SI9420023A - Imidazoloquinoxalinone derivatives as eaa antagonists - Google Patents

Abstract

Described are imidazoloquinoxalinones of the formula (I) in which A and R1 to R6 are as defined in the description, plus their preparation. The compounds described can be used in the preparation of drugs for use in the treatment of neurodegenerative ailments and neurotoxic disorders of the central nervous system as well as in the preparation of spasmolytics, anti-epileptics, anxiolytics and anti-depressants.

Description

wherein A and R ¹ through R ^{6 have} the meaning indicated in the description as well as their preparation. The compounds of the invention can be used for the preparation of medicaments for the treatment of neurodegenerative disorders and non-toxic disorders of the central nervous system, as well as for the preparation of spasmolytics, antieptileptics, anxiolytics and antidepressants.

BASF AKTIENGESELLSCHAFT

Imidazolinoquinoxalinone derivatives as EAA antagonists

The present invention relates to novel imidazolo-quinoxalinones, to methods for their preparation as well as to their use for disease control.

DE-OS 3 004 750 and DE-OS 3 004 751 describe a range of imidazolo-quinoxalinone substances having anti-allergic effects. Further, protection is required for substituted imidazolo-quinoxalinones as phosphodiesterase inhibitors or. as agents that affect the circulatory system in US 5 166 344 (= EP 400 583).

In the central nervous system sector, various heterocycles are listed in US 5 163196 (= EP 518 530), including some imidazolo-quinoxalinones, which act as excitatory antagonists of amino acids (EAA antagonists). Further, 5 182 386 describes imidazolo-quinoxalines, which represent antagonists or. inverse GABA receptor agonists and can be used to suppress anxiety, sleep disorders, spasmodic conditions as well as to improve memory.

We have now found that the new imidazolo [1,2-a] quinoxalinones of formula I

where it is

A is a saturated or unsaturated alkylene group having 1 to 5 C atoms or a bond,

R ⁶ represents a formyl group or a carboxyl group, which may be in the form of its salt with a physiologically acceptable amine or metal cation, a COOR ⁷ moiety, wherein R ⁷ represents a C 1 -C 8 -alkyl moiety, a cycloalkyl group of 3 to 8 C atoms in a ring, a benzyl residue, of one of the residues - (CH 2) n-OR ⁸ , in which n is n for a number 2 to 4 and R ^{8 is} for a C 1 -C ₃ -alkyl group; A C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₆ alkylcarbonyl, nitrile, tetrazolyl, carbonylaminotetrazole, aldoxime, C ₁ -C ₄ alkoxyaldoxime, or optionally substituted carbamoyl group, and

R ^x -R ⁴ , which are the same or different, represent the atoms of hydrogen, fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C1-C6-alkanoylamino, C1-C5-alkyl, CL-C5-alkoxy, mono - or a dialkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, aminosulfonyl, di-C 1 -C 6 alkylaminosulfonyl or C 1 -C 6 alkoxycarbonyl group, or is one of the pairs R ¹ , R ² ; R ² , R ³ or R ³ , R ^{4 is} also a group - (CH 2) ₄ - or -CH = CH-CH = CH-,

R ⁵ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or optionally chlorine, fluorine, trifluoromethyl or a C ₁ -C ₄ alkyl substituted phenyl group, but cannot be simultaneously

And the embroidery

R ^{6 is a} carbonyl, ethoxycarbonyl, hydroxymethyl, formyl, tetrazolyl group, a carboxylic acid amide group or a 5-aminotetrazolyl group,

R ¹ , R ⁴ , R ^{5 are} hydrogen atoms and

R ² and R ^{3 are} identical and chlorine or bromine atoms in positions 7 and 8, new, highly effective antagonists of the so-called excitatory effective amino acids (EAA antagonists). They are therefore particularly suitable for the treatment of neurological disorders.

Preferred compounds are those which carry one or two electrophilic substituents, such as halogen atoms, nitro or trifluoromethyl groups, in the benzene ring as substituents R ² to R ⁴ .

In the imidazole ring, the preferred substitution in R ⁵ is given by a methyl, ethyl or phenyl group, while R ⁶ preferably represents a carboxylic acid group or a carboxylic ester group linked directly to the ring or an ethylene chain.

The carboxylic acids can be conveniently converted into their metal salts or with ammonia or suitable organic nitrogen bases into physiologically tolerable ammonium salts.

Particularly preferred are the following compounds, such as:

a. 4,5-Dihydro-7-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid

b. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid

c. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

d. 4,5-Dihydro-7,8-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid

e. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

f. 4,5-Dihydro-8-chloro-1-isopropyl-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

Mr Rücker 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

h. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] 4 quinoxaline-2-carboxylic acid ethyl ester

i. 4,5-Dihydro-1-isopropyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline

2-carboxylic acid

j. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline2-acrylic acid

k. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluonnetyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid methyl ester

l. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

m. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-propionic acid

n. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

o. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

p. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid

q. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

r. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

s. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid methyl ester

t. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

in. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

v. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester

w. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

x. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-propionic acid

y. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester.

The compounds of formula I can be prepared in a known manner by various methods.

Imidazole of formula II can be analogous to the procedure described in EP 400 583

R ⁵ AR ⁶

wherein R ¹ to R ⁵ and A have the indicated meaning and R ⁶ denotes a nitrile group, a carboxylic acid ester group, an aldehyde or alkanoyl group, reacted with a double-activated carbon acid derivative, such as phosgene, diphenylcarbonate, or preferably carbonyl diimidazole, in an inert aprotic solvent at elevated temperature from 150 to 200 ° C.

Suitable solvents are tetralin, decalin, 1,2-dichlorobenzene or 1,3-dimethylethylene or -propylene urea.

There are obtained compounds of formula I in which R ⁶ represents a nitrile group, a formyl group, a carboxyl ester group or an alkanoyl group.

Preferred compounds are those wherein R ¹ to R ⁴ and A have the above meanings and R ⁶ represents the residue of the carboxyl ester group.

Compounds of formula I in which R ⁶ represents an ester group may be subjected to acidic or alkaline hydrolysis to give compounds of formula I wherein R ⁶ represents a carboxy group.

The hydrolysis takes place preferably under alkaline conditions, e.g. in the presence of alkali hydroxide or sodium hydrogen carbonate, in a solvent such as water, lower alcohol, tetrahydrofuran or mixtures thereof. The organic acids thus obtained are optionally converted into a physiologically acceptable amine or metal salt. They are meant in particular to alkali metal salts such as sodium and potassium, alkaline earth metals such as calcium, other metals such as aluminum, and organic base salts such as morpholine, piperidine, mono-, di- and triethanolamine or tris- (hydroxymethyl) of aminomethane.

