CA2158167A1 - Novel imidazoloquinoxalinones, their preparation and use - 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

-~ 0050/439~6 2 1 5 8 ~ 6 7 Novel imidazolo-quinoxalinones, their preparation and use Description The present invention relates to novel imidazolo-quinoxalinones, processes for their preparation, and their use for controlling diseases.

10 DE-A 3 004 750 and DE-A 3 004 751 describe a number of imidazolo-quinoxalinones substances [sic] which have antiallergic effects.
Furthermore, substituted imidazolo-quinoxalinones are claimed as phosphodiesterase inhibitors or agents having a cardiovascular effect in US 5 166 344 (= EP 400 583).
In the CNS sector, US 5 163 196 (= EP 518 530) specifies various heterocycles, including some imidazolo-quinoxalinones, which dis-play an effect as antagonists of the amino acids with an excit-atory effect (EAA antagonists). Furthermore, US 5 182 386 de-20 scribes imidazolo-quinoxalines which are antagonists or inverse agonists of the GABA receptor and can be used to control anxiety states, sleep disturbances, convulsive states and to improve memory.

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

Rs A-R6 R4 ~
R3 ~ N ~ N

R2 ~ NH~ 0 R

where A is a saturated or unsaturated alkylene group with 1-5 C atoms or a bond, R6 is a formyl group or a carboxyl group which can be in the form of its salt with a physiologically tolerated amine or metal cation, the radical CoOR7 where R7 is C1-C8-alkyl, cycloalkyl with 3-8 C atoms in the ring, benzyl, -(CH2)n-OR3 where n is 2-4 and R8 is Cl-C3-alkyl, or is C1-C4-hydroxyalkyl, C1-C4-alkylcar-bonyl, nitrilo [sic], tetrazolyl, carbonylaminotetra-~ ~ 0050/43966 2 1 5 8 1 6 7 zole [sic], aldoxime [sic], Cl-C3-alkoxyaldoxime or unsubstituted or substituted carbamoyl, and R1-R4 which [sic] are identical or different and are each hydrogen, fluorine, chlorine, bromine, trifluorome-thyl, trifluoromethoxy, cyano, nitro, amino, C1_C6_alkanoylamino, Cl-C5-alkyl, C1-C5-alkoxy, mono-or dialkylamino, C1-C6-alkylthio, C1-C6-alkylsulfinyl, Cl-C6-alkylsulfonyl, aminosulfonyl, di-C1-C6-alkyl-aminosulfonyl or Cl-C4-alkoxycarbonyl, or one of the pairs Rl and R2, R2 and R3 or R3 and R4 is also -(CH2)4- or --CH=CH--CH=CH--, R5 is hydrogen, Cl--C5--alkyl or phenyl which is unsubsti-tuted or substituted by chlorine, fluorine, tri-fluoromethyl or Cl_4-alkyl, but where the following are not simultaneously possible 20 A is a bond R6 is carboxyl, ethoxycarbonyl, hydroxymethyl, formyl, tetrazolyl, carboxamide [sic] or 5-aminotetrazolyl, 25 Rl, R4 and R5 are each hydrogen and R2 and R3 are identical and are each chlorine or bromine in positions 7 and 8, 30 are novel, highly effective antagonists of amino acids with excitatory activity (EAA antagonists). They are therefore par-ticularly suitable for the therapy of neurological disturbances.
Preferred compounds are those which have as substituents R2 _ R4 35 in the benzene ring or one or two electron-attracting substi-tuents such as halogen atoms, nitro or trifluoromethyl groups.
The preferred substituent R5 in the imidazole ring is methyl, ethyl or phenyl, whereas R6 is preferably a carboxyl group or an 40 ester thereof which is directly linked to the ring or to an ethylene chain (A = bond).
The carboxylic acids can be converted in a conventional way into their metal salts or into physiologically tolerated ammonium 45 salts with ammonia or suitable organic nitrogen bases.

0050/43966 ~ 2 1 5 8 1 6 7 The following compounds are particularly preferred:

a. 4,5-dihydro-7-chloro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid b. 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid c. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid d. 4,5-dihydro-7,8-dichloro-1-methyl-4-oxoimidazolo[1,2-a]quin-oxaline-2-carboxylic acid 15 e. 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid f. 4,5-dihydro-8-chloro-1-isopropyl-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid g. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo[1,2-a]quinoxaline-2-carboxylate h. ethyl 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-carboxylate i. 4,5-dihydro-1-isopropyl-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-carboxylic acid 30 j. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-acrylic acid k. methyl 4,5-dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxo-imidazolo[1,2-a]quinoxaline-2-carboxylate 1. 4,5-dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid m. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-propionic acid n. 4,5-dihydro-8-chloro-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-carboxylic acid 45 o. ethyl 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylate ~ 0050/43966 2 1 ~ 8 1 6 7 p. 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid q. ethyl 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo[l,2-a]quinoxaline-2-carboxylate r. 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-carboxylic acid 10 s. methyl 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo[l,2-a]quinoxaline-2-propionate t. 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-propionic acid u. 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxa-line-2-propionic acid v. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo[l~2-a]quinoxaline-2-propionate w. 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-propionic acid 25 x. 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[l,2-a]quinoxaline-2-propionic acid y. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo[l,2-a]quinoxaline-2-propionate.
The compounds of the formula I can be prepared by various conven-tional methods.

In a process similar to that described in EP 400 583, an imida-35 zole of the formula II

Rs A-R6 R4 ~
R3 ~N~N II
R2 ~NH2 Rl 45 where Rl - R5 and A have the stated meanings, and R6 is a nitrile, carboxylic ester, aldehyde or alkanoyl group, can be reacted with a doubly activated carbonic acid derivative such as phosgene, di-- ~ 0050/43966 ~ 1 5 8 1 6 7 phenyl carbonate or, preferably, carbonyldiimidazole in an inert, aprotic solvent at from 150 to 200C.

Suitable solvents are tetralin, decalin, 1,2-dichlorobenzene or 5 1,3-dimethylethylene- or -propyleneurea.

This results in compounds of the formula I where R6 is a nitrile, formyl, carboxylic ester or alkanoyl group.
10 Preferred compounds are moreover those where Rl - R4 and A have the abovementioned meanings, and R6 is a carboxylic ester group.

Compounds of the formula I where R6 is an an ester group can be subjected to acidic or alkaline hydrolysis to give compounds of 15 the formula I where R6 is carboxyl.

