AU720083B2

AU720083B2 - New quinoxalindione derivatives, their production and use in pharmaceutical agents

Info

Publication number: AU720083B2
Application number: AU18674/97A
Authority: AU
Inventors: Andreas Huth; Martin Kruger; Roland Neuhaus; Eckhard Ottow; Herbert Schneider; Dieter Seidelmann; Lechoslaw Turski
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1995-11-24
Filing date: 1996-11-15
Publication date: 2000-05-25
Anticipated expiration: 2016-11-15
Also published as: NZ330492A; CA2238023A1; CZ160498A3; ZA969832B; NO982349L; MX9804068A; CN1202891A; EP0876357A1; IL124534A0; HUP9902041A2; DE19545251A1; HUP9902041A3; EE9800163A; AU1867497A; JP2000500471A; WO1997019066A1; KR19990071596A; NO982349D0; SK68298A3; PL326844A1

Description

WO 97/19066 PCT/DE96/02227 New Quinoxalinedione Derivatives, their Production and Use in Pharmaceutical Agents The invention relates to quinoxalinedione derivatives, their production and use in pharmaceutical agents.

It is known from numerous publications that quinoxaline derivatives have an affinity for the quisqualate receptors and, because of the affinity, are suitable as pharmaceutical agents for the treatment of diseases of the central nervous system.

Thus, for example, 6-methyl-l-alkyl-substituted quinoxaline-2,3dione derivatives are described in W09308173, and 6-methyl- and 7-ethyl-l-hydroxy-quinoxaline-2,3-diones are described in EPA- 0377112. These compounds have the drawback that they do not have the good solubility that is necessary for pharmaceutical agents and at the same time do not have good affinity for the quisqualate receptor.

The object was therefore to synthesize new compounds that are very readily soluble, have a specifically antagonistic effect on the AMPA receptor and thus are suitable as pharmaceutical agents for the treatment of diseases, which are mediated by the hyperactivity of excitatory amino acids.

The compounds according to the invention have formula I

R

N 0

R

SN 0 R7 I H in which R means -(CH 2

-CRH-(CH

2 -Z and

R

5 means C,6 alkyl substituted with halogen, -OR, -NR 9

R'

0 SO-R", SOO-R"', S COR 2 optionally substituted aryl or optionally substituted hetaryl; C 2 alkenyl, which can be substituted with halogen, -OR, -NR 9 R'o, SO-R", COR 2 optionally substituted aryl or optionally substituted hetaryl; or -CH R, S R and R T are the same or different and mean hydrogen, Pb halogen, NO 2 -cyano, NR 16

R'

7 -COR OR' optionally substituted aryl, optionally substituted hetaryl, C-6 alkyl, which can be substituted with halogen, -OR, NR 9 R'O, SO-R", COR' 2 optionally substituted aryl or optionally substituted hetaryl, C 2 6 alkenyl, which can be substituted with halogen, -OR 8

-NR

9 R'o, SOO-R" 11

COR'

2 optionally substituted aryl or optionally substituted hetaryl, SO 6R 1 or -CH= Rs 5

R

2 means hydrogen or q-R0 R means hydrogen, hydroxy, C 1 -6 alkoxy or NR 19

R

20 n, m and q each mean 0, 1, 2 or 3, Z means POXY, OPOXY, SO0R 21 C0 2

R

22 cyano or tetrazole, Re and R 18 mean hydrogen, C,.

6 alkyl optionally substituted" with halogen, o and p in each case mean 0, 1 or 2, R" and R" mean hydrogen, C 1 alkyl or aryl,

R

1 means substituted aryl,

R

1 2

R

1 4

R

21 and R 22 mean OH, C.

6 alkoxy or NR2R 24

R

1 5 means oxygen, =NOH or

C,

1 Alkyl 0 X and Y are the same or different and mean hydroxy, C 16 I alkoxy, C 1 4 alkyl or NR 25

R

26

R

9 and R 10

R

1 6 and R 17

R

19 and R 20

R

23 and R 24

R

25 and R 26 are the same or different and mean hydrogen, C..

