SK281518B6 - Quinoxaline derivates with affinity for quisqualate-receptors - Google Patents

Abstract

The present invention relates to quinoxalinedione-carboxylic acid and quinoxalinedione-phosphonic acid derivatives of the general formula (I) in which the substituents have the meanings given in the description, their preparation and their use in medicaments. The compounds of formula (I) as well as their physiologically acceptable salts are useful as medicaments for the treatment of diseases caused by hyperactivity of excitatory amino acids, such as glutamate or aspartate, owing to their affinity for the quasiqualate receptors.

Description

Technical field

The invention relates to quinoxalinedione-carboxylic acid and quinoxalinedione-phosphonic acid derivatives, processes for their preparation and their use in medicaments.

BACKGROUND OF THE INVENTION

Quinoxaline derivatives are known to have an affinity for quasiqualate receptors and, based on this affinity, are useful as medicaments for the treatment of central nervous system diseases.

WO 9 113 878 describes substituted 1-carboxyalkyl-quinoxaline-2,3-dione derivatives, but a potentiating and selective glycine-antagonistic effect is reported in these

SUMMARY OF THE INVENTION

Compounds of the present invention have been found to exhibit their good ability to bind to quasiqualate receptors as compared to the quinoxalines known from EP-A-315959 and WO91 / 13878.

The present invention provides compounds of formula (I):

in which

R ¹ is C 1 -C 12 alkyl, substituted with R ² , C 2 -C 12 alkenyl, substituted with R ² , C 2 -C 12 alkynyl, substituted with R ² , C 3 -C 7 cycloalkyl , substituted with R ² , - (CH 2) n -aryl having 6 to 12 carbon atoms in the aryl group which is substituted by R ² in the aryl or alkyl moiety, or - (CH 2) _n -hetaryl group which is in the hetaryl or alkyl group moiety by R ^2,

R ⁴ represents a hydrogen atom, a C 1 -C 12 alkyl group, substituted with R ² , a C 2 -C 12 alkenyl group, a substituted R ² , a C 2 -C 12 alkynyl group, a substituted R ² group, a C 3 -C 3 cycloalkyl group 7-carbon atoms, substituted with R ² , - (CH 2) n -aryl having 6 to 12 carbon atoms in the aryl which is substituted by R ² in the aryl or alkyl radical, or - (CH 2) n -hetaryl group which is hetaryl or alkyl moiety by R ^2, and

R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are hydrogen, halogen, nitro, NR ⁹ R ¹⁰ , NHCOR ¹¹ , SO ₂ R ¹² , cycloalkoxy of 3 to 7 carbon atoms, COR ¹³ , cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 4 alkoxy or imidazole, optionally substituted with cyano, C 1 -C 4 alkyl or -C 1 -C 1 -alkyl up to 6 carbon atoms in the alkyl;

R ⁵ and R ⁶ or R ⁷ and R ⁸ represent a fused benzene ring, wherein

R ² is -CO-R ³ or -PO-XY and R ² is one to two same or different, n is 0,1,2,3,4 or 5,

R ³ is hydroxy, alkoxy of 1 to 6 carbon atoms, or -NR ⁹ R ^10,

X and Y are the same or different and are hydroxy, alkoxy of 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms or the group -NR ^10,

R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a saturated 5- or 6-membered heterocycle which may contain an additional oxygen or sulfur atom, together with the nitrogen atom,

R ¹ 'represents an alkyl group having 1 to 6 carbon atoms or a phenyl group,

R ¹² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group or a dialkylamino group having 1 to 4 carbon atoms in each alkyl, and

R ¹³ represents hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or -NR'R ¹⁰ as well as their isomers or salts, provided that when R ⁴ represents a hydrogen atom, and R 'represents an alkyl group having 1 to 6 carbon atoms, substituted with R ² = -COR ³ , cannot be R, R ⁶ , R ⁷ or R ⁸ , a hydrogen atom, a nitro group, a halogen atom, or an alkyl group of 1 to 6 carbon atoms.

The compounds of formula (I) also include possible tautomeric forms and E- and Z-isomers or, if an optically active center is present, also racemates or enantiomers.

The substituents are preferably in the 6- and / or 7- position,

R ² stands once or twice by identical or different in any position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl radicals.

An alkyl group refers to an appropriate straight or branched alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl a group, hexyl, heptyl, octyl, nonyl or decyl, alkyl groups having 1 to 6 carbon atoms are preferred.

Alkenyl contains in particular alkenyl radicals having 2 to 6 carbon atoms which may be straight or branched, such as 2-propenyl, 2-butenyl, 3-methyl-2-propenyl, 1-butenyl, 1-propenyl and vinyl.

Particularly suitable alkynyl radicals are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, in particular radicals having 2 to 4 carbon atoms.

C 3 -C 7 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, especially cycloalkyl of 3 to 5 carbon atoms.

Aryl include phenyl, e.g., naffylovú, biphenylyl and indenyl, especially _(CH2) "- phenyl, where n = 0,1 or 2 above.

Suitable heterocyclic radicals are 5- or 6-membered heteroaromates having 1 to 3 nitrogen atoms, such as pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine and triazine.

The term halogen atom refers to a fluorine, chlorine, bromine and iodine atom.

When R ⁹ and R ¹⁰ together with the nitrogen atom form a saturated heterocycle, for example piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine are meant.

When R ¹ is alkyl of 1 to 12 carbon atoms, then the R ⁵ to R ⁸ substituents that particular NO2, NR'R ', NHCOR ^11, SO 2 R ^12, cycloalkoxy having 3 to 7 carbon atoms, COR ^13, CN , trifluoromethyl, alkoxy of 1 to 4 carbon atoms, optionally substituted imidazole, or a fused benzene ring. Compounds of formula (I) wherein R ² = -PO-XY are characterized by very good aqueous solubility.

Physiologically acceptable salts are salts with organic and inorganic bases, such as well-soluble salts with alkali metals and alkaline earth metals such as N-methyl glucamine, dimethylglucamine, ethyl glucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, sovacase and 1-amino-2,3,4-butantrial.