The starting compounds for process la can be obtained by the following synthesis scheme:

Scheme I:

R ⁴

R ² V ^X NO ₂

Ri

III reductions

R ⁵ AR> = <

HN ^ N

R ³

K2CO3 solvent

IV

R ⁵ AR,> = <z N rV ~

NH ₂

R ³

R

R ⁵ AR,> = <

³ A N ' _Z N

XX

It is known that ortho-halogensubstituted nitrobenzenes with N ₁ unsubstituted imidazoles can be metabolised in suitable solvents such as dimethyl sulfoxide, dimethylformamide or acetonitrile, at temperatures between 0 and 140 ° C and with the addition of a base, e.g. of potassium carbonate.

It is further known that the substitution of the halogen atom with the 4- and 4,5-disubstituted imidazoles proceeds so that the nucleophilic strand on the least sterically hindered N-atom of the imidazole proceeds, so that in this case uniform products are formed.

The reduction of nitro compounds can proceed in a known manner, e.g. by catalytic hydrogenation with palladium or nickel catalysts or also with tin (Il) chloride.

o-halogen-nitrobenzenes of formula III are commercially available or can be prepared by known methods.

Compounds of formula I wherein R ^{6 represents a} hydroxyalkyl, aldehyde, oxime or oximeter group are prepared by the operations described below. These exist in that the compounds of formula I in which R ⁶ represents a carboxylic acid ester group are reduced to give compounds of formula I in which R ⁶ represents a hydroxyalkyl group.

This reduction can be carried out using a complex metal hydride, such as e.g. lithium boron hydride, in a suitable solvent such as ether or tetrahydrofuran. The reduction is preferably carried out at elevated temperature, especially at the boiling point of the solvent.

If desired, these hydroxyalkyl compounds can be converted by oxidation by an oxidizing agent such as chromium oxide or manganese dioxide to aldehydes of formula I (R ⁶ = formyl group).

Oximes and oximeters can be obtained from aldehydes of formula I by metabolism with hydroxylamine and hydroxylamine-O-alkyl ethers.

Compounds of formula I, in which R ⁶ is optionally substituted carbamoyl or carbonylaminotetrazole group, are obtained in such a way that the acid or its activated form of formula I, wherein R ⁶ represents a carboxylic acid residue, is reacted with ammonia, amines or 5-amino -tetrazole.

As amines are suitable, in particular C ^ C ^ alkylamines, and nitro or _CF3 group or 1-2 C-C ^ alkyl groups, C _M alkoxy groups or halogen atoms on the phenyl ring substituted aniline, benzylamine and phenethylamine.

Either acid chloride is used for this metabolism or the metabolism is carried out in the presence of carbonyldiimidazole. Preferably we work in dimethylformamide.

Compounds of formula I with a carbonylaminotetrazole residue of R ⁶ (R ⁶ = CO-NHCHN ₄ ) can be obtained by known methods by condensation of a basic acid with 5-aminotetrazole of formula IV

N.

H2N j «

IV

The reactions are generally carried out in an inert solvent, such as e.g. methylene chloride, dioxane, tetrahydrofuran or dimethylformamide, preferably in the presence from a peptide chemistry of a known condensing reagent, such as Ν, Ν′-carbonyldiimidazole or N, N niticyclohexylcarbodiimide, at temperatures from 20 ° C to 120 ° C.

If substituents R ¹ and R ² are not already present in the starting compounds, they can also be introduced subsequently. This can be achieved by electrophilic aromatic substitution of the resulting compound of formula I, in which R ¹ and / or R ² represent hydrogen atoms, by known methods such as those described e.g. in Houben-Weyl zv. Χ / 1, p. 471 ff. IX, p. 572 ff., And zv. V / 3, p. 873.

A process for the preparation of nitro compounds of formula I wherein R ¹ , R ⁴ to R ⁶ and A have the above meanings and R ² or R ³ are hydrogen, nitro or alkyl atoms, with at least one of R ² residues or R ^{3 is a} nitro group, characterized in that a compound of formula I wherein R 1, R ⁴ to R ⁶ and A have the above meaning and R ² or R ³ is a hydrogen atom or an alkyl group, at least one of the residues R ² or R ^{3 is} a hydrogen atom, nitrated with nitric acid or sulfuric acid potassium nitrate at low temperature. Concentration of nitric acid at 0 ° C proved to be advantageous.

Synthesis of compounds of formula I, wherein R ¹ to R ⁵ and A have the above meaning and R ⁶ represents a tetrazolyl residue, proceeds by known methods, such as e.g. described in Synth. 1973, 80, by synthesis of the corresponding nitriles with hydrochloric acid or one of its salts, e.g. with alkali or alkaline earth azides, optionally in the presence of Lewis acids, such as aluminum and tin chloride or ammonium chloride.

A combination of sodium azide with ammonium chloride is preferred. Generally, the reaction is carried out in the presence of an inert solvent, such as benzene, tetrahydrofuran or dimethylformamide, at temperatures between room temperature and 150 ° C. Tetrazolyl compounds are very acidic and can be conveniently converted into their salts with physiologically acceptable amine or metal cations.

Compounds I of the invention are suitable as active substances in human medicine and can be used for the preparation of medicaments for the treatment of neurodegenerative disorders and non-toxic disorders of the central nervous system, as well as for the preparation of spasmolytics, antiepileptics, anxiolytics and antidepressants.

The pharmacological efficacy of compounds I of the invention was investigated on the isolated membrane material of the rat brain. For this purpose, the membrane material was treated in the presence of the compounds of the invention with the radiolabelled ³ H-2amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ( ³ H-AMPA) and ³ H-2amino-3-hydroxy -5-methyl-4-isoxazolpropionic acid ( ³ H-AMPA) and ³ H-5,7 dichloroquinurenic acid, both of which bind to specific receptors (AMPA or NMDA receptor (N-methyl-D-aspartate)) . Then, the radioactivity of the treated membranes was measured by scintillation counting. The amounts of bound ³ H-AMPA and ³ H-5,7-dichloroquinuric acid, respectively, can be determined by radioactivity binding. the displaced quantities of these radiolabelled substances, respectively. The dissociation constant K _I = (I = inhibitor) resulting from this, which is a measure of the delinquent effect of the active ingredient of the invention, was determined by iterative nonlinear regression analysis with a statistical analysis system (SAS) on an IBM computer similar to Ligand, PJ Munson or D. Rodbard (Analytical Biochm. 107,220 (1980), Ligand: Versatile Computerized Approach for Characterization of Ligand Binding Systems).

