JPH11508902A - New quinoxaline- and quinoxalinealkane-phosphonic acids - Google Patents

Abstract

(57) [Summary] Formula I Wherein R ₁ is a free or partially esterified phosphono, R ₂ and R ₃ are independently hydrogen or an aliphatic group, and groups R ₄ , R ₅ and R ₆ are independently hydrogen, an aliphatic hydrocarbon. Hydrogen group, free or etherified hydroxy, free or etherified mercapto or oxidized free or etherified mercapto, unsubstituted or aliphatically substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amide Quinoxaline- and quinoxalinylalkane-phosphonic acids and their isomers and / or salts, wherein the sulfamoyl bromide, halogen or trifluoromethyl, and X is a divalent aliphatic group, have NMDA-antagonistic properties, Can be used to treat pathological conditions responsive to inhibition of the NMDA-sensitive receptor.

Description

DETAILED DESCRIPTION OF THE INVENTION         New quinoxaline- and quinoxalinealkane-phosphonic acids   The present invention provides compounds of formula I (In the formula, R₁Is a free or partially esterified phosphono, R_TwoAnd R_ThreeIs independently hydrogen or an aliphatic group, Group R_Four, R_FiveAnd R₆Are independently of each other hydrogen, an aliphatic hydrocarbon radical, free or Hydroxy, free or etherified mercapto or oxidized free or -Mercapto telluride, unsubstituted or aliphatically substituted amino, nitro, free Or esterified or amidated carboxy, cyano, free or amidated sulfo Famoyl, halogen or trifluoromethyl, and X is a divalent aliphatic group] Novel quinoxaline- and quinoxalinylalkane-phosphonic acids and their mutual Isomers and / or salts, pharmaceutical compositions containing the novel compounds and pharmaceuticals It relates to its use as an active ingredient.   Free or esterified carboxy is, for example, carboxy, lower alkoxy Rubonyl, or unsubstituted or lower alkyl, lower alkoxy, hydroxy, ha Phenyl-lower substituted by logen and / or trifluoromethyl Alkoxycarbonyl.   Free or partially esterified phosphonos are, for example, lower alkyl phosphonos. You.   Aliphatic group R₁And / or R_TwoIs, for example, lower alkyl, lower alkenyl or Or a lower alkynyl group; a group R₁O and R_TwoO is, for example, hydroxy or lower Alkoxy, but also lower alkenyloxy or lower alkynyloxy. Can get.   Aliphatic hydrocarbon groups are, for example, lower alkyl or lower alkenyl groups, Or a lower alkynyl group.   Free or etherified mercapto or oxidized free or etherified mercapto Is, for example, mercapto, lower alkylthio, lower alkanesulfinyl or Lower alkanesulfonyl, but lower alkenylthio, lower alkynylthio , Lower alkene sulfinyl, lower alkene sulfonyl, lower alkyne sulfin It can also be ynyl or lower alkynesulfonyl.   Amino unsubstituted or substituted with an aliphatic group is, for example, amino or N-mono. Or N, N-di-lower alkylamino.   Free or esterified or amidated carboxy is, for example, carboxy, low Lower alkoxycarbonyl; unsubstituted or lower alkyl, lower alkoxy, hydro Phenyl substituted by xy, halogen and / or trifluoromethyl Lower alkoxycarbonyl; carbamoyl, N-mono- or N, N-di-lower Alkylcarbamoyl, or N-phenylcarbamoyl or N-phenyl- N-lower alkyl-carbamoyl, each having an unsubstituted or phenyl moiety Lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoro Substituted by oromethyl.   Free or amidated sulfamoyl is, for example, sulfamoyl or N-mo No- or N, N-di-lower alkylsulfamoyl.   Halogen is a source of up to 35 (inclusive), for example, fluorine, chlorine or bromine. It is a halogen having a child number.   The divalent aliphatic group includes, for example, lower alkylidene, lower alkylene, lower alkenyl. It is a len or lower alkynylene group.   In the above and below, "lower" groups and compounds are, for example, up to 7 (inclusive) It is understood that groups and compounds preferably contain up to 4 (inclusive) carbon atoms.   Di-lower alkylamino is, for example, dimethylamino, diethylamino, dip Di-C such as propylamino, diisopropylamino or dibutylamino₁− C_FourAlkylamino.   Di-lower alkylcarbamoyl is, for example, dimethylcarbamoyl, diethyl Carbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl or dicarbamoyl Di-C such as butylcarbamoyl₁-C_FourAlkylcarbamoyl.   Di-lower alkylsulfamoyl is, for example, dimethylsulfamoyl, die Tilsulfamoyl, dipropylsulfamoyl, diisopropylsulfamoy Or di-C such as dibutylsulfamoyl₁-C_FourAlkylsulfamoyl It is.   Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbo Nyl, propyloxycarbonyl, isopropyloxycarbonyl or butyl C such as oxycarbonyl₁-C₇Alkoxycarbonyl, preferably C₁-C_Four Alkoxycarbonyl, but isobutyloxycarbonyl, secondary butyloxy Cicarbonyl, tertiary butyloxycarbonyl or pentyloxycarbonyl, It can also be a hexyloxycarbonyl or heptyloxycarbonyl group.   Lower alkane sulfinyl is, for example, methanesulfinyl, ethanesulfinyl C such as nil, propanesulfinyl or butanesulfinyl₁-C₇Arca Sulfinyl, preferably C₁-C_FourAlkanesulfinyl but pentane It can be a sulfinyl, hexanesulfinyl or heptanesulfinyl group You.   Lower alkane sulfonyl is, for example, methanesulfonyl, ethanesulfonyl C such as nil, propanesulfonyl or butanesulfonyl₁-C₇Arca Sulfonyl, preferably C₁-C_FourAlkanesulfonyl, but pentane It can also be a sulfonyl, hexanesulfonyl or heptanesulfonyl group You.   Lower alkene sulfinyl is, for example, prop-2-enesulfinyl or C, such as but-2-enesulfinyl_Three-C_FourAlkenesulfinyl.   Lower alkenesulfonyl is, for example, prop-2-ensulfonyl or C, such as but-2-enesulfonyl_Three-C_FourAlkenesulfonyl.   Lower alkenyl is, for example, C 4 such as allyl or methallyl._Three-C_FourAlkene It is.   Lower alkenylene can be straight or branched and can be attached at any desired position, e.g. For example, a linear or branched C_Two-C₇Alkenylene, especially vinylene, 1,3-prop C such as -2-enylene or 1,4-but-2-enylene_Two-C_FourAlkylene It is.   Lower alkenyloxy is, for example, such as allyloxy or methallyloxy. Na C_Three-C_FourAlkenyloxy.   Lower alkynyl can be, for example, a C such as propargyl._Three-C_FourAlkynyl .   Lower alkynyloxy can be, for example, C 2 O, such as propargyloxy._Three-C_FourAl Quinyloxy.   Lower alkynylthio is, for example, a C such as propargylthio._Three-C_FourAlkini Lucio.   Lower alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyl C such as pyroxy or butyloxy₁-C₇Alkoxy, preferably C₁− C_FourAlkoxy, but isobutyloxy, secondary butyloxy, tertiary butyloxy It can also be a xy or pentyloxy, hexyloxy or heptyloxy group You.   Lower alkyl is, for example, especially methyl or, secondarily, ethyl, propyl, i. C such as isopropyl or butyl₁-C₇Alkyl, preferably C₁-C_FourArchi But isobutyl, secondary butyl, tertiary butyl or pentyl, hexyl, etc. Or a heptyl group such as C_Five-C₇It can also be an alkyl group.   Lower alkylamino is, for example, especially methylamino, ethylamino, propyl C such as amino, isopropylamino or butylamino₁-C₇Alkylam No, C₁-C_FourAlkylamino, but isobutylamino, secondary butylamino, Tertiary butylamino or pentylamino, hexylamino or heptylamino C as a group_Five-C₇It can also be an alkylamino group.   Lower alkylcarbamoyl is, for example, methylcarbamoyl, ethylcarbamoyl Yl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl Like C₁-C₇Alkylcarbamoyl, preferably C₁-C_FourAlkyl carbamo But isobutylcarbamoyl, secondary butylcarbamoyl, tertiary butyl Carbamoyl or pentylcarbamoyl, hexylcarbamoyl or hepti C such as rucarbamoyl group_Five-C₇It can also be an alkylcarbamoyl group.   Lower alkylidene can be straight or branched, for example, methylene, ethyl Den, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene Linear or branched C such as₁-C_FourAlkylidene.   Lower alkylene is, for example, straight chain C₁-C_FourAlkylene, for example of the formula-(CH_Two)_n− (Ia) (wherein n is, for example, 2, 3 or 4).   Lower alkynylene is, for example, straight chain C_Two-C_FourAlkynylene, for example of the formula -C≡ ( CH_Two)_n-2-(Ic) (where n is, for example, 2, 3 or 4).   Lower alkenylene is, for example, a straight chain C_Two-C_FourAlkenylene, for example of the formula -CH = CH- (OH_Two)_n-2-(Ib) (where n is, for example, 2, 3 or 4).   Lower alkyl phosphonos include, for example, methyl phosphono, ethyl phosphono, propyl C such as luphosphono, isopropylphosphono or butylphosphono₁-C₇Al Quilphosphono, but isobutylphosphono, secondary butylphosphono, tertiary butyl Phosphono or pentylphosphono, hexylphosphono or heptylphosphono group Like C_Five-C₇It can also be an alkylphosphono group.   