyl ether, dipolar aprotic solvents such as N, N—dimethylformamide, N—methyl—2 —pyrro_'Lidone , acetonitrile, nitrobenzene, dimethyl sulfoxide, or mixture s of these solvents. Two—phase systems wi th 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 such as alkali metal hydride or alkaline earth metal hydride such as tert.—butylate, an organolithium compound butyllithium or lithium diisopropylamide, an sodium hydride or calcium hydride, an alkali metal or an organic base The fluoride such as potassium fluoride, such as triethylamine or pyridine, may be useful. reaction is usually carried out at temperatures between -10 and 160°C, preferably at room temperature. this nucleophilic substituents in compounds XVII and XVIII which do not To carry out reaction, any 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 such as, for example, protective customary groups acetyl or benzyl, which can then be eliminated.

The compounds XVII which are required for the abovemen— tioned reaction and in which the definitions described under 1) apply to R1, R2, R3 and R4, n is 0, IL, 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, triazolyl or benzotriazolyl, are prepared by reacting a compound of the formula I where _ 33 _ is hydrogen and X is oxygen, apply to R1, R2, R3 and the definitions des— and R4 , for R cribed suitable under 1) with a carbonic acid derivative, 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. for example of an The presence of a suitable base, 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 furthermore relates to to 3) The invention compounds as described under 1) present as pharmaceuti- in par- cals, preferably for treating viral diseases, ticular 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 cau sed by HIV.

'I‘he present invention furthermore relates to the use of Compounds of the abovementioned formula I or Ia _34_ the preparation of pharmaceuticals for the treatment of viral diseases.

The compounds mentioned and elucidated above under 1)- ) are preferred for this use.

The pharmaceuticals according to the invention can be administered enterally (orally), parenterally (intra- venously), 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 glidants, which fillers and extenders, solvents, emulsifiers, flavorings, colorings and/or buffer substances are customary in pharmacology. .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- stjmulating 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 mediunx additionally" contains 20% fetal calf serum and 40 IU/ml recombinant interleukin 2, Cells: Lymphocytes which have been isolated from fresh donor blood kn! means of Ficollu gradient centrifugation are cultured for 36 medium with an addition of 2 pg/ml phytohenegglutinin. (wellcome) at After lO% of DMSO has been added, the cells are frozen at a density of 5 X 106 and stored in liquid the test, the defrosted, washed in RPMI medium and cultured for 3 — 4 hours in complete °C under 5% of COL nitrogen. For cells are days in the complete medium.

Mixture: The test preparations were dissolved in DMSO at a con- centration of l6.7 mg/ml and diluted in cmmplete medium to 1 mg/ml. .4 ml of medium was introduced into 24—multiwell dishes. O.l ml of the dissolved preparatuni was added U3 the upper row of the dish, and, by transferring 0.1 ml portions, a geometric dilutimi series was established. Controls without prepmation always contained 0.4 ml of complete nediunl Cmmaining 0.5% of DMso_ Lymphocyte cultures with a cell damity of 5 x l05 cells/ml l/50 supernatant from HIV—infected lymphocyte cultures. volume The were infected by adding titer of these culture supenxmtants vms determined by end—point titration as l — 5 x lO6 infedfious units/ml.

Aftezr 30 minutes‘ incubatixxi at 37°C, the infected lymphocytes were removed by’ centrifugatimiaand taken up in an equal volume of Hedium. from this cell gugpQnSlOD, 0.6 nfl. aliquots were tnransferred. into all of the test plate. incubated we.“ 5 The mixtures were ; 2 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 determined as inhibitory the supernatants from the culture plates mwre tested for were observed was HIV. AS a cells concentration against control, the presence of HIV antigen with the aid of an) HIV antigen test following the manufacturer's instructions (Organon>. _ 37 _ Results: The results from this test are shown in Table 1, Compound of T—cell culture Example No. assay MIC (pg/ml) III 0.8 IV > 0.8 VI—A 0.16 VI—B 20 VI-C < 0.8 VII < 0.16 X 0.8 XII < 0.8 XIII < 0.16 XIV < 0.16 -7 0.08 -21 0.16 -23 0.08 -24 0.08 -25 0.4 -26 0.4 -29 < 0.4 L3—3o < 0.01 _38_ Compound of T-cell culture Example No. assay MIC (Hg/ml) 3-33 0.4 3-36 < 2.0 3-44 < 0.8 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 j< 4.0 _ 39 _ Compound of T—ce11 culture Example No. assay MIC (pg/ml) 6-1 0.4 6-16 < 0.8 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 17-3 < 0.01 +7-7 0 04 7-10 < 0.04 _ 40 _ Compound of T-cell culture Example No. assay MIC (Hg/ml) 7-11 < 0.01 7-12 < 0.8 7-13 < 0.08 7-14 < 0.08 7-16 .4 7-21 < 0.01 7-22 < 0.01 7-23 < 0.01 -4 0.4 -5 < 0.8 -9 < 0.8 -10 0.08 -13 0.08 -14 < 0.8 -17 0.8 -18 < 0.8 -20 < 0.8 -21 < 0.8 -27 .8 -28 < 0.8 11-1 < 0.8 11-2 > 0.8 11-3 < 0.8 11-4 .8 11-11 0.0 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 Amer- sham/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 ul volume per batch — the manufacturer's RT concentrate (5000 U/ml) was diluted in Tris—HCl buffer 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 pl of mixture were transferred to 4,5 ml of Tris—HCl buffer, lO mM; pH 7.4; O.l5 M NaCl, and the tritium activity was measured by means of a {5-a counter.

Assay For a pre—assay for inhibitory activity, the substances _ 42 _ were (iissolved in DMSO (stock solution c = 1 mg/ml), and tested as a 104, 104, 10%, etc., dilution in DMSO.

To determine Icm values, the inhibitor stock solutions were diluted further in TTis—HCl buffer, 50 mM, pH 8, and tested in suitable concentrations.

The concentration corresponding to a 50% enzyme inhibi- tion was determined from a plot of RT activity versus log Cum- The test results are shown in Table la.

Table 1a Compound of Reverse Transcriptase Assay _Example No. Icw (pg/ml) V 7.5 VI-A 0.08 VI-C 0.8 ;[II 0.1 XIII 0.04 _ 43 _ Compound of Reverse Transcriptase Example No. Assay ICw (Pg/ml) 3-75 0.1 — 1 3-76 0.018 -81 approx. 1 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 -1 0.08 -2 0.07 -3 0.07 -7 0.1 -10 0.11 -11 0.01 -12 approx. 1 7-13 0.1 — 1 7-16 approx. 1 _ 44 _ Compound. of Reverse Transcriptase Example No. Assay Icm (pg/ml) -9 approx. 1 -10 approx. 1 -13 approx. 1 -17 approx. 1 -18 0.1-1 -20 0.1-1 -21 0.1-1 -27 0 1-1 -28 0 1-1 11-11 0 1-1 -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—O.1 7-15 0.01-0.1 7-17 0.01—O.1 7-18 0.01—O.1 7-19 0.01—O.1 Fgompound of Reverse Transcriptase Assay Example No. ICW (pg/ml) 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 Icbo = 0.08 pg/ml The examples which follow and the contentcof the patent _45- claims illustrate the present invention in greater detail.

Example I (38)—6—Chloro—3—methyl—3,4—dihydroquinoxalin—2(1H)—one A) (S)—RF(3-Chloro—6—nitrophenyl)alanine (21.0 g, 0.109 mol) and 23.0 g of L—alanine were refluxed for 48 hours in ,4—Dichloronitrobenzene (0.258 nml) 4OO1nl of 2—methoxyethanol with an addition of 120 ml of 2N The subsequently concentrated in vacuo, and the residue was sodium hydroxide solution. mixture was taken up in aqueous sodium hydrogen carbonate solution. the using ethyl acetate, with 6N three times then and the yellow product was extracted mixture was extracted the hydrochloric acid, extract was acidified using ethyl acetate. The organic phase was washed once with saturated aqueous sodium chloride solution and dried (nagnesium sulfate), and the solvent was removed under reduced pressure. 14.7 g (55%) of a yellow solid of melting point l67—169°C remained (after crystallization from ethyl acetate).

H MMR (270 MHZ, d6—DMSO): 5 = 1.47 (d, J = 7 Hz, 3 H), 4.57 (quintet, J = 7 Hz, 1 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(1H)—one The product of Example IA (14.0 g, 0457 mol) was dis- OO ml of methanol and lmdrogenated with Raney nickel catalysis at room tenperature, solved in using 1 atm hydrogen. After the calculated emnount of hydrogen. had been taken up, the catalyst was remmmd by filtration with suction, and the reaction solution was concentrated in vacuo. The residue was purified by _46.. silica gel chromatography using ethyl acetate/heptane = 112 and 1:1 as the eluent. The yield was 6.0 9 (53%) of a brownish solid of melting point l22—l23°C (after recrystallization from isopropanol/heptane).

H NMR (60 MHZ, d5-DMSO): 5 = 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 [o<]D23 = +77.3° (c = 1, MeOH) C) (3R)—6—Chloro—3—methyl—3,4—dihydroquinoxalin— 2(1H)—one The compound was prepared from D—alanine by the methods described under Example IA and IB. Melting point l23—l24°C isopropanol/heptane) The NMR data agree with those of the compound described (after recrystallization from in Example IB. [or]D23 = —81.0° (c = 1, MeOH) D) (3RS)—6—Chloro—3—methyl—3,4—dihydroquinoxalin— (1H)—one The compound was prepared starting from D,L—alanine by the methods described ixi Examples IA and. IB. Melting 110°C isopropanol/heptane) The NMR data agree with those of the compound described point (after recrystallization from in Example IB.

The following Compounds of the fornuila I xuere synthesized analogously using the corresponding haloaromatic compounds and amino acid derivatives; Exannble II (38)»3—Benzyl~7—chloro—3,4—dihydroqunmxalin—2(1H)—one - 47 _ A) (S) —N— (4—chloro—2~nitrophenyl) —phenylalanine (8.3 g, 0.05 mol) (0.025 mol) of 2,5—dichloronitrobenzene were dissolved in 40 ml of (DMSO), L—Phenylalanine and 4.8 g anhydrous dimethyl sulfoxide and the stirred solution was heated to 80°C under an argon atmosphere. (4.2 g, 0.025 mol), was added dropwise in the course of Potassium tert.—butylate dissolved in 30 ml of DMSO, 40 minutes. Stirring was continued for 3 hours at 80 to 90°C, the mixture was allowed to cool, phenylalanine was removed by filtration with suction and unreacted 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. obtained in the form of a red oil which The product was (6.7 g, 84%). purification. was further reacted without ) (3S) —3—Benzyl—7—chloro—3 , 4 —dihydroquinoxalin— 2(lH)—one The product of Example IIA (12 g) was dissolved in 300 ml of anhydrous methanol and hydrogenated at room with palladium/charcoal catalysis, using when the off with and the concentrate temperature atm hydrogen. reaction had ended, solids were filtered suction, the liquid was concentrated, 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°. in NMR (270 MHZ, de-DMSO): 6 = 2.9 (m, 2 H), 4.08 (m, 1 H) , 6.09 (d, l H), 6.7 (m, 2 H), 6.78 (In, l H), 7.2 (m, 5 H), 10.34 ppm (br. s, l H).

