SK2798A3 - Novel quinoxaline- and quinoxalinylalkane-phosphonic acids - Google Patents

Abstract

Quinoxaline- and quinoxalinylalkane-phosphonic acids of formula (I), wherein R1 is free or esterified carboxy or free or partially esterified phosphono, R2 and R3 are each independently of the other hydrogen or an aliphatic radical, the radicals R4, R5 and R6 are each independently of the others hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy, free or etherified mercapto or oxidised free or etherified mercapto, unsubstituted or aliphatically substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl and X is a divalent aliphatic radical, and their tautomers and/or salts have NMDA-antagonistic properties and can be used in the treatment of pathological conditions that are responsive to blocking of NMDA-sensitive receptors.

Description

Technical field

The invention relates to novel quinoxaline- and quinoxalinylalkanephosphonic acids, to a process for their preparation and to intermediates used in the process, to a pharmaceutical composition comprising these novel compounds, and to their use.

SUMMARY OF THE INVENTION

The invention relates to novel quinoxaline- and quinoxalinylalkanephosphonic acids of the general formula I

in which

R ¹ is a free or partially esterified phosphono group, R ² and R ³ are each independently hydrogen or an aliphatic radical, R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy, free or etherified mercapto or oxidized free or etherified mercapto, unsubstituted or aliphatic substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, trifluoromethyl, and halogen;

X represents a divalent aliphatic residue, and tautomers and / or salts thereof, pharmaceutical compositions containing these novel compounds, and their use as active ingredients in medicaments.

A free or esterified carboxy group is, for example, a carboxy group, a lower alkoxycarbonyl group or a phenyl (lower) alkoxycarbonyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and / or a trifluoromethyl group.

A free or partially esterified phosphono group is, for example, a lower alkylphosphono group.

Aliphatic radicals ^R2 and / or ^R3 as lower alkyl, lower alkenyl or lower alkynyl groups. The groups R ² and R ³ 0 0, for example, hydroxy or lower alkoxy, but may also be a lower alkenyloxy or lower alkynyloxy.

Aliphatic hydrocarbon radicals are, for example, lower alkyl groups, lower alkenyl groups, but may also be lower alkynyl groups.

The free or etherified mercapto group or oxidized free or etherified mercapto group is, for example, mercapto, lower alkyl, lower alkanesulfinyl or lower alkanesulfonyl, but may also be lower alkenylthio, lower alkynylthio, lower alkenesulfonyl, lower alkenesulfonyl, lower alkenesulfonyl group.

An unsubstituted or aliphatic substituted amino group is, for example, an amino group or an N-mono- or N, Ndi (lower) alkylamino group.

Free or esterified or amidated carboxy is, for example, carboxy, lower alkoxycarbonyl, phenyl (lower) alkoxycarbonyl, which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl; carbamoyl, N-mono- or N, Ndi (lower) alkylcarbamoyl, or N-phenylcarbamoyl or N-phenyl-N- (lower) alkylcarbamoyl, each of which is unsubstituted or substituted on the phenyl moiety by a lower alkyl group , lower alkoxy, hydroxy, halogen and / or trifluoromethyl.

A free or amidated sulfamoyl group is, for example, a sulfamoyl or N-mono- or N, N-di (lower) alkylsulfamoyl group.

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

A bivalent aliphatic residue is, for example, a lower alkylidene residue, a lower alkylene residue, a lower alkenyl residue, or a lower alkynylene residue. /

It is understood that the lower and lower moieties and compounds mentioned above are, for example, moieties and compounds containing up to 7 (inclusive), and preferably up to 4 (inclusive) carbon atoms.

Di (lower) alkylamino is, for example, C 1 -C 4 dialkylamino in each alkyl moiety, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, or dibutylamino.

A di (lower) alkylcarbamoyl group is, for example, a dialkylcarbamoyl group having 1 to 4 carbon atoms in each alkyl moiety, such as dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, or dibutylcarbamoyl.

Di (lower) alkylsulfamoyl is, for example, C 1 -C 4 dialkylsulfamoyl in each alkyl moiety, such as dimethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, diisopropylsulfamoyl, or dibutylsulfamoyl.

Lower alkoxycarbonyl is, for example, C 1 -C 7 alkoxycarbonyl, preferably C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, but also one, butyloxy, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl or pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl.

A lower alkanesulfinyl group is, for example, an alkanesulfinyl group having 1 to 7 carbon atoms, preferably an alkanesulfinyl group having 1 to 4 carbon atoms, such as methanesulfinyl, ethanesulfinyl, propanesulfinyl or butanesulfinyl, but may also be pentanesulfinyl, hexanesulfinyl.

A lower alkanesulfonyl group is, for example, an alkanesulfonyl group having 1 to 7 carbon atoms, preferably an alkanesulfonyl group having 1 to 4 carbon atoms, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl, but may also be pentanesulfonyl or hexanes.

A lower alkenesulfinyl group is, for example, a C 3 -C 4 alkenesulfinyl group such as prop-2-sulfenesyl or but-2-enesulfinyl.

Lower alkanesulfonyl is, for example, C 3 -C 4 alkenesulfonyl, such as prop-2-enesulfonyl or but-2-enesulfonyl.

I

Lower alkenyl is, for example, C 3 -C 4 alkenyl, such as allyl or methalyl.

The lower alkenesulfonyl group may be straight or branched and may be attached at any desired position, and is, for example, straight or branched alkenyl of 2 to 7 carbon atoms, in particular alkenyl of 2 to 4 carbon atoms such as vinylene, 1,3 -prop-2-enylene or 1,4-but-2enylene.

Lower alkenyloxy is, for example, C 3 -C 4 alkenyloxy, such as allyloxy or metalyloxy.

Lower alkynyl is, for example, C 3 -C 4 alkynyl such as propargyl.

Lower alkynyloxy is, for example, C 3 -C 4 alkynyloxy, such as propargyloxy.

Lower alkynylthio is, for example, C 3 -C 4 alkynylthio such as propargylthio.

Lower alkoxy is, for example, C 1 -C 7 alkoxy, preferably C 1 -C 4 alkoxy, such as methoxy, ethoxy, propyloxy or butyloxy, but can also be isobutyloxy, butoxy, p-butyloxy, p-butyloxy hexyloxy or heptyloxy.

A lower alkyl group is, for example, an alkyl group having 1 to 7 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, in particular a methyl group or, secondly, an ethyl, propyl or butyl group, but may also be isobutyl, sec-butyl , tert-butyl or C 5 -C 7 alkyl, such as pentyl, hexyl or heptyl.

Lower alkylamino is, for example, C 1 -C 7 alkylamino, preferably C 1 -C 4 alkylamino, such as, in particular, methylamino, ethylamino, propylamino, isopropylamino or butylamino, but may also be isobutylamino, sec-butylamino, sec-butylamino, sec-butylamino a (C 5 -C 7) alkylamino group such as a pentylamino group, a hexylamino group or a heptylamino group.

Lower alkylcarbamoyl is, for example, C 1 -C 7 alkylcarbamoyl, preferably C 1 -C 4 alkylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, or butylcarbamoyl however, it may be isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl or C5-C7alkylcarbamoyl in the alkyl moiety, such as pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoyl.

The lower alkylidene group may be straight or branched and is, for example, a straight or branched alkylidene group having 1 to 4 carbon atoms, such as methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2- butylidene group.

A lower alkylene group is, for example, a straight C 1 -C 4 alkylene group, for example a group of formula Ia

- (CH ₂ ) _n - (Ia) in which n has a value of, for example, 2, 3 or 4.

A lower alkynylene group is, for example, a straight alkynylene group having 2 to 4 carbon atoms, for example a group of the formula Ic

-OC- (CH ₂ ) n ₂ - (Ic) wherein n has a value of, for example, 2, 3 or 4.