Lower alkylthio is, for example, methylthio, ethaneylthio, propylthio or Is C such as butylthio₁-C₇Alkylthio, preferably C₁-C_FourAlkylthio But can also be a pentylthio, hexylthio or heptylthio group.   N-phenyl-N-lower alkyl-carbamoyl is, for example, N-methyl-N -Phenyl-carbamoyl, N-ethyl-N-phenyl-carbamoyl, N-phenyl Enyl-N-propyl-carbamoyl or N-butyl-N-phenylcarbamo N-phenyl-C such as yl₁-C_FourAlkyl-carbamoyl.   Phenyl-lower alkoxycarbonyl is, for example, benzyloxycarbonyl Or unsubstituted such as α-phenylethoxycarbonyl or C₁-C_FourAlkyl -, C₁-C_FourAlkoxy-, hydroxy-, halo- and / or trifluoro Methyl-substituted phenyl-C₁-C_FourAlkoxycarbonyl.   Tautomers are particularly preferred where the group R₁And R_TwoOf the formula I wherein one or both are hydrogen Is considered. Such tautomers of the compounds of formula I have the structural formula I ', I "or I"' Is best described by   The compounds of the formula I may form salts with bases or may contain at least one group R_Four, R_Five And R₆Is an unsubstituted or aliphatically substituted amino, Can be formed.   Salts of a compound of Formula I with a base include, for example, pharmacologically acceptable bases such as, for example, Non-toxic metal salts derived from the metals of the groups Ia, Ib, IIa and IIb, such as alkali metal salts, Especially sodium or potassium salts, alkaline earth metal salts, especially calcium or Salts with magnesium salts, and also ammonia or organic amines or quaternary amines Monium base, optionally C-hydroxylated aliphatic amine, especially ethanol , Diethanol- or triethanol-amine, tris (hydroxymethyl) meth Mono-, di- or tertiary amines such as tylamine or 2-hydroxy-tert-butylamine Or tri-lower alkylamines such as methyl-, ethyl- or diethyl- A min, mono-, di- or tri- (hydroxy-lower alkyl) amine, or 2 N- (hydroxy) such as-(dimethylamino) ethanol or D-glucamine -Lower alkyl) -N, N-di-lower alkylamine or N- (polyhydroxy -Lower alkyl) -N-lower alkylamine, or quaternary aliphatic ammonium amine. Ammonium salt with droxide, for example tetrabutylammonium hydroxide It is.   Depending on the total salt and the number of acid groups, the partial salt, ie, 1 mole per mole of acid of formula I , 2 or 3, preferably 2 equivalents of base, or 1,2 per mole of base of formula I Or also contains 3 equivalents, preferably 1 equivalent, of both salts of the acid.   Use of pharmacologically unacceptable salts is also possible for isolation or purification purposes It is. Only pharmacologically acceptable, non-toxic salts can be used therapeutically and are therefore No.   The compounds of the formula I have potent pharmacological properties. In particular, they are the N-mes of warm-blooded animals. Chill-D-aspartate-sensitive (NMDA-sensitive) excited amino acid receptor Promotes and has a selective antagonism. In vitro, for example, Sills M., Fagg G., Pozza M., Angst Ch., Brundish D., Hur t S., Wilusz E., Williams M .: [^ThreeH] CGP39653: In rat brain N-methyl-D-aspartate antagonis with low nanomolar affinity in Radioligand. Eur. J. Pharmacol. 192, pages 19-24 (1991). It can be proved by the following experimental method. In this experiment, L-^ThreeNM of H-glutamic acid The extent to which binding to the DA-sensitive receptor is inhibited is measured. 50% replacement (IC₅₀) The required concentration is in the nano to low milli-molar range, ie from about 0.0005 to 1 It is in the range of μmmol. The NMDA-antagonistic properties of the new compounds, however, However, its inhibitory effect on NMDA-induced convulsions in vivo, for example in mice Can also be proved.   Due to its properties, compounds of the formula I and pharmaceutically acceptable salts thereof are therefore Pathological conditions in response to inhibition of NMDA-sensitive receptors, such as cerebral ischemia, and Disorders, such as ischemic disorders of the eyes and eyes, and migraines or local or general spasticity Very useful for the treatment of vascular and muscle spasms such as spasms, and especially spasms such as epilepsy Suitable for.   The anticonvulsant effect of the present invention may be, for example, in mice induced by electric shock or auditory spasticity. Can be measured for an enhanced protective effect against convulsions, or Use of a modified electric shock mouse model or Chapman et al., Arzneimittel 34, 1261 (1984). Electric In the shock mouse model, for example, the compound of the present invention comprises about 1 to 10 mg / kg. i.p.ED₅₀Having.   Anticonvulsant characteristics of a compound provided by the present invention for use in the treatment of migraine Sex is described, for example, in R. Marannes et al, Brain Res. 457, 226 (1988). Can basically be demonstrated by the inhibitory-inhibitory action in rats according to the experimental method described above. In this model, the compounds provided by the present invention have a "diffusion suppression" threshold. Lower the dose to about 3 to 30 mg / kg i.p.   The invention particularly relates to R₁Is lower alkylphosphono, R_TwoAnd R_ThreeAre independently of each other hydrogen, lower alkyl, lower alkenyl or Lower alkynyl, such as pargyl, Group R_Four, R_FiveAnd R₆Are independently of each other hydrogen, lower alkyl, lower alkenyl , Lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, lower Alkynyloxy, mercapto, lower alkylthio, lower alkanesulfinyl , Lower alkanesulfonyl, lower alkenylthio, lower alkynylthio, lower Alkenesulfinyl, lower alkanesulfonyl, amino, lower alkylamino No, di-lower alkylamino, nitro, carboxy, lower alkoxycarbonyl Unsubstituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and Bi / Or trifluoromethyl-substituted phenyl-lower alkoxycarbonyl; Moyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl; phenyl Carbamoyl or N-phenyl-N-lower alkylcarbamoyl, each of which It is an unsubstituted or phenyl moiety substituted with lower alkyl, lower alkoxy, hydroxy, Substituted with halogen and / or trifluoromethyl; cyano, phospho , Lower alkyl phosphono, di-lower alkyl phosphono, halogen or triflu Oromethyl, and X is lower alkylidene, lower alkylene, lower alkenylene or lower alkynyl Is Len It relates to compounds of formula I and tautomers and / or salts thereof.   The invention provides, inter alia, R₁Is phosphono, R_TwoAnd R_ThreeAre independently of each other hydrogen or C such as methyl or ethyl₁-C_Four Alkyl, Group R_Four, R_FiveAnd R₆Are independently of each other C, such as hydrogen, methyl or ethyl₁− C_FourC such as alkyl, methoxy or ethoxy₁-C_FourAlkoxy, methylthio C like Oh₁-C_FourAlkylthio, amino, nitro, carboxy, methoxy- Or C such as ethoxy-carbonyl₁-C_FourAlkoxycarbonylcarbamoyl , C such as methylcarbamoyl₁-C_FourAlkyl carbamoyl, dimethyl carb Mo-like di-C₁-C_FourAlkylcarbamoyl, halogen or trifluoro Methyl, and X is methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- Or C, such as 2,2-butylidene₁-C_FourAlkylidene, C₁-C_FourAlkylene For example, the formula-(CH_Two)_n-(Ia), C_Two-C_FourAlkenylene, for example of the formula -CH = CH- (CH_Two)_n-2-(Ib) or C_Two-C_FourAlkynylene, for example, of the formula -C≡ (C H_Two)_n-2-(Ic), in each case n is for example 2, 3 or 4 It relates to compounds of formula I and tautomers and / or salts thereof.   The invention particularly relates to R₁Is phosphono, R_TwoIs hydrogen or C such as methyl or ethyl₁-C_FourAlkyl, R_ThreeIs hydrogen, Group R_Four, R_FiveAnd R₆Are independently of each other C, such as hydrogen, methyl or ethyl₁− C_FourAlkyl, nitro, halogen or trifluoromethyl, and X is C, such as methylene or ethylidene₁-C_FourAlkylidene or a compound of the formula-(C H_Two)_n-(Ia), -CH = CH- (CH_Two)_n-2-(Ib) or -C≡ (CH2)_n-2− ( Groups of Ic), in each case n is 2, 3 or 4 It relates to compounds of formula I and tautomers and / or salts thereof.   The invention relates in particular to the compounds of the formula I and their salts, in particular the pharmacologically acceptable compounds described in the examples. Pertaining to its salts.   The process for preparing the compounds of the present invention comprises a phosphono-protecting group and, if desired, a group R_B And / or R_cWith the formula II [Wherein, R_AIs a protected phosphono group, R_BIs the group R_TwoOr a hydroxy-protecting group, R_cIs the base R_ThreeOr a hydroxy-protecting group, and R_Four, R_FiveAnd R₆Is as defined) From the compound of formula I and, if desired, the resulting compound is converted to a different compound of formula I , And the isomer mixture of the compound obtained by this method is separated into each component. The free compound isolated in the preferred isomer and / or obtained in this way can be converted to a salt, Or converting the salt obtained by this method into the free compound.   