Mg; (M+ Hf : 273, (M - 92)* = 181.

The compounds in Table 2 were prepared as described in the above examples .

Table 2 H 1 J o / \/ \// R ‘ I /‘V \ ‘ H . R 3 R 5 No R13 R3 R5 M.p. °C 1 5—Cl CH3 H Wax 2 6—Cl C21-I5 H 120 3 6—Cl C21-I4COOH H 4 6—Cl —CH2CH2CO— 6—Cl (CH3) 3CH H 6 6—Cl (CH3) 2CHCH2 H 011 7 6—Cl C2H5 (CH3) CH H Oil 8 6—C1 C5H5CH2 H 156—157 [1 6—Cl CH3SCH2CH2 H 97 6—Cl CI-13SCI-12 H 149 11 6—Cl CH3(oH) H 12 6—Cl CH3CH2CH3 H 75-77 13 7—C1 CH3 H 142 14 17—Cl (CH3) 2CH H Oil L15» 7—Cl CH3SC2H4 H 98 D6 8-Cl CH3 H 17 6.7-C12 CH3 H No R23 R3 R5 M.p. °C 12;: 7—F CH3 H 230 19 6—F CH3 H Wax 6-? CH3 C3H5 182 I 21 1 6-17 C5H5CH2 C3H5 Lzw [ 7—CF3 CH3 H 147 ”CH3OC2H4O C2H5 H 107 24 5_Cl C2H4OH H 211 6—Cl CH2—S—Bn H 170 26 6—Cl CH2—S—i.—Pr H 190 27 6—C1 C1 t.—Bu H 128 28 6—C1 C4H9 H 115 En = benzyl i_pr : isopropyl t_Bu : tert . —butyl Example III (35)—4—N—(Benzy1oxycarbonyl) — 6-ch1oro—3—methyl—3 , 4—di— hydroquinoxa1in—2 (1H) —one (1.0 g, solved in 20 ml of dichloromethane. .1 mmol) ml of 2N aqueous The compound of Example IB was dis- Sodium hydrogen carbonate solution were added, and o_9 ml (90%; 5.7 mmol) of benzyl chloroformate was added with ice—coo1ing and vigorous stirring. The two- phase system was subsequently stirred for 60 hours at After 30 0,2 m]_ of benzyl chloroformate was added. when the the temperature. hours, another IOOII1 (1.3 mmol) reaction was complete, the phases were separated, 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.

H NMR (270 MHZ, dg-DMSO): 5 = 1.15 (d, J = 7 Hz, 3 H), 4,85 (q, J=7H2, 1H), 5.20 (d, J :12 Hz, 1H), 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, (.1; 2 Hz, 1 H), 10.81 ppm (br. s, 1 H).

Ms; (M + H)‘ = 381 :«.ample IV _50_ (38) —4—N— (Benzyloxycarbonyl) —6~ch1oro—3—methyl—8—nitro— 3 , 4-dihydroquinoxalin—2 (1H)—one The compound of Example III (1.5 g, 4.5 mmol) was nitrated in glacial acetic acid (15 ml). A total of 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.).

H NMR (270 MHZ, d6~DMSO): 6 = 1.22 (d, J = 8 Hz, 3 H), 4.89 (q, J = 8 Hz, 1 H), 5.24 (d, J = 12 Hz, 1 H), 5.31 (d, J: 12 Hz, 1H), 7.35 — 7.5 (m, 5H), 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—dihydroquinoxalin—2 (lH) —one The compound of Example IV (1.5 g, 4.0 mmol) was dis- solved 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.

H NMR (270 MHZ, d5-DMSO)= 5 = 1.11 (d, J = 8 Hz, 3 H), 4.79 (q, J: 81-Iz, 1H), 5.15 (d, J=12 Hz, 1H), 5.24 (d, J: 12 Hz, 1 H), 5.38 (br. s, 2 H). 6.42 (S, 1 H), 7.3~7.4 (m, 6 H), 10.59 ppm (br. s, 1 H). _ 51 _ MS: (M+H)*=346 Example VI A) (3S)—6—Chloro—3—methyl—4—N—(3~methyl—2—buten—1—yl)— ,4—dihydroquinoxalin—2(1H)-one The compound of Example IE (1.0 g, 5.0 mmol) was dis- solved in 20 ml of acetonitrile and alkylated with 3—methyl—2—buten—l—yl bromide (90%; 0.92 ml, 7.0 mmol) at room temperature in the presence of 1.0 g (7.0 mmol) After 7 hours, the The mixture was filtered off with of pulverulent potassium carbonate. reaction had ended. suction, the filtrate was concentrated in. vacuo, and the product was purified by silica gel chromatography The yield using ethyl acetate/heptane = 1:2 as eluent. was 0.97 g (72%) of brownish solid of melting point 117—118°C (after "crystallization from methyl tert.— butyl ether/heptane).

H NMR (270 MHZ, d5-DMSO): 5 = 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), 10.47 ppm (br. s, l H)- MS: (M + H)* = 265 [QLF3 : +168.0° (c = 1, MeOH) B) (3R)-6—Chloro-3—methyl—4—N—(3—methyl—2—buten-1—yl)- ,4—dihydroquinoxalin—2(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 with described in Example VIA. —172° (c : 1, MeOH) agreed those of the compound [<7]1''):l : C) (3RS)—6—Chloro—3—methyl—4—N—(3—methyl-2—buten-l—yl)— 3,4~dihydroquinoxalin—2(1H)—one _ 52 _ The compound was prepared by the Hethod described in Example VIA starting with the compound of Example ID.

Melting’ point l48—l49°C (after recrystallization from isopropanol/diethyl ether) The NMR data with described in Example VIA. agreed those of the compound Example VII (35)—6—Chloro—3—methyl—4—N—(2—buten~l—yl)-3,4—dihydro— quinoxalin—2(lH)—one The substance was prepared analogously to the compound described in Example VIA, but with 2-buten—l—yl bromide as the alkylating agent. Melting point 87—88°C (after crystallization from diethyl ether/heptane) H NMR (270 MHZ, d6—DMSO): 5 = l.Ol (d, J = 8 Hz, 3 H), l.7O (dd, J5: 8, 1 Hz, 3 H), 3.63 (dd, J = 16, 6 Hz, 1 H), 3.85 - 4.0 km 2 H), 5.47 (m, l H), 5.75 (m, l H), 6.65 — 6.8 (m, 3 H), lO.48 ppm.(br. s, l H).

MS: (M + HY = 251 Example VIII 4—N—(Isopropenyloxycarbonyl)~3,3,7—trimethyl—3,4—di— hydroquinoxalin—2(lH)—one (0.4 g, anhydrous ,3,7—Trimethyl—3,4—dihydroquinoxalinr2(lH—one) ml of and the stirred solution was treated at room 0.24 ml (2.2 mmol) of The Hdxture was stirred for 6 hours at with the .1 nmml) were dissolved. in pyridine, temperature with isopropenyl chlorofOImat€- temperature and treated water, room precipitate which formed was filtered offxuith suction, (69%) of washed with water and dried“ This gave 0.4 g colorless crystals of melting point l85T.

H NMR (270 MHZ, de-DMSO): 6 = l..5 (S, 6 H), 1.9 (S, 3 H), 2.25 (s, 3 H), 4.7 (m. 2 H), 6.7 — 6.9 (m, 2 H). 7,15 (d, J = 8 Hz, 1 H), lO.6 ppm (br. 3 l H).

MS: 4 : Example IX (3S) —6—Chloro—4—N— (4—methoxyphenoxycarbonyl) —3—methyl— , 4—dihydroquinoxalin—2 (1H) —one The compound of Example IB (0.5 g, 2.55 mmol) was dis- solved in 10 ml of anhydrous N,N—dimethylformamide, and 0.41 ml (2.8 mmol) To the stirred mixture there was first added dropwise 0.42 ml (2.8 mmol) another 0.21 ml (18 hours), of triethylamine were added. of 4—methoxyphenyl chloroformate and, after (1.9 mmol) - When the reaction hours , was complete the solvent was stripped off under reduced pressure, the residue was taken up in and the mixture was washed with water 0.48 g (54%) concentrati on. Melting ethyl acetate, and dried of a white solid —190°C (after recrystallization from isopl’0paI1Ol) (sodium sulfate) . remained after point H NMR (270 MHz, d6—DMSO): 5 = 1.24 (d, J = 8 Hz, 3 H), 3.77 (s, 3H), 4.94 (q, J=8Hz, 1H), 6.97 (dd, J = 8, 2 Hz, 1 H), 7.03 (d, J: 8 Hz, 1H), 7.2 - 7.3 (m, 3 H), 7.78 (s, 1 H), 10.89 ppm (br. s, 1 H).

MS: (M + H)* = 347 Example X (38) —6—Chloro—4—N— (4—fluorophenoxycarbonyl) —3—methyl— 3, 4 —dihydroquinoxalin—2 (lH) —one The compound was prepared analogously to the compound described in Example VIA, but 4—fluoropheny1 chlorofor- mate was used as acylating agent. Melting point 168—l70°C (after crystallization from isopropanol) ”H NMR (270 MHz, de‘DMSO): 5 = 1.24 (d, J : 8 Hz, 3 H), 4.94 (q, J=8HZ, 1H), 7.03 (d, 8 Hz,1H), 7.2-7.5 (nu, 51-1), 7.83 (d, J=2I-IZ, 1H), 1 H) .

Ms: (M + H)‘ = 335 .90 ppm (br. s, '/zarnple XI _ 54 _ (35) —6—Chloro—4—N— (4—chloropher1oxycarbonyl) —3—methyl— 3, 4—dihydroquinoxalin—2 (lH) —one The compound was prepared analogously to the compound described in Example VIA, but 4~chlorophenyl chlorofor- mate was used as acylating agent. Melting point l85—l88°C (after crystallization from isopropanol/diethyl ether) H NMR (270 MHZ, d5-DMSO): 5 = 1.25 (d, J = 8 HZ, 3 H), 4.94 (q, J = 8 Hz, 1 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), .91 ppm (br. s, l H).

