SK72793A3 - Quinoxaline derivatives with afinity for quisqualate receptors - Google Patents

Abstract

Quinoxaline derivates have the formula (I), in which R1 is C1-12-alkyl substituted by R2, C2-12-alkenyl substituted by R2, C2-12-alkinyl substituted by R2, C3-7-cycloalkyl substituted by R2, -(CH2)n-C6-12-aryl substituted by R2 in the aryl or alkyl residue or -(CH2)n-hetaryl substituted by R2 in the hetaryl or alkyl residue; R4 is hydrogen, C1-12-alkyl substituted by R2, C2-12-alkenyl substituted by R2, C2-12-alkinyl substituted by R2, (CH2)n-C6-12-aryl substituted by R2 in the aryl or alkyl residue, or -(CH2)n-hetaryl substituted by R2 in the hetaryl or alkyl residue; R5, R6, R7 and R8 are the same or different and represent hydrogen, halogen, nitro, NR9R10, NHCOR11, SO2R12, C3-7-cycloalkyloxy, COR13, cyano, CF3, C1-6-alkyl, C1-4-alkoxy or imidazole possibly substituted by cyano, C1-4-alkyl or -COO-C1-6-alkyl or R5 and R6 or R7 and R8 represent a condensated benzene ring, and R2 stands for -CO-R3, or -PO-XY and is present once or twice in the same or a different form. Also disclosed are the preparation of these derivates and their use in medicaments.

Description

QUINOXALINE DERIVATIVES, METHOD OF MANUFACTURING AND USE THEREOF

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.

SUMMARY OF THE INVENTION

They have been found to exhibit receptors in comparison with WO 91/13878.

with its good compounds of the present invention, with quinoxalines known from EP-A-315 959 the ability to bind to quasiqualate

The present invention relates to compounds of 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 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 radical,

I, or - (CH _{2) n} -hetarylovú group which is in the hetaryl or alkyl 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 C atoms, substituted with R ^2, - (CH2Jn-aryl of 6 to 12 aryl carbon atoms, which is in the aryl or alkyl moiety by ^R2, or - (CH2) _n hetaryl which is hetaryl or C 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 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 a group --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, the

R represents a hydroxy group, an alkoxy group having 1 to 6 carbon atoms

Q ΙΑ atoms or -NR R group,

X and Y are the same or different and are hydroxy, (C1-C6) alkoxy, (C1-C4) alkyl or -NRR,

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 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 represents hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or -NR ⁹ R ¹⁰ as well as their isomers or salts thereof, provided that when R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represents a hydrogen atom, R ¹ cannot be a carbamoylmethyl group, a 1-carboxy-1-phenylmethyl group or a straight alkyl group having 1 to 6 carbon atoms which is in the 1- position substituted by a carboxyl group or a COO-alkyl group having 1 to 6 carbon atoms And when R ^{@ 1} represents a straight alkyl group having 1 to 6 carbon atoms which is in the 1- position substituted by a carboxyl group or a COO alkyl group having 1 to 6 carbon atoms in the alkyl group, the substituents R @ ⁶ and / or or R ⁷ and R ⁶ and R ^{7 respectively} denote fluorine, chlorine or bromine and R ⁴ -R ⁸ is in each case a hydrogen atom, and when R ¹ represents a -CH ₂ -COOH group, then

(a) R ⁶ and R ⁷ do not simultaneously denote a methyl group; or

b) R ⁶ or R ^{7 is} not nitro; R ⁴ -R ⁸ is in each case a hydrogen atom.

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.

The substituent R ^{2 is} one to two times the same or different at any position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl residue.

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.

The alkenyl group 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, in particular C 3 to C 5 cycloalkyl.

Aryl radicals are, for example phenyl, naphthyl, biphenylyl and indenyl, especially _{(CH2) n-phenyl,} where n = 0, 1 or 2 above.

Suitable hetaryl residues 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, it is meant, for example, piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine.

When a substituent with carbon atoms, no ₂ , NR ⁹ R ¹⁰ , NHCOR ^{11 with} carbon atoms,

R ¹ is alkyl of 1 to 12 after the R ⁵ to R ⁸ in particular as substituents, SO ₂ R ^12, cycloalkoxy

COR ^{X 3} , cyano, C 3-7 trifluoromethyl, C 1 -C 1 alkoxy, optionally substituted imidazole or fused benzene ring. The compounds of formula I wherein R ² = -PO-XY have a high solubility in water.