The following in vitro investigations were performed:

1. Binding of ³ H-2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ( ³ H-AMPA)

For preparation of the membrane portion, freshly collected large rat brain was homogenized together with about 15 times the volume of buffer solution A from 30 mM a, a, α-tris- (hydroxymethyl) -methylamine hydrochloride (TRIS-HC1) and 0.5 mM ethylenediaminetetraacetic acids (EDTA) - pH 7.4 - using an UltraTURRAX mixer. Following the determination of the supernatant, the membrane material containing the protein in the sediment was washed three times by suspending in buffer solution A and then centrifuged at 48,000 g each for 20 minutes. Subsequently, the membrane material was suspended in 15 times the volume of buffer solution A and incubated for 30 minutes at 37 ° C. The protein material was then washed twice by centrifugation and suspension and frozen at -70 ° C until use.

For the binding assay, the thawed protein material was washed twice at 37 ° C by centrifugation at 48,000 g (20 minutes) followed by suspension in buffer solution B of 50 mM TRIS-HC1, 0.1 M potassium thiocyanate and 2.5 mM calcium chloride - pH 7.1. Subsequently, 0.25 mg of membrane material, 0.1, / xCi ³ H-AMPA (60 Ci / mmol) as well as compound I was dissolved in 1 ml of buffer solution and incubated on ice for 60 minutes. The incubated solution was filtered through a CF / B filter (Whathman), which was treated with a 0.5% aqueous polyethyleneimine solution for at least 2 hours earlier. The filtrate was then washed with 5 ml of cold buffer solution B to separate bound and free ³ H-AMPA from each other. After varying the radioactivity of bound ³ H-AMPA in membrane material by scintillation counting, the Kj value was determined by regression analysis by evaluating the displacement curves.

2. Binding of ³ H-5,7-dichloroquinurenic acid

For preparation of the membrane material, freshly removed large rat brain was homogenized together with 10 times the volume of buffer solution A 'from 50 mM TRIS-HC1 and 10 mM EDTA - pH 7.4. The suspension was centrifuged for 20 minutes at 48,000 g. After deciding the supernatant, the sediment membrane material was washed twice with suspension in buffer solution A 'and then each time with 20 minutes centrifugation and suspension. After resuspending the membrane in buffer solution A 'and freezing in liquid nitrogen, the suspension was thawed again at 37 ° C and incubated after a further washing process for 15 minutes at 37 ° C. The protein material was then washed 4 times with centrifugation and suspension and frozen until used at -70 ° C.

For the binding assay at 37 ° C, the thawed protein material was washed twice by centrifugation at 48000 g (20 minutes) and then suspended in buffer solution B 'from 50 mM TRIS-HC1 - pH 7.4. Then 0.15 mg of the membrane material 0.3 μ-Ci ³ H-5,7-dichloroquinurenic acid (16 Ci / mmol) was dissolved as well as compound I in 1 ml of buffer solution B 'and incubated on ice for 30 minutes. The incubated solution was centrifuged at 150,000 g for 2 minutes. After the solution of the supernatant, the sediments were suspended twice with 1.5 ml of cold buffer solution B 'each. After measuring the radioactivity of membrane-bound ³ H-5,7-dichloroquinurenic acid in the sediment, the Kj value was obtained by evaluating the displacement curves by regression analysis.

Medicinal preparations are prepared in a conventional manner, e.g. by mixing the active substance with other conventional carriers and diluents.

Medicinal preparations can be administered in a variety of administration routes, such as oral, parenteral, subcutaneous, intraperitoneal and topical. Formulations such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are thus possible.

The therapeutic compositions of the invention contain, in addition to conventional drug excipients, a therapeutically effective amount of compound I. For topical external use, e.g. in powders and ointments, the active substances may be at their usual concentrations. Generally, the active ingredients are in the amount of 0.001 to 5% by weight, preferably 0.02 to 0.5% by weight.

For internal use, the preparations are given in single doses. In each dose, 0.1 to 50 mg, preferably 0.1 to 10 mg, of the active ingredient per kg body weight. The preparations can be administered daily in one or more doses depending on the type and severity of the disease. The daily dose is generally at 0.1 to 20 mg per kg body weight when given orally. 0.01 to 10 mg per kg bodyweight for parenteral administration.

In accordance with the desired mode of administration, the therapeutic compositions of the invention are in addition to the active ingredient carriers and diluents. Pharmaceutical-technical auxiliaries, such as ethanol, isopropanol, oxetylated castor oil, oxetylated hydrated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin, and paraffin, can be used for topical external use. For internal use, for example, milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone. Furthermore, the preparations may contain antioxidant agents such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavor enhancers, stabilizers, emulsifiers and bleaches. Substances contained in the preparation in addition to the active substance, as well as the substances used in the preparation of the pharmaceutical preparation, must be toxicologically sound and tolerable for the active substance in question.

The following examples further illustrate the invention.

Description of experiments

A Preparation of output products

a. 1- (2-Nitrophenyl) -imidazoles

Rs A-Rs

1-) 1- (2-Nitro-4-trifluoromethylphenyl) -5-carboxy-4-methyl-imidazole

Mixture of 10.45 g (0.05 mol) of 2-fluoro-4-trifluoromethyl-nitrobenzene, 7.7 g (0.05 mol) of 4 (5) -carbethoxy-5 (4) -methylimidazole and 13.8 g of potassium The carbonate was heated in 100 ml of acetonitrile for 4 hours with stirring until boiling.

The cooled reaction mixture was mixed with 1000 ml of water, extracted with 250 ml of methylene chloride and the methylene chloride phase dried with magnesium sulfate. The dried solution was evaporated and the residue was brought to crystallization by trituration with ether. The substance is sufficiently pure for the following metabolites.

Yield: 11.4 g (66% of theory)

M.p .: 142-144 ° C.

The following compounds are obtained by varying the nitrobenzene derivative, imidazole, solvent, temperature and reaction time.

