CZ138793A3 - Quinoxaline derivatives, process of their preparation and their use in medicaments - Google Patents

Abstract

Quinoxaline derivates have the formula (I), in which R<1> is C1-12-alkyl substituted by R<2>, C2-12-alkenyl substituted by R<2>, C2-12-alkinyl substituted by R<2>, C3-7-cycloalkyl substituted by R<2>, -(CH2)n-C6-12-aryl substituted by R<2> in the aryl or alkyl residue or -(CH2)n-hetaryl substituted by R<2> in the hetaryl or alkyl residue; R<4> is hydrogen, C1-12-alkyl substituted by R<2>, C2-12-alkenyl substituted by R<2>, C2-12-alkinyl substituted by R<2>, (CH2)n-C6-12-aryl substituted by R<2> in the aryl or alkyl residue, or -(CH2)n-hetaryl substituted by R<2> in the hetaryl or alkyl residue; R<5>, R<6>, R<7> and R<8> are the same or different and represent hydrogen, halogen, nitro, NR<9>R<10>, NHCOR<11>, SO2R<12>, C3-7-cycloalkyloxy, COR<13>, cyano, CF3, C1-6-alkyl, C1-4-alkoxy or imidazole possibly substituted by cyano, C1-4-alkyl or -COO-C1-6-alkyl or R<5> and R<6> or R<7> and R<8> represent a condensated benzene ring, and R<2> stands for -CO-R<3>, 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, their production and their use in pharmaceuticals

Technical field

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

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

It has been found that the compounds of the present invention are distinguished by their good ability to bind to quasiqualate receptors as compared to the quinoxalines known from EP-A-315 959 and WO 91/138 78.

The present invention provides compounds of formula I

(I) in which

R ¹ represents alkyl having 1 to 12 carbon atoms substituted by R, alkenyl having 2 to 12 carbon atoms substituted by R ^2, alkinyl having 2 to 12 carbon atoms substituted by R ^2, cycloalkyl having 3 to 7 carbon atoms, substituted 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 group which is substituted in the hetaryl or alkyl radical R ² , r 4 is hydrogen, C 1 -C 12 alkyl substituted with R ² , C 2 -C 12 alkenyl substituted with 2

R, (C 2 -C 12) alkynyl, substituted with R, (C 3 -C 7) cycloalkyl, substituted with R ² - (CH ₂ ) _n -aryl (C 6 -C 12) aryl, which is in aryl or an alkyl radical substituted with R, or a - (CH 2) _n -hetaryl group substituted with R ² in the hetaryl or alkyl radical; and

R, R, R, and R ° are the same or different and are hydrogen, halogen, nitro, NR 4 R 6, NHCO 2 R, SC 4 R ² , C 3 -C 7 cycloalkoxy, COR ¹ · ^, cyano, trifluoromethyl, alkyl having from 1 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms or an imidazole group optionally substituted by cyano, alkyl having 1 to 4 carbon atoms or -COO-alkyl having 1 to Or (C 6 -C 6) alkyl;

S 7 R

R and R or R and R denote a fused benzene ring, wherein

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

R represents a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or an -NR 6 R 6 -Q,

X and Y are the same or different and are hydroxy, C 1 -C 6 -alkoxy, C 1 -C 4 -alkyl, or -NR 4 R 10, and are the same or different and are hydrogen, C 1 -C 4 -alkyl. carbon atoms or, together with a nitrogen atom, a saturated 5- or 6-membered heterocycle which may contain an additional oxygen or sulfur atom,

R ¹¹ represents alkyl having 1 to 6 carbon atoms or phenyl, _in

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

R is hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or -NR 4 R 6 -θ as well as isomers or salts thereof, provided that when R ⁴ , R ⁶ , R ⁶ and R ^{6 are} R @ ¹ cannot be a carbamoylmethyl group, a 1-carboxy-1-phenylmethyl group or a straight-chain alkyl group having 1 to 6 carbon atoms which is in the 1- position substituted by a carboxyl group or a C1-6 alkyl group substituents 7 6 7 and / or C 1 -C 6 -alkyl C 1 -C 6 alkyl and when R1 represents a straight C 1 -C 6 alkyl group which is in the 1-position substituted by a carboxyl group or a COO alkyl group; R, or R and R 'denote fluorine, chlorine or bromine and R ⁴ - R® is always a hydrogen atom and if R ¹ denotes a group -CH 2 COOH, and 6 7

(a) R and R 'do not simultaneously represent a methyl group; or

b) R 4 or R 4 does not represent a nitro group and R ⁴ -R ⁴ 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.