MS: (M + H)* = 351 Example XII (3s) —4—N— (2 —Bromoethyloxycarbonyl) — 6—chloro—3 -methyl- 3, 4—dihydroquinoxalin—2 (lH) —one The compound was prepared analogously to the compound described in Example VIA, but 2—bromoethyl chloroformate was used for the acylation. Melting point l33—l36°C (after Crystallization from isopropanol) H NMR (270 MHZ, d5-DMSO): 5 = 1.16 (d, J = 3 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, lH), 7.74 (d, J=2Hz, ll-I), lO.84 ppm (br. s, lH).

MS: (M + H)* = 348 Example XIII (38) —6-Chloro—N— (isopropenyloxycarbonyl) —3—methyl— 3, 4—dihydroquinoxalin—2 (lH) —one The substance was prepared analogously to the compound described in Example VIA, but isopropenyl chloroformate was used for the acylation. Melting point l58—l59°C ‘H NMR (270 MHZ, CDCI3): 6 = 1.33 (d, J = 8 Hz, 3 H), 2.0:: (s, 3 H), 4.79 (s, 1 H), 4.83 (s, 1 H), 5.17 (q, .1 : 8 Hz, 1 H), 6.86 (d, J = 8 Hz, 1H), 7.12 (dd, J : 8, 2 Hz, 1 H), 7.74 (br. s, l H), 9.28 ppm (br. s, l H).

MS: (M + H)* = 281 Example XIV (3S)—6—Chloro—3—methyl—4—N—(VinyloXyCarbonyl)—3,4—di— hydroquinoxalin—2 (lH) ~one The substance was prepared analogously to the compound described in Example VIA, but vinyl chloroformaue was used for the acylation. Melting point l77—l79°C H NMR (270 MHz, CDCl3)I <5 = 1.33 (d, J = 8 Hz, 3 H), 4.96 (dd, J = 14, 2 Hz, l H), 5.20 (q, J = 8 Hz, 1 H), 6.83 (d, J = 8 Hz, 1H), 7.12 (dd, J= 8, 2 Hz, l H), 7.2 — 7.3 (m, 2 H), 7.71 (br. s, l H), 9.42 ppm (br. s, l H).

MS: (M + H)* = 267 Example XV and Example XVI —Chloro-3, 4—dihydroquinoxalin—2 (lH) —one was reacted with 3—methyl—2—buten-l—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—l—yl)-3,4—dihydro— quinoxalin—2 (lH) —one Melting point l50—l5l°C (after recrystallization from ethyl acetate) H NMR (270 MHz, d5-DMSO): 5 = 1.72 (s, 6 H), 3,57 (5, 2 H), 3.80 (d, J : 7 Hz, 2 H), 5.20 (m, 1 H), 6.7 — 6.8 (m, 3 H), lO.49 ppm (br. s, l H).

MS: (M + H)‘ = 251 —Chloro—4—N— (3—methyl—2—buten—l—yl) (l, l—dimethyl— 2—propen—l—yl) -3 , 4—dihydroquinoxalin—2 (lH) —one Melting point llO—ll2°C (after crystallization from heptane) H NMR (270 MHz, d5-DMSO): 5 = 0.94 (s, 3 H), 0.97 (s, 3 H) l.65 (S, 3 H), 1.66 (S, 3 H), 3.77 (dd, J = l6, 7 H: l H), 4.23 (dd, J = 16, 7 HZ, 1 H), 4.8 — 4.9 Um _. 56 _ 2H), 5.02 (m, 1H), 5.75 (dd, J=l7, 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: M Smmvm mmmv E HUIW W HHO Smwu £0 E Honw v o 3 Smwum £0 m m o: £5 £0 m N mm mmoovmmu 3.5 m H U0 .Q.S Cam .O.Z.. m m z //K N : .u\ c \ Q) . «-4 I).

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Example XVII 6, 7-Dimethoxy—3—methyl—3 , 4—dihydroquinoxalin—2 (1H) —one (34-2 g, hydrogenated in 500 ml of methanol with Raney nickel After the calculated , 5—Dimethoxy-1 , 2—dinitrobenzene O . 15 mol) was catalysis using 1 atm hydrogen. 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 (6.2 g, 19%) .

°C was diethyl ether A analytically pure sample of melting point obtained by silica gel chromatography using ethyl acetate as the eluent.

H NMR (60 MHZ, a6—DMso>: 5 = 1.22 (d, J = 7 Hz, 3 H), 3.63 (S, 3 H), 3.67 (S, 1 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: H 1 O /N\/ R1“ H Table 4 No. Rln R3 R5 X M.p. °C 1 6, 7-(CH3O)2 CH3 IPOC O 133 2 6, 7—(CH30)2 CH3 IPOC S 3 6—C6H5S7- CH3 CSH9 O 115 4 C5H5S CH3 C5H9 O 107 6—CeH5S CH3 H 0 6 7—C5H5S CH3 H O 7 6,7(CH3O)2 CH3 H O 1.5].

Key: C5H9 = 3—methyl—2—buten—1—yl IPOC i sopropenyloxycarbonyl Example XVIII (3RS) —6—Chloro—4—N- (cyclopropyl) —3—methyl—3 , 4—dihydro— quinoxalin—2 (lH) —one A) (2RS) -N— (4—Chloro—2—cyclopropylaminophenyl) — (2 —bromopropionamide) (2.10 g, in 100 ml of methanol with — Ch loro— 2 — cyclopropylaminoni trobenz ene O . O] Raney nickel catalysis , mol) was hydrogenated using 1 atm hydrogen. After the calculated amount of hydrogen had been taken up, the the and the solvent was stripped process was stopped, Catalyst was removed by irjltration with suction, 01‘! in vacuo. To remove water completely, the mixture and reconcentrated. (1.80 g), which was dissolved in was: taken up twice in methanol ~ Ch I oro— 2 — cyclopropylaminoani line : ined in the form of a brown oil, _ 59 _ l,2—dimethoxyethane and cooled. to (0.01 mol) anhydrous ml of anhydrous “6OoCI of 2-bromopropionyl A solution of 1.1 ml ml of added dropwise, with stirring. chloride in 1,2-dimethoxyethane was slowly and stirring of the reaction mixture was continued for 2 -60 — —70°C. —20°C and ‘poured into 150 nfl of ice- hours at The mixture was then allowed to warm to approx- Cold, saturated solution. aqueous sodium hydrogen carbonate The mixture was extracted twice using ethyl and the organic phase was washed once with dried sulfate) vacuo. After crystallization ether/pentane, 2.51 g (79%) of melting point 130°C remained. acetate, concentrated in diethyl water, (sodium and with the desired product of H 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 HL 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%), 0.281nl (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 chrmmatography using ethyl acetate/heptane : 1:2 as eliuang The yield. was 200 mg (ggg) of white crystals of nelting pmint 167°C (after crystallization from pentane).

‘H NMR (270 MHZ, d6—DI\/ISO): 5 = 0.40 (m, 1 H), 0.63 (m, 3 H), 0.76 (mm 1 H), 0.98 (nu l H), EH12 (d, J = 7 Hz, H), 3-47 (m. 1H), 3.87 (q, J = 7 Hz, 1 H), 6.78 (s, 2 H), 7.0 (S, 1 H), 10.46 ppn1(br. s, 1 HL Mg; (M + H)+ = 2 lb The following compounds of the formula I were synthesized analogously to the procedure élescribed in Example XVIII using the correspondingly substituted ortho-nitroanilines and 2—halo carboxylic acid derivatives and, if appropriate, derivatized. further: Table 5 H E N X . / R ‘ n I: \ ‘ R 3 N : i R 4 R 5 No. Rln R3 R4 R5 x M.p. °c l 6—Cl CH3 H C51-I5 O l9l 2 6—Cl CH3 CH3 C3H5 O 3 6—Cl CH3 CH3 C3H5 S 4 6—Cl CH3 CH3 C3H5 O y 5 6—Cl CH3 CH3 C3H5 s Key: C31-I5 = cyclopropyl C6H5 = phenyl Example XIX 7—Chloro»l—N— (cyclopropyl) -3 , 3—dimethyl—3,4— dih}/dro- quinoxalin—2 (lH) ~one —Ch loro—2—cyclopropylaminoni trobenzene (2 . 0 g, .4 mmol) was hydrogenated as described in Example XVII IA. The resulting 4—chloro— 2—c3/clopropylaminoaniline (1.70 g) was taken up in ml of dichloromethane. l.6 ml (2.01 mmol) of chloroform, l.8 ml (2.45 mmol) of acetone and O.lO g (0.4 mmol) of benzyltriethylammonium chloride were acldecl, and the reaction solution was cooled to 10°C. ml of 50% strength sodium hydroxide solution xmere slowly added dropwise with. vigorous stirring; during which process the reaction temperature should not After stirring for 5 hours at 10°C, the exceed 10°C- were diluted and separated. The organic phase phases was washed once with water, dried (magnesium sulfate) and evaporated in VaCu0- 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/h€ptaUe)- H NMR (270 MHz, d6~DMs0): 6 = 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, 2 Hz, 1 H), 7.19 ppm (d, J = 2 Hz, 1 H).

Ms; (M + H)* = 251 The following compounds of the formula I were synthesized hi analogous inanner and, if appropriate, derivatized further: Table 6: H I / /N\¢O 3 1 .