The compounds of formula (I) as well as their physiologically acceptable salts are useful as medicaments because of their affinity for the quasiqualate receptors. Based on their spectrum of activity, the compounds of the present invention are suitable for the treatment of diseases caused by hyperactivity of excitatory amino acids such as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and have a high affinity for AMPA receptors by suppressing the radiolabeled specific antagonist (RS) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), they are particularly suitable for the treatment of diseases which can be affected by excitatory amino acid receptors, in particular AMPA receptors, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy, hypoglycemia, psychosis, muscle stiffness, emesis, pain conditions, anoxia and deficits after ischemia.

The present invention also encompasses combinations of compounds of the present invention with dopamine antagonists such as lisuride, terguride, bromocriptine, amantadine derivatives, hemanthine and derivatives thereof, and compounds disclosed in EP-A-351352 as well as combinations with L-DOPA and L- DOPA and benzerazide. In combination, the dose administered of the prior art drug is reduced and its effect is synergistic.

The affinity of the compounds of the present invention for central AMPA receptors is assayed in vitro in classical binding assays. It binds with high affinity to the 3 H-AMPA-labeled binding sites.

To test the quality of activity and in vivo efficacy, the compounds are tested after intravenous administration in mice. After pretreatment with the compounds of the present invention, dose-dependent seizures induced by intracerebroventricular injection of AMPA are antagonized.

table

A = 1- (trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid

B = 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid.

These findings indicate that these compounds are potent centrally active AMPA antagonists. They are therefore suitable for the treatment of morbidity conditions associated with disorders of glutamate metabolism. They are particularly suitable for the treatment of cerebral ischemia of various origins, Parkinson's disease as well as the other diseases mentioned in the preceding paragraphs.

For the use of the compounds of the present invention as medicaments, they are formulated into pharmaceutical preparations which contain, in addition to the active ingredient for enteral or parenteral administration, suitable pharmaceutical, organic or inorganic carrier materials such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories or capsules, or in liquid form, for example as solutions, suspensions or emulsions. Optionally, they additionally contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.

Especially suitable for parenteral use are injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil. Surfactant adjuvants, such as salts of gallic acid or animal or plant phospholipids, but also mixtures thereof, as well as mixtures thereof, may also be used as carrier systems. liposomes or parts thereof.

Especially suitable for oral administration are tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, or corn or potato starch. The application may also take place in liquid form, for example as a juice to which a sweetener may optionally be added.

The dosage of the active ingredient may vary depending upon the mode of administration, the age and weight of the patient, the type and severity of the disease being treated, and similar factors. The daily dose is 0.5 to 1000 mg, preferably 50 to 200 mg, wherein the dose may be administered as a single dose or may be divided into two or more doses per day.

The present invention further provides a process for the preparation of the compounds of formula (I) which comprises the steps of:

(a) a compound of formula (II)

wherein R ¹ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} as defined above, cyclizes with reactive oxalic acid derivatives and optionally reacts with a compound of formula

R ⁴ '- X wherein

X is halogen, tosylate, mesylate or triftalate;

R ⁴ 'has the meaning given for R ⁴ with the exception of a hydrogen atom;

(b) a compound of formula (III)

(III), wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R 10 are ^as defined above, is reacted with a compound of formula

R ¹ -X to the compound of formula (I) and, if necessary, the ester group is saponified or the acid group is esterified or amidated, or the nitro group is reduced to an amino group, or the amino group is alkylated or acylated, or the amino group is replaced by halogen or cyano or the amino group is reacted with 2-azabutadiene of formula (IV)

U and V mean leaving groups,

R ¹¹ represents a hydrogen atom, a cyano group or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl and R ¹² represents a hydrogen atom or a COO alkyl group having 1 to 6 carbon atoms in the alkyl to imidazole derivative, or isomers separated, or they form salts.

The cyclization of compounds of formula (II) with a reactive oxalic acid derivative is carried out in one or two steps. Preferred is a two-step process wherein the diamine is reacted with an oxalic acid derivative such as oxalic acid ester polochloride in polar solvents such as dimethylformamide or cyclic or acyclic ethers, or halogenated hydrocarbons such as tetrahydrofuran, diethyl ether or methylene chloride , in the presence of a base such as organic amines, for example triethylamine, pyridine, Hunig's base or diethylaminopyridine. The subsequent cyclization can be carried out basic or also acid, but preferably in an acidic medium, with the alcohol being added to the solvent.

The introduction of the substituents R ¹ and R ⁴ is carried out by conventional alkylation methods by reacting the quinoxalinedione with a compound of the formulas R ¹ -X or R ⁴ '-X in which X is halogen, tosylate, mesylate or especially triftalate, in the presence of a base , at room temperature or at elevated temperature in aprotic solvents. The anion can also be produced before the compound of formula R ¹ - X or R ⁴ '- X is added. Suitable bases are, for example, alkali metal compounds such as potassium carbonate, sodium hydroxide, alkali metal alcoholates and especially metal hydrides such as is sodium hydride. Alternatively, the alkaline compounds can be reacted under phase transfer conditions. When mixtures of compounds having the substituent R ¹ or R ^{4 are obtained} , these are separated by conventional procedures.

Suitable solvents for the reaction include aprotic polar solvents such as dimethylformamide or N-methylpyrrolidone, but also cyclic ethers such as dioxane or tetrahydrofuran. If, in process variant b) is conveniently carried out by reaction with 2 moles of compound ^R1 - X under otherwise analogous reaction conditions, are introduced, of substituents R @ ¹ and R @ ^4th

Optionally, the subsequent saponification of the ester group may be basic or preferably acidic by hydrolyzing the reaction mixture at elevated temperature to the boiling point in the presence of acids such as higher concentrated hydrochloric acid in solvents such as trifluoroacetic acid or alcohols. Phosphonic acid esters are preferably hydrolyzed by heating with higher concentrated aqueous acids, such as concentrated hydrochloric acid, or treatment with trimethylsilyl bromide, followed by treatment with water.