4 alkyl, aryl or together with the nitrogen atom form a 5-7-membered saturated heterocycle that can contain another oxygen, sulfur or nitrogen atom and can be substituted or form an unsaturated Sheterocycle that can contain 1-3 N atoms and can be substituted, as well as their isomers or salts, whereby R 5 does not mean CF 3 or CH 3 and when R means C,6 alkyl substituted with halogen, -NR 9 'Ro or SOoR" one of R and R 7 does not mean Ci-C 6 alkyl substituted with halogen, -NR 9

R'

1 or SOoR".

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

Substituents R 5

R

6 and R 7 can be in any position, preferably in 6- and/or 7-position.

Alkyl is defined respectively as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl, whereby C,.

4 alkyl radicals are preferred.

If the alkyl radical is halogenated, the latter can be present in perhalogenated form in one or more places.

Alkenyl means, for example, vinyl, l-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1-butenyl, methallyl.

Halogen is defined respectively as fluorine, chlorine, bromine and iodine.

The aryl radical has respectively 6-12 carbon atoms, such as, for example, naphthyl, biphenyl and especially phenyl.

Hetaryls are defined as optionally substituted heteroaromatic compounds with 1-2 N, O or S atoms, such as, e.g., thiophene, furan, oxazole, thiazole or optionally substituted 6ring-heteroaromatic compounds with 1-3 N-atoms, such as pyridine, pyrimidine, triazine, quinoline and isoquinoline.

As substituents of the aryl and hetaryl radicals, which occur in one to three places, in each case halogen, C 14 alkoxy, nitro, trifluoromethyl or C 14 alkyl are suitable.

If R 9 and R 10

R

16 and R 17

R

19 and R 20

R

23 and R 24 or R 25 and R 26 together with the nitrogen atom form a saturated heterocycle, then, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine is meant. The heterocycle can be substituted in one to three places with C1.

4 alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen. For example, N-methyl-piperazine, 2,6dimethylmorpholine, phenylpiperazine or 4-(4-fluorobenzoyl)piperidine can be mentioned.

If R 9 and R 10

R

16 and R 1 7

R

19 and R 20

R

2 and R 24 or R 25 and R 26 together with the nitrogen atom form an unsaturated heterocycle, then, for example, imidazole, pyrazole, pyrrole and triazole can be mentioned, which can be substituted in one to two places with cyano, C 1 4 alkyl, phenyl or CO 2

C,.

6 alkyl.

Compounds in which R 5 means alkyl, which can be substituted with -OR 8

-NR

9

SOO-R

11

COR

12 optionally substituted aryl or optionally substituted hetaryl, can be viewed as preferred.

If an acid function is contained, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as the salts with N-methylglucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1amino-2,3,4-butanetriol.

If a basic function is contained, the physiologically compatible salts of organic and inorganic acids are suitable, such as HC1, H 2

SO

4 phosphoric acid, citric acid, tartaric acid, etc.

The compounds of formula I as well as their physiologically compatible salts can be used as pharmaceutical agents because of their affinity for the AMPA receptors. Because of their action profile, the compounds according to the invention are suitable for the treatment of diseases that are caused by hyperactivity of excitatory amino acids, such as, for example, glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and show a high specific affinity for the AMPA receptors, in which they displace the radiolabeled specific agonist (RS)a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) from the AMPA receptors, they are especially suitable for the treatment of those diseases that are affected by the receptors of excitatory amino acids, especially the AMPA receptor.

According to the invention, the compounds can be used for the treatment of neurological and psychiatric disorders that are triggered by the overstimulation of the AMPA receptor. The neurological diseases that can be treated functionally and preventatively include, for example, neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis and olivopontocerebellar degeneration. According to the invention, the compounds can be used for the prevention of postischemic cell destruction, cell destruction after cerebral trauma, in a stroke, hypoxia, anoxia and hypoglycemia and for treatment of senile dementia, AIDS dementia, neurological symptoms that are linked with HIV infections, multiinfarct dementia as well as epilepsy and muscle spasms. The psychiatric diseases include anxiety conditions, schizophrenia, migraine, conditions of pain, as well as the treatment of sleep disorders and the withdrawal symptoms after drug abuse, such as in alcohol, cocaine, benzodiazepine or opiate withdrawal. In addition, the compounds can be used in the prevention of tolerance development during long-term treatment with sedative pharmaceutical agents, such as, for example, benzodiazepines, barbiturates and morphine. Moreover, the compounds can be used as anesthetic agents (anesthesia), antianalgesics or anti-emetics.

