CA2157231A1 - Oxa- or thia-aliphatically bridged quinoxaline-2,3-diones - Google Patents

Abstract

Oxa- or thia-aliphatically bridged quinoxaline-2,3-diones of the general formula I

Description

20072/A 21 S ~ 2 3 1 Oxa- or thia-aliphatically brid~ed quinoxaline-2,3-diones The invention relates to novel oxa- or thia-aliphatically bridged quinoxaline-2,3-diones of the general formula I

,A2 (CH2)n R,~ ~ (I), wherein A1 is lower alkylidene or a group of the formula >CH-A4-R4 (la), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (la), ~C=O (Ib) or >CH(OH)-A5-R4 (Ic), A3 is oxy, optionally oxidised thio or a group >C(=O) (Ib), A4 is lower alkylene, As is lower alkylene or a direct bond, n is 0 or 1 , R, and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-and/or lower alkanoyl-substituted amino, nitro, lower alkanoyl, free or etherified or esterified hydroxy, free or esterified or amidated carboxy, cyano, optionally halogenated lower alkyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, free or esterified or amidated carboxy, free or esterified phosphono or 5-tetrazolyl, and to the salts thereof, to pharmaceutical compositions comprising the novel compounds and to the use thereof as medicinal active ingredients.

-2- 21~7231 Optionally oxidised thio is thio, sulfinyl or sulfonyl.

Unsubstituted or lower alkyl- and/or lower alkanoyl-substituted amino is, for example, amino, lower alkylamino, lower alkanoylamino, di-lower alkylamino or N-lower alkanoyl-N-lower alkylamino.

Free or etherified or esterified hydroxy is, for example, free hydroxy or hydroxy etherified by a lower alkanol or esterified by a lower alkanoic acid, especially hydroxy, lower alkanoyloxy or lower alkoxy, but may also be lower alkenyloxy or lower alkynyloxy.

Optionally halogenated lower alkyl is, for example, lower alkyl or polyhalo-lower alkyl, especially trifluoromethyl.

Unsubstituted or lower alkanoyl-substituted amino is, for example, amino or lower alkanoylamino.

Free or esterified or amidated carboxy is, for example, carboxy, lower alkoxycarbonyl, carboxy-lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl; phenyloxycarbonyl, benzoyloxy-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, each of which is unsuhstitllted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; carbamoyl, lower alkylcarbamoyl, lower alkenylcarbamoyl, di-lower alkylcarbamoyl, di-lower alkylamino-lower alkylcarbamoyl, amino-lower alkylamino-lower alkylcarbamoyl, 2-oxoimidazolidin-1-yl-lower alkylcarbamoyl, unsubstituted or amino-lower alkylamino- or 2-oxoimidazolidin-1-yl-substituted lower alkyleneamino-lower alkylcarbamoyl, such as amino-lower alkylamino-lower alkylene-carbamoyl or 2-oxoimidazolidin-1-yl-lower alkylenecarbamoyl, oxa-lower alkyleneamino-lower alkylcarbamoyl, unsubstituted or carboxy- or lower alkoxycarbonyl-substituted cycloalkylcarbamoyl, cycloalkyl-lower alkylcarbamoyl, unsubstituted or oxo-substituted azacycloalkylcarbamoyl, optionally benzo-fused lower alkylenecarbamoyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkylcarbamoyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo-, amino, lower-alkoxycarbonylamino-, nitro-, carboxy-, lower alkoxycarbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenyl- or N-lower alkyl-N-phenyl-carbamoyl, optionally ` - 21S723~

partially hydrogenated N-naphthylcarbamoyl, N-indanylcarbamoyl, N-heteroaryl- or N-heteroaryl-lower alkyl-carbamoyl, mono- or dihydroxy-lower alkylcarbamoyl, mono- or di-lower alkoxy-lower alkylcarbamoyl, polyhalogeno-lower alkylcarbamoyl, free or esterified mono- or di-carboxy-lower alkylcarbamoyl, cyano-lower alkylcarbamoyl, free or esterified carboxy-lower alkenylcarbamoyl or free or etherified N-hydroxycarba",oyl, such as N-hydroxycarbamoyl, N-lower alkoxycarbamoyl, N-lower alkoxy-N-lower-alkylcarbamoyl, N-lower alkenyloxycarbamoyl or unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo-and/or trifluoromethyl-substituted N-phenyloxy-, N-phenyl-lower alkoxy- or N-phenyl-lower alkenyloxy-carbamoyl .

Unsubstituted or carboxy- or lower alkoxy-substituted cycloalkylcarbamoyl is, for example, C3-C7cycloalkylcarbamoyl, carboxy-C3-C7cycloalkylcarbamoyl or C,-C4alkoxycarbonyl-C3-C7cycloalkylcarbamoyl, such as 1-carboxy-, 1-methoxycarbonyl- or 1-ethoxycarbonyl-cyclopropylcarbamoyl.

Free or esterified phosphono may be fully or partially esterified and is, for example, phosphono, lower alkylphosphono, di-lower alkylphosphono or tri-lower alkylphosphono.

Optionally benzo-fused lower alkylenecarbamoyl is, for example, azaridino- or 2-methyl-azaridino-carbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidino-carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl or N'-lower alkyl-piperazinocarbonyl, such as N'-methylpiperazinocarbonyl.

Unsubstituted or oxo-substituted azacycloalkylcarbamoyl is, for example, 3-aza-2-oxo-cycloheptylcarbamoyl .

Optionally partially hydrogenated naphthylcarbamoyl is, for example, naphthylcarbamoyl or 5,6,7,8-tetrahydronaphthylcarbamoyl.

Free or esterified carboxy-lower alkenylcarbamoyl is, for example, carboxy-loweralkenylcarbamoyl or lower alkoxycarbonyl-lower alkenylcarbamoyl.

21~Z~-Free or esterified mono- or di-carboxy-lower alkylcarbamoyl is, for example, carboxy-lower alkylcarbamoyl, lower alkoxycarbonyl-lower alkylcarbamoyl, dicarboxy-lower alkylcarbamoyl or di-lower alkoxycarbonyl-lower alkylcarbamoyl.

Hereinbefore and hereinafter, lower radicals and compounds will be understood as being, for example, those having up to and including 7, especially up to and including 4, carbon atoms.

Di-lower alkylamino is, for example, N,N-di-C1-C7alkylamino, preferably N,N-di-C,-C4alkyl-amino, such as especially dimethylamino, or, secondly, diethylamino, dipropylamino, diiso-propylamino or dibutylamino.

Amino-lower alkylamino-lower alkylcarbamoyl is, for example, N-(amino-C2-C4alkylamino-C~-C4alkyl)carbamoyl, such as N-[2-(2-aminoethylamino)ethyl]carbamoyl.

Amino-lower alkylamino-lower alkylenecarbamoyl is, for example, amino-C2-C4alkylamino-piperidinocarbonyl, such as 4-(2-aminoethylamino)piperidinocarbonyl.

Carboxy-lower alkoxycarbonyl is, for example, carboxy-C1-C4-alkoxycarbonyl, such as carb-oxymethoxycarbonyl, 2-carboxyethoxycarbonyl, 3-carboxypropyloxycarbonyl or 4-carb-oxybutyloxycarbonyl .

Carboxy-lower alkenylcarbamoyl is, for example, carboxy-C2-C4alkenylcarbamoyl, such as carboxyvinylcarbamoyl, 3-carboxyprop-2-en-2-ylcarbamoyl or 3-carboxyprop-2-en-1-yl-carbamoyl.

Carboxy-lower alkylcarbamoyl is, for example, carboxy-C1-C4alkylcarbamoyl, such as carb-oxymethylcarbamoyl, 2-carboxyethylcarbamoyl or 1-carboxy-2,2-dimethyl-propylcarbamoyl.

Cyano-lower alkylcarbamoyl is, for example, cyano-C,-C4alkylcarbamoyl, especially cyano-methylcarbamoyl .

21572'.~ 1 Cycloalkylcarbamoyl is, for example, N-C3-C6cycloalkylcarbamoyl, such as cyclopropyl-carbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl or cyclohexylcarbamoyl, but may also be polycyclic cycloalkylcarbamoyl, such as bicyclo[2.2.1]heptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl.

Cycloalkyl-lower alkylcarbamoyl is, for example, N-(C3-C6cycloalkyl)-C,-C4alkylcarbamoyl, such as N-(cyclopropylmethyl)carbamoyl, N-(cyclobutylmethyl)carbamoyl, N-(cyclopentyl-methyl)carbamoyl or N-(cyclohexylmethyl)carbamoyl.

Dihydroxy-lower alkyl is, for example"B,~-dihydroxy-C3-C4alkyl, such as 2,3-dihydroxypropyl.

Dihydroxy-lower alkylcarbamoyl is, for example, N,N-di(hydroxy-C2-C4-alkyl)carbamoyl, such as N,N-di(2-hydroxymethyl)carbamoyl, N-(2-hydroxyethyl)-N-hydroxymethyl-carbamoyl or N,N-di(2-hydroxyethyl)carbamoyl.

Dicarboxy-lower alkylcarbamoyl is, for example, dicarboxy-C1-C4alkylcarbamoyl, such as di-carboxymethylcarbamoyl .

Di-lower alkoxy-lower alkylcarbamoyl is, for example, di-C,-C4alkoxy-C,-C4alkylcarbamoyl, such as dimethoxymethoxycarbonyl or diethoxymethoxycarbonyl.

Di-lower alkylamino-lower alkylcarbamoyl is, for example, N,N-di-C,-C4alkylamino-C2-C4alkylcarbamoyl, such as N-(2-dimethylaminoethyl)carbamoyl.

Di-loweralkylcarbamoyl is, forexample, N,N-di-C,-C7alkylca,La",oyl, preferdbly N,N-di-C,-C4alkylcarbamoyl, such as especially dimethylcarbamoyl, or, secondly, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl.

Di-lower alkoxycarbonyl-lower alkylcarbamoyl is, for example, di-C,-C4alkoxycarbonyl-C,-C4alkylcarbamoyl, such as dimethoxycarbonylmethylcarbamoyl or diethoxycarbonylmethyl-carbamoyl.

6 21j~t2~Jl Di-lower alkylphosphono is, for example, di-C,-C7alkylphosphono, preferably di-C,-C4alkyl-phosphono, such as especially dimethylphosphono, or, secondly, diethylphosphono,dipropylphosphono, diisopropylphosphono or dibutylphosphono.

Halogen is, for example, halogen having an atomic number of up to and including 35, such as chlorine or fluorine, also bromine.

Hydroxy-lower alkylcarbamoyl is, for example, N-(hydroxy-C2-C4alkyl)carbamoyl, such as hydroxymethylcarbamoyl or 2-hydroxyethylcarbamoyl.

Heteroarylcarbamoyl is, for example, fur-2-ylcarbamoyl, thien-2-ylcarbamoyl,-thiazol-2-yl-carbamoyl or N-benzthiazol-2-ylcarbamoyl.

Heteroaryl-lower alkylcarbamoyl is, for example, fur-2-yl-C,-C4alkylcarbamoyl, thien-2-yl-C,-C4alkylcarbamoyl or thiazol-2-yl-C1-C4alkylcarbamoyl, such as fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl, thiazol-2-ylmethylcarbamoyl or N-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl)methylcarbamoyl.

N-Lower alkanoyl-N-lower alkyl-amino is, for example, N-C,-C7alkanoyl-N-C~-C4alkylamino, especially N-C,-C4alkanoyl-N-C,-C4alkylamino, such as N-formyl-N-methylamino, N-acetyl-N-methyl-amino, N-acetyl-N-ethyl-amino, N-ethyl-N-propionyl-amino, N-methyl-N-propionyl-amino, N-butyryl-N-methyl-amino or N-isobutyryl-N-methyl-amino.

Lower alkanoyl is, for example, N-C1-C7alkanoyl, especially N-C~-C4alkanoyl, such as formyl, acetyl, propionyl, butyryl or isobutyryl, but may also be Cs-C7alkanoyl, such as piva-loyl.

Lower alkanoylamino is, for example, N-C,-C7alkanoylamino, especially N-C,-C4alkanoyl-amino, such as formylamino, acetylamino, propionylamino, butyrylamino or isobutyrylamino, but may also be C5-C7alkanoylamino, such as pivaloylamino.

215723~

Lower alkanoyloxy is, for example, N-C~-C7alkanoyloxy, especially N-C1-C4alkanoyloxy, such as formyloxy, acetoxy, propionyloxy, butyryloxy or isobutyryloxy, but may also be Cs-C7alkanoyloxy, such as pivaloyloxy.

Lower alkanoyloxy-lower alkoxycarbonyl is, for example, N-C,-C4alkanoyloxy-C,-C4alkoxy-carbonyl, such as acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, tertiary butyryl-oxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

Lower alkenylcarbamoyl is, for example, C2-C4alkenylcarbamoyl, such as allylcarbamoyl.

Lower alkoxycarbonyl-lower alkoxycarbonyl is, for example, C,-C4alkoxycarbonyl-C,-C4-alkoxycarbonyl, such as methoxycarbonylmethoxycarbonyl, ethoxycarbonylmethoxy-carbonyl or 2-methoxycarbonylethoxycarbonyl.

Lower alkoxycarbonyl-lower alkenylcarbamoyl is, for example, C,-C4alkoxycarbonyl-C2-C4-alkenylcarbamoyl, such as methoxycarbonylvinylcarbamoyl, ethoxycarbonylvinylcarbamoyl, 3-methoxycarbonylprop-2-en-2-ylcarbamoyl, 3-ethoxycarbonylprop-2-en-2-ylcarbamoyl, 3-methoxycarbonylprop-2-en-1-ylcarbamoyl or 3-ethoxycarbonylprop-2-en-1-ylcarbamoyl.

Lower alkoxycarbonyl-lower alkylcarbamoyl is, for example, C,-C4alkoxycarbonyl-C,-C4alkyl-carbamoyl, such as methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, 2-methoxycarbonylethylcarbamoyl or 1-methoxycarbonyl-2,2-dimethyl-propylcarbamoyl.
Lower alkoxy-lower alkylcarbamoyl is, for example, C,-C4alkoxy-C,-C4alkylcarbamoyl, such as methoxymethylca,L,a",oyl, 2-methoxyethylcarbamoyl or ethoxymethylcarbamoyl.

Lower alkenyloxy is, for example, C3-C4alkenyloxy, such as allyloxy or methallyloxy.

N-Lower alkenyloxycarl.an,oyl is, for example, N-C2-C4alkenyloxycarbamoyl, such as N-vinyloxycarbamoyl, N-allyloxycarbamoyl or N-methallyloxycarbamoyl.

Lower alkynyloxy is, for example, C3-C4alkynyloxy, such as propargyloxy.

~1572~1 Lower alkoxy is, for example, C,-C7alkoxy, preferably C1-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, secondary butyl-oxy, tertiary butyloxy or a C5-C7alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.

N-Lower alkenyloxycarbamoyl is, for example, N-C2-C4alkenyloxycarbamoyl, such asN-vinyloxycarbamoyl, N-allyloxycarbamoyl or N-methallyloxycarbamoyl.

Lower alkoxycarbonyl is, for example, C1-C7alkoxycarbonyl, preferably C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but may also be isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiary butyloxycarbonyl or a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.

Lower alkyl is, for example, C,-C7alkyl, preferably C,-C4alkyl, such as especially methyl or, secondly, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, secondary butyl, tertiary butyl or a Cs-C7alkyl group, such as a pentyl, hexyl or heptyl group.

Lower alkylamino is, for example, N-C,-C7alkylamino, preferably N-C,-C4alkylamino, such as especially methylamino or, secondly, ethylamino, propylamino, isopropylamino or butylamino, but may also be isobutylamino, secondary butylamino, tertiary butylamino or a Cs-c7alkylamino group, such as a pentylamino, hexylamino or heptylamino group.

Lower alkylcarbamoyl is, for example, N-C,-C7alkylcarbamoyl, preferably N-C,-C4alkyl-carbamoyl, such as especially methylcarbamoyl or, secondly, ethylcarbamoyl, propyl-carbamoyl, isopropylcarbamoyl or butylcarbamoyl, but may also be isobutylcarbamoyl, secondary butylcarbamoyl, tertiary butylcarbamoyl or a C5-C7alkylcarbamoyl group, such as a pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoyl group.

Lower alkylene may be straight-chained or branched and bonded in any desired position and is, for example, straight-chained or branched C1-C7alkylene, preferably C1-C4alkylene, such as methylene, 1,2-ethylene, 1,3- or 1,2-propylene, 1,4-, 1,3- or 2,3-butylene or, secondly, 1,5-, 1,4- or 2,5-pentylene.

- 9~ 7 2 0~ 1 Lower alkylidene may be straight-chained or branched and geminally bonded in any desired position and is, for example, straight-chained or branched C1-C7alkylene, preferably C,-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or2,2-butylidene or, secondly, 1,1- or 2,2-pentylidene.

N-Lower alkyl-N-phenyl-carbamoyl is, for example, N-C~-C4alkyl-N-phenyl-carbamoyl, such as especially N-methyl-N-phenyl-carbamoyl or, secondly, N-ethyl-N-phenyl-carbamoyl, N-propyl-N-phenyl-carbamoyl, N-isopropyl-N-phenyl-carbamoyl or N-butyl-N-phenyl-carbamoyl, but may also be N-isobutyl-N-phenyl-carbamoyl, N-sec-butyl-N-phenyl-carbamoyl or N-tert-butyl-N-phenyl-carbamoyl.

Lower alkylphosphono is, for example, C,-C7alkylphosphono, preferably C,-C4alkyl-phosphono, such as especially methylphosphono or, secondly, ethylphosphono, propyl-phosphono, isopropylphosphono or butylphosphono, but may also be isobutylphosphono, sec-butylphosphono, tert-butylphosphono or a Cs-C7alkylphosphono group, such as a pentylphosphono, hexylphosphono or heptylphosphono group.

Oxa-lower alkyleneamino-lower alkylcarbamoyl is, for example, N-(morpholino-C2-C4alkyl)-carbamoyl, such as especially N-(2-morpholinoethyl)ethylcarbamoyl.

2-Oxoimidazolidin-1-yl-lower alkylenecarbamoyl is, for example, N-(2-oxoimidazolidin-1-yl-C4-Csalkylene)carbamoyll such as N-[4-(2-oxoimicl~ol d;n-1-yl)piperidinocarbonyl.

2-Oxoimidazolidin-1-yl-loweralkylcarbamoyl is, forexample, N-(2-oxo.."ida~olidin-1-yl-C2-C5alkyl)carbamoyl, such as N-(2-oxoimidazolidin-1-yl)ethylcarbamoyl.

Phenyl-lower alkoxycarbamoyl is, for example, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C~-C4alkoxycarbamoyl, such as benzyloxycarbamoyl or 1-phenylethoxycarbamoyl.

Phenyloxy-lower alkoxycarbonyl is, for example, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- andlor trifluoromethyl-substituted phenyloxy-C,-C4alkoxycarbonyl, such as phenyloxymethoxycarbonyl or 2-phenyloxyethoxycarbamoyl.

2~572~1 N-Phenyl-lower alkenyloxycarbamoyl is, for example, N-phenyl-C2-C4alkenyloxycarbamoyl, such as N-phenylvinyloxycarbamoyl or N-(3-phenylprop-2-enyloxy)carbamoyl.

Phenyl-lower alkoxycarbonyl is, for example, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C,-C4alkoxycarbonyl, such as benzyloxycarbonyl or 1-phenylethoxycarbonyl.

Phenyl-lower alkylcarbamoyl is, for example, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C,-C4alkylcarbamoyl, such as benzylcarbamoyl or 2-phenylethylcarbamoyl.

Tri-lower alkylphosphono is, for example, tri-C,-C7alkylphosphono, preferably tri-C1-C4alkyl-phosphono, such as especially trimethylphosphono, or, secondly, triethylphosphono, tri-propylphosphono, triisopropylphosphono or tributylphosphono.

Compounds of formula I having acidic groups, for example those compounds in which at least one of the radicals R" R2 and R4 is or contains carboxy, phosphono or tet,a~olyl, may form salts with bases. Compounds of formula I may also form acid addition salts.
Salts of compounds of formula I with bases are, for example, salts thereof with pharma-ceutically acceptable bases, such as non-toxic metal salts derived from metals of groups la, Ib, lla and llb, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quatemary ammonium bases, such as optionally C-hydroxyl-ated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)amines, such as ethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)ethanol or D-glucamine or choline, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.

~ ~723~

Acid addition salts of compounds of formula I are, for example, the pharmaceutically acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulramales (cyclamates).