A lower alkenylene group is, for example, a straight C 2 -C 4 alkenylene group, for example a group of formula Ib

-CH = CH- (CH ₂ ) _n - ₂ - (Ib) wherein n has a value of, for example, 2, 3 or 4.

Lower alkylphosphono is, for example, alkylphosphono having 1 to 7 carbon atoms, such as methylphosphono, ethylphosphono, propylphosphono, isopropylphosphono or butylphosphono, but may also be isobutylphosphono phosphono, sec-butylphosphono or sec-butylphosphono. a group, hexylphosphono or heptylphosphono.

Lower alkylthio is, for example, alkylthio of 1 to 7 carbon atoms, preferably alkylthio of 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio or butylthio, but may also be pentylthio, hexylthio or heptylthio.

N-phenyl-N- (lower) alkylcarbamoyl is, for example, N-phenyl-N-alkylcarbamoyl of 1 to 4 carbon atoms in the alkyl moiety, such as N-methyl-N-phenylcarbamoyl, N ethyl-N-phenylcarbamoyl, N-phenyl-N-propylcarbamoyl or N-butyl-N-phenylcarbamoyl.

Phenyl (lower) alkoxycarbonyl is, for example, unsubstituted or C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen and / or C 1 -C 4 trifluoromethyl substituted in the alkoxy moiety, such as e.g. benzyloxycarbonyl or α-phenylethoxycarbonyl.

The existence of tautomers is contemplated, in particular, in the case of compounds of the formula I in which one or both of the radicals r ' and R ² is hydrogen. Tautomers of such compounds of formula I are best illustrated by formula I ', I''orI'''.

R

(I ')

R '(I)

d)

The compounds of formula (I) may form salts with bases or, if at least one of R 1, R 5 and R 6 is unsubstituted or aliphatic substituted amino, they may form internal salts.

The salts of the compounds of the formula I with bases are, for example, their salts and pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, for example alkali metal salts, especially sodium or potassium salts, metal salts alkaline earths, especially calcium or magnesium salts, as well as ammonium salts with ammonia or organic amines or quaternary ammonium bases such as optionally C-hydroxylated aliphatic amines, in particular mono-, dialkyl or tri (lower) alkylamines, for example methyl, ethyl or diethylamine , mono-, di- or tri (hydroxy (lower) alkyl) amines such as ethanol-, diethanol- or triethanolamine, tris (hydroxymethyl) methylamine or 2-hydroxytert-butylamine or N- (hydroxy (lower) alkyl) - N, N-di (lower) alkylamines such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.

The invention includes both complete salts and, depending on the number of acid groups, partial salts, i.e. salts with 1, 2 or 3, preferably 2, base equivalents per mole of acid of the formula

I.

li.

Pharmaceutically unacceptable salts may also be used for isolation or purification purposes. Only pharmaceutically acceptable non-toxic salts are used therapeutically and are therefore preferred.

!

The compounds of formula I exhibit valuable pharmacological properties. In particular, they exhibit a pronounced and selective antagonistic action on N-methyl-D-aspartic acid-sensitive excitatory amino acid receptors (NMDA-sensitive excitatory amino acid receptors) in warm-blooded animals. This can be demonstrated in vitro using, for example, the experimental procedure described by Sills M, Fagg G, Pozza M, Angst Ch, Brundish D, Hurt S, Wilusz E, Williams M .: [ ³ H] CGP 39653: A new N-methyl-D-aspartate radioligand antagonist with low nanomolar affinity in rat brain. Eur. J. Pharmacol. 192, p. 19-24 (1991). In this experiment, it is determined to what extent L-1 H-glutamic acid binding to NMDA-sensitive receptors is inhibited. The concentration required for 50% displacement (IC 50) is in the nanomolar to lower millimolar range, i.e. at concentrations of about 0.0005 to 1 mmol. However, the NMDA-antagonistic properties of the novel compounds can also be demonstrated in vivo, for example in mice, by their inhibitory action against NMDA-induced convulsions.

Due to these properties, the compounds of formula I and their pharmaceutically acceptable salts are very suitable for the treatment of pathological conditions, the active receptors, which respond to blocking NMDA-sensitive, for example ischemic disorders such as cerebral ischemia and ischemic disorders of eyes, vascular and muscular spasms such as migraine. or local or total convulsions and especially convulsions such as epilepsy.

The anticonvulsant properties of the compounds of the invention can be determined, for example, in mice by their strong protective action against electric shock-induced or audiogenic convulsions, using, for example, the established mouse-shock model using electric shocks or the experimental procedure described by Chapman et al., Arzneimittel-Forsch. 34, 1261 (1984). In an electric shock mouse model, for example, the compounds of the invention exhibit an ED 50 value of from about 1 to 10 mg / kg intraperitorally.

The antispastic properties upon which the compounds of the invention are useful for the treatment of migraine can be demonstrated, for example, in rats, by their inhibitory action on depression, according to the experimental procedure described by R. Marannes et al., Brain Res. 457,226 (1988). In this model, the compounds of the invention lower the threshold of spreading depression and shorten its duration, in a dose range of about 3 to 30 mg intraperitoneally.

In particular, the invention relates to compounds of formula I in which:

R ^{@ 1} is lower alkylphosphono, R @ ² and R @ ² are each independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl such as propargyl.

R ⁴ , R ² and R ® are each independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, mercapto, lower alkylthio, lower alkano, alkanesulfonyl, lower alkenylthio, lower alkynylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, lower alkylamino, di (lower) alkylamino, nitro, carboxy, lower alkoxycarbonyl or lower-alkoxy, / and trifluoromethyl substituted phenyl (lower) alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di (lower) alkylcarbamoyl, phenylcarbamoyl or N-phenyl-N- (lower) and alkylcarbamoyl, each of which is unsubstituted or substituted on the phenyl moiety by lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl, cyano, phosphono, lower alkylphosphono, di (lower) alkylphosphono, and represents a lower alkylidene group, a lower alkenyl group, a lower alkenylene group or a lower alkynylene group, and tautomers and / or salts thereof.

In particular, the invention relates to compounds of the formula I in which they represent a phosphono group, R @ ² and R @ ³ each independently represent a hydrogen atom or a C1 -C4 alkyl group such as a methyl or ethyl group, the radicals R @ 1, R @ ³ and R ® are each independently hydrogen, C 1 -C 4 alkyl, such as methyl or ethyl, C 1 -C 4 alkoxy, such as methoxy or ethoxy, C 1 -C 4 alkylthio, such as C 1 -C 4 alkyl, e.g. is methylthio, amino, nitro, carboxy, C 1 -C 4 alkoxycarbonyl, such as methoxy or ethoxycarbonyl, carbamoyl, C 1 -C 4 alkylcarbamoyl, such as methylcarbamoyl, C 1 -C 4 alkyl in each alkyl moiety, such as dimethylcarbamoyl a, halogen or trifluoromethyl, and

X is C1 -C4 alkylidene, such as methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene, C1-C4 alkylene, for example a group of formula Ia

- (CH ₂ ) _n (Ia), a C 2 -C 4 alkenylene group, for example a group of the formula Ib

-CH = CH- (CH ₂ ) _n -2 (Ib), or an alkynylene group having 2 to 4 carbon atoms, for example Ic

-C = C- (CH ₂ ) n- ₂ "(Ic) wherein n in all cases has a value of, for example, 2, 3 or 4, and tautomers and / or salts thereof.

