DE4344486A1 - New quinoxaline-di:one derivs. - Google Patents

Abstract

Quinoxalinedione derivs. of formula (I) and their isomers and salts, are new. R<1> = (CH2)nCR<2>H(CH2)m-Z; R<5>-R<8> = H, T, CF3, NO2, halo, NR<9>R<10>, CN, SOPR<11>, SO2NR<12>R<13>, SO3H, SO3T or OR<14>; T = 1-6C alkyl; R<2> = H or (CH2)qR<3>; R<3> = H, OH, OT or NR<15>R<16>; r,m,q = 0, 1, 2 or 3; Z = POXY, OPOXY, OR<17>, NR<18>R<19>, NHCOR<20>, NHSO2R<21>, SO2R<22>, CO2R<23>, halo, CN or tetrazolyl; R<11> = H, T or phenyl; p = 0, 1 or 2; R<12>, R<13>, R<17>, R<23> = H or Q; Q = 1-4C alkyl; R<14> = H, or Q; Q = 1-4C alkyl; R<14> = H, or Q (opt. substd. by 1-3 halo); R<20>, R<21> = T, phenyl (opt. substd. by halo), or heteroaryl; R<22> = HO, TO or NR<24>R<25>; X,Y = OH, TO, Q or NR<18>R<19>; R<9>,R<10> = H, COT, phenyl, or T (opt. substd. by QO, NH2, NHQ or N(Q)2); or NR<9>R<10> = a 5-7 membered satd. heterocycle (which contains one other N, O or S atom and which is opt. substd.), or an unsatd. 5-membered heterocycle (which contains 1-3N atoms and which is opt. substd.); R<15>, R<16>,R<18>,R<19> = H, Q or phenyl; or NR<15>R<16> and/or NR<18>R<19> = a gp. as NR<9>R<10>; R<24>, R<25> = H or Q; or NR<24>R<25> = a satd. 5-7 membered heterocycle (which contains one other S, O or N atom and which is opt. substd.). Provided that (a) when R<2> is H and Z is CO2R<23> or POXY, then R<5>-R<8> are not H; (b) when R<2> is H, Z is POXY or CO2R<23> and R<5>, R<6>, R<7> or R<8> is CF3, NO2, NH2, halo or Me, the cpds. (I) are disubstituted.; (c) when R<1> is methanephosphonic acid and R<6> is CN or substd. imidazolyl, then R<5>, R<7> and R<8> cannot all be H; (d) when R<1> is methanephosphonic acid, R<6> is CF3 or NO2 and R<7> is imidazolyl, then R<5> and R<8> cannot both be H; and (e) when R<1> is CH2COOH and R<5> and R<8> are H, then R<6> and R<7> cannot both be halo or Me.

Description

The invention relates to quinoxalinedione derivatives, their preparation and use in Medicines.

Quinoxaline derivatives are known to have affinity for the quisqualate receptors and because of its affinity as a drug for the treatment of diseases of the central nervous system.

The compounds according to the invention have the formula I.

wherein
R¹ - (CH₂) _n -CR²H- (CH₂) _m -Z and
R⁵, R⁶, R⁷ and R⁸ are the same or different and are hydrogen C _1-6 alkyl, CF₃, nitro, halogen, NR⁹R¹⁰, cyano, SO _p R¹¹, SO₂NR¹²R¹³, SO₃H, SO₃C _1-6 alkyl or OR¹⁴
mean where
R² is hydrogen or - (CH₂) _q -R³,
R³ is hydrogen, hydroxy, C _1-6 alkoxy or NR¹⁵R¹⁶,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, OR¹⁷, NR¹⁸R¹⁹, NH-COR²⁰, NH-SO₂R²¹, SO₂R²², CO₂R²³ or tetrazole,
R11 H, C _1-6 alkyl, phenyl,
p 0, 1 or 2
R¹², R¹³, R¹⁷ and R²³ are hydrogen or C _1-4 alkyl,
R¹⁴ is H or optionally substituted 1-3 times by halogen C _1-6 alkyl,
R²⁰ and R²¹ are C _1-6 alkyl, phenyl or hetaryl,
R²² hydroxy, C _1-6 alkoxy or NR²⁴R²⁵,
X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR⁹R¹⁰,
R⁹ and R¹⁰ are the same or different and are hydrogen, phenyl or C _1-6 alkyl, which may optionally be substituted by C _1-4 alkoxy or an amino group optionally mono- or di-substituted by C _1-4 alkyl, or together form a 5- or 6-membered saturated heterocycle with the nitrogen atom, which may contain and be substituted by another N, S or O atom or form an unsaturated 5-membered heterocycle which may contain 1-3 N atoms,
R¹⁵ and R¹⁶, R¹⁸ and R¹⁹ are the same or different and form hydrogen, C _1-4 alkyl, phenyl or together with the nitrogen atom a 5- or 6-membered saturated heterocycle which contains another oxygen, sulfur or nitrogen atom and can be substituted can form or an unsaturated 5-membered heterocycle which can contain 1-3 N atoms,
R²⁴ and R²⁵ are the same or different and form hydrogen, C _1-4 -alkyl or together with the nitrogen atom a saturated 5- or 6-membered heterocycle which may contain a further oxygen, sulfur or nitrogen atom, and their isomers or salts,
where if R² is hydrogen and Z is POXY or CO₂R²³,
R⁵-R⁸ are not hydrogen and if R² is hydrogen, Z POXY or CO₂R²³ and
R⁵, R⁶, R⁷ or R⁸ are CF₃, NO₂, halogen, NH₂ or methyl, disubstituted compounds of the formula I are present and
if R¹ is methylphosphonic acid, R⁷ imidazole and R⁶ CF₃ or NO₂, R⁵ and R⁸ cannot simultaneously be hydrogen and
if R¹ -CH₂-COOH and R⁵ and R⁸ are hydrogen, R⁶ and R⁷ cannot simultaneously be halogen or methyl.