Also included are both total and partial salts, that is to say salts with 1, 2 or 3, preferably 2, equivalents of base per mole of acid of formula I or salts with 1, 2 or 3 equivalents, prefer-ably 1 equivalent, of acid per mole of base of formula 1.

For the purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used thera-peutically, however, and they are therefore preferred.

The compounds of formula I have valuable pharmacological properties. They exhibit a selective non-competitive antagonistic action with respect to N-methyl-D-aspartic-acid-sensitive (NMDA-sensitive) excitatory amino acid receptors of warm-blooded animals. In particular they are ~p~hle of binding to strychnine-insensitive glycine modulators of the NMDA-receptor. The binding capacity of the compounds prepared according to the invention and their salts to strychnine-insensitive glycine binding sites of the NMDA-receptor can be determined in vitro, for example in the experimental procedure according to Baron et al., Eur. J. Pharmacol., Molec. Pharmacol. Section 206, pages 149-154 (1991) and Canton et al., J. Pharm. Pharmacol. 44, pages 812-816 (1992) on rat cortex membranes and rat hippocampus membranes. In those experimental procedures it is determined to what extent [3Hl-5,7-dichlorokynurenic acid (3H-DCKA) is displaced, there being determined the percentage inhibition and optionally, by testing a number of concentrations, the concen-tration (ICso) required for 50 % displacement. The concentration required for 50 % displace-ment (IC50) lies in the nanomolar and lower millimolar range, that is to say at concentrations of approximately from 0.01 to 10 ~mol.

By virtue of those properties the compounds of formula I and the pharmaceutically accept-able salts thereof are excellently suitable for the prophylactic and therapeutic treatment of ~7~31 pathological conditions that are responsive to the glycine-antagonistic blocking of NMDA-sensitive receptors, for example neurodegenerative disorders, such as those arising from stroke, hypoglycaemia, anoxia or symptoms of cerebral paralysis; cerebral ischaemic disorders, such as cerebral ischaemia, cerebral ischaemia in cardiosurgery or cardiac arrest, perinatal asphyxia, epileptic fits, Huntington's chorea, Alzheimer's disease and Parkinson's disease, amyotrophic lateral sclerosis, spinal and cerebral trauma, and also symptoms of poisoning resulting from neurotoxins or drug abuse; and ischaemic disorders of the eyes; vascular and muscular spasms, such as migraine or local or general spasticity;
convulsions, such as epilepsy; and anxiety states and pain, such as trigeminal neuralgias.

The anticonvulsive properties of the compounds according to the invention can be deter-mined in vivo, for example in mice with reference to their pronounced protective action with respect to convulsions induced by electric shock or by metrazole, it being possible to use, for example, the well-established electric shock mouse model or the mouse model for mel,a~Gle induced convulsions according to Schmutz et al., Naunyn-Schmiedeberg's Arch.
Pharmacol. 342, 61-66 (1990).

The invention relates, for example, to compounds of formula I wherein A~ is methylene or a group of the formula >CH-A4-R4 (la), A2 is lower alkylidene and A3 is oxy, thio, sulfinyl, sulfonyl or carbonyl, or A2 is carbonyl and A3 is oxy, thio, sulfinyl or sulfonyl, A4 is lower alkylene, n isOor1, R, and R2 are each independently of the other hydrogen, amino, lower alkylamino, lower alkanoylamino, di-lower alkylamino, N-lower alkanoyl-N-lower alkylamino, hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkyl, polyhalo-lower alkyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, lower alkoxycarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkoxycarbonyl, carbamoyl, cyano or lower alkylcarbamoyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo-and/or trifluoromethyl-substituted phenylcarbamoyl or di-lower alkylcarbamoyl, and to the salts thereof.

`- 21~3~-The invention relates, for example, also to compounds of formula I wherein A1 is lower alkylidene or a group of the formula >CH-A4-R4 (la), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (la) or >C=O (Ib), A3 is oxy or optionally oxidised thio, A4 is lower alkylene, n isOor1, R1 and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-and/or lower alkanoyl-substituted amino, free hydroxy or hydroxy etherified by a lower alkanol, optionally halogenated lower alkyl or halogen, R3 is hydrogen, hydroxy or unsubstituted or lower alkanoyl-substituted amino, and R4 is hydrogen, cyano, tel,a~olyl or free or esterified or amidated carboxy, such as those compounds wherein A1 is a group of the formula ~CH-A4-R4 (la), A2 is lower alkylidene, A3 is oxy, optionally oxidised thio or carbonyl, A4 is lower alkylene, R1 and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-and/or lower alkanoyl-substituted amino, free hydroxy or hydroxy etherified by a lower alkanol, optionally halogenated lower alkyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano or free or esterified or amidated carboxy, and to the salts thereof.

The invention relates especially to compounds of formula I wherein A1 is lower alkylidene or a group of the formula >CH-A4-R4 (la), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (la), ~C=O (Ib) or ~CH(OH)-A5-R4 (Ic), A3 is oxy, thio, sulfinyl or sulfonyl or a group ~C(=O) (Ib), A4 is lower alkylene, A5 is lower alkylene or a direct bond, n isOor1, - 21~7231 R1 and R2 are each independently of the other hydrogen, amino, lower alkylamino, lower alkanoylamino, di-lower alkylamino, N-lower alkanoyl-N-lower alkyl-amino, nitro, lower alkanoyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, lower alkyl, polyhalo-lower alkyl or halo-gen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, carboxy, lower alkoxycarbonyl, carboxy-lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-oxycarbonyl, benzoyloxy-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, carbamoyl, lower alkyloarl,al"oyl, lower alkenylcarbamoyl, di-lower alkylcarbamoyl, di-lower alkylamino-lower alkylcarbamoyl, amino-lower alkylamino-lower alkylcarbamoyl, 2-oxoimidazolidin-1-yl-lower alkyloa, L ar, loyl, amino-lower alkylamino-lower alkylenecarbamoyl, 2-oxGi" ,ida~olidin-1-yl-lower alkylenecarbamoyl, oxa-lower alkyleneamino-lower alkylcarbamoyl, 3- to 7-membered cycloalkylca,l,a",oyl, 3- to 7-membered carboxycycloalkylcarbamoyl, 3- to 7-membered lower alkoxycarbonylcycloalkylcarbamoyl, 3- to 7-membered cycloalkyl-lower alkylcarbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridino-carbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpho-linocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, N'-lower alkylpiperazinocarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkylcart,amoyl, unsubstitùted or lower alkyl-, lower alkoxy-, hydroxy-, halo-, amino-, lower-alkoxycarbonylamino-, nitro-, carboxy-, lower alkoxycarbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-lower alkyl-N-phenylcarbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl,, N-indanylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, N-benzthiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-ylmethylcarbamoyl, N-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl)methylcarbamoyl, mono-or dihydroxy-lower alkylcarbamoyl, mono- or di-lower alkoxy-lower alkylcarbamoyl, polyhalo-lower alkylcarbamoyl, carboxy-lower alkylcarbamoyl, lower alkoxycarbonyl-lower alkylcarbamoyl, dicarboxy-lower alkylcarbamoyl, di-lower alkoxycarbonyl-lower alkylcarbamoyl, cyano-lower alkylcarbamoyl, carboxy-lower alkenylcarbamoyl or lower alkoxycarbonyl-lower alkenylcarbamoyl, N-hydroxycarbamoyl, N-lower alkoxycarbamoyl, N-lower-alkoxy-N-lower-alkyl-carbamoyl, N-lower alkenyloxycarbamoyl or unsubstituted or - ~1572~1 lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyloxycarbamoyl, N-phenyl-lower alkoxycarbamoyl or N-phenyl-lower alkenyl-oxycarbamoyl, phosphono, lower alkylphosphono, di-lower alkylphosphono or tri-lower alkyl-phosphono or 5-tetrazolyl, and to the salts thereof.

The invention relates above all to compounds of formula I wherein A, is slraight-chained or branched C,-C7alkylene, preferably C1-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, or a group of the formula >CH-A4-R4 (la), A2 is straight-chained or branched C,-C7alkylene, preferably C,-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, or a group of the formula >CH-A4-R4 (la) or ~CH(OH)-As-R4 (Ic), A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C,-C7alkylene, preferably C,-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene, As is C,-C4alkylene, such as methylene, 1 ,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, or a direct bond, n isOor1, R, and R2 are each independently of the other hydrogen, amino, N-C,-C4alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino or butylamino, N-C~-C7alkanoyl-amino, such as formylamino, acetylamino, propionylamino, butyrylamino or isobutyrylamino, N,N-di-C~-C4alkylamino, such as dimethylamino, diethylamino, dipropylamino, diisopropyl-amino or dibutylamino, N-C,-C7alkanoyl-N-C~-C4alkylamino, such as N-formyl-N-methyl-amino, N-acetyl-N-methyl-amino, N-acetyl-N-ethyl-amino, N-ethyl-N-propionyl-amino, N-methyl-N-propionyl-amino, N-butyryl-N-methyl-amino or N-isobutyryl-N-methyl-amino, nitro, N-C,-C4alkanoyl, such as formyl, acetyl, propionyl, butyryl or isobutyryl, pivaloyl, hydroxy, N-C,-C4alkanoyloxy, such as formyloxy, acetoxy, propionyloxy, butyryloxy or isobutyryloxy, pivaloyloxy, C,-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, seconday butyloxy or tertiary butyloxy, C3-C4alkenyloxy, such as allyloxy or methallyloxy, C3-C4alkynyloxy, such as propargyloxy, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxy-carbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl or tert-butyloxycarbonyl, carbamoyl, 21~7231 -cyano, C1-C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, halogen or trifluoromethyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, carboxy, C,-C~alkoxycarbonyl, such as methoxycarbonyl, ethoxy-carbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl or tert-butyloxycarbonyl, carboxy-C1-C4alkoxycarbonyl, such as carboxymethoxycarbonyl, 2-carboxyethoxycarbonyl, 3-carboxypropyloxycarbonyl or 4-carboxybutyloxycarbonyl, C1-C4alkoxycarbonyl-C1-C4alkoxycarbonyl, such as methoxy-carbonylmethoxycarbonyl, ethoxycarbonylmethoxycarbonyl or 2-methoxycarbonylethoxy-carbonyl, N-C1-C4alkanoyloxy-C,-C4alkoxycarbonyl, such as acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, tert-butyryloxymethoxycarbonyl or pivaloyloxymethoxy-carbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyloxycarbonyl, benzoyloxy-C1-C4alkoxycarbonyl or phenyl-C,-C4alkoxy-carbonyl, such as benzyloxycarbonyl or benzoyloxymethoxycarbonyl, carbamoyl, N-C1-C4-alkylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropyl-carbamoyl, butylca,ba"loyl, isobutylcarbamoyl, sec-butylcarbamoyl or tert-butylcarbamoyl, C2-C4alkenylcarbamoyl, such as allylcarbamoyl, N,N-di-C1-C4alkylcarbamoyl, such as dimethylcarbamoyl, or, secondly, diethylcarbamoyl, dipropylcarbamoyl, diisopropyl-carbamoyl or dibutylcarbamoyl, C3-C7cycloalkylcarbamoyl, such as cyclopropyl- orcyclohexyl-carbamoyl, carboxy-C3-C7cycloalkylcarbamoyl, such as 1-carboxycarbamoyl, C1-C4alkoxycarbonyl-C3-C7cycloalkylcarbamoyl, such as 1-methoxycarbonyl- or 1-ethoxy-carbonyl-cyclopropylcarbamoyl, 3- to 7-membered N-(C3-C6cycloalkyl)-C1-C4alkylcarbamoyl, such as N-(cyclopropylmethyl)carbamoyl, N-(cyclobutylmethyl)carbamoyl, N-(cyclopentyl-methyl)carbamoyl or N-(cyclohexylmethyl)carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridinocarbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidino-carbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazino-carbonyl, N'- C,-C4alkyl-, such as N'-methyl-piperazinocarbonyl, unsubstituted or C1-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C1-C4alkylcarbamoyl, such as benzylcarbamoyl or 2-phenylethylcarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo-, trifluoromethyl-, amino, C1-C4alkoxycarbonylamino, such as methoxy- or ethoxycarbonylamino, nitro-, carboxy-, C1-C4alkoxycarbonyl-, such as methoxy-or ethoxy-carbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-C1-C4alkyl-N-phenylcarbamoyl, such as N-methyl-N-phenyl-~ 1 ~, 7 2 ~ ~

carbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, indanylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, N-benzthiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-ylmethylca,l,amoyl, N-(3-oxo-2,3-dihydro-4H-1,4-benzoxa~in-7-yl)methylcarbamoyl, N-(hydroxy-C2-C4alkyl)carbam-oyl, such as hydroxymethylcarbamoyl or 2-hydroxyethylcarbamoyl, N,N-di(hydroxy-C2-C4-alkyl)carbamoyl, such as N,N-di(2-hydroxyethyl)carbamoyl, C,-C4alkoxy-C1-C4alkyl-carbamoyl, such as methoxymethylcarbamoyl, 2-methoxyethylcarbamoyl or ethoxymethyl-carbamoyl, di-C,-C4alkoxy-C,-C4alkylcarbamoyl, such as dimethoxymethoxycarbamoyl or diethoxymethoxycarbamoyl, polyhalo-C2-C4alkylcarbamoyl, such as 2,2,2,-trifluoroethylcarbamoyl, carboxy-C,-C4alkylcarbamoyl, such as carboxymethy!carbamoyl, 2-carboxyethylcarbamoyl or 1-carboxy-2,2-dimethyl-propylcarbamoyl, C,-C4alkoxycarbonyl-C,-C4alkylcarbamoyl, such as methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethyl-carbamoyl, 2-methoxycarbonylethylcarbamoyl or 1-methoxycarbonyl-2,2-dimethyl-propylcarbamoyl, dicarboxy-C,-C4alkylcarbamoyl, such as dicarboxymethylcarbamoyl, or di-C,-C4alkoxycarbonyl-C,-C4alkylcarbamoyl, such as dimethoxycarbonylmethylcarbamoyl or diethoxycarbonylmethylcarbamoyl, cyano-C,-C4alkylcarbamoyl, especially cyanomethyl-carbamoyl, carboxy-C2-C4alkenylcarbamoyl, such as carboxyvinylcarbamoyl, 3-carboxyprop-2-en-2-ylcarbamoyl or 3-carboxyprop-2-en-1-ylcarbamoyl, C,-C4alkoxycarbonyl-C2-C4alkenylcarbamoyl, such as methoxycarbonylvinylcarbamoyl, ethoxycarbonylvinyl-carbamoyl, 3-methoxycarbonylprop-2-en-2-ylcarbamoyl, 3-ethoxycarbonylprop-2-en-2-ylcarbamoyl, 3-methoxycarbonylprop-2-en-1-ylcarbamoyl or 3-ethoxycarbonylprop-2-en-1-ylcarbamoyl, N-hydroxycarbamoyl, N-C,-C4alkoxycarbamoyl, such as methoxycarbamoyl, ethoxyca,bamoyl, propyloxycarbamoyl, isopropyloxycarbamoyl, butyloxycarbamoyl orespecially tert-butyloxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, such as N-vinyloxycarbam-oyl, N-allyloxycarbamoyl or N-methallyloxycarbamoyl, or unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyloxycarbamoyl, N-phenyl-C,-C4alkoxycarbamoyl, such as benzyloxycarbamoyl or 1-phenylethoxycarbamoyl, or N-phenyl-C2-C4alkenyloxycarbamoyl, such as N-phenylvinyloxycarbamoyl or N-(3-phenyl-prop-2-enyloxy)carbamoyl, phosphono, C,-C4alkylphosphono, such as methylphosphono, ethylphosphono, propylphosphono, isopropylphosphono or butylphosphono, di-C,-C4alkyl-phosphono, such as especially dimethylphosphono, diethylphosphono, dipropylphosphono, diisopropylphosphono or dibutylphosphono, tri-C1-C4alkylphosphono, such as especially -18- 21~ 7 2 3 ~

trimethylphosphono, or, secondly, triethylphosphono, tripropylphosphono, triisopropyi-phosphono or tributylphosphono, or 5-tetrazolyl, and to the salts thereof.

The invention relates above all, for example, to compounds of formula I wherein A, is methylene or a group of the formula ~CH-A4-R4 (la), A2 is straight-chained or branched C,-C7alkylidene, such as methylene, 1,1-ethylidene, 1,1-or 2,2-propylidene, 1,1- or 2,2-butylidene or, secondly, 1,1- or 2,2-pentylidene, A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C1-C7alkylene, such methylene, 1,2-ethylene, 1,3- or 1,2-propylene, 1,4-, 1,3- or 2,3-butylene or 1,5-, 1,4- or 2,5-pentylene, n isOor1, R, and R2 are each independently of the other hydrogen, amino, N-C,-C7alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino or butylamino, also isobutyl-amino, sec-butylamino, tert-butylamino or a C5-C7alkylamino group, such as a pentylamino, hexylamino or heptylamino group, N-C,-C7alkanoylamino, such as formylamino, acetyl-amino, propionylamino, butyrylamino or isobutyrylamino, also Cs-C7alkanoylamino, such as pivaloylamino, N,N-di-C,-C7alkylamino, such as dimethylamino, diethylamino, dipropyl-amino, diisopr~pylamino or dibutylamino, N-C,-C7alkanoyl-N-C,-C4alkylamino, such as N-formyl-N-methyl-amino, N-acetyl-N-methyl-amino, N-acetyl-N-ethyl-amino, N-ethyl-N-propionyl-amino, N-methyl-N-propionyl-amino, N-butyryl-N-methyl-amino or N-isobutyryl-N-methyl-amino, hydroxy, C,-C7alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, also isobutyloxy, secondary butyloxy or tertiary butyloxy, C3-C4alkenyloxy, such as allyloxy or methallyloxy, C3-C4alkynyloxy, such as propargyloxy, C,-C7alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, also isobutyl, secondary butyl, tertiary butyl or a Cs-c7alk group, such as a pentyl, hexyl or heptyl group, trifluoromethyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, carboxy, C,-C7alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but may also be isobutyloxy-carbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl or a pentyloxycarbonyl, hexyloxy-carbonyl or heptyloxycarbonyl group, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C,-C4alkoxycarbonyl, carbamoyl, tetrazolyl, cyano, C,-C4alkylcarbamoyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo-~1~723~
-_ - 19-and/or trifluoromethyl-substituted phenylcarbamoyl or N,N-di-C1-C7alkylcarbamoyl, such as dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl, and to the salts thereof.