In particular, the invention relates to compounds of formula I in which:

R ¹ is a phosphono group,

R ² is H or alkyl of 1 to 4 carbon atoms, such as methyl or ethyl,

R ³ is H radicals R ^4, R ⁵ and R ⁶ independently of one another are hydrogen, alkyl having 1 to 4 carbon atoms, such as methyl or ethyl, nitro, halogen or trifluoromethyl, and

X represents a C 1 -C 4 alkylidene group such as a methylene group or an ethylidene group or a group of formula Ia, Ib or Ic

- (CH ₂ ) _n (Ia) -CH = CH- (CH ₂ ) _n -2- (Ib) -C? C- _{(CH2) n} _ ₂ - (Ic)

wherein n is in all cases for example 2, 3 or 4, and tautomers and / or salts thereof.

In particular, the invention relates to the compounds of formula I exemplified in the Examples and salts thereof, in particular pharmaceutically acceptable salts.

The process for preparing the compounds of the invention comprises removing the phosphono protecting group and, if desired, the R ^B and / or R 6 groups from the compound of formula II

wherein R ^A is a protected phosphono group, R ^B is a R 6 group or a hydroxyl-protecting group, R ^c is a R ^B group or a hydroxyl-protecting group, and R 6, R 8 and R 6 are as defined above and, when if desired, converting the resulting compound to another compound of formula I, separating the mixture of isomers obtainable by the process into individual components and isolating the particular preferred isomer, and / or converting the free compound obtainable by the process into a salt or converting the salt obtainable by the process to the corresponding free compound.

Suitable phosphono protecting groups and hydroxyl protecting groups are conventional phosphono protecting groups and hydroxyl protecting groups known in the art. In particular, the protected phosphono group R 6 is a phosphone group in the form of an ester, for example in the form of an esterified phosphono group such as a di (lower) alkyl phosphono group or substituted by a lower alkoxy group or lower alkyl halogen and / or nitro group substituted diphenyl or dibenzylphosphono group. Suitable protecting groups of the hydroxyl function in the meaning of R ^B and R ^C are the addition of R ¹ and R ² particularly silyl groups such as tri (lower) alkylsilyl, for example trimethylsilyl, and also unsubstituted or lower alkyl, lower alkoxy, halogen and / or nitro substituted phenyl or benzyl groups.

Said protecting groups are removed by conventional means, for example by solvolysis or hydrogenolysis,

For example, reaction of a compound of formula II wherein R ^A is an esterified phosphono group, R ^B is a R ² group other than hydrogen and R ^c is a R ² group other than a hydrogen atom with an acid hydrolyzing agent provides, for example, a compound of formula I wherein R ¹ is a phosphono group and R ² and R ³ are hydrogen atoms. Acidic hydrolyzing agents are, for example, mineral acids such as hydrohalic acids or sulfuric acid, if desired in admixture with a protic solvent such as acetic acid. Such agents include, for example, from about 30% to about 35% of a solution of hydrobromic acid in acetic acid, a mixture of concentrated, for example, about 35%, hydrochloric acid in acetic acid, or a mixture of equal portions of concentrated, such as about 35%, hydrochloric acid or concentrated sulfuric acid. water and acetic acid. The reactions are preferably carried out at elevated temperature, for example at a temperature in the range of about 80 ° C to about 120 ° C, for example at boiling point.

However, it is also possible to control the reaction in a conventional manner such that an esterified phosphono group, such as a di (lower) alkylphosphono group, is only partially solvolyzed, for example to a lower alkylphosphono group, and / or by removing only one of the hydroxyl protecting groups R ^B and Rf. For example, reaction of a compound of formula II wherein ^RA is esterified phosphono, R ³ is R ² other than a hydrogen atom, a tri (lower) alkyl-halosilane or hexamethyldisilazane and then with a lower alkanol, lower alkenol or lower alkynol, yields the compound of of formula I wherein R 1 is a phosphono group, R ² is a hydrogen atom and R ² is a lower alkyl group, a lower alkenyl group or a lower alkynyl group. The reactions with the silyl compound are preferably carried out in a halogenated hydrocarbon such as dichloromethane, and further reactions with the alcohol are preferably carried out in the presence of water.

The starting materials of formula II in which X represents a lower alkylidene group can be prepared, for example, as follows:

in the compound of formula III

in which R @ 1, R @ ² , R @ 6 and X are as defined above, the nitro group is reduced to the amino group in a conventional manner, for example by hydrogenation in the presence of a hydrogenation catalyst such as Raney nickel; the resulting compound of formula IV

(IV) is subjected in a conventional manner to its reactive derivatives, for example diethyloxalate;

of formula V is oxalic acid or is a diester of oxalic acid, the resulting quinoxaline-2,3-dione

(V) oxo groups in a conventional manner, for example by reaction with oxychlorophosphoric followed by phosphorous and / or chloride cia with an alcohol of the formula

VIb or VIb

R ² -OH

R ³ -OH is converted to groups of formula (VIb) of the formula -OR 4 or -OR 4; in the resulting compound of formula VII

(VII)

-XH 2 O is in a conventional manner, for example using N-bromosuccinimide, halogenated at the α-position relative to the benzene ring, and to obtain the compound of formula II wherein R ^a is esterified "phosphono, such as di (lower) alkylphosphono , the resulting compound of formula VIII

(VIII) wherein Hal represents a halogen atom, for example bromine, is reacted with a phosphorous acid triester such as three (lower) alkyl phosphite such as trimethyl or triethyl phosphite.

In this process for the preparation of the compounds of the formula II, the introduction of the substituents R @ 1, R @ 5 and / or R @ 4 having a meaning other than hydrogen is preferably carried out in the step of the intermediates of the formula III.

Compounds of formula II in which X represents a bivalent aliphatic radical X 'which is not a lower alkylidene group and is, for example, a group of formula Ia, Ib or Ic

- (CH ₂ ) _n - (1a)

CH = CH _(CH2) n-2 ^- db)

-C? C- _{(CH2) r.} 2- (Ic) wherein n is 2, 3 or 4 can be prepared, for example, the compound of formula IX (IX)

by a conventional method, for example in the presence of palladium and triphenylphosphine, preferably in dimethylformamide, at a temperature of about 80 ° C to about 120 ° C, with a compound of formula X

(X) in the resulting compound of formula XI

(XI), if desired, the extracyclic triple bond in a conventional manner, for example by catalytic hydrogenation, preferably in the presence of palladium on carbon, reducing the double or single bond; the resulting compound of formula XII

(XII) is halogenated in a conventional manner, for example by reaction with a halogen halide introducing agent, for example by reaction with 1,1'-carbonyldiimidazole and quaternization of an imidazolyl group, for example with an alkyl halide, and the resulting halogenated subsequent compound of formula XIII

(XIII) is further reacted in a conventional manner, for example as described above, with a reagent introducing an R ^A group such as phosphite, for example three (lower) alkyl phosphite, or triethyl phosphite. This method is suitable for compounds of formula (II) wherein rA of trimethylpropyl acid is an esterified phosphono group, a phosphonium group having an value of 3, or as most preferably di (lower) alkyl4.

In the preparation of compounds of formula (II), a group of formula (IIc) of formula (II) in which X

-CH = CH- (Icl) or Ia, starting with, for example, a compound of formula VIII or XIII, the terminal halomethyl group is converted in a conventional manner, for example by reaction and 2-nitropropane in an alcoholic solution, to the formyl group, resulting aldehyde; reacting with methanediphosphonic acid tetra (lower) alkyl ester in conventional manner to give the corresponding compound of formula XVI

(XVI) and, if desired, the extracyclic double bond is hydrogenated to a single bond. The resulting intermediates in which X contains at least one hydrogen atom in the α-position relative to the benzene ring, thus representing a 1,1- (lower) alkylidene group, for example a methylene group, are converted in a conventional manner, for example by reaction with an alkali metal disilazide such as tetramethyldisilazide sodium, and then an alkylating agent such as a lower alkyl iodide of the formula RI to the corresponding compounds of the formula wherein X represents a lower alkylidene moiety, for example of the formula -XR or -X (R) R, which is linked via a chain member.