The esterification of the carboxylic acid or phosphonic acid is carried out in a known manner by means of the corresponding alcohols in the acid or in the presence of an activated acid derivative. Possible activated acid derivatives are, for example, chlorides, imidazolides or acid anhydrides. For phosphonic acids, reaction with the orthoesters of the corresponding alcohols is possible. The ester is also reacted with the addition product of dicyclohexylcarbodiimide and the corresponding alcohol. The methyl ester can be obtained by reaction with diazomethane.

The amidation is carried out on the free acids or on their reactive derivatives, such as acid chlorides, mixed anhydrides, imidazolides or azides, by reaction with the corresponding amines at room temperature.

The reduction of the nitro group to the amino group is carried out catalytically in polar solvents at room temperature or at elevated temperature under a hydrogen atmosphere. Suitable catalysts are metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally on supports. Ammonium formate may be used in place of hydrogen in a known manner. Reducing agents such as stannous chloride or titanium tetrachloride as well as complex metal hydrides, optionally in the presence of heavy metal salts, may also be used. It may be advantageous to introduce an ester group before the reduction.

When amino alkylation is desired, it can be alkylated using known methods, for example using alkyl halides. Reductive amination with an aldehyde and a reducing agent such as sodium borohydride is also possible. The acylation is carried out by known methods. For example, the reaction is carried out in an aqueous medium in the presence of a base with the corresponding acid anhydrides or acid halides.

The introduction of the cyano group can be carried out by means of a Sandmeyer reaction; for example, diazonium salts, intermediates formed from amino compounds with nitriles, cyanides in the presence of copper (I) cyanide or nickel potassium cyanide, can be reacted.

SK 281518-6

The introduction of halogen such as chlorine, bromine or iodine through the amino group can take place in a non-aqueous or aqueous medium. For example, according to Sandmeyer, it is carried out in an aqueous medium by reacting diazonium salts, intermediates formed with nitrites, with copper (I) chloride or copper (I) bromide in the presence of the corresponding acid, preferably hydrochloric or hydrobromic acid, or potassium iodide. In a non-aqueous medium, the hydrochloride is reacted in a known manner with i-amylnitrite and, for example, methylene iodide or bromoform in an aprotic solvent such as dimethylformamide. The fluorine introduction is carried out, for example, by the Balz-Schieman reaction of diazonium tetrafluoroborate.

The reaction of the amino group with the 2-azabutadiene of formula IV to imidazole derivatives is carried out in the presence of acids at a temperature ranging from 0 ° C to 150 ° C. The leaving groups U and V may be the same or different; especially suitable are dialkylamines having 1 to 3 carbon atoms, such as dimethylamine, diethylamine and dipropylamine, and cyclic amines, such as pyrrolidine. For example, the reaction is carried out by first mixing the amino derivative and azadiene in an organic acid, such as formic acid, acetic acid, propionic acid, or trifluoroacetic acid, and then heating the reaction mixture to boiling (up to about 120 ° C).

The acids may serve both as a reagent and as a solvent. However, solvents such as alcohols, ethers, ketones, esters such as ethyl acetate, hydrocarbons such as toluene, or halogenated hydrocarbons such as carbon tetrachloride may also be added.

The amount of acid may vary within wide limits, but is used in excess. Preferably, a 3 to 10-fold excess of acid, based on the amine and azadiene, is selected.

Mixtures of isomers may be separated by conventional methods such as crystallization, chromatography or conversion to diastereomers, for example by salt formation or enantiomers or E / Z isomers.

Salts are prepared by conventional methods by mixing a solution of the compound of formula (I) with an equivalent amount or with an excess of an alkali metal or alkaline earth metal compound optionally in solution and separating the formed precipitate or treating the solution by conventional methods.

Unless the production of the starting compounds is described, these are known or can be produced analogously to known compounds or by the methods described herein.

For example, compounds of formula (II) can be prepared by preparing 2,4-dinitroarylamines according to the method of Sanger by reacting o-halo nitroaromatics, preferably o-fluoro-nitroaromatics, such as dinitrofluorobenzene, in aqueous solution. with amino acid derivatives in the presence of a base, such as sodium carbonate or sodium bicarbonate, at a temperature ranging from 0 ° C to reflux and then reduced. This reaction can also be transferred to other substituted 2-nitrohalogen compounds. The diarylamino compounds can also be obtained by Ullmann reaction from dinitrochlorobenzene with an aromatic amine. High boiling solvents such as dimethylformamide or collidine and solid potassium carbonate and powdered copper are used as the base for this reaction. It is also possible to produce the corresponding o-nitroanilines by alkylation or by using substituted aldehydes by reductive alkylation. The subsequent reduction of the o-nitro group is carried out in the presence of more nitro groups selectively with sodium sulfide in the presence of ammonia as well as ammonium chloride, in polar solvents at room temperature or at elevated temperature. In some cases, it is advantageous to carry out the reaction with esters and to hydrolyze them in the last step.

The separation of enantiomers may be carried out in the final step or in intermediate steps using optically active auxiliary bases such as brucine or 1-phenethylamine, or also by chromatography over optically active carrier materials. However, the enantiomers may also be prepared synthetically by reacting the corresponding optically active amino acids with the corresponding fluoronitroaromatics by the method of Sanger and further treating the aminonitroaromatics as indicated.

The following examples illustrate the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester and 3- (7-nitro-2,3-dioxo-1,2-methyl ester) 3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid

1.03 g (5 mM) of 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was introduced under nitrogen and 50 ml of dimethylformamide at room temperature while avoiding moisture. 330 mg (11 mM) of sodium hydride (80%) are added to the batch in three portions and the reaction mixture is stirred for one hour at room temperature. 1.26 g (5.5 mM) of methyl 3-bromomethylbenzoate in 5 ml of dimethylformamide are then added dropwise and the mixture is stirred for 3.5 hours. After concentration, the residue is partitioned between water and ethyl acetate acidified with acetic acid. The organic phase is separated, dried, filtered and concentrated. The residue is chromatographed on silica gel with dichloromethane / ethyl alcohol = 95: 5. In addition to 211 mg of methyl ester, this residue is obtained

3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, which is not further purified, 222 mg of methyl 3- (7-nitro-2,3-) - dioxo-1,2,3,4-tetrahydroquinoxaline-1-methyl) -benzoic, m.p. 265-267 ° C.