The invention relates especially to compounds of formula I wherein one of the radicals A, and A2 is a group of the formula >CH-A4-R4 (la) and the other is straight-chained or branched C,-C4alkylene, such as methylene, 1 ,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C,-C4alkylene, such as methylene, 1 ,1-ethylidene, 1,1-or 2,2-propylidene, 1,1- or 2,2-butylidene, n isO, R, and R2 are each independently of the other hydrogen, nitro, N-C,-C4alkanoyl, such as formyl, acetyl, propionyl, butyryl or isobutyryl, pivaloyl, hydroxy, C,-C4alkoxy, such as methoxy, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, carbamoyl, cyano, C1-C4alkyl, such as methyl or ethyl, halogen, trifluoromethyl or halogen, R3 is hydrogen and R4 is hydrogen, carboxy, C,-C7alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, C,-C4alkoxycarbonyl-C,-C4alkoxycarbonyl, such as methoxycarbonylmethoxycarbonyl, 1-ethoxycarbonylmethoxycarbonyl or 2-methoxycarbonylethoxycarbonyl, N-C~-C4alkanoyloxy-C,-C4alkoxycarbonyl, such as tert-butyryloxymethoxycarbonyl; phenyloxycarbonyl, benzoyloxy-C,-C4alkoxycarbonyl or phenyl-C,-C4alkoxycarbonyl, such as benzyloxycarbonyl or benzoyloxymethoxycarbonyl, each of which is unsubstituted or substituted by C1-C4alkyl, C,-C4alkoxy, hydroxy, halogen and/or by trifluoromethyl; carbamoyl, N-C,-C4alkylcarbamoyl, such as methylcarbamoyl, butylcarbamoyl or tert-butylcarbamoyl, C2-C4alkenylcarbamoyl, such as allylcarbamoyl, N,N-di-C,-C4alkylcarbamoyl, such as dimethylcarbamoyl, diethylcarbamoyl or dibutylca,L,ar"oyl, C3-C7cycloalkylcarbamoyl, such as cyclo-propylcarbamoyl, C,-C4alkoxycarbonyl-C3-C7cycloalkylcarbamoyl, such as 1-methoxy-carbonyl- or 1-ethoxycarbonyl-cyclopropylcarbamoyl, 3- to 7-membered N-(C3-C6cycloalkyl)-C,-C4alkylcarbamoyl, such as N-(cyclopropylmethyl~carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridinocarbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, unsubstituted or C,-C4alkyl-, C1-C4-alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C,-C4alkylcarbamoyl, such as benzylcarbamoyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-, nitro-, carboxy-, C,-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-C,-C4alkyl-N-phenylcarbamoyl, such as N-methyl-N-phenyl-carbamoyl, naphthyl-carbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-yl-methylcarbamoyl, C,-C4alkoxy-C,-C4alkylcarbamoyl, such as methoxymethylcarbamoyl, 2-methoxyethylcarbamoyl or ethoxymethylcarbamoyl, di-C,-C4alkoxy-C1-C4alkylcarbamoyl, such as dimethoxymethoxycarbonyl or diethoxymethoxycarbonyl, carboxy-C1-C4alkyl-carbamoyl, such as carboxymethylcarbamoyl, 2-carboxyethylcarbamoyl or 1-carboxy-2,2-dimethyl-propylcarbamoyl, C1-C4alkoxycarbonyl-C1-C4alkylcarbamoyl, such as methoxy-carbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, 2-methoxycarbonylethylcarb-amoyl or 1-methoxycarbonyl-2,2-dimethyl-propylcarbamoyl, dicarboxy-C,-C4alkylcarbamoyl, such as dicarboxymethylcarbamoyl, or di-C1-C4alkoxycarbonyl-C1-C4alkylcarbamoyl, such as dimethoxycarbonylmethylcarbamoyl, carboxy-C2-C4alkenylcarbamoyl, such as 3-carboxy-prop-2-en-2-ylcarbamoyl, C1-C4alkoxycarbonyl-C2-C4alkenylcarbamoyl, such as 3-methoxy-carbonylprop-2-en-2-ylcarbamoyl, 3-ethoxycarbonylprop-2-en-2-ylcarbamoyl, 3-methoxy-carbonylprop-2-en-1-ylcarbamoyl or 3-ethoxycarbonylprop-2-en-1-ylcarbamoyl, N-hydroxycarbamoyl, N-C1-C4alkoxycarbamoyl, such as methoxycarbamoyl, ethoxycarbamoyl, propyloxycarbamoyl, isopropyloxycarbamoyl, butyloxycarbamoyl or especially tert-butyloxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, such as N-vinyloxycarbamoyl, N-allyl-oxycarbamoyl or N-methallyloxycarbamoyl, or unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyl-C1-C4alkoxycarbamoyl,- such as benzyloxycarbamoyl or 1-phenylethoxycarbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl, such as N-phenylvinyloxycarbamoyl or N-(3-phenylprop-2-enyloxy)carbamoyl, phosphono or S-tetrazolyl, and to the salts thereof.

The invention relates especially, for example, to compounds of formula I wherein A1 is methylene or a group of the formula ~CH-A4-R4 (la), - 21~7231 A2 is a group of the formula ~CH-A4-R4 (la) or, when A, is a group of the formula >CH-A4-R4 (la), A2 is straight-chained or branched C,-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C,-C4alkylene, such as methylene, 1,2-ethylene, 1,3- or 1,2-propylene or 1,4-, 1,3- or 2,3-butylene, n isO, R, and R2 are each independently of the other hydrogen, hydroxy, C,-C4alkoxy, such as methoxy, C,-C4alkyl, such as methyl or ethyl, trifluoromethyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, also isobutyloxycarbonyl, sec-butyloxycarbonyl or tert-butyloxycarbonyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C,-C4alkoxycarbonyl, carbamoyl, C,-C4alkylcarbamoyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenylcarbamoyl, N,N-di-C,-C4alkylcarbamoyl, such as dimethyl-carbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl, or 5-tet, a~olyl, and to the salts thereof.

The invention relates preferably to compounds of formula I wherein one of the radicals A, and A2 is a group of the formula ~CH-A4-R4 (la) and the other is methylene, A3 is thio, A4 is methylene, n isO, R, and R2 are each independently of the other hydrogen, C,-C4alkyl, such as methyl or ethyl, trifluoromethyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted benzoyloxy-C,-C4alkoxy-carbonyl, such as benzoyloxymethyloxycarbonyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, 21572~

hydroxy-, halo- and/or trifluoromethyl-, nitro-, carboxy-, C,-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, and/or trifluoromethyl-substituted N-phenylcarbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, furyl-2-carbamoyl, thien-2-yl-carbamoyl, thiazol-2-ylcarbamoyl, bicyclo[2.2.1]heptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, N-C1-C4alkoxycarbamoyl, such as methoxy-carbamoyl or tert-butyloxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, such as N-allyloxy-carbamoyl or N-methallyloxycarbamoyl, or unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyl-C~-C4alkoxycarbamoyl, such as benzyloxycarbamoyl or 1-phenylethoxycarbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl, such as N-phenylvinyloxycarbamoyl or N-(3-phenylprop-2-enyloxy)carbamoyl, or 5-tetrazol-yl, and to the salts thereof.

The invention relates preferably, for example, to compounds of formula I whereinone of the radicals A, and A2 is methylene or a group of the formula >CH-A4-R4 (la) and the other is methylene, A3 is thio, n isO, R, and R2 are each independently of the other hydrogen, C,-C4alkyl, such as methyl or ethyl, trifluoromethyl or halogen, R3 is hydrogen, and R4 is carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxy-carbonyl, isopropyloxycarbonyl or butyloxycarbonyl, 5-tetrazolyl or unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenylcarbamoyl, and to the salts thereof.

The invention relates above all to compounds of formula I

~15723~

S~
,~N~O (I') ~N O

wherein R, and R2 are each independently of the other hydrogen, C,-C4alkyl, such as methyl or ethyl, trifluoromethyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted benzoyloxy-C,-C4alkoxy-carbonyl, such as benzoyloxymethyloxycarbonyl, bicyclo[2.2.1]heptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-, nitro-, carboxy-, C,-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, and/or trifluoromethyl-substituted N-phenylcarbam-oyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, furyl-2-carbamoyl, thien-2-yl-carbamoyl, thiazol-2-ylcarbamoyl, bicyclo[2.2.1lheptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, N-C,-C4alkoxycarbamoyl, such as methoxy-carbamoyl or tert-butyloxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, such as N-allyloxy-carbamoyl or N-methallyloxycarbamoyl, or unsubstituted or C,-C4alkyl-, C,-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyl-C~-C4alkoxycarbamoyl, such as benzyloxycarbamoyl or 1-phenylethoxycarbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl, such as N-phenylvinyloxycarbamoyl or N-(3-phenylprop-2-enyloxy)carbamoyl, or ~-tetrazol-Yl.and to the salts thereof.

The invention relates specifically to the compounds of formula I mentioned in the Examples and to the salts of those compounds, especially the pharmaceutically acceptable salts thereof.

21~7~

The process for the preparation of the novel compounds of formula I is based on methods known perse and is carried out, for example, as follows:
a) a compound of formula ll ~A2--(CH2)n A3 A~

R~ Y, (Il), wherein one of the radicals Y, and Y2 is a group of the formula -C(=O)-Y3 (lla) wherein Y3 iS a functionally modified carboxy group, and the other is hydrogen, or in each case a salt thereof, is cyclised intramolecularly, or b) a compound of formula lll N~O (Ill), wherein X, is a group of the formula -A2-(CH2)n-CH(Y3)-A4-R4 (Illa) or-A2-(CH2)n-CH=A'4-R4 (Illb) wherein Y3 is a nucleofugal leaving group and A'4 is a lower alkanylylidene group corresponding to the group A4, X2 is hydrogen and R1, R2, R3, A,, A2, A3 and A4 are as defined, is cyclised intramolecularly or c) in a compound of formula IV

~A2--(CH2)n A3 A'~

R,~ ~ (IV), wherein A'1 is a group of the formula >C=A'4-R4 (Illa) wherein A'4 is lower alkanylylidene, the extracyclic double bond is reduced to a single bond, and in each case, if desired, a resulting compound is converted into a different compound of formula 1, a mixture of isomers obtainable in accordance with the process is separated into the components and the preferred isomer is isolated, and/or a free compoundobtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the corresponding free compound.

The intramolecular cyclisation of compounds of formula ll according to process variant a) is effected in customary manner, if necessary in an inert organic solvent, such as acetone, tetrahydrofuran, dioxane or dimethylror")anl.de, where appropriate in admixture with water and/or in the presence of a basic condensation agent, such as a tertiary aliphatic amine, such as triethylamine, or a tertiary aromatic nitrogen base, such as pyridine, or a metal base, such as an alkali metal hydroxide, alkali metal carbonate or alkali metal amide, for example sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium amide, advantageously with heating, for example in a temperature range of approximately from 25 to 120, preferably from 50 to 100.

Starting materials of formula ll are preferably prepared in situ and cyclised intramolecularly without being isolated. For example, compounds of formula ll wherein Y1 is a group of the formula -C (=O) -Y3(11a) and Y2 is amino are obtained by condensing a compound of formula llb ,A2--(CH2)n A3 A~
~ H (llb), R,~

in customary manner, for example in the presence of a tertiary amine, such as triethylamine, in dichloromethane, with a reactive oxalic acid derivative, for example with a compound of the formula Y3-C(=O)-C(=O)-Y'3 (llc), wherein Y3 and Y'3 are identical or different nucleophilic leaving groups and Y3 is preferably halogen and Y'3 is preferably etherified hydroxy, such as lower alkoxy, nitrating the reaction product of formula lld ,A2--(CH2)n (lld) in customary manner, for example with nitric acid and sulfuric acid, and then reducing the product of the nitration. There is formed as intermediate a compound of formula lle ,A2--(CH2)n ~ (lle)~

which is cyclised according to the invention in situ under the conditions of its fo",)alion.

Intermediates of formula llb wherein A1 is a group of the formula ~CH-A4-R4 (la), A2 and A4 are methylene, A3is preferably thio, R1 and R2 are as defined, R3 is hydrogen, R4is an esterified carboxy group and n is 0, are prepared, for example, by condensing a compound of formula ~H

Rl~NH2 (lle) in customary manner with an ~-haloacetoacetic acid ester of the formula Hal-A2-C(=O)-CH2-R4(llf)orin a compound offormulallg A,A2 ~,HN (119) converting the carbonyl group into thiocarbonyl in customary manner, for example in accordance with Lawesson, condensing the reaction product of formula llh A3~ ~f~
~,HN (llh) with a haloacetic acid ester of the formula Hal-CH2-COOR (lli; R = lower alkyl?, treating the reaction product of formula llj A--A2yS~COOR
~HN (llj) R~

with triphenylphosphine, and in each case in the reaction product of formula llk A~A2y~ R
~,HN (llk) reducing the extracyclic double bond to a single bond in customary manner, for example by reaction with sodium cyanoborohydride or with a stereoselective homogeneous rhodium catalyst.

In accordance with an alternative procedure, the intermediate of formula lle can be reacted with a 3-haloprop-2-enoic acid ester directly to form the corresponding compound of formula llb.

~1S7231 According to another modification of this process, the compound of the formula lle can be reacted, in a manner known per se, for example in tetrahydrofuran, with (S)-epichlorohydrine yielding a compound of the formula llv HO
A3~""~CI
,~,NH2 (llv) (llv) l ll which is then cyclisised, in a manner known per se, for example by treatment with potassium hydroxide in ethanol, to the corresponding compound of the llw OH
A3~
~,NH (llw), l ll the hydroxy group of which is then according to known methods replaced by one of the groups R4, for example, by cyano, optionally esterified or amidated carboxy, tel,d~olyl oor optionally esterified phosphono.

Compounds of formula lle are in turn obtained, for example, by hydrolysing corresponding compounds of formula llh r~/N (llm) Rl~No2 or by reducing, for example with sodium thiosulfate, corresponding disulfides of formula lln 2 1 ~ ~ 2 Rl~No2 A3~A3 (lln).
,~,NH2 R1t 11 In analogous manner, it is also possible to obtain intermediates of formula llb.wherein A, and A2 are methylene and A3 is thio by reacting the compound of formula lle with an aqueous haloacetic acid, for example with chloroacetic acid.

Compounds of formula ll wherein A, is a group >CH-A4-R4 (la), A2 is methylene, A3 is oxy, A4 is methylene, n is O, Y, is a group of the formula -C (=O) -Y3 (lla) and Y2 is amino can advantageously be prepared also by condensing a compound of formula llo OH
~ NH (llo) R,t 11 in customary manner with an ~-haloacetoacetic acid ester of the formula Hal-CH2-C(=O)-CH2-R4 (llp, Hal = halogen) and removing the group Hal from the reaction product of formula llq Hal~

o~R4 ,~NH (llq) R~
R2 ~N2 in customary manner, for example by treatment with sodium hydride in tetrahydrofuran, with the ring being extended, reducing the nitro group in the resulting product of formula llr 2157 2~ ~

O~R4 ,NH (llr) to amino in customary manner, for example by catalytic hydrogenation with Raney nickel in ethanol, and then reducing the extracyclic double bond to a single bond, for example with sodium cyanoborohydride in ethanol, and condensing the resulting product of formula lls O~R4 ~,NH (lls) in custo",ary manner, for example in the presence of a tertiary amine, such as triethyl-amine, in dichloromethane, with a reactive oxalic acid derivative, for example with a compound of the formula Y3-C(=O)-C(=O)-Y'3 (llc), wherein Y3 and Y'3 are identical or different nucleophilic leaving groups and Y3 is preferably halogen and Y'3 is preferably etherified hydroxy, such as lower alkoxy. The corresponding compound of formula ll is formed as intermediate and is cyclised according to the invention in situ under the conditions of its fo""alion.

In analogous manner compounds of formula ll wherein A, is methylene or a group ~C(=O) (Ib), A2 is methylene, A3 is oxy, n is 0, Y1 is a group of the formula -C(=O)-Y3 (lla) and Y2 is amino can advantageously also be prepared by reacting a compound of formula llt HO
Rl~NH2 (llt) with an aqueous haloacetic acid, for example with chloroacetic acid; in a resulting compound of formula llu ~l~723l 0~0 ~,NH (llu) in customary manner reducing the nitro group to amino and, if desired, the carbonyl group to methylene, and condensing the reaction product with a reactive oxalic acid derivative, for example with a compound of the formula Y3-C(=O)-C(=O)-Y'3 (llc) wherein Y3 and Y'3 are identical or different nucleophilic leaving groups and Y3 is preferably halogen and Y'3 is pr~ferably etherified hydroxy, such as lower alkoxy. The corresponding compound of formula ll is formed as intermediate and is cyclised according to the invention in situ under the conditions of its formation.

For the preparation of compounds of formula ll wherein A3 is oxidised thio, i.e. sulfinyl or sulfonyl, the thio group in one of the intermediates mentioned above wherein A3 is thio is oxidised in customary manner, advantageously at the stage of the preparation of the respective nitro compound in accordance with lld ----~ lle.

For the preparation of compounds of formula ll wherein R, and R2 are other than hydrogen and R, is, for example, halogen bonded in the 3-position with respect to the A3group, those substituents are introduced preferably at the stage of the intermediate of formula llb, lln or lls.

In starting materials of formula lll according to process variant b) nucleophilic leaving groups are, for example, reactive esterified hydroxy groups, such as hydroxy groups esterified by a mineral acid or sulfonic acid, especially halogen atoms, for example chlorine, bromine or iodine, or hydroxy groups esterified by an aliphatic or an unsubstituted or substituted aromatic sulfonic acid, for example lower alkanesulfonyloxy, such as methanesulfonyloxy, or unsubstituted or substituted benzenesulfonyloxy, such as benzenesulfonyloxy, bromo-benzenesulfonyloxy or toluenesulfonyloxy, also tertiary amino groups, such as di-lower alkylamino, or lower alkyleneamino that is optionally interrupted by oxygen, sulfur or by nitrogen, for example pyrrolidino, piperidino, morpholino or thiomorpholino.

21572~

Functionally modified carboxy groups are, for example, free or esterified or anhydridised carboxy groups, such as carboxy, lower alkoxycarbonyl, especially methoxy- or ethoxy-carbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or nitro-substituted phenyloxycarbonyl, halocarbonyl, such aschlorocarbonyl, or lower alkanoyloxycarbonyl, especially formyloxycarbonyl, acetoxy-carbonyl or pivaloyloxycarbonyl.

The intramolecular cyclisation of compounds of formula lll is effected in customary manner, if necessary in an inert organic solvent, such as tetrahydrofuran, dioxane or dimethylform-amide, and/or in the presence of a basic condensation agent, such as a tertiary aliphatic amine, such as triethylamine, or a tertiary aromatic nitrogen base, such as pyridine, or a metal base, such as an alkali metal hydroxide, alkali metal carbonate or alkali metal amide, for example sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium amide, advantageously with heating, for example in a temperature range of approximately from 25 to 120, preferably from 50 to 100.

The starting materials of formula lll can be prepared by methods known perse.

For example, compounds of formula lll wherein n is 0, A2 is lower alkylidene and A3 is oxy or thio are obtained by condensing a compound of formula Illa Hal R1~J~NH2 (Illa) wherein Hal is a halogen atom, such as a chlorine or bromine atom, with a reactive derivative of carbonic acid, such as a haloformic acid lower alkyl ester of the formula Hal-C(=O) -COOR (Illb; R= alkyl, unsubstituted or substituted phenyl), nitrating the reaction product of formula Illc Hal Rl~ (Illc) 2lr~2 in the o-position with respect to Hal and to the amino group in customary manner, for example with potassium nitrate and sulfuric acid, condensing the reaction product of formula Illd Hal ,~NO2 Rl~L (Illd) HN

O~COOR
with a compound of the formula H-A~A2~CH2)n-C(H)=A'4-R4, and in the resulting compound of formula Ille A3-A2~A'4`R

,~N2 R1~HN (Ille) O~COOR
reducing the nitro group to amino in cuslo",ary manner, for example using tin(ll) chloride;
the reaction product cyclises spontaneously under the conditions of its formation to the corresponding quinoxalinedione of formula lll.

The reduction of the extracyclic double bond in compounds of formula IV in accordance with process variant c) is carried out in customary manner, for example by reaction with a di-light metal hydride, such as sodium cyanoborohydride, or by catalytic hydrogenation, for example in the presence of Raney nickel.

Starting materials of formula IV can be obtained, for example, by condensing a compound of formula ~H

R~NH2 (lle) 2157 ~3 ~-in customary manner with an cD-haloacetoacetic acid ester of the formula Hal-A2-C(=O)-CH2-R4 (llf), condensing the reaction product of formula IVa A,A2~`R
~,NH (IVa) R~J

in customary manner, for example in the presence of a tertiary amine, such as triethyl-amine, in dichloromethane, with a reactive oxalic acid derivative, for example v~lith a compound of the formula Y3-C(=0)-C(=0)-~3 (llc) wherein Y3 and Y'3 are identical or different nucleophilic leaving groups and Y3 is pr~rer~bly halogen and Y'3 is preferably etherified hydroxy, such as lower alkoxy, nitrating the reaction product of formula IVb in customary manner, for example with nitric acid and sulfuric acid, and then reducing the product of the nitration. A compound of formula IVc A,A2~ J

~NH2 (IVc) is formed as intermediate and is cyclised in situ under the conditions of its formation to form the corresponding compound of formula IV wherein n is 0 and A'4 is methine.

Compounds of formula lle are in tum obtained, for example, by hydrolysing corresponding compounds of formula llh A3~
r~/N
Rlt R ~No2 2 (llh) or by reducing corresponding disulfides of formula lli R,~ N2 R1+ 11 ~NH2 ,~ NH2 Rl~No2 2 (lli), for example with sodium thiosulfate.

For the pr~paralion of compounds of formula IV wherein A3 is oxy, A2 is methylene, A'4 is methine and n is 0, it is also possible to condense a compound of formula llj OH
R,~ NH (I Ij) in customary manner with an ~o-h~'cacetoacetic acid ester of the formula Hal-CH2-C(=O)-CH2-R4 (llk, Hal = halogen), to remove the group Hal from the reaction product of formula llk Hal o~R4 ~NH (llk) R~NO2 in customary manner, for example by treatment with sodium hydride in tetrahydrofuran, with the ring being extended, to reduce the nitro group in the resulting product of formula llm - 36 2 1 ~ 7 2 3 ~

O~R4 ~,NH (llm) to amino in customary manner, for example by catalytic hydrogenation with Raney nickel in ethanol, and to condense the reaction product in customary manner, for exa""~'e in the presence of a tertiary amine, such as triethylamine, in dichloromethane, with a reactive oxalic acid derivative, for example with a compound of the formula Y3-C(=O)-C(=O)-Y'3 (llc) wherein Y3 and Y'3 are identical or different nucleophilic leaving groups and Y3 is preferably halogen and Y'3 is pr~:ferdbly etherified hydroxy, such as lower alkoxy, there likewise being formed as intermediate a compound of formula IVc which cyclises in situ under the conditions of its formation to form the corresponding compound of formula IV wherein n is O
and A'4 is methine.