Suitable as phosphono- and hydroxy-protecting groups are known in the art. Customary phosphono- and hydroxy-protecting groups. Protected phosphono group R_AIs special Ester forms, such as di-lower alkylphosphono or unsubstituted or lower alkyl Ru-, lower alkoxy-, halo- and / or nitro-substituted diphenyl- Is an esterified phosphono such as a dibenzyl-phosphono group. Protected hydroxy Group R_BAnd R_cSuitable as is a group R₁And R_TwoIn addition to tri-lower al Kirsilyl, for example silyl groups such as trimethylsilyl, also unsubstituted or lower Alkyl-, lower alkoxy-, halo- and / or nitro-substituted phenyl Or a benzyl group.   The described protecting groups can be removed by customary methods, for example by solvation or hydrolysis. .   For example, in the formula, R_AIs an esterified phosphono, R_BIs a group R other than hydrogen_TwoAnd R_cBut A group R other than hydrogen_ThreeThe treatment of a compound of formula II with an acid hydrolyzing agent is, for example, , R₁Is phosphono and R_TwoAnd R_ThreeWherein R is hydrogen. acid The hydrolyzing agent is, for example, an inorganic acid such as hydrogenated halide acid or sulfuric acid and is required. If so, it is a mixture with a protic solvent such as acetic acid. Such reagents For example, or about 30% to about 35% hydrofluoric acid solution in acetic acid, eg, in acetic acid About 35% hydrochloric acid or about 35% in concentrated sulfuric acid, water and acetic acid , Hydrochloric acid. The reaction is advantageously carried out at an elevated temperature, for example from about 80 ° C. It is carried out at about 120 ° C., for example, at the boiling point.   However, if the reaction is carried out with an esterified phosphonate such as a di-lower alkyl phosphono, Is only partially solvated to the lower alkyl phosphono stage, for example, and And / or hydroxy-protecting group R_BAnd R_cCustomary so that only one of the It is also possible to control in a way. For example, in the formula, R_AIs esterified phospho No, R_BIs a group R other than hydrogen_TwoAnd R_cIs a group R other than hydrogen_ThreeOf a compound of formula II which is Treatment with tri-lower alkylhalosilane or hexamethyldisilazane and subsequent Treatment with lower alkanols, lower alkenols or lower alkynols is performed according to the formula Medium, R₁Is phosphono, R_ThreeIs hydrogen and R_TwoIs lower alkyl, lower alkenyl or Produces compounds of formula I which are lower alkynyl. Reaction with silyl compounds The reaction is preferably carried out in a halogenated hydrocarbon such as dichloromethane and further alcohol Is carried out in the presence of water.   Wherein the starting material of formula II wherein X is lower alkylidene is, for example, Can be manufactured:   Formula III [Wherein, R_Four, R_Five, R₆And X are as defined) In the compounds of formula (I), the nitro group is converted to amino in a conventional manner, for example, a hydrogenation catalyst, for example, Reduction by hydrogenation in the presence of Raney nickel; resulting formula IV Oxalic acid or an oxalic acid diester such as oxalic acid Reacting with its reactive derivative such as diethyl; the resulting formula V In the quinoxaline-2,3-dione of formula (I), the oxo group is replaced by customary methods, e.g. Treatment with phosphorus oxychloride and / or phosphorus pentachloride,_Two-OH (VIa) or Is R_Three-OH (VIb) is reacted with an alcohol and converted to formula -OR_TwoOr -OR_ThreeStrange Wherein the resulting formula VII In the compounds of formula (I), the group -XH at the α-position with respect to the benzo ring is customary -Halogenation using -bromosuccinimide, wherein R_AIs di-lower alk For the preparation of compounds of formula II which are esterified phosphonos such as luphosphono, VIII [Wherein Hal is a halogen, for example, bromine] With a tri-lower alkyl such as trimethyl or triethyl phosphite Reaction with phosphonas acid triesters such as phosphites.   In the synthesis of this compound of formula II, the substituent R_Four, R_Fiveand/ Or R₆Is preferably acted on at the intermediate stage of the formula III.   In the formula, X is a divalent aliphatic group X ′ other than lower alkylidene; H_Two) n- (Ia), -CH = CH- (CH_Two)_n-2-(Ib) or -C≡C- (CH_Two)_n-2 -(Ic) Compounds of formula II wherein n is 2, 3 or 4 are, for example, compounds of formula IX In a customary manner, for example in the presence of palladium / triphenylphosphine At about 80 to about 120 ° C., preferably in dimethylformamide, And, if desired, the resulting formula XI In which the exocyclic triple bond is replaced by a double or single bond in a conventional manner, for example Catalyzed hydrogenation, preferably in the presence of palladium on carbon; resulting formula XI I Of the compound of formula (I) with customary methods, for example by reaction with a reagent which inserts a reactive halogen Hal, eg For example, halogenation by reacting with 1,1′-carbonyldiimidazole, Subsequently, the imidazolo group is quaternized by means of, for example, a lower alkyl halide, and And the resulting formula XIII The halogenated compounds of the formula (I) can be further processed in customary manner, for example Esters, for example tri-lower alcohols such as trimethyl or triethyl phosphite A group R such as a killed phosphorous acid_ACan be produced by reacting . This method is particularly useful in the formula where R_AIs an esterification such as di-lower alkylphosphono Suitable for the preparation of compounds of formula II wherein the phosphono group and n is 3 or 4.   Wherein X is a group of formula -CH = CH- (Ic1) or Ia. For example, using a compound of formula VIII or XIII as starting material, The romethyl group is customarily prepared, for example with 2-nitropropane in an alcoholic solution. The reaction is converted to formyl and the resulting aldehyde is converted to methanedioxide in a customary manner. Reaction with phosphonic acid tetra-lower alkyl esters, the corresponding formula XVI And, if desired, replacing the exocyclic double bond with a hydrogen Become In the resulting formula, X is at least one in the α-position to the benzo ring An intermediate having a hydrogen atom of 1,1,1-lower alkylidene such as methylene By customary methods such as, for example, alkali metal disilazides such as sodium tetramethyi. Treated with rudisilazide, and then, such as a lower alkyl iodo of formula RI Treatment with an alkylating agent, wherein X represents a lower alkylidene group, for example a chain member Formula X—R or —X (R) —R₁To the corresponding compound Convert.   The compounds obtained in this way can be converted into other compounds of the formula I in the customary manner.   For example, in the formula, R₁A compound of formula I wherein is a partially esterified phosphono, Hydrolysis by the method of the example, wherein R₁To the corresponding compound of the formula wherein is phosphono it can.   In addition, where R_TwoAnd / or R_ThreeA compound of formula I wherein is an aliphatic group, Solvate by the method of_TwoAnd / or R_ThreeA compound of formula I wherein is hydrogen Or the corresponding tautomer of formula I "', for example as described above, is a hydroxy-protecting group R_BAnd R_cIs formed for the removal of Conversely, in the formula, R_TwoAnd / or R_Three Or a tautomer thereof of formula I ', I "and / or 1"' The body is treated in a customary manner, for example with a strong salt such as phosphorus oxychloride and / or phosphorus pentachloride. Treatment with a halogenating agent followed by an aliphatic alcohol to insert an aliphatic group, wherein R_Two And / or R_ThreeOr a corresponding compound of formula I wherein is an aliphatic group, And / or its isomeric form of I "'.   In addition, the resulting group R_Four, R_FiveAnd R₆At least one of the etherified mel A compound of formula I which is a capto, such as a lower alkylthio, is prepared in a conventional manner, R_Four, R_FiveAnd / or R₆Is an oxidized esterified mercapto, such as a lower alkane It can be oxidized to a compound of formula I which is rufinyl or lower alkanesulfonyl.   