The following are produced in an analogous manner:

4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester, m.p. 308 DEG-314 DEG C., 4- (7-nitro-2, methyl ester, m.p. 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. > 300 DEG C., 2- (6-nitro-2,3-dioxo-1,2,3) ethyl ester, 4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 279 DEG-283 DEG-284 DEG C., 2- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1) -ethyl ester. 1- (3-methoxycarbonyl-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 258 DEG-265 DEG C. (decomposition) 1,1- (3-ethoxycarbonylpropyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 215 DEG-217 DEG C., 1- (3-ethoxycarbonylpropyl) -7-nitroquinoxaline-2,3- (1 H, 4 H) -dione, m.p. 215-217 ° C,

Diethyl ester of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 114 ° C / 129-131 ° C, diethyl ester 4 - (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid (without further purification) 3- (6-trifluoromethyl-2,3-dioxo-diethyl ester) 1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -1-propene-1-phosphonic acid, 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethyl ester Methyl) -1-propin-1-phosphonic acid diethyl ester of 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, tere 1- (6-trifluoromethyl-2,3-dioxo-1,2) -butyl ester

3,4-tetrahydroquinoxalin-1-yl) -methanecarboxylic acid;

Example 2

In addition, 503 mg of 3- [4- (3-methoxycarbonylbenzyl) -6-nitro-2,3-dioxoic acid can be isolated at a double dose of methyl 3-bromomethylbenzoate and otherwise complete reaction as described in Example 1. 1,2,3,4-tetrahydroquinoxalin-1-ylmethyl-benzo m.p. 238-240 ° C.

The following are produced analogously:

4- [4- (4-Methoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] -benzoic acid methyl ester, m.p. 225-227 ° C, ethyl ester 2- [4- (2-ethoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] benzo m.p. 230-234 ° C,

1,4-bis- (3-methoxycarbonyl-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 181-183 ° C.

Example 3

A) 4- (2,4-Dinitrophenyl) aminobenzoic acid ethyl ester

1.01 g (5 mM) of 1-chloro-2,4-dinitrobenzene, 1.01 g (6 mM) of 4-aminobenzoic acid ethyl ester, 13 mg (0.2 mM) of copper powder and 961 mg (7 mM) of carbonate Potassium (powder) is stirred for 25 minutes at a bath temperature of 180 ° C under an argon atmosphere, avoiding moisture.

After concentration, the residue is taken up in water, made alkaline with ammonia and shaken with ethyl acetate. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel using cyclohexane / ethyl acetate = 8: 2 to give 768 mg of 4- (2,4-dinitrophenyl) -aminobenzoic acid ethyl ester, m.p. 99-102 ° C.

The following are produced in an analogous manner:

3- (2,4-dinitrophenyl) aminobenzoic acid ethyl ester, m.p. 108-110 ° C; 3- (2,4-dinitrophenyl) aminophenylphosphonic acid ethyl ester (further processed without further purification); 4-Dinitrophenyl) aminobenzoic acid (further processed without further purification).

B) 4- (2-Amino-4-nitrophenylamino) -benzoic acid ethyl ester

566 mg (1.7 mM) of ethyl 4- (2,4-dinitrophenyl) -aminobenzoic acid, 761 mg (12.2 mM) of ammonium chloride, 0.68 ml of concentrated ammonia, 154 ml of ethyl alcohol and 6 ml of distilled water are added. jointly submitted at an internal temperature of 78 ° C (bath temperature of 90 ° C). 1.27 g (5.68 mM) of sodium sulfide (35%) was added in three portions and the reaction mixture was stirred for one hour. The batch is aspirated at room temperature and washed first with water and then with diethyl ether. 535 mg of 4- (2-amino-4-nitrophenylamino) -benzoic acid ethyl ester (further processed without further purification) is obtained.

The following are produced in an analogous manner:

ethyl 3- (2-amino-4-nitrophenylamino) -benzoic acid, m.p. 145-150 ° C; ethyl 3- (2-amino-4-nitrophenylamino) -phenylphosphonic acid, m.p. 160-163 ° C;

C) 4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester

582 mg (2.3 mM) of ethyl 4- (2-amino-4-nitrophenylamino-benzoic acid ester) is introduced with 488 mg (4.8 mM) of triethylamine into 27 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under an argon atmosphere and at room temperature. A solution of 659 mg (4.8 mM) of oxalic acid ethyl ester and 8 ml of dried tetrahydrofuran is added dropwise to the batch, and the reaction mixture is stirred for 2 hours at room temperature, then 0.2 ml of triethylamine and 0.1 ml are added. The mixture is filtered and the filtrate is concentrated, the residue is partitioned between water and ethyl acetate and the organic phase is concentrated in 25 ml of 1N hydrochloric acid and 25 ml of ethyl acetate. ml of ethyl alcohol was refluxed for 2 hours, and the precipitated product was filtered off with suction, washed with water and dried to give 220 mg of 4- (6-nitro-2,3-dioxo-1-ethyl ester). 2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid (further processed without purification).

An analogous procedure produces:

3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester, m.p. 258 DEG-263 DEG C., 3- (6-nitro-2) ethyl ester 1,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphono.

Example 4

A) 2- (2,4-Dinitrophenyl) aminobenzoic acid

1.37 g (10 mM) of 2-aminobenzoic acid and 2 g (18.7 mM) of sodium carbonate in 40 ml of water are mixed with 1.86 g (10 mM) at a bath temperature of 40 ° C with vigorous stirring.

2,4-dinitrobenzene and stirred for 2 hours. The batch is then diluted with about 400 ml of water and precipitated with 4 N hydrochloric acid. The product is filtered off with suction, washed with water and dried. 2.8 g of 2- (2,4-dinitrophenyl) aminobenzoic acid of melting point 266 DEG-270 DEG C. is obtained.