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, dimethyl-glucamine, 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 novel compounds act as antagonists of excitatory amino acids and have a high affinity for AMPA receptors, they suppress the radiolabeled specific antagonist (RS) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) are particularly suitable for the treatment of diseases which may be affected by amino acid receptors, particularly AMPA receptors, such as

Parkinson's disease, Alzheimer's disease, excitatory is, for example, Huntington's disease, epilepsy, hypoglycemia, psychosis, muscle stiffness, emesis, pain conditions, anoxia, and post-ischemia deficits.

The present invention also encompasses combinations of the compounds of the present invention with dopamine antagonists such as lisuride, terguride, bromocriptine, amantadine derivatives, hemanthine and derivatives thereof, and the compounds described in EP-A-351 352 as well as combinations with L-DOPA and L-DOPA. -DOPA and benzerazide. In combination, the dose administered of the prior art drug is reduced and its effect synergistically increased.

The affinity of the compounds of the present invention for central AMPA receptors is tested 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, the seizures induced by intracerebroventricular injection of AMPA are dose-dependent.

ΓΗ

table

compound AMPA-binding (IC ₅₀ [μιηοΐ]) A 2.22 B 1.79

l.

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-phosphinic acid.

These findings indicate that these compounds are potent centrally effective 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.

».

I f: b

For the use of the drug compounds, these are carried out which, in addition to the active ingredient, contain suitable inorganic arabic tablet preparations, for example in addition to the present invention as pharmaceutical preparations, for enteral or parenteral pharmaceutical, organic or water, gelatin, magnesium stearate, talc, and the like. The pharmaceutical form, such as starch, also effectively comprises carrier materials, gum, milk sugar, oils, polyalkylene glycols sa may be in solid dragee, lace or capsule, or in liquid form, such as solutions, suspensions or emulsions. They optionally contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.

Injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.

F

Surfactant adjuvants such as, for example, gallic acid salts or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or components thereof, can also be used as carrier systems.

Especially suitable for oral administration are tablets, dragees, 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 on 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.

Another object of the present invention is to provide a process for the preparation of the compounds of the formula I, which comprises:

a) a compound of formula II

i (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 the formula

R ⁴ '- X »

in which j

X represents a halogen atom, tosylate, mesylate or triftalate and R ⁴ 'has the meaning given for R ⁴ with the exception of a hydrogen atom, or

b) a compound of formula III

wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} as defined above, reacted with a compound of the formula

R ^{@ 1} - X to a compound of formula I and, if desired, 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 replaced by halogen or cyano, or is reacted with 2-azabutadiene of formula IV

in which

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 ³ · ³ represents a hydrogen atom or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl to the imidazole derivative, or isomers separated, or salts formed.

The cyclization of the compounds of the formula II with a reactive oxalic acid derivative is carried out in one or two steps. Preferred is a two-step process in which 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 quinoxalindione with a compound of the formulas R ¹ -X or R ⁴ '-X in which

X 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 made prior to the addition of compound of formula R ¹ - X ⁴ and R '- X As bases, e.g., alkali metal compounds, such as potassium carbonate, sodium hydroxide, alkali alcoholates and especially metal hydrides, such as sodium hydride. Alternatively, the alkaline compounds can be reacted under phase transfer conditions. When mixtures of compounds with the substituent R ^{1 are obtained} , optionally

R ⁴ , these are separated by conventional procedures

Suitable solvents for the reaction include aprotic and polar solvents such as dimethylformamide or

N-methylpyrrolidone, but also cyclic ethers such as dioxane or tetrahydrofuran. When in process variant b) the reaction is allowed to proceed with 2 mol of the compound R ^x -X under otherwise analogous reaction conditions, the substituents R ¹ and R ⁴ are introduced simultaneously.

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. The 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.

and

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. | ί

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.

ú • -í

If alkylation of the amino group is desired, it can be alkylated by 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 medium is in the presence of a base with acids or acid halides.

Introduction of the cyano group with the Sandmeyer reaction; for example, the reaction carried out in aqueous corresponding anhydrides can be carried out by means of reacting diazonium salts, intermediates formed from amino compounds with nitriles, with cyanides. in the presence of copper cyanide or with potassium cyanide.