In addition, where the group R_Four, R_FiveAnd R₆Of formula I wherein at least one of is hydrogen In a compound, a group R in which a hydrogen atom is other than hydrogen_Four, R_FiveOr R₆Can be replaced by For example, halogenation, nitration or insertion of lower alkanoyl is done in the usual way. The latter is, for example, a reactive lower alkanol such as lower alkanolic acid chloride. Phenolic acid, preferably halogenated in the presence of aluminum trichloride The reaction is carried out in a hydrocarbon at the boiling point, if necessary. In addition, nitro is more commonly used Can be converted to amino by methods such as reduction, and halogens can be converted by conventional methods, e.g. Can be removed by hydrolysis.   The salts obtained can be prepared in a manner known per se, for example with alkali metal hydroxides, metals. Bases such as carbonates or metal bicarbonates or other salt-forming bases mentioned first, or Alternatively, they can be converted to the free compounds by treatment with an inorganic acid, for example an acid such as hydrochloric acid.   The resulting salt can be converted into different salts in a manner known per se; With a suitable metal salt such as a sodium, barium or silver salt of a different acid in a solvent The treatment results in an acid addition salt (the inorganic salt formed here is insoluble and therefore Salt) from the acid, and conversion back to the salt to form the basic salt Can be converted to   The compounds of formula I, including their salts, can also be obtained in the form of hydrates or used for crystallization Solvent.   In view of the close relationship between the free form of the new compound and its salt form, The above and below descriptions of the salts are, where appropriate and convenient, It is to be understood that each includes the corresponding salt and free compound.   The resulting diastereoisomeric and racemic mixtures are pure diastereomeric Rheomers or racemates are known based on differences in the physicochemical properties of the components Separation by methods such as chromatography and / or fractional crystallization.   The racemate obtained can be obtained by known methods, such as optically active solutions with the aid of microorganisms. Diastereoisomeric mixtures or racemates obtained by recrystallization from Acidic, basic or acidic compounds present in the body and in optically active auxiliary compounds, such as compounds of formula I Reacts with optically active acids, bases or optically active alcohols, depending on the functionally modifiable group To form a functional derivative such as a diastereoisomer salt or ester; The separation into diastereomers which can liberate the desired enantiomer in a suitable customary manner Separation into optical antipods can be achieved by separating them. Bases, acids suitable for this purpose And alcohols such as, for example, strychnine, cinchonine or brucine Optically active alkaloid base, or D- or L- (1-phenyl) ethyl alcohol Min, 3-pipecoline, ephedrine, amphetamine and similar synthesis The resulting base, quinic acid or D- or L-tartaric acid, D- or L-di-o- Toluyl tartaric acid, D- or L-malic acid, D- or L-mandelic acid or D -Or an optically active carboxylic acid such as L-camphorsulfonic acid or sulfo Acid, and like vomeol or D- or L- (1-phenyl) ethanol Optically active alcohol.   The present invention starts from a compound obtained as an intermediate at any stage of the synthesis. Use the remaining steps or use the starting material as a salt or In addition, it relates to processes in which the starting materials are formed under the reaction conditions.   The invention also relates to new starting materials which have been specially developed for the preparation of the compounds according to the invention. Also, for example, the formula XVII (In the formula, Group R_Four, R_FiveAnd R₆Are independently of one another an aliphatic hydrocarbon radical, free or ether Hydroxy, free or etherified mercapto or oxidized free or ether Mercapto, unsubstituted or aliphatically substituted amino, nitro, free or Is esterified or amidated carboxy, cyano, free or amidated sulfa Moyl, halogen or trifluoromethyl, R_BIs the group R_TwoOr a hydride such as lower alkoxy or phenyl-lower alkoxy A roxy-protecting group, R_cIs the group R_ThreeOr hydro, such as lower alkoxy or phenyl lower alkoxy. A xy-protecting group, and R_DIs the expression − (CH_Two)_Two-R_E(XVIIa),-(CH_Two)_n-1-CH = O (XVIIb), -C≡ (CH_Two)_n-2 -R_E(XVIIc), -C≡C- (CH_Two)_n-2-CH = O (XVIId), -CH = CH- (CH 2)_n-2-R_E(XVIIe) or -CH = CH- (CH_Two)_n-2-CH = O (XVIIf) (wherein R_EAre free radicals such as hydroxy, halogen, lower alkanesulfonyloxy. Or reactive esterified hydroxy, or unsubstituted or lower alkyl-, halo- And / or nitro-substituted benzenesulfonyloxy or naphthalenesul Phonyloxy, and n is 2, 3 or 4) Group) Starting materials which lead to the compounds of the formula I, which are initially mentioned as particularly preferred , Their preparation and their use as intermediates.   The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. And a process for producing the same.   Pharmaceutical composition of the present invention comprising the compound of the present invention or a pharmacologically acceptable salt thereof Is administered to warm-blooded animals enterally, such as orally and rectally, and parenterally The composition may contain the pharmacologically active ingredient alone or a pharmacologically acceptable carrier. Include with. The daily dosage of the active ingredient depends on the age and individual condition and on the form of administration. Depends on the situation.   The novel pharmaceutical composition is, for example, from about 10% to about 80%, preferably from about 20% to Contains about 60% active ingredient. Enteral or parenteral pharmaceutical compositions of the invention may be, for example, Unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories. Also. They may be prepared in a manner known per se, for example by means of conventional mixing, granulating, sugaring methods. It can be manufactured in a battering, dissolving or lyophilizing process. For example, a pharmaceutical composition for oral administration is The active ingredient and the solid carrier are combined, and the resulting mixture is granulated if desired. Or granules, if desired or necessary, after the addition of suitable excipients, It can be obtained by processing into a sugar-coated core.   Suitable carriers are, in particular, sugars such as lactose, saccharose, mannitol or Are sorbitol, cellulose preparations and / or calcium phosphates, such as Fillers such as tricalcium phosphate or calcium hydrogen phosphate, and also For example, starches using corn, wheat, rice or potato starch , Gelatin, tragacanth, methylcellulose and / or polyvinyl Binders such as pyrrolidone, if desired starch and also carboxy as described above Methyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or algin Disintegrants, such as the salts thereof, such as sodium acid salt. Excipients are, in particular, glidants, Fluid conditioners and lubricants such as silicic acid, talc, stearic acid or Is a salt thereof such as magnesium stearate or calcium stearate, And / or polyethylene glycol. Dragee cores are suitable and desired It is provided in a more enteric, coated form that includes, among other things, gum arabic, Luc, polyvinylpyrrolidone, polyethylenglycol and / or dioxide Sugar solutions which may contain titanium or suitable for the production of enteric coatings Coating solution in organic solvent or solvent mixture, acetyl cellulose phthalate Cellulose or hydroxypropyl methylcellulose phthalate Used as product solution. Dyes or pigments can be identified or have different activities, for example. It may be added to a tablet or dragee coating for the purpose of indicating the amount of the ingredient.   Other orally administrable pharmaceutical compositions include hard gelatin capsules and also gelatin and Sealed capsules containing a plasticizer such as glycerol or sorbitol It is.   Hard gelatin capsules may contain, for example, fillers such as lactose, Binders and / or lubricants such as talc or magnesium stearate, And, if desired, the active ingredient in the form of granules in a mixture with stabilizers. Soft In Pusel, the active ingredient is preferably fatty oil, paraffin oil or liquid poly Dissolve or suspend in a liquid such as ethylen glycol, and add a stabilizer as well. Addition is possible.   Suitable enterally administrable pharmaceutical compositions are, for example, combinations of the active ingredient with a suppository base. Including Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffins. Hydrocarbons, polyethylenglycols or higher alkanols. Activity Enteral gelatin capsules containing a combination of ingredients and a suppository base are also possible. You. Suitable suppository bases are, for example, liquid triglycerides, polyethylenglycol Or paraffin hydrocarbons.   