The compounds of the general formula I also include the possible tautomeric compounds Form and include the E or Z isomers or, if a chiral center is present is, the racemates or enantiomers.

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

Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl, with C _1-4 alkyl radicals being preferred.

Halogen is fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and Bromine to understand.

Form R⁹ and R¹⁰, R¹⁵ and R¹⁶, R¹⁸ and R¹⁹, R²⁴ and R²⁵ together with the nitrogen atom a saturated heterocycle, for example piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine is meant. C _1-4 alkyl groups such as N-methylpiperazine may be mentioned as substituents of the heterocycle.

Form R⁹ and R¹⁰, R¹⁵ and R¹⁶, R¹⁸ and R¹⁹, together with the nitrogen atom an unsaturated heterocycle, for example imidazole and pyrazole.

If an acidic function is present, the physiologically tolerated salts are salts Suitable organic and inorganic bases such as the readily soluble alkali and Alkaline earth metal salts as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glukamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl amino methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is included, the physiologically acceptable salts are more organic and inorganic acids such as HCl, H₂SO₄, phosphoric acid, citric acid, Tartaric acid u. a.

The compounds of formula I and their physiologically tolerable salts are on Because of their affinity for the quisqualate receptors, they can be used as drugs. On Because of their activity profile, the compounds according to the invention are suitable for Treatment of diseases caused by hyperactivity like excitatory amino acids Glutamate or aspartate can be caused. Since the new connections as Antagonists of excitatory amino acids act and have a high specific affinity the AMPA receptors by showing the radiolabeled specific agoni most (RS) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from the AMPA Repress receptors, they are particularly suitable for the treatment of such sick units that work via the receptors of excitatory amino acids, especially the AMPA Receptor can be influenced.

According to the invention, the compounds can be used for treatment neurological and psychiatric disorders caused by overstimulation of the AMPA Receptor are triggered. Neurological diseases include neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, chorea Huntington, amyotrophic lateral sclerosis, olivopontocerebellar degeneration, prevention post-ischemic cell death, cell death after brain trauma or Stroke, senile dementia, multi-infarct dementia as well as epilepsy and muscle spasms. Psychiatric disorders include anxiety, schizophrenia, migraines,  Pain conditions, gastrointestinal disorders and pain, as well as the treatment of Withdrawal symptoms after drug abuse such as alcohol, cocaine, benzodiazepine or Opiate withdrawal.

For the use of the compounds according to the invention as drugs, these are described in brought the form of a pharmaceutical preparation that in addition to the active ingredient for enteral or parenteral application suitable pharmaceutical, organic or anor ganic inert carrier materials, such as water, gelatin, gum arabic, Milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, for example as a tablet tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, Suspensions or emulsions are present. If necessary, they also contain Auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for Change in osmotic pressure or buffer.

For parenteral use, especially injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated Castor oil, suitable.

Surface-active auxiliaries such as salts of bile acids can also be used as carrier systems or animal or vegetable phospholipids, but also mixtures thereof as well Liposomes or their components can be used.