The following are produced in an analogous manner:

3- (2,4-Dinitrophenylamino) -propionic acid, m.p. 134-137 ° C; 4- (2,4-dinitrophenylamino) -phenylphosphonic acid, m.p. 271-272 ° C (decomposition); 2- (2) (4-dinitrophenylamino) -phenylphosphonic acid (further processed without purification), (2,4-dinitrophenylamino) -methanephosphonic acid, m.p. 225 DEG-227 DEG C., 2- (2,4-dinitrophenylamino) -ethanephosphonic acid (further processed) without purification), 3- (2,4-dinitrophenylamino) -phenyl phosphonic acid, (2-nitro-1-naphthylamino) -methanephosphonic acid, (1-nitro-2-naphthylamino) -methanephosphonic acid, 1- (2- nitro-1-naphthylamino) -ethane-1-phosphonic acid, 1- (1-nitro-2-naphthylamino) -ethane-1-phosphonic acid, (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphonic acid, 1- (2-Nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid 1- (2,4-dinitrophenylamino) -ethane-1-phosphonic acid 3- (2,4-dinitrophenylamino) -propan-1 - phosphonic acid 4- (2,4 (2-nitro-4-fluorophenylamino) -butane-1-phosphonic acid, (2-nitro-4-fluorophenylamino) -methanephosphonic acid, (2-nitro-4-chlorophenylamino) -methanephosphonic acid, (2-nitro-4-bromophenylamino) -methanephosphonic acid, (2-nitro-4-methylphenylamino) -methanephosphonic acid, 1- (2-nitro-4-fluorophenylamino) -ethane-1-phosphonic acid, 1- (2-nitro-4-chlorophenylamino) -ethane-1-phosphonic acid, 1- (2-nitro-4-bromophenylamino) -ethane-1-phosphonic acid, 1- (2-nitro-4-methylphenylamino) -ethane-1-phosphonic acid, 1-phenyl-1- (2-nitro- 4-Trifluoromethyl-phenylamino) -methanephosphonic acid, 1-methyl-1- (2-nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, 1- (2-nitro-4-trifluoromethyl-phenylamino) - hexane-1-phosphonic acid, 1-methyl-2- (2-nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, 2- (2-nitro-4-trifluoromethyl-phenylamino) -propane-1 -phosphonic acid 1-methyl-2- (2-nitro-4-trifluoromethyl-phenylamino) -propane-1-phosphonic acid 1- (2-ni) tro-4-trifluoromethyl-phenylamino) -cyclopropane-1-phosphonic acid, (+) - 1- (2-methyl-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, (-) - 1- (2- nitro-4-trifluoromethyl-phenylamino) ethane-l-phosphonic acid,

P, P-dimethyl- (2,4-dinitrophenylamino) -methane-phosphoroxide, P-methyl- (2,4-dinitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2,4 1- [5- (imidazol-1-yl) -2,4-methyl-4-trifluoromethyl-phenylamino] -methyl-phosphonic acid.

B) 1- [5- (Imidazol-1-yl) -2,4-dinitrophenylamino] -ethane-1-phosphonic acid

600 mg of 5-fluoro-2,2-dinitrofluorobenzene is introduced into 40 ml of water and 10 ml of ethanol at 40 DEG C. and treated dropwise with a solution of 376 mg of racemic aminoethylphosphonic acid in 10 ml of water and 600 mg of sodium carbonate. The reaction mixture was stirred for 1.5 hours and after distilling off the ethanol, it was extracted against acetic acid. The aqueous phase is mixed with 200 mg of imidazole and heated at 11 ° C for 2 hours. An additional 200 mg of imidazole is then added and reheated for 2 hours at 110 ° C. Next, the mixture is acidified with 4 N hydrochloric acid, the insoluble matter is filtered off, and the filtrate is washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethyl alcohol. The ethanol extract was concentrated and chromatographed on silica gel using methanol / butyl alcohol / water / ammonia = 75: 25: 17: 3 to give 300 mg of 1- [5- (imidazol-1-yl) -2,4 acid. -dinitrophenylsamino] -ethane-1-phosphono.

C) 2- (2-Amino-4-nitrophenylamino) -benzoic acid

1.80 g (6 mM) of 2- (2,4-dinitrophenylamino) -benzoic acid, 2.66 g (42.6 mM) of ammonium chloride, 2.4 ml of concentrated ammonia, 52 ml of ethyl alcohol and 21 ml of distilled water are added. at an internal temperature of 78 ° C (bath temperature of 90 ° C). 4.44 g (20 mM) of sodium sulfide (35%) are added in three portions and the reaction mixture is stirred for one hour. The batch is then filtered off with suction at room temperature and washed successively with water and shaken with ethyl acetate. The organic phase is dried, filtered and concentrated. The aqueous phase is acidified with 1 N hydrochloric acid and filtered off with suction. 1.1 g of 2- (2-amino-4-nitrophenylamino) -benzoic acid is obtained (worked up without purification).

The following are produced in an analogous manner:

3- (2-Amino-4-nitrophenylamino) -propionic acid, 4- (2-amino-4-nitrophenylamino) -phenylphosphonic acid, 2- (2-amino-4-nitrophenylamino) -phenylphosphonic acid, (2-amino) 4-nitrophenylamino) methylphosphonic acid, (2-amino-4-nitrophenylamino) ethylphosphonic acid, 1- (2-amino-4-nitrophenylamino) ethane-1-phosphonic acid, 3- (2-amino-4- nitrophenylamino) -propane-1-phosphonic acid, 4- (2-amino-4-nitrophenylamino) -butane-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -cycloprojan-1-phosphonic acid .

P, P-dimethyl- (2-amino-4-nitrophenylamino) -methanephosphine oxide, P-methyl- (2-amino-4-nitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2 amino-4-nitrofenylaminoj-methylphosphonic acid.

D) (2-Amino-4-trifluoromethyl-phenylamino) -methanephosphonic acid

894 mg of (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphonic acid in 180 ml of ethanol are mixed with 3 g of Raney nickel and hydrogenated for 3 hours at room temperature and under normal hydrogen pressure. The catalyst is then filtered off with suction and the filtrate is concentrated. The product was used in step E) without further purification.