No. ^r 2 ^r 3 ^R S A ^R 6 Tal. ° C 2) H H ch ₃ - COOEt 94-96 3) H ch ₃ ch ₃ - COOEt 110 4) H F ch ₃ - COOEt 122-124 5) H H H CH, COOEt oil 6) Cl H ch ₃ - COOEt 112-115 7) cf ₃ Cl ch ₃ - COOEt 118-119 8) Cl H H - coch ₃ 151 9) cf ₃ H ch ₃ - COOEt 142-144 10) H i-BuO CH ₃ - COOEt 65 H) Cl Cl ch ₃ - COOEt 152 12) H H ^C 2 ^H 5 - COOMe 110-113 13) COOEt H ^CH 3 - COOEt 119 14) cf ₃ H ί-ςΗ, - COOEt oil 15) cf ₃ Cl C ₂ ^H 5 - COOMe 142-144 16) ch ₃ ch ₃ ch ₃ - COOEt 128-132 17) cf ₃ H ch ₃ -CH = CH- COOMe 168-172 18) Cl Cl H - COOMe 160-163 19) cf ₃ H H - COOMe 146-150 20) no ₂ H ch ₃ - COOEt 128-131 21) cf ₃ Cl H - COOMe 99-103 22) F Nr ch ₃ - COOEt 140-145 23) Nr ch ₃ ch ₃ - COOEt 133-134 24) Nr H ch ₃ - COOEt 125-130 25) H Cl ch ₃ -CH = CH- COOEt 128-129 26) cf ₃ Cl H -CH, - COOEt 122-123 27) cf ₃ H ^C 6 ^H 5 -CH = CH- COOEt 164-165 28) cf ₃ Cl ch ₃ -CH = CH- COOEt 208-209 29) cf ₃ H ch ₃ -CH = CH- COOMe 168-173 30) (ch ₃ ) ₂ nso ₂ H ch ₃ - COOEt 248-250 31) cf ₃ H ^C 6 ^H 5 - COOEt 138-141 32) cf ₃ o H ch ₃ - COOEt 98-101 33) ch ₃ conh H ch ₃ - COOEt 129-134 34) i-Bu H ch ₃ - COOEt oil 35) cf ₃ Cl ch ₃ -ch ₂ ch ₂ - COOEt 185-190 36) Cl (6-C1) ch ₃ - COOEt 143-144

37) F Br CH ₃ - COOEt 133-134

b. 1- (2-aminophenyl) -imidazoles

R ₅ AR

1-) 1- (2-amino-4-trifluoromethylphenyl) -5-carboxy-4-methyl-imidazole

11.6 g (0.034 mol) of 1- (2-nitro-4-trifluoromethylphenyl) -5-carboxy-4-methylimidazole (cf. aal) is hydrated with 2 g of palladium-on-carbon catalyst (10% Pd) in 100 ml of ethanol at room temperature under atmospheric pressure. At the end of the hydrogen uptake, the catalyst-free solution was evaporated in vacuo and the remaining residue was crystallized with a little ether.

Yield: 9.8 g (93% of theory)

M.p .: 189-190 ° C.

The compounds listed below are obtained in an analogous manner, using Raney nickel as the catalyst for chlorine-containing compounds.

No. ^R 2 ^R 3 ^R 5 A ^R 6 Tal. ° C 2) H H ch ₃ COOEt 139 3) H ch ₃ ch ₃ - COOEt 123 4) H F ch ₃ - COOEt 188 5) H H H ch ₂ COOEt oil 6) Cl H ch ₃ - COOEt 165 Ό cf ₃ Cl ^CH 3 - COOEt 202-205

8) Cl H H coch ₃ 210 9) H i-BuO CH ₃ - COOEt oil 10) Cl Cl ch ₃ - COOEt 224 11) H H ^C 2 ^H 5 - COOEt 141-143 12) COOEt H ch ₃ - cooch ₃ 158-160 13) cf ₃ H iC ₃ ^H 7 - COOEt 98-103 14) cf ₃ Cl ^C 2 ^H 5 - COOEt 196-198 15) ch ₃ ch ₃ ch ₃ - COOEt 154-158 16) Cl Cl H - COOMe 197-200 17) cf ₃ H H - COOMe 209-212 18) no ₂ H ch ₃ - COOEt 114-117 19) cf ₃ Cl H - COOMe 237-241 20) cf ₃ H ch ₃ -ch ₂ -ch ₂ - COOMe 99-103 21) F Nr ch ₃ - COOEt 172-174 22) Nr ch ₃ ch ₃ - COOEt 204-206 23) Nr H ch ₃ - COOEt 190-195 24) t-Bu H CH - COOEt 143-144 25) Cl (6-C 1) CH ₃ - COOEt 189-190 26) i-Bu H ch ₃ - COOEt 143-145 27) ch ₃ conh H ch ₃ - COOEt 100-103 28) cf ₃ o H ch ₃ - COOEt 157-160 29) cf ₃ H ^C 6 ^H 5 - COOEt 273-275 30) (ch,) ₂ nso ₂ H ch ₃ - COOEt 248-250 31) no ₂ H ch ₃ -ch ₂ -ch ₂ - COOEt 163-164 32) cf ₃ Cl ch ₃ -ch ₂ -ch ₂ - COOEt 128-129 33) cf ₃ H ^C 6 ^H 5 -ch ₂ -ch ₂ - COOEt 114-116 34) cf ₃ Cl H -ch ₂ - COOEt 151-152 35) H Cl ch ₃ -ch ₂ -ch ₂ - COOEt 112-113

B. Preparation of finished products

Metabolism of 1- (2-aminophenyl) -imidazoles with carbonyldiimidazole:

EXAMPLE 1

4,5-Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

3.5 g (0.143 mol) of 1- (2-aminophenyl) -4-carboxy-5-methylimidazole, (0.154 mol) of carbonyldiimidazole are heated with stirring in 50 ml of 1,2-dichlorobenzene

1.5 hours until boiling.

After cooling, the solid was aspirated, washed with acetone and the product recrystallized from DMF.