O

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

The term alkyl refers to an appropriate straight or branched alkyl radical such as methyl, exyl, propyl, isopropyl, buxyl, isobuxyl, sec-buxyl, X-t-buxyl, penyl, isopenyl a group, a hexyl group, a hepxyl group, an okxyl group, a nonyl group or a decyl group, alkyl groups having 1 to 6 carbon axomes being preferred.

The alkenyl group contains especially alkenyl residues with 2 to 6 carbon axoms, which may be straight or branched, such as 2-propenyl, 2-butenyl, 3-methyl-2-propenyl, 1-buxenyl, 1-propenyl and vinyl.

Suitable alkynyl radicals are especially exhinyl, 1-propynyl, 2-propynyl, 1-buxinyl, especially those having from 2 to 4 carbon axoms.

C 3-7 cycloalkyl refers to cyclopropyl, cyclobuxyl, cyclopenxyl, cyclohexyl and cyclohepxyl, with cycloalkyl groups having from 3 to 5 carbon axoms being particularly suitable.

Aryl zbyxky uvésx may be for example phenyl, nafxylovou, biphenylyl and indenyl,, are particularly (CH _{2) n} -phenyl with n = 0,1 or 2 respectively.

Suitable hexaryl moieties are 5- or 6-membered hexeroaromatics having 1 to 3 nitrogen axoms, such as pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine and triazine.

The term halogen atom refers to a fluorine, chlorine, bromine and ios 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 ^ represents an alkyl group having 1 to 12 carbon atoms, and R ³ are particular substituents R® to as N02, NR ⁹ R ^10, NHCOR ^11, SO 2 R ^12, cycloalkoxy having 3 to 7 carbon atoms, COR ^13, cyano, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, an optionally substituted imidazole or a fused benzene ring. Compounds of formula I wherein R = -PO-XY are characterized by very good water solubility.

Physiologically acceptable salts are salts with organic and inorganic bases, such as the well-soluble salts with alkali metals and alkaline earth metals, as well as with 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-butanetriol.

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 can be influenced via excitatory amino acid receptors, in particular AMPA receptors, such as Parkinson's disease, Alzheimer's disease. Huntington's disease, epilepsy, hypoglycaemia, psychosis, muscle stiffness, emesis, pain conditions, anoxia and deficits after ischeraia.

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 benserazide. In combination, the administered dose of the prior art drug decreases and its effect synergistically increases.

The affinity of the compounds of the present invention for central AMPA receptors was tested in vitro in classical binding assays. It binds with high affinity to the binding sites, labeled with ² H-AMPA.

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

Table Compound AMPA-binding (IC ^ q [gmol]) AND 2.22 (B) 1.79

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) -proppan-1-phosphonic acid.

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

For the use of the compounds of the present invention as medicaments, these are converted 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. If desired, they additionally contain auxiliaries such as preservatives, stabilizers, 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.

Surfactant adjuvants, such as salts of gallic acid 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, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, or corn or potato starch. The application can also take place in liquid form, for example as juice, to which optionally a sweetener is 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 can be administered as a single dose or divided into two or more doses per day.

The present invention further provides a process for the preparation of the compounds of formula (I), the process comprising:

a) a compound of formula II

wherein R ¹ , R ² , 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 4 'wherein:

X is halogen, tosylate, mesylate or triftalate; and

Λ * Λ

R is as defined for the substituent R @ 1 except for the hydrogen atom;

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

R @ ¹ - X to a 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 araino group is alkylated or acylated; is reacted with 2-azabutadiene of formula IV

U V in which

U and V are leaving groups, rH is a hydrogen atom, a cyano group or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl and

2

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

The cyclization of the compounds of formula II with a reactive oxalic acid derivative is carried out in one or two steps. Preferred is a two-step process in which 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 an organic amine, for example triethylamine, pyridine, Hunig's base or diethylaminopyridine. Subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, with the alcohol being added to the solvent.