The pharmacological action of the compounds of formula I was determined using the test described below: Male NMRI mice at a weight of 18-22 g were kept under controlled conditions (0600-1800 hours of a light/dark cycle, with free access to food and water), and their assignment to groups was randomized. The groups consisted of 5-16 animals.

The observation of the animals was performed between 0800 and 1300 hours.

AMPA was sprayed into the left ventricles of mice that were allowed to move freely. The applicator consisted of a cannula with a device made of stainless steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed up to 180 seconds until clonic or tonic seizures set in. The clonic movements, which last longer than 5 seconds, were counted as seizures. The beginning of the clonic seizures was used as an end point for determining the seizure threshold. The dose that was necessary to raise or reduce the seizure threshold by

(THRDS

0 was determined in 4-5 experiments. The THRD 5 0 limit and the confidence limit were determined in a regression analysis.

The results of these tests show that the compounds of formula I and their acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the production of pharmaceutical agents for symptomatic and preventive treatment of diseases that are triggered by a change in the function of the AMPA-receptor complex.

Treatment with the compounds according to the invention prevents or delays the cell damage that occurs as a result of disease and functional disorders and reduces the concomitant symptoms.

The indications can be shown by conventional pharmacological tests.

For use of the compounds according to the invention as pharmaceutical agents, the latter are put in the form of a pharmaceutical preparation, that, besides the active ingredient for enteral or parenteral administration, contains suitable pharmaceutical, organic or inorganic inert vehicles, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, etc. The pharmaceutical preparations can be in solid form, for example, as tablets, coated tablets, suppositories, capsules or in liquid form, for example, as solutions, suspensions or emulsions.

Moreover, they optionally contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

Especially suitable for parenteral use are injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxy-ethoxylated castor oil.

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

Especially suitable for oral use are tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch. The use can even be carried out in liquid form, such as, for example, as juice, to which a sweetener is optionally added.

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

The production of the compounds according to the invention is carried out according to methods that areknown in the art.

For example, compounds of formula I are attained in that a) a compound of formula II

NH-R

1 in which R 5

R

6 and R 7 have the above-mentioned meaning, is cyclized with oxalic acid or reactive oxalic acid derivatives and optionally then the ester group is saponified or the acid group is esterified or amidated or a tetrazole group is introduced or alcohols are oxidized to aldehydes or thioethers to sulfoxides or sulfones or sulfoxides to sulfones, or aldehydes are converted into oximes or nitrons or the isomers are separated or the salts are formed.

Compounds of formula II are obtained by, for example, in a compound of formula III

R

5

NHR'

R

7

NO

2 in which R' has the above-mentioned meaning, and R 5

R

6 and R 7 mean a leaving group or R 5

R

6 or R 7 a leaving group being replaced by SR 1 3 or by optionally substituted C 2 6 alkenyl and optionally then the double bond of the alkenyl group being hydrogenated or cleaved by oxidation, the aldehyde being reacted to an alkenyl compound or the aldehyde being reduced to alcohol; the OH group being converted into a leaving group and substituted in a nucleophilic manner and then the nitro group being reduced.