Yield: 3.0 g (77% of theory)

C ₁₄ H ₁₃ N ₃ O ₃ mm271 Mp. > 300 ° C

Analogously, we get:

4,5-Dihydro-1,8-dimethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₅ H ₁₅ N ₃ O ₃ mm285 Mp. Mp 255-257 ° C

4,5-Dihydro-8-fluoro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

CHFN, O, m.m. 289 Tal. Mp 255-257 ° C

12 33

4. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₅ H ₁₂ F ₃ N ₃ O ₃ mm 339 Tal. 270-271 ° C

5. 4,5-Dihydro-8-isobutoxy-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C _lg H ₂₁ N ₃ O ₄ mm 343 Tal. 190-195 ° C

6. 4,5-Dihydro-7-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₄ H ₁₇ C1XXXX mm 305 Tal. 277-279 ° C

12 3 3

7. 4,5-Dihydro-4-oxo-imidazolo [1,2-a] quinoxaline-2-acetic acid ethyl ester

C ₁₄ H ₁₃ N ₃ O ₃ mm271 Mp. 265-270 ° C

8. 4,5-Dihydro-1-ethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid methyl ester

C ₁₄ H ₁₃ N ₃ O ₃ mm271 Mp. 264-266 ° C

9,4,5-Dihydro-2-acetyl-7-chloro-4-oxo-imidazolo [1,2-a] quinoxaline

C ₁₂ H ₈ C1N ₃ O ₂ mm 261 Mp. > 320 ° C

4,5-dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2,7di-carboxylic acid diethyl ester

C ₁₇ H ₁₇ N ₃ O ₅ mm 343 Tal. 295-300 ° C

11. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₅ H _n ClF ₃ N ₃ O ₃ mm 373 Tal. 310-315 ° C

12. 4,5-Dihydro-1-isopropyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₇ H ₁₆ F ₃ N ₃ O ₃ mm 367 Tal. Mp 215-220 ° C

13. 4,5-Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-acrylic acid methyl ester

C ₁₅ H ₁₃ N ₃ O ₃ mm 283 Mp. > 300 ° C

14. 4,5-Dihydro-7,8-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid ethyl ester

C ₁₄ H _n Cl ₂ N ₃ O ₃ mm 340 Tal. 285 ° C (dec)

15. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-acrylic acid ethyl ester

C ₁₇ H ₁₄ F ₃ N ₃ O ₃ mm 365 Tal. > 280 ° C

16. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₅ H _n ClF ₃ N ₃ O ₃ mm 373 Tal. 304-308 ° C

17. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid ethyl ester

Ο., Η ,, ΝΌ. m.m. 316 Tal. > 300 ° C

12 4 5

18. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid methyl ester

C ₁₆ H, .F, N, O-mm 353 Tal. 203-206 ° C

14 3 3 3

19. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid methyl ester

C ₁₃ H ₇ C1F ₃ N ₃ O ₃ mm 345 Tal. 270-280 ° C

20. 4,5-Dihydro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline · 2-carboxylic acid methyl ester

C ₁₃ H ₈ F ₃ N ₃ O ₃ mm 311 Tal. 281-283 ° C

21. 4,5-Dihydro-8-bromo-7-fluoro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₄ H _n BrFN ₃ O ₃

m.m. 368

Tal. 298-300 ° C

22. 4,5-Dihydro-7-isobutyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid methyl ester

C _lg H ₂₁ N ₃ O ₃ mm 327 Tal. 270-273 ° C

23. 4,5-Dihydro-7-acetamido-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid ethyl ester

C _lfi H ₁₆ N ₄ O ₄ mm 328 Tal. > 300 ° C

24. 4,5-Dihydro-7-bromo-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid ethyl ester

Ο.Η ,, ΒγΝ, Ο, m.m.350 Tal. > 300 ° C

12 33

25. 4,5-Dihydro-1-methyl-7-trifluoromethoxy-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₅ H ₁₂ F ₃ N ₃ O ₄ mm 355 Tal. > 300 ° C

26. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₂₀ H ₁₄ F ₃ N ₃ O ₃ mm 401 Tal. 292-295 ° C

27. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester

C ₁₇ H ₁₅ C1F ₃ N ₃ O ₃ mm 402 Tal. 233-235 ° C

28. 4,5-Dihydro-8-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester

C ₁₆ H ₁₆ C1N ₃ O ₃ mm 334 Tal. 291-293 ° C

29. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] 20 quinoxaline-2-acetic acid ethyl ester

C ₁₅ H _in C1F ₃ N ₃ O ₃ mm373 Mp. > 300 ° C

30. 4,5-Dihydro-7-dimethylaminosulfonyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₆ H ₁₈ N ₄ O ₅ S mm378 Tal. > 300 ° C

31. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2propionic acid ethyl ester σ, Η ,, Ν, Ο. m.m. 344 Tal. 250-255 ° C

16 4 5

32. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester

C ₂₂ H _lg F ₃ N ₃ O ₃ mm 429 Tal. Mp 192-193 ° C

33. 4,5-Dihydro-1,7,8-trimethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₆ H ₁₇ N ₃ O ₃ mm 299 Tal. > 300 ° C

34. 4,5-Dihydro-7-t-butyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

C ₁₈ H ₂₁ N ₃ O ₃ mm 327 Mp. Mp 184-185 ° C

35. 4,5-Dihydro-7,9-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid ethyl ester

C. Ή ,, Ο, Ν, Ο, m.m. 340 Tal. 261-267 ° C

11 2 3 3

Hydrolysis of imidazolinoquinoxaline carboxyl esters:

EXAMPLE 36

4.5-Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid g (0.107 mol) was mixed with 500 ml of 2N sodium hydroxide and 300 ml of ethanol after Example 1 of the obtained ester. at 80 ° C. After cooling, it is acidified with concentrated hydrochloric acid and the product is sucked off. Recrystallized from DMF.

Yield: 23 g (88% of theory)

C ₁₂ H ₉ N ₃ O ₃ mm243 Mp. > 300 ° C

In an analogous way we get:

37.4.5-Dihydro-1,8-dimethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₃ H _n N ₃ O ₃ mm257 Tal. > 300 ° C

38.4.5-Dihydro-8-fluoro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H _g FN ₃ O ₃ mm 261 Tal. > 300 ° C

39.4.5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₃ H _g F ₃ N ₃ O mm 311 Tal. > 300 ° C

40. 4,5-Dihydro-8-isobutoxy-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₆ H ₁₇ N ₃ O ₄ mm 315 Tal. 270-275 ° C

41.4.5-Dihydro-1-ethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

m.m. 257

Tal. 335-340 ° C

42. 4,5-Dihydro-7-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H ₈ C1N ₃ O ₃ mm277 Tal. > 320 ° C

43. 4,5-Dihydro-4-oxo-imidazolo [1,2-a] quinoxaline-2-acetic acid

m.m. 243 Tal. 320-325 ° C

44.4.5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₃ H ₇ C1F ₃ N ₃ O ₃ mm 345 Tal. > 300 ° C

45.4.5-Dihydro-1-isopropyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid

C ₁₅ H ₁₂ F ₃ N ₃ O ₃ mm 339 Tal. 245-250 ° C

46.4.5- Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-acrylic acid ςΚ, Ν, Ο, m.m. 269 Tal. > 300 ° C