Tablets, coated tablets or capsules with talc are particularly suitable for oral use and / or hydrocarbon carriers or binders, such as lactose, maize or Potato starch, suitable. The application can also be in liquid form, such as Example as juice, to which a sweetener may be added.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the Patients, type and severity of the disease to be treated and similar factors vary ieren. The daily dose is 0.5-1000 mg, preferably 50-200 mg, the dose being as a single dose to be administered once or divided into 2 or more daily doses can be given.

The compound of the invention is prepared in accordance with known methods Methods. For example, compounds of the formula I are obtained by

• a) a compound of formula II wherein R¹ to R⁸ have the above meaning, cyclized with oxalic acid or reactive oxalic acid or
• b) a compound of formula III wherein R¹ has the meaning given above and one of the substituents R⁵ ′, R⁶ ′, R⁷ ′ or R⁸ ′ represents a leaving group, is substituted nucleophilically and, if desired, subsequently saponifies the ester group or esterifies or amidates the acid group or the nitro group is reduced to the amino group or the alkyl group or acylated or the amino group replaced by halogen or cyano or introducing a nitro group or performing an ether cleavage or separating the isomers or forming the salts.

The cyclization to compounds of the formula I is carried out in a known manner using oxalic acid single-stage in an acidic environment or with a reactive oxalic acid derivative single-stage or also two-stage. The two-stage process in which the diamine with an oxalic acid derivative such as the oxal ester half chloride or reactive Oxalic acid imidazolide derivatives in polar solvents such as cyclic or acyclic Ethers or halogenated hydrocarbons, for example tetrahydrofuran, Diethyl ether or methylene chloride in the presence of a base such as organic amines  for example, triethylamine, pyridine, Hunig base or dimethylaminopyridine becomes. The subsequent cyclization can be basic or acidic, but preferably in acidic environment are carried out, alcohol being added to the solvent can.

Suitable bases for the two-stage process are also alkali metal hydrides such as NaH be used in inert solvents such as hydrocarbons.

Halogens such as fluorine, chlorine and bromine are the escape groups in process variant b), or O-mesylate, O-tosylate, O-triflate or O-nonaflate. The nucleophile Substitution is carried out according to methods known from the literature in the presence of a base and is activated by an activating electron-withdrawing group such as B. Nitro, Cyano, Trifluoromethyl favors preferably in the o-position.

Primary and secondary amines which contain N are examples of nucleophiles Heteroaromatics, cyanide, alcoholates, thiolates and the like. a. suitable. The implementation can be done in polar solvents such as alcohols, halogenated hydrocarbons, Dimethylacetamide or water or without solvent. When Bases are inorganic bases such as alkali or alkaline earth metal hydroxides or carbonates or organic bases such as cyclic, alicyclic and aromatic amines, such as DBU, Hunig base, pyridine or dimethylaminopyridine.

In the case of amines, the nucleophile itself can be used in excess as a base, whereby one can optionally work without further solvent.

The optionally subsequent saponification of an ester group can be basic or preferably acidic, by raising the temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous Hydrochloric acid optionally in solvents such as trifluoroacetic acid or Alcohols hydrolyzed. Phosphonic acid esters are preferred by heating in highly concentrated aqueous acids such as concentrated hydrochloric acid optionally with the addition of an alcohol or by treatment with Trime thylsilyl bromide in inert solvents such as. B. acetonitrile and subsequent Treatment hydrolyzed with water.

The esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se Way with the appropriate alcohol under acid catalysis or in the presence of a activated acid derivative. Activated acid derivatives include, for example, acid chloride,  -imidazolide or anhydride in question. In the case of phosphonic acids, esterification can be used by reaction with orthoesters, optionally with the addition of catalysts such as p- Reach toluenesulfonic acid.

The amidation takes place on the free acids or on their reactive derivatives as in for example, acid chlorides, mixed anhydrides, imidazolides or azides Reaction with the corresponding amines at room temperature.

The nitro group is reduced to the amino group catalytically in polar solutions average at room temperature or elevated temperature. As catalysts are metals like Raney nickel or noble metal catalysts such as palladium or platinum if appropriate Suitable for carriers. Instead of hydrogen, ammonium formate can also be used in a known manner to be used. Reducing agents such as tin (II) chloride or titanium (III) chloride can are used as well as complex metal hydrides possibly in the presence of Heavy metal salts. Iron can also be used as a reducing agent. The reaction is in Presence of an acid such as e.g. B. acetic acid or ammonium chloride optionally under Added a solvent such as water. It can be beneficial before Reduction to introduce the ester group. In the presence of several nitro groups in the Molecule can also selectively the desired ortho-standing nitro group in a conventional manner can be reduced with Na₂S.