The cyclization to compounds of formula I is carried out single-stage with oxalic acid in a known way in an acid environment or single-stage with a reactive oxalic acid derivative or else two-stage. Regarded as preferable is the twostage process in which the diamine is reacted with an oxalic acid derivative such as oxalic ester semi-chloride or reactive oxalic acid derivatives, such as, imidazolides in polar solvents, such as cyclic or acyclic ethers or halogenated hydrocarbons, for example, tetrahydrofuran, diethyl ether or methylene chloride or else in water according to Schotten Baumann in the presence of a base such as organic amines, for example triethylamine, pyridine, HUnig base or dimethylaminopyridine or else soda or sodium hydroxide solution. The subsequent cyclization can be performed in a basic or else acidic manner, but preferably in an acid environment, whereby solubilizer such as alcohol or acetonitrile can be added to the reaction mixture.

Alkali hydrides such as NaH, which are used in inert solvents, such as hydrocarbons or ethers, represent suitable bases for the two-stage process.

As leaving groups of the compounds of formula III, halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, Otosylate, O-triflate or 0-nonaflate are suitable.

The nucleophilic substitution for introducing the -S-R 13 group is performed with the corresponding thiol in the presence of bases such as, alkali or alkaline-earth hydroxides or -carbonates in polar protic or aprotic solvents, such as, e.g., water, alcohols or dimethylformamide.

The substitution by alkenyl compounds is carried out under catalysis of transition metal complexes such as Pd(0), e.g., palladium tetrakistriphenylphosphine or Pd such as, e.g., palladium-bistri-o-tolylphosphine-dichloride or nickel(0) according to methods that are known in the literature optionally in the presence of a base and is fostered by an activating electron-attracting group, such as, nitro, cyano, trifluoromethyl, preferably in o-position.

As nucleophiles, for example, the corresponding boronic acids or -boranes or tin-organic compounds, zinc-organic compounds, Grignard compounds or else alkenyls as such are suitable. The reaction can be performed in polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether. As bases, inorganic bases, such as alkali or alkaline-earth hydroxides or -carbonates, or organic bases, such as cyclic, acyclic and aromatic amines, such as pyridine, triethylamine, DBU, Hinig base, optionally with the addition of water are suitable.

The oxidative cleavage of the alkenyl compounds into aldehyde can be carried out according to methods that are known in the literature. Preferred is the ozonization into solvents, such as, halogenated hydrocarbons or alcohols or else mixtures thereof at temperatures of -78 0 C to room temperature.

The ozonide that forms is reductively cleaved into aldehyde by trapping with thiourea, trialkylphosphites or preferably with triarylphosphines.

The aldehyde can be subjected to olefinization reactions, such as, a Peterson olefinization, a Wittig reaction or Wittig-Horner reaction to produce an optionally substituted alkenyl compound. To this end, the aldehyde is reacted with the previously produced anion, of a correspondingly substituted phosphonium salt or phosphonic acid ester in solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane. As bases, alkali hydrides, alkali amides, alkali alcoholates, such as, for example, potassium tert-butylate, alkali- or alkaline-earth carbonates or -hydroxides, optionally in the presence of phase transfer catalysts, such as, crown ethers, or else organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane optionally in the presence of salts such as lithium bromide are suitable.

According to processes that are known in the literature, the aldehyde.can be reduced to alcohol. Preferably, the reduction with complex metal hydrides, such as, sodium boranate, is performed in solvents such as alcohol.

According to methods that are known in the literature, the hydroxy group can be converted according to various processes into leaving groups, such as chloride, bromide, iodide, triflate, mesylate or tosylate. Preferably, it is converted with tosyl chloride in the presence of bases, such as, triethylamine, ethyldiisopropylamine or dimethylaminopyridine into solvents such as halogenated hydrocarbons or ethers into chloride.

The nucleophilic substitution is carried out by nucleophiles such as amines or thiols in solvents such as alcohols, halogenated hydrocarbons or ketones or without solvent optionally with the addition of a base such as alkali or alkaline-earth hydroxide or -carbonate or else organic bases, such as, e.g., triethylamine, ethyldiisopropylamine or dimethylaminopyridine.

The reduction of the nitro group is carried out in the usual way catalytically or by reduction with iron powder in acetic acid at a higher temperature or else with sodium sulfide and ammonium hydroxide in alcohol. The reduction of the alkenyl group is carried out in the usual way catalytically and then usually proceeds together with the reduction of the nitro group.