The hydrolysis is preferably carried out under alkaline condi-tions, for example in the presence of an alkali metal hydroxide or of sodium bicarbonate in a solvent such as water, a lower 20 alcohol, tetrahydrofuran or mixtures thereof. The organic acids obtained in this way are converted if required into a physiologi-cally tolerated amine or metal salt. By this is meant, in par-ticular, salts of the Al k~l; metals such as sodium and potassium, of the alkaline earth metals such as calcium, of other metals 25 such as aluminum, and salts of organic bases such as morpholine, piperidine, mono-, di- or triethanolamine or tristhydroxy-methyl)aminomethane.
The starting compounds for the process Ia [sic] can be obtained 30 as shown in the following scheme:

'~ 0050/43966 ~ ~ 21 5 81 6 7 Scheme I:

Rs A-R
R3~Hal Rs A RR3~N)~N
R2 NO2 HN~,NSolvent R2~No2 Rl III IV V
o Rs A-R
R4 ~
Reduct ~on R3~,N~N

R2~NH2 R' II
It is known that ortho-halonitrobenzenes can be reacted with imidazoles which are not substituted on nitrogen atom N1 in suit-able solvents such as dimethyl sulfoxide, dimethylformamide or 20 acetonitrile at from 0 to 140C with the addition of a base, eg.
potassium carbonate.

It is furthermore known that substitution of the halogen atom by 4- and 4,5-disubstituted imidazoles takes place in such a way 25 that the nucleophilic attack takes place on the least sterically hindered N atom of the imidazole so that homogeneous products are obtained in this case.

The nitro compounds can be reduced in a conventional way, for 30 example by catalytic hydrogenation with palladium or nickel cata-lysts or else using tin(II) chloride.

o-Halonitrobenzenes of the formula III can be bought or prepared by conventional methods.
Compounds of the formula I where R6 is a hydroxyalkyl, aldehyde, oxime or oxime ether group are prepared by the operations des-cribed hereinafter. These comprise reducing compounds of the formula I where R6 is a carboxylic ester group to give compounds 40 of the formula I where R6 is hydroxyalkyl.

This reduction can be carried out with a complex metal hydride such as lithium borohydride in a suitable solvent such as ether or tetrahydrofuran. The reduction is preferably carried out at 45 elevated temperature, in particular at the boiling point of the solvent.

. ~ 0050/43966 _ 2 1 ~ 3 1 e 7 t 7 If required, these hydroxyalkyl compounds can be converted by oxidation with an oxidizing agent such as chromium oxide or man-ganese dioxide into aldehydes of the formula I (R6 5 fOrmyl), 5 Oximes and oxime ethers can be obtained from aldehydes of the formula I by reaction with hydroxylamine and hydroxylamine O-alkyl ethers.

Compounds of the formula I where R6 is unsubstituted or substi-10 tuted carbamoyl or carbonylaminotetrazole [sic] are obtained by reacting an acid or an activated form thereof of the formula I
where R6 is carboxyl with ammonia, amines or 5-aminotetrazole.

Particularly suitable amines are Cl-C6-alkylamines and aniline, 15 benzylamine and phenethylamine which are substituted on the phenyl ring by one nitro or CF3 group or 1-2 Cl_4-alkyl groups, Cl_4-alkoxy groups or halogen atoms.

This reaction is carried out either using the acid chloride or in 20 the presence of carbonyldiimidazole. This is preferably carried out in dimethylformamide.
Compounds of the formula I with a carbonylaminotetrazole [sic]
radical for R6 (R6 = CO-NH-CHN4) can be obtained by known methods 25 by condensing the fundamental carboxylic acid with 5-aminotetra-zole of the formula IV

3 0 H2N ~/ ,N, IV

As a rule, the reaction is carried out in an inert solvent such 35 as methylene chloride, dioxane, tetrahydrofuran or dimethylforma-mide, preferably in the presence of a condensing agent known from peptide chemistry, such as N,N'-carbonyldiimidazole or N,N'-di-cyclohexylcarbodiimide, at from 20 C to 120 C.
40 If the substituents Rl and R2 are not yet present in the starting compounds, they can be introduced subsequently. This can take place by an electrophilic aromatic substitution of a resulting compound of the formula I where Rl and/or R2 is hydrogen by con-ventional methods as described, for example, in Houben-Weyl, Vol.
45 X/l, pages 471 et seq., Vol. IX, pages 572 et seq. and Vol. V/3, page 873.

~ 0050/43966 21~167 One process for preparing nitro compounds of the formula I where Rl, R4 - R6 and A have the abovementioned meanings, and R2 or R3 is a hydrogen, nitro or alkyl group, it being necessary for at least one of the radicals R2 or R3 to be nitro, comprises nitrating a 5 compound of the formula I where Rl, R4 - R6 and A have the above-mentioned meanings, and R2 or R3 is hydrogen or alkyl, it being necessary for at least one of the radicals R2 or R3 to be hydro-gen, with nitric acid or sulfuric acid/potassium nitrate at low temperature. The use of concentrated nitric acid at 0 C has proved 10 advantageous for this.

Compounds of the formula I where Rl - R5 and A have the abovemen-tioned meanings, and R6 is tetrazolyl, are synthesized by conven-tional methods as described, for example, in Synth. 1973, 80, by 15 reacting the corresponding nitriles with hydrazoic acid or one of its salts, for example with alkali metal or alkaline earth metal azides, in the presence or absence of Lewis acids such as alumi-num chloride and tin chloride or of ammonium chloride. The com-bination of sodium azide with ammonium chloride is preferred. The 20 reaction is generally carried out in the presence of an inert solvent such as benzene, tetrahydrofuran or dimethylformamide at from room temperature to 150C. The tetrazolyl compounds are strong acids and can be converted in a conventional way to their salts with physiologically tolerated amine or metal cations.
The compounds I according to the invention are suitable as active ingredients of drugs for human medicine and can be used to pro-duce drugs for the treatment of neurodegenerative disorders and neutoxic [sic] disturbances of the central nervous system and for 30 producing spasmolytics, antiepileptics, anxiolytics and anti-depressants.

The pharmacological activity of the compounds I according to the invention was investigated on membrane material isolated from rat 35 cerebra. To do this, the membrane material was treated in the presence of the compounds according to the invention with the radiolabeled substances 3H-2-amino-3-hydroxy-5-methyl -4-isoxazolepropionic acid (3H-AMPA) and 3H-2-amino-3-hydroxy-5-methyl -4-isoxazolepropionic acid (3H-AMPA) 40 [sic] and 3H-5,7-dichlorokynurenic acid, which bind to specific receptors (AMPA and NMDA receptors (N-methyl-D-aspartate) respectively). The radioactivity of the treated membranes was then measured by scintillation counting. The amount of bound 3H-AMPA and 3H-5,7-dichlorokynurenic acid, or in each case the 45 amounts of these radiolabeled substances displaced, can be determined from the bound radioactivity. the dissociation constant KI ( I = inhibitor) which results from this and is a - ~ 0050/43966 ~ 2 1 5 ~ 1 6 7 , ~_ . g measure of the displacing action of the active ingredient according to the invention was found by iterative non-linear regression analysis using the statistical analysis system (SAS) on an IBM computer, similar to the nLigand" program of P.J. Mun-5 son or [sic] D. Rodbard (Analytical Biochm. [sic] 107 (1980) 220,ligand: Versatile Computerized Approach for Charakterization of Ligand Binding Systems).