\ NZX—-R. 1: R4 R- No. Rim R3 R4 R5 M.p.°C 1 6—Cl CH3 CH3 Cfih 179 ‘;H__ 7—c1 CH3 CH3 C5119 171 3 6,7- H3H3O)2 CH3 CH3 H 4 6, 7‘ (CH3O) 2 CH3 CH3 C51-19 ~_;.__M_ CH3 CH3 SC5I-11; 113 C6H5 CH3 H ‘/11.’ C5H5 CH3 C5H9 8 6-C1 CH3 CH3 IPOC 128 9 7-C1 CH3 CH3 IPOC 169 7—CH3 CH3 CH3 C5H9 168 11 6-CH3O CH3 CH3 H 200 12 6-CH3O CH3 CH3 C5H9 13 8 13 6/7—COOH CH3 CH3 H > 240 14 6 /7-COOH CH3 CH3 C5H9 180 8-CH3 CH3 CH3 H 140 16 8-CH3 CH3 CH3 C5Hg 160 17 8-CH3 CH3 CH3 IPOC 127 18 6 /7—CH3 C2H5 C2H5 H 160 19 6-CH3 C2H5 C2H5 C5H9 100 7-CH3 C2H5 C2H5 C5H9 110 21 7-1:‘ CH3 CH3 H 120 22 7-1’ CH3 CH3 C5119 155 23 7*C2H5O CH3 CH3 CH3 H 155 24 7-C2H5O CH3 CH3 CH3 C5Hg 123 6-COOH CH3 CH3 CH3 C5H9 245 26 7,8—(CH3)2 CH3 CH3 H 196 27 7,8-(CH3)2 CH3 CH3 C5}-I9 155 28 6,7-(CH3)2 CH3 CH3 H 248 29 6,7-(CH3)2 CH3 CH3 CSH9 200 6~C1,7- CH3 CH3 H 211 (2 , 3 -C12C5H3O) 31 6—C1,7~ CH3 CH3 C5Hg: 205 R (2,3—C12C5H3O) 2 7-F CH3 CH3 IPOC 175 3 7-C2H5O CH3 CH3 CH3 IPOC 150 No. Rln R3 R4 R5 M.p . °C 34 6/7—CI-13 CH3 CH2 IPOC 152 3L 7, 8- (CH3)2 CH3 CH3 IOPC 147 3(» 6,7—(CH3)2 CH3 CH3 IPOC 161 “M 7~C5H5 CH3 CH3 H 167 3333‘-—M_3_ 7—C5H5O CH3 CH3 CH3 C5H; 138 “ 7-C5H5O CH3 CH3 CH3 IOPC 181 _g_ 5—CH3 CH3 CH3 H 1 82 6-CH30, CH3 CH3 H > 2 7- <4—pyridyl> 42 6—C1, CH3 CH3 H 219 7—piperidino 43 6/7—C1,7/6- CH3 CH3 H 236 morpholino unixture) 44 6/7(N—methy1— CH3 CH3 H > 240 piperazin— l—yl) 45 6/7—C1,7/6- CH3 CH3 H 147 (N—methy1— piperazin— 1—y1) 46 6—C1 CH3 CH3 H 152— 154 47 7—C1 CH3 CH3 H 48 6—C1 CH3 CH3 ALOC 128- 129 49 7-C1 CH3 CH3 ALOC 144 50 6—Cl CH3 CH3 COOGHCH3)2 118 51 7—C1 CH3 CH3 COOGHCH3)2 171 52 7- (4—F—Ph—SO2O) CH3 CH3 H 53 7- (4-F—Ph—SO20) CH3 CH3 IPOC 204 54 6~C1,7— CH3 CH3 IPOC 152 piperidino 55 6—C1,7— CH3 CH3 IPOC 113 morpholino 56 6—C1,7—(N— CH3 CH3 IPOC 168 methyl- piperazin—1— yl) 57 6—C1,7—NEt; CH3 CH- H 141 No Rim R3 R‘ R5 M.p. °c 58 6—C1,7—NEt; CH3 CH3 IPOC Oil wggmm 6,7—C12 CH3 CH3 1-1 232 60 H 6,7—C12 CH3 CH3 IPOC 171 61 7—(N—rnethy1— CH3 CH3 E1 198 ‘piperaziny1— ._.74_ —yl) 62 7- (N—methyl— CH3 CH3 IPOC 123 piperazinyl—l- yl) 63 6-CH3O CH3 CH3 IPOC 128 64 7~CL — (CH2)3- IPOC 172 65 7—Cl — (CH2)4— IPOC 181 66 6—Cl —(CH2)3- IPOC 157- 158 67 6—Cl —(CH2)4- IPOC 179- 180 68 6—Clq CH3 CH3 COOC2H5 l37 69 6—Cl CH3 CH3 COOC3H7 125 Key; C51-I9 = 3—methyl—2—buten—l—yl sCeH11 = 4—methy1—3—penten—2—yl IPOC = isopropenyloxycarbonyl Example XX 3, 3—Dimethyl—4—N— (3—methyl—2 —buten—l—yl) -3, 4 —dihydro— quinoxalin—2 (lH) —one The compound was prepared analogously to the compound described in Example VIA, starting from 3,3—dimethyl— ,4—dihydroquinoxa1in—2(lH)—One (J. T. Lai, Synthesis l982, 7l). Melting point l46—l47°C (after crystallization from methyl tert.—butyl ether/heptane) 1H NMR (270 MHz, d6-DMS0): 5 = 1.27 (s, 3H), 1.68 (s, 3 H), 1.72 (s, 3 H), 3.88 (d, J : 7 Hz, 1H), 5.15 (m, 1H),6.60(d,J:7Hz,lH),6.67 (t,J=7Hz,lH), 6.781 (d, J = 7 Hz, 1 H), 6.87 (t, J : 7 Hz, 1 H). .33 ppm (br. s, 1 H).

MS: (M + H)+ = 245 Example XXI 4 —N~ (3-Methl/1buten—l-yl) - 3 , 4-dihydroquinoxalirh I3 (1)) ) —one—3 —spiro—l ' —cyclohexane. ')‘hr~ compound was prepared analogously to the compound described in Example VIA, starting from spiro[cyclo— hexane—1,3'-'(3',4'—dihydroquinoxalin—(1'H)—one)] (J. T.

Lai, synthesis 1982, 71). Melting point 82-83°C (after crystallization from heptane) H NMR (270 MHz, d6—DMSO): 5 = 1.25 - 1.75 (m, 10 H), 3.75 (d, J = 6Hz, 2H), 5.07 (m, lH), 6.7 — 7.0 (m, 4 H), lO.15 ppm (br. s, 1 H).

MS: (M + H)* = 285 Example XXII —N— (3—Methyl—2—buten—1—yl) -3 , 4—dihydroquinoxaline— (1H)—thione—3—spiro—1‘—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)—l,3—dithia— 2 , 4—diphosphetane 2 , 4—di sulfide (Lawesson ' s reagent) in ml of anhydrous toluene. The mixture was in vacuo, and the products subsequently concentrated 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.

H NMR (270 MHZ, d5—DMSO): 5 = 1.1 — 1.9 (m, 16 H), 3.64 (d, J=7Hz, 2H), 4.99 (m, 1H), 6.95-7.1(m,3H), 7.18 (d, J=7Hz, lH), 12.2 ppm (br.s, lH).

MS: (M + H)* = 301 , 4—Dihydroquinoxaline—2 (lH) —thione—3—spiro—l ' —cyclo— hexane was isolated as a further product in a yield of mg (26%); yellow crystals of melting point 178°C.

H NMR (270 MHZ, CDCl3 5 = 1.25 ~ 2.2 (m, 10 H), 4.18 (br. s, l H), 6.7 — 6.8 (m, 3 H), 6.97 (In, 1 H), 9.42 ppm (br. s, l H).

MS: (M + H)“‘ = 233.

Example XXIII (38) —6—Chloro—4—N- (isopropenyloxycarbonyl) -3 —methyl— 3 , 4 ~ dihydroquinoxaline—2 (1H) —thior1e _ 75 _ The compound of Example XIII (0.5 g, 1,78 mmol), dis- solved 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).

H NMR (270 MHZ, dyIMSO): 5 = 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, 1 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 ,4—dihydroquinoxalin—2(1H)—ones: Table 7 ‘ 1 O . / N\.// L I 5 ,- K :3 7’ 834 R5 No. Rln R3 R4 R5 M. p. °C 1 CH3 H C5H9 119 2 6—Cl CH3 H C5Hg 109- 110 3 6—Cl CH3 H C5H5 92 4 C5H5 CH3 C5Hg 6—C1 CH3 CH3 C5H9 157 6 7—Cl CH3 CH3 C3H3 160 7 7—C1 CH3 CH3 H 170 8 6-Cl CH3 H ALOC 143- 145 9 6—C1 CH3 CH3 IPOC 153 7—C1 CH3 CH3 IPOC 174 11 6—Cl CH3 CH3 H 175 12 6—C1 C3H3 H IPOC l76~ 177 13 6-C1 C21-I5 H ALOC 159- 161 14 6,7—(CH3)2 CH3 CH3 C5Hg 173 6—C1 C3H7 H IPOC 154» __ 155 16 6—Cl C3H~, H ALOC 98-100 1/ 6—C1 CH3 H (2—C5H4N) — 175- CH2 178 12: 6—C1 CH3 H (3—C5H4N) — 77 _ CH; 19 6—C1 CH3 CH3 ALOC 153- 154 No. R1,, R3 R4 R5 M.p. °C 2 o 6-Cl CH3 CH3 COOCH (CH3) 1 5 1 2 21 6—Cl CH2SCH3 H IPOC 128 22 6-01 CH3 CH3 COOC2I-I5 163 23 6—Cl CH3 CH3 COOC3H7 164 24 6-Cl C2H5 H (2—C5H4N)- 162— CH2 164 6-Cl C4H9 H IPOC 132 26 6*C1 CH3scH3 I COOCH (CH3) 124 2 27 6—Cl CH2SCH3 H (2—C5H4N) — 159 CH; 28 6—CH3O CH2SCH3 H IPOC 154 -CH3O CHQSCHB COOCH (CH3) 163 6-Cl CH2SCH3 CH2C5H4 Oil Cl Key: C5H9 = 3—methyl—2-buten~l—yl IPOC j $sopropenyloX3/carbonyl ALOC = allyloxycarbonyl C5H4N = pyridyl Example XXIV (3RS ) ~3—Methyl—4—N— (3-methyl—2—buten—l—yl) — 2—methylthio—3, 4—dih3/droquinoxaline (3RS) ~3—Methyl—4—N— (3—methyl—2—buten—l—y1) — ,4-dihydroquinoxaline—2(lH) —thione (Table 7, No. l) (0.49 g, 2.0 mmol) were dissolved in 20 ml of ethanol (95%), and the solution was treated with 5.1 ml (2.2 mmol) of a l% 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 chrr>matOgraph€d 01’1 Silica 991- 500 mg (96%) of a yellow _79_ oil were isolated using ethyl acetate/heptane = 1:6. in NMR d6-DMSO): 5 = 0.96 (a, J = 7 Hz, 3 H), 1.72 (s, 6 H), 2.44 (s, 3 H), 3.71 (dd, J = 15, 6 Hz, 1H), 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, 1H), 7.11ppm (d,J=8Hz,lH).

MS: (M + Hr‘ = 261 The following compound of the formula I was synthesized in the same manner: -Isopropenyloxycarbonyl—2— (isopropenyloxycarbonyl) — thio—3 , 3, 7 , 8~tetramethyl—3 , 4—dihydroquinoxaline.

Melting point: 115°C Example XXV (3RS) —3—Methyl—4—N— (3—methy1—2—buten—1-yl) -3 , 4—dihydro— quinoxalin—2 (lH) —one (4.86 g, dissolved in 50 ml of N,N—dimethylformamide, (0.033 mol) of 3—methyl— in the presence of 4.60 g The (3RS ) —3—Methyl—3 , 4—dihydroquinoxalin—2 (lH) —one 0.03 mol) alkylated with 4.2 ml (90%) of pulverulent potassium carbonate. was 2~buten—l~yl bromide (0.033 mol) reaction mixture was stirred at room temperature until reaction of the educt was Complete. The solvent was the residue was taken up in then stripped off in vacuo, ethyl acetate and water, the phases were separated, 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- °C .