The introduction of substituents R and R ⁴ is carried out using conventional alkylation methods that quinoxalinedione reacted with a compound of formula R - X, or R - X, wherein X represents halogen, tosylate, mesylate or especially triflate, in the presence of a base, at a temperature room temperature or at elevated temperature, in aprotic solvents. The anion can also be produced before it was added the compound of formula R ¹ - or R ⁴ X - X. Suitable bases are, for example, alkali metal compounds such as potassium carbonate, sodium hydroxide, alkali metal alcoholates and especially metal hydrides such as sodium hydride. Alternatively, the alkaline compounds can be reacted under phase transfer conditions. When mixtures are obtained by a compound having substituents R or R ^4, then these 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. When process variant b) is allowed to proceed with 2 moles of the compound R1-X under otherwise analogous reaction conditions, substituents R1 are simultaneously introduced. and R ⁴ .

Optionally, the subsequent saponification of the ester group may be basic or preferably acidic such that it is hydrolyzed at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as 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.

The esterification of the carboxylic acid or phosphonic acid is carried out in a manner known per se by means of the corresponding alcohols in the acid or in the presence of an activated acid derivative. Suitable acid derivatives are, for example, acid chlorides, imidazolides or acid anhydrides. For phosphonic acids, reaction with orthoesters of the corresponding alcohols is possible. Reaction with the addition product of dicyclohexylcarbodiimide and the corresponding alcohol also leads to the ester. 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 can 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 by methods known per se, 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, formed intermediately from amino compounds, with nitriles, with cyanides in the presence of copper (I) cyanide or with nickel potassium cyanide, can be reacted.

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 the diazonium salts formed intermediate 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-amyl nitrite and, for example, methylene iodide or bromoform in an aprotic solvent such as dimethylformamide. The introduction of fluorine 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 in the range of 0 ° C to 150 ° C. The leaving groups U and V may be the same or different; particularly 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 can serve both as a reaction medium 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 into enantiomers or E / Z isomers.

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

If the preparation of the starting compounds is not described, they are known or can be produced analogously to known compounds or by the methods described herein.

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 nitroarnates, 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. 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 are used for this reaction, and powdered copper as a base. It is also possible to prepare 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 selectively with sodium sulfide in the presence of multiple nitro groups 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 preferred to carry out the reaction with esters and to hydrolyze them in the final 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, 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-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 atmosphere and 50 ml of dimethylformamide at room temperature while avoiding moisture. In three portions, 330 mg (11 mM) of sodium hydride (80%) was added to the batch, and the reaction mixture was stirred for one hour at room temperature. 1.26 g (5.5 mM) of 3-bromomethylbenzoic acid methyl ester in 5 ml of dimethylformamide was then added dropwise to the batch and stirred for 3.5 hours. After concentration, the residue is partitioned between a mixture of water and ethyl acetate acidified with acetic acid. The organic phase was separated, dried, filtered and concentrated. The residue is chromatographed on silica gel with dichloromethane / ethanol = 95: 5. In addition to 211 mg of methyl 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester, which is not further purified, 222 mg of methyl acid ester is obtained. 3- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -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-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. &gt; 300 ° C, 2- (6-nitro-2,3-dioxo-1,2,3-ethyl ester) 279-C / 283-284 ° C, 2- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1-yl) ethyl ester, 4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid. -ylmethyl) -benzoic acid (further processing without further purification),

1- (3-methoxycarbonyl-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 258 DEG-265 DEG C. (decomposition),

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-1,2,2) -ethyl ester 114,4 C / 129-131 ° C, 4- (7-nitro-2,3-dioxo-1,2,3-diethyl ester), 3,4-tetrahydro-quinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid (further processed without purification), 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1- 3- (6-nitro-prop-1-phosphonic acid diethyl ester) 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1-propyne-1-phosphonic acid diethyl ester 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic tert-butyl ester (4-tetrahydroquinoxalin-1-yl) -methanecarboxylic acid.

Example 2

In addition, 503 mg of 3- [4- (3-methoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1] can be isolated at a double dose of methyl 3-bromomethylbenzoate and otherwise complete reaction as described in Example 1. 2,3,4-tetrahydroquinoxalin-1-yl-methyl] -benzoic, 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] -benzoic acid, 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 ml) 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 the ingress of 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 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), 2- (ethyl ester) 2,4-dinitrophenyl) aminobenzoic acid (further processed without further purification).

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

566 mg (1.7 mM) of 4- (2,4-dinitrophenyl) -aminobenzoic acid ethyl ester, 761 mg (12.2 mM) of ammonium chloride, 0.68 ml of concentrated ammonia, 15 ml of ethanol and 6 ml of distilled water are added. jointly submitted 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 are obtained (further processed without further purification).