For the preparation of compounds of formula IV wherein A3 is oxy or especially thio, A2 is methylene, A'4 is methine and n is 0, it is also possible to convert the carbonyl group in a compound of formula 119 ~3,HN (119) into thiocarbonyl in customary manner, for example in accordance with Lawesson, to condense the reaction product of formula llh ~,A2~f~ S
I

~HN (llh) _ ~37~ 2157231 with a haloacetic acid ester of the formula Hal-CH2-COOR (lli; R = lower alkyl) and to treat the reaction product of formula llj A--A2~ S ~, COOR
_~HN (llj) with triphenylphosphine.

Compounds oblai. ,able in accordance with the process can be converted in customary manner into different compounds of formula 1.

For example, a compound of formula I wherein R4 is carboxy can be esterified to the corresponding compound of formula I wherein R4 is esterified carboxy. Similarly, a compound of formula I wherein R4 is free or esterified carboxy can be a",;dated to form the corresponding compound of formula I wherein R4 is amidated carboxy. Conversely, a compound of formula I wherein R4 is cyano or esterified or amidated carboxy can be hydrolysed to form the corresponding compound of formula I wherein R4 and optionally R5 are carboxy. It is also possible to hydrolyse a cyano group R5 to carbamoyl.

Furthermore, in obtainable compounds of formula I wherein A3 is thio, the thio group can be oxidised to sulfinyl or sulfonyl in customary manner, for example by reaction with a suitable peroxy compound, such as m-chloroperbenzoic acid or permonophthalic acid.

Moreover, in a compound of formula I wherein R, and/or R2 are hydrogen, the hydrogen atom can be replaced by a radical R1 and/or R2 that is other than hydrogen.

For example, lower alkanoyl can be introduced in customary manner, for example by reaction with a reactive lower alkanoic acid derivative, such as a lower alkanoic acid chloride or lower alkanoic acid nitrile, in the presence of aluminium trichloride, and in the case of reaction with a lower alkanoic acid nitrile if necessary in the presence of boron trichloride, preferably in a halogenated hydrocarbon, if necessary at boiling temperature.

38 21~72~1 Resulting salts can be converted into the free compounds in a manner known perse, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or another of the salt-forming bases mentioned at the beginning, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another of the salt-forming acids mentioned at the beginning.

Resulting salts can be converted into different salts in a manner known perse; acid addition salts, for example, by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and is therefore eliminated from the reaction equilibrium, and basic salts by freeing of the free acid and conversion into a salt again.

The compounds of formula 1, including their salts, may also be obtained in the form of hydrates or may include the solvent used for crystallisation.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinabove and hereinbelow any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient.

Resulting diastereoisomeric mixtures and mixtures of racemates can be separated into the pure diastereoisomers or racemates in known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and/or fractional crystallisation.

Resulting racemates can also be resolved into the optical antipodes in accordance with known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example depending on the acidic, basic or functionally modifiable groups present in compounds of formula 1, with an optically active acid, base or an optically active alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from 7 2 ~ ~

which the desired enantiomer can be freed in the appropriate customary manner. Bases, acids and alcohols suitable for that purpose are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluylld, laric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, and optically active alcohols, such as borneol or D- or L-(1-phenyl)ethanol.

The invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a salt or, espe-cially, is formed under the reaction conditions.

The invention relates also to novel starting materials, which have been developed specifically for the preparation of the compounds according to the invention, especially the group of starting materials that result in the compounds of formula I described at the beginning as being preferred, to the processes for their preparation and to their use as intermediates.

The invention relates also to pha""aceutical compositions comprising the compounds according to the invention or pharmaceutic^"y acceptable salts thereof as active ingre-dients, and to processes for the preparation thereof.

The pharmaceutical compositions according to the invention, which comprise the compound according to the invention or pharmaceutically acceptable salts thereof, are for enteral, such as oral and also rectal, and parenteral administration to (a) warm-blooded animal(s), the compositions comprising the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier. The daily dose of the active ingredient depends upon age and individual condition and upon the mode of administration.

The novel pharmaceutical compositions comprise, for example, from approximately 10 % to approximately 80 %, preferably from approximately 20 % to approximately 60 %, active ingredient. Pharmaceutical compositions according to the invention for enteral or parenteral - 40 - 2 1 ~ 7 2 3 1 administration are, for example, those in unit dose forms, such as dragées, tablets, capsules or suppositories, and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or Iyophilising processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, after the addition of suitable excipients, to form tablets or dragée cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellu'~se preparations and/or calcium phosphates, for example tri-calcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose andlor polyvinylpyrrolidone, if desired disintegrators, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow agents, fiow-conditioners and lul,ricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided with suitable, optionally enteric, coatings, there being used interalia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol andlor titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the prep&rdlion of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.

Other orally adrl,inisL,dble pharmaceutical compositions are hard gelatin capsules and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.

-41- 2~S7231 Suitable rectally acl",inislrdble pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material.
Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules which comprise a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilisers.

The dosage of the active ingredient depends upon the species of warm-blooded animal, age and individual condition and also upon the mode of administration. In a normal case the approximate daily dose for oral ad",inisL(dlion to a patient weighing about 75 kg is estimated to be from approximately 10 mg to approximately 500 mg.

The following Examples serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar. The ring atoms of 4,5-dioxy-2,3,5,6-tetrahydro-4H-1-X-3a,6-diazaphenalenes according to the invention are numbered in accordance with the following formula: 2 1x~l3 ~N~O

Example 1: 3,3-Dihydro-6H-1-oxa-3a,6-diaza-phenalene-4,5-dione - 42 - 2 1 ~ 7 2 ~ 1 1.03 9 (6.86 mmol) of 3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine are dissolved in 23 ml (167.7 mmol) of diethyl oxalate and the solution is rotated on a rotary evaporator at 80 and 20 mbar for 22 hours. The resulting suspension is filtered and the residue is washed with ether and dried under reduced pressure at 60. 1.05 9 (5.14 mmol = 75%) of the title compound are obtained in the form of brown crystals; m.p. 288 after sublimation at 200 and 0.13 mbar;
H-NMR (D~DMSO, 300 MHz): 4.03 (t, J=4.8 Hz, 2H, H2C-N); 4.32 (t, J=5.0 Hz, 2H, H2C-O);

4.03 (t, J=4.8 Hz, 2H, H2C-N); 6.69-6.77 (m, 2H, H(arom.)C(4, 6)); 7.00-7.05 (m, 1H, H(arom.)C(5)); 12.02 (s br,1H, HN); C-NMR (D~DMS0, 74 MHz): 40.35 (H2C-N); 63.61(H2C-O); 108.08 (HC); 110.66 (HC); 114.06 (C); 123.97 (HC); 126.62 (C); 143.88 (C(1));
153.29 (C=O); 154.22 (C=O).

Example 2: In a manner analogous to that described in Example 1 and in the description it is also possible to prepare the following compounds of formula l:

8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;

8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl-(N-phenYI)-acetamide;

8-chloro-6H-1 -thia-3a,6-diaza-phenalene-3,4,5-trione;

8-chloro-1,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1 -thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

8-bromo-1,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

8-chloro-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;

_, -43- 2157231 8-bromo-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;

8-chloro-1 ,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1-thia-3a,6-diaza-phenalen-3-yl-(N-phenyl)-acetamide;

8-bromo-1 ,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1-thia-3a,6-diaza-phenalen-3-Yl-(N-phenyl) acetamide;

4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

4,5-dioxo-2,3,5,6-tetrahydro4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid;

4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-(N-phenyl)acetal,l;de;

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid and 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl-(N-phenyl)-acetamide.

Example 3: In a manner analogous to that described in Example 1 and in the description it is also possible to prepare the following compounds of formula l:

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid ethyl ester;

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid;

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid N-phenylamide;

- 44 - 2 1~ 7 23 ~

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetamide;

8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-2-ylacetonitrile;

8-bromo-2(1 H-tetrazol-5-ylmethyl)-2,3-dihydro-6H-1-thia-3a,6-diaza-phenalene-4,5-dione.

Example 4: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester 4.58 9 (11 mmol) of 7-bromo-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl-acetic acid ethyl ester dissolved in 12 ml of concentrated sulfuric acid are nitrated at -10 with 12 ml of fuming nitric acid. The mixture is stirred overnight at 0 to complete the reaction, poured into ice-water and extracted three times with ethyl acetate, and the organic phases are washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is removed.
The crude, nitrated intermediate is dissolved in 50 ml of acetone and at 0 slowly added dropwise to a mixture of 140ml of 15 % TiCI3 in approximately 10 % hydrochloric acid, 75 ml of water and 110 ml of acetone and the mixture is stirred at 0 for 18 hours. The resulting white precipitate is filtered off, washed neutral with a large amount of water and dried under a high vacuum at 60. 2.51 9 (6.52 mmol) = 59 % of 8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester are obtained in the form of a beige powder; 1H-NMR (CDCI3, 300MHz): 1.25 (t, 3H); 2.69 (dd, 1H); 2.99 (dd,1H); 3.26 (dd, 1H); 3.38 (dd, 1H); 4.11 (q, 2H); 5.70 (m,1H); 7.11 (d,1H); 7.22 (d, 1H); 11.78 (sbr, 1H); 13C-NMR (CDCI3, 75MHz, APT): 15.2 (CH3); 28.7 (CH2); 36.6 (CH2); 48.1 (C); 62.2 (CH2); 117.8 (C); 117.9 (CH); 121.2 (C); 124.0 (C); 126.5 (CH); 127.9 (C); 155.0 (NC=O);
155.6 (NC=O); 171.0 (C=O); FD-MS: 284,286 (M+); analysis: C 43.98% (43.65); H 3.72%
(3.40); N 7.13% (7.27); TLC: (dichloromethane/methanol = 9:1) Rf = 0.53.

The preparation of the starting materials is described below:

a) 3,4-Dihydro-2H-benzo~1,41thiazin-3-yl-acetic acid ethyl ester 8 9 (34 mmol) of (4H-benzo[1,4]thiazin-3-ylidene)-acetic acid ethyl ester are dissolved in 50 ml of ethanol, and 0.5 ml of 0.1% ethanolic bromocresol green solution and 0.5 ml of 5N
HCI/ethanol are added. 2.14 9 (34 mmol) of sodium cyanoborohydride are added in 4 portions at room temperature and the reaction mixture is kept acidic by the dropwise -45- ~1572~

addition of HCI/ethanol. After 2 hours' stirring at room temperature to complete the reaction the solvent is removed on a rotary evaporator and the residue is taken up in ethyl acetate and washed with water and saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, concentrated and purified on a column of silica gel (eluant:
petroleum ether/ethyl acetate = 8:2). 6.1 9 (25.6 mmol) = 75% of (3,4-dihydro-2H-benzo-[1,4]thiazin-3-yl)-acetic acid ethyl ester are obtained in the form of a yellow oil; 1 H-NMR
(CDCI3, 200MHz): 1.28 (t, 3H); 2.51-2.89 (m, 3H); 3.05 (dd, 1H); 4.07 (m,1H); 4.17 (q, 2H);
4.60 (sbr, 1H, NH); 6.48 (dd,1H); 6.62 (m,1H); 6.85-7.02 (m, 2H); 13C-NMR (CDCI3, 50MHz): 15.3; 31.4; 41.6; 48.4; 61.8; 116.7 (2x); 119.1; 126.9; 128.6; 142.1; 172.8; FD-MS:
237 (M+); TLC: (petroleum ether/ethyl acetate = 9:1) Rf = 0.24.

b) 7-Bromo-3,4-dihydro-2H-benzo~1,41thiazin-3-yl-acetic acid ethyl ester A solution of 3.7 9 (20.6 mmol) of N-bromosuccinimide in 45 ml of dimethylformamide is added dropwise at 0 to 4.9 9 (20.6 mmol) of (3,4-dihydro-2H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester in 45 ml of dimethylformamide and the mixture is stirred at room tempera-ture for 18 hours, then freed of solvent under a high vacuum at 50. The resulting oil is taken up in dichloromethane, washed with water and saturated sodium chloride solution, and the organic phases are dried over magnesium sulfate, concentrated and chromato-graphed on silica gel (petroleum ether/ethyl acetate = 9:1). 6.3 9 (97%) of 7-bromo-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl-acetic acid ethyl ester are obtained in the form of a yellow oil; 1H-NMR (CDCI3, 300MHz): 1.28 (t, 3H); 2.54-2.84 (m, 3H); 3.00 (dd, 1H); 4.06 (m, 1H);
4.18 (q, 2H); 4.68 (sbr, 1H, NH); 6.36 (d, 1H); 6.97 (dd, 1H); 7.11 (d, 1H); 13C-NMR (CDCI3, 75MHz): 15.2; 31.1; 41.5; 48.3; 61.9; 110.3; 117.9; 118.4; 129.6; 130.6; 141.1; 172.7;
FD-MS: 315, 317 (M~); TLC: (petroleum ether/ethyl acetate = 9:1) Rf = 0.09.

c) 2-(7-Bromo-3-ethoxycarbonylmethyl-2,3-dihydro-benzo~1,4]thiazin-4-yl)-2-oxo-acetic acid ethyl ester 2.8 ml (25.27 mmol) of oxalic acid monoethyl ester chloride are added at 0 under argon to 6.66 9 (21.06 mmol) of (7-bromo-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl-acetic acid ethyl ester and 5.9 ml (42.12 mmol) of triethylamine in 5 ml of dichloromethane and the mixture is stirred at room temperature for 2 hours, then diluted with 40 ml of dichloromethane and washed with saturated sodium chloride solution, 2N hydrochloric acid, water and again with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, - 46 - 2 1 ~ 7 2 3 1 concentrated and chromatographed on silica gel (petroleum ether/ethyl acetate = 17:3).
8.1 9 (19.5 mmol) (96.4%) of (7-bromo-3-ethoxycarbonylmethyl-2,3-dihydro-benzo[1,4]-thiazin-4-yl)-oxo-acetic acid ethyl ester are obtained in the form of a yellowish-orange oil;
1H-NMR (CDCI3, 200MHz): presumably mixture of rotamers: 1.10-1.30 (2xt, 3H); 2.55 (dbr, 2H); 3.00 (ddbr,1H); 3.49 (ddbr,1H); 4.02-4.18 (quart,m, 4H); 5.49 (m, 1H); 6.89 (d, 1H);
7.18 (dd, 1H); 7.40 (d,1H).
FD-MS: 415, 417 (M+); TLC: (petroleum ether/ethyl acetate = 7:3) Rf = 0.28.

Example 5: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid 4.1 9 (10.64 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester are stirred in 180 ml of methanol at room temperature for 4 hours with 26.6 ml of 2N aqueous sodium hydroxide solution, then rendered acidic with 48 ml of 2N hydrochloric acid. The resulting precipitate is filtered off, washed neutral with a large amount of water and dried under a high vacuum (60). 3.62 9 (10.12 mmol) = 95% of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid are obtained in the form of a white powder; melting point: >300; 1H-NMR (d6-DMSO, 300MHz):
2.55 (dd, 1H); 2.76 (dd, 1H); 3.27 (m, 2H); 5.48 (m, 1H); 7.06 (d,1H); 7.22 (d, 1H); 12.11 (sbr,1H); 12.59 (sbr, 1H); 13C-NMR (CDC13, 75MHz, APT): 28.0 (CH2); 36.5 (CH2); 46.9 (C); 62.2 (CH2); 115.6 (C); 115.7 (CH); 121.6 (C); 123.4 (C); 124.1 (CH); 129.0 (C); 154.1 (NC=O); 154.9 (NC=O); 172.4 (C=O); FD-MS: 356, 358 (M+); analysis: C 40.69% (40.35); H
2.67% (2.54); N 7.88% (7.84).

` - 215723~

Example 6: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid sodium salt 5.6 ml of 0.1 N sodium hydrogenate carbonate solution are added to a suspension of 200 mg (560 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid in 40 ml of water and the mixture is boiled under reflux for 1 hour, filtered and Iyophilised.

Example 7: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid potassium salt Preparation analogous to Example 6.

Example 8: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid triethylammonium salt A suspension of 200 mg (560 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid in 40 ml of 1 N triethylammonium hydrogen carbonate is heated at 60 for 1 hour, filtered, concen(,~led on a rotary evaporator/under a high vacuum and Iyophilised from 8 ml of water.

Example 9: 2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-Yl)-N
phenyl-acetamide 274 ~l (3 mmol) of aniline are added at room temperature under argon to a solution of 714.4 mg (2 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid, 540.5 mg (4 mmol) of 1-hydroxybenzol,ia~ole and 766.8 mg (4 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) in 10 ml of dimethyl-formamide and the mixture is stirred for 24 hours. The mixture is poured into ice-water, and the precipitate is filtered off, washed with a large amount of water and dried under a high vacuum (60). 741.5 mg (1.72 mmol) = 86% of 2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide are obtained in the form of a beige powder; m.p: 285-290; 1H-NMR (d6-DMSO,200MHz): 2.62 (dd, 1H); 2.90 (dd, 1H); 3.30 (m, 2H); 5.68 (m, 1H); 7.06 (m, 2H); 7.30 (m, 3H); 7.55 (m, 2H); 10.00 (sbr, 1H); 12.10 (sbr, 1 H); El-MS: 433, 431 (M+); 313, 311; 299, 297; analysis: contains 0.41% water: C 50.00%
(49.80); H 3.35% (3.30); N 9.49% (9.68).

- 48 ~ 2 lS~ 23 1 Example 10: In a manner analogous to that described in Example 9 it is also possible to prepare the following amides with the correponding free amines (primary, secondary, anilines) as coupling partners.