For parenteral administration, especially the aqueous form of the active ingredient in water-soluble form, for example in the form of a water-soluble salt, Solutions, and also fatty oils, such as sesame oil, or synthetic fatty acid esters, such as A suitable lipophilic solvent or medium such as ethyl oleate or triglyceride With a suspension of the active ingredient such as the corresponding oily injection suspension used, or Additives such as sodium carboxymethylcellulose, sorbitol and / or Or an aqueous injection suspension containing dextran and optionally also a stabilizing agent. You.   The dosage of the active ingredient depends on the age and individual condition and also on the mode of administration . In the usual case, a suitable daily dose of oral dose for a patient of about 75 kg will be from about 10 mg to about Calculated as 500 mg.   The following examples serve to illustrate the invention; temperature is in degrees Celsius and pressure is in mbar. Show.   Example 1:7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quino Oxalin-5-ylmethanephosphonic acid   0.68 g (1.62 mmol) of 7-bromo-2,3-dimethoxy-quinoxaline- 5-ylmethanephosphonic acid diethyl ester was added for 15 minutes at 130 ° to 20 ml of Heat in a 33% solution of hydrofluoric acid in acetic acid. Cool the reaction mixture to room temperature, 80 ml of diethyl ether are added and stirring is continued for 30 minutes. The crystalline precipitate is filtered off and Wash with ethyl ether and dry to give the title compound; m.p.> 300 °;¹H -NMR (300 MHz) DMSO-d₆Medium; δ (ppm) = 12.02 (s, 1H); 30-11.70 (m, 1H); 7.18 (m, 2H); 3.32 (d, 2H, J = 22.5) Hz).   Starting materials can be prepared, for example, as follows:   a)7-bromo-5-methyl-2,3-dioxo-1,2,3,4-tetrahydro -Quinoxaline   22.6 ml (440 mmol) of bromine were converted to 55.7 g (366 mmol) of Add dropwise to the solution of 2-methyl-6-nitro-aniline. A suspension forms. Suspension The solution is stirred at room temperature for 1 hour, poured into 2000 ml of ice-water and suction filtered. Washing with water And drying gives an orange solid. 40 g of it in 600 ml of ethanol Dissolve, add 6 g of Raney nickel and stir under hydrogen atmosphere to 12300 ml Perform until hydrogen is taken in. Filter the catalyst through diatomaceous earth, filter cake Is washed vigorously with ethanol. Combine the filtrate and washing solution and evaporate under reduced pressure. Concentrate by filtration. The distillation residue was taken up in 1000 ml of 2N hydrochloric acid and 31. 15 g (346 mmol) of oxalic acid are added and heating at reflux is continued overnight. Following the reaction mixture Cool to room temperature, pour into 1000 ml of ice water, filter by suction, wash with water and dry You. The resulting solid is slurried with a small amount of acetone, stirred for 30 minutes, and suction filtered again. Wash first with acetone and then with diethyl ether, dry and title Compound is obtained in the form of a brown solid, m.p.> 300 °;¹H-NMR (200 MHz) DMS O-d₆Medium; δ (ppm) = 11.95 (s, 1H); 11.31 (s, 1H); 7.13 (s, 2) H); 2.32 (s, 3H).   b)7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethanephosphone Acid diethyl ester   38.13 g (149.5 mmol) of 7-bromo-5-methyl-2,3-oxo-1, 2,3,4-tetrahydro-quinoxaline and 68.5 g (329 mmol) of pentachloride Carefully mix the phosphorus, finely grind and slowly 160 ° in the sulfonation flask At which point phosphorus oxychloride begins to distill. The reaction mixture is slowly added for an additional 2 Heat to 00 ° until no more phosphorus oxychloride is collected, then allow to cool. And pour into 2000 ml of water. The separated precipitate is filtered off with suction, washed with water and dried and then dried. The mixture is taken up in 2000 ml of dichloromethane and filtered. Filter residue from dichloromethane And the filtrate is dried over magnesium sulfate and concentrated by evaporation. Dry and dry 25 g of 7-bromo-2,3-dichloro-5-methyl in the form of a brown solid. Obtain lu-quinoxaline, which is slurried with 300 ml of methanol. 47ml A solution of 227 mmol of sodium methanolate in methanol is added to it . Heating reflux was continued for 3 hours to remove excess methanol and to remove 500 ml of the remaining product. Partition between ethyl acetate and 500 ml of water. The aqueous phase is again mixed with 500 ml of ethyl acetate. Extract by shaking. The organic phase is continuously washed with 300 ml water and 300 ml Wash with sodium chloride solution and combine and dry over magnesium sulfate. Eva Concentration by poration and crystallization from methanol gave a white crystalline form of 1 6.39 g of 7-bromo-2,3-dimethoxy-5-methyl-quinoxaline are obtained. . 14.72 g of these crystals, 10.6 g (59.6 mmol) of N-bromosuccin Imide and 0.86 g (5.2 mmol) of AIBN were added to 300 ml of tetrachlorometa Reflux with heating for 4 hours. After filtration, the filtration residue is washed with tetrachloromethane, The combined filtrate is concentrated by evaporation. Under nitrogen, the distillation residue (7-bro Mo-2,3-Dimethoxy-5-bromomethyl-quinoxaline) Heat to reflux for 15 hours in a chill. The excess triethyl phosphite is removed and the residue is Purify by silica gel chromatography using ethyl acetate as eluent to obtain the title compound. Get¹H-NMR (200 MHz) DMSO-d₆Medium; δ (ppm) = 7.8 (m, 1H) 7.65 (s, 1H); 4.03 (s, 3H); 3.96 (m, 4H); 3.75 (d, 2H) , J = 22.5 Hz); 1.10 (t, 6H, J = 7 Hz).   Example 2:2,3-dioxo-1,2,3,4-tetrahydro-quinoxane- 5-ylmethanephosphonic acid   4.21 g (10.8 mmol) of 7-bromo-2,3-dimethoxy-quinoxaline- 5-ylmethanephosphonic acid dimethyl ester and 1.2 g of triethylamine Was dissolved in 100 ml of methanol, and 0.4 g of palladium on carbon was added. The mixture is stirred under a hydrogen atmosphere until 258 ml of hydrogen are taken up. Filter the catalyst Take, wash with methanol and concentrate and dry by evaporation. 2 residue Dissolve in 0 ml acetic acid; add 20 ml water and 20 ml conc. Continue for hours. The reaction mixture is cooled to room temperature, poured into 200 ml of water, filtered off with suction and Wash with hexane, acetone and diethyl ether and dry to give the title compound as a cloudy white solid M.p.> 280 °;¹H-NMR (200 MHz) DMSO-d₆Medium; δ (p pm) = 12.0 (s, 1H); 11.6-11.1 (m, 1H); 7.03 (m, 3H); 30 (d, 2H, J = 20 Hz).   Starting materials can be prepared, for example, as follows:   a)7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethanephosphone Acid dimethyl ester   16.39 g (57.9 mmol) of 7-bromo-2,3-dimethoxy-5-methyl- Quinoxaline, 11.2 g (60.8 mmol) N-bromosuccinimide and 0.8 g. 514 g (3.13 mmol) of AIBN in 300 ml of tetrachloromethane for 4 hours Heat to reflux. After filtration, the filter residue is washed with dichloromethane. The combined filtrate Is extracted by shaking with 500 ml of 1N hydrochloric acid and saturated sodium chloride solution. You. Extract the aqueous phase by shaking with dichloromethane, combine all organic phases, Dry over magnesium sulfate and concentrate by evaporation. 21.0 g of solid are obtained. Dissolve 15.7 g of it in 200 ml of trimethyl phosphite, Heat to reflux overnight. The excess trimethyl phosphite is then removed and the residue is washed with ethyl acetate. Purify by silica gel chromatography, eluting with toluene to obtain the title compound;¹ H-NMR (300 MHz) DMSO-d₆Medium; δ (ppm) = 7.83 (m, 1H); 7.6 6 (s, 1H); 4.08 (s, 3H); 4.05 (m, 3H); 3.87-3.58 (m, 8 H).   Example 3:7-bromo-6-nitro-2,3-dioxo-1,2,3,4-tetra Hydro-quinoxalin-5-ylmethanephosphonic acid   5.43 g (13.9 mmol) of 7-bromo-2,3-dimethoxy-quinoxaline- 5-ylmethanephosphonic acid dimethyl ester and 1.45 g (18.0 mmol) of nitric acid Ammonium salt was added to 10 ml equal parts of dichloromethane and trichloromethane. Heat at 60 ° in the mixture. Then in one hour, 15.15 g (72.2 g) of acetic acid free Drop water. The reaction mixture was stirred for 3 hours, allowed to cool to room temperature and 200 ml of water And twice, each time by shaking with 200 ml of saturated sodium bicarbonate solution I do. The aqueous phases are each back-extracted with 200 ml of dichloromethane. Organic combined The phases are dried over magnesium sulfate and concentrated by evaporation. The residue Elute ethyl acetate first and then ethyl acetate / diethyl ether (10: 1) The solution is purified by chromatography on silica gel and crystallized from methanol. 