The following are produced in an analogous manner:

145-150 ° C, 3- (2-amino-4-nitrophenylamino) -benzoic acid ethyl ester, 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-nitrophenylamino) -benzoic acid ethyl ester are introduced with 488 mg (4.8 mM) of xriexhylamine in 27 ml of dried xexrahydrofuran at Xeplox bath 4 ° C under argon and Xmosphere and while avoiding moisture. A solution of 659 mg (4.8 mM) of oxylic acid exyl ester oxyl chloride and 8 ml of dried xexrahydrofuran was added dropwise to the batch, and the reaction mixture was stirred for 2 hours at room temperature. 0.2 ml of xriexhylamine and 0.1 ml of exyl oxyl oxalic chloride were added thereto, and the mixture was stirred for 1 hour at Xeplox mix. The batch is filtered and the filtrate is concentrated. The residue obtained is partitioned between water and an exoxylic acid ester and the organic phase is concentrated. The residue thus obtained is boiled under reflux for 2 hours in 25 ml of 1 N hydrochloric acid and 25 ml of exyl alcohol. The precipitated product is filtered off with suction, washed with water and dried. XakXo 220 mg of 4- (6-nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl) -benzoic acid exyl ester (further processing without purification) is obtained.

The following are produced in an analogous manner:

3- (6-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl) -benzoic acid exyl ester of xeplox at 258-263 ° C; 3- (6-nitro-2-exyl ester) 3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl) -phenylphosphonic acid.

Example 4

A) 2- (2,4-Dinixrophenyl) 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) of 2.4 at a bath temperature of 40 ° C with vigorous stirring. -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. are obtained.

The following are produced in an analogous manner:

134-137 ° C, 3- (2,4-dinitrophenylamino) -propionic acid, m.p. 271-272 ° C (decomposition), 2- (2) (4-dinitrophenylamino) -phenylphosphonic acid (further processed without purification), (2,4-dinitrophenylamino) -methanephosphonic acid, m.p. 225-227 ° C, 2- (2,4-dinitrophenylamino) -ethanephosphonic acid (further processed without purification, 3- (2,4-dinitrophenylamino) -phenylphosphonic acid, (2-nitro-1-naphthylamino) -methanephosphonic acid, (1-nitro-2-naphthylamino) -methanephosphonic acid, 1- (2-nitro- 1-naphthylamino) -ethan-1-phosphonic acid, 1- (1-nitro-2-naphthylamino) -ethan-1-phosphonic acid, (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphinic acid, 1- (2-Nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid,

1- (2,4-dinitrophenylamino) -ethane-1-phosphonic acid, acid 3- (2,4-dinitrophenylamino) -propane-1-phosphonic acid, acid 4- (2,4-dinitrophenylamino) -butane-1-phosphonic,

(2-Nitro-4-fluorophenylamino) -methanephosphonic acid, (2-nitro-4-chlorophenylamino) -methanephosphonic acid, (2-nitro-4-bromophenylamino) -methanephosphonic acid, (2-nitro-4-methylphenylamino) -methanf osfon,

1-  (2-nitro-4-fluorophenylamino) -ethan-1-phosphonic acid, 1-  (2-nitro-4-chlorophenylamino) -ethan-1-phosphonic acid, 1- • (2-nitro-4-bromophenylamino) -ethan-1-phosphonic acid,

1- (2-nitro-4-methylphenylamino) -ethan-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-mexhyl-2- (2-nitro-4-trifluoromethyl-f) enylamino) 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) -methanephosphine oxide, P-methyl- (2,4-dinitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2] 1- [5- (imidazol-1-yl) -2-nitro-4-trifluoromethyl-phenylamino] methylphosphonic acid, 4-dinitrophenylamino] methylphosphonic acid.

B) 1- [5- (Imidazol-1-yl) -2,4-dinitrophenylamino] -ethan-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 was mixed with 200 mg of imidazole and heated at 11 ° C for 2 hours. An additional 200 mg of imidazole was then added and reheated to 110 ° C for 2 hours. The mixture was acidified with 4 N hydrochloric acid, the insoluble matter was filtered off, and the filtrate was washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethanol. 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. -dinitrophenylamino] -ethan-1-phosphonium.