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-methyl-N-phenyl-acetan,ide; m.p.: 148-152; 1H-NMR (d6-DMSO,200MHz): 2.27-2.85 (m, approx.
2H); 3.10-3.40 (m, approx. 2H); 3.18 (s, 3H); 5.55 (m,1H); 7.00-7.48 (m, 7H); 12.05 (sbr, 1H);
FD-MS: 445, 447 (M+); analysis: C 49.69% (51.13); H 3.78% (3.61); N 10.43% (9.41);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-thiazol-2-yl-acetamide; yield: 92%; m.p.: 260-261; 1H-NMR (d6-DMSO, 300MHz): 2.72 (dd, 1H); 3.05 (dd, 1 H); 3.27 (s, 2H); 5.67 (m, 1 H); 7.09 (d, 1 H); 7.22 (d,1 H); 7.28 (d, 1 H); 7.46 (d,1 H);
12.14 (sbr, 1H) 12.26 (sbr, 1H); FAB-MS: 439, 414 (M+); analysis: C 39.03% (41.01);
H 3.19% (2.52); N 12.00% (12.75);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyclopropyl-methyl-acetamide; yield: 82%; m.p.: 250-253; 1H-NMR (d6-DMSO, 300MHz): 0.12-0.14 (m, 2H); 0.36-0.40 (m, 2H); 0.84-0.89 (m, 1H); 2.35-2.68 (m, 2H); 2.89-2.95 (m, 2H); 3.19-3.29 (m, 2H); 5.55 (m,1H); 7.07 (d, 1H); 7.25 (d,1H); 8.04-8.08 (m, 1H); 12.11 (sbr, 1H); FD-MS:
409, 411 (M+); analysis: C 45.19% (46.84); H 4.00% (3.93); N 9.78% (10.24);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyclopropyl-acetamide; yield: 60%; m.p.: 180-185; 1H-NMR (d6-DMSO, 300MHz): 0.34-0.39 (m, 2H);
0.55-0.61 (m, 2H); 0.84-0.89 (m, 1H); 2.29-2.61 (m, approx. 3H); 3.20 (sbr, 2H); 5.53 (m, 1H); 7.07 (d, 1H); 7.24 (d, 1H); 8.04 (d,1H) 12.01 (sbr, 1H); FD-MS: 395, 397 (M+);

2-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-aminol-3,3-dimethyl-butyric acid tert-butyl ester; yield: 96%; m.p.: 149-154; 1H-NMR
(d6 DMSO, 300MHz): 0.92 (d, 9H); 1.40 (d, 9H); 2.80-2.92 (m, 1H); 3.13-3.20 (m, 2H); 4.01 -49- 215~231 (dd, 1H); 5.55 (m, 1H); 7.07 (m, 1H); 7.26 (m, 1H); 8.08 (dd, 1H); 12.09 (sbr, 1H); FAB-MS:
527, 529 (M++1); 492, 494 (M-tBu); analysis: C 50.19% (49.32); H 3.35% (5.36); N 7.36%
(7.98); TLC: (dichloromethane/methanol = 9:1) Rf = 0.26;

N-adamantan-1 -yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide; m.p.: 210-215>; FD-MS: 489, 491 (M+); analysis: C 53.51% (53.88);
H 5.77% (4.93); N 10.00% (8.57).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N,N-dibutYl-acetamide; yield: 77%; 1H-NMR (d6-DMSO, 300MHz): 0.81-0.91 (m, 6H); 1.17-1.27 (m, 4H);
1.39-1.43 (m, 4H); 2.44-2.86 (m, 2H); 3.15-3.30 (m, 6H); 5.50 (m, 1H); 7.08 (m, 1H); 7.25 (m, 1H); 12.13 (sbr, 1H); FAB-MS: 468, 470 (M++1); analysis: C 50.67% (51.28); H 5.44%
(5.59); N 9.07% (8.97).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-YI)-N-(2-oxo-azepan-3-yl)-acetan,.~E; yield: 45%; m.p.: 305-307; 1H-NMR (d6-DMSO, 300MHz): 1.17-1.89 (m, 6H); 2.18-3.30 (m, 6H);4.38 (m, 1H); 5.53 (m, 1H); 7.07 (m, 1H); 7.25 (m, 1H); 7.77 (m, 1H); 7.97 (m, 1H); 12.11 (sbr, 1H); FAB-MS: 467, 469 (M++1); analysis: C 50.26%
(50.67); H 4.62% (4.48); N 9.86% (9.33);

N-allyl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-ace~a",ide; yield: 49%; m.p.: 150-153; 1H-NMR (d6-DMSO, 300MHz): 2.42 (dd, 1H); 2.58 (dd, 1H); 3.21 (d, 2H); 3.69 (m, 2H); 5.03-5.15 (m, 2H); 5.56 (m, 1H); 5.74-5.84 (m, 1H);
7.07 (m, 1H); 7.24 (m, 1H); 7.77 (m, 1H); 8.16 (t, 1H); 12.11 (sbr, 1H).; El-MS: 395, 397 (M+); analysis: C 44.83% (45.47); H 3.69% (3.56); N 10.33% (10.60);

8-bromo-3-~2-(2,3-dihydro-indol-1 -yl)-2-oxo-ethyll-2,3-dihydro-6H-1 -thia-3a,6-diaza-phen-alene-4,5-dione; yield: 99% (beige crystals); m.p.: 270-273; 1H-NMR (d6-DMSO, 300MHz):
3.00-3.62 (m, approx. 6H); 4.02 (d, 2H); 5.64 (m, 1H); 7.00-7.28 (m, 5H); 8.08 (d, 1H); 12.15 (sbr, 1H); FD-MS: 457, 459 (M+); analysis: C 51.20% (52.41); H 4.18% (3.52); N 10.20%
(9.71 );

-50- 21372~

8-bromo-3-(2-oxo-2-piperidin-1 -yl-ethyl)-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione; yield: 89% beige crystals; m.p.: 170-172; 1H-NMR (d6-DMSO, 300MHz): 1.40-1.60 (m, 8H); 2.30-3.60 (m, 6H); 5.52 (m,1H); 7.07 (d, 1H); 7.24 (d, 1H); 12.10 (sbr, 1H); FD-MS:
423, 425 (M+); analysis: C 47.60% (48.12); H 4.36% (4.28); N 9.80% (9.90);

8-bromo-3-~2-(2-methyl-aziridin-1 -yl)-2-oxo-ethyll-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione; yield: 62% (beige crystals); m.p.: 193-195 1H-NMR (d6-DMSO, 300MHz): 1.08 (m, 3H); 2.62 (m, 2H); 3.21-3.72 (m, approx. 5H); 3.90-4.41 (m,1H); 5.57 (m,1H); 7.07 (d,1H); 7.24 (d, 1H); 12.10 (sbr,1H); FD-MS: 395,397 (M+); analysis: C 43.81 % (45.47); H 3.77% (3.56); N 11.66% (11.60).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,2-di-methoxy-ethyl)-acetar"ide; yield: 69% (beige crystals); m.p.: 190-192; 1H-NMR (d6-DMSO, 300MHz): 2.28-2.72 (m, 2H); 3.10-3.20 (m, 4H); 3.21 (2xs, 6H); 4.32 (t,1H); 5.58 (m, 1H);
7.07 (d,1H); 7.24 (d, 1H); 8.09 (t, 1H); 12.10 (sbr, 1H); FD-MS: 443, 445 (M+); analysis:
C 41.74% (43.25); H 4.06% (4.08); N 9.10% (9.46);

4-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-aminol-benzoic acid methyl ester; yield: 59% beige crystals; m.p.: 145-147; 1H-NMR
(d6 DMSO, 300MHz): 2.60-2.95 (m, 2H); 3.22 (m, 2H); 3.80 (s, 3H); 5.68 (m, 1H); 7.07 (d, 1H); 7.23 (d, 1H); 7.70 (d, 2H); 7.91 (d, 2H); 10.20 (s,1H); 12.10 (sbr, 1H); FD-MS: 489, 491 (M+);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(5,6,7,8-tetrahydro-naphthalen-1-yl)-acetamide; yield: 97% beige crystals; m.p.: 323-325; 1H-NMR
(d6-DMSO, 300MHz): 1.62-1.73 (m, 4H); 2.60-2.95 (m, 6H); 3.22 (m, 2H); 5.65 (m, 1H);

6.90-7.30 (m, 5H); 9.25 (s, 1H); 12.15 (sbr,1H); FD-MS: 485, 487 (M+); analysis: C 54.28%
(54.33); H 4.18% (4.14); N 9.51% (8.64);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-furan-2-yl-methyl-acetamide; yield: 82% beige crystals; m.p.: 202-203 -51 - 21~723 1 1H-NMR (d6-DMSO, 300MHz): 2.20-2.71 (m, 2H); 3.21 (m, 2H); 4.23 (m, 2H); 5.68 (m,1H);
6.22 (d, 1H); 6.39 (d, 1H); 7.07 (d, 1H); 7.22 (d, 1H); 7.58 (d, 1H); 8.48 (t, 1H); 12.10 (sbr, 1H); FD-MS: 435, 437 (M+); analysis: C 46.31% (46.80); H 3.33% (3.23); N 9.66% (9.63).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2-methoxy-ethyl)-acetamide; yield: 38% beige crystals; m.p.: 135-137 1H-NMR (d6-DMSO, 300MHz): 2.20-2.71 (m, 2H); 3.21 (m, 6H); 3.23 (s, 3H); 5.68 (m, 1H);

7.07 (d, 1H); 7.22 (d, 1H); 8.08 (m,1H); 12.12 (sbr, 1H); FD-MS: 413, 415 (M+); analysis:
C 42.96% (43.49); H 3.92% (3.89); N 10.01% (10.14).

Example 11: 1-~2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-cyclopropane-carboxylic acid methyl ester 165.2 mg (1090 mmol) of 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride are added at room temperature under argon to a solution of 259.6 mg (727 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid, 196.4 mg (1454 mmol) of 1-hydroxybenzotriazole, 279 mg (1454 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and 153 ~11 (1090 mmol) oftriethylamine in 10 ml of dimethylformamide and the mixture is stirred for 48 hours. The mixture is then poured into acidified ice-water and the precipitate is filtered off, washed with a large amount of water and dried under a high vacuum (60). 220.3 mg (485 mmol) = 67%
of 1-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-cyclopropane-carboxylic acid methyl ester are obtained in the form of a beige powder;
m.p: 186-188; 1H-NMR (d6-DMSO, 300MHz): 1.02 (m, 2H); 1.34 (m, 2H); 2.37-2.59 (m, approx. 3H); 3.21 (sbr, 2H); 3.58 (s,3H); 5.54 (m, 1H); 7.07 (m,1H); 7.24 (m, 1H); 8.65 (s, 1H); 12.11 (sbr, 1H), FAB-MS: 454, 456 (M+); analysis: C 44.95% (44.23); H 3.82% (3.55);
N 9.24% (9.25).

Example 12: In a manner analogous to Example 11, it is also possible to prepare the following amides with amine hydrochlorides as coupling partners:

-52- 21572~J~ ~

N-adamantan-2-yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide; yield: 91%; m.p.: 183-185; 1H-NMR (d6-DMSO, 300MHz): 1.40-2.00 (m, approx. 15H); 2.74 (m, 1H); 3.19 (m, 2H); 3.82 (m, 1H); 5.57 (m, 1H); 7.07 (d, 1H); 7.26 (d, 1H); 7.84 (d, 1H); 12.10 (sbr, 1H); FAB-MS: 490, 492 (M++1).
analysis: C 53.58% (53.88); H 5.08% (4.93); N 8.67% (8.57);

N-bicyclo~2.2.11hept-2-yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide; yield: 88%; m.p.: 215-222; 1H-NMR (d6-DMSO, 300MHz): 0.8-1.8 (m, approx. 7H); 2.00-2.40 (m, approx. 3H); 2.65 (m, 1H); 3.16 (m, 2H); 3.87 (m, 1H);
5.54 (m, 1H); 7.07 (d, 1H); 7.25 (d, 1H); 7.91 (m, 1H); 12.10 (sbr, 1H); FAB-MS: 450, 452 (M++1); analysis: C 45.56% (46.26); H 4.26% (4.10); N 11.88% (11.99);

2-(8-bromo-4,~dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-tert-butoxy-acetamide; yield: 29%; m.p.: 175-180; 1H-NMR (d6-DMSO, 300MHz): 1.14 (s, 9H); 2.25-3.40 (m, 4H); 5.55 (m, 1H); 7.07 (m, 1H); 7.27 (m, 1H); 10.45 (sbr, 1H); 12.11 (sbr, 1H);
FAB-MS: 428, 430 (M++1);

N-benzyloxy-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide; yield: 93%; m.p.: 140-148; 1H-NMR (d6-DMSO, 300MHz): 2.28-2.45 (m, 2H);
3.12-3.23 (m, 2H); 4.77 (q, 2H); 5.55 (m, 1H); 7.07 (m, 1H); 7.24 (m, 1H); 7.38 (sbr, 5H);
11.14 (sbr, 1H); 12.12 (sbr, 1H); FAB-MS: 462, 464 (M++1); analysis: C 49.14% (49.36);
H 3.77% (3.49); N 9.72% (9.09).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-prop-2-ynyl-acetam.de; yield: 73%; m.p.: 181-182; 1H-NMR (d6-DMSO, 300MHz): 2.40 (dd, 1H); 2.68 (dd, 1H); 3.13 (s, 1H); 3.20 (d, 2H); 3.85 (m, 2H); 5.54 (m, 1H); 7.07 (m, 1H); 7.24 (m, 1H);
8.46 (m, 1H); 12.11 (sbr, 1H); FAB-MS: 394, 396 (M++1).
Analysis: C 44.92% (45.70); H 3.33% (3.07); N 10.43% (10.66);

2-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-aminol-malonic acid dimethyl ester; yield: 51% beige crystals; m.p.: 143-145; 1H-NMR

~15723~

(d6 DMSO, 300MHz): 2.38 (m, 1H); 2.80 (m, 1H); 3.20 (m, 2H); 3.72 (s, 6H); 5.17 (d, 1H);
5.57 (m, 1H); 7.07 (m, 1H); 7.24 (m,1H); 9.01 (t, 1H); 12.11 (sbr, 1H); FD-MS: 485, 487 (M+); analysis: C 40.68% (41.99); H 3.47% (3.32); N 8.64% (8.64).

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyano-methyl-acelan,ide; yield: 54% beige crystals; m.p.: 212-214 1 H-NMR (d6-DMSO, 300MHz): 2.40-2.50 (m,1 H); 2.70 (m, 1H); 3.20 (m, 2H); 3.72 (s, 6H);
4.13 (d,1H); 5.57 (m, 1H); 7.07 (m, 1H); 7.24 (m,1H); 8.75 (t,1H); 12.11 (sbr, 1H); FD-MS:
394, 396 (M+);

3-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-aminol-propionic acid methyl ester; yield: 43% brown crystals;
m.p.: 240-242; 1H-NMR (d6-DMSO, 300MHz): 2.25-2.75 (m, approx. 4H); 3.18 (s, 2H);
3.28 (t, 2H); 3.60 (s, 3H); 5.57 (m, 1H); 7.07 (m, 1H); 7.23 (m, 1H); 8.13 (t, 1H); 12.11 (sbr, 1H).
FD-MS: 441, 443 (M+);

N-allyloxy-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide; yield: 77% beige crystals; m.p.: 162-165 1H-NMR (d6-DMSO, 300MHz): 2.23-2.40 (m, 2H); 3.18 (m, 2H); 4.23 (m,2H); 5.25 (2xd, 2H); 5.57 (m, 1H); 5.90 (m, 1H); 7.07 (m,1H); 7.24 (m, 1H); 11.09 (sbr, 1H); 12.11 (sbr,1H);
FD-MS: 411, 413 (M+); analysis: C 43.53% (43.70); H 3.72% (3.42); N 10.47% (10.19);

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-methoxy-acetamide; yield: 90% beige crystals; m.p.: 182-185 1H-NMR (d6-DMSO, 300MHz): 2.23-2.40 (m, 2H); 3.19 (m, 2H); 3.58 (s, 3H); 5.57 (m, 1H);
5.90 (m, 1H); 7.07 (m,1H); 7.24 (m, 1H); 11.14 (sbr, 1H); 12.10 (sbr, 1H); FD-MS: 385, 387 (M+); analysis: C 39.03% (40.43); H 3.50% (3.13); N 10.24% (10.88);

-54- 21Y~72~l Example 13: 2-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-benzoic acid methyl ester A solution of 754.5 mg (2.11 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid, 590.6 mg (2.32 mmol) of N,N-bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-CI), 705.3 ~l of triethylamine and 300.5 ~ll of anthranilic acid methyl ester in 10 ml of dimethylformamide is heated under argon at 60 for 3 hours, then 590.6 mg (2.32 mmol) of BOP-CI (= bis(oxo-3-oxazolidinyl~phosphinic acid chloride) and 705 3 tll of triethylamine are added and the mixture is stirred for a further 2 hours at 60 and for 15 hours at room temperature. The mixture is then poured into acidified ice-water and the resulting precipitate is filtered, washed neutral with a large amount of water and dried under a high vacuum (60). 987.2 mg (2.01 mmol) = 95% of 2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-benzoic acid methyl ester are obtained in the form of a beige powder; m.p.: 165-175; 1 H-NMR (d6-DMSO, 300MHz): 2.72-2.97 (m, 2H); 3.24-3.33 (m, 2H); 3.83 (s, 3H); 5.63 (m, 1H); 7.09 (d, 1H);
7.22 (t,1H); 7.28 (d, 1H); 7.61 (t, 1H); 7.89 (d, 1H); 8.12 (d, 1H); 10.58 (sbr, 1H) 12.13 (sbr, 1H); FAB-MS: 490, 492 (M++1); analysis: C 46.98% (48.99); H 3.51% (3.29); N 8.70%
(8.57).

Example 14: Analogously to Example 13 it is also possible to prepare 3-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-but-2-enoic acid methyl ester; yield: 47% beige powder; m.p.: 160-167; FD-MS: 453, 455 (M+); analysis:
C 45.38% (44.95); H 3.80% (3.55); N 9.35% (9.25).

Example 15: 2-~2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetYlaminol-benzoic acid 5 ml of 2N sodium hydroxide solution are added to a slurry of 149 mg (303.9 mmol) of 2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-benzoic acid methyl ester in 80 ml of methanol and the reaction mixture is stirred at room temperature for 4.5 hours. 8 ml of 2N hydrochloric acid are added, the methanol is removed on a rotary evaporator, and the resulting precipitate is filtered off, washed neutral with a large amount of water and dried under a high vacuum (60). 105 mg (220 mmol) = 73% of 2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-~ 1 ~ 7 2 3 1 amino]-benzoic acid are obtained in the form of a beige powder; m.p.: 205-212; 1 H-NMR
(d6-DMSO, 300MHz): 2.72-2.97 (m, 2H); 3.23-3.33 (m, 2H); 5.63 (m,1H); 7.09 (d, 1H); 7.17 (t, 1H); 7.27 (d, 1H); 7.60 (t,1H); 7.86 (d, 1H); 8.39 (d, 1H); 11.21 (sbr,1H) 12.12 (sbr, 1H);
FD-MS: 475, 477 (M+); analysis: C 45.04% (47.91); H 3.03% (2.96); N 8.35% (8.82).

Example 16: In a manner analogous to that described in Example 15, it is also possible to prepare the following compounds:

3-~2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetyl-aminol-propionic acid; yield: 79% beige powder;
m.p.: 284-286; 1H-NMR (d6-DMSO, 300MHz): 2.25-2.75 (m, approx. 4H); 3.18-3.28 (m, approx. 4H); 5.59 (m, 1H); 7.07 (d,1H); 7.23 (d,1H); 8.08 (t, 1H); 12.15 (sbr, 2H); FD-MS:
427, 429 (M+);

~2-(8-bromo-4,5-dioxo-2,3.5.6-tetrahYdro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-acetic acid; (with decarboxylation); yield: 42% white crystals, m.p.: 193-195; 1H-NMR
(d6 DMSO, 300MHz): 2.20-3.75 (m, approx. 6H); 5.57 (m, 1H); 7.07 (d, 1H); 7.24 (d, 1H);
8.18 (t, 0.5H); 8.67 (d, 0.5H); 12.13 (sbr, 1H).
FD-MS: 413, 415 (M+);

Example 17: 1-r2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-cyclopropane-carboxylic acid 10 ml of 2N hydrochloric acid are added to a solution of 84.3 mg (186 mmol) of 1-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-cyclopropane-carboxylic acid methyl ester in 40 ml of dioxane and the mixture is stirred at room temperature for 18 hours. 20 ml of hydrochloric acid are added and the mixture is stirred at room temperature for 24 hours and concentrated on a rotary evaporator. The resulting precipitate is washed neutral with a large amount of water and dried under a high vacuum (60). 53.2 mg (121 mmol) = 65% of 1-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-cyclopropane-carboxylic acid are obtained in the form of a beige powder; m.p.: 300-302; 1H-NMR (d6-DMSO, 300MHz): 0.97 (m, 2H);

-56- 21~723~

1.30 (m, 2H); 2.36-2.63 (m, approx. 3H); 3.21 (sbr, 2H); 5.52 (m, 1H); 7.07 (m, 1H); 7.24 (m, 1H); 8.55 (s, 1H); 12.09 (sbr, 1H); 12.36 (sbr, 1H); FAB-MS: 440, 442 (M+).

Example 18: 2-~2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylaminol-3,3-dimethyl-butyric acid 2 ml of trifluoroacetic acid are added to a solution of 113 mg (214.6 mmol) of 2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-3,3-dimethyl-butyric acid tert-butyl ester in 5 ml of dichloromethane and the mixture is stirred at room temperature for 5 hours. The solvents are removed on a rotary evaporalor and the residue is dissolved in 1 ml of dimethylformamide and stirred into 50 ml of ice-water. The product that precipitates is filtered off, washed with a large amount of water and dried under a high vacuum (60). 32.8 mg (70 mmol) = 33% of 2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetylamino]-3,3-dimethyl-butyric acid are obtained in the form of a white powder, m.p.: 195-198; 1H-NMR (d6-DMSO, 300MHz): 0.93 (d, 9H); 2.85-2.96 (m, 1H); 3.15-3.19 (m, 2H); 4.10 (dd, 1H); 5.55 (m, 1H); 7.07 (m, 1H); 7.26 (m, 1H);
8.10 (dd, 1H); 12.12 (sbr, 1H); 12.55 (sbr, 1H); FAB-MS: 470, 472 (M++1); TLC: (dichloro-ethane/ethanol = 9:1) Rf = 0.07.

Example 19: 2,2-Dimethyl-propionic acid (8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetoxymethyl ester A mixture of 201.4 mg (563.9 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid, 42.9 mg (310.1 mmol) of K2C03 and 98.3 ~lg(676.6 mmol) of pivalic acid chloromethyl ester in 5 ml of dimethylformamide is stirred at room temperature overnight. The mixture is poured into ice-water and concentrated slightly at 50, and the product that precipitates is filtered off, washed with water and dried under a high vacuum (60). 56.5 mg (120 mmol) = 21% of 2,2-dimethyl-propionic acid (8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetoxymethyl ester are obtained in the form of a white powder, m.p.: 163-167; 1H-NMR (d6-DMSO, 300MHz):
1.07-1.24 (m, 9H); 2.65-2.93 (m, 2H); 3.20 (m, 2H); 5.48 (m, 1H); 5.70 (m, 2H); 7.06 (d, 1H);
7.25 (d, 1H); 12.14 (sbr, 1H); FD-MS: 470, 472 (M+).