11 3 3

47.4.5-Dihydro-7,8-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

m.m. 312 Tal. > 300 ° C

48. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-acrylic acid

C ₁₅ H ₁₀ F ₃ N ₃ O ₃ mm 337 Tal. > 320 ° C

49.4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C H CIF ^ N O m.m.359 Tal. > 300 ° C

9 3 3 3

50. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H _g N ₄ O ₅ mm288 Mp. > 300 ° C

51.4.5-Dihydro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H ₆ F ₃ N ₃ O ₃ mm297 Mp. > 300 ° C

52. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

C ₁₅ H ₁₂ F ₃ N ₃ O ₃ mm339 Mp. > 300 ° C

53.4.5-Dihydro-1,7,8-trimethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C, .H., N, O, nun. 271 Tal. > 300 ° C

13 3 3

54.4.5-Dihydro-7-bromo-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H _g BrN ₃ O ₃ mm322 Tal. > 300 ° C

55.4.5-Dihydro-8-bromo-7-fluoro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid

C ₁₂ H _? BrFN ₃ O ₃ mm 340 Mp. > 300 ° C

56.4.5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid for ₁₂ h _with cif ₃ n ₃ o ₃

m.m. 331

Tal. > 300 ° C

57. 4,5-Dihydro-7-t-butyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₆ H ₁₇ N ₃ O ₃ mm299 Mp. > 300 ° C

58. 4,5-Dihydro-7,9-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₂ H ₇ C1 ₂ N ₃ O ₃ nun. 312 Tal. > 300 ° C

59.4.5-Dihydro-7-isobutyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C _1A H ₁₇ N, 0, mm299 Mp. 256-259 ° C lo 1/3 3

60.4.5-Dihydro-7-acetamido-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C, K, NA m.m. 300 Tal. > 350 ° C

12 4 4

61. 4,5-Dihydro-1-methyl-7-trifluoromethoxy-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₃ H ₈ F ₃ N ₃ O ₄ mm 327 Tal. > 300 ° C

62. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

C ₁₈ H ₁₀ F ₃ N ₃ O ₃ mm 373 Tal. > 300 ° C

63. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

CHFNO m.m. 356 Tal. > 300 ° C

7 3 4 5

64. 4,5-Dihydro-7- (dimethylaminosulfonyl) -1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

CH, .N, O ₄ S mm350 Tal. > 300 ° C

14 4 5

65.4.5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

C ,, H..F, N .CL m.m. 384 Tal. > 300 ° C

11 3 4 5

66. 4,5-Dihydro-1-methyl-8-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

CKJiO. m.m. 316 Tal. > 300 ° C

12 4 5

67. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

C ₁₅ H _n ClF ₃ N ₃ O ₃ mm 373 Tal. > 300 ° C

68.4.5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-propionic acid

C ₂₀ H ₁₄ F ₃ N ₃ O ₃ mm 401 Tal. 275-279 ° C

69.4.5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-acetic acid

C ₁₃ H ₇ C1F ₃ N ₃ O ₃ mm 345 Tal. > 300 ° C

70.4.5-Dihydro-8-chloro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline 2-propionic acid

C.H..C1NO, m.m.351 Tal. > 300 ° C

11 45

71. 4,5-Dihydro-8-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid c ₁₄ h ₁₂ cin ₃ o ₃

m.m. 306

Tal. > 300 ° C

Reduction of esters

EXAMPLE 72

4,5-dihydro-2-hydroxymethyl-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline g (0.11 mol) according to Example 4 of the 4,5-dihydro-1 ethyl ester obtained -methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid was mixed with 3.65 g of lithium boron hydride in 500 g of dry tetrahydrofuran for 48 hours at room temperature and then heated for another 5 hours to the boil.

After the addition of 100 ml of 2-N-hydrochloric acid in the cooled reaction mixture (gas evolution!), The solvent was distilled off in vacuo, 300 ml of water was added and the product was aspirated. It is recrystallized from dimethylformamide.

Yield: 26 g (78% of theory)

C ₁₃ H ₁₀ F ₃ N ₃ O ₂ mm297 Mp. > 300 ° C

In an analogous way we get:

73.4.5-Dihydro-1,7-dimethyl-2-hydroxymethyl-4-oxo-imidazolo [1,2-a] quinoxaline

C ₁₃ H ₁₃ N ₃ O ₂ mm243 Mp. > 300 ° C

74.4.5-Dihydro-2-hydroxymethyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline

C ₁₂ H _n N ₃ O ₂ mm 229 Tal. 231-233 ° C

75.4.5-Dihydro-7-chloro-2-hydroxymethyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline

C ₁₂ H _1q C1N ₃ O ₂ mm 263 Tal. > 300 ° C

Oxidation of hydroxyalkyl compounds into aldehydes

EXAMPLE 76

4.5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carbaldehyde

20.0 g (0.067 mol) of Example 72 obtained 4.5-dihydro-2-hydroxymethyl-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline was mixed with 58 g of activated manganese dioxide (0 , 67 moles) in 500 ml of dimethylformamide for 2 hours at 100 ° C.

The hot filtered solution was then evaporated in vacuo, the residue was mixed with ether and filtered off with suction.

17 g (85% of theory) are obtained.

C ₁₃ H ₈ F ₃ N ₃ O ₂ mm215 Tal. > 300 ° C

Analogously, we get:

77.4.5-Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carbaldehyde

C ₁₂ H ₉ N ₃ O ₂ mm227 Mp. > 300 ° C

Preparation of oximes and oximeters

EXAMPLE 78

4,5-dihydro-2-hydroxyiminomethyl-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline

1.0 g (0.0037 mol) according to Example 76 of the obtained 4,5-dihydro-1-methyl-7-trifluoro-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carbaldehyde are heated together with 0, 47 g (0.0067 mol) of hydroxylamine hydrochloride, 0.6 g of sodium acetate, 10 ml of water and 12.5 ml of ethanol for 5 hours while stirring until boiling. After cooling, the precipitate was aspirated and washed with ethanol, water and some acetone.

0.5 g (48% of theory) are obtained.