The introduction of halogen, such as chlorine, bromine or iodine, via 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, formed intermediately with nitrites, with copper (II) 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-amyl nitrite and, for example, methylene iodide or bromoform in an aprotic solvent such as dimethylformamide. The introduction of the fluorine network is carried out, for example, by the Balz-Schieman reaction of diazonium tetrafluoroborate.

ί

I · '*

i i p

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

f. heat to boiling (up to about 120 ° C). I ··

d.

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. Preference is given to triple to;

t. 10-fold excess of acid, based on amine and azadiene. I j 'i.

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

t; , ľ

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

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

'ΐ h

For example, the compounds of formula II can be prepared by producing 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 derivatives. amino acids 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 means of substituted aldehydes by reductive alkylation. The subsequent reduction of the o-nitro group is carried out in the presence of multiple 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 can also be prepared synthetically by reacting the corresponding optically active amino acids with the corresponding fluoronitroaromatics by the Sanger method and further treating the aminonitroaromatics as described above.

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-tetrahydro-quinoxalin-l-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 using dichloromethane / ethanol = 95: 5.

In addition to 211 mg of the methyl ester, this 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 acid ester

3- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1-methyl) -benzoic acid, 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 3-dioxo-1,2,3,4-tetrahydroquinolin-1-ylmethyl) -benzoic acid, m.p. > 300 ° C, 2- (6-nitro-2,3-dioxo-1-ethyl ester) (2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p.

284 ° C, 2- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid ethyl ester (processed without further purification) 1- (3-methoxycarbonyl- 2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) dione, m.p. 258-265 ° C (dec.), 1- (3-ethoxycarbonylpropyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 215-217 ° C;

1- (3-ethoxycarbonylpropyl) -7-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 215 DEG-217 DEG C., diethyl 4- (6-nitro-2,3-dioxo-1), m.p. M.p. 114 ° C / 129-131 ° C; diethyl 4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid; tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid (without further purification), diethyl 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -1-propene- 3- (6-Trifluoromethyl-2-propyl) -1-propyne-1-phosphonic acid diethyl ester of 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -1-phosphonic acid diethyl ester 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) tert-butyl ester, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid tert-butyl ester -l-yl) -methanecarboxylic acid-amidoxime

Example 2!

In addition, 503 mg of 3- [4- (3-methoxycarbonylbenzyl) -6-nitro] -acetic acid can be isolated at a double dose of methyl 3-bromomethylbenzoate and otherwise complete reaction as described in Example 1.

2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] -benzoic acid, 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 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 (powdered) was 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 with cyclohexane / ethyl acetate = 8: 2 and 768 mg of ethyl ester are obtained.

4- (2,4-dinitrophenyl) aminobenzoic, m.p. 99-102 ° C. j ·

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 ethanol and 6 ml of distilled water are introduced together at an internal temperature of 78 ° C (bath temperature 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.

In an analogous manner the following are produced:

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 4- (2-amino-4-nitrophenyl-amino) -benzoic acid ethyl ester was introduced with 488 mg (4.8 mM) of triethylamine into 27 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under argon. atmospheres and moisture. A solution of 659 mg (4.8 mM) of oxalic acid ethyl ester and 8 ml of dried tetrahydrofuran was added dropwise to the batch, and the reaction mixture was stirred for 2 hours at room temperature. Then 0.2 ml of triethylamine and 0.1 ml of ethyl oxalic acid chloride are added and stirred for one 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. The residue thus obtained is refluxed in 25 ml of 1 N hydrochloric acid and 25 ml of ethyl alcohol for 2 hours. The precipitated product is filtered off with suction, washed with water and dried. 220 mg of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester (further processed without purification) are obtained.

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 , 3-dioxo-l, 2,3,4-tetrahydro-quinoxalin-l-yl) -fenylfosfónovej.

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. 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 r

It is filtered off with suction, washed with water and dried. 2.8 g of 2- (2,4-dinitrophenyl) aminobenzoic acid of melting point are obtained

Mp 266-270 ° C. í i '!

In an analogous manner:

3- (2,4-Dinitrophenylamino) -propionic acid, m.p.