The following in vitro tests were carried out:
1. Binding of 3H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (3H-AMPA) To prepare the membrane part [sic], freshly removed rat cere-bra were homogenized together with about 15 times the volume of a buffer solution A composed of 30 mM a~ -tris(hydroxy-methyl)methylamine hydrochloride (TRIS-HCl) and 0,5 mM ethy-lenediaminetetraacetic acid (EDTA), pH 7,4, using an Ultra-TURRAX. After removal of the supernatant liquid, the protein-cont~in;ng membrane material present in the sediment waswashed three times by suspending in buffer solution A and subsequently centrifuging at 48,000 g for 20 min each time.
The membrane material was then suspended in 15 times the volume of buffer solution A and incubated at 37C for 30 min.
The protein material was subsequently washed twice by centri-fugation and suspension and frozen at -70C until used.

For the binding assay, the protein material was thawed at 37C and washed twice by centrifuging at 48,000 g (20 min) and subsequently suspending in a buffer solution B composed of 50 mM TRIS-HCl, 0.1 M potassium thiocyanate and 2,5 mM
calcium chloride, pH 7.1. Subsequently, 0.25 mg of membrane material, 01. [sic] ~Ci of 3H-AMPA (60 Ci/mmol) and compound I
were dissolved in 1 ml of buffer solution B and incubated on ice for 60 min. The incubated solution was filtered through a CF/B filter (Whathman [sic]) which had previously been treated with a 0.5% strength aqueous solution of polyethyle-neimine for at least 2 h. The filtrate [sic] was subsequently washed with 5 ml of cold buffer solution B in order to sepa-rate bound and free 3H-AMPA from one another. After measure-ment of the radioactivity of the bound 3H-AMPA in the mem-brane material by scintillation counting, the KI was deter-mined by regression analysis of the displacement plots.

- ~ 0050/43966 21~8167 2. Binding of 3H-5,7-dichlorokynurenic acid To prepare the membrane material, freshly removed rat cerebra were homogenized together with 10 times the volume of a buffer solution A' composed of 50 mM TRIS-HCl and 10 mM EDTA
- pH 7.4. The suspension was centrifuged at 48,000 g for 20 min. After removal of the supernatant liquid, the membrane material present in the sediment was washed twice by suspend-ing in buffer solution A' and subsequently centrifuging and suspending [sic] for 20 minutes each time. After resuspension of the membranes in buffer solution A' and freezing in liquid nitrogen, the suspension was thawed again at 37C and, after a further wash, incubated at 37C for 15 min.

The protein material was subsequently washed four times by centrifugation and suspension and frozen at -70C until used.

For the binding assay, the protein material was thawed at 37C and washed twice by centrifuging at 48,000 g (20 min) and subsequently suspending in a buffer solution B' composed of 50 mM TRIS-HCl, pH 7.4. Subsequently, 0.15 mg of membrane material, 0.3 ~Ci of 3H-5,7-dichlorokynurenic acid (16 Ci/
mmol) and compound I were dissolved in 1 ml of buffer solu-tion B' and incubated on ice for 30 min. The incubated solu-tion was centrifuged at 150 000 g for 2 min. After removal of the supernatant liquid, the sediments were suspended twice in 1.5 ml of cold buffer solution B' each time. After measure-ment of the radioactivity of the 3H-5,7-dichlorokynurenic acid bound to the membranes in the sediment, the KI was found by regression analysis of the displacement plots.

The drug formulations are produced in a conventional way, eg. by mixing the active ingredient with the other [sic] conventional excipients and diluents.
The drug formulations can be administered in various ways, such as orally, parenterally, subcutaneously, intraperitonally and topically. Thus, possible presentations are tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, 40 creams, lotions, dusting powders and sprays.

The drug formulations according to the invention contain a thera-peutically effective amount of the compound I in addition to con-ventional ancillary substances. For local external use, eg. in 45 dusting powders and ointments, the active ingredients can be present in the conventional concentrations. The amount of active 21~8167 ingredients present is, as a rule, from 0.001 to 5% by weight, preferably 0.02 to 0.5% by weight.
On internal use, the preparations are administered in single 5 doses. From 0.1 to 50 mg, preferably 0.1 to 10 mg, of active ingredient are given by kg of body weight in a single dose. The formulations can be administered in one or more dosages each day depending on the nature and severity of the disorders. The daily dose is, as a rule, from 0.1 to 20 mg per kg of body weight on 10 oral administration and from 0.01 to 10 mg per kg of body weight on parenteral administration.

Besides the active ingredient, the drug formulations according to the invention contain conventional excipients and diluents appro-15 priate for the desired mode of administration. For local externaluse it is possible to use pharmaceutical ancillary substances such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid 20 paraffin, petrolatum and wool fat. Suitable for internal use are, for example, lactose, propylene, glycol, ethanol, starch, talc and polyvinylpyrrolidone.

It is furthermore possible for antioxidants such as tocopherol 25 and butylated hydroxyanisole and butylated hydroxytoluene, flavorings, stabilizers, emulsifiers and bleaches [sic] to be present.
The substances present in the formulation besides the active 30 ingredient, as well as the substances used in producing the pharmaceutical formulation, must be toxicologically acceptable and compatible with the particular active ingredient.
The following examples explain the invention in detail.
Description of the experiments A Preparation of the starting materials 40 a. 1-(2-nitrophenyl)imidazoles ~ ` 0050/43966 21581~7 Rs A--R6 R3 ~N,~N
1 1l R2--~N2 1) 1-(2-Nitro-4-trifluoromethylphenyl)-5-carbethoxy-4-methyl-imidazole A mixture of 10.45 g (0.05 mol) 2-fluoro-4-trifluoromethylnitro-benzene, 7.7 g (0.05 mol) of 4(5)-carbethoxy-5(4)-methylimidazole and 13.8 g of potassium carbonate in 100 ml of acetonitrile was 15 boiled for 4 h.

The reaction mixture was cooled, 1000 ml of water were added, the mixture was extracted with 250 ml of methylene chloride, and the methylene chloride phase was dried with magnesium sulfate. The 20 dried solution was evaporated and the residue was induced to crystallize by trituration with ether. The substance is suffi-ciently pure for the following reactions.