‘H NMR (270 MHz, d5—DMSO): 6 = 0.99 (d, J : 7 Hz, 3 H), 1.71.; (S, 6 H), 3.67 (dd, J = 15, 7 Hz, 1 H), 3.86 (q, J :5 '7 Hz, 1 H), 3.88 (dd, J = 15, 7 Hz, 1 H), 5.21 (m, 1 H) , 6.65 - 6.9 (m, 4 H), 10.31 ppm (br. s, l H).

MS: (M + H>* = 231 Example XXVI 3 , 3a~Dihydropyrrolo [1, 2 —a] quinoxaline— l , 4 (2I{ , 5H) —dione -1 mOl) and L—glutamic heated in 100 ml of with stirring, and 300 ml of added Stirring was then continued for another 3 hours at this —Fluoronitrobenzene (14.1 g, acid (45.0 g, 0.3 11101) 2—me-thoxyethanol at 95°C, were N sodium hydroxide solution were drOpwise_ After cooling, the solution was treated temperature. with 4 00 ml of atmospheric pressure with Raney nickel as catalyst. methanol and hydrogenated under 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 was filtered off with suction, washed with water and alcohol and subsequently dried, melting point °C, decomposition.

H NMR (60 MHZ, de—DMSO): 5 = 1.9 — 2.7 (m, 4 H), 4.5 (t, J:8Hz, 1H), 6.8-7.3 (m, 3 H),7.8—8.2 (m, 1 H), 10.7 ppm (br. s, 1 H).

Mg; (M+H)+ = 202 Example XXVII 7—PhenoXysulfonyl— 3 , 3a~dihydf0PYl”l’OlO [1, 2-a] quinoxaline~l , 4 (2H , SH) —dione The compound was obtained in analogous manner by reacting phenyl 4—chloro—3—nitrobenzenesulfonate with L—glutamic acid, melting point 140°C (decomp.) .

H NMR (60 MHZ, c'{5—DMSO): 5 = 1.6 — 2.5 (m, 4 H), 4.07 (t, J:6Hz, 1H), 6.7- 7.6 (In, 8 H), 10.57 ppm (br. s, 1 H).

Ms; (M + H)+ = 3 _ 81 _ Example XXVIII 3—CarboXymethyl—3,4-dihydroquinoxalin—2(1H)—one (14.1 g, 0.1 mol) were heated to 95°C in lOO1nl of 300 ml of 2N sodium hydroxide solution were added dropwise. Stirring at this —F1uoronitrobenzene and L—aspartic (40.0 g, 0.3 mol) -methoxyethanol, with acid stirring, and was then continued for 1. hour temperature.

After the ml of nethanol and hydrogenated under atmospheric solution had cooled, it was treated with pressure with Raney nickel as catalyst. when the uptake of hydrogen had ended, the catalyst was removed Eur filtration with. suction, and the solution was concentrated under reduced pressure.

The with hydrochloric ml of 2N acidified residue was mixture with acid. subsequently and dried the solvent was stripped off, Concentrated, neutralized sodium acetate extracted with ethyl acetate. The rmxture was with sodium sulfate, and the residue was then obtahfled which was first oily’ and stirring with water crystallized upon melting _point l52—l54°C.

H NMR (60 MHZ, d6~DMSO): 5=2.5—2.7 (dd partly concealed, 2 H), 4.1 (td, J = 6, 2 Hz,1 H), 5.98 (br. s, 1H), 6.5-6.9 (m, 4H), 10.30 (br. s, 1H), 12.37 ppm (br. s, 1 H).

MS: Mi: 206 calculated C 58.2; H 4.8;N 13_6% C 58-4; H4.7; N 13.7% CHN analysis: found Example XXIX —PhenoXysul fOnyl—3, 4 —dihydrOquinoxalin—2(1I—I)—one A) Methyl N—[(2q1itro— 4—phenoxysulfonyl)phenyl]g1yn:inate 4—chloro—3—nitrotuenzenesulfmmte (62 .7 g, (100.4 g, Phenyl .2 mol) and methyl glycinate hydrochloride _ 82 _ 0.8 mol) , dissolved in 250 ml of methanol, were treated with 200 ml of the refluxed for 15 minutes. After cooling, the mixture was with l l of filtration with and mixture was triethylamine, subjected to The treated 2N acetic acid, and washed with water. ethyl and (ii i sopropyl suction residue was recrystallized from acetate and washed with methanol ether, melting point l20—l23°C.

B) 7—Phenoxysulfonyl—3 , 4-dihydroquinoxalin-2 (lH) —one Methyl N— [ (2—nitro—4—phenOxysulfonyl)phenyl ] glycinate (36.6 g, 0.1 mol) were hydrogenated under atmospheric pressure in a mixture of 250 ml of N,N—dimethylformamide and 250 ml of methanol, with Raney nickel as catalyst. When the uptake of hydrogen had ended, and the solution was the catalyst was removed by filtration with freed from solvent in 40 ml of suction, vacuo. residue was dissolved in and the mixture was heated for one vme thoxyethanol, in a steam bath. resulting precipitate was filtered off with melting point 253—254°C. hour suction and washed with methanol, H NMR <50 MHz, d5-DMSO): as = 4.0 (d, J = 4 Hz, 2 H), 6.6 — 7.6 (m, 9 H), 10.43 ppm (br. S, lH).

Ms: (M + H)’ = 305 Example XXX 4 ~ (3 ~Methyl—2—buten—l—yl) —7—phenoxysulfonyl— 3, 4 ~ dihydroquinoxalin—2 (lH) - one -- Phenoxysulfonyl—3 , 4—dihydroquinoxalin~2 (lH) -one (1.52 g, 5.0 mmol) stirred for 8 hours at lOO°C with 2 ml of 3—methyl— 2—buL:en-—l—yl bromide. After the treated with water and extracted with ethyl acetate. in 20 ml of N,N—dimethylacetamide Wo1.‘:'. cooling, mixture was ’I‘h<'~- solution was dried using magnesium sulfate and then concentrated, and the residue was chromatographed over a 2:21 lica gel column using ethyl acetate/heptane = l:l. _83_ contained the substance and the product was The fractions which evaporated on a rotary evaporator, were subsequently stirred with pentane and filtered off with suction, melting point 132°C.

H NMR (270 MHZ, d6—DMSO): 5 = 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: Table 8 H i N\/ O / / re‘ ' I n \ /——R 3 N \ . I R 4 Q R- Two Rln R3 R4 R5 M.p. 0c I 7-C5H5-O-S02 H CH2OH H 199 2 7-—C5H5—O—SO2 H CH2OH C5H9 120 3 7~C5H5-O-S02 H CH2COOH H 230 decomp. 4 7—C5H5-O-S02 H CHQCOOH C5H9 '7-CeH5-O-S02 H CH2CONH; H 272 decomp. (1 7-C6H5-O-S02 H CHQCONH; CSH9 '[ 7-C5H5-O-S02 H CH2—4—Imi H 216 decomp. 'r_?_‘ * 7~C6H5—O-SO2 H CH2—4~Imi C5H9 EL” 7—C6H5-S02 H H H 280 decomp. 1107 _W_ 7-C6H5-S02 H H C5H5-CO 277 decomp. :14.‘ V# 7—C5H5‘O*SO2 H CH3 H 148 11.‘ ‘N %-‘C6H5‘O—SO2 H CH3 C5H9 Oil No. R1,, R3 R4 R5 M.p. 0c 13 7—CeH5—SO2 H CH3 H 198 —C5H5—SO2 H CH3 C5H9 Oil —C5H5—SO2 H CH3 IPOC 108 —CsH5-O—SO2 H H H -C5H5OSO2 H H COCH3 270 —C5H5—OSO2 H CH3 IPOC resin Key: C5H9 = 3—methyl—2—buten—l—yl 4—Imi = 4—imidazolyl IPOC = isopropenyloxycarbonyl Example XXXI —Chloro—7—phenoxysu1fonyl -1, 2 , 3 , 3a—tetrahydro— pyrrolo [2, 1—c]—quinoxa1in— 4 (SH) —One A) Phenyl 2,4—dich1oro-3—nitrobenzenesulfonate , 6—Dich1oronitrobenzene was stirred for 7 hours at 130°C with an of After the was the sulfochloride was filtered off with suction, washed to excess chlorosulfonic acid. cooling, mixture poured onto ice, 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 hou: with cooling, stirring was then continued for a the mixture was further 4 hours at room 200 ml of resulting filtered off with 10°C, washed with water and dried in vacuo at 80°C, melting point 102°C. temperature, then treated with Water, pr(~=(.'ipitate was suction at B) N-[(3—Chloro—2—r1itro— 4wphenoxysulfonyl)phenyl]proline 2 , 4—dichloro—3-ni trobenzenesulfonate I—’hr.=nyl (34 . 8 g, _ 85 _ (0.6 mol) solution . 0 g hydroxide ml of 2N 200 ml of 2—methoxyethanol were stirred for 10 minutes at 80°C.

The 50°C concentrated hydrochloric acid and poured onto ice. .1 mol) , of L—proline, sodium and acidified at using The washed wi th clear solution was precipitate was filtered off with suction, water to neutrality and dried at 80°C. Melting point °C (after recrystallization from methanol) C) 6—Chloro—7-phenoxysulfonyl— 1 , 2 , 3 , 3a—tetrahydropyrrolo [2 , l—c]—quinoxalir1—4(5H)—one N—[ (3—Chloro—2—nitro—4-phenoxysulfonyl)phenyl]proline (38,o 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 the concentrated, the residue together with 2N hydrochloric removed by filtration with suction, solution was acid was heated for approximately 30 minutes in a steam bath, washed with water to neutrality. subjected to filtration with suction and Melting point 197°C cooled, (after recrystallization from glacial acetic acid) Example XXXII - (4 —Methyl—l—piperazinyl) -3 — (2—methylpropyl) — —phenoxysulfonyl—3 , 4—dihydroquinoxalin—2 (1H) —one A) Phenyl 2—chloro—4— (4—methyl—l—piperazinyl) —3—nitro— benz enesul fonate Phenyl 2 , 4—dichloro—3—nitrobenzer1esulfonate (l7 .4 g, 0.05 mol) and 25 ml of methylpiperazine in lOO ml of isopx: opanol were refluxed for 10 minutes and subsc;-quently concentrated. The residue was stirred with ml of 50% methanol, filtered off with suction, and washed with 50% methanol and finally with water.