If an alkylation of an amino group is desired, it can be carried out by customary methods for example, alkylated with alkyl halides.

The cyano group can be introduced using the Sandmeyer reaction; for example, the intermediates formed from the amino compounds with nitrites react ten diazonium salts with alkali metal cyanides in the presence of Cu-I cyanide.

The introduction of the halogens chlorine, bromine or iodine via the amino group can, for example also take place according to Sandmeyer, by forming the intermediate formed with nitrites Diazonium salts with Cu (I) chloride or Cu (I) bromide in the presence of the corresponding Acid such as hydrochloric acid or hydrobromic acid or reacted with potassium iodide.

If an organic nitrous acid ester is used, the halogens can e.g. B. by Introduce addition of methylene iodide or tetrabromomethane.

Fluorine can be introduced, for example, through the Balz Schiemann reaction of Diazonium tetrafluoroborates.  

The introduction of a NO₂ group succeeds through a number of known nitration methods. For example, with nitronium tetrafluoroborate in inert solvents such as halogenated hydrocarbons or nitrated in sulfolane or glacial acetic acid.

The ether cleavage is carried out by the usual methods, for example by reaction with Trimethylbromosilane optionally with the addition of alkali iodide in an inert Solvents such as acetonitrile at a temperature of 0 ° C to the boiling point of Solvent.

The isomer mixtures can be prepared using customary methods such as, for example, crystallization, Chromatography or salt formation separated into the enantiomers or E / Z isomers become.

The salts are prepared in a conventional manner by adding a solution to the Compound of formula I with the equivalent amount or an excess of an alkali or Alkaline earth compound, which may be in solution, added and the Nieder cut off or work up the solution in the usual way.

As far as the preparation of the starting compounds is not described, these are known or analogous to known compounds or processes described here producible.  

Preparation of the starting compounds

• 1. A) 2.05 g of mono-tert-butoxycarbonylethylenediamine are mixed with 1.25 g (0.86 ml) of 4-fluoro-3-nitro- 1-trifluoromethylbenzene heated to 50 ° C bath temperature for 30 min. The mass solidified yourself. Then is chro on silica gel with methylene chloride: ethanol = 10: 1 matographed. 2.2 g of [1-N-carbo-t-butoxy 2N- (2-nitro-4-trifluoromethylphen yl)] ethylenediamine.
• B) N- (2-nitro-4-trifluoromethyl) ethylenediamine, 2.2 g of 1-N-carbo-t-butoxy-2-N- (2-nitro-4- trifluoromethylphenyl) ethylenediamine in 60 ml of ethanol with 60 ml of 1N hydrochloric acid for 2 h heated to 110 ° C. After concentration, 1.77 g of N- (2-nitro-4- trifluoromethylphenyl) ethylenediamine as hydrochloride.
• C) [N-1- (Benzoyl) -N-2- (2-nitro-4-trifluoromethylphenyl)] ethylenediamine. 570 mg N- (2-nitro- 4-trifluoromethylphenyl) ethylenediamine hydrochloride are dissolved in 15 ml of methylene chloride first mixed with 424 mg triethylamine and then with 295 mg benzoyl chloride. After 2 hours Stirring at room temperature is extracted twice with water. The organic phase is dried, filtered and concentrated. 690 mg of [N-1- (benzoyl) -N-2- (2-nitro- 4-trifluoromethylphenyl)] ethylenediamine.

The following is produced analogously:
[N-1- (methanesulfonyl) N-2 - (- 2-nitro-4-trifluoromethylphenyl)] ethylenediamine.

• 2. A) 1- (2-nitro-4-trifluoromethylphenylamino) -2-methoxyethane 3.75 g of 2-methoxyethylamine and 10.5 g of 4-fluoro-3-nitro-1-trifluoromethylbenzene are in 200 ml of water with 10 g of sodium carbonate heated to 100 ° C bath temperature for 2 h. At the The product, which can be isolated by suction, cools down. (9.8 g). The aqueous mother liquor is acidified with 4N hydrochloric acid and three times with 100 ml each Extracted ethyl acetate. The collected organic extracts are dried, filtered and constricted. Another 2.7 g are obtained. Total yield 12.5 g 1- (2-nitro-4- trifluoromethylphenyl) amino-2-methoxyethane.
• 3. A) 1.1 g of 2,4-difluoronitrobenzene are mixed with 2.8 g of diethyl aminomethanephosphonate for 2 h heated to 40 ° C. Then is on silica gel with methylene chloride: ethanol = 10: 1  chromatographed. 1.6 g of N- (2-nitro-5- fluorophenyl) aminomethanephosphonic acid diethyl ester.