134 DEG-137 DEG C., 4- (2,4-dinitrophenylamino) -phenylphosphonic acid, m.p. 271 DEG-272 DEG C. (decomposition) 2- (2,4-dinitrophenylamino) -phenylphosphonic acid is processed without purification), acid (2, 225 DEG-227 DEG C., 2- (2,4-dinitrophenylamino) -ethanephosphonic acid is processed without purification;

with temperature j (further on)

3- (2,4-Dinitrophenylamino) -phenylphosphonic 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-l-phosphonic acid,

acid 4 1- (2,4-dinitrophenylamino) -ethane-1-phosphonic acid, acid 3- (2,4-dinitrophenylamino) -propan-l-phosphonic acid, acid 4- (2,4-dinitrophenylamino) -butan-l-phosphonic acid, acid (2-nitro-4-fluoro-phenylamino) -methanephosphonic acid (2-nitro-4-chloro-phenylamino) -methanephosphonic acid (2-nitro-4-bromo-phenylamino) -methanephosphonic acid (2-nitro-4-methylphenylamino) -methanephosphonic acid l- (2-nitro-4-fluoro-phenylamino) ethane-l-phosphonic acid, acid 1- (2-nitro-4-chloro-phenylamino) ethane-l-phosphonic acid, acid 1- (2-nitro-4-bromo-phenylamino) ethane-l-phosphonic acid, acid 1- (2-nitro-4-methylphenylamino) ethane-l-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) 1-Methyl-2- (2-nitro-4-trifluoromethyl-phenylamino) -propane-1-phosphonic acid, 1- (2-nitro-4-trifluoromethyl-phenylamino) -cyclopropane-1-phosphonic acid, (+) ) -1- (2-nitro-4-trifluoromethyl-phenylamino) ethane-1-phosphonic acid, (-) - 1- (2-nitro-4-trifluoromethyl-phenylamino) ethane-1-phosphonic acid,

P, P-dimethyl- (2,4-dinitrophenylamino) -methane-phosphine oxide, P-methyl- (2,4-dinitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2,4 -dinitrophenylamino] -methylphosphonic acid, 1- (5- (imidazol-1-yl) -2,4-nitro-4-trifluoromethylphenylamino] -methylphosphonic 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

* P h and boiled with ethyl alcohol. Ethanol extract and concentrated; and chromatographed on silica gel using methanol / butyl alcohol / water / ammonia = 75: 25: 17: 3. 300 mg of 1- [5- (imidazol-1-yl) -2,4-dinitrophenylaf] are obtained. Míno] ethane-l-phosphonic acid. | · T;

H

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 introduced at an internal temperature of 78 ° C (bath temperature 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 acid are obtained

2- (2-amino-4-nitrophenylamino) -benzoic acid (processed 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) -cyclopropane-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-nitro-phenylamino] methylphosphonic acid.

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

894 mg of (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphonic acid is mixed with 3 g of Raney nickel in 180 ml of ethanol and hydrogenated at room temperature and under normal hydrogen pressure for 3 hours. 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) -methane-1-phosphonic acid, ..............

(2-amino-4-methylphenylamino) -methanephosphonic acid, 1- (2-amino-4-methylphenylamino) -ethan-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-1-phosphonic acid, 1-methyl- 2- (2-amino-4-trifluoromethyl-phenylamino) ethane-1-phosphonic acid, 2- (2-amino-4-trifluoromethyl-phenylamino) -propane-1-

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-amino-phenylamino] -methylphosphonic acid, 1- (4- fluoro-2-aminophenylamino) ethane-l-phosphonic acid.

F

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

i. '

211 mg (0.9 mM) of 3- (2-amino-4-nitrophenylamino) -1

t. of propionic acid are introduced with 200 mg (2 mM) of triethylamine into 20 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under an argon atmosphere and avoiding the ingress of moisture. A solution of 270 mg (2 mM) of oxalic acid ethyl ester and 5 ml of dried tetrahydrofuran is added dropwise to the batch, and the reaction mixture is stirred for 2 hours.

Stir for 2 hours at room temperature. Then f

0.05 ml of triethylamine and 0.05 ml of ethyl oxalic acid chloride were added and the mixture was stirred for another 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

d. and thicken. 120 mg of acid i are obtained

3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid, m.p. 148-156 ° C (dec.).

The following are produced in an analogous manner:

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

- benzo with a melting point> 255 ° C, . !