Example 20: In a manner analogous to that described in Example 19, it is also possible to prepare benzoic acid (8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-~_ 57 ~l57231 3-yl)-acetoxymethyl ester; yieid: 71%; m.p.: 140-148; 1H-NMR (d6-DMSO, 300MHz): 2.65-2.98 (m, 2H); 3.20 (m, 2H); 5.52 (m,1H); 5.96 (m, 2H); 7.07 (d,1H); 7.24 (m, 1H); 7.57 (m, 2H); 7.70 (m, 1H); 8.00 (m, 2H); 12.11 (sbr,1H); FD-MS: 490, 492 (M+); analysis: C 48.89%
(48.89); H 3.23% (3.08); N 5.96% (5.70).

Example 21: In a manner analogous to that described in Example 9, it is also possible to prepare 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid methoxyca,l,onyl methyl ester; yield: 56%.; m.p.: 185-191; 1H-NMR (d6-DMSO, 300MHz): 2.65-2.98 (m, 2H); 3.24 (m, 2H); 3.62 (s, 3H); 4.73 (s, 2H); 5.53 (m,1 H); 7.08 (d, 1H); 7.26 (d, 1H); 12.13 (sbr,1H); FD-MS: 428, 430 (M+); analysis: C 41.16% (41.97);
H .14% (3.05); N 7.69% (6.53).

Example 22: 2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide In a screw-threaded bomb tube, 1.0 9 (2.6 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester in 30 ml of 4N methanolic ammonia solution is heated at 100 for 8 hours. The product that precipitates is filtered off, washed with ethanol and dried under a high vacuum (60). 370 mg (1.04 mmol) = 40% of 2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide are obtained in the form of a grey powder; m.p. ~320; 1 H-NMR (d6-DMSO, 300MHz): 2.32-2.70 (m, 2H); 3.17-3.30 (m, 2H); 5.52 (m, 1H); 6.99 (sbr); 7.06 (d, 1H); 7.24 (d,1H); 7.45 (sbr, 1H); 11.58 (sbr,1H); FD-MS: 355, 357 (M~); analysis: C 40.55% (40.46); H 3.19%
(2.83); N 11.40% (11.80); TLC: (dichloromethane/methanol = 9:1) Rf = 0.07.

Example 23: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetonitrile 396 ~11 (4.32 mmol) of phosphorus oxychloride are squirted under argon into a solution, heated to 90, of 770 mg (2.16 mmol) of 2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide in 20 ml of dimethylformamide and the mixture is stirred for 2 hours. The mixture is then poured into ice-water and the resulting precipitate is filtered off, washed with a large amount of water and dried under a high vacuum (60). The resulting intermediate (imine chloride) is filtered over a small amount of silica gel with dichloromethane, dried, dissolved in 30 ml of dioxane and hydrolysed at room temperature -58- ~.57231 with 3.16 ml of 1 N sodium hydroxide solution for 2 hours. The mixture is again poured into ice-water and then acidified with a small amount of hydrochloric acid. The resulting precipitate is filtered off, washed with water and dried under a high vacuum (60). 421.5 mg (1.25 mmol) = 58% of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetonitrile are obtained in the form of an ochre-yellow powder, m.p.: 235-250; 1H-NMR (d6-DMSO, 300MHz): 2.95-2.99 (m, 2H); 3.27 (m, 2H); 5.55 (m, 1 H); 7.09 (d, 1H); 7.29 (d,1H); 12.19 (s,1H); FD-MS: 337, 339 (M+).
Analysis: (contains approx.1 equiv. water): C 40.53% (42.62); H 2.67% (2.38); N 11.52%
(12.43); TLC: (dichloromethane/methanol = 19:1) Rf = 0.11.

Example 24: 8-Bromo-3-(2H-tetrazol-5-ylmethyl)-2,3-dihydro-6H-1-thia-3a,6-diaza-phenalene-4,5-dione A solution of 200 mg (591 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetonitrile,115.3 mg (1.774 mmol) of sodium azide and 122.1 mg (887 mmol) of triethylamine hydrochloride in 5 ml of N-methyl-2-pyrrolidone is heated at 150 under N2 for 4 hours. The mixture is allowed to cool, and then poured into 100 ml of ice-water, acidified with hydrochloric acid and extracted twice with 150 ml of ethyl acetate each time. The organic phases are then washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is dried under a high vacuum (60). The resulting oil is taken up in 5 ml of dimethyl-fo""anlide and the product is precipitated by being stirred into 100 ml of acidified ice-water.
The precipitate is washed with water and dried under a high vacuum.101.3 mg (266.4 mmol) = 45% of 8-bromo-3-(2H-tetrazol-5-ylmethyl)-2,3-dihydro-6H-1-thia-3a,6-diaza-phenalene-4,5-dione are obtained in the form of a brown powder; m.p.: 238-242;
1H-NMR (d6-DMSO, 300MHz) : 3.20-3.40 (m, 4H); 5.58 (m, 1H); 7.10 (d, 1H); 7.30 (d,1H);
12.14 (s, 1H) 16.20 (sbr, 1H); FD-MS: 380, 382 (M+).

Example 25: 3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Enantiomerically pure 3(S)-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester is obtained by HPL-chromatographic separation of the racemate. Column: Chiracel OJ 10x50cm; hexane/ethanol = 7:3; 150 ml/min; approx.45 bar; det.: 220 nm. Subsequent purification of the enantiomerically pure fractions ` - 21S723~

(removal of phthalates) by flash column chromatography: silica gel, d;:hloromethane/-methanol = 9:1.; [a]D = + 104.4 (c = 0.25, dimethylformamide); 1H-NMR (CDCI3, 300MHz):
identical to racemate (Example 4); El-MS: 384, 386 (M+); analysis: C 44.42% (43.65);
H 3.73% (3.40); N 7.06% t7.27).

Example 26: 3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-Phenalen-3 acetic acid ethyl ester Preparation analogous to racemate cleavage according to Example 25 [a]D = - 111.2 (c =
0.25, dimethylro"l~a"..de); 1H-NMR (CDCI3, 300MHz): identical to racemate (Example 1).
El-MS: 384, 386 (M+); analysis: C 43.61% (43.65); H 3.59% (3.40); N 6.93% ~7.27).

Example 27: 3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid Preparation analogous to Example 5 from enantiomerically pure 3(S)-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester; [a]D = + 94.4 (c = 0.25, dimethylformamide); 1 H-NMR (CDC13, 300MHz): identical to racemate (Example 2); El-MS: 356, 358 (M+); analysis: C 40.38% (40.35); H 3.15% (2.54); N 7.36%
(7.84).

Example 28: 3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-Y
acetic acid Preparation analogous to Example 5 from enantiomerically pure 3(R)-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester; [a]D = - 87.6 (c = 0.25, dimethylro"~amide); 1 H-NMR (CDC13, 300MHz): identical to racemate (Example 2); El-MS: 356, 358 (M+); analysis: C 40.35% (40.35); H 3.09% (2.54); N 7.23%
(7.84).

Example 29: 2-(3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide Preparation analogous to Example 5 from enantiomerically pure 3(S)-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid; [a]D = + 128.0 (c = 0.25, 215~

dimethylformamide); 1H-NMR (CDCI3, 300MHz): identical to racemate (Example 5); El-MS:
431, 433 (M+); analysis: C 49.95% (50.01); H 3.64% (3.26); N 9.19% (9.72).

Example 30: 2-(3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide Preparation analogous to Example 5 from enantiomerically pure 3(R)-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid; [a]D = - 124.4 (c = 0.25, dimethylror"~an.:de; 1 H-NMR (CDCI3, 300MHz): identical to racemate (Example 5); El-MS:
431, 433 (M+); analysis: C 49.96% (50.01); H 3.69% (3.26); N 9.36% (9.72).

Example 31: 8-Chloro-2,3,5,6-dihydro-6H-1-thia-3a,6-diaza-phenalene-4,5-dione Prepared from (7-chloro-2,3-dihydro-benzo[1,4lthiazin-4-yl)-oxo-acetic acid ethyl ester analogously to Example 4. Yield: 24%. A solution of 1.0 9 ( 2.6 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester in 30 ml of glacial acetic acid and 25 ml of 30 % water2 is heated at 100 for 18 hours. The solution is then concentrated almost to dryness and 300 ml of ice-water are added thereto. The product that precipitates is filtered off, washed neutral with water and dried under a high vacuum (60). 670 mg (1.61 mmol) = 62 % of 8-bromo-1,1,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester are obtained in the form of a white powder, m.p.: >330o; 1 H-NMR (d6-DMSO, 300MHz): 3.20-3.23 (m, 2H); 4.25-4.29 (m, 2H); 6.93 (d, 1H); 7.12 (d, 1H); 12.11 (sbr, 1H); El-MS: 254, 256 (M++1); analysis:
C 47.15% (47.16); H 2.77% (2.81); N 10.92% (1 1.00); TLC: (dichloromethane/methanol = 19:1) Rf = 0.32.

The preparation of the starting material is described below:

a) (7-Chloro-2,3-dihydro-benzo~1,41thiazin-4-yl)-oxo-acetic acid ethyl ester Prepared from 7-chloro-3,4-dihydro-2H-benzo[1,41thiazine (CAN: 106016-84-6) analogously to Example 4b; 1H-NMR (CDC13, 300MHz): 1.14 (t, 3H); 3.21 (t, 2H); 4.03 (t, 2H); 4.16 (quart, 2H); 6.97 (m, 2H); 7.22 (d, 1 H); FD-MS: 285, 287 (M+); TLC: (dichloromethane/-petroleum ether = 1:1 ) Rf = 0.10.

~1~7~ ~

Example 32: 8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Prepared analogously to Example 4; yield: 33%; m.p.: 222-226; 1H-NMR (CDCI3, 200MHz): 1.25 (t, 3H); 2.69 (dd, 1H); 3.00 (dd, 1H); 3.26 (dd, 1H); 3.93 (dd, 1H); 4.18 (q, 2H); 5.78 (m, 1H); 7.08 (dd, 1H); 7.12 (dd, 1H); 12.65 (sbr, 1H); FD-MS: 340, 342 (M+) TLC: (dichloromethane/methanol = 9:1) Rf = 0.56.

The preparation of the starting materials is described below:

a) (7-chloro-3,4-dihydro-2H-benzo~1,41thiazin-3-yl)-acetic acid ethyl ester Prepared analogously to Example 4a starting from (7-chloro-4H-benzo[1,4]-3-ylidene)-acetic acid ethyl ester; yield: 78%; 1H-NMR (CDC13, 300MHz): 1.28 (t, 3H); 2.57 (dd, 1H); 2.70 (dd, 1H); 2.81 (dd, 1H); 3.01 (dd, 1H); 4.06 (m, 1H); 4.18 (q, 2H); 4.67 (sbr, 1H, NH); 6.40 (d, 1H); 6.84 (dd, 1H); 6.98 (dd, 2H); 13C-NMR (CDCI3, 75MHz): 15.2; 31.2; 41.5; 48.3;
61.9; 117.5, 117.9; 123.4; 126.7; 127.8; 140.6; 172.7; TLC: (petroleum ether/ethyl acetate = 9:1) Rf = 0.12.

b) (7-chloro-3-ethoxycarbonylmethyl-2,3-dihydro-benzo~1,41thiazin-4-yl)-oxo-acetic acid ethyl ester Preparation analogous to Example 4c; 1 H-NMR (CDCI3, 300MHz): presumably a mixture of rotamers: 1.09-1.25 (2xt, 3H); 2.56 (m, 2H); 3.00 (ddbr, 1H); 3.48 (ddbr, 1H); 4.11 (quart, 4H); 5.49 (m, 1H); 6.94 (d, 1H); 7.02 (dd, 1H); 7.25 (d, 1H); FD-MS: 371, 373 (M+).
TLC: (hexane/ethyl acetate = 4:1) Rf = 0.21.

Example 33: 8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid Preparation analogous to Example 5; yield: 82%; melting point ~300o; 1 H-NMR (d6-DMSO, 300MHz): 2.56 (dd, 1H); 2.77 (dd, 1H); 3.28 (m, 2H); 5.50 (m, 1H); 6.95 (d, 1H); 7.15 (d, 1H); 12.13 (sbr, 1H); 12.58 (sbr, 1H); FD-MS: 312, 314 (M+).

~15723~

Example 34: 2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide Preparation analogous to Example 9; yield: 64%; melting point: >300; 1H-NMR (d6-DMSO, 300MHz): 2.62 (dd, 1 H); 2.90 (dd, 1 H); 3.28 (m, 2H); 5.67 (m, 1H); 6.96 (d, 1H); 7.04 (m, 1H); 7.17 (d, 1H); 7.30 tm, 2H); 7.55 (d, 2H); 10.04 (s, 1H); 12.15 (sbr, 1H).
FD-MS: 387, 389 (M+); analysis: C 55.61% (55.74); H 3.90% (3.64); N 10.94% (10.83).

Example 35: 8-Bromo-1,1,4,5-tetraoxo-2,3,5,6-tetrahydro-1H,4H-6-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester A solution of 1.0 g (2.6 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester in 30 ml of glacial acetic acid and 25 ml of 30% water2 is heated at 100 for 18 hours and then concentrated almost to dryness. 300 ml of ice-water are added. The product that precipitates is filtered off, washed neutral with water and dried under a high vacuum (60). 670 mg (1.61 mmol) = 62% of 8-bromo-1,1,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester are obtained in the form of a white powder; m.p.: 257-261; 1H-NMR (d6-DMSO, 300MHz): 1.20 (t, 3H); 2.68-2.90 (m, 1H); 3.08-3.25 (m, 1H); 4.05 (m, 2H); 4.11 (q, 2H); 5.62 (m, 1H); 7.50 (d, 1H); 7.73 (d, 1H); 12.50 (sbr, 1H); FD-MS: 416, 418 (M+); analysis: C 38.51% (40.30); H 3.09%
(3.14); N 6.84% (6.71); TLC: (dichloromethane/hexane/methanol = 6:3:1) Rf = 0.21.

Example 36: 8-Bromo-1, 1 ,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-yl-acetic acid Preparation analogous to Example 5; yield: 83%.; melting point: 281-284; 1H-NMR(d6 DMSO, 300MHz): 2.50 (dd, 1H); 3.18 (dd, 1H); 4.05 (m, 2H); 5.58 (m, 1H); 7.50 (d, 1H);
7.72 (d, 1H); 12.50 (sbr, 2H); FD-MS: 388, 390 (M+); analysis: C 37.26% (37.03); H 2.49%
(2.33); N 7.19% (7.20).

Example 37: 2-(8-Bromo-1, 1 ,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide Preparation analogous to Example 5; yield: 88%; melting point: 185-190; 1H-NMR
(d6 DMSO, 200MHz): 2.75-2.90 (m, 1H); 3.15-3.25 (m, 1H); 4.05 (m, 2H); 5.80 (m, 1H);
7.08 (m, 1H); 7.30 (m, 2H); 7.56 (m, 3H); 7.77 (m, 1H); 10.09 (s, 1H); 12.50 (sbr, 1H);

21572~1 FD-MS: 463, 465 (M+); analysis: C 46.48% (46.56); H 3.47% (3.04); N 9.87% (9.05); TLC:
(dichioromethane/methanol = 9:1) Rf = 0.20.

Example 38: 8-Ghloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-Phenalen-3acetic acid ethyl ester A solution of 4.2 g (15.51 mmol) of 5-amino-7-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl-acetic acid ethyl ester in 52 ml of oxalic acid diethyl ester is rotated on a rotary evaporator at 80 and 60 mbar for 18 hours. The resulting solid is suspended in Et2O, filtered, washed with 250 ml of Et2O and dried under a high vacuum (80). 3.35 9 ( 10.31 mmol) = 66% of 8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester are obtained in the form of white crystals, m.p.: 265: 1 H-NMR (d6-DMSO, 300MHz):
1.16 (t, 3H); 2.62 (m, 2H); 4.07 (q, 2H); 4.12 (m, 1H); 4.48 (d, 1H); 4.97 (m, 1H); 6.79 (d, 1H); 6.88 (d, 1H); 12.14 (sbr, 1H); FD-MS: 324, 326 (M+).

The preparation of the starting materials is described below:

a) 2-(2-chloromethyl-4-nitro-2,3-dihydro-benzo-oxazol-2-yl)-acetic acid ethyl ester A mixture of 30 g (194.6 mmol) of 2-hydroxy-6-nitroaniline and 26.5 ml of 4-chloro-aceto-acetic acid ethyl ester in 130 ml of benzene is boiled in a water separator for 12 hours. The solvent is removed and the brown, semi-crystalline residue is subjected to flash chromato-graphy on silica gel (eluant: petroleum ether/ethyl acetate = 9:1). 49.7 g (165.3 mmol) =
85% of (2-chloromethyl-4-nitro-2,3-dihydro-benzo-oxazol-2-yl)-acetic acid ethyl ester are obtained in the form of fluorescent-orange crystals; m.p.: 90-91; 1H-NMR (CDCI3, 300MHz): 1.24 (t, 3H); 3.09 (d, 1H); 3.28 (d, 1H); 3.92 (dd, 2H); 4.19 (q, 2H); 6.63 (t, 1H);
6.82 (d, 1H); 7.09 (sbr, 1H, NH); 7.48 (d, 1H); 13C-NMR (CDC13, 50MHz): 14.5; 41.6; 48.1;
62.1; 100.6; 112.2; 116.4; 118.7; 135.8; 151 5; 169.2; FD-MS: 300, 302 (M+); TLC:
(petroleum ether/ethyl acetate = 9:1) Rf = 0.23 b) 2-(6-chloro-2-chloromethyl-4-nitro-2,3-dihydro-benzooxazol-2-yl)-acetic acid ethyl ester A solution of 45 g (149.7 mmol) of (2-chloromethyl-4-nitro-2,3-dihydro-benzo-oxazol-2-yl)-acetic acid ethyl ester and 24 g (179.6 mmol) of N-chlorosuccinimide in 500 ml of dimethylformamide is heated at 60 for 18 hours. The solution is concentrated on a rotary ~15723~

evaporator/under a high vacuum, and the brownish-orange residue is taken up in dichloromethane, washed twice with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator (50). 58.2 g (~100%) of (6-chloro-2-chloromethyl-4-nitro-2,3-dihydro-benzooxazol-2-yl)-acetic acid ethyl ester are obtained in the form of a reddish-orange oil that is pure according to NMR; 1 H-NMR
(CDCI3, 200MHz): 1.26 (t, 3H); 3.18 (AB-syst., 2H); 3.90 (dd, 1H); 4.18 (q, 2H); 6.69 (dd, 1H); 7.12 (sbr, 1H, NH); 7.48 (d, 1H); TLC: (dichloromethane/hexane = 7:3) Rf = 0.27.

c) (7-chloro-5-nitro-4H-benzo~1,41Oxazin-3-ylidene)-acetic acid ethyl ester A solution of 30 g (89.51 mmol) of 6-chloro-2-chloromethyl-4-nitro-2,3-dihydro-benzooxazol-2-yl)-acetic acid ethyl ester in 150 ml of THF is added dropwise at 0-5 to a suspension of 4.7 g (107.4 mmol) of sodium hydride (in the form of a 55% suspension in oil) in 150 ml of THF. The mixture is stirred for 30 minutes and then heated to room temperature and stirred for 1 hour. The solvent is removed on a rotary evaporator (50) and the semi-crystalline, black oil is chromatographed on silica gel (dichloromethane/hexane = 7:3) . After crystal-lisation from ether/hexane, 20.3 g (68 mmol) (76%) of (7-chloro-5-nitro-4H-benzo[1,4]-oxazin-3-ylidene)-acetic acid ethyl ester are obtained in the form of orange crystals; m.p.:
162-163; 1H-NMR (CDCI3, 300MHz): 1.33 (t, 3H); 4.28 (q, 2H); 4.67 (d, 2H); 4.98 (s, 1H);
7.18 (dd, 1H); 7.89 (d, 1H); 12.27 (sbr, 1H); TLC: (dichloromethane/hexane = 7:3) Rf =
0.40.

d) 5-amino-7-chloro-4H-benzo~1,41Oxazin-3-ylideneacetic acid ethyl ester 7.0 g (23.44 mmol) of 7-chloro-5-nitro-4H-benzo[1,4]oxazin-3-ylideneacetic acid ethyl ester are hydrogenated in 300 ml of ethanol with 2 g of Raney nickel at room temperature and under normal pressure for 6 hours. The reaction mixture is filtered and concentrated and the residue is chromatographed on silica gel (dichloromethane/hexane = 7:3) . After crystallisation from ethanollhexane, 5.67 g (21.1 mmol) (90%) of 5-amino-7-chloro-4H-benzo[1,4]oxazin-3-ylideneacetic acid ethyl ester are obtained in the form of fine pink needles; m.p.: 158-159 1H-NMR (CDCI3, 200MHz): 1.28 (t, 3H); 3.55 (sbr, 2H, NH2); 4.17 (q, 2H); 4.51 (s, 2H);
4.72 (s, 1H); 6.42 (d, 1H); 6.45 (d, 1H); 9.95 (sbr, 1H, NH); FD-MS: 268, 270 (M+); TLC:
(dichloromethane/hexane = 7:3) Rf = 0.21.