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 ethanol and 21 ml of distilled water were added. The mixture was charged at an internal temperature of 78 ° C (bath temperature 90 ° C). 4.44 g (20 mM) of sodium sulfide (35%) was added in three portions and the reaction mixture was stirred for one hour. The batch is then filtered off with suction at room temperature and washed successively with water and diethyl ether. The filtrate was evaporated to an aqueous phase 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 are 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) -ethan-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) -methanphosphine oxide, P-methyl- (2-amino-4-nitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2] -amino-4-nitrophenylamino] -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 treated 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, the following are produced:

1- (2-Amino-1-naphthylamino) -ethan-1-phosphonic acid, 1- (1-Amino-2-naphthylamino) -ethan-1-phosphonic acid, 1- (2-Amino-1-naphthylamino) -methanephosphonic acid, 1- (1-amino-2-naphthylamino) -methanephosphonic acid,

1- (2-Amino-4-trifluoromethyl-phenylamino) -ethan-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -methane-1-phosphonic acid, (2-amino-4-methylphenylamino) - methanphosphonic 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) -ethan-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -hexane-1-phosphonic acid, 1-Mexethyl-2- (2-amino) 4-Trifluoromethyl-phenylamino) -ethan-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 acid -l- Phosphonic acid, (4-fluoro-2-aminophenylamino) -methanephosphonic acid,

[5- (Imidazol-1-yl) -4-trifluoromethyl-2-amino-phenyl amino] methylphosphonic acid, 1- (4-fluoro-2-aminophenylamino) -ethan-1-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-nitrophenyl-30 amino) -propionic acid are introduced with 200 mg (2 mM) of triethylamine in 20 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under argon and avoiding access to moisture. 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 were then added and the mixture was stirred at room temperature for a further hour. 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 ethanol 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 ° 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-tetrahydroquinoxalin-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-tetrahydro-benzo (f) quinoxalin-4-yl) -methanephosphonic acid (2,3-dioxo-1,2,3,4-tetrahydro-benzo (f) quinoxalin-4-yl) (1) -ethane-1-phosphonic acid, (2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-1-yl) -methanephosphonic acid, (2,3-dioxo-1,2,3) (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, 4-tetrahydro-benzo (f) quinoxalin-1-yl) -ethan-1-phosphonic acid m.p. 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) 285 DEG-287 DEG C. (6-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1, 2,3,4-tetrahydroquinoxalin-1-yl) -butane-1-phosphonic acid (6-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid (6-bromo-2,3-dioxo-1,2-yl) -methanephosphonic acid (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 DEG C., 1- (6-chloro-2,3-dioxo-1), m.p. 2.3 1,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid 1- (6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid 1- (6-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, 1- (6-trifluoromethyl-2,3-dioxo-) 1,2,3,4-tetrahydroquinoxalin-1-yl) -1-phenyl-methane-1-phosphonic acid, m.p. 245 ° C, 1- (6-trifluoromethyl-2,3-dioxo-1,2,3) 1,4-tetrahydroquinoxalin-1-yl) -1-methyl-ethane-phosphonic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -hexan-1 -phosphonic acid, 1-methyl-2- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, 2- (6-trifluoromethyl- 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, 1-mexhyl-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 acid) -1,2,3,4-tetrahydroquinoxalin-1-yl) -exane-1-phosphonic acid = + 7.4 ° (c = 0.505; H ₂ O), (-) - 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid [α ² θ246 ^ = - 5.9 ° (c = 0.510; H ₂ O), β-mexyl- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphinic acid, m.p. 320 to 325 ° C (decomposition), (β, P-dimethyl) - (6-nitro-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-tetrahydroxhinoxalin-1-yl] methylphosphonic acid,

[6-Trifluoromethyl-7- (imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroxhinoxalin-1-yl] methylphosphonic acid.

Example 5

3- (6-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl-methyl) -benzoic acid

211 mg (0.6 mM) of 3- (6-nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid mexyl ester were added to 4 ml of 4 N hydrochloric acid 4 ml of xrifluoroacetic acid are added and the reaction mixture is stirred for 3.5 hours at a bath temperature of 110 ° C. The batch is diluted with water and sucked off after cooling on the xeplox bowl. The filter cake was washed with water and ethyl alcohol and dried. 3- (6-Nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox m.p. > 330 ° C is obtained.