Me] :1 3‘ ng point 94—95°C (after recrystalli zation from cycl cuhexane) _ 86 _ B) N—[(3-(4-Methyl—l—piperaziny1)~2—nitro—6—phenoxy— sulfonyl)—phenyl]leucine hydrochloride —chloro—4—(4—methyl—l—piperazinyl)—3—nitro— (41.1 g, 0.1 mol) were stirred for 8 hours at Phenyl L—leucine °C in a 50 ml of hydroxide benzenesulfonate and (39.3 g, 0.3 mol) mixture of 100 Nd. of N,N—dimethylformamide, ml of 2N the reaction mixture was —methoxyethanol and sodium solution. When cold, acidified with concentrated hydrochloric acid. precipitate was taken up ill ethyl acetate, and the mixture was dried using sodium sulfate and freed frmn solvent in vacuo. This gave an orange oil.

C) 8-(4—Methyl—l—piperazinyl)—3—(2—methylpropyl)— —phenoxysulfonyl—3,4—dihydroquinoxalin—2(lH)—one hydrochloride N—[(3-(4~Methyl—l—piperazinyl)—2—nitro—6—phenoxy— sulfonyl)—phenyl]leucine (25.3 g, 0.05 mol) in 250 ml of methanol and 25 ml of glacial acetic acid was hydrogenated under atmospheric pressure hydrochloride using Raney nickel as catalyst.

When the uptake of hydrogen had ended, the Catalyst was removed 13/ 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 concamrated in vacuo. rendered alkaline using ammonia, residue was dissolved in xmater, the mixture was 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 renderai neutral using ethanolic hydrochloric acid. The precipitate was filtered off with suction, washed uuth diisopropyl ethé)’ and dried, xnelting; point. 90°C and above (deCOmp.).

MS: M+ : 4 -87..

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: Table 9 No R3 R4 R5 M.p.°C l l H (CH3) 2CHCH2 CSHS H CH3 1-1 100 decomp. (HCl) H CH3 C51-I9 H H H 126-127 (base) H H C5H9 Key; = 3—methyl—2-buten—l—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 (0.1 mol) of cyclohexanone were introduced into 20 ml of l,2—dichloroethane. Trif1uoro— acetic acid (1.9 ml, 0.025 mol) was added dropwise, duyjng which process a clear solution formed with genL1e heating. 2.1 g (0.01 mol) of sodium Lrj Q} cetoxyborohydride were added, the exothermic re(;(j(_'_ion was then allowed to proceed for 30 minutes _ 88 - and quenching was then effected by carbonate with stirring, adding saturated aqueous sodium hydrogen The phases were separated, the organic phase washed with dried crude product was solution. saturated sodium chloride was aqueous solution, (magnesium sulfate) and concentrated.

The using ethyl acetate/heptane = chromatographed on silica gel 1:1. 1.l5g (94%) of the desired product were obtained, melting point 131-132°C (toluene/heptane) . 11-I NMR (270 MHZ, d6~DMSO): 6 = 0.97 (d, J = 7 Hz, 3 H), 1.0 -2.0 (m, 10 H), 3.39 (m, 1H), 3.91 (q, J27 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 T 0 .. ¢,V,”\// “ \ ‘ ; RA ‘$5 )No R1,. R3 R4 R5 M.p. 0c 1 CH3 H C2H5 106-107 L CH: H CI-12C (CH3); 162 3 CHa H c-CSH9 120 4 6—C1 CH3, H C-C4H7 100 6—C1 CH: H C5H11 94-95 (» 6—C1 C1-1;. H CH2C (CH3)3 158-160 _ _ 6—C1 C3H5 H CHQC (CH3); 158-159 E4 6—C1 CH3 H CI-I=CI-ICHO 140-146 __E-' _ 6—C1 CH3 H CH2C_=.CH3 166-l68fi ‘H! fi6—C1 CH3 H 2—piColyl 198-199 »'1_jJ____> 6—C1 CH3 H 3-picolyl 136 No. R1,; R3 R4 R5 M.p. 0c 12 6-C1 CH3 H 4—pico1y1 191-193 13 6-C1 CH3 H furany1—2—methy1 116-118 14 6-C1 CH3 H CH2C5H4—4—Br 149-150 6-C1 CH3 H CH2C5H4~4—CN 95-96 16 6-C1 CH3 H CH2CeH4—4-N02 117 17 6-C1 CH3 H CH2C6H4‘3'NO2 125 18 6-C1 CH3 H CH2C5H4~2-N02 153-154 19 6~Cl CH3 H CH2C6H4C1 122-123 6-C1 CH3 H CH2C5I3-C1 156-157 21 6-C1 CH3 H CH2C5H4-2—C1 138 22 6-C1 CH3 H CH2C5H4~4—F 147 23 6-C1 CH3 H CH2C5H4—4-C5Hg 164-165 24 6-Cl CH3 H CH2C6H4“4-OC6H5 Oil 6-C1 CH3 H CH2C5H4~4—CH3 60-62 26 6-C1 CH3 H CH2C5H4-4—COOCH3 139 27 6-C1 CH3 H CH2C5I-I4-2, 6-C12 190-191 28 6-C1 CH3 H CH2CeH4-3, 5-C12 139-140 29 6-C1 CH3 H naphthylmethyl 164-166 6-C1 CH3 H naphthyl—2-methyl 161-164 31 6-C1 CH3 H CH2CH2OCH3 78-79 32 6-C1 CH3 H cyclohexenyl Oil 33 6-C1 CH3 H C2H4-C.sH5 128 34 6-C1 CH3 H thienyl-3—methy1 141-142 6-Cl CH3. H (5-methy1t:h:Leny1)—2— 58-60 methyl 36 6-C1 CH3 H (3—rnethy1thier1yl) 124 methyl -C1 CH3 H thienylmethyl 121-123 38 6-C1 CH3 H CH3CH=-C6H5 59 39 6-C1 CH2SCH3 H CH2C5H4—2—Cl 128 £10 6-C1 CH2SCH3 H CH2C5H4—2-NO; 134 41 6-Cl CH2SCH3 H 2-picolyl Oil 4.7 6-C1 CH2SCH3 H CH2C5H3—2 , 4-C12 143 4:3 6-C1 CH;..- H CH2C5H3-2, 4—Cl2 Oil __‘_ i .pr -C1 CH2S-Bn H CH2C5H3-2, 4-C12 Oil N45 5_c1 CH2S-H CH2C5H3—2, 4-C _ 90 _ 3 4 No. R1,, R R R M.p.°C 46 6—C1 Cfih H 2—PiColyl 160-162 47 6—C1 CH3 H (6—CH3)2—PiCOly1 158 Key; C5Hn = 3—methyl—1—butyl c—Cdh = cyclobutyl vinyl ketone were stirred of anhydrous and a catalytic amount of triethylamine for 20 hours at room temperature in 20 ml ethanol.

Silica gel chromatography with methyl tert.—buty1 ether/heptane = 2:1 gave 620 mg (87%) of the desired product, melting point 108—l09°C (methyl tert.—butyl ether/heptane).

H NMR (270 MHZ, d5—DMSO): 5 = 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, 1 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 (33)—6—Ch1oro—4~N—chlorocarbony1—3—H@thyl—3,4—dihydro— quinoxa1in—2(1H)—one The compound of Example IB (2.0 g, 0.01 mol) in 100 ml oj anhydrous toluene was heated with bis- (trichloromethyl) carbonatte (triphosgene) (1.5 g, 0.005 mol) for 1 hour at 80°C in the presence of 2 ml (0.014 mol) of triethylandne. After cooling, the mjxLure was washed with xmater and saturated. aqueous sodium chloride solution arui dried and the solvent was removeci under reduced pressure. magnesium sulfate), 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 = lzl as eluent. Melting point l42—l44°C. in NMR (270 MHZ, d6—DMSO): 5 = 1.25 (d, J = 7 Hz, 3 H), 3.83 (q, J": 7 Hz, l 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—dihydroquinoxalin—2(lH)—one (3.0 mmol) of 2—methoxyethanol To a solution of 0.24 ml in 10 HQ of anhydrous added 0.16 g of a 55% and the reaction mixture was stirred for .50 g (1.9 mmol) of ,2-dimethoxyethane there was suspension of sodium hydride in mineral oil, nunutes at room temperature. the compound of Example XXXV was subsequently added, with ice—cooling, and the ndxture 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 = lzl) and crystallization from ether/heptane, 0.29 g (51%) of the desired product was obtained, melting point 93—94°C. in NMR (200 MHZ, d6-DMSO)! 5 = 1.13 (d, JJ = 7.5 Hz, 3 H), 3.32 (s, 3 H), 3.6 (Kb 2H), 4.24 (m, l H), 4.35 (m, l H), 4.81 (q, J = 7.5 Hz, 1 H), 6.98 (d, J = 9 Hz, J H), 7.2 (dd, J = 9, 3 Hz, 1 H), 7.66 (d, .7 = 3 Hz, 1 H, l0.8l ppm (br. 2, l H).

MS: (M + H)* : 299 Exampl e XXXVI I (35)—6—Ch1oro—3—methy1—4—N-[(pheny1thio)carbonyl)]— 3,4—dihydroquinoxa1in—2(1H)—one (3.0 mmol) ml of 1,2-dimethoxyethane there was added 0.17 g of with To a. solution of 0.31 ml of thiophenol in a 55% suspension of sodium hydride in.minera1 oil, and the mixture was stirred for 1 hour at 0.5 g (1.9 mmol) Example XXXV were introduced, again widi ice—cooling, room temperature. of the compound of ice—cooling, and stirring was then continued for 2 hours at room temperature. For working—up, the mixture was treated saturated aqueous sodium chloride solution, with extracted twice with ethyl acetate and dried The solid (sodium sulfate), and the solvent wuas stripped off. residue was recrystallized from heptane/isopropanol, o_35 g (35%), melting point 194—195°C.

H NMR (200 MHz, d6-DMSO): 5 = 1.10 (d, J = 7 Hz, 3 H), 4_93 (q, J = 7 Hz, 1 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 - C5H5SH + H)* 223 The following compounds of the formula I were synthesized in analogous manner.