The following is produced analogously:
N (2-nitro-4-fluorophenyl) aminomethanephosphonic acid diethyl ester
1- [N- (2-Nitro-4-fluorophenyl) amino] ethanephosphonic acid diethyl ester
1- [N- (2-Nitro-5-fluorophenyl) amino] ethanephosphonic acid diethyl ester
1- (2-nitro-4-trifluoromethylphenylamino) -4-methoxypropanephosphonic acid diethyl ester.

• B) 331 mg of diethyl N-benzophenoniminylmethanephosphonate are mixed with 40 mg of aliquat 336 and with 209 mg of 2-methoxy-1-bromethane and at 0 ° C with 280 mg powdered potassium hydroxide added; then 3.5 h at room temperature touched. The batch is mixed with methylene chloride and 180 mg of silica gel, briefly stirred and vacuumed. The concentrated filtrate is over silica gel with cyclohexane: ethyl acetate = 1: 1 chromatographed. 180 mg of 2- (N-benzophenoniminyl) -4-methoxy are obtained diethyl propanephosphonate.
• C) 2.0 g of diethyl 2- (N-benzophenoniminyl) -4-methoxypropanephosphonate are in 30 ml of 1N HCl and 30 ml of diethyl ether were stirred at room temperature for 3 h. It will be the organic phase separated and the water phase extracted again with diethyl ether. The organic phase contains benzophenone and is discarded. The aqueous phase is evaporated to dryness, taken up in 15 ml saturated sodium chloride solution, with Na₂CO₃ neutralized and extracted three times with 50 ml of methylene chloride. The organic phase will dried, filtered and concentrated to give 800 mg of 2-amino-4-methoxy diethyl propanephosphonate.
• 4. A) 790 mg of N- (2-nitro-5-fluorophenyl) aminomethanephosphonic acid diethyl ester in 50 ml Ethanol mixed with 2.5 g of Raney nickel and under normal hydrogen pressure  Room temperature hydrogenated for 2 h. After the catalyst has been suctioned off, the mixture is concentrated. You get 660 mg of diethyl N- (2-amino-5-fluorophenyl) aminomethanephosphonate.

The following are produced analogously:
N- (2-Amino-4-fluorophenyl) aminomethanephosphonic acid diethyl ester
N- (2-Amino-4-trifluoromethylphenyl) aminomethanephosphonic acid diethyl ester
1- [N- (2-Amino-4-fluorophenyl) amino] ethanephosphonic acid diethyl ester
1- [N- (2-Amino-5-fluorophenyl) amino] ethanephosphonic acid diethyl ester
1- (2-amino-4-trifluoromethylphenyl) amino-2-methoxyethane
N-1- (methanesulfonyl) -N-2 - (- 2-amino-4-trifluoromethylphenyl) ethylenediamine
N-1- (Benzoylamino) -N-2- (2-amino-4-trifluoromethylphenyl) ethylenediamine.

• 5. A) 660 mg of N (-2Amino-5-fluorophenyl) aminomethanephosphonic acid diethyl ester are in 70 ml of absolute tetrahydrofuran with 509 mg of triethylamine. About this solution slowly becomes a solution of 685 mg of oxalic acid ethyl chloride in 30 ml of tetrahydrofuran dripped. The mixture is stirred for 4 h at room temperature. After vacuuming the precipitated salts, the filtrate is concentrated in a mixture of 23 ml of ethanol and 23 ml of 1N hydrochloric acid boiled for 2 h at a bath temperature of 110 ° C. It gets dry concentrated and the residue on silica gel with methylene chloride: ethanol = 10: 1 chromatographed. 561 mg (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline-1- yl) diethyl methanephosphonate.

The following are produced analogously:
(6-Fluoro-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl) diethyl methanephosphonate
1 - [(7-Fluoro-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl)] - ethanophosphonic acid diethyl ester
1 - [(6-Fluoro-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin1-yl)] - ethanophosphonic acid diethyl ester.

example 1

Analogously to the preparation of the starting compound 5. A), the following are obtained:
6-trifluoromethyl-1- (1-methoxyeth-2-yl-1,2,3,4-tetrahydro-2,3-dioxo-c-hinoxaline.
6-trifluoromethyl-1- (1-N-benzoylaminoeth-2-yl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline
6-trifluoromethyl-1- (1-N-methanesulfonylaminoeth-2-yl) -1,2,3,4-tetrahy-dro-2,3-dioxo quinoxaline
1- (6-trifluoromethyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl) -3-m-ethoxy propanephosphonic acid diethyl ester.