The compounds obtainable by this process can be converted into other compounds of the general formula (I) by conventional means.

For example, a compound of formula I wherein rA is a partially esterified phosphono group can be hydrolyzed in a conventional manner to the corresponding compound of formula I wherein R ¹ is a phosphono group.

In addition, a compound of formula I wherein R ³ and / or R ³ is an aliphatic moiety can be solvolyzed in a conventional manner to the corresponding compound of formula I wherein R ³ and / or R ³ represents a hydrogen atom or the corresponding tautomer of formula I ' , for example as described above, to remove hydroxyl protecting groups R ^B and R ^c . Conversely, a compound of formula I wherein R ³ and / or R ³ is hydrogen, or a tautomer thereof of formula I ', I''and / or I'', can be converted by introducing an aliphatic residue in a conventional manner, for example by reaction with a strong halogenating agent such as phosphorus oxychloride and / or phosphorus pentachloride, then with an aliphatic alcohol, into the corresponding compound of formula I, wherein R ³ and / or R ³ is an aliphatic radical, or a corresponding tautomer of formula I ', I''and / or L ^"of .

In addition, the resulting compound of formula I wherein at least one of R ⁴ , R ⁸ and R ® is an etherified mercapto group, for example a lower alkylthio group, can be oxidized in a conventional manner to the corresponding compound of formula I wherein R ⁴ , R ³ or and R 6 represents an oxidized etherified mercapto group, for example a lower alkanesulfin group or a lower alkanesulfonyl group.

Moreover, in the compounds of formula I in which at least one of R ^4, R ³ and R® is a hydrogen atom, to replace the hydrogen by another radical R ^4, R ³ or R than hydrogen. For example, halogenation, nitration or the introduction of a lower alkanoyl group may be conveniently carried out, for example by reaction with a reactive derivative of a lower alkanoic acid such as a lower alkanoic acid chloride in the presence of aluminum chloride, preferably in a halogenated hydrocarbon, in if necessary at boiling point. In addition, the nitro group can be converted in a conventional manner, the amino group can be removed, for example by reduction, and the halogen can be removed in a conventional manner, for example by hydrogenolysis.

The resulting salts can be converted to the free compounds in a manner known per se, for example by reaction with a base such as an alkali metal hydroxide, metal carbonate or metal bicarbonate, or other base-forming salts mentioned above, or with an acid such as a mineral acid such as hydrochloric acid, or other acid-forming salts mentioned above.

The resulting salts can be converted to the free compounds in a manner known per se, acid addition salts, for example by reaction with a suitable metal salt such as sodium, barium or silver salt, other acids, in a suitable solvent in which the inorganic salt formed is insoluble and it is thus eliminated from the reaction equilibrium and the basic salt by liberating the free acid and converting it to the salt again.

The compounds of formula I, including their salts, may also be obtained in the form of hydrates or may contain the solvent used in the crystallization.

Due to the close similarity between the novel compounds in free form and in the form of their salts, it is understood herein that the references to the free compounds and their salts also include the corresponding salts and free compounds, respectively, as appropriate and expedient.

The resulting diastereomeric mixtures and mixtures of racemates can be separated into the pure diastereoisomers or racemates in a known manner by virtue of the physical chemical differences between the components, for example by chromatographic methods and / or fractional crystallization.

The resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by microorganisms or by reaction of the resulting diastereomeric mixture or racemate and an optically active compound, for example, depending on which acidic or basic or functionally modifiable groups are present. in compounds of formula I, by reaction with an optically active acid, base or optically active alcohol to form mixtures of diastereomeric salts or functional derivatives such as esters and separating them into diastereoisomers from which the desired enantiomer can be liberated in a convenient conventional manner. Bases, acids and alcohols suitable for this purpose are, for example, optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L- (1-phenyl) ethylamine, 3pipecoline, 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 Ldi-o-tolyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid acid and optically active alcohols such as borneol or D- or L- (1-phenyl) ethanol.

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

The invention also relates to novel starting compounds which have been developed specifically for the preparation of compounds of the invention, for example compounds of formula XVII

(XVII) wherein the radicals R @ 1, R @ 5 and R @ 4 each independently represent a hydrogen atom, an aliphatic hydrocarbon radical, a free or etherified hydroxy group, a free or etherified mercapto group or an oxidized free or etherified mercaptoxy group, unsubstituted or aliphatic substituted amino group; free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl,

R ^b is R ² or a hydroxyl-protecting group such as a lower alkoxy or phenyl (lower) alkoxy group, r C is R ² or a hydroxyl-protecting group such as a lower alkoxy group or a phenyl (lower) alkoxy group, and

R ^d is XVIIa, XVIIb, XVIIc,

XVIId, XVIIe or XVIIf

- _{(CH2) n-IO} (Xviii) - (CH ₂ ) n -CH = O (XVIIb) -C =C- (CH ₂ ) _{n 2 2} -R ⁶ (XVIIc) -C = C- (CH ₂ ) _{r 2} -CH = O (XVIId) CH = CH (CH ₂₎ n R ₂ ^p (Xviii) -CH = CH- (CH ₂ ) _n -2-CH = O (XVIIf)

where

RE represents a free or reactive esterified hydroxy group such as a hydroxy group, a halogen atom, a lower alkanesulfonyloxy group, or an unsubstituted or lower alkyl group, a halogen and / or nitro substituted benzenesulfonyloxy group or a naphthalenesulfonyloxy group, in particular 2, to obtain the compounds of formula (I) described above as preferred, their preparation and their use as intermediates.

The invention also relates to pharmaceutical compositions comprising as active ingredients compounds of the invention or pharmaceutically acceptable salts thereof, and processes for their preparation.

The pharmaceutical compositions of the invention containing the compounds of the invention, or pharmaceutically acceptable salts thereof, are intended for enteral, such as oral and rectal, and parenteral administration to a warm-blooded animal (or warm-blooded animal), these compositions containing a pharmacologically active ingredient alone or together. with a pharmaceutically acceptable carrier. The daily dose of the active ingredient depends on the age and and on the individual condition of the patient and the route of administration.

The novel pharmaceutical compositions contain, for example, from about 10% to about 80%, preferably from about 20% to about 60%, of the active ingredient. The pharmaceutical compositions of the invention for enteral or parenteral administration are, for example, pharmaceutical compositions in unit dosage forms such as dragees, tablets, capsules or lace as well as ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, mixing, dissolving or lyophilizing processes. For example, pharmaceutical compositions for oral administration may be obtained by mixing the active ingredient with solid carriers, optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary, after adding suitable excipients, into tablets or dragee cores.

Suitable carriers are, in particular, fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or dibasic calcium phosphate, and also binders such as starch pastes based on, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants such as the aforementioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof such as sodium alginate. In particular, the auxiliaries are flow improvers, flow modifiers and lubricating agents, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are coated with suitable coatings, optionally protected from gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or ¹ coating solutions in suitable organic solvents or mixtures solvents, or, for the preparation of gastric juice-protecting coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to distinguish different doses of the active ingredient.

Other pharmaceutical compositions for oral administration are hard gelatin capsules as well as soft sealed capsules formed by gelatin and a plasticizer such as glycerol or sorbitol. Hard gelatine capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as lactose, with binders such as starches and / or lubricants such as talc or magnesium stearate and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oils or liquid polyethylene glycols, and stabilizers may also be added.