In a substantially analogous manner:

1- (2-Amino-1-naphthylamino) -ethane-1-phosphonic acid, 1- (1-amino-2-naphthylamino) -ethane-1-phosphonic acid, 1- (2-Amino-1-naphthylamino) - methanephosphonic acid, 1- (1-amino-2-naphthylamino) -methanephosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl- phenylamino) -methan-1-phosphonic acid, (2-amino-4-methylphenylamino) -methanephosphonic acid, 1- (2-amino-4-methylphenylamino) -ethane-1-phosphonic acid, 1-phenyl-1- (2 -amino-4-trifluoromethyl-phenylamino) -methanephosphonic acid, 1-methyl-1- (2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) ) -hexane-17

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-phosphonic acid, 1-methyl-2- (2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, 2- (2-amino-4-trifluoromethyl-phenylamino) -propane-1-phosphonic acid, 1-methyl-2- (2-amino-4-trifluoromethyl-phenylamino) -propane-1-phosphonic acid, (+) - 1- (2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, (-) - 1- (2-Amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, (4-chloro-2-aminophenylamino) -methanephosphonic acid, 1- (4-chloro-2-aminophenylamino) -ethane-1-phosphonic acid, (4-fluoro-2-aminophenylamino) -methanephosphonic acid, [5- (imidazol-1-yl) -4-trifluoromethyl-2-aminophenylamino] methylphosphonic acid, 1- (4-fluoro- 2-aminophenylamino) ethane-l-phosphonic acid.

E) 3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid

211 mg (0.9 mM) of 3- (2-amino-4-nitrophenylamino) -propionic acid is placed with 200 mg (2 mM) of triethylamine in 20 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under argon and to prevent access humidity. A solution of 270 mg (2 mM) of oxalic acid ethyl ester and 5 ml of dried tetrahydrofuran was added dropwise to the batch, and the reaction mixture was stirred at room temperature for 2 hours. 0.05 ml of triethylamine and 0.05 ml of ethyl oxalic acid chloride are then added and the mixture is stirred for a further hour at room temperature. The batch is then filtered and the filtrate is concentrated. The residue is partitioned between water and ethyl acetate, and the organic phase is concentrated. This residue is taken up in 15 ml of ethyl alcohol and 15 ml of 1 N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110 ° C. The batch is then concentrated, taken up in a small amount of water and concentrated. 120 mg of 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid, m.p. 148 DEG-156 DEG C. (decomposition), are obtained.

The following are produced in an analogous manner:

2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p. > 255 DEG C., 4- (6-nitro-2,3- Dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, m.p. > 252 ° C, 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline- 1-yl) -phenylphosphonic acid, m.p. > 310 ° C, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalm-1-yl) -methanephosphonic acid, m.p. 180-200 ° C (decomposition), 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 304 DEG-308 DEG C. (decomposition), acid (2, 3-Dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-4-yl) -methanephosphonic acid (2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalm-4-yl) (1-Phosphonic acid) - (2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-1-yl) -methanephosphonic acid (2,3-dioxo-1,2,3) (4-tetrahydrobenzo (f) quinoxalin-1-yl) -ethan-1-phosphonic acid (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) 202 DEG C., 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 274 DEG C., 1 - ( 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, m.p. 297-300 ° C (dec.), 3- (6-nitro- 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, m.p. 200 ° C (with foaming), 4- (6-nitro-2,3-dioxo) -1,2,3,4-tetrahydroquinoxalin-1-yl) -butane-1-phosphonic acid, m.p. 285 DEG-287 DEG C., (6-fluoro-2,3-dioxo-1,2,3,4- (6-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, (6-bromo-2,3-dioxo-tetrahydroquinoxalin-1-yl) -methanephosphonic acid 1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, (6-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, 1- (6-Fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, m.p. 259 ° C, 1- (6-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid, 1- (6-bromo-2,3-) - dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid 1- (6-methyl-2,3,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1- yl) -ethane-1-phosphonic acid, 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalm-1-yl) -1-phenyl-methane-1-phosphonic acid, m.p. 245 ° C, 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1-methyl-ethanephosphonic acid, 1- (6-trifluoromethyl- 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -hexane-1-phosphonic acid, 1-methyl-2- (6-trifluoromethyl-2,3-dioxo-1,2,3) 2- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, 4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid , 1-methyl-2- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid 1- (6-trifluoromethyl-2) , 3-dioxo-1,2,3,4-tetrahydro-quinoxalin-1 -yl) -cyclopropane-1-phosphonic acid, (+) - 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid [a ²⁰ _546] = + 7.4 ° (c = 0.505; H ₂ O), (-) - 1- (6-Trifluoromethyl-2,3,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) ethane-1-phosphonic acid [a ²⁰ 546] ⁼ -5.9 ° (c = 0.510; H ₂ O), β-methyl- (6-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphinic acid, m.p. 320 up to 325 ° C (decomposition), (β, β-dimethyl) - (6-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphine oxide, m.p. 325-330 ° C (decomposition), [6-nitro-7- (imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methylphosphonic acid, [6-trifluoromethyl- 7- (imidazol-1-yl) -2,3-dioxo-1,2

3,4-tetrahydroquinoxalin-1-yl) methylphosphonic acid.

Example 5

3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) -benzoic acid

211 mg (0.6 mM) of 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester was added to 4 ml of 4 N hydrochloric acid , 4 ml of trifluoroacetic acid are added and the reaction mixture is stirred for 3.5 hours at a bath temperature of 110 ° C. After cooling to room temperature, the batch is diluted with water and filtered off with suction.

SK 281518-6

The filter cake was washed with water and ethyl alcohol and dried. 3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. > 330 ° C, is obtained.