Table 11 1* //~ \ "V/“ R ‘ n I I , _ \ /fin .3 R 4 No Rln R3 R4 R5 M.p. °C 1 6-Cl CH3 H COOCH2CH=CHCH3 116-117 2 6—C1 CH3 H COOCH2=C (CH3)2 87-89 3 6—C1 CH3 H COOCH2C=_-‘CH 147 4 6-Cl CH3 H COOCH2CaCCH3 135 6-Cl CH3 H COSCH2C5H5 158 6 6-Cl CH3 H COSCH2CH=CH2 Oil 7 6-C1 CH3 H COOCH2C (CH3) =CH2 125-127 8 6-Cl CH3 H COOC (CH3)3 9 6—C1 CH3 H COO—cyc1ohex—2-en-1—y1 6-C1 CH3 H COOCH(CH2OCH(CH3)2) 2 Oil 11 6-Cl CH3 H COOCH(CH3) 2 141-142 12 6-Cl CH3 H COOC2H4N (CH3)2 Oil 13 6—C1 CH3 H COOC2H4SCH3 108-110 14 6-C1 CH3 H COSC5H5 194-195 6-C1 CH3 H COOCH2C5H4-2—NO2 227-231 16 6—C1 CH3 H COOCH2CeH4-3—NO2 183-185 17 6-Cl CH3 H COOCH2C6H4Cl 177-180 18 6-Cl CH3 H COOCH2C5H4-2—C1 164 19 6-Cl CH3 H COOCH2CH=CHCH2CI-13 Oil 6—C1 CH3 H COO(3-picolyl) 160-161 21 6—C1 CH3 H COO(2—pico1y1) 114-116 -Cl CH3 H COOCH2C6H4‘4"NO2 230-233 23 6-C1 CH3 H COOCH2CI-12C (CH3) =CH; Oil 24 6-C1 CH3 H CO— (4-methy1piperaz:Ln—1- Oil ‘3 3 yl) 28 6—C1 CH3 CO—N(CH2)5 218-220 6—C1 CH3 CO—N(CH2)4 200-203 ._94_ Rln R3 R4 R5 M.p. °c 6~Cl CH3 H CO—morpholin—1—y1 193-195 6—Cl CH3 H CO-HNCH2Ph 94-96 -Cl CH3 H cyc1opropy1—methyloxy~ 119-122 carbonyl

Claims (6)

Patent Claims: A compound of the formula I or Ia, R2

1 x N / (I) R3 N Is R4 re N x\\ 2 R H ’ R4 [5 and. physiologically where, R acceptable salts thereof, in the formulae I and la, n is zero, one or CWO , the individual substituents R? independently of one another are Or fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, Cr4h~alkyl, C1~Cralkoxy, (C1-C4- alkoxy)-(Cy{h—alkoXyl, C1—C4—alkylthio, nitro, amino, C1—C4—alkylandno, diUh—C4—alkyl)amino, piperidino, morpholino, l—pyrrolidinyl, 4- Q:C4—acyloxy, C;~ (C1- sulfamoyl methylpiperazinyl, Ch—C4—acyl, C4—acylamino, cyano, carbanmyl, carboxyl, C4—alkyl)oxycarbonyl, hydroxysulfonyl, a phenyl, phenoxy, phenylthio, l0 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, 6 where R can be R 2 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1—C4—alkyl, C1- C4—alkoxy, (C1—C4—alkyl) oxycarbonyl, phenyl , phenoxy, is hydrogen and R5 is C1—C5—alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1~C4-alkoxy, C1-C4- alkylamino, di (C1—C4—alky1)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C2—C5—alkenyl, optionally substituted by fluorine, chlorine, hydroxyl , C1—C4—aCyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4—alkoxy, C1-C4- alkylamino, di (C1—C4—alkyl)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or Carbamoyl; allenyl, C3—Cg—alkynyl, optionally substituted by fluorine, chlorine, hydroxyl , C1—C4~acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4—alkoxy, C1-C4- alkylamino, di (C1—C4—alkyl)amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3—Cg—cycloalky1, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1~C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1—C4—alkyl) amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3—Cg—cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-Cralkyl, C1-C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1—C4—alkyl) amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3—C5—cycloalkyl) — (C1—C2—alkyl), optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, di (C1—C4—alkyl) amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C1—C4—alkylamino, (C3—C5—cycloalkenyl ) — (C1—C2—alkyl) , optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1—C4—alkyl) amino, C1-C4- alkylthio, oxo, thioxo, carboxyl or carbamoyl; C1—C5—alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkyl, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—alkoxy, C1-Cralkylamino, C1—C4—alkeny1amino, di (C1-C4- alkyl)amino, C1—C4—alkylt:hio, oxo, thioxo, carboxyl or carbamoyl; C2—C5—alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl; (C3—C5—cycloalkyl) carbonyl, (C5—C5—cycloalkenyl) Carbonyl , (C3—C6—cycloalkyl) — (C1—C2—alkyl) carbonyl, (C5-C5-cycloalkenyl) — (C1—C2—alkyl) carbonyl , C1-C5-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C1-C4- alkoxy, C1—C4—alkylamino, di(C1—C4—alkyl)amino, C1—C4—alkylthio; C2-Cralkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1- C4—alkoxy; C2—C.3—alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1- C4—alkoXy; C1—C5—alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1— C4-alkoxy; C2-Cvalkenylthiocarbonyl, optionally substitu—ted by fluorine, chlorine, hydroxyl, C1—C4—alkoxy; C1-C5-alkylamino— and di(C1—C5—alkyl)amino— carbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkoxy; pyrrolidin—l—yl, morpholino—, piperidino—, piperazinyl— or 4—methylpiperazin—l—ylcarbonyl; C2-C5—alkenylamino— and di(C1-C5—alkenyl) — aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C1- and pi C4-alkoxy; C1-C4-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—alkoxy; C1-Cralkenylsulfonyl; aryl, arylcarbonyl, (arylthio) carbonyl , aryloxycarbonyl, arylaminocarbonyl , (arylamino) thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl, substituted by up to two each of which is independent of one alkyl radical to contain in each case 1 to 3 carbon radicals R6 which are another, it being possible for the 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-, 3- or 4-picolyl- oxycarbonyl, 2- or 3-furylmethyloxycarbonyl or

2- or

3-thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R6 which are independent of one another, and R4 are identical or different and, independently of one another, are hydrogen, C1-C

4-alkyl which fluorine, C1-C4- phenoxy, C1-C4-alkoxy, C1- C:L*C4— C1-C4- is optionally substituted by chlorine, hydroxyl , amino , mercapto, acyloxy, benzoyloxy , di (C1-C4-alkyl)amir1o, C1-C4-alkylsulfonyl, C4—alkylamino, alkylthio, alkylsulfinyl, carboxyl or carbamoyl; C2—C5—alkenyl, optionally substituted by fluorine or chlorine; C3—C5—cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C1—C4—acyloxy, benzoyloxy, benzyloxy, phenoxy, C1—C4—a1ky1amino, di (C1-C4- C1—C4—alkylthio, C1—C4~ alkylsulfonyl, C1—C4—alkylsulfinyl, carboxyl or C1-C4—alkoxy, alkyl ) amino, carbamoyl; C3—Cg—cycloalkenyl, Optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl, each of which is substituted by up to two radicals R6 which are independent of one another, R.3 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, C1-C4- acyloxy, benzoyloxy, C1—C4—a1koxy, oxo, thioxo, carboxyl or carbamoyl, and the aryl groups mentioned in the preceding definitions are aromatic groups having 6-14 carbon atoms, the heterocyclic rings or heteroaryl groups mentioned in the preceding definitions contain l—l3 carbon atoms and l-6 heteroatoms selected from the group consisting of O, S and N, where in the case of an N- containing ring saturated in this position, N—Z is present, in which ring Z is H or R5 having the respective definitions described above, x is oxygen or sulfur, with the exception of those compounds in which R3 and R4 are both hydrogen, and compounds in which R5 is COCHCl2, and compounds in which n is l, R1, R3 and R4 are methyl and R5 is acetyl, and compounds 3 in which n is zero, R and R4 are methyl or phenyl and R5 is ethoxycarbonyl. A compound of the formula I or Ia as claimed in claim 1, wherein the abovementioned substituents have the following meaning: n is zero, one or two, the individual substituents R1 independently of one another are fluorine, chlorine, bromine, trifluoromethyl , hydroxyl, C1—C4—alkyl, (C1-C4- alkoxy) — (C1—C2—alkoxy) , C1—C4—alkylthio, nitro, di (C1-C4—alkyl)amino, Ci-C4-alkoxy, amino, C1~C4—alkylamino, piperidino, morpholino, l—pyrrolidinyl, 4- methylpiperazinyl, C1—C4—acyl, C1—C4—acyloxy, C1- C4—acylamino, cyano, carbamoyl, carboxyl, (C1- C4—alkyl ) oxycarbonyl , hydroxysul fonyl or sulfamoyl or a phenyl, phenoxy. phenyl thi o, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2- pyridyl, 3—pyridyl or 4—pyridyl radical which 1O — 102 — is substituted by in) to two radicals R6 which are independent of one another, where R5 can be R 2 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, Cy%h—alkyl, C1- C4—alkoxy, (C1—C4—alkyl)oxycarbonyl, phenyl or phenoxy, is hydrogen and R5 is C1—C5—a1kyl, optionally substituted by Cy%1—alkoxy or C1- C4—alkylthio; C2—C5—alkenyl , optionally substituted by oxo; allenyl; C3—Cg—alkynyl, in particular 2—butynyl; C3-C5—cycloalkyl; C5—C5—cycloalkenyl; (C3—C6—cycloalkyl)—(C1—C2—alky1L cyclopropylmethyl, optionally substituted by Cy%h—alkyl; in particular (C3—C5—cycloalken§/1)—(C1—C2—alkyl), in particular cyclohexenylmethyl; ~. —l03— C1—C5—alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C1-C4- alkoxy, C1—C4—alkylamino, C1—C4—alkenylamino, di(C1—C4—alkyl)amino or C1-C4-alkylthio; C2—C5—alkenylcarbonyl; C1—C5—alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C1—C4— alkoxy, C1—C4—alkylamino, di (C1-C4—alkyl) amino, C1—C4—alkylthio; C2—C5—alker1yloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl ; C2—C5—alkynyloxycarbonyl, in particular propynyloxycarbonyl or butynyloxycarbonyl; C1 —C6—alkylthiocarbonyl; C2—C5—alkenylthiocarbonyl , in particular allylthiocarbonyl; C1—C5—alkylamino— and di (C1—C6—alkyl) amino- carbonyl; pyrrolidin—1—yl , morpholino—, piperidino—, piperazinyl — or 4 —methylpiperazin— 1 ~ylcarbonyl; C2—C6—alkenylamino— and di (C1-C5—alkenyl)amino— carbonyl; C1—C4—alkylsulfonyl; C1-C4-alkenylsulfonyl; - l0 or aryl which is substituted by up to two radicals R6 which are independent of one another, in particular phenyl, arylcarbonyl, in (arylthio) carbonyl , particular benzoyl, aryloxycarbonyl, arylaminocarbonyl , (aryl — amino) thiocarbonyl , arylalkylamino—carbonyl , arylsulfonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl , arylalkoxycarbonyl , aryl (alkylthio) carbonyl , it being possible for the alkyl radical in each case to contain 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—furylcarbonyl, 2- or 3—thienylcarbonyl, 2—, 3- or 4- picolyloxycarbonyl , 2- or 3- furylmethyloxycarbonyl or 2 — or 3 — thienylmethyloxycarbonyl, each of which is substituted by up to two radicals R6 which are independent of one another, and R4 are identical or different and independently of one another are hydrogen, C1—C4—alkyl, optionally substituted by hydroxyl, mercapto, C1-C4-alkoxy, C1—C4—alkylthio, C1—C4—alkyl— sulfonyl, C1—C4—alkylsu1finyl, carboxyl or carbamoyl ; C2—C5—alkenyl, — 105 — aryl, benzyl, thienyl or thienylmethyl, each of which is substituted by up to two radicals R6 which are independent of one another, R6 being as defined above, R3 and R5 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 oxo or thioxo, and the aryl groups mentioned. in the preceding definitions are aromatic groups having 6-14 carbon atoms, the heterocyclic rings or heteroaryl groups mentioned in the preceding definitions contain 1-13 carbon atoms and. 1-6 heteroatoms selected from the group consisting of O, S and N, where in the case of an N~ containing ring saturated in this position, N—Z is present, in which ring Z is H or R5 having the respective definitions described above, X is oxygen or sulfur. A compound of the formula I or Ia as claimed in claim 1 or 2, wherein the abovementioned substituents have the following meanings: n is zero or one, the individual substituents R1 independently of one another are fluorine, chlorinez bromine, Q—C2—alkyl, C1- C2—alkoxy, C2—C4—acyl., cyano; R2 is hydrogen and R5 is 2O 25 3 O C2—C5—alkenyl; C3—Cg—alkynyl, in particular 2—butynyl; (C3—C6—cycloalkyl) — (C1—C2—alkyl), in particular cyclopropylmethyl , optionally substituted by C1—C4—alkyl; (C3—C5—cycloalkenyl) — (C1—C2—alky1) , in parti cular cyc lohexenylmethyl; C2—C5—alky1carbonyl; C2—C5—alkenylcarbonyl; C1—C6—alkyloxycarbonyl; C2-Cyalkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2-Cyalkynyloxycarbonyl, in particular propynyloxycarbonyl or butynyloxycarbonyl; C2—C5—alkenylthiocarbonyl, in particular allylthiocarbonyl; C1—C4—alkylsulfonyl; C1—C4—alkenylsulfonyl; or which is substituted by up to two radicals R6 which are independent of one another, in particular benzyl or arylalkenyl, it being possible for the alkyl radical to contain in each case 1 to 3 carbon atoms and for the l0 l5 2O — 107 — 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 R5 which are independent of one another, where R6 is fluorine, chlorine, bromine, cyano, C1-C2- alkyl or Cy%b—alkoxy, and R3 and R4 are identical or different and independently of one another are hydrogen, C1~C4—alkyl, optionally substituted by hydroxyl, mercapto, C1—C4—alkoxy or C1—C2—alkylthio, and X is oxygen or sulfur. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises A) for preparing compounds of the formula I where X is oxygen and the radicals R3 R9, R}, R4 and R5 are as defined in claim 1, reacting a compound of the formula II 5 i o N /' R3 (11) N R4 with the definitions rnentioned in clainifil applying 20 3 to R1, R and R4, with a compound of the formula III R—Z (III) where R has the meanings for R5 and R2 which have been mentioned in claim l with the exception of hydrogen, hydroxyl, C1-C6-—alkoxy, aryloxy, C1-C