Suitable pharmaceutical compositions for rectal administration are, for example, lace, which consist of a mixture of the active ingredient with a lace base material. Suitable base materials for lace are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin capsules for rectal use that contain a combination of the active ingredient with a base material can also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Particularly suitable for parenteral administration are aqueous solutions of the active ingredient in water-soluble form, for example in the form of a water-soluble salt, as well as suspensions of the active ingredient, such as corresponding oily injection suspensions, in which suitable lipophilic solvents or carriers such as fatty oils, for example sesame oil or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

The dose of the active ingredient depends on the species of warm-blooded animal, its age and individual condition, as well as the route of administration. Typically, the approximate daily dose for oral administration to a patient weighing about 75 kg is estimated to be about 10 mg to about 500 mg.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

7-Bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid

0.68 g (1.62 mmol) of 7-bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid diethyl ester was heated at 130 ° C for 15 minutes in 20 ml of a 33% solution of hydrobromic acid in acetic acid. The reaction mixture is allowed to cool to room temperature, 80 ml of diethyl ether are added and the mixture is stirred for 30 minutes. The crystalline precipitate is filtered off, washed with diethyl ether and dried to give the title compound, m.p. > 300 ° C.

H-NMR (300 MHz; in DMSO) = 12.2 (s, 1H), 11.30-11.70 (m, 1H), δ (ppm)

7.18 (m, 2H); 3.32 (d, 2H, J = 22.5 Hz)

The starting material can be prepared as follows:

a) 7-Bromo-5-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline

To a solution of 55.7 g (366 mmol) of 2-methyl-6-nitroaniline in 500 mL of acetic acid was added dropwise 22.6 mL (440 mmol) of bromine. A suspension is formed which is stirred for 1 hour at room temperature, poured into 2000 ml of ice-water and filtered under vacuum. Washing with water and drying gave an orange-colored solid. 40 g of this material is dissolved in 600 ml of ethanol, 6 g of Raney nickel are added and the mixture is shaken under a hydrogen atmosphere until 12,300 ml of hydrogen are consumed. The catalyst was filtered through a pad of diatomaceous earth and the filter cake was washed thoroughly with ethanol. The filtrate and washings were combined and concentrated under reduced pressure. The residue is taken up in 1000 ml of 2N hydrochloric acid, 31.15 g (346 mmol) of oxalic acid are added and the mixture is heated at reflux overnight. The reaction mixture was then allowed to cool to room temperature, poured into 1000 ml of ice-water, filtered under vacuum, washed with water and dried. The resulting solid was suspended in a small amount of acetone, stirred for 30 minutes, filtered again under vacuum, washed first with acetone and then with diethyl ether and dried to give the title compound as a brownish solid, m.p. ° C.

1 H-NMR (200 MHz; in DMSO): δ (ppm) = 11.95 (s, 1H), 11.31 (s, 1H), 7.13 (s, 2H), 2.32 (s , 3H)

(b) 7-Bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphinic acid diethyl ester

38.13 g (149.5 mmol) of 7-bromo-5-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline and 68.5 g (329 mmol) of phosphorus pentachloride are mixed carefully, the mixture Stir gently and slowly heat to 160 ° C at the sulfonation flask, at which point phosphorus oxychloride begins to distill off. The reaction mixture was then slowly heated to 200 ° C until further phosphorus oxychloride separated, then allowed to cool and poured into 2000 mL of water. The precipitate which separated is filtered off under reduced pressure, washed with water and dried, then taken up in 2000 ml of dichloromethane and filtered. The filter residue was washed with dichloromethane and the combined filtrates were dried over magnesium sulfate, concentrated by evaporation and dried to give 25 g of 7-bromo-2,3-dichloro-5-methylquinoxaline as a tan solid which was suspended in 300 g. ml of methanol. To this suspension was added a solution of 227 mmol of sodium methoxide in 47 mL of methanol. The mixture was heated to boiling for 3 hours, excess methanol was removed and the remaining product was extracted between 500 mL of ethyl acetate and 500 mL of water. The aqueous phase is extracted again by shaking with 500 ml of ethyl acetate. The organic phases are washed successively with 300 ml of water and 300 ml of saturated sodium chloride solution, combined and dried over magnesium sulphate. Concentration by evaporation and crystallization from methanol gave 16.39 g of 7-bromo-2,3-dimethoxy-5-methylquinoxaline as white crystals. 14.72 g of these crystals, 10.6 g (59.6 mmol) of N-bromosuccinimide and 0.86 g (5.2 mmol) of AIBN (azobisisobutyronitrile) are heated to reflux in 300 ml of carbon tetrachloride for 4 hours. filtration, the filter residue is washed with carbon tetrachloride and the combined filtrates are concentrated by evaporation. The residue (7-bromo-2,3-dimethoxy-5-bromomethyl-quinoxaline) was heated to reflux in triethyl phosphite for 15 hours. Excess triethylphosphite was removed and the residue was chromatographed on silica gel using ethyl acetate as eluent to give the title compound.

@ 1 H-NMR (200 MHz; in DMSO): .delta. (ppm) = 7.8 (m, 1H), 7.65 (s, 1H), 4.03 (s, 3H), 3.96 (m) .

4H), 3.75 (d, 2H, J = 22.5Hz), 1.10 (t, 6H, J = 7Hz)

Example 2

2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid

4.21 g (10.8 mmol) of 7-bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid dimethyl ester and 1.2 g of triethylamine are dissolved in 100 ml of methanol, 0.4 g of palladium on carbon are added and the reaction mixture is added. The mixture is stirred under a hydrogen atmosphere until 258 ml of hydrogen are consumed. The catalyst is filtered off, the filter residue is washed with methanol and the mixture is concentrated to dryness by evaporation. The residue was dissolved in 20 ml of acetic acid, 20 ml of water and 20 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, poured into 200 ml of water, filtered under vacuum, the filter residue was washed with water, acetone and diethyl ether and allowed to dry to give the title compound as off-white crystals at temperature. mp > 280 ° C.

@ 1 H-NMR (200 MHz; in DMSO): .delta. (Ppm) = 12.0 (s, 1H), 11.6-11.1 (m, 1H), 7.03 (m, 3H) .

3.30 (d, 2H, J = 20Hz)

The starting material can be prepared as follows:

(a) 7-Bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphinic acid dimethyl ester

16.39 g (57.9 mmol) of 7-bromo-2,3-dimethoxy-5-methylquinoxaline,

11.2 g (60.8 mmol) of N-bromosuccinimide and 0.514 g (3.13 mmol) of AIBN (azobisisobutyronitrile) are heated to reflux in 300 ml of tetrachloromethane for 4 hours. After filtration, the filter residue is washed with dichloromethane. The combined filtrates were extracted successively with 500 ml of 1N hydrochloric acid and saturated sodium chloride solution with shaking. The aqueous phases are extracted with shaking with dichloromethane and all organic phases are combined, dried over magnesium sulphate and concentrated by evaporation. 21.0 g of solid are obtained. 15.7 g of this solid are dissolved in 200 ml of trimethyl phosphite and the mixture is heated at reflux overnight. The excess triethyl phosphite is then removed and the residue is purified by chromatography on silica gel using ethyl acetate as eluent to give the title compound.

@ 1 H-NMR (300 MHz; in DMSO): .delta. (Ppm) = 7.83 (m, 1H), 7.66 (s, 1H), 4.08 (s, 3H), 4.05 ( m.

3H), 3.87-3.58 (m, 8H)

Example 3

7-Bromo-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid

5.43 g (13.9 mmol) of 7-bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid dimethyl ester and 1.45 g (18.0 mmol) of ammonium nitrate are heated at 60 ° C in 10 ml of a mixture of the same parts of dichloromethane and trichloromethane. 15.15 g (72.2 mmol) of acetic anhydride are then added dropwise over 1 hour. The reaction mixture is stirred for 3 hours, allowed to cool to room temperature and extracted with shaking with 200 ml of water and twice with 200 ml of saturated sodium bicarbonate solution. The aqueous phases are back-extracted with 200 ml of dichloromethane each time. The combined organic phases are dried over magnesium sulphate and concentrated by evaporation. The residue is purified by chromatography on silica gel, eluting first with ethyl acetate and then with a 10: 1 mixture of ethyl acetate and diethyl ether, and crystallizing from methanol. The resulting 7-bromo-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid dimethyl ester was dissolved in 5 ml of acetic acid, 5 ml of water and 5 ml of concentrated hydrochloric acid and the mixture was heat to reflux for 24 hours. The reaction mixture is allowed to cool to room temperature, concentrated to dryness by evaporation and crystallized from ethanol / diethyl ether to give the title compound in crystalline form, m.p. > 250 ° C.