GJELF-NO, m.m. 310 Tal. Mp 320-322 ° C

9 3 4 2

In an analogous way, we prepare:

79.4.5-Dihydro-2-hydroxyiminomethyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline

C 'H _and NO, mm 242 Tal. 315-320 ° C

10 4 2

In a similar manner, the following is prepared using hydroxylamine-O-methyl- or -O-ethyl-ether-hydrochloride and the corresponding aldehydes:

80.4.5-Dihydro-2-methoxyiminomethyl-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline (ΤΤΤ, Ν, Ο, m. 256 mp> 320 ° C

12 4 2

81. 4,5-Dihydro-2-methoxyiminomethyl-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline

C. H, F, N .O, m.m. 324 Tal. 299-303 ° C

11 3 4 2

82.4.5-Dihydro-2-ethoxyiminomethyl-1-methyl-imidazolo [1,2-a] quinoxaline

C ₁₄ H ₁₄ N, 0- mm 270 m.p. 315-316 ° C

14 4 2

83.4.5-Dihydro-2-ethoxyiminomethyl-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline

Ο, Η, Τ, ΝΌ, m.m. 338 Tal. 292-295 ° C

13 3 4 2

Preparation of nitriles:

EXAMPLE 84

84. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid nitrile

1.5 g (0.005 mol) in Example 78 of the described oxime were heated with 20 ml of acetanhydride for hours until refluxed. Then the nozzle is placed on a solution of soda, sucked off and the crude product is taken up in methylene chloride and methanol.

0.7 g (50% of theory) are obtained.

C _n H ₇ F ₃ N ₃ O mm 278 Tal. > 300 ° C

Preparation of tetrazole compounds

EXAMPLE 85

85.4,5-Dihydro-1-methyl-2- (5-tetrazolyl) -7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline

1.15 g (0.004 mol) of the described nitrile was heated with 0.45 g of sodium azide (0.007 mol) and 0.4 g of ammonium chloride in 50 ml of dimethylformamide for 16 hours until refluxing.

Then the nozzle is mixed with water, aspirated, the residue washed with acetone and sucked again.

0.5 g (37% of theory) were obtained.

C ₁₃ H _g F ₃ N ₇ O mm 335 Tal. > 300 ° C

EXAMPLE 86

4,5,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid (5-tetrazolyl) amide

2.0 g (0.006 mol) of Example 41 was obtained with pre-treatment with 3.9 g (0.024 mol) of carbonyldiimidazole in 30 ml of dimethylformamide for 2 hours at 80 ° C; then a solution of 0.6 g (0.006 mol) of anhydrous 5-aminotetrazole in 10 ml of dimethylformamide was added and heated for another 5 hours with stirring at 80 ° C. For treatment, the filtrate is suctioned, the filtrate is placed on ice, acidified, the precipitate is suctioned off and the product thus obtained is recrystallized from dimethylformamide with 2% water.

Yield 0.8 g (about 30% of theory)

C ₁₄ H ₉ F ₃ N _g O ₂ mm378 Tal. > 300 ° C

Preparation of nitro compounds

EXAMPLE 87

4,5-Dihydro-1-methyl-8-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

2.5 g (0.01 mol) of Example 39 of the obtained 4,5-dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid were added over 15 minutes in proportions of k 25 ml of hydrochloric acid at a density of 1.50 at 0 ° -5 ° C with stirring and then stirring for an additional 1 hour. Then the nozzle is placed on ice and the separated product is washed with water and acetone.

Yield: 2.3 g (82% theory)

C ₁₂ H _g N ₄ O ₅ mm288 Mp. > 320 ° C

EXAMPLE 88

88. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester 4,5 (dihydro) ethyl ester -1-Methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid, prepared according to Example 4, was dissolved in 50 ml of concentrated sulfuric acid and 1.8% at room temperature were added. g of potassium nitrate. After 24 hours at room temperature, warm to another 2 hours at 60 ° C. For treatment, place the nozzle on ice and extract the product, and then rinse it with methylene chloride.

Yield: 4.1 g (73% of theory) ^C , 5 ^H -1 ^F 3 ^N A

m.m. 384

Tal. 284-286 ° C

EXAMPLE 89

In a similar way, nitration of 4,5-dihydro-1-methyl-7-trifluoromethyl4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid methyl ester (prepared according to Example 18) yields 4,5-dihydro- 1-Methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid

C, KJJiA mm ^{398 Ta} l · 246-250 ° C

13 3 4 5 and 4,5-dihydro-8-cor-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester (obtained from Example 28)

90. 4,5-Dihydro-8-chloro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester:

C ₁₆ H ₁₅ C1N ₄ O ₅ mm 379 Tal. 172-174 ° C

Reduction / Hydration of Nitro Compounds

EXAMPLE 91

4,5-Dihydro-8-amino-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

1.7 g of 4,5-dihydro-1-methyl-8-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2carboxylic acid (prepared according to Example 88) (0.055 mol) were dissolved in ice / methanol as solvent and hydrated using 1.5 Pd-C catalyst (10% Pd) at room temperature and 25 ° C.

After conventional treatment, 11.2 g (68% of theory) of amino compounds are obtained.

m.m. 295

Tal. > 340 ° C

On a tablet, press the tablets in the usual manner with the following composition:

Examples of pharmaceutical preparations

EXAMPLE

40 mg 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-quinoxaline-2-carboxylic acid 120 mg cornstarch 13.5 mg gelatin 45 mg milk sugar 2.25 mg aerosil ^R (chemically pure silica in submicroscopically fine distribution) 6.75 mg potato starch (as 6% glue)

EXAMPLE B

In the usual way, prepare the dragees with the following composition:

20 mg 4,5-Dihydro-1-methyl-7-trifluonnetyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid 60 mg the mass of the nucleus 60 * mg sugar coating masses

The kernel mass consists of 9 parts of corn starch, 3 parts of milk sugar and 1 part of Luviskol ^R VA 64 (vinylpyrrolidone-vinyl acetate-polymerizable 60:40, cf. Pharm. Ind. 1962, 586). The sugar coating mass consists of 5 parts of cane sugar, 2 parts of cornstarch, 2 parts of calcium carbonate and 1 part of talc. The dragees thus prepared are then provided with a coating which is resistant to gastric juice.

EXAMPLE C g of 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid was dissolved in 5000 ml of water with the addition of NaCl and adjusted to pH

6.0 with 0.1 N NaOH to give a blood isotonic solution. Each time 5 ml of this solution is filled into ampoules and sterilized.