7-Bromo-6-nitro-2,3-dioxo-1,2,3,4-tetrahydride obtained Lo-quinoxalin-5-ylmethanephosphonic acid dimethyl ester was added to 5 ml of acetic acid, Dissolve in 5 ml of water and 5 ml of concentrated hydrochloric acid and heat to reflux for 24 hours. Chamber the reaction mixture Cool to warm, dry concentrate by evaporation, ethanol / diethyl ether To give the title compound in crystalline form; m.p.> 250 °;¹H-NMR (3 00MHz) DMSO-d₆Medium; δ (ppm) = 12.28 (s, 1H); 11.70 (s, 1H) ); 7.36 (d, 1H, J = 3.75 Hz); 3.34 (d, 2H, J = 22.5 Hz).   Example 4:1- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro -Quinoxalin-5-yl) ethanephosphonic acid   1 of sodium hexamethyldisilazide in 5.23 ml of tetrahydrofuran A 1.86 g (4.76 mmol) solution in 20 ml of tetrahydrofuran at -20 DEG is prepared. l) 7-Bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid Add dropwise to the solution of dimethyl ester. After 20 minutes, 6.75 g (47.6 mmol) of iodine Methyl chloride was added and the reaction mixture was heated at reflux for 3 hours and 100 ml of saturated ammonium chloride were added. And extracted twice by shaking twice with 200 ml each time of ethyl acetate. You. Combine the extracts, dry over magnesium sulfate and dry by evaporation. Concentrate to dryness, first ethyl acetate and then ethyl acetate / diethyl ether (10: Purify by silica gel chromatography using 1) as an eluent. Methanol / di Crystallization from ethyl ether gives the title compound; m.p.> 300 °;¹H- NMR (200 MHz) DMSO-d₆Medium; δ (ppm) = 12.02 (s, 1H); 11.9 0-11.60 (s, 1H); 7.30 (m, 1H); 7.19 (m, 1H); 3.68 (qd, 1H, J¹= 7.5Hz, J^Two= 22.5 Hz); 1.39 (dd, 3H, J¹= 7.5Hz, J^Two= 17.5 Hz).   Example 5:7-bromo-3-methoxy-2-oxo-1,2,3,4-tetrahi Dro-quinoxalin-5-ylmethanephosphonic acid   7.47 g (48.8 mmol) of trimethylbromosilane are added at 0 ° to 25 ml of dichloromethane. 1.91 g (4.88 mmol) of 7-bromo-2,3-dimethoxy-kilomethane in dichloromethane It is added dropwise to a solution of noxalin-5-ylmethanephosphonic acid dimethyl ester. Anti The reaction mixture is warmed to room temperature and stirred overnight. Dichloromethane and excess trimethyl The bromosilane is removed and the residue is dried for 3 hours at room temperature under 0.1 torr. Residue Is dissolved in 20 ml of methanol, 0.3 ml of water is added and stirring is continued for 3 hours. The precipitate obtained by suction filtration is washed with methanol and diethyl ether, dried and To give the title compound; m.p. 245-250 °;¹H-NMR (200 MHz) DMSO- d₆Medium; δ (ppm) = 12.40 (s, 1H); 7.38 (m, 1H); 7.26 (m, 1H); 3.99 (s, 3H); 3.42 (d, 2H, J = 22.5 Hz).   Example 6:7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quino Oxalin-5-ylacetic acid   Tetrabutylammonium cyanide was added to 40 ml of water and 40 ml of dichloromethan. 2.35 g (6.5 mmol) of 7-bromo-2,3-dimethoxy-5-bromo in tan Add to methyl-quinoxaline and stir the reaction mixture overnight. Separate the organic phase, Wash with water. The aqueous phase is back-extracted with dichloromethane. Combine the organic phases and add sulfuric acid Dry over gnesium and concentrate by evaporation. Distillation residue Silica gel with ethyl acetate / ethyl acetate (first 20: 1, then 15: 1, last 10: 1) Purify by chromatography and take up in 10 ml of tetrahydrofuran. 5 ml of 2 Add N hydrochloric acid and continue heating at reflux overnight. The reaction mixture is cooled to room temperature and taken up in 50 ml of water Pour, suction filter, wash with water and dry. The filtration residue is slurried with 3 ml of water Add 3 ml of acetic acid and 3 ml of concentrated sulfuric acid and heat to reflux for 5 hours. Reaction mixing Cool the material to room temperature, pour into 50 ml of ice water, filter, wash with water, dry and title Compound; m.p.> 280 °;¹H-NMR (200 MHz) DMSO-d₆Medium; 6 (p pm) = 12.05 (s, 1H); 11.57 (s, 1H); 7.22 (m, 2H); 3.86 (s) , 2H).   Example 7:3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro -Quinoxalin-5-yl) propanephosphonic acid   0.584 g (1.45 mmol) of 3- (7-chloro-2,3-dimethoxyquinoxali N-5-yl) propanephosphonic acid diethyl ester at 110 ° for 20 minutes, 25 m Heat in a 33% solution of hydrofluoric acid in 1 acetic acid. Cool the reaction mixture to room temperature 80 ml of diethyl ether are added and stirring is continued for 30 minutes. Filter the crystalline precipitate Wash with diethyl ether and dry to give the title compound; m.p. 220-2 22 °.   Starting materials can be prepared, for example, as follows:   a) 5-Iodo-2,3,7-trichloroquinoxaline   406.9 g (1.953 mmol) of phosphorus pentachloride in 1200 ml of phosphorus oxychloride 195.9 g (0.93 mmol) of 7-chloro-5-iodo-quinoxaline-dione And the reaction mixture is stirred at reflux for 18 hours. Excess oxychloride Is removed from the reaction mixture at a bath temperature of 150 ° C. Residue in 6000 ml of ice water Pour, stir the resulting suspension for 2 hours, filter with suction and wash with copious amounts of water. filtration The residue is dried in vacuo at 60 ° C. and the light brown form of 5-iodo-2,3,7-trichloro Lo-quinoxaline is obtained and crude crystals can be reacted without further purification.   b)7-chloro-2,3-dimethoxy-5-iodo-quinoxaline   205 g (0.828 mmol) of 5-iodo-2,3,7-trichloro-quinoxali The solution is inserted into 2255 ml of methanol at room temperature and the solution in 463.9 ml of methanol is added. An about 5.4 molar solution of thorium methanolate is added. The reaction mixture is then Reflux while heating. The reaction mixture is cooled to 0 ° C. and the suspension is filtered off with suction. Filtration residue Was washed with methanol and dried at 60 ° C. in vacuo to give the crude product in diethyl ether. And purified by continuous extraction with 7-chloro-2,3-di-melting point 94-96 ° C. Methoxy-5-iodo-quinoxaline is obtained.   c)3- (7-chloro-2,3-dimethoxy-quinoxalin-5-yl) -prop -2-yn-1-ol   12.9 g (36.8 mmol) of 7-chloro-2,3-dimethoxy-5-iodo-ki Noxaline, 7.6 ml (128.4 mmol) of propargyl alcohol, 2.1 g (3 mm ol) of bis (triphenylphosphine) palladium dichloride, 6.6 ml (47.4) mmol) of triethylamine and 0.34 g (1.8 mmol) of copper (I) iodide were added to 12 Insert into 5 ml of dimethylformamide and heat in a bath at a temperature of 70 ° C. Reaction mixing The thing is stirred at that temperature for 3.5 hours and then allowed to cool to room temperature. Add ethyl acetate Then, the reaction mixture is extracted with water, 1N hydrochloric acid and brine. Aqueous phase with ethyl acetate Wash. The organic phases are combined, dried over sodium sulphate, filtered off with suction and concentrated. You. Silica gel chromatography of the crude product with hexane / ethyl acetate (3: 1) To give 3- (7-chloro-) in the form of brown crystals having a melting point of 137-140 ° C. 2,3-dimethoxy-quinoxalin-5-yl) -prop-2-yn-1-ol Get.   d)3- (7-chloro-2,3-dimethoxy-quinoxanlin-5-yl) -pro Pan-1-ol   2.05 g (7.36 mmol) of 3- (7-chloro-2,3-dimethoxy-quinoxali N-5-yl) -prop-2-yn-1-ol in 20 ml of tetrahydrofuran Approximately 0.4 g of Raney nickel in water until water is taken up in twice the molar amount. Simplify. The hydrogenation mixture is suction filtered through a glass fiber filter and the filtrate is concentrated. To give a beige 3- (7-chloro-2,3-dimethyl) with a melting point of 104-105 ° C. Toxi-quinoxalin-5-yl) -propan-1-ol is obtained.   e)5- (3-bromopropyl) -7-chloro-2,3-dimethoxyquinoxaline   0.5 g (1.77 mmol) of 3- (7-chloro-2,3-dimethoxy-quinoxaline -5-yl) -propan-1-ol and 0.287 g (1.77 mmol) of 1,1 ' -Carbonyldiimidazole with N_TwoInsert in 5 ml of acetonitrile below. 0. 75 ml of allyl bromide are added and the reaction mixture is stirred at room temperature for 30 minutes and at reflux for 2 hours. Mix. The reaction mixture was cooled to room temperature, diethyl ether was added and the extract was extracted with water, 0% Perform with 0.1 N hydrochloric acid, saturated sodium bicarbonate solution and brine. Aqueous phase Wash with toluene. The organic phases are combined, dried over sodium sulphate and 5- (3-bromopropyl) -7-chloride in the form of a yellow oil. Rolo-2,3-dimethoxy-quinoxaline was obtained and used without further purification. To use.   f)3- (7-bromo-2,3-dimethoxy-quinoxalin-5-yl) propane Phosphonic acid diethyl ester   0.52 g (1.5 mmol) of 5- (3-bromopropyl) -7-chloro-2,3-di Dissolve methoxy-quinoxaline in 10 ml of trimethyl phosphite and heat to reflux overnight. I do. Next, excess trimethyl phosphite was removed, and ethyl acetate was used as an eluent. Purify by silica gel chromatography to obtain the title compound.   