Example 2

1 g of 6-trifluoromethyl-1- (1-methoxyeth-2-yl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline are in 20 ml of absolute acetonitrile with 3.15 ml of trimethylbromosilane and 1.4 g Sodium iodide added and heated to 80 ° C bath temperature for 1 h. After adding 25 ml Water is extracted with ethyl acetate. The organic phase is separated off and concentrated and chromatographed over silica gel with toluene: glacial acetic acid: water = 10: 10: 1. To Concentration of the appropriate fractions and stirring with ethanol gives 330 mg of 6- Trifluoromethyl-1- (1-hydroxyeth-2-yl) -1,2,3,4-tetrahydro-2,3-dioxoquinoxalinedione.

Example 3

615 mg (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl) methanephosphonic acid diethyl ester in 60 ml methylene chloride with 743 mg nitronium tetrafluoroborate ver puts. The mixture is stirred at room temperature for 2 h. 50 ml of water are added and extracted three times with methylene chloride after separation of the organic phase. The Collected organic phase is dried, filtered and concentrated. The backlog will Chromatographed on silica gel with methylene chloride: ethanol = 10: 1. 350 mg are obtained (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) -methane-phosphonic acid di ethyl ester.

The following is produced analogously:
(6-fluoro-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) diethyl methanephosphonate.
1 - [(6-Fluoro-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)] diethyl ethanephosphonate.
1 - [(7-Fluoro-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)] diethyl ethanephosphonate.

Example 4

140 mg (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) methane phosphon acid diethyl esters are heated to a bath temperature of 120 ° C. with 129 mg of morpholine for 1.5 h. After concentration in vacuo, the residue is poured over silica gel using toluene: glacial acetic acid: water = 10: 10: 1 chromatographed. After concentration of the corresponding fractions, you get 300 mg (7-morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) methanephos diethylphosphate.  

The following is produced analogously:
[6- (N-imidazolyl) -7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl] methanephosphonic acid diethyl ester.
1- [6- (N-Imidazolyl) -7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 - yl] ethanephosphonic acid diethyl ester.
1- [7- (N-Imidazolyl) -6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 - yl] ethanephosphonic acid diethyl ester.
(6-Morpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) diethyl methanephos.
1 - [(6-Morpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl -)] ethanophosphonic acid diethyl ester.

1 - [(7-Morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl -)] ethanphos diethylphosphate.

Example 5

375 mg (7-fluoro-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) methane phosphon acid diethyl ester are added to a solution consisting of 200 mg trifluoroethanol 60 mg Sodium hydride (80%) was made in 20 ml of absolute tetrahydrofuran. After Addition is heated to 70 ° C bath temperature for 4.5 h. It is concentrated in 50 ml of water added, acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The organic phase is dried, filtered and concentrated. The backlog is over Chromatograph silica gel with toluene: glacial acetic acid: water = 10: 10: 1. After narrowing the corresponding fractions and stirring with ethanol are obtained in the form of the back stood 19 mg (6-nitro-7-trifluoroethoxy-1,2,3,4-tetrahydro-2,3-dioxo-hinoxalin-1-y-l) -me thanphosphonic acid ethyl ester.

Example 6

259 mg (6-nitro-7-morpholino-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl) - methanphos diethyl phonate are dissolved in 10 ml of absolute acetonitrile with 628 mg of trimethyl bromine added silane and stirred for 1 h at room temperature. Little water is added and evaporated to dryness. The residue is over silanized silica gel with methanol as Chromatographed eluent. 60 mg (6-nitro-7-morpholino-1,2,3,4-tetra are obtained hydro-2,3-dioxo-quinoxalin-1-yl) methanephosphonic acid.

The following is produced analogously:
1- (6-trifluoromethyl-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) -3-m-ethoxypropanephosphonic acid.
(6-Morpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) methanephosphonic acid.
1 - [(6-Morpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl -)] ethanephosphonic acid.
1 - [(7-Morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl -)] ethanephosphonic acid.

Example 7

250 mg [(6- (N-imidazolyl) -7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 - yl] methane Diethyl phosphonic acid are in 3 ml of concentrated hydrochloric acid for 2.5 h on 110 ° C bath temperature warmed. After concentration, it is taken up in water and the precipitated Aspirated product. 100 mg of [6- (N-imidazolyl) -7-nitro-1,2,3,4-tetrahydro-2,3- dioxoquinoxalin-1-yl] methanephosphonic acid.