^{@ 1} H-NMR (300 MHz; in CDCl3): .delta. (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-tetrahydroquinoxalin-5-yl) ethanephosphonic acid

To a solution of 1.8 6 g (4.16 mmol) of 7-bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid dimethyl ester in 20 mL of tetrahyrofuran at -20 ° C was added dropwise 5.23 mL of 1 M sodium hexamethyldisilazide solution. in tetrahydrofuran. After 20 minutes, methyl iodide (6.75 g, 47.6 mmol) was added and the reaction mixture was heated at reflux for 3 hours, digested with 100 mL of saturated ammonium chloride solution and extracted twice by shaking with 200 mL of ethyl acetate. The extracts are combined, dried over magnesium sulphate, concentrated to dryness by evaporation and chromatographed on silica gel using ethyl acetate and then ethyl acetate / diethyl ether (10: 1) as the eluent. Crystallization from a mixture of methanol and diethyl ether gives the title compound, m.p.

300 ° C.

@ 1 H-NMR (200 MHz; in DMSO): .delta. (Ppm) = 12.02 (s, 1H), 11.90 - 11.60 (s, 1H), 7.30 (m, 1H) .

7.19 (m, 1H), 3.68 (qd, 1H, J ¹ = 7.5 Hz, J ² = 22.5 Hz),

1.39 (dd, 1H, J ¹ = 7.5Hz, J ² = 17.5Hz)

Example 5

7-Bromo-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid

To a solution of 7-bromo-2,3-dimethoxyquinoxalin-5-ylmethanephosphonic acid dimethyl ester (1.91 g, 4.88 mmol) in dichloromethane (25 mL) was added dropwise 7.47 g (48.8 mmol) at 0 ° C. trimethylbromosilane. The reaction mixture was warmed to room temperature and stirred overnight. Dichloromethane and excess trimethyl bromosilane were removed and the residue was dried for 3 hours at room temperature under 1 mm Hg. The residue was dissolved in 20 ml of methanol, 0.3 ml of water was added and the mixture was stirred for 3 hours. The precipitate which separated was filtered off under vacuum, washed with methanol and diethyl ether and dried to give the title compound, m.p. 245-250 ° C.

@ 1 H-NMR (200 MHz; in CDCl3): .delta. (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-tetrahydroquinoxalin-5-ylacetic acid

To 2.35 g (6.5 mmol) of 7-bromo-2,3-dimethoxy-5-bromomethyl-quinoxaline in 40 ml of water and 40 ml of dichloromethane was added tetrabutylammonium cyanide and the reaction mixture was stirred overnight. The organic phase is separated and washed with water. The aqueous phase is back-extracted with dichloromethane. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation. The residue is purified by chromatography on silica gel, eluting with hexane: ethyl acetate (20: 1, then 15: 1, then 10: 1), and then taken up in 10 ml of tetrahydrofuran. 5 ml of 2N hydrochloric acid are added and the mixture is heated at reflux overnight. The reaction mixture was allowed to cool to room temperature, poured into 50 ml of water, filtered under reduced pressure, washed with water and dried. The filter residue is suspended in 3 ml of water, 3 ml of acetic acid and 3 ml of concentrated sulfuric acid are added, and the mixture is heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, poured into 50 mL of ice water, filtered, washed with water and dried to give the title compound, m.p. > 280 ° C.

@ 1 H-NMR (200 MHz; in DMSO): .delta. (Ppm) = 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-tetrahydroquinoxalin-5-yl) propanephosphonic acid

0.584 g (1.45 mmol) of 3- (7-chloro-2,3-dimethoxy-quinoxalin-5-yl) -propanephosphonic acid diethyl ester was heated at 110 ° C for 20 minutes in 25 ml of a 33% solution of hydrobromic acid in acetic acid. The reaction mixture is allowed to cool to room temperature, 80 ml of diethyl ether are added and the mixture is stirred for 30 minutes. The crystalline precipitate is filtered off, washed with diethyl ether and dried to give the title compound, m.p. 220-222 ° C.

The starting material can be prepared as follows:

a) 5-iodo-2,3,7-trichloroquinoxaline

To a mixture of 195.9 g (0.93 mol) of 7-chloro-5-iodoquinoxalindione in 1200 ml of phosphorus oxychloride was added 406.9 g (1.953 mol) of phosphorus pentachloride and the reaction mixture was stirred at reflux for 18 hours. The excess phosphorus oxychloride was distilled off from the reaction mixture at a bath temperature of 150 ° C. The residue was poured into 6000 ml of ice water, the resulting suspension was stirred for 2 hours, filtered under vacuum and the filter residue was washed with plenty of water. The filter residue is dried under vacuum at 60 ° C to give 5-iodo-2,3,7-trichloroquinoxaline as pale brown crude crystals which can be used in the next reaction without further purification.

b) 7-chloro-2,3-dimethoxy-5-iodoquinoxaline

205 g (0.828 mol) of 5-iodo-2,3,7-trichloroquinoxaline are added to 2255 ml of methanol at room temperature and 463.9 ml of an approximately 5.4 M solution of sodium methoxide in methanol are added. The reaction mixture was then heated to reflux and stirred for 18 hours. The reaction mixture was cooled to 0 ° C and the suspension was filtered under vacuum. The filter residue is washed with methanol, dried under vacuum at 60 ° C and the crude product is purified by continuous extraction with diethyl ether to give 7-chloro-2,3-dimethoxy-5-iodoquinoxaline, m.p. 94 96 ° C.

c) 3- (7-chloro-2,3-dimethoxyquinoxalin-5-yl) prop-2-yn-1-ol

12.9 g (36.8 mmol) of 7-chloro-2,3-dimethoxy-5-iodoquinoxaline, 7.6 ml (128.4 mmol) of propargyl alcohol, 2.1 g (3 mmol) of bis (triphenylphosphine) palladium- of dichloride, 6.6 ml (47.4 mmol) of triethylamine and 0.34 g (1.8 mmol) of copper (I) iodide are added to 125 ml of dimethylformamide and the mixture is heated to a bath temperature of up to 70 ° C. at room temperature for 3.5 hours and then allowed to cool to room temperature. Ethyl acetate was added and the reaction mixture was extracted with water, 1N hydrochloric acid and brine. The aqueous phase was washed with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered under reduced pressure and concentrated. Chromatography of the crude product on silica gel using 3: 1 hexane / ethyl acetate as eluent gave 3- (7-chloro-2,3-dimethoxyquinoxalin-5-yl) prop-2-in-1-ol as brown crystals mp 137-140 ° C.

d) 3- (7-Chloro-2,3-dimethoxy-quinoxalin-5-yl) -propan-1-ol

2.05 g (7.36 mmol) of 3- (7-chloro-2,3-dimethoxyquinoxalin-5-yl) prop-2-yn-1-ol is hydrogenated in 20 ml of tetrahydrofuran with about 0.4 g of Raney-nickel to normal pressure until twice the molar amount of hydrogen has been removed. The hydrogenation mixture is filtered under vacuum through a glass fiber filter and the filtrate is concentrated to give 3- (7-chloro-2,3-dimethoxyquinoxalin-5-yl) propan-1-ol as beige crystals, m.p. 105 ° C.

e) 5- (3-bromopropyl) -7-chloro-2,3-dimethoxyquinoxaline

0.5 g (1.77 mmol) of 3- (7-chloro-2,3-dimethoxyquinoxalin-5-yl) propan-1-ol and 0.287 g (1.77 mmol) of 1,1'-carbonyldiimidazole are introduced under a nitrogen atmosphere into 5 ml of acetonitrile. Allyl bromide (0.75 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes and refluxed for 2 hours. The reaction mixture was cooled to room temperature, diethyl ether was added, and the mixture was extracted with water, 0.1 N hydrochloric acid, saturated sodium bicarbonate solution and brine. The aqueous phases are washed with diethyl ether. The organic phases are combined, dried over sodium sulfate, filtered through a pad of silica gel and concentrated to give 5- (3-bromopropyl) -7-chloro-2,3-dimethoxyquinoxaline as a yellow oil which is used without further purification.

f) 3- (7-Chloro-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-dimethoxyquinoxaline is dissolved in 10 ml of trimethylphosphite and the mixture is refluxed overnight. Excess trimethyl phosphite is then removed and the residue is purified by chromatography on silica gel using ethyl acetate as eluent to give the title compound.