Example 8:3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro -Quinoxalin-5-yl) prop-2-inphosphonic acid   The title compound is obtained in a similar manner as described in Example 7, but in step e), 3- ( 7-chloro-2,3-dimethoxy-quinoxalin-5-yl) -prop-2-yne -1-ol is converted to 3- (7-chloro-2,3-dimethoxy-quinoxalin-5-yl Used in place of) -propan-1-ol.   Example 9:3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro -Quinoxalin-5-yl) prop-2-enphosphonic acid   The title compound is obtained in a manner analogous to that described in Example 7, but with hydrogenation in step d). This is performed until an equimolar amount of hydrogen has been incorporated.   Example 10:2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydride (Roquinoxalin-5-yl) ethenephosphonic acid   0.88 g (1.5 mmol) of 2- (7-bromo-2,3-dimethoxy-1,2,3,4- Tetrahydro-quinoxalin-5-yl) ethene-diphosphonate The stell is placed in a 33% solution of hydrofluoric acid in 30 ml of acetic acid at 110 ° for 30 minutes. Heat. The reaction mixture was cooled to room temperature, 100 ml of diethyl ether was added, and the mixture was stirred. The stirring was continued for 30 minutes, and the crystalline precipitate was collected by filtration, washed with diethyl ether, dried, and The title compound is obtained; m.p.> 300 °.   Starting materials can be prepared, for example, as follows:   a)7-bromo-5-formyl-2,3-dimethoxy-quinoxaline   N at 0 ° C_TwoIn the following, 1.38 g (60 mmol) of sodium was gradually added to 200 ml of methanol. Dissolve in the gel. At 0 ° C, 5.85 ml (65 mmol) of 2-nitropropane was added dropwise. I do. Then 18.1 g (50 mmol) of 5- (bromomethyl) -7-bromo-2,3- Add dimethoxy-quinoxaline. The beige suspension is heated at reflux for 1 hour. The reaction mixture is poured into 600 ml of water and the methanol is distilled off. The residue was washed twice with ethyl acetate And the organic phase is dried over sodium sulphate and filtered off with suction. Concentrate the filtrate The residue is dried under a high vacuum and beige crystals having a melting point of 179-182 ° C. are obtained. 7-Bromo-5-formyl-2,3-dimethoxy-quinoxaline is obtained in the form.   b)2- (7-bromo-2,3-dimethoxy-1,2,3,4-tetrahydro-quino Oxalin-5-yl) ethenediphosphonic acid tetraethyl ester   N at 0 ° C_TwoUnderneath, 0.35 g (15.5 mmol) of sodium was gradually added to 50 ml of ethanol. Dissolve in knol. While stirring at 0 ° C., 2.9 g (10 mmol) of methanediphospho Acid was added dropwise thereto and the reaction mixture was warmed to room temperature and 2.97 g (10 mmol) of 7-bromo-5-formyl-2,3-dimethoxyquinoxaline Add. The reaction mixture was stirred for 2 hours, poured into 200 ml of ice water, neutralized with hydrochloric acid and Extract by shaking with 50 ml of diethyl ether each time. Combined ether extraction Dry the product over sodium sulfate and concentrate by evaporation under reduced pressure to give the title The compound is obtained as a yellow oil, which can be reacted without further purification.   Example 11:2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydride (Roquinoxalin-5-yl) ethanephosphonic acid   Analogously to the method described in Example 10, except that the intermediate of step b) is Hydrogenate in the presence of ney nickel until equimolar amounts of hydrogen are incorporated.   Example 12:4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydride (Roquinoxalin-5-yl) butanephosphonic acid   The title compound is obtained analogously to the method described in example 7, but in step c) Instead of propargyl alcohol a corresponding amount of but-3-inol is added obtain.   Example 13: In the same manner as described in Examples 1 to 12, the following compounds were obtained. Can be manufactured: 1- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethanephosphonic acid; 2- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethanephosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Propanephosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Butanephosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-1-enephosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-3-enphosphonic acid; 2- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethenephosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Prop-2-enphosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Prop-2-inphosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-3-enphosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) propanephosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-yl) butanephosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) prop-2-enephosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline -5-yl) prop-2-inphosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-3-enephosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-1-enephosphonic acid; 1- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali 2--5-yl) ethanephosphonic acid; 2- (7-chloro-2,3-dioxo-1,2, 3,4-tetrahydro-quinoxalin-5-yl) ethanephosphonic acid; 2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethenephosphonic acid; 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-3-enphosphonic acid, and 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-1-enephosphonic acid.   Example 14: 50 mg each of 2,3-oxo-1,2,3,4-tetrahydroquinoxa Tablets containing phosphorus-5-ylmethanephosphonic acid or a salt, such as the sodium salt, are Can be manufactured as described:Composition (10000 tablets) Active ingredient 500.0 g Lactose 500.0g Potato starch 8.0g gelatin Talc 60.0g Magnesium stearate 10.0g Silicon dioxide (highly dispersed) 20.0g Ethanol appropriate amount.   Mixing the active ingredient with lactose and 292 g of potato starch, and The mixture is moistened with an ethanolic solution of gelatin and granulated through a sieve. Dry After drying, the remaining potato starch, magnesium stearate, talc and Mix the silicon oxides, each mixture 145.0 mg containing 50 mg of active ingredient Compression into tablets, if desired; tablets can be scored to allow for greater volume control You.   Example 15: 3 mg each of 2,3-dioxo-1,2,3,4-tetrahydro-quinoki Salin-5-ylmethanephosphonic acid or a salt, such as a sodium salt, with the active ingredient Sterile filtered aqueous gelatin solution containing 20% cyclodextrin as dissolving agent The solution is heated with a sterile gelatin solution containing phenol as a preservative, under aseptic conditions. And mix so that 1.0 ml of the solution has the following composition: Active ingredient 3mg Gelatin 150.0mg Phenol 4.7mg 1.0 ml of distilled water containing 20% cyclodextrin as a solubilizer   Example 16: 5 mg of 2,3-dioxo-1,2,3,4-tetrahydro-quinoki Sarin-5-ylmethanephosphonic acid or a salt such as the sodium salt, 5 mg of the above Sterile drying for injections containing one of the compounds of the formula I described in the examples as active ingredient The substance was treated with 20 mg of mannitol and 20% cyclodextrin as solubilizer Dissolve in 1 ml aqueous solution. The solution is sterile-filtered and sterilized under 2 ml And freeze hard and freeze-dry. Before use, freeze the lyophilizate in 1 ml of distilled water. Or 1 ml of physiological sodium chloride solution. Intramuscular or intravenous solution To be administered. Formulation can also be placed in a double chamber disposable syringe You.   Example 17: 100 mg of 2,3-oxo-1,2,3,4-tetrahydro-quino Oxalin-5-ylmethanephosphonic acid or a salt, e.g. 000 film-coated tablets can be manufactured as follows: Active ingredient 1000g 680 g of corn starch 200g colloidal silica Magnesium stearate 20g Stearic acid 50g Sodium carboxymethyl starch 250g Water   50 g of corn, one of the compounds of the formula I described in the preceding example as active ingredient Mix the mixture of starch and colloidal silica with 250 g of corn starch Mass of starch paste made from starch and 2.2 kg of demineralized water To manufacture. Pass the humidified mass through a sieve of 3 mm mesh size and fluidize bed dryer And dry at 45 ° for 30 minutes. Pass the dried granules through a 1mm mesh sieve , 330g corn starch, magnesium stearate, stearic acid And pre-sifted mixture of sodium carboxymethyl starch (1mm sieve) Mix with.   Example 18: In the same manner as described in Examples 14 to 17, It is also possible to prepare a pharmaceutical composition comprising any one different compound.