4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, m.p. > 252 DEG C., 2- (6-nitro-2,3) acid -dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, m.p. > 310 ° C;

L h (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1H acid

180 ° C (decomposition), I '

I

I [

I '

t. · t

2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 304 DEG-308 DEG C. (dec.), m.p.

(2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-4-yl) acid

-methanephosphonic acid (2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-4-yl)

-ethane-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) |

-ethane-1-phosphonic acid, (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline)

202 ° C, 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 274 ° C "à

1- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phonic 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-acid); , 3,4-tetrahydro-quinoxalin-l-yl)

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

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

(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 DEG C., 1- (6-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) 1- (6-Bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, 1- (6-methyl) -ethane-1-phosphonic acid -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) ethane-1-phosphonic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4- tetrahydroquinoxalin-1-yl) -1-phenyl-methane-1-phosphonic melting point

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), 4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid 2- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propan-1-yl- 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-tetrahydroquinoxalin-1-yl) -cyclopropane-1-phosphonic acid, (+) - 1- (6-trifluoromethyl-2,3-dioxo-1,2,3), 4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid [.alpha.] D @ 20 = + 7.4 DEG (c = 0.505;

h ₂ o), (-) - 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid [0 ^ 545] = 5 , 9 ⁰ (c = 0.510;

h ₂ °), P-methyl- (6-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphinic acid, m.p. 320 DEG-325 DEG C. (decomposition), (P, P-Dimethyl) - (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquihoxalin-1-yl) -methanephosphine oxide, m.p. 325-330 ° C (dec.), [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-l, 2,3,4tetrahydrochinoxalín-yl) methylphosphonic

Example 5

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

211 mg (0.6 mM) of methyl 3- (6-nitro-2,3-dioxo-)

1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) -benzoic acid is added to 4 ml of 4 N hydrochloric acid, mixed with 4 ml of trifluoroacetic acid 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. The filter cake was washed with water and ethyl alcohol and dried. An acid is obtained

3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) benzo m.p. > 330 ° C.

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) - 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p.

298-300 ° C, 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, mp 329-334 ° C, 2- (7) -nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 328-330 ° 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-ylmethyl) -benzoic acid, m.p. > 310 ° C, 4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid mp 320-324 ° C, 4- (4-carboxymethylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid m.p.> 310 ° c, 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p. > 345 DEG 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,

1- (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-ethyl) ester

1.2.3.4-Tetrahydroquinoxalin-1-yl-methyl) -phenylphosphonic acid is refluxed 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-propyne-1-phosphinic acid, 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1-propene L-phosphinic acid.

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:

(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid οηο-Ν, Ν-dimethylamide, (6-nitro-2-bis-N, N-dimethylamide) , 3-dioxo-l, 2,3,4-tetrahydro-quinoxalin-l-yl) -methane.

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 are gradually added under a nitrogen atmosphere. Pd / C (10%)

300 mg of ammonium formate and 18 ml of water are added and the reaction mixture is heated at 80 ° C for one hour. After cooling, the catalyst is filtered off, the filtrate is evaporated and the residue is freeze-dried. 200 mg of acid are obtained

1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid as a white solid.

1- (6-Amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1H-acid was prepared in an analogous manner.

-etánfosfdnová.

Example 9

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

tetrahydro-quinoxalin-l-yl] -metánfosfdnová

200 mg of 1,4-bis-dimethylamino-3-carbethoxy-2-azabutadiene-1,4 are treated with 3 ml of glacial acetic acid while cooling, and the reaction mixture is stirred for 10 minutes at room temperature. 180 mg of acid are then added to the batch

1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, dissolved in 3 ml of glacial acetic acid, was stirred overnight 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-carbethoxy-imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] methanephosphonic acid is obtained as an oily liquid.

The following are produced in an analogous manner:

1- (6- (4-Cyano-5-methyl-imidazol-1-yl) -2,3-dioxo-1,2,3,4------)

J Tetrahydroquinoxalin-1-yl] -methanephosphonic acid.

s

J ί

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. Éadová kúp! is removed and the batch is heated at 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] acid. m.p. 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] ethane-1-phosphonic acid, 1- [6-bromo-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] methanephosphonic acid 1 - [6-cyano-2,3-dioxo-l, 2,3,4-tetrahydro-quinoxalin-l-yl] methanephosphonic.