Example 8

3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-phosphonic acid

The title compound is obtained in an analogous manner to that described in Example 7, except that in step (e), 3- (7-chloro-2,3-dimethoxy-quinoxalin-5-yl) -propane is used in place of step (e).

3- (7-Chloro-2,3-dimethoxy-quinoxalin-5-yl) -prop-2-yn-1-ol.

Example 9

3- (7-Chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enephosphonic acid

The title compound is obtained in an analogous manner to that described in Example 7, except that in step d) hydrogenation is carried out until an equimolar amount of hydrogen is taken.

Example 10

2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethenephosphonic acid

0.88 g (1.5 mmol) of 2- (7-bromo-2,3-dimethoxy-1,2,3,4-tetrahydroquinoxalin-5-yl) -ethenephosphonic acid tetraethyl ester was heated at 110 ° C for 30 min. ml of a 33% solution of hydrobromic acid in acetic acid. The reaction mixture was allowed to cool to room temperature, 100 mL of diethyl ether was added, the mixture was stirred for 30 minutes and the crystalline precipitate was filtered off, washed with diethyl ether and dried to give the title compound, m.p. > 300 ° C.

The starting material can be prepared as follows:

a) 7-Bromo-5-formyl-2,3-dimethoxyquinoxaline

1.38 g (60 mmol) of sodium are dissolved in portions in 200 ml of methanol at 0 [deg.] C. under nitrogen. 5.85 ml (65 mmol) of 2-nitropropane are added dropwise at 0 ° C. Then 18.1 g (50 mmol) of 5- (bromomethyl) -7-bromo-2,3-dimethoxyquinoxaline are added. The beige suspension was heated to reflux for 1 hour with stirring. The reaction mixture is poured into 600 ml of water and the methanol is distilled off. The residue is extracted twice with ethyl acetate, the organic phases are dried over sodium sulphate and filtered under reduced pressure. The filtrate was concentrated and the residue was dried under high vacuum to give 7-bromo-5-formyl-2,3-dimethoxyquinoxaline as beige crystals, m.p. 179 182 ° C.

b) 2- (7-Bromo-2,3-dimethoxy-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanediphosphonic acid tetraethyl ester

0.35 g (15.5 mmol) of sodium is dissolved in portions in 50 ml of ethanol at 0 ° C under nitrogen. 2.9 g (10 mmol) of methanediphosphonic acid tetraethyl ester are added dropwise at 0 ° C, the reaction mixture is allowed to warm to room temperature and 2.97 g (10 mmol) of 7-bromo-5-formyl-2 are added. 3-dimethoxy-quinoxaline. The reaction mixture is stirred for 2 hours, poured into 200 ml of ice water, neutralized with hydrochloric acid and extracted three times by shaking with 50 ml of diethyl ether each time. The combined ether extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a yellowish oil, which was used in the subsequent reaction without further purification.

Example 11

2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid

The title compound was prepared in an analogous manner to that described in Example 10, except that the intermediate of step b) was hydrogenated in the presence of 0.5 g of Raneynicl until an equimolar amount of hydrogen was taken.

Example 12

4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butanephosphonic acid

The title compound was prepared in an analogous manner to that described in Example 7 except that in step c) an appropriate amount of but-3-ol was added instead of propargyl alcohol.

Example 13

The following compounds can be prepared in an analogous manner to that described in Examples 1 to 12:

1- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid,

2- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid,

3- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) propanephosphonic acid,

4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butanephosphonic acid,

4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-enephosphonic acid,

4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enphosphonic acid,

2- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethenephosphonic acid,

3- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enophosphonic acid,

3- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-ynophosphonic acid,

4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enphosphonic acid,

3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) propanephosphonic acid,

4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butanephosphonic acid,

3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enophosphonic acid,

3- (7-Bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) -prop-2-ylphosphonic acid,

4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enephosphonic acid,

4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-enephosphonic acid,

1- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid,

2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid,

2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethenephosphonic acid,

4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enphosphonic acid; and

4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-enephosphonic acid,

Example 14

Tablets each containing 50 mg of 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid or a salt thereof, for example sodium salt, may be prepared as follows:

Ingredients (per 10,000 tablets) active ingredient 500.0 g lactose 500.0 g potato starch gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g highly dispersed silica 20.0 g ethanol q.s.

The active ingredient is mixed with lactose and 292 g of potato starch, moistened with an ethanolic gelatin solution and granulated through a sieve. After drying, the remainder of the potato is mixed

4Ί starch, magnesium stearate, talc and silica, and compressed into tablets, each weighing 145.0 mg and containing 50 mg of the active ingredient. If desired, tablets may be provided with score slots for more accurate dose adjustment.

Example 15

A sterile filtered aqueous solution of gelatin with a 20% cyclodextrin solubilizer containing 3 mg of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-ylmethanephosphonic acid or a salt thereof, for example the sodium salt, as an active ingredient, is mixed with sterile a solution of gelatin containing phenol as a preservative, under heating and aseptic conditions, so that 1.0 ml of the solution has the following composition:

active ingredient 3 mg

gelatin 150, 0 mg phenol 4.7 mg distilled water with 20% cyclodextrins as a solubilizer 1.0 ml

Example 16

For the preparation of a sterile dry substance for injection containing 5 mg of 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid or a salt thereof, for example sodium salt, 5 mg of one of the compounds of the formula I mentioned in of the preceding examples, as active ingredient dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrins as solubilizers. The solution is sterile filtered and transferred under aseptic conditions to a 2 ml ampoule, deep-frozen and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. This solution is administered intramuscularly or intravenously. This formulation can also be administered using dual-chamber disposable syringes.

Example 17

000 film-coated tablets each containing 100 mg 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonate

or phonic acid; or its salts, for example sodium salt, maybe prepare as follows: active ingredient 1000 g maize starch 680 g colloidal silicon dioxide 200 g magnesium stearate 20 g stearic acid 50 g Sodium carboxymethyl starch 250 g Water qs

A mixture of one of the compounds of the formula (I) mentioned in the previous examples, as active ingredient, 50 g of corn starch and colloidal silica is processed to a moist mass using a starch paste prepared from 250 g of corn starch and 2.2 kg of demineralized water. The wet mass is passed through a 3 mm sieve and dried in a fluid bed dryer at 45 ° C for 30 minutes. The dry granules are pressed through a 1 mm sieve, mixed with a mixture of 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch, previously sieved through a 1 mm sieve, and the resulting mixture is compressed into slightly domed tablets.

Example 18

In a manner analogous to that described in Examples 14 to 17, pharmaceutical preparations may also be prepared which contain another compound according to any one of Examples 1 to 13.