-65- ~1572~1 e) 5-amino-7-chloro-3,4-dihydro-2H-benzo~1,41oxazin-3-ylacetic acid ethyl ester Preparation analogous to Example 4a; yield 94% yellowish oil; 1H-NMR (CDC13, 300MHz):
1.27 (t, 3H); 2.55 (d, 2H); 3.38 (sbr, 3H, NH, NH2); 3.89-3.95 (m, 2H); 4.14-4.23 (m, 3H);
4.17 (q, 2H); 6.33 (dd, 1H); 6.38 (dd, 1H); 13C-NMR (CDC13, 50MHz): 14.7; 37.2; 47.3;
61.4; 68.8; 108.8; 109.5; 119.7; 125.0; 137.2; 145.8; 171.9; TLC: (dichloromethane) Rf =
0.13.

Example 39: 8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid P,eparalion analogous to Example 5; yield: 98% whitish-beige crystals; melting point: 236-240; 1H-NMR (d6-DMSO, 200MHz): 2.52 (t, 3H); 4.12 (dd, 1H); 4.50 (d, 2H); 4.94 (td, 1H);
6.83 (d, 1H); 6.88 (d, 1H); 12.13 (s, 1H); 12.65 (sbr, 1H); FD-MS: 296, 298 (M+); analysis:
C 44.31% (46.36); H 3.43% (3.43); N 8.57% (9.01); Cl 4.56% (4.58).

Example 40: 8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid sodium salt Preparation analogous to Example 2a.

Example 41: 2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide Preparation analogous to Example 9; yield: 93% pale beige crystals; m.p.: 263-265;
1H-NMR (d6-DMSO, 200MHz): 2.60-2.73 (m, 2H); 4.15 (dd, 1H); 4.50 (d, 2H); 5.10 (m, 1H);
6.82 (d, 1H); 6.88 (d, 1H); 7.05 (t, 1H); 7.30 (t, 2H); 7.55 (d, 2H); 10.05 (s, 1H); 12.10 (sbr, 1H); FD-MS: 371, 373 (M+); analysis: C 55.11% (58.15); H 4.03% (3.80); N 11.11% (11.30);
Cl 9 94% (9 54).

Example 42: In a manner analogous to that described in Example 41 it is also possible to prepare 2-(8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl)-N-methyl-N-phenyl-acetamide; yield: 82% beige crystals; 1H-NMR (d6-DMSO, 300MHz): 2.32 (d, 2H); 3.15 (s, 3H); 4.07 (d, 1H); 4.45 (d, 1H); 4.97 (m, 1H); 6.70 (d, 1H); 6.78 (d, 1H);

-66 215~31 7.28-7.45 (m, 5H); FD-MS: 385, 387 (M+); analysis: C 58.08% (59.15); H 4.34% (4.18);
N 12.00% (10.89); TLC: (dichloromethane/methanol/NH3 = 700:50:1) Rf = 0.37.

Example 43: N-Adamantan-1-yl-2-(8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl)-acetamide Preparation analogous to Example 9. Beige powder; m.p.: 235-238; 1H-NMR (d3-DMSO
200MHz): 1.60-2.05 (m, approx.15H); 2.32-2.46 (m, 2H); 4.10 (dd, 1H); 4.38 (d, 1H); 4.11 (q, 2H); 4.97 (m, 1H); 6.78 (d, 1H); 6.88 (d, 1H); 7.50 (sbr, 1H); 12.10 (sbr, 1H); FD-MS:
429, 431 (M+).

Example 44: 2-(8-Ghloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl)-N, N-bis(2-hydroxy-ethyl)acetamide Preparation analogous to Example 9; yield: 15% white crystals; m.p.: 220-222; 1H-NMR
(d3-DMSO 300MHz): 1.60-1.82 (m, 2H); 3.42 (m, 6H); 4.12 (d, 1H); 4.25 (d, 1H); 4.72 (dbr, 2H); 4.97 (d, 1H); 6.80 (d, 1H); 6.88 (d, 1H); 12.10 (sbr, 1H); FD-MS: 383, 385 (M+) Example 46: 2,3-Dihydro-6H-1-oxa-3a,6-diaza-phenalene-4,5-dione Preparation analogous to Example 38; yield 75% yellow crystals; m.p.: 291; 1H-NMR
(d6 DMSO, 300MHz): 4.03 (t, 2H); 4.32 (t, 2H,); 4.03 (t, 2H); 6.69-6.77 (m, 2H); 7.00-7.05 (m, 1H); 12.02 (s br, 1H, HN); 13C-NMR (d6-DMSO, 74MHz): 40.35; 63.61; 108.08; 110.66;
114.06; 123.97; 126.62; 143.88; 153.29; 154.22; FD-MS: 204 (M+); analysis: C 58.68%
(58.82); H 4.04% (3.95); N 13.33% (13.72).

- 67 ~15 ~ '~ 3 i Example 46: 4,5-Dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Analogous to Example 38; yield: 79% white crystals; m.p.: 256-257; 1H-NMR (d6-DMSO, 300MHz): 1.71 (t, 3H); 2.66 (m, 2H); 4.09 (q, 2H); 4.15 (m,1H); 4.48 (d, 1H); 5.00 (tbr, 1H);
6.74-6.83 (m, 2H); 7.07 (t, 1H); 12.08 (sbr,1H); 13C-NMR (d6-DMSO, 50MHz): 14.1; 33.9;
46.7; 60.8; 66.1; 108.5; 110.7; 113.3; 124.1; 126.8; 143.3; 153.0; 154.2; 170.2;
El-MS: 290 (M+); analysis: C 57.79% (57.93); H 5.03% (4.86); N 9.70% (9.65).

The preparation of the starting materials is described below:

a) 5-nitro-4H-benzor1,41Oxazin-3-ylideneacetic acid ethyl ester Preparation analogous to Example 37c; yield: 97% yellow crystals; m.p.: 142; 1 H-NMR
(CDCI3, 300MHz): 1.33 (t, 3H); 4.28 (q, 2H); 4.66 (s, 2H); 4.94 (s, 1H); 7.16 (t, 1H); 7.19 (d, 1H); 7.89 (dd, 1H); 12.25 (sbr, 1H); FD-MS: 264 (M+); TLC: (petroleum ether/ethyl acetate =9:1) Rf=0.43.

b) 5-amino-3,4-dihydro-2H-benzo~1,41oxazin-3-ylacetic acid ethyl ester 1.0 9 (3.78 mmol) of 5-nitro-4H-benzo[1,4]oxazin-3-ylideneacetic acid ethyl ester is hydrogenated at from room temperature to 50 in 50 ml of ethanol with 0.2 9 of 10% Pd/C
under normal pressure for 50 hours. The reaction mixture is filtered and concentrated and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate = 8:2). 753 mg (3.19 mmol) = 84% of 5-amino-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl-acetic acid ethyl ester are obtained in the form of an orange oil; 1 H-NMR (CDCI3, 200MHz): 1.25 (t, 3H); 2.55 (d, 2H); 3.40 (sbr, 3H); 3.80-3.97 (m, 2H); 4.05-4.15 (m,1H); 4.18 (q, 2H); 6.31-6.40 (m, 2H);
6.60 (t,1 H); FD-MS: 236 (M+); TLC: (ethyl acetate/petroleum ether = 7:3) Rf = 0.17.

Example 47: 7,9-Dibromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Preparation analogous to Example 4b with 2 equivalents of N-bromosuccinimide. Yield:
92% white crystals; m.p.: 285-290; 1H-NMR (d3-DMSO 300MHz): 1.18 (t, 3H); 2.61 (d, 2H);
4.08 (q, 2H); 4.15 (d, 1H); 4.60 (d,1H); 5.02 (m,1H); 7.68 (s, 1H); 11.28 (sbr, 1H); FD-MS:
446, 448, 450 (M+).

` 21~23~

Example 48: 8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Preparation analogous to Example 38; yield 15% beige crystals; m.p.: 222-227; 1H-NMR
(d6-DMSO, 200MHz): 1.17 (t, 3H); 2.62 (m, 2H); 4.08 (q, 2H); 4.12 (m, 1H); 4.50 (d,1H);
4.97 (m, 1H); 6.95 (d, 1H); 7.00 (d, 1H); 12.11 (sbr,1H); FD-MS: 368, 370 (M+).

The preparation of the starting materials is described below:

a) 5-nitro-3,4-dihydro-2H-benzo~1,4loxazin-3-ylacetic acid ethyl ester A solution of 1.0 9 (3.33 mmol) of (2-chloromethyl-4-nitro-2,3-dihydro-benzo-oxazol-2-yl)-acetic acid ethyl ester in 5 ml of THF is added at 0-5 to 145 mg (3.33 mmol) of 55%
sodium hydride dispersion in 5 ml of THF. The mixture is stirred for 15 minutes at 0 and for 1 hour at room temperature. 2.1 9 (33.26 mmol) of sodium cyanoborohydride are then added and the mixture is cooled to 0 and 15 ml of 5N ethanolic hydrochloric acid are added dropwise. The mixture is concentrated on a rotary evaporator and the residue is taken up in dichloromethane and washed with water and saturated sodium chloride solution.
The organic phases are dried over magnesium sulfate and concentrated and the orange crude product is subjected to flash chromatography. 389 mg (1.46 mmol) = 44% of (5-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-acetic acid ethyl ester are obtained in the form of an orange oil; 1 H-NMR (CDCI3, 200MHz): 1.28 (t, 3H); 2.63 (m, 2H); 3.96-4.20 (m, 3H); 4.21 (q, 2H); 6.56 (t, 1H); 7.00 (d, 1H); 7.78 (d, 1H); 8.21 (sbr, 1H, NH); FD-MS: 266 (M+); TLC:
(dichloromethane/hexane = 8:2) Rf = 0.28.

b) 7-bromo-5-nitro-3,4-dihydro-2H-benzo~1,41oxazin-3-ylacetic acid ethyl ester Preparation analogous to Example 4b; yield: 53% orange oil; 1H-NMR (CDC13, 200MHz):
1.29 (t, 3H); 2.61 (d, 2H); 3.98-4.20 (m, 3H); 4.21 (q, 2H); 7.10 (d, 1H); 7.92 (d, 1H); 8.26 (sbr, 1 H, NH); TLC: (dichloromethane/hexane = 8:2) Rf = 0.38 c) 5-amino-7-bromo-3,4-dihydro-2H-benzo~1,41oxazin-3-ylacetic acid ethyl ester 811 mg (3.6 mmol) of tin(ll) chloride dihydrate are added to a solution of 248 mg (0.72 mmol) of (7-bromo-5-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-acetic acid ethyl ester in 10 ml of ethanol and the mixture is stirred at 80 for 5 hours. The solvent is -69 2 15~ 2 3 ~

removed and the residue is taken up in dichloromethane and washed twice with water. The organic phases are dried over magnesium sulfate and concentrated. 225 mg of (5-amino-7-bromo-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-acetic acid ethyl ester are obtained in the form of a brown oil which is used further without being purified.

Example 49: 8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-Phenalen-3acetic acid butyl ester In a water separator, 3.0 9 (10.11 mmol) of 8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl-acetic acid are heated under reflux overnight in approx. 100 ml of CCI4, 1.02 ml (11.12 mmol) of 1-butanol and 27.1 1ll of concentrated sulfuric acid. A further 15 ml of 1-butanol and 100 ~l of concentrated sulfuric acid are added and the mixture is heated for 6 hours. The solvent is removed and the residue is taken up in dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed and the residue is crystallised from dich'oromethane/petroleum ether. 2.59 9 (7.34 mmol) = 73% of 8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-acetic acid butyl ester are obtained in the form of brownish-beige crystals; 1 H-NMR (d6-DMSO, 200MHz):
0.87 (t, 3H); 1.30 (m, 2H); 1.50 (m, 2H); 2.65 (m, 2H); 4.00 (t, 2H); 4.15 (dd, 1H); 4.50 (dbr, 1H); 4.97 (t(m), 1H); 6.81 (d,1H); 6.88 (d,1H); 12.15 (sbr,1H); FD-MS: 352, 354 (M+); TLC:
(dichloromethane/methanol = 19:1) Rf = 0.33.

Example 50: 8-Methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid ethyl ester Preparation analogous to Example 4.

The preparation of the starting materials is described below:

a) (7-methyl-3,4-dihydro-2H-benzo~1,41thiazin-3-yl)-acetic acid ethyl ester Prepared from (7-methyl-4H-benzo[1,4]-3-ylidene)-acetic acid ethyl ester analogously to Example 4a; 1H-NMR (CDCI3, 300MHz): 1.28 (t, 3H); 2.57 (dd,1H); 2.70 (dd, 1H); 2.81 (dd, 1H); 3.01 (dd, 1H); 4.06 (m,1H); 4.18 (q, 2H); 4.67 (sbr, 1H, NH); 6.40 (d,1H); 6.84 (dd, 1H); 6.98 (dd, 2H); TLC: (petroleum ether/ethyl acetate = 9:1) Rf = 0.12.

70 215~

b) 2-(7-methyl-3-ethoxycarbonylmethyl-2,3-dihydro-benzo[1,41thiazin-4-yl)-2-oxo-acetic acid ethyl ester Prepared analogously to Example 4c; 1H-NMR (CDCI3, 300MHz): presumably a mixture of rotamers: 1.09-1.25 (2xt, 3H); 2.56 (m, 2H); 3.00 (ddbr,1H); 3.48 (ddbr, 1H); 4.11 (quart, 4H); 5.49 (m, 1 H); 6.94 (d, 1H); 7.02 (dd,1 H); 7.25 (d,1 H); FD-MS: 371, 373 (M+);
TLC: (hexane/ethyl acetate = 4:1) Rf = 0.21.

Example 52: In a manner analogous to that described in Examples 4 to 48, it is also possible to prepare 8-methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid.

Example 53: In an analogous manner as described in 1 to 52, also the following compounds can be manufactured: beschrieben kann man auch folgende Verbindungen der Formel I
herstellen:

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-ethoxy-acelam.de, melting point 202-204;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-hydroxy-acetamide, melting point 220-221 ;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,2,2-trifluoroethyl)-acetamide, melting point 270-271;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-methoxy-N-methyl-acetamide, melting point 201-202;

2-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-acetic acid ethyl ester, melting point 200-201;

2-[2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H -1 -thia-3a ,6-diaza-phenalen-3-yl)acetylamino)-propionic acid methyl ester, melting point 283-285;

21572~1 2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,3,4,5,6-pentafluorobenzyloxy)-acetamide, melting point 147-148;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-phenoxy-acetamide, melting point 192-193;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N -(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-acetamide, melting point 300-301;

2-[2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)acetylamino)-5-(tertiary-butyloxycarbonylaminomethyl)benzoic acid methyl ester, melting point 94-95;

2-[2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-5-(tertiary-butyloxycarbonylaminomethyl) benzoic acid, melting point ~ 300;

4-[2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-benzoic acid, melting point 298-300;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3,5-bistrifluoromethylphenyl)-acetamide, melting point > 250;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-chlor-5-trifluoromethylphenyl)-acetamide, melting point 192-198;

2-~8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2-methoxyphenyl)-acetamide, melting point > 250;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-trifluoromethoxyphenyl)-acetamide, melting point 14Z-162;

2157~31 2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(4-methoxyphenyl)-acetamide, melting point ~ 250;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,5-dimethoxyphenyl)-acetamide, melting point > 250;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-fluoro-5-trifluoromethyl-phenyl)-acetamide, melting point 163-170;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(4-phenoxyphenyl)-acetamide, melting point 137-145;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(4-(4-chlorphenoxy)phenyl]-acetamide, melting point 104-120;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3,4,5-trimethoxyphenyl)-aceldr"ide, melting point 240-246;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide, melting point 198-205;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3-phenoxyphenyl)-acetamide, melting point 120-128;

2-(8-bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(1 -cyano-1 -methylethyl)-acetamide, melting point.~ 250;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-methoxy-5-methyl-phenyl)-acetamide, melting point.~ 250;

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H- 1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(3-methoxy-phenyl)-acetamide, melting point 98-110;

~1S723~

2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(3,5-dimethoxy-phenyl)-acetamide, melting point 130-138;

8-Methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid, melting point ~ 250;

2-(8-methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-phenyl-acetamide, melting point > 250;

2-(8-methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H -1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(tertiary-butyloxy)-acetamide, melting point ~ 250.

Example 54: Tablets, each comprising 50 mg of active ingredient, for example 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid, or a salt thereof, can be prepared as follows:

Composition (10 000 tablets) active ingredient 500.0 g lactose 500 0 g potato starch 352.0 g gelatin 8.0 9 talc 60.0 g magnesium stearate 10.0 9 silicon dioxide (highly dispersed) 20.0 9 ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silicon dioxide are mixed in and the mixture is compressed to form tablets each weighing 145.0 mg and comprising 50 mg of active ingredient; if desired, the tablets may be provided with dividing notches for finer adaptation of the dose.

~ 74 21572~ 1 Example 55: A sterile-filtered aqueous gelatin solution, containing 20 % cyclodextrins as solubiliser, comprising 3 mg of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl-acetic acid or a salt, for example the sodium salt, thereof as active ingredient, is so mixed, with heating and under aseptic conditions, with a sterile gelatin solution containing phenol as preservative, that 1.0 ml of solution has the following composition:

active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water with 20 % cyclodextrins as solubiliser 1.0 ml Example 56: For the preparation of a sterile dry substance for injection, comprising 5 mg of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid or a salt, for example the sodium salt, thereof, 5 mg of one of the compounds of formula I
mentioned in the preceding Examples as active ingredient are dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol and 20 % cyclodextrins as solubiliser. The solution is sterile-filtered and, under aseptic conditions, introduced into a 2 ml ampoule, frozen and Iyophilised. Before use, the Iyophilisate is dissolved in 1 ml of dis tilled water or 1 ml of physiological saline. The solution is administered intramuscularly or intravenously.
This formulation can also be introduced into double-chamber disposable syringes.
Example 57: For the preparation of 10 000 film-coated tablets, each comprising 100 mg of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid or a salt, for example the sodium salt, thereof, the method of preparation is as follows:

active ingredient 1000 9 corn starch 680 9 colloidal silicic acid 200 9 magnesium stearate 20 9 stearic acid 50 9 sodium carboxymethyl starch 250 9 water q. s.

2 l~7 231 A mixture of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, 50 9 of corn starch and the colloidal silicic acid is processed to form a moist mass with a starch paste consisting of 250 9 of corn starch and 2.2 kg of demineral-ised water. The mass is forced through a sieve of 3 mm mesh size and dried in a fluidised-bed drier at 45 for 30 minutes. The dried granules are then pressed through a sieve of 1 mm mesh size, mixed with a previously sieved mixture (1 mm sieve) of 330 9 of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly biconvex tablets.

Example 58: In a manner analogous to that described in Examples 54 to 57 it is also possible to prepare pharmaceutical compositions comprising another compound according to any one of Examples 1 to 53.

Claims (10)

1. A novel oxa- or thia-aliphatically bridged quinoxaline-2,3-dione of the general formula I

(I), wherein A1 is lower alkylidene or a group of the formula >CH-A4-R4 (Ia), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (Ia), >C=O (Ib) or >CH(OH)-A5-R4 (Ic), A3 is oxy, optionally oxidised thio or a group >C(=O) (Ic), A4 is lower alkylene, A5 is lower alkylene or a direct bond, n is 0 or 1, R1 and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-and/or lower alkanoyl-substituted amino, nitro, lower alkanoyl, free or etherified or esterified hydroxy, free or esterified or amideated carboxy, cyano, optionally halogenated lower alkyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, free or esterified or amideated carboxy, free or esterified phosphono or 5-tetrazolyl, or a salt thereof.