Claims (6)

Claims 1. Imidazolo [1,2-a] quinoxalinones of formula I wherein A is a saturated or unsaturated alkylene group having 1 to 5 C atoms or a bond, R ⁶ represents a formyl group or a carboxyl group which may be in the form of its salt with a physiologically acceptable amine or metal cation, a COOR ⁷ residue, wherein R ⁷ represents a C 1 -C 8 alkyl radical, a cycloalkyl group having 3 to 8 C atoms in ring, a benzyl residue, of one of the residues - (CH2) n-OR ⁸ , in which n stands for numbers 2 to 4 and R ⁸ for a C 1 -C 8 alkyl group, a C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkylcarbonyl, nitrile, tetrazolyl , a carbonylaminotetrazole, aldoxime, C 1 -C 4 alkoxyaldoxime, or optionally substituted carbamoyl group, R ² represents a fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ^ C ^ alkyl, C ^ C ^ alkoxy, mono- or dialkylamino, C _t -C ₆ alkylthio, C ^ C ^ alkylsulfinyl, A C ₁ -C ₄ alkylsulfonyl, aminosulfonyl, diC ₁ -C ₄ alkylaminosulfonyl or C ₁ -C ₄ alkoxycarbonyl group, R ¹ , R ³ , R ⁴ , which are the same or different, represent hydrogen, fluorine, chlorine or bromine atoms, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C 1-6 alkyl, C 1 -C 6 alkoxy, mono- or dialkylamino, C 1 -C 1-6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, aminosulfonyl, di-C 1 -C 6 alkylaminosulfonyl or C 1 -C 4 alkoxycarbonyl group or is one of the pairs R ¹ , R ² ; R ² , R ³ or R ³ , R ^{4 is} also a group - (CH 2) ₄ - or -CH = CH-CH = CH-, R ⁵ represents a hydrogen atom, a C 1 -C 4 alkyl group or optionally a chlorine, fluorine, trifluoromethyl or C 1-6 alkyl substituted phenyl group which cannot be simultaneously And the embroidery, R ^{6 is a} formyl, ethoxycarbonyl, hydroxymethyl, aldehyde, tetrazolyl group, carboxylic acid amide group or 5-aminotetrazolyl group, R ¹ , R ⁴ , R ^{5 are} hydrogen atoms and R ² and R ^{3 are} identical and the chlorine or bromine atoms 7 and 8, respectively. Compounds according to claim 1, characterized in that R ² represents a chlorine or bromine atom, trifluoromethyl, trifluoromethoxy or nitro group; R ³ is a hydrogen or chlorine atom or a nitro group, R ⁴ represents a hydrogen or chlorine atom; R ⁵ is a methyl, ethyl or phenyl group; A represents a bond, a vinyl or ethylene group, and R ⁶ represents a carboxylic acid group or an ester group. Compounds according to claim 1, characterized in that they are selected from the group consisting of: a. 4,5-Dihydro-7-chloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2 carboxylic acid b. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2 carboxylic acid c. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid d. 4,5-Dihydro-7,8-dichloro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid e. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid f. 4,5-Dihydro-8-chloro-1-isopropyl-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid Mr Rücker 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester i. 4,5-Dihydro-1-isopropyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid j. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline2-acrylic acid k. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid methyl ester l. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid m. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-propionic acid n. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid o. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester p. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid q. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester r. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] 37 quinoxaline-2-carboxylic acid s. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid methyl ester t. 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid in. 4,5-Dihydro-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid v. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester w. 4,5-Dihydro-8'chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid x. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid y. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-propionic acid ethyl ester. Medicaments characterized in that they contain compounds of formula I or their therapeutically tolerable salts. Compounds of formula I according to claim 1 for use in the control of diseases. A process for the preparation of imidazolo [1,2-a] quinoxalinones of formula I R ⁵ AR ⁶ where A is a saturated or unsaturated alkylene group having 1 to 5 C atoms or a bond, R ⁶ represents a formyl group or a carboxyl group, which may be in the form of its salt with a physiologically acceptable amine or metal cation, a COOR ⁷ residue, wherein R ⁷ represents a C 1 -C 8 alkyl radical, a cycloalkyl group of 3 to 8 C atoms in ring, a benzyl residue, of one of the residues - (CH2) n-OR ⁸ , in which n stands for numbers 2 to 4 and R ⁸ for a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkylcarbonyl, nitrile , tetrazolyl, carbonylaminotetrazole, aldoxime, C 1 -C 4 -alkoxydoxime or optionally substituted carbamoyl group, and R ^x -R ⁴ , which are the same or different, represent atoms of hydrogen, fluorine, chlorine, or bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C ₁ -C _with -alkyl, C ₁ -C 6 alkoxy, mono- or dialkylamino, C ₁ -C ₆ -alkylthio, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, aminosulfonyl, di-C 1 -C ₆ -alkylaminosulfonyl or C ₁ -C ₆ alkoxycarbonyl group, R ⁵ represents a hydrogen atom, a C 1 -C 6 alkyl group or optionally a chlorine, fluorine, trifluoromethyl or C 1 -C 6 alkyl substituted phenyl group, but which cannot be simultaneously And the embroidery R ^{6 is a} carbonyl, ethoxycarbonyl, hydroxymethyl, formyl, tetrazolyl group, a carboxylic acid amide group or a 5-aminotetrazolyl group, R ¹ , R ⁴ , R ^{5 are} hydrogen atoms and R ² and R ^{3 are} identical and chlorine or bromine atoms in position 7 or 8, characterized in that the compound of formula II wherein R ¹ to R ⁵ and A has the indicated meaning and R ⁶ represents a nitrile group, a carboxylic acid ester group, aldehyde or an alkanoyl group is reacted with a doubly activated carbonic acid derivative and a. - if R ⁶ in the final product of formula I represents a COOH- group, the ester thus obtained is saponified (R ⁶ = COOR ⁷ ), or b. - if R ⁶ in the final product of Formula I represents a hydroxyalkyl, aldehyde, oxime or oximeter group - the ester thus obtained (R ⁶ = COOR ⁷ ) is reduced and the hydroxyalkyl compound thus obtained is then oxidized to the aldehyde, where appropriate, hydroxylamine or. hydroxylamine-O-alkyl ethers in oxime or ca. oximeter or c. - if R ⁶ in the final product of Formula I, optionally substituted carbamoyl or carbonylaminotetrazole group - according to a) the acid obtained is optionally reacted in activated form with ammonia, amine or 5-aminotetrazole, or d. - if R ⁶ is a tetrazolyl residue, the compound of formula I with R ⁶ in the meaning of a nitrile group is reacted with hydrochloric acid or one of its salts, and the compounds thus obtained are nitrated and / or converted into their physiologically tolerable salts, as appropriate.