Yield: 11.4 g (66% of theory) 25 Melting point: 142 - 144C

The following compounds were obtained by varying the nitrobenzene derivative, the imidazole, the solvent, the temperature and the reaction time.
No. R~ R~ R~ A R~ M.p. C
2) H H CH3 - COOEt 94-96 3) H CH3 CH3 - COOEt 110 35 4) H F CH3 - COOEt 122-124 5) H H H CH2 COOEt oil 6) Cl H CH3 - COOEt 112-115 7) CF3 Cl CH3 - COOEt 118-119 8) Cl H H - COCH3 151 40 9) CF3 H CH3 - COOEt 142-144 10) H i-BuO CH3 - COOEt 65 11) Cl Cl CH3 - COOEt 152 12) H H C2Hs - COOMe 110-113 13) COOEt H CH3 - COOEt 119 45 14) CF3 H i-C3H7 - COOEt oil 15) CF3 Cl C2H5 - COOMe 142-144 16) CH3 CH3 CH3 - COOEt 128-132 ~ - 0050/43966 No. R7 R~ R~ A R~ M.p. C
17) CF3 H CH3 -CH=CH- COOMe168-172 18) Cl Cl H - COOMe160-163 l9) CF3 H H - COOMe146-150 5 20) No2 H CH3 - COOEt128-131 21) CF3 Cl H - COOMe99-103 22) F Br CH3 - COOEt140-145 23) Br CH3 CH3 ~ COOEt133-134 24) Br H CH3 - COOEt125-130 lO 25) H Cl CH3 -CH=CH- COOEt128-129 26) CF3 Cl H -CH2- COOEt122-123 27) CF3 H C6Hs -CH=CH- COOEt164-165 28) CF3 Cl CH3 -CH=CH- COOEt208-209 29) CF3 H CH3 -CH=CH- COOMe168-173 15 30)(CH3)2NSO2H CH3 - COOEt248-250 31) CF3 H C6H5 ~ COOEt138-141 32) CF30 H CH3 - COOEt98-101 33) CH3CONHH CH3 - COOEt129-134 34) i-Bu H CH3 - COOEt oil 20 35) CF3 Cl CH3 -CH2CH2- COOEt 185-190 36) Cl (6-Cl) CH3 - COOEt143-144 37) F Br CH3 - COOEt133-134 b. l-(2-Aminophenyl)imidazoles Rs A--R

R3 ~N,~;N

1) l-(2-Amino-4-trifluoromethylphenyl)-5-carbethoxy-4-methyl-imidazole 11.6 g (0.034 mol) of 1-(2-nitro-4-trifluoromethylphenyl)-5-car-bethoxy-4-methylimidazole (cf. Aal) were hydrogenated with 2 g of palladium/carbon catalyst (10% Pd) in 100 ml of ethanol at 40 room temperature under atmospheric pressure. After uptake of hy-drogen was complete, the catalyst was removed from the solution which was then concentrated under reduced pressure, and the resi-due was induced to crystallize with a little ether.

45 Yield: 9.8 g (93~ of theory) Melting point: 189 - 190C

. 0050/43966 21~8167 The compounds listed below were obtained in a similar way, using Raney nickel as catalyst for chlorine-containing compounds.

No. R~ R~ R~ A R~ M.p. C

2) H H CH3 - COOEt 139 3) H CH3 CH3 - COOEt 123 4) H F CH3 - COOEt 188 5) H H H CH2 COOEt oil 10 6) Cl H CH3 - COOEt 165 7) CF3 Cl CH3 - COOEt 202-205 8) Cl H H - COCH3 210 9) H i-Buo CH3 - COOEt oil 10) Cl Cl CH3 - COOEt 224 15 11) H H C2H5 - COOEt 141-143 12) COOEt H CH3 - COOCH3 158-160 13) CF3 H i-C3H7 - COOEt98-103 14) CF3 Cl C2H5 - COOEt196-198 15) CH3 CH3 CH3 - COOEt154-158 20 16) Cl Cl H - COOMe197-200 17) CF3 H H - COOMe209-212 18) No2 H CH3 - COOEt114-117 19) CF3 Cl H _ COOMe237-241 20) CF3 H CH3 -CH2-CH2- COOMe 99-103 25 21) F Br CH3 - COOEt172-174 22) Br CH3 CH3 - COOEt204-206 23) Br H CH3 - COOEt190-195 24) t-Bu H CH3 - COOEt143-144 25) Cl (6-Cl) CH3 - COOEt189-190 30 26) i-Bu H CH3 - COOEt143-145 27)CH3CONH H CH3 - COOEt100-103 28) CF30 H CH3 - COOEt157-160 29) CF3 H C6H5 ~ COOEt273-275 30)(CH3)2NSO2H CH3 - COOEt248-250 35 31) No2 H CH3 -CH2-CH2_ COOEt 163-164 32) CF3 Cl CH3 -CH2-CH2- COOEt 128-129 33) CF3 H C6H5 -CH2-CH2- COOEt 114-116 34) CF3 Cl H -CH2- COOEt151-152 35) H Cl CH3 -CH2-CH2- COOEt 112-113 B. Preparation of the final products Reaction of 1-(2-aminophenyl)imidazoles with carbonyldiimidazole:

45 Examples [sic] 1 0050/43966 ^ ~ 1 5 81 ~ 7 ~.

Ethyl 4,5-dihydro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylate 3.5 g (0.143 mol) of 1-~2-aminophenyl)-4-carbethoxy-5-methylimi-5 dazole [lacuna] (0.154 mol) of carbonyldiimidazole in 50 ml of 1,2-dichlorobenzene were boiled for 1.5 h.

After cooling, the solid was filtered off with suction, washed with acetone and recrystallized from DMF.
Yield: 3.0 g (77% of theory) ClqHl3N3o3 MW 271 M.p.: > 300C

The following were obtained in a similar way:
lS
2. Ethyl 4,5-dihydro-1,8-dimethyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylate Cl5HlsN3o3 MW 285 M.p. 255-257C
3. Ethyl4,5-dihydro-8-fluoro-l-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylate Cl4Hl2FN3o3 MW 289 M.p. 255-257C
4. Ethyl 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate Cl5Hl2F3N303 MW 339 M.p. 270-271C
5. Ethyl 4,5-dihydro-8-isobutoxy-l-methyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylate C18H21N304 MW 343 M.p. 190-195C

6. Ethyl4,5-dihydro-7-chloro-l-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylate Cl4Hl2clN3o3 MW 305 M.p. 277-279C

7. Ethyl 4,5-dihydro-4-oxoimidazolo[1,2-a]quinoxaline-2-acetate Cl4Hl3N303 MW 271 M.p. 265-270C

45 8. Methyl 4,5-dihydro-1-ethyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylate 21~81~