2. A compound according to claim 1 of formula I wherein A1 is lower alkylidene or a group of the formula >CH-A4-R4 (Ia), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (Ia), >C=O (Ib) or >CH(OH)-A5-R4 (Ic), A3 is oxy, thio, sulfinyl or sulfonyl or a group >C(=O) (Ib), A4 is lower alkylene, A5 is lower alkylene or a direct bond, n is 0 or 1, R1 and R2 are each independently of the other hydrogen, amino, lower alkylamino, lower alkanoylamino, di-lower alkylamino, N-lower alkanoyl-N-lower alkyl-amino, nitro, lower alkanoyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, lower alkyl, polyhalo-lower alkyl or halo-gen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, carboxy, lower alkoxycarbonyl, carboxy-lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-oxycarbonyl, benzoyloxy-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkenylcarbamoyl, di-lower alkylcarbamoyl, di-lower alkylamino-lower alkylcarbamoyl, amino-lower alkylamino-lower alkylcarbamoyl, 2-oxoimidazolidin-1-yl-lower alkylcarbamoyl, amino-lower alkylamino-lower alkylenecarbamoyl, 2-oxoimidazolidin-1-yl-lower alkylenecarbamoyl, oxa-lower alkyleneamino-lower alkylcarbamoyl, 3- to 7-membered cycloalkylcarbamoyl, 3- to 7-membered carboxycycloalkylcarbamoyl, 3- to 7-membered lower alkoxycarbonylcycloalkylcarbamoyl, 3- to 7-membered cycloalkyl-lower alkylcarbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridino-carbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpho-linocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, N'-lower alkylpiperazinocarbonyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkylcarbamoyl, unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo-, nitro-, carboxy-, lower alkoxycarbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-lower alkyl-N-phenylcarbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, N-indanylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, N-benzthiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-ylmethylcarbamoyl, N-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl)methylcarbamoyl, mono- or dihydroxy-lower alkylcarbamoyl, mono- or di-lower alkoxy-lower alkylcarbamoyl, polyhalo-lower alkylcarbamoyl, carboxy-lower alkylcarbamoyl, lower alkoxycarbonyl-lower alkylcarbamoyl, dicarboxy-loweralkylcarbamoyl, di-lower alkoxycarbonyl-lower alkylcarbamoyl, cyano-lower alkylcarbamoyl, carboxy-lower alkenylcarbamoyl or lower alkoxycarbonyl-lower alkenylcarbamoyl, N-hydroxycarbamoyl, N-lower alkoxycarbamoyl, N-lower alkoxy-N-lower alkylcarbamoyl, N-lower alkenyloxycarbamoyl or unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo-and/or trifluoromethyl-substituted N-phenyloxycarbamoyl, N-phenyl-lower alkoxycarbamoyl or N-phenyl-lower alkenyloxycarbamoyl, phosphono, lower alkylphosphono, di-loweralkylphosphono or tri-lower alkylphosphono or 5-tetrazolyl, or a salt thereof.

3. A compound according to claim 1 of formula I wherein A1 is straight-chained or branched C1-C7alkylene or a group of the formula >CH-A4-R4 (Ia), A2 is straight-chained or branched C1-C7alkylene or a group of the formula >CH-A4-R4 (Ia) or >CH(OH) -A5-R4 (Ic), A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C1-C7alkylene, A5 is C1-C4alkylene or a direct bond, n is 0 or 1, R1 and R2 are each independently of the other hydrogen, amino, N-C1-C4alkylamino, N-C1-C7alkanoylamino, N,N-di-C1-C4alkylamino, N-C1-C7alkanoyl-N-C1-C4alkylamino, nitro, N-C1-C4alkanoyl, pivaloyl, hydroxy, N-C1-C4alkanoyloxy, pivaloyloxy, C1-C4alkoxy, C3-C4alkenyloxy, C3-C4alkynyloxy, carboxy, C1-C4alkoxycarbonyl, carbamoyl, cyano, C1-C4alkyl, halogen or trifluoromethyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, carboxy, C1-C7alkoxycarbonyl, carboxy-C1-C4alkoxycarbonyl, C1-C4-alkoxycarbonyl-C1-C4alkoxycarbonyl, N-C1-C4alkanoyloxy-C1-C4alkoxycarbonyl, pivaloyloxy-methoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoro-methyl-substituted phenyloxycarbonyl, benzoyloxy-C1-C4alkoxycarbonyl or phenyl-C1-C4alkoxycarbonyl, carbamoyl, N-C1-C4alkylcarbamoyl, C2-C4alkenylcarbamoyl, N,N-di-C1-C4 alkylcarbamoyl, C3-C7cycloalkylcarbamoyl, carboxy-C3-C7cycloalkylcarbamoyl, C1-C4alkoxy-carbonyl-C3-C7cycloalkylcarbamoyl, 3- to 7-membered N-(C3-C6cycloalkyl)-C1-C4alkyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridino-carbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, N'-C1-C4alkyl-piperazinocarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C1-C4alkylcarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo-, trifluoromethyl-, amino-, C1-C4alkoxycarbonylamino-, nitro-, carboxy-, C1-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, phenyl-, phenyloxy-and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-C1-C4alkyl-N-phenyl-carbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, N-indanylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, N-benzthiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-ylmethylcarbamoyl, N-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl)methylcarbamoyl, N-(hydroxy-C2-C4alkyl)carbamoyl, N,N-di(hydroxy-C2-C4-alkyl)carbamoyl, C1-C4alkoxy-C1-C4alkylcarbamoyl, di-C1-C4alkoxy-C1-C4alkylcarbamoyl, carboxy-C1-C4alkylcarbamoyl, C1-C4alkoxycarbonyl-C1-C4alkylcarbamoyl, polyhalo-C2-C4alkylcarbamoyl, dicarboxy-C1-C4alkylcarbamoyl, di-C1-C4alkoxycarbonyl-C1-C4alkylcarbamoyl, cyano-C1-C4alkylcarbamoyl, carboxy-C2-C4alkenylcarbamoyl, C1-C4alkoxycarbonyl-C2-C4alkenylcarbamoyl, N-hydroxycarbamoyl, N-C1-C4alkoxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyloxycarbamoyl, N-phenyl-C1-C4alkoxycarbamoyl or N-phenyl-C2-C4alkenyloxycarbamoyl, phosphono, C1-C4alkylphosphono, di-C1-C4alkylphosphono, tri-C1-C4alkylphosphono or 5-tetrazolyl, or a salt thereof.

4. A compound according to claim 1 of formula I wherein one of the radicals A1 and A2 is a group of the formula >CH-A4-R4 (Ia) and the other is straight-chained or branched C1-C4alkylene, A3 is oxy, thio, sulfinyl or sulfonyl, A4 is straight-chained or branched C1-C4alkylene, n is 0, R1 and R2 are each independently of the other hydrogen, nitro, N-C1-C4alkanoyl, pivaloyl, hydroxy, C1-C4alkoxy, carboxy, C1-C4alkoxycarbonyl, carbamoyl, cyano, C1-C4alkyl, halogen, trifluoromethyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, C1-C7alkoxycarbonyl, C1-C4alkoxycarbonyl-C1-C4alkoxycarbonyl, N-C1-C4alkanoyloxy-C1-C4alkoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyloxycarbonyl, benzoyloxy-C1-C4alkoxycarbonyl or phenyl-C1-C4alkoxycarbonyl, carbamoyl, N-C1-C4alkylcarbamoyl, C2-C4alkenylcarbamoyl, N,N-di-C1-C4alkylcarbamoyl, C3-C7cycloalkylcarbamoyl, C1-C4alkoxy-carbonyl-C3-C7cycloalkylcarbamoyl, 3- to 7-membered N-(C3-C6cycloalkyl)-C1-C4alkyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, azaridinocarbonyl, 2-methylazaridino-carbonyl, 2,3-dihydroindolin-1-ylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C1-C4alkylcarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo-and/or trifluoromethyl-, nitro-, carboxy-, C1-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, phenyl-, phenyloxy- and/or trifluoromethyl-substituted N-phenylcarbamoyl or N-C1-C4alkyl-N-phenyl-carbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, fur-2-ylmethylcarbamoyl, thien-2-ylmethylcarbamoyl or thiazol-2-ylmethylcarbamoyl, C1-C4alkoxy-C1-C4alkyl-carbamoyl, di-C1-C4alkoxy-C1-C4alkylcarbamoyl, carboxy-C1-C4alkylcarbamoyl, C1-C4alkoxy-carbonyl-C1-C4alkylcarbamoyl, dicarboxy-C1-C4alkylcarbamoyl, di-C1-C4alkoxycarbonyl-C1-C4-alkylcarbamoyl, C1-C4alkoxycarbonyl-C2-C4alkenylcarbamoyl, N-hydroxycarbamoyl, N-C1-C4alkoxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyl-C1-C4alkoxy-carbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl, phosphono or 5-tetrazolyl, or a salt thereof.

5. A compound according to claim 1 of formula I wherein one of the radicals A1 and A2 is a group of the formula >CH-A4-R4 (Ia) and the other is methylene, A3 is thio, A4 is methylene, n is 0, R1 and R2 are each independently of the other hydrogen, C1-C4alkyl, trifluoromethyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, C1-C4alkoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted benzoyloxy-C1-C4alkoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-, nitro-, carboxy-, C1-C4alkoxycarbonyl- and/or trifluoromethyl-substituted N-phenylcarbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydronaphthylcarbamoyl, furyl-2-carbamoyl, thien-2-yl-carbamoyl, thiazol-2-ylcarbamoyl, bicyclol2.2.1]heptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, N-C1-C4alkoxycarbamoyl, N-C2-C4alkenyl-oxycarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoro-methyl-substituted N-phenyl-C1-C4alkoxycarbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl or 5-tetrazolyl, or a salt thereof.

6. A compound according to claim 1 of formula I' (I'), wherein R1 and R2 are each independently of the other hydrogen, C1-C4alkyl, trifluoromethyl or halogen, R3 is hydrogen, and R4 is hydrogen, carboxy, C1-C4alkoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted benzoyloxy-C1-C4alkoxycarbonyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-, nitro-, carboxy-, C1-C4alkoxycarbonyl-, such as methoxy- or ethoxy-carbonyl-, and/or trifluoro-methyl-substituted N-phenylcarbamoyl, naphthylcarbamoyl, 5,6,7,8-tetrahydro-naphthylcarbamoyl, furyl-2-carbamoyl, thien-2-ylcarbamoyl, thiazol-2-ylcarbamoyl, bicyclo[2.2.1]heptyl-, bicyclo[2.2.2]octyl- or adamantyl-carbamoyl, 3-aza-2-oxo-cycloheptylcarbamoyl, N-C1-C4alkoxycarbamoyl, N-C2-C4alkenyloxycarbamoyl, unsubstituted or C1-C4alkyl-, C1-C4alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted N-phenyl-C1-C4alkoxycarbamoyl, N-phenyl-C2-C4alkenyloxycarbamoyl or 5-tetrazolyl, or a salt thereof.

7. 2-(3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;

2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-benzoic acid;
3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
3(S)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
Dihydro-6H-1-oxa-3a,6-diaza-phenalene-4,5-dione;
4,5-Dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl-N-phenyl-acetamide;
4,5-Dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
4,5-Dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid;

8-Bromo-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Bromo-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
8-Bromo-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-yl-N-phenyl-acetamide;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-yl-N-phenyl-acetamide;
8-Chloro-1,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Chloro-1 ,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1 -thia-3a,6-diaza-phenalen-3-ylacetic acid;
8-Chloro-1 ,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1 -thia-3a,6-diaza-phenalen-3-yl-N-phenyl-acetamide;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl-N-phenyl-acetamide;
8-Chloro-6H- 1 -thia-3a,6-diaza-phenalene-3,4, 5-trione;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-2-ylacetamide;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-2-ylacetonitrile;
8-Bromo-2-(1 H-tetrazol-5-ylmethyl)-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;

8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid ethyl ester;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-2-ylacetic acid N-phenylamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetylamino-acetic acid;
1 -[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-cyclopropane-carboxylic acid methyl ester;
1 -[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-cyclopropane-carboxylic acid;
2,2-Dimethyl-propionic acid (8-bromo-4, 5-dioxo-2,3, 5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetoxymethyl ester;
2-(3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;
2-(8-Bromo-1,1 ,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H ,4H-6-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-methyl-N-phenyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-thiazol-2-yl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyclo-propylmethyl-acetamide;
2-(8-Bromo-4,5-dioxo-2 ,3 ,5,6-tetrahydro-4H- 1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyclopropyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N, N-dibutyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2-oxo-azepan-3-yl)-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,2-dimethoxy-ethyl)-acetamide;

2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(5,6,7,8-tetrahydro-naphthalen-1 -yl)-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-furan-2-ylmethyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2-methoxyethyl)-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-tert-butoxy-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-prop-2-ynyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-cyano-methyl-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-methoxy-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide;
2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;
2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl)-N-methyl-N-phenyl-acetamide;
2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl)-N,N-bis(2-hydroxy-ethyl)acetamide;
2-(8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-phenyl-acetamide;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-3,3-dimethyl-butyric acid tert-butyl ester;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-malonic acid dimethyl ester;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-benzoic acid methyl ester;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-3,3-dimethyl-butyric acid;
3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;

3(R)-8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
3-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-propionic acid methyl ester;
3-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-propionic acid;
4,5-Dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
4-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-benzoic acid methyl ester;
7,9-Dibromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Bromo-1,1,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Bromo-1,1,4,5-tetraoxo-2,3,5,6-tetrahydro-1 H,4H-6-thia-3a,6-diaza-phenalen-3-ylacetic acid;
8-Bromo-3-(2-oxo-2-piperidin-1 -yl-ethyl)-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;
8-Bromo-3-(2H-tetrazol-5-ylmethyl)-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;
8-Bromo-3-[2-(2,3-dihydro-indol-1 -yl)-2-oxo-ethyl]-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;
8-Bromo-3-[2-(2-methyl-aziridin-1 -yl)-2-oxo-ethyl]-2,3-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid.
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid methoxycarbonyl-methyl ester;
8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-ylacetonitrile;
8-Chloro-2,3,5,6-dihydro-6H-1 -thia-3a,6-diaza-phenalene-4,5-dione;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid;

8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,6-diaza-phenalen-3-ylacetic acid butyl ester;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-Chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
8-methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid ethyl ester;
8-methyl-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
3-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetyl-amino]-but-2-enoic acid methyl ester;
Benzoic acid (8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)--acetoxymethyl ester;
1N-Adamantan-1-yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide;
1N-Adamantan-1-yl-2-(8-chloro-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -oxa-3a,6-diaza-phenalen-3-yl)-acetamide;
1 N-Adamantan-2-yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-acetamide;
1 N-Allyl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide;
1N-Allyloxy-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide;
1N-Benzyloxy-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide;
1N-Bicyclo[2.2.1]hept-2-yl-2-(8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-yl)-acetamide;
12,3-Dihydro-6H-1-oxa-3a,6-diaza-phenalene-4,5-dione;
2-(8-Bromo-4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-ethoxy-acetamide;
2-(8-Bromo4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-hydroxy-acetamide;
2-(8-Bromo-4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,2,2-trifluoroethyl)-acetamide;

2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-methoxy-N-methyl-acetamide;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-acetic acid ethyl ester;
2-[2-(8-Bromo-4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-propionic acid methyl ester;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,3,4,5,6-pentafluorobenzyloxy)-acetamide;
2-(8-Bromo-4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-phenoxy-acetamide;
2-(8-Bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-7-ylmethyl)-acetamide;
2-[2-(8-Bromo4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-5-(tertiary butyloxycarbonylaminomethyl) benzoic acid methyl ester;
2-[2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)acetylamino)-5-(tertiary butyloxycarbonylaminomethyl) benzoic acid;
4-[2-(8-Bromo-4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)acetylamino)-benzoic acid;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3,5-bistrifluoromethylphenyl)-acetamide;
2-(8-Bromo4,5-dioxo-2,3,5 ,6-tetrahydro-4H -1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-chloro-5-trifluoromethylphenyl)-acetamide;
2-(8-Bromo4,5-dioxo-2 ,3,5,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-methoxyphenyl)-acetamide;
2-(8-Bromo-4,5-dioxo-2 ,3,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-trifluoromethoxyphenyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(4-methoxyphenyl)-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2,5-dimethoxyphenyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(2-fluoro-5-trifluoromethyl-phenyl)-acetamide;

2-(8-Bromo4 ,5-dioxo-2 ,3,5 ,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(4-phenoxyphenyl)-acetamide;
2-(8-Bromo-4,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N -(4-(4-chlorophenoxy)phenyl]-acetamide;
2-(8-Bromo-4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3,4,5-trimethoxyphenyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2 ,3 ,5,6-tetrahydro4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2 ,3 ,5 ,6-tetrahydro4H -1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3-phenoxyphenyl)-acetamide, 2-(8-Bromo-4,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(1 -cyano-1-methylethyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(2-methoxy-5-methyl-phenyl)-acetamide;
2-(8-Bromo-4 ,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3-methoxy-phenyl)-acetamide;
2-(8-Bromo4,5-dioxo-2,3,5,6-tetrahydro-4H-1 -thia-3a,6-diaza-phenalen-3-yl)-N-(3,5-dimethoxy-phenyl)-acetamide;
8-Methyl4,5-dioxo-2,3,5,6-tetrahydro-4H-1-thia-3a,6-diaza-phenalen-3-ylacetic acid;
2-(8-Methyl-4,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-phenyl-acetamide or 2-(8-Methyl-4,5-dioxo-2 ,3 ,5 ,6-tetrahydro-4H-1 -thia-3a ,6-diaza-phenalen-3-yl)-N-(tertiary butyloxy)-acetamide or in each case a salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof together with customary pharmaceutical excipients and carriers.

9. A process for the preparation of a novel oxa- or thia-aliphatically bridged quinoxaline-2,3-dione of the general formula I

(I), wherein A, is lower alkylidene or a group of the formula >CH-A4-R4 (Ia), A2 is lower alkylidene or a group of the formula >CH-A4-R4 (la), >C=O (Ib) or >CH(OH)-A5-R4 (Ic), A3 is oxy, optionally oxidised thio or a group >C(=O) (Ib), A4 is lower alkylene, A5 is lower alkylene or a direct bond, n is 0 or 1, R1 and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-and/or lower alkanoyl-suhstituted amino, nitro, lower alkanoyl, free or etherified or esterified hydroxy, free or esterified or amideated carboxy, cyano, optionally halogenated lower alkyl or halogen, R3 is hydrogen or hydroxy, and R4 is hydrogen, cyano, free or esterified or amideated carboxy, free or esterified phosphono or 5-tetrazolyl, or a salt thereof, which process comprises:
a) cyclising intramolecularly a compound of formula II

(II), wherein one of the radicals Y1 and Y2 is a group of the formula -C(=O) -Y3 (IIa) wherein Y3 is a functionally modified carboxy group, and the other is hydrogen, or in each case a salt thereof, or b) cyclising intramolecularly a compound of formula III

(III), wherein X1 is a group of the formula -A2-(CH2)n-CH(Y3)-A4-R4 (IIIa) or -A2- (CH2)n-CH=A'4-R4 (IIIb) wherein Y3 is a nucleofugal leaving group and A'4 is a lower alkanylylidene group corresponding to the group A4, X2 is hydrogen and R1, R2, R3, A1, A2, A3 and A4 are as defined, or c) in a compound of formula IV

(IV), wherein A'1 is a group of the formula >C=A'4-R4 (IIIa) wherein A'4 is lower alkanylylidene, reducing the extracyclic double bond to a single bond, and in each case, if desired, converting a resulting compound into a different compound of formula 1, separating a mixture of isomers obtainable in accordance with the process into the components and isolating the preferred isomer, and/or converting a free compound obtainable in accordance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound.

10 The use of a compound according to any one of claims 1 to 7 in the treatment of neuro-degenerative disorders arising from stroke, hypoglycaemia, anoxia or symptoms of cerebral paralysis, cerebral ischaemia, cerebral ischaemia in cardiosurgery or cardiac arrest, peri-natal asphyxia, epileptic fits, Huntington's chorea, Alzheimer's disease and Parkinson's disease, amyotrophic lateral sclerosis, spinal and cerebral trauma, and also symptoms of poisoning resulting from neurotoxins or drug abuse, and ischaemic disorders of the eyes, vascular and muscular spasms, migraine or local or general spasticity, convulsions, epilepsy, anxiety states and pain, and trigeminal neuralgias.