5- di(C1-C5- alkyl)amino, arylamino and C1—Cs~acylamino, and Z acyloxy, amino, C1~C6—alkylamino, is a leaving group, OI B) preparing compounds of the formula I where X is sulfur and R1, R2, R3, R4 claim 1 by reacting a Compound of the formula I and R5 are as defined in where X is oxygen and the definitions mentioned in claim l apply to R1, R2, R3, R4 and R5, treating with a sulfurizing reagent, or C) preparing compounds of the formula Ia where X and the radicals R1 to R5 are as defined in claim 1, by reacting a compound of the formula IV Riff / (IV) ‘ I " §)\ R 3 (Na) N ' R 4 20 where the definitions mentioned in claim 1 apply to R1, R3 III , R4 and R5, with a compound of the formula R2—Z (III) where the definitions described in Claim l for formula I and Ia apply to R2 with the exception of hydrogen, hydroxyl, C1-Ce—alkoxy, aryloxy, C1—C5— di(C1—C5— alkyl)amino, arylamino and C1-C5—acylamino, and Z acyloxy, amino, C1—C5—alkylamino, 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 in claim 1 by cyclizing a compound of the formula V R2 NH C0-Y (V) /HRS N I R4 R5 where R1 to R5 are as defined in claim 1 and Y is hydroxyl, C1—C4—alkoxy, optionally halogenated, C1- 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 in claim l apply to R1 to R3, from the quinoxalinones of the formula XI / (XI) where R1 to R3 are as defined at the outset, by addition of hydrogen onto the C=N bond, or F) preparing compounds of the formula I where X is oxygen and R1 to R5 are as defined in claim 1, from compounds of the formula VI (VI) 2 and R5 are as defined in claim I, by where R1, R 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 in claim 1, or with or(trihalomethyl)alkanols of the formula XIV I-Ial3C—C (OH) —R3R4 (XIV) where Hal is Cl, Br or I, in which R3 and R4 are as defined at the outset, or G) preparing compounds of the formula I where X is oxygen and R1, R2, R3, R4 and R5 are as defined in claim I, by reacting a compound of the formula I where X is oxygen and the definitions mentioned in claim 1 apply to R1, R2, R5 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 —lll— 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 in claim 1 and R5 is C1—C5—alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoXy, C1—C4~alkylamino, di (C1—C4—alkyl) amino, C1—C4—alkylthio, carboxyl , carbamoyl, C3—C5—alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1—C4—alkyl) amino, C1—C4—alkylthio, carboxyl, carbamoyl, C3-Cg—alkynyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1—C4—alkyl) amino, C1-C4—alkylthio, carboxyl , carbamoyl, C4-C8-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1-C4—acyloxy, benzoyloxy, C1—C4—alkoxy, C1—C4—alkylamino, di(C1— C1—C4—alkylthio, C5—C8—cycloalkenyl, C4—alkyl) amino, carboxyl, carbamoyl , optional ly substituted by fluorine, chlorine, hydroxyl, C1-C4- acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1-C4- alkylamino, di(C1—C4—alkyl)amino, C1—C4—alkylthiO, carboxyl or carbamoyl, by reductive alkylation of a compound of the formula I where R5 is hydrogen and X is oxygen and the definitions mentioned in claim 1 apply to R1, R2, R3 formula XVI, and R4, with a carbonyl compound of the R”—C(=O)—R"' (XVI) l0 where R” and R"' are identical or different and independently of one another are hydrogen, C1-C5- alkyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloxy, benzoyloxy , phenoxy, C1-C4-alkoxy, C1—C4—alkylamino, di (C1-C4- alkyl)amino, C1—C4—alky1thio, carboxyl, carbamoyl, C3—C5—alkenyl, optionally substituted by fluorine, chlorine , hydroxyl , C1—C4—aCyl0xy, benzoyloxy, phenoxy, C1—C4—alkoXy, C1-C4-alkylamino, di (C1-C4- alkyl) amino , C1—C4—alkylthio , Carboxyl , carbamoyl , C3—C7—alkynyl, optionally substituted by fluorine, chlorine , hydroxyl , C1—C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylamino, di (C1-C4- alkyl)amino, C1—C4—alkylthio, carboxyl, carbamoyl, substituted by C4—C3—cycloalkyl, optionally fluorine, chlorine, hydroxyl, C1-C4—acyloxy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1-C4-—a]_kylaminO, di (C1—C4—alkyl) amino, C1—C4—alkylthio, carboxyl , carbamoyl, C5—cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4—acyloXy, benzoyloxy, phenoxy, C1—C4—alkoxy, C1—C4—alkylaminO, di(C1—C4—alkyl)amino, C1~C4—alkylthio or carboxyl, 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 in claim 1 and R5 alkylthiocarbonyl, C2—C5—alkenyloxycarbonyl, C2-C

6- is C1—C5—alkyloxycarbonyl, C1-C6- alkenylthiocarbonyl, C2—C5—alkynyloxycarbonyl, C1- C5-alkylaminocarbonyl, C3-C5-alkenylaminocarbonyl, di (C1—C5—alkyl) aminocarbonyl, pyrrolidin—l—yl , morpholino-, piperidino-, piperazinyl—, 4—methyl— piperazin—l—ylcarbonyl, optionally substituted by fluorine or chlorine, or aryloxycarbonyl, arylthio (carbonyl) , arylaminocarbonyl, (arylalkylthio)carbonyl or arylalkylaminocarbonyl, each of which is substituted by up to two radicals 1O 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 R ! N X / R3 N (XVII) 0 (CH2), I U where the definitions mentioned in claim 1 apply to R1, R2, R3 and R4, n is O, l, 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 C1—C5—alkoxy, C2—Ce—alkenyloxy, C2-C6- alkynyloxy, C1—C5—alkylthio, C2—Cg—alkenylthio, C1- C6—alkylamino and di (C1—C6—alkyl) amino, C3-C6- alkenylamino— and di(C1—C5—alkyl)amino, optionally substituted by fluorine, chlorine, hydroxyl, C1—C4— alkoxy, pyrrolidin—l—yl, morpholino—, piperidino—, piperazinyl— or 4—methylpiperazin—l—yl, or aryloxy, arylthio, arylamino, arylalkyloxy, arylalkylthio, arylalkylamino, 2-, 3~ or 4—pyridyl—, 2- or 3—furyl, 2- or 3—thienyl, 2-, 3- or 4—picolyloxy, 2- or 3—furtylmethyloxy or 2- or 3—thienylmethyloxy, each of which is substituted by up to two 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. 5 6. l0 l5 8. — ll4 — A Compound of the formula I or Ia as claimed in one or more of claims 1-3 for use as a pharmaceutical. A pharmaceutical comprising an effective amount of at least one compound of the formula Ia as claimed in one or more of claims 1-3. A process for the preparation of a pharmaceutical as claimed in claim 6, which Comprises formulating the effective amount of a compound of the formula I or Ia together with custonary pharmaceutical auxiliaries to give a suitable dosage form. The use of a compound of the fmmmla I or Ia as claimed in one or more of Claims 1-3 for the preparation of pharmaceuticals for the treatment viruses, in particular of diseases caused by diseases caused by HIV. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.