Cl4Hl3N3o3 MW 27.1 M.p. 264-266C

9. 4,5-Dihydro-2-acetyl-7-chloro-4-oxoimidazolo[1,2-a]quinoxa-line Cl2H8clN3o2 MW 261 M.p. > 320C

10. Diethyl 4,5-dihydro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2,7-dicarboxylate Cl7Hl7N3os MW 343 M.p. 295-300OC

11. Ethyl4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoi-midazolo[l,2-a]quinoxaline-2-carboxylate Cl5HllclF3N3O3 MW 373 M.p. 310-315C

12. Ethyl4,5-dihydro-1-isopropyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylate Cl7Hl6F3N3O3 MW 367 M.p. 215-220C

13. Methyl 4,5-dihydro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-acrylate Cl5Hl3N3O3 MW 283 M.p. > 300C

14. Ethyl 4,5-dihydro-7,8-dichloro-1-methyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylate Cl4Hllcl2N3O3 MW 340 M.p. 285C (decomposition) 15. Ethyl 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-acrylate Cl7Hl4F3N3O3 MW 365 M.p. > 280OC

16. Ethyl 4,5-dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxoi-midazolo[l,2-a]quinoxaline-2-carboxylate Cl5HllClF3N3O3 MW 373 M.p. 304-308C

17. Ethyl 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylate Cl4Hl2N4O5 MW 316 M.p. > 300C

- ~ 0050~43966 18. Methyl 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionate Cl6Hl4F3N3O3 MW 353 M.p. 203-206C
19. Methyl 4,5-dihydro-8-chloro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate C13H7ClF3N3O3 MW 345 M.p. 270-280C
20. Methyl 4,5-dihydro-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylate Cl3H8F3N3O3 MW 311 M.p. 281-283C
21. Ethyl 4,5-dihydro-8-bromo-7-fluoro-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate C14HllBrFN3O3 MW 368 M.p. 298-300C
22. Ethyl 4,5-dihydro-7-isobutyl-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate Cl8H2lN3o3 MW 327 M.p. 270-273C
23. Ethyl 4,5-dihydro-7-acetamido-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate Cl6Hl6N4o4 MW 328 M.p. > 300C
24. Ethyl 4,5-dihydro-7-bromo-1-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylate Cl4Hl2BrN3O3 MW 350 M.p. > 300OC
25. Ethyl 4,5-dihydro-1-methyl-7-trifluoromethoxy-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate C1sHl2F3N3O4 MW 355 M.p. > 300C
26. Ethyl 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate C2oHl4F3N3o3 MW 401 M.p. 292-295OC

0050/43966 2 1 ~ 8 1 ~ 7 ,~

27. Ethyl4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoi-midazolo[1,2-a]quinoxaline-2-propionate Cl7HlsClF3N33 MW 402 M.p. 233-235C

28. Ethyl4,5-dihydro-8-chloro-1-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-propionate Cl6Hl6clN3o3 MW 334 M.p. 291-293C
29. Ethyl 4,5-dihydro-8-chloro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-acetate Cl5HllClF3N3O3 MW 373 M.p. > 300C
30. Ethyl 4,5-dihydro-7-dimethylaminosulfonyl-1-methyl-4-oxoimi-dazolo[1,2-a]quinoxaline-2-carboxylate Cl6HlsN4Oss MW 378 M.p. >300C
31. Ethyl 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]qui-noxaline-2-propionate Cl6Hl6N4os MW 344 M.p. 250-255C
32. Ethyl 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionate C22H1sF3N3O3 MW 429 M.p. 192-193C
33. Ethyl 4,5-dihydro-1,7,8-trimethyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylate Cl6Hl7N3O8 MW 299 M.p. > 300C
34. Ethyl 4,5-dihydro-7-t-butyl-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate Cl8H2lN8O3 MW 327 M.p. 184-185C
35. Ethyl 4,5-dihydro-7,9-dichloro-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylate C14Hllcl2N3O3 MW 340 M.p. 261-267C

` 0050/43966 Hydrolysis of imidazoloquinoxalinecarboxylates:

Example 36 5 4,5-Dihydro-l-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carb-oxylic acid 29 g (0.107 mol) of the ester obtained in Example 1 were stirred with 500 ml of 2N sodium hydroxide solution and 300 ml of ethanol 10 at 80C for 1.5 h. After cooling, the mixture was acidified with concentrated hydrochloric acid and the product was filtered off with suction and recrystallized from DMF.

Yield: 23 g (88% of theory) 15 C12HgN3O3 MW 243 M.p.: > 300C

The following were obtained in a similar way:

37. 4,5-Dihydro-1,8-dimethyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid C13H11N303 MW 257 M.p. > 300C

38. 4,5-Dihydro-8-fluoro-l-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid c12H8FN3O3 MW 261 M.p. > 300c 39. 4,5-Dihydro-l-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl3H8F3N3o MW 311 M.p. > 300C

40. 4,5-Dihydro-8-isobutoxy-l-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid Cl6Hl7N3o4 MW 315 M.p. 270-275C

41. 4,5-Dihydro-1-ethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-car-boxylic acid C13H11N3O3 MW 257 M.p. 335-340C

42. 4,5-Dihydro-7-chloro-l-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid , ooSO/43966 '~ 2 1 5 8 1 6 7 Cl2HgclN3o3 MW 277 M.p. > 320C

43. 4,5-Dihydro-4-oxoimidazolo[1,2-a]quinoxaline-2-acetic acid Cl2HsN3o3 MW 243 M.p. 320-325C

44. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl3H7clF3N3o3 MW 345 M.p. > 300C

45. 4,5-Dihydro-l-isopropyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl5Hl2F3N3O3 MW 339 M.p. 245-250C

46. 4,5-Dihydro-l-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-acrylic acid Cl4Hl1N3O3 MW 269 M.p. > 300C

47. 4,5-Dihydro-7,8-dichloro-1-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid C12H7cl2N3O3 MW 312 M.p. > 300C
48. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-acrylic acid ClsHloF3N3O3 MW 337 M.p. > 320C

49. 4,5-Dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl4HgClF3N3O3 MW 359 M.p. > 300C
50. 4,5-Dihydro-l-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid Cl2H8N4Os MW 288 M.p. > 300C

51. 4,5-Dihydro-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid Cl2H6F3N3O3 MW 297 M.p. > 300C

'- ~` 0050/43966 ' 2158~67 52. 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionic acid Cl5Hl2F3N3o3 MW 339 M.p. > 300C