Example 11

6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethanephosphonic acid

100 mg of 6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methanephosphonic acid was 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-tetrahydroquinoxalin-1-ylmethanephosphonic acid, 1- (6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1) 1- (6-Bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-ethanephosphonic acid) -ylethanephosphonic acid.

Example 12

Dissolve 100 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid in 20 ml of water and adjust the pH to saturated sodium carbonate solution

9.5. To this mixture is added 0.2 ml of acetic anhydride,

Stir for 36 hours and concentrate. The residue obtained is dissolved in as little water as possible, applied to an ion exchanger (IR 120, 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-tetrahydroquinoxaline-) are obtained.

1-yl) -methanephosphonic acid, m.p. 120 ° C.

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 having 6 to 12 carbon atoms in the aryl 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 represents hydrogen, alkyl having 1 to 12 C _x 9 atoms, substituted by R, alkenyl having 2 to 12 carbon atoms, substituted by R ^2, an alkynyl group of 2 to 12 carbon atoms, substituted by R ^2, cycloalkyl n having 3-7 carbon atoms, substituted with R, - (CH 2) n -aryl having 6 to 12 carbon atoms in the aryl, which is substituted with R ² in the aryl or alkyl radical, or - (CH 2) _n -hetaryl, which is in the 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 , Ί 9 SO ₂ R 8, 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 -COO-alkyl (C 1 -C 6) 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 ⁹ R 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 '- ^ - 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 ⁹ R ¹⁰ as well as their isomers or salts. provided that when R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent a hydrogen atom, the substituent R ¹ cannot be a carbamoylmethyl group, a 1-carboxy-1-phenylmethyl group or a straight alkyl group having 1 to 6 carbon atoms in 1-position substituted by carboxyl or COO-alkyl of 1 to 6 carbon atoms in the alkyl when R ¹ represents a straight alkyl group of 1 to 6 carbon atoms which is in the 1-position substituted by carboxyl or COO-alkyl of 1 to 6, carbon atoms, are not substituents ^R6 and / or R ^7, or R ⁶ and R ⁷ is fluoro, chloro or bromo and R ⁴ - R ⁸ are each hydrogen atom, and when R ¹ is -CH ₂ COOH , then (a) R ⁶ and R ⁷ do not simultaneously denote a methyl group; or b) R ** or R ^{7 is} not nitro and R ⁴ -R ⁸ is each hydrogen. 2. 3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester; 4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) -ethyl-1- (3-ethoxycarbonyl-propyl-6-nitroquinoxaline) -2,3- (1H, 4H) -dione diethyl ester 1-yl-methyl) -phenylphosphonic acid, 2- [4- (2-ethoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] -benzoic acid 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-1,2-ethyl ester), 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-yl-methyl) -phenylphosphonic acid (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, (+) - 1- (6-trifluoromethyl) -1-yl-methanephosphonic acid -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid (-) - 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4- tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethane-1-phosphonic acid, 4- (6-nitro- 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -butane-1-phosphonic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) -1-yl) -phenylethane-1-phosphonic acid, P-methyl- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphinic acid, (P, P- 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-tetrahydroquinoxalin-1-yl) methanephosphonic acid, 1- (6-amino-2,3) dioxo-l, 2,3,4-tetrahydro-quinoxalin-l-yl) -methanephosphonic acid, ----------------- 41 1- (6- (Carbethoxy-imidazol-1-yl) -2,3-dioxo-1,2,3,4) 1- (8-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid-tetrahydro-quinoxalin-1-yl) -methanephosphonic acid 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) propane-1-phosphonic acid according to claim 1. Compound-based medicament according to claims 1 and 2. Use of the compounds according to claims 1 and 2 for the manufacture of medicaments. 5. A process for the preparation of compounds of the formula I which comprises: a) a compound of formula II in which R ^x, R ^5, R ^6, R ⁷ and R ⁸ as defined above, is cyclized with reactive oxalic acid derivatives and optionally reacted 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 ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R 6, and R® as defined above, is reacted with a compound of formula I to form a compound of formula I and, if desired, 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 for halogen or cyano, or the amino group is reacted with 2-azabutadiene of formula IV R in which U and V mean cleavage 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 the imidazole derivative, or isomers separated or salts formed. Medicament according to claim 5 in combination with L-DOPA and / or L-DOPA antagonists and / or benzerazide.