The following is produced analogously:
(6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-yl) methane-phosphonic acid.
(7-nitro-6-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) methane-phosphonic acid.
1- [6- (N-Imidazolyl) -7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 - yl] ethanephosphonic acid.
1- [7- (N-Imidazolyl) -6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 - yl] ethanephosphonic acid.
1 - [(6-Fluoro-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)] eth-anphosphonic acid.
1 - [(7-Fluoro-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)] eth-anphosphonic acid.

Example 8 N- (6 trifluoromethyl-7-morpholinoquinoxaline-2,3-dione-1-yl) methanephosphonic acid

A 3.3 g (30 mmol) aminomethanephosphonic acid are dissolved in 120 ml water and 120 ml Ethanol together with 3.37 g (31.8 mmol) of soda and 7.8 g (97%, 30 mmol) 3-trifluoromethyl-4,6-dichlomitrobenzene added and 4 h at 120 ° C bath temperature at Reflux stirred. After the ethanol has been stripped off on a rotary evaporator, three times with Extracted 100 ml of ethyl acetate. The organic phase is washed with a little water. she contains starting material and is discarded. The collected aqueous phase is with 4N hydrochloric acid acidified to pH 1 and extracted three times with 100 ml of ethyl acetate. The  organic phase is washed with water, dried, filtered and concentrated. Man receives 6.85 g (68% of theory) of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid melting point 207.3 ° C.

B, C 6.85 g (20.5 mmol) of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphon acid are stirred in 20 ml of morpholine for 3.5 h at a bath temperature of 120 ° C. It will be on Rotary evaporator evaporated to dryness and the residue with 100 ml Triethyl orthoformate and 779 mg (4.1 mmol) of p-toluenesulfonic acid for 3.8 h 150 ° C bath temperature warmed. After being evaporated to dryness on a rotary evaporator taken up in 100 ml of water, mixed with common salt and three times with 100 ml of ethyl acetate extracted. The collected ethyl acetate phase is diluted with saline washed, dried, filtered and concentrated. Yield 10.6 g (<100% of theory, still contains Morpholine hydrochloride) on N- (2-nitro-4-trifluoromethyl-5-morpholino-phenyl) amino methanephosphonic acid ethyl ester.

D 10.6 g (∼20 mmol) of N- (2-nitro-4-trifluoromethyl-5-morpholino-phenyl) aminomethane ethyl phosphate are dissolved in 250 ml of ethanol with 4.5 g of palladium on carbon (10%) hydrogenated under normal hydrogen pressure at room temperature for 3.5 h. After vacuuming the Catalyst over diatomaceous earth and concentration of the filtrate gives 9.2 g (<100% of theory, still contains morpholine hydrochloride) on N- (2-amino-4-trifluoromethyl-5-morpholino phenyl) aminomethanephosphonic acid ethyl ester.

E 1.26 g (2.7 mmol) of N- (2-amino-4-trifluoromethyl-5-morpholino-phenyl) aminomethane Phosphonic acid ethyl ester in 60 ml of absolute tetrahydrofuran together with 0.79 ml (5.7 mmol) triethylamine submitted. The mixture is added dropwise with a solution of 0.63 ml (5.7 mmol) of oxalic acid ethyl chloride in 20 ml of tetrahydrofuran. The mixture is then stirred at room temperature for 3 h. The approach is sucked off and that Concentrated filtrate. The residue of the concentrated filtrate is in 20 ml of ethanol and 20 ml 1 N hydrochloric acid was added and the mixture was stirred at a bath temperature of 110 ° C. for 2 h. After subtracting the Ethanol under vacuum is diluted to 30 ml with water and three times with 30 ml each Ethyl acetate shaken out. The collected ethyl acetate phase is washed once with 30 ml of water washed, dried, filtered and concentrated. 1.13 g (89.7% of theory) are obtained [(6- Trifluoromethyl-7-morpholinoquinoxaline-2,3-dione) -1yl] methanephosphonic acid ethyl ester of Melting point 192.6 ° C.  