53. 4,5-Dihydro-1,7,8-trimethyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid Cl4H13N3O3 MW 271 M.p. > 300C
54. 4,5-Dihydro-7-bromo-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid C12H8BrN3O3 MW 322 M.p. > 300C
55. 4,5-Dihydro-8-bromo-7-fluoro-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylic acid Cl2H7BrFN3O3 MW 340 M.p. > 300C
56. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylic acid C12HsClF3N3O3 MW 331 M.p. > 300C
57. 4,5-Dihydro-7-t-butyl-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid Cl6Hl7N3o3 MW 2g9 M.p. > 300C
58. 4,5-Dihydro-7,9-dichloro-1-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid Cl2H7cl2N3O3 MW 312 M.p. > 300C
59. 4,5-Dihydro-7-isobutyl-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid Cl6Hl7N3O3 MW 299 M.p. 256-259C

60. 4,5-Dihydro-7-acetamido-l-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid Cl4Hl2N4O4 MW 300 M.p. > 350C

'- ~ 0050/43966 ~ 2158167 61. 4,5-Dihydro-l-methyl-7-trifluoromethoxy-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl3HgF3N3o4 MW 327 M.p. > 300C

62. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid Cl8HloF3N3O3 MW 373 M.p. > 300C
63. 4,5-Dihydro-l-methyl-8-nitro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylic acid Cl3H7F3N4Os MW 356 M.p. > 300C
64. 4,5-Dihydro-7-(dimethylaminosulfonyl)-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylic acid Cl4Hl4N4Oss MW 350 M.p. > 300C
65. 4,5-Dihydro-l-methyl-8-nitro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionic acid Cl5HllF3N4os MW 384 M.p. > 300C
66. 4,5-Dihydro-1-methyl-8-nitro-4-oxoimidazolotl,2-a]quinoxa-line-2-propionic acid Cl4Hl2N4O5 MW 316 M.p. > 300C
67. 4,5-Dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-propionic acid C15Hl1ClF3N3O3 MW 373 M.p. > 300C
68. 4,5-Dihydro-1-phenyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionic acid C2oHl4F3N3o3 MW 401 M.p. 275-279C
69. 4,5-Dihydro-8-chloro-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-acetic acid C13H7clF3N3O3 MW 345 M.p. ~ 300C

~ t--' 2158167 70. 4,5-Dihydro-8-chloro-1-methyl-7-nitro-4-oxoimidazo-lo r 1,2-a]quinoxaline-2-propionic acid Cl4HllclN4os MW 351 M.p. > 300C

71. 4,5-Dihydro-8-chloro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-propionic acid Cl4Hl2clN3o3 MW 306 M.p. > 300C
Reduction of esters Example 72 15 4,5-Dihydro-2-hydroxymethyl-1-methyl-7-trifluoromethyl-4-oxoimi-dazolo[1,2-a]quinoxaline 37 g (0.11 mol) of the ethyl 4,5-dihydro-1-methyl-7-trifluorome-thyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate obtained in 20 Example 4 were stirred with 3.65 g of lithium borohydride in 500 g of dry tetrahydrofuran at room temperature for 48 h and then boiled for a further 5 h.

The reaction mixture was cooled and then 100 ml of 2N hydrochlo-25 ric acid were added (evolution of gas) and the solvent was dis-tilled off under reduced pressure, 300 ml of water were added and the product was ~iltered off with suction and recrystallized from dimethylformamide.
30 Yield: 26 g (78% of theory) C13HloF3N3O2 MW 297 M.p. > 300C
The following were obtained in a similar way:
35 73. 4,5-Dihydro-1,7-dimethyl-2-hydroxymethyl-4-oxoimidazo-lo[1,2-a]quinoxaline Cl3Hl3N3O2 MW 243 M.p. > 300C

40 74. 4,5-Dihydro-2-hydroxymethyl-1-methyl-4-oxoimidazo~
lo[1,2-a]quinoxaline Cl2HllN3O2 MW 229 M.p. 231-233C
45 75. 4,5-Dihydro-7-chloro-2-hydroxymethyl-1-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline ~ 21~8167 Cl2HloclN3o2 MW 263 M.p. > 300C

Oxidation of hydroxyalkyl compounds to aldehydes:

5 Example 76 4,5-Dihydro-l-methyl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carbaldehyde 10 20.0 g (0.067 mol) of the 4,5-dihydro-2-hydroxymethyl-1-meth-yl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline obtained in Example 72 were stirred with 58 g of activated manganese dioxide (0.67 mol) in 500 ml of dimethylformamide at 100C for 2 h.

15 The solution was filtered hot and then evaporated under reduced pressure, and the residue was stirred with ether and filtered off with suction.

Yield: 17 g (85~ of theory) 20 Cl3H8F3N3O2 MW 215 M.p. > 300 C

The following was obtained in a similar way:
77. 4,5-Dihydro-l-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carbaldehyde Cl2HgN3O2 MW 227 M.p. > 300OC

Preparation of oximes and oxime ethers Example 78 4,5-Dihydro-2-hydroxyiminomethyl-1-methyl-7-trifluoromethyl-4-ox-oimidazolo[l,2-a]quinoxaline 1.0 g (0.0037 mol) of the 4,5-dihydro-1-methyl-7-trifluorome-thyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carbaldehyde obtained in Example 76 was boiled with 0.47g t0.0067 mol) of hydroxylamine hydrochloride, 0.6 g of sodium acetate, 10 ml of water and 40 12.5 ml of ethanol for 5 h. After cooling, the precipitate was filtered off with suction and washed with ethanol, water and a little acetone.
Yield: 0,5 g (48% of theory) 45 Cl3HgF3N4O2 MW 310 M.p. 320 - 322C

'- 0050/43966 ~ 2 1 5 8 1 6 7 The following were prepared in a similar way:

79. 4,5-Dihydro-2-hydroxyiminomethyl-1-methyl-4-oxoimidazo-lo[l,2-a]quinoxaline Cl2HloN4o2 MW 242 M.p. 315 - 320C

The following were prepared in a similar way in principle using hydroxylamine 0-methyl or 0-ethyl ether hydrochloride and the appropriate aldehydes:

80. 4,5-Dihydro-2-methoxyiminomethyl-l-methyl-4-oxoimidazo-lo[1,2-a]quinoxaline Cl3Hl2N4o2 MW 256 M.p. > 320C
81. 4,5-Dihydro-2-methoxyiminomethyl-1-methyl-7-trifluorome-thyl-4-oxoimidazolo[1,2-a]quinoxaline Cl4HllF3N4o2 MW 324 M.p. 299 - 303C

82. 4,5-Dihydro-2-ethoxyiminomethyl-1-methyl-imidazolo[1,2-a]qui-noxaline Cl4Hl4N4o2 MW 270 M.p. 315 - 316C
83. 4,5-Dihydro-2-ethoxyiminomethyl-1-~ethyl-7-trifluorome-thyl-4-oxoimidazolo[1,2-a]quinoxaline Cl5H13F3N4O2 MW 338 M.p. 292 - 295C
Preparation of nitriles:

Example 84 84. 4,5-Dihydro-l-methyl-7-trifluoroethyl-4-oxoi~idazo-lo[l,2-a]quinoxaline-2-carbonitrile 1.5 g (0.005 mol) of the oxime described in Example 78 were refluxed with 20 ml of acetic anhydride for 5 h. The mixture was then added to sodium carbonate solution, and the crude product was filtered off with suction and recrystallized from methylene chloride and methanol.
Yield: 0.7 g (50~ of theory) Cl3H7F3N3O MW 278 M.p. > 300C

- ~ 0050/43966 ~ 2 1 ~ 8 1 6 7 Preparation of tetrazole compounds Example 85 5 85. 4,5-Dihydro-l-methyl-2-(5-tetrazolyl)-7-trifluoromethyl-4-ox-oimidazolo~l,2-a]quinoxaline 1.15 g ( O . 004 mol) of the described nitrile were refluxed with 0.45 g of sodium azide (0.007 mol) and 0.4 g of ammonium chloride in 50 ml of dimethylformamide for 16 h.

Water was then added to the mixture, and the residue was fil-tered off with suction and washed with acetone.

Yield: 0.5 g ( 37% of theory) Cl3H8F3N7O MW 335 M.p. > 300C

Example 86 20 86. 4,5-Dihydro-l-methyl-7-trifluoromethyl-4-oxoimidazo-lo[l,2-a]quinoxaline-2-carboxylic acid (5-tetrazolyl)amide 2.0 g (0.006 mol) of the acid obtained in Example 41 were pretreated with 3.9 g ( O . 024 mol) of carbonyldiimidazole in 30 ml of dimethylformamide at 80C for 2 h; subsequently a solution of 0.6 g ( O . O 0 6 mol) of anhydrous 5-aminotetrazole in lo ml of dimethyl~ormamide was added, and the mixture was heated at 80C for a further 5 h. The mixture was worked up by filtration with suction, the filtrate was poured into ice, the mixture was acidified, the precipitate was filtered off with suction, and the resulting product was recrystallized from dimethylformamide contA; n; ng 2% water.
Yield 0.8 g ( about 30% of theory) Cl4HsF3Nso2 MW 378 M.p. > 300C

Preparation of nitro compounds:

Example 87 4,5-Dihydro-l-methyl-8-nitro-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid 2.5 g (0.01 mol) of the 4,5-dihydro-1-methyl-4-oxoimidazo-45 lo[l,2-a]quinoxaline-2-carboxylic acid obtained in Example 39 were added in portions over the course of 15 min to 25 ml of ni-tric acid of density 1.50 while stirring at 0-5C, and the mixture - ~ 0050/43966 21581~7 was then stirred for a further 1 h and subsequently poured into ice, and the precipitated product was washed with water and ace-tone.

5 Yield: 2.3 g (82% of theory) C12HsN4Os MW 288 M.p. > 320C
Example 88 lO 88. Ethyl 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoi-midazolo[1,2-a]quinoxaline-2-carboxylate 5 g (0.015 mol) of ethyl 4,5-dihydro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate, pre-pared as in Example 4, were dissolved in 50 ml of concen-trated sulfuric acid and, at room temperature, 1.8 g of po-tassium nitrate were added in portions. The mixture was stirred at room temperature for 24 h and then heated at 60C
for 2 h. The mixture was worked up by pouring into ice, and the precipitated product was filtered off with suction and subsequently washed with methylene chloride.
Yield 4.1 g (73% of theory) C15HllF3N4Os MW 384 M.p. 284-286C
Example 89 In a similar way, nitration of methyl 4,5-dihydro-1-methyl-7-tri-fluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-propionate (pre-30 pared as in Example 18) resulted in methyl 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-propionate 35 Cl6Hl3F3N4Os MW 398 M.p. 246-250C
and of ethyl 4,5-dihydro-8-chloro-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-40 line-2-propionate (obtained as in Example 28) resulted in 90. ethyl 4,5-dihydro-8-chloro-1-methyl-7-nitro-4-oxoimidazo-lo[1,2-a]quinoxaline-2-propionate, Cl6HlsclN4os MW 379 M.p. 172-174C

' ~ 0050/43966 2 1 5 8 1 6 7 Reduction/hydrogenation of nitro compounds Example 91 5 4,5-Dihydro-8-amino-1-methyl-4-oxoimidazolo[1,2-a]quinoxa-line-2-carboxylic acid 1.7 g of 4,5-dihydro-1-methyl-8-nitro-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid (prepared as in Example 88) 10 (0.055 mol) were dissolved in glacial acetic acid/methanol and hydrogenated using 1.5 [lacuna] Pd-C catalyst (10% Pd) at room temperature and 25C [sic].
The usual workup resulted in 11.2 g (68% of theory) of amino com-15 pound.
Cl2HloN403 Mg [sic] 295 M.p. > 340C

Examples of pharmaceutical formulations:
Example A
Tablets of the following composition are produced in a tabletting machine in a conventional way:
mg of 4,5-dihydro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylic acid 120 mg of corn starch 30 13.5 mg of gelatin mg of lactose 2.25 mg of AerosilR (chemically pure silica in submicroscopically fine dispersion) 6.75 mg of potato starch (as 6% paste) Example B
Coated tablets of the following composition are produced in a conventional way:
mg of 4,5-dihydro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxa line-2-carboxylic acid mg of core composition 45 60 mg of coating composition . ~ 0050/43966 ` 21581~7 the core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of LuviskolR VA 64 (60:40 vinylpyrrolidone/vi-nyl acetate copolymer, cf. Pharm. Ind. 1962, 586). The coating composition comprises 5 parts of sucrose, 2 parts of corn starch, 5 2 parts of calcium carbonate and 1 part of talc. The coated tab-lets produced in this way are subsequently provided with an en-teric coating.

Example C
10 g of 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-10[1,2-a]quinoxaline-2-carboxylic acid are dissolved in 5000 ml of water with the addition of NaCl and adjusted to pH 6,0 with 0.1 N NaOH to produce a solution isotonic with blood. 5 ml por-15 tions of this solution are dispensed into ampoules and steril-ized.