The following are produced in an analogous manner:

3- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. > 330 ° C, 3- [4- (3-carboxybenzyl) acid (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 298-300 ° C, 2- (6-nitro-2,3) acid -dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 329-334 ° C, 2- (7-nitro-2,3-dioxo-1,2,3), 4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 328 DEG-330 DEG C., 2- [4- (2-carboxybenzyl) -6-nitro-2,3-dioxo-1,2,3,4] -tetrahydroquinoxalin-1-yl-methyl) -benzoic acid, m.p. > 300 ° C, 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) - benzoic acid, m.p. > 310 DEG C., 4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) benzoic acid, m.p. 320 DEG-324 DEG C .; 4- (4-carboxymethylbenzyl) -6-nitro-2,3-dioxo-1,2, -

3,4-tetrahydroquinoxalin-1-yl-methyl) -benzoic acid, m.p. > 310 ° C, 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid mp> 345 ° C, 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p.> 250 ° C, 1- (3) -carboxy-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 242-243 ° C;

1,4-bis- (3-carboxy-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 241-247 ° C; 1- (3-carboxypropyl) -6-nitroquinoxaline- 2,3- (1H, 4H) -dione, m.p. 230-232 ° C;

- (3-carboxypropyl) -7-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 325-327 ° C (dec.), 1- (6-trifluoro-2,3-dioxo-1) acid (2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid, m.p. 320 ° C.

Example 6

4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid

582 g (1,4 mM) of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquimoxalin-1-ylmethyl) -phenylphosphonic acid ethyl ester was heated at reflux for 2 hours with 6 ml of concentrated hydrochloric acid. After cooling, the batch is mixed with water and aspirated. The filter cake is then dried to give 53 mg of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrachinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 253-265 ° C. (decomposition).

The following are produced in an analogous manner:

4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. > 250 DEG C., 3- (6-nitro-2, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 304-307 ° C (dec.), 3- (6-trifluoromethyl-2,3-dioxo-1), 2,3,4-tetrahydroquinoxalin-1-yl) -1-propin-1-phosphinic acid, 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1-propene-1-phosphine.

Example 7

(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid monoethyl ester and diethyl ester

To 300 mg of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid in 5 mL of absolute dimethylformamide was added dropwise 0.29 mL of thionyl chloride at -15 ° C. After the addition was complete, the reaction mixture was stirred for 20 minutes at a bath temperature of 4 ° C, then 0.35 ml (276 mg) of ethyl alcohol was added and stirred at room temperature for 1.5 hours. After concentration in vacuo, the residue is chromatographed on silica gel with toluene / glacial acetic acid / water = 10: 10: 1. First, diethyl ester of (6-nitro-2,3-dioxo-1,2,3,4) is obtained. 220 DEG-260 DEG C. followed by (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid monoethyl ester, mp 197 ° C, whereby the diethyl ester is obtained in an amount of 100 mg and the monoethyl ester in an amount of 36 mg.

The following are produced in an analogous manner:

Μοηο-Ν, Ν-dimethylamide (6-nitro-2,3-dioxo-1,2) -

(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid bis-N, N-dimethylamide 3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid 3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid bis-N, N-dimethylamide.

Example 8

1- (6-Amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid

300 mg of 1- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid are dissolved in 60 ml of methanol and 50 mg of Pd / C are added successively under a nitrogen atmosphere. (10%), 300 mg of ammonium formate and 18 ml of water and the reaction mixture was heated at 80 ° C for 1 h. After cooling, the catalyst is filtered off, the filtrate is evaporated and the residue is freeze-dried. 200 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid are obtained in the form of a white solid.

The following are produced in an analogous manner:

1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid.

Example 9

1- [6- (4-Carbethoxy-imidazol-1-yl) -2,3-dioxo-1,2, -

3,4-tetrahydro-quinoxalin-l-yl] -methanephosphonic

200 mg of 1,4-bis-dimethylamino-3-carbethoxy-2-azabutadiene-1,4 are mixed with 3 ml of glacial acetic acid while cooling and the reaction mixture is stirred for 10 minutes at room temperature. Then 180 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid dissolved in 3 ml of glacial acetic acid was added to the batch and the mixture was stirred through night at room temperature. It is then heated for 4 hours at a bath temperature of 100 ° C. After concentration, 50 mg of 1- [6- (4-carbethoxyimidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] methanephosphonic acid is obtained as an oily liquid.

SK 281518-6

The following are produced in an analogous manner:

Example 12 1- [6- (4-Cyano-5-methyl-imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid.

Example 10

1- [6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid

180 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid was added dropwise to 10 ml of 25% sulfuric acid. After stirring for 5 minutes, a salt suspension is formed which is cooled to 0 ° C and a solution of 60 mg of sodium nitrite in 2 ml of water is added dropwise. After stirring for 15 minutes at 0 ° C, the reaction mixture is practically dissolved and a solution of 180 mg of potassium iodide in 2 ml of water is added dropwise. Remove the ice bath and heat to 100 ° C for 2 hours. The cooled reaction mixture is then neutralized with concentrated ammonia solution and evaporated to dryness. The residue obtained is boiled with ethyl alcohol and a small amount of water, filtered and the filtrate is concentrated. Chromatography on silanized silica gel with water / methanol = 4: 1 gives 40 mg of 1- [6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid having a temperature of mp 295-297 ° C.

In an analogous or literature-known manner, the following are produced:

1- [6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -ethan-1-phosphonic acid, 1- [6-bromo-2,3-dioxo-1] 1,2,3,4-tetrahydroquinoxalin-1-yl] -ethane-1-phosphonic acid 1- [6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid 1- [6-cyano-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid.

Príkladll

6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methanephosphonic acid

100 mg of 6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethanephosphonic acid is dissolved in concentrated hydrochloric acid and evaporated to dryness.

The hydrochloride obtained is dried well, taken up in 10 ml of dimethylformamide and treated successively with 4 ml of methylene iodide and 0.6 ml of isoamylonitrile. After two hours in a bath at 80 ° C, everything is dissolved. The mixture was evaporated in a bead column vacuum and the residue was chromatographed on silanized silica gel 60 (reverse phase) using water / methanol = 4: 1 as the mobile phase. 20 mg of 6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethanephosphonic acid, m.p. 295 DEG-297 DEG C., is obtained.

The following are produced in an analogous manner:

6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1-yl-methanephosphonic acid 1- (6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) 1- (6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1-yl-ethanephosphonic acid) -1-yl-ethanephosphonic acid.