The following are produced in an analogous manner:

3- (7-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox at> 330 ° C, 3- [4- (3-carboxybenzyl) 6-Nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox at 298-300 ° C, 2- (6-nixro-2,3) acid -dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox m.p. 329-334 ° C (dec.), 2- (7-nixro-2,3-dioxo-1,2,2-oxoic acid) 3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox melting at 328 DEG-330 DEG C., 2- [4- (2-carboxybenzyl) -6-nixro-2,3-dioxo-1,2, 3,435

-tetrahydroquinoxalin-1-yl-methyl) -benzoic acid, m.p. > 300 ° C, 4- (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- (4-carboxymethylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p.> 310 ° C, acid 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-trifluoromethyl-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 mg (1.4 mM) of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid ethyl ester was heated at reflux for 2 hours. 6 hours with concentrated hydrochloric acid. After cooling, the batch is reduced with water and aspirated. The filter cake was then dried to give 53 mg of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 253-265. ° C (dec.).

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-yl) -phenylphosphonic acid, m.p. 304-307 ° C (dec.), 3- (6-trifluoromethyl-2,3-dioxo-1), 2,3,4-tetrahydroquinoxalin-1-yl) -1-propyne-1-phosphonic acid, 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1 -propene-1-phosphonic 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, after which 0.35 ml (276 mg) of ethanol was added and stirred at room temperature for 1.5 hours. After concentration in vacuo, the residue is chromatographed on silica gel using toluene / glacial acetic acid / water = 10: 10: 1. First, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid diethyl ester of melting point 220 DEG-260 DEG C. is obtained, followed by (6-nitro) monoethyl ester. -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, m.p. 197 [deg.] C, 100 mg of diethyl ester and 36 mg of monoethyl ester.

The following are produced in an analogous manner:

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

Example

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 were dissolved in 60 ml of methanol and 50 mg of Pd were gradually added under a nitrogen atmosphere. / C (10%), 300 mg of ammonium formate and 18 ml of water, and the reaction mixture was 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 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid are obtained in the form of a white solid.

It is 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-tetrahydroquinoxalin-1-yl] -methanephosphonic acid

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. 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 are added to the batch and the mixture is stirred over 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-carbethoxy-iraidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid is obtained in the form of an oily substance. 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-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 were added dropwise to 10 ml of 25% sulfuric acid. After stirring for 5 minutes, a salt suspension is formed which is cooled to 0 DEG C. and a solution of 60 mg of sodium nitrite in 2 ml of water is added dropwise. After stirring at 0 ° C for 15 minutes, 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 the batch to 100 ° C for 2 hours. The cooled reaction mixture was then neutralized with concentrated ammonia solution and evaporated to dryness. The residue is boiled with ethanol and a small amount of water, filtered and the filtrate is concentrated. Chromatography on silanised 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. m.p. 295 DEG-297 DEG.

The following are produced in an analogous or literature-known manner:

1- [6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -ethan-1-phosphonic acid, 1- [6-bromo-2,3-dioxoic acid -1,2,3,4-tetrahydroquinoxalin-1-yl] -ethan-1-phosphonic acid 1- [6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-40

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

Example 11

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 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 silanised 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-yl-methanephosphonic acid of melting point 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-yl-methanephosphonic acid 1- (6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) 1-yl) -ethanephosphonic acid, 1- (6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid.

Example 12

100 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid are dissolved in 20 ml of water and the pH is adjusted to 9 with saturated sodium carbonate solution. , 5. 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 (IR 120, strongly acidic) and eluted with water. The appropriate fractions were collected, concentrated and dried. 110 mg of 1- (6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanesulfonic acid, m.p. 120 DEG C., are obtained.

Claims (6)