Claims (6)

We claim:

1. An imidazolo[1,2-a]quinoxalinone of the formula I

where A is a saturated or unsaturated alkylene group with 1-5 C
atoms or a bond, R6 is a formyl group or a carboxyl group which can be in the form of its salt with a physiologically tolerated amine or metal cation, the radical COOR7 where R7 is C1-C8-alkyl, cycloalkyl with 3-8 C atoms in the ring, benzyl, -(CH2)n-OR8 where n is 2-4 and R8 is C1-C3-alkyl, or is C1-C4-hydroxyalkyl, C1-C4-alkylcarbonyl, nitrilo [sic], tetrazolyl, carbonylaminotetrazole [sic], aldoxime [sic], C1-C3-alkoxyaldoxime or unsubstituted or substi-tuted carbamoyl, R2 is fluorine, chlorine, bromine, trifluoromethyl, trifluo-romethoxy, cyano, nitro, amino, C1-C5-alkyl, C1-C5-alkoxy, mono- or dialkylamino, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl, C1-C6-alkylsulfonyl, aminosulfonyl, di-C1-C6-al-kylaminosulfonyl or C1-C4-alkoxycarbonyl, R1, R3 and R4 which [sic] are identical or different and are each hydrogen, fluorine, chlorine, bromine, trifluorome-thyl, trifluoromethoxy, cyano, nitro, amino, C1-C5-alkyl, C1-C5-alkoxy, mono- or dialkylamino, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, aminosulfonyl, di-C1-C6-alkylaminosulfonyl or C1-C4-alkoxycarbonyl, or one of the pairs R1 and R2, R2 and R3 or R3 and R4 is also -( CH2)4- or -CH=CH-CH=CH-, R5 is hydrogen, C1-C5-alkyl or phenyl which is unsubstituted or substituted by chlorine, fluorine, trifluoromethyl or C1-4-alkyl, but where the following are not simultaneously possible A is a bond R6 is formyl, ethoxycarbonyl, hydroxymethyl, aldehyde [sic], tetrazolyl, carboxamide [sic] or 5-aminotetrazolyl, R1, R4 and R5 are each hydrogen and R2 and R3 are identical and are each chlorine or bromine in positions 7 and 8.

2. A compound as claimed in claim 1, where R2 is chlorine, bro-mine, trifluoromethyl, trifluoromethoxy or nitro; R3 is hy-drogen, chlorine or nitro, R4 is hydrogen or chlorine; R5 is methyl, ethyl or phenyl; A is a bond or a vinyl or ethylene group, and R6 is a carboxylic acid or ester group.

3. A compound as claimed in claim 1, selected from the group consisting of a. 4,5-dihydro-7-chloro-1-methyl-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid b. 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]qui-noxaline-2-carboxylic acid c. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid d. 4,5-dihydro-7,8-dichloro-1-methyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid e. 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimi-dazolo[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 g. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate h. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazo-lo[1,2-a]quinoxaline-2-carboxylic acid i. 4,5-dihydro-1-isopropyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid j. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-acrylic acid k. methyl 4,5-dihydro-8-chloro-1-ethyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate l. 4,5-dihydro-8-chloro-1-ethyl-7-trifluoromethyl-4-oxoimi-dazolo[1,2-a]quinoxaline-2-carboxylic acid m. 4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-propionic acid n. 4,5-dihydro-8-chloro-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid o. ethyl 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylate p. 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-carboxylic acid q. ethyl 4,5-dihydro-1-methyl-8-nitro-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate r. 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimi-dazolo[1,2-a]quinoxaline-2-carboxylic acid s. methyl 4,5-dihydro-1-methyl-8-nitro-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-propionate t. 4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimi-dazolo[1,2-a]quinoxaline-2-propionic acid u. 4,5-dihydro-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]qui-noxaline-2-propionic acid v. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-propionate w. 4,5-dihydro-8-chloro-1-methyl-7-trifluoromethyl-4-oxoimi-dazolo[1,2-a]quinoxaline-2-propionic acid x. 4,5-dihydro-1-phenyl-7-trifluoromethyl-4-oxoimida-zolo[1,2-a]quinoxaline-2-propionic acid y. ethyl 4,5-dihydro-8-chloro-1-methyl-7-trifluoro-methyl-4-oxoimidazolo[1,2-a]quinoxaline-2-propionate.

4. A drug containing a compound of the formula I or its thera-peutically tolerated [sic] salts.

5. A compound of the formula I as claimed in claim 1 for use for controlling diseases.

6. A process for preparing imidazolo[1,2-a]quinoxalinones of the formula I

I

where A is a saturated or unsaturated alkylene group with 1-5 C
atoms or a bond, R6 is a formyl group or a carboxyl group which can be in the form of its salt with a physiologically tolerated amine or metal cation, the radical COOR7 where R7 is C1-C8-alkyl, cycloalkyl with 3-8 C atoms in the ring, benzyl, -(CH2)n-OR8 where n is 2-4 and R8 is C1-C3-alkyl, or is C1-C4-hydroxyalkyl, C1-C4-alkylcarbonyl, nitrilo [sic], tetrazolyl, carbonylaminotetrazole [sic], aldoxime [sic], C1-C3-alkoxyaldoxime [sic] or unsubstituted or substituted carbamoyl, and R1-R4 which [sic] are identical or different and are each hy-drogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, C1-C5-alkyl, C1-C5-alkoxy, mono- or dialkylamino, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, aminosulfonyl, di-C1-C6- alkylaminosulfonyl or C1-C4-alkoxycarbonyl, R5 is hydrogen, C1-C5-alkyl or phenyl which is unsubstituted or substituted by chlorine, fluorine, trifluoromethyl or C1-4-alkyl, but where the following are not simultaneously possible A is a bond R6 is carboxyl, ethoxycarbonyl, hydroxymethyl, formyl, te-trazolyl, carboxamide [sic] or 5-aminotetrazolyl, R1, R4 and R5 are each hydrogen and R2 and R3 are identical and are each chlorine or bromine in positions 7 and 8, which comprises reacting a compound of the formula II

II

where R1 - R5 and A have the stated meanings, and R6 is a ni-trile, carboxylic ester, aldehyde or alkanoyl group, with a doubly activated carbonic acid derivative, and a. if R6 in the final product of the formula I is COOH, hy-drolyzing an ester (R6=COOR7) obtained in this way or b. if R6 in the final product of the formula I is a hydroxy-alkyl, aldehyde, oxime or oxime ether group, reducing an ester (R6=COOR7) obtained in this way and, where ap-propriate, subsequently oxidizing the resulting hydroxy-alkyl compound to the aldehyde and reacting the latter with hydroxylamine or hydroxylamine O-alkyl ethers to give the oxime or oxime ether, or c. if R6 in the final product of the formula I is an unsub-stituted or substituted carbamoyl or carbonylaminotetra-zole [sic] group, reacting an acid obtained as in a) where appropriate in activated form with ammonia, an amine or 5-aminotetrazole or d. if R6 is a tetrazolyl radical, reacting a compound of the formula I where R6 is a nitrile [ sic ] group with hydra-zoic acid or one of its salts, and, where appropriate, nitrating the compounds obtained in this way and/or converting them into their physiologically tolerated salts.