F 1.13 g (2.4 mmol) [(6-trifluoromethyl-7-morpholinoquinoxaline-2,3-dion-1-yl)] methanephos Phonic acid ethyl ester in 40 ml of acetonitrile with 2.56 g (16.7 mmol) of trimethylbromosilane added and stirred for 2.5 h at room temperature. After standing overnight Room temperature is mixed with water and stirred for 30 min at room temperature. After concentration in vacuo, the residue is poured over silica gel with methanol: butanol: Water: concentrated ammonia = 75: 25: 17: 3 chromatographed. You get after Concentrate the appropriate fractions in water, stir with Ion exchanger IR 120 (strongly acidic form, Amberlite, 20-50 mesh) and again Concentrate and freeze-dry 450 mg (45.8% of theory) [(6-trifluoromethyl-7- morpholinoquinoxaline-2,3-dione) -1yl] methanephosphonic acid with a melting point of <300 ° C., 1 H NMR in DMSO: 7.9 s, 1H; 7.4 s, 1H; 4.35 d, 11 Hz, 2H: 3.7 t 5 Hz, 2H; 2.9 t, 5Hz, 2H.

Claims (3)

1. Compounds of formula I. wherein
R¹ - (CH₂) _n -CR²H- (CH₂) _m -Z and
R⁵, R⁶, R⁷ and R⁸ are the same or different and are hydrogen C _1-6 alkyl, CF₃, nitro, halogen, NR⁹R¹⁰, cyano, SOpR¹¹, SO₂NR¹²R¹³, SO₃H, SO₃C _1-6 alkyl or OR¹⁴, where
R² is hydrogen or - (CH₂) _q -R³,
R³ is hydrogen, hydroxy, C _1-6 alkoxy or NR¹⁵R¹⁶,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, OR¹⁷, NR¹⁸R¹⁹, NH-COR²⁰, NH-SO₂R²¹, SO₂R²², CO₂R²³ or tetrazole,
R11 H, C _1-6 alkyl, phenyl,
p 0, 1 or 2
R¹², R¹³, R¹⁷ and R²³ are hydrogen or C _1-4 alkyl, R¹⁴ H or optionally 1-3 times substituted by halogen C _1-6 alkyl,
R²⁰ and R²¹ are C _1-6 alkyl, phenyl or hetaryl,
R²² hydroxy, C _1-6 alkoxy or NR²⁴R²⁵,
X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR⁹R¹⁰,
R⁹ and R¹⁰ are the same or different and are hydrogen, phenyl or C _1-6 alkyl, which may optionally be substituted by C _1-4 alkoxy or an amino group optionally mono- or di-substituted by C _1-4 alkyl, or together form a 5- or 6-membered saturated heterocycle with the nitrogen atom, which may contain and be substituted by another N, S or O atom or form an unsaturated 5-membered heterocycle which may contain 1-3 N atoms,
R¹⁵ and R¹⁶, R¹⁸ and R¹⁹ are the same or different and form hydrogen, C _1-4 alkyl, phenyl or together with the nitrogen atom a 5- or 6-membered saturated heterocycle which contains another oxygen, sulfur or nitrogen atom and can be substituted can form or an unsaturated 5-membered heterocycle which can contain 1-3 N atoms,
R²⁴ and R²⁵ are the same or different and form hydrogen, C _1-4 -alkyl or together with the nitrogen atom a saturated 5- or 6-membered heterocycle which may contain a further oxygen, sulfur or nitrogen atom, and their isomers or salts,
where if R² is hydrogen and Z is POXY or CO₂R²³,
R⁵-R⁸ are not hydrogen and if R² is hydrogen, Z POXY or CO₂R²³ and
R⁵, R⁶, R⁷ or R⁸ are CF₃, NO₂, halogen, NH₂ or methyl, disubstituted compounds of the formula I are present and
if R¹ is methylphosphonic acid, R⁷ imidazole and R⁶ CF₃ or NO₂, R⁵ and R⁸ cannot simultaneously be hydrogen and
if R¹ -CH₂-COOH and R⁵ and R⁸ are hydrogen, R⁶ and R⁷ cannot simultaneously be halogen or methyl. 2. Medicament based on the compounds of formula I according to claim 1. 3. A process for the preparation of the compounds of formula I, characterized in that

• a) a compound of formula II wherein R¹ to R⁸ have the above meaning, cyclized with oxalic acid or reactive oxalic acid or
• b) a compound of formula III wherein R¹ has the meaning given above and one of the substituents R⁵ ′, R⁶ ′, R⁷ ′ or R⁸ ′ represents a leaving group, is substituted nucleophilically and, if desired, subsequently saponifies the ester group or esterifies or amidates the acid group or the nitro group is reduced to the amino group or the alkyl group or acylated or the amino group replaced by halogen or cyano or introducing a nitro group or performing an ether cleavage or separating the isomers or forming the salts.