PATENT CLAIMS 1. Quinoxaline derivatives of the general formula I ¹ . with which R1 represents an alkyl group having 1 to 12 carbon atoms, a substituted R, an alkenyl group having 2 to 12 carbon atoms, a substituted R, an alkynyl group having 2 to 12 carbon atoms, a substituted R, a cycloalkyl group having 3 to 7 carbon atoms, - (CH ₂ ) _n -aryl having 6 to 12 carbon atoms in aryl which is substituted with R ² in the aryl or alkyl radical, or - (CH ₂ ) _n -hetaryl group which is substituted with R ² in the hetaryl or alkyl radical , R 4 denotes a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, substituted with R ² , an alkenyl group having 2 to 12 carbon atoms, substituted with 2 R, (C 2 -C 12) alkynyl, substituted with R, (C 3 -C 7) cycloalkyl, substituted with R ² - (CH ₂ ) _n -aryl (C 6 -C 12) aryl, which is in aryl or alkyl radical substituted with R or - (CH _{2) n} -hetarylovou group which is a hetaryl or alkyl radical substituted with R ² c <7 fl R, R, R and R are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, an NR R group, an NHCOR 4 group, a St 2 R ⁴ group, a C 3 -C 7 cycloalkoxy group, a COR group ¹² , 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 6 alkyl atoms in alkyl, or A 7 fl R and R or R and R denote a fused benzene ring, wherein R ² represents a group -CO-R ² or -PO-XY and R ² is one to two same or different, n is 0,1,2,3,4 or 5, R ² represents hydroxyl, alkoxy having 1 to 6 carbon atoms or -NR ⁹ R · ^, X and Y are the same or different and represents hydroxyl, alkoxy having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, or -NR ⁹ R ^10, 9 10 R and R are the same or different and denote a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or, together with a nitrogen atom, a saturated 5- or 6-membered heterocycle which may contain an additional oxygen or sulfur atom; or a phenyl group, R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an amino group or a dialkylamino group having from 1 to 4 carbon atoms in each alkyl, and R represents a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms or a group -NR ⁴ R ⁶ , and their isomers or salts thereof, provided that when R ⁴ , R ⁵ , R ⁶ , R ⁷ and R @ 6 denotes a hydrogen atom, R @ 1 cannot be a carbamoylmethyl group, a 1-carboxy-1H-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 C1 -C6 alkyl group 6 carbon atoms in the alkyl and when R1 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; 6 carbon atoms in the alkyl, R1 substituents cannot And / or R and R and R &apos; respectively denote fluorine, chlorine or 48 bromine and R-R is in each case a hydrogen atom and, if R1 denotes a -CH2-COOH group, then 6 7 (a) R ° and R 'do not simultaneously represent a methyl group; or b) r ⁶ or R ^{7 is} not a nitro group and R ⁴ -R ® is a hydrogen atom. 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-texrahydroquinoxaline) - diethyl ester 1- (3-exoxycarbonyl-propyl) -6-nixoquinoxaline) -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-yl-methyl] - benzoic acid, 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester, 3- (6-nitro-2,3-dioxoic acid) 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-lin-1-yl-methyl) -phenylphosphonic acid, (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid 3,4-tetrahydroquinoxacic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,4) (3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, (+) - 1- (6-trifluoromethyl-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, 1- (6-nitro-2,3-dioxo-1) 2,3,4-tetrahydroquinoxalin-1-yl) -ethan-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-tetrahydroquinoxalin-1-yl) -phenylethane-1-phosphonic acid, P-methyl- (6-nitro) -2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-1-yl) -methanephosphine, (β, β-dimethyl) - (6-nitro-2,3-dioxo-1,2,3) 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, 4-tetrahydroquinoxalin-1-yl) -methanephosphine oxide, (6-nitro-2) 1,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -me thanphosphonic acid, 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, 1- [6- (carbethoxy-imidazol-1-yl)] -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid 1- (8-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalim-1) 3- (6-Nixro-2,3-dioxo-1,2,3,4-oxohydroquinoxalin-1-yl) -propane-1-phosphonic acid, according to claim 1. A medicament based on the compounds of 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), characterized in that: a) a compound of formula II 1 <A 7 Q in each case Rm, R, R °, R 'and R ° are as defined above, cyclizes with reactive oxalic acid derivatives and optionally reacted with a compound of formula R ⁴ '- X in cxerem X is a halogen, xosylax, mesylax or xrifxalax axom; and R ⁴ has the meanings given for R ⁴ with subsxixuenx retracts graticule AXOM hydrogen or AND b) reacting a compound of formula III in which R a is as defined above with a compound of 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 reduced to the amino group or the amino group is alkylated or acylated or the amino group is exchanged for halogen or cyano, or amino, is reacted with 2-azabutadiene of formula IV AT N In (IV) in which U and V denote 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 Ϊ O R represents a hydrogen atom or a COO-alkyl group having 1 6 carbon atoms in an alkyl to an imidazole derivative, or isomers separated, or salts formed. Medicament according to claim 5 in combination with L-DOPA and / or L-DOPA antaonists and / or benserazide.