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Claims (1)

[Claims]   1. Formula I (In the formula, R₁Is a free or partially esterified phosphono, R_TwoAnd R_ThreeIs independently hydrogen or an aliphatic group, Group R_Four, R_FiveAnd R₆Are independently of one another hydrogen, aliphatic hydrocarbon radicals, free or Hydroxy, free or etherified mercapto or oxidized free or -Mercapto telluride, unsubstituted or aliphatically substituted amino, nitro, free Or esterified or amidated carboxy, cyano, free or amidated sulfo Famoyl, halogen or trifluoromethyl, and X is a divalent aliphatic group] Novel quinoxaline- and quinoxalinylalkane-phosphonic acids and their mutual The isomers or salts thereof.   2. Where: R₁Is phosphono or lower alkylphosphono, R_TwoAnd R_ThreeAre independently of each other hydrogen, lower alkyl, lower alkenyl or Lower alkynyl, such as pargyl, Group R_Four, R_FiveAnd R₆Are independently of each other hydrogen, lower alkyl, lower alkenyl, Lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, lower alcohol Ruquinyloxy, mercapto, lower alkylthio, lower alkanesulfinyl, Lower alkane sulfonyl, lower alkenylthio, lower alkynylthio, lower alcohol Lucenesulfinyl, lower alkanesulfonyl, amino, lower alkylamino , Di-lower alkylamino, nitro, carboxy, lower alkoxycarbonyl; Non Substituted or lower alkyl-, lower alkoxy-, hydroxy-, halo- and / or Or trifluoromethyl-substituted phenyl-lower alkoxycarbonyl; Moyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl; phenyl Carbamoyl or N-phenyl-N-lower alkylcarbamoyl, in each case non- Substituted or substituted phenyl moiety with lower alkyl, lower alkoxyhydroxy, halogen And / or substituted with trifluoromethyl; cyano, phosphono, lower Alkylphosphono, di-lower alkylphosphono, halogen or trifluoromethyl Chill, and X is lower alkylidene, lower alkylene, lower alkenylene or lower alkynyl Len 2. The compound according to claim 1, which is of formula I or a tautomer thereof, or a salt thereof. Compound.   3. Where: R₁Is phosphono, R_TwoAnd R_ThreeAre independently of each other hydrogen or C such as methyl or ethyl₁-C_Four Alkyl, Group R_Four, R_FiveAnd R₆Are independently of each other C, such as hydrogen, methyl or ethyl₁− C_FourC such as alkyl, methoxy or ethoxy₁-C_FourAlkoxy, methylthio C like Oh₁-C_FourAlkylthio, amino, nitro, carboxy, methoxy- Or C such as ethoxy-carbonyl₁-C_FourAlkoxycarbonyl, carbamoy C, such as methylcarbamoyl₁-C_FourAlkyl carbamoyl, dimethyl car Di-C like Bamoyl₁-C_FourAlkyl carbamoyl, halogen or trifur Oromethyl, and X is methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- Or C, such as 2,2-butylidene₁-C_FourAlkylidene 2. The compound according to claim 1, which is of formula I or a tautomer thereof, or a salt thereof. Compound.   4. Where: R₁Is phosphono, R_TwoAnd R_ThreeAre independently of each other hydrogen or C such as methyl or ethyl₁-C_Four Alkyl, Group R_Four, R_FiveAnd R₆Are independently of each other C, such as hydrogen, methyl or ethyl₁− C_FourC such as alkyl, methoxy or ethoxy₁-C_FourAlkoxy, methylthio C like Oh₁-C_FourAlkylthio, amino, nitro, carboxy, methoxy- Or C such as ethoxy-carbonyl₁-C_FourAlkoxycarbonyl, carbamoy C, such as methylcarbamoyl₁-C_FourAlkyl carbamoyl, dimethyl car Di-C like Bamoyl₁-C_FourAlkyl carbamoyl, halogen or trifur Oromethyl, and X is C₁-C_FourAlkylidene, C₁-C_FourAlkylene, C_Two-C_FourAlkenylene or C_Two-C_FourAlkynylene 2. The compound according to claim 1, which is of formula I or a tautomer thereof, or a salt thereof. Compound.   5.7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-ylmethanephosphonic acid; 2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-ylmethane Phosphonic acid; 7-bromo-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quino Oxalin-5-ylmethanephosphonic acid; 1- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethanephosphonic acid or 7-bromo-3-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoki Salin-5-ylmethanephosphonic acid or a salt thereof.   6.3- (7-Chloro-2,3-dioxo-1,2,3,4-tetrahydro-quino Oxalin-5-yl) propanephosphonic acid; 3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline -5-yl) prop-2-inphosphonic acid; 3- (7-chloro-2,3-dioxo-1,2,3,4 tetrahydro-quinoxaline -5-yl) prop-2-enphosphonic acid; 2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethenephosphonic acid; 2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethanephosphonic acid; 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) butanephosphonic acid; 1- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethanephosphonic acid; 2- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethanephosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Propanephosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Butanephosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-1-enphosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-3-enphosphonic acid; 2- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Ethenephosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Prop-2-enphosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) Prop-2-inphosphonic acid; 4- (2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl) But-3-enphosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) propanephosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) butanephosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) prop-2-enephosphonic acid; 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) prop-2-inphosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-3-enephosphonic acid; 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline -5-yl) but-1-enphosphonic acid; 1- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethanephosphonic acid; 2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethanephosphonic acid; 2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) ethenephosphonic acid; 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-3-enephosphonic acid or 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali N-5-yl) but-1-enephosphonic acid, or a salt thereof.   7. 7. The method according to claim 1, for therapeutic treatment of the human or animal body. Compound.   8. Customary excipients may be in free or pharmacologically acceptable salt forms together with pharmaceutical excipients. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7.   9. A phosphono-protecting group and, if desired, a group R_BAnd / or R_cTo Formula II [Wherein, R_AIs a protected phosphono group, R_BIs the group R_TwoOr a hydroxy-protecting group, R_cIs the base R_ThreeOr a hydroxy-protecting group, and R_Four, R_FiveAnd R₆Is as defined) From the compound of formula I and, if desired, the resulting compound is converted to a different compound of formula I , And the isomer mixture of the compound obtained by this method is separated into each component. The free compound isolated in the preferred isomer and / or obtained in this way can be converted to a salt, Or converting the salt obtained in this way to the free compound (In the formula, R₁Is a free or partially esterified phosphono, R_TwoAnd R_ThreeIs independently hydrogen or an aliphatic group, Group R_Four, R_FiveAnd R₆Are independently of one another hydrogen, aliphatic hydrocarbon radicals, free or Hydroxy, free or etherified mercapto or oxidized free or -Mercapto telluride, unsubstituted or aliphatically substituted amino, nitro, free Or esterified or amidated carboxy, cyano, free or amidated sulfo Famoyl, halogen or trifluoromethyl, and X is a divalent aliphatic group] Novel quinoxaline- and quinoxalinylalkane-phosphonic acids and their mutual A method for producing a isomer or a salt thereof.   10. A method for inhibiting NMDA-sensitive receptors, comprising administering a compound according to claim 1. Pathological conditions that have reacted, such as cerebral ischemia and ischemic diseases such as ocular ischemic disease Vascular and muscular spasms such as migraine or local or generalized spasms, And treatment of convulsions, especially epilepsy.   11. Formula XVII (In the formula, Group R_Four, R_FiveAnd R₆Are independently of one another an aliphatic hydrocarbon radical, free or ether Hydroxy, free or etherified mercapto or oxidized free or ether Mercapto, unsubstituted or aliphatically substituted amino, nitro, free or Is esterified or amidated carboxy, cyano, free or amidated sulfa Moyl, halogen or trifluoromethyl, R_BIs the group R_TwoOr a hydride such as lower alkoxy or phenyl-lower alkoxy A roxy-protecting group, R_cIs the group R_ThreeOr hydro, such as lower alkoxy or phenyl lower alkoxy. A xy-protecting group, and R_DIs the expression − (CH_Two)_n-R_E(XVIIa),-(CH_Two)_n-1-CH = O (XVIIb), -C≡ (CH_Two)_n-2 -R_E(XVIIc), -C≡C- (CH_Two)_n-2-CH = O (XVIId), -CH = CH- (CH_Two )_n-2-R_E(XVIIe) or -CH = CH- (CH_Two)_n-2-CH = O (XVIIf) (wherein R_EAre free radicals such as hydroxy, halogen, lower alkanesulfonyloxy. Or reactive esterified hydroxy, or unsubstituted or lower alkyl-, halo- And / or nitro-substituted benzenesulfonyloxy or naphthalenesul Phonyloxy, and n is 2, 3 or 4) Group) And its use as an intermediate.