Claims (11)

PATENT CLAIMS A quinoxaline- or quinoxalinylalkanephosphonic acid of the general formula I in which ^R1 is free or partially esterified phosphono, R ^ and R ^ are each independently hydrogen or an aliphatic radical, the radicals R ^4, R ⁵ and R ⁶ independently of one another are hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy, free or etherified mercapto or oxidized free or etherified mercapto, unsubstituted or aliphatic substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or halo; X represents a divalent aliphatic residue, or a tautomer thereof, or a salt thereof or a tautomer thereof. A quinoxaline- or quinoxalinylalkanephosphonic acid of the general formula I according to claim 1, in which R ¹ is phosphono or lower alkylphosphono, the symbols R and R 3 independently of one another are hydrogen, lower alkyl, lower alkenyl or lower alkynyl, such as propargyl, the radicals R ^4, R ⁵ and R ⁶ independently each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a mercapto group, a lower alkylthio group, a lower alkanesulfinyl group, a lower alkanesulfonyl group, , lower alkanesulfonyl, amino, lower alkylamino, di (lower) alkylamino, nitro, carboxy, lower alkoxycarbonyl, unsubstituted or lower alkyl, lower alkoxy, hydroxy , halogen and / or trifluoromethyl substituted phenyl (lower) alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di (lower) alkylcarbamoyl, phenylcarbamoyl or N-phenyl-N- (lower) alkylcarbamoyl, each of which is unsubstituted or substituted on the phenyl moiety by lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl, cyano, phosphono, lower alkylphosphono, di (lower) alkylphosphono, halogen atom or trifluoromethyl and X represents a lower alkylidene group, a lower alkenyl group, a lower alkenylene group or a lower alkynylene group, or a tautomer thereof, or a salt thereof or a tautomer thereof. A quinoxaline- or quinoxalinylalkanephosphonic acid of the general formula I according to claim 1, wherein: R 1 is phosphono, R ^ and R ^ each independently are hydrogen, or alkyl of 1 to 4 carbon atoms, such as methyl or ethyl, radicals R.4, R5 _and R6 independently of one another are H , (C 1 -C 4) alkyl, such as methyl or ethyl, (C 1 -C 4) alkoxy, such as methoxy or ethoxy, (C 1 -C 4) alkylthio, such as methylthio, amino, nitro, carboxy, alkoxycarbonyl C 1 -C 4 alkoxy, such as methoxy or ethoxycarbonyl, carbamoyl, C 1 -C 4 alkylcarbamoyl, such as methylcarbamoyl, C 1 -C 4 dialkylcarbamoyl in each alkyl moieties such as dimethylcarbamoyl, halogen or trifluoromethyl, and X represents a C 1 -C 4 alkylidene group such as methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene, or a tautomer or salt thereof, or its tautomer. The quinoxaline- or quinoxalinylalkanephosphonic acid of the formula I according to claim 1, wherein: R ¹ is a phosphono group, R 2 and R 4 are each independently hydrogen or C 1 -C 4 alkyl, such as methyl or ethyl; R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, C 1 -C 4 alkyl, such as methyl or ethyl, C 1 -C 4 alkoxy, such as methoxy or ethoxy, C 1 -C 4 alkylthio, such as methylthio, amino, nitro, carboxy, (C 1 -C 4) alkoxycarbonyl, such as methoxy or ethoxycarbonyl, carbamoyl, alkylcarbamoyl group 1-4 carbon atoms in the alkyl moiety such as methylcarbamoyl, dialkylcarbamoyl of 1-4 carbon atoms in each alkyl moiety such as dimethylcarbamoyl, halogen or trifluoromethyl, and X represents a C 1 -C 4 alkylidene, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene group, or a tautomer thereof, or a salt thereof or a tautomer thereof. The quinoxaline- or quinoxalinylalkanephosphonic acid of the general formula I according to claim 1, which is 7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid, 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid, 7-bromo-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid, 1- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid, or 7-bromo-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethanephosphonic acid, or a salt of any of these acids. 6. A compound of the formula I as claimed in claim 1 which is: 3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) propanephosphonic acid, 3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaliri-5-yl) prop-2-phosphinic acid, 3- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enephosphonic acid, 2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethene-phosphonic acid, 2- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid, 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butanephosphonic acid, 1- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid, 2- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid, 3- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) propanephosphonic acid, 4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butanephosphonic acid, 4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-enephosphonic acid, 4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enphosphonic acid, 2- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethenephosphonic acid; 3- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enephosphonic acid, 3- (2,3-Dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) -prop-2-phosphonic acid, 4- (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enphosphonic acid, 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) propane-phosphonic acid, 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) butane-phosphonic acid, 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-enephosphonic acid, 3- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) prop-2-phosphinic acid, 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-ene-phosphonic acid, 4- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-ene-phosphonic acid, 1- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethane-phosphonic acid, 2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethanephosphonic acid, 2- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) ethenephosphonic acid, 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-3-enephosphonic acid, or 4- (7-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) but-1-enephosphonic acid, or a salt of any of these acids. A quinoxaline- or quinoxalinylalkanephosphonic acid of the formula I according to any one of claims 1 to 6 for the therapeutic treatment of the human or animal body. A pharmaceutical composition comprising a quinoxaline- or quinoxalinylalkanephosphonic acid of the formula I according to any one of claims 1 to 7 in free form or in the form of a pharmaceutically acceptable salt, together with conventional pharmaceutical carriers and / or excipients. A process for the preparation of quinoxaline- or quinoxalinylalkanephosphonic acid of the general formula I (I) in which: R ^{@ 1} is a free or partially esterified phosphono group, R @ ⁴ and R @ 3 are each independently hydrogen or an aliphatic radical, R @ ⁴ , R @ 4 and R @ 3 are each independently hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy , free or etherified mercapto or oxidized free or etherified mercapto, unsubstituted or aliphatic substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl X represents a divalent aliphatic residue, or a tautomer thereof, or a salt thereof or a tautomer thereof, characterized in that the phosphono group is removed and, if desired, the group R® and / or R * from the compound of formula II in which: R ^A is a protected phosphono group, R ^B is a hydroxyl function or protecting group, R ^c is a hydroxyl function or protecting group, and R ^, R ^ and R ^ are as defined above and, if desired, carry out the resulting compound to another quinoxaline- or quinoxalinylalkanephosphonic acid of formula (I), separating the mixture of isomers obtainable in this way into the individual components and isolating the particular preferred isomer and / or converting the free quinoxaline- or quinoxalinylalkanephosphonic acid obtainable in this manner into a salt or converting it in the corresponding way free compound. A method of treating pathological conditions that respond to blocking NMDA-sensitive receptors, for example ischemic disorders such as cerebral ischemia and ischemic disorders of the eyes, vascular and muscular spasms such as migraine or local or general seizures, and in particular convulsions such as epilepsy, characterized by comprising administering a quinoxaline or quinoxalinylalkanephosphonic acid of formula I according to claim 1. A compound of formula XVII (XVII) wherein R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, an aliphatic hydrocarbon radical, a free or etherified hydroxy group, a free or etherified mercapto group or an oxidized free or etherified mercapto group, unsubstituted or aliphatic substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl, rB means a group R ² or protective functions, a hydroxyl group -C represents a group R ³ or a protecting group a hydroxyl group a rD represents a group of the general formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe or XVIIf - (CH ₂ ) _n -R ^E (Xviii) - (CH ₂ ) - -01 = 0 (XVIIb) -C =C- (CH ₂ ) _{n 2 2} -R ^E (XVIIc) -C? C- (CH _{2) n} -CH ₂ _ H (XVIId) -CH = CH- (CH ₂ ) _n - ₂ -R ^E (Xviii) -CH = CH- (CH ₂ ) n-2-CH = O (XVIIf) where RE represents a free or reactive esterified hydroxy group, and n has a value of 2, 3 or 4 and its use as an intermediate.