100 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid is dissolved in 20 ml of water and the pH is adjusted to 9 with saturated sodium carbonate solution. , fifth To this mixture was added 0.2 mL of acetic anhydride, stirred for one hour, and concentrated. The residue obtained is dissolved in as little water as possible, applied to an ion exchanger (IR120, strongly acidic) and eluted with water. The corresponding fraction was collected, concentrated and dried. 110 mg of 1- (6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, melting at 120 ° C, are obtained.

Claims (6)

Quinoxaline derivatives of the general formula (I) in which R ¹ is C 1 -C 12 alkyl, substituted with R ² , C 2 -C 12 alkenyl, substituted with R ² , C 2 -C 12 alkynyl, substituted with R ² , C 3 -C 7 cycloalkyl , substituted with R ² , - (CH 2) n - aryl of 6 to 12 carbon atoms in the aryl group which is substituted with R ² in the aryl or alkyl radical, or - (CH 2) _n -hetaryl group which is in the hetaryl or alkyl radical substituted by R ^2, R ⁴ is hydrogen, C 1 -C 12 alkyl, substituted with R ² , C 2 -C 12 alkenyl, R ² substituted, C 2 -C 12 alkynyl, substituted with R ² , C 3 -C 3 cycloalkyl 7-carbon atoms, substituted with R ² , - (CH 2) n -aryl having 6 to 12 carbon atoms in the aryl which is substituted with R ² in the aryl or alkyl moiety, or - (CH 2) _n -hetaryl group that is in the hetaryl or substituted alkyl radical R ² and R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are hydrogen, halogen, nitro, NR'R ¹⁰ , NHCOR ¹¹ , SO ₂ R ¹² , cycloalkoxy having 3 to 7 carbon atoms, COR ¹³ , cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 4 alkoxy or imidazole, optionally substituted with cyano, C 1 -C 4 alkyl or C 1 -C 4 -alkyl Or 6 carbon atoms in the alkyl; R ⁵ and R ⁶ or R ⁷ and R ⁸ represent a fused benzene ring, wherein R ² is -CO-R ³ or -PO-XY and R ² is one to two same or different, n is 0,1,2,3, 4 or 5, R ³ is hydroxy, alkoxy of 1 to 6 carbon atoms, or -NR ⁹ R ^10, X and Y are the same or different and are hydroxy, C 1 -C 6 alkoxy, C 1 -C 4 alkyl or -NR'R ¹⁰ , R 1 and R ¹⁰ are the same or different and represent a hydrogen atom, a C 1 -C 4 alkyl group or a saturated 5- or 6-membered heterocycle which may contain an additional oxygen or sulfur atom together with the nitrogen atom, R ¹¹ represents an alkyl group having 1 to 6 carbon atoms or a phenyl group, R ¹² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group or a dialkylamino group having 1 to 4 carbon atoms in each alkyl, and R ¹³ is hydroxy, alkoxy of 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms or the group -NR ^10, as well as their isomers or salts. provided that when R ⁴ represents a hydrogen atom, and R 1 represents an alkyl group having 1 to 6 carbon atoms, substituted by R ² = -COR ³ , they cannot be R, R ⁶ , R ⁷ , and / or R ⁸ , a hydrogen atom, a nitro group , a halogen atom, or an alkyl group having 1 to 6 carbon atoms Compounds of formula (I) according to claim 1 which are 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester, 1- (3-ethoxycarbonyl-propyl-6-nitroquinoxaline) -2,3- (1H, 4H) -dione, diethyl 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) 1-ylmethyl-phenylphosphonic acid 2- [4- (2-ethoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] ethyl ester 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester 3- (6-nitro-2,3-dioxo) -benzoic acid ethyl ester -1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methylphosphonic acid, 4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid (6-trifluoromethyl-2,3-dioxo-1,2,3,4) 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid -tetrahydroquinoxalin-1-yl) -methanephosphonic acid (+) - 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid (-) - 1- (6-trifluoromethyl-2,3) acid -dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid 1- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane 1- (6-Trifluoromethyl-4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalm-1-yl) -butan-1-phosphonic acid) 2,3-Dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylethane-1-phosphonic acid, P-methyl- (6-nitro-2,3-dioxo-1,2,3,4) -tetrahydroquinoxalin-1-yl] -methanephosphonic acid, (β, β-dimethyl) - (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphine oxide, 3- (6) -nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1 - yl) -methanephosphonic acid 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid 1- [6- (carbetoxy-imidazol-1-yl) ) -2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1- yl) -methanephosphonic acid 1- (8-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid 3- (6-nitro-2,3-dioxo) 1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphones. Medicament comprising the compounds according to claims 1 and 2. Use of the compounds according to claims 1 and 2 for the manufacture of medicaments. A process for the preparation of compounds of formula (I), characterized in that: a) a compound of formula (II) wherein R ¹ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} as defined above, cyclizes with reactive oxalic acid derivatives and optionally reacts with a compound of formula R ⁴ '- X wherein X is halogen, tosylate, mesylate or triftalate; R ⁴ 'has the meaning given for R ⁴ with the exception of a hydrogen atom, s or s; (b) compound of formula (III) * react with a compound of formula R ¹ -X to the compound of formula (I) and, if necessary, the ester group is saponified or the acid group is esterified or amidated, or the nitro group is reduced to an amino group, or the amino is alkylated or acylated or exchanged for halogen or cyano; the amino group is reacted with the 2-azabutadiene of formula (IV) wherein U and V are leaving groups, in particular dialkylamino groups having 1 to 3 carbon atoms in the alkyl group, preferably diethylamine and dipropylamine groups and cyclic amino groups, in particular pyrrolidine groups R ¹¹ being hydrogen atom, cyano or COO-alkyl group having 1 to 6 carbon atoms and R ¹² represents a hydrogen atom or a COO-alkyl group of 1 to 6 carbon atoms in the alkyl to the imidazole derivative, or isomers separated, or salts formed. Medicament, characterized in that it comprises a compound according to claims 1 and 2 in combination with L-DOPA and / or L-DOPA antagonists and / or benzerazide.