The oxidation of thioethers to sulfoxides or sulfones is carried out according to methods that are known in the literature. For example, sulfoxides can be obtained selectively by oxidation with sodium periodate in a mixture of methanol and water. Sulfones can be produced either from the corresponding sulfoxides or from the thioethers by oxidation with sodium periodate in a mixture of carbon tetrachloride, acetonitrile and water under catalysis by ruthenium(III).

The optionally subsequent saponification of an ester group can be carried out in a basic or preferably acidic manner, by hydrolyzing the reaction mixture at a higher temperature up to the boiling temperature in the presence of acids, such as highly concentrated aqueous hydrochloric acid optionally in solvents, such as, for example, trifluoroacetic acid or alcohols.

Phosphonic acid esters are preferably hydrolyzed by heating in highly concentrated aqueous acids, such as, for example, concentrated hydrochloric acid optionally with addition of an alcohol or by treatment with a trimethylsilyl halide in inert solvents, such as, acetonitrile and subsequent treatment with water.

The esterification of the carboxylic acid or phosphonic acid is carried out in a way that is known in the art with the corresponding alcohol under acid catalysis or in the presence of an activated acid derivative. As activated acid derivatives, for example, acid chloride, acid imidazolide or acid anhydride are suitable. In phosphonic acids, the esterification can be achieved by reaction with orthoesters optionally by addition of catalysts such as p-toluenesulfonic acid.

The amidation is carried out on the free acids or on their reactive derivatives, such as, for example, acid chlorides, mixed anhydrides, imidazolides or azides, by reaction with the corresponding amines at room temperature.

The introduction of the tetrazole is possible by reaction of the corresponding nitrile with an azide, such as, e.g., trimethylsilylazide, hydrazoic acid or sodium azide, optionally by addition of a proton source such as, ammonium chloride or triethylammonium chloride in polar solvents such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone at temperatures up to the boiling point of the solvent.

The oxidation of an alcohol can be carried out according to processes that are known in the literature. The variant according to Jones (chromium trioxide in sulfuric acid) preferably is used in solvents such as acetone.

The reaction of the aldehyde to oximes and nitrons is carried out according to methods that are known in the literature with the hydrochlorides of the corresponding hydroxylamines, optionally with the addition of a base, preferably in solvents such as alcohols or aromatic hydrocarbons or else mixtures thereof.

The mixtures of isomers can be separated into the enantiomers or E/Z isomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.

The production of the salts is carried out in the usual way, by a solution of the compound of furmula I being mixed with the equivalent amount or excess base or acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.

If the production of the starting compounds is not described, they are known or can be produced analogously to known compounds, for example, according to W093/08173, W094/25469 or according to processes that are described here.

The following examples are to explain the process according to the invention: WO 97/19066 PCT/DE96/02227 Production of Starting Materials: 3.3 g (30 mmol) of aminomethanephosphonic acid is introduced into 120 ml of water and 120 ml of acetonitrile together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene and stirred at reflux for 4 hours at a bath temperature of 120 0 C. After the acetonitrile is drawn off in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is made acidic at pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)aminomethanephosphonic acid with a melting point of 207.3C is obtained.

1.67 g of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)aminomethanephosphonic acid is mixed in 25 ml of triethyl orthoformate with 190 mg of p-toluenesulfonic acid, and it is heated for 3 hours to a bath temperature of 150 0 C. After concentration by evaporation in a vacuum, it is taken up in 25 ml of water and extracted three times with 25 ml of ethyl acetate each. The collected ethyl acetate phase is washed once with water, dried, filtered and concentrated by evaporation. 2 g 100% of theory) of N-(2-nitro-4-trifluoromethyl-5-chlorophenyl)-aminomethanephosphonic acid diethyl ester is obtained.

Analogously produced is: N-(2-Nitro-4-trifluoromethyl-5-phenylthio)-phenylaminomethanephosphonic acid diethyl ester 8.5 g of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)aminomethanephosphonic acid diethyl ester is mixed in 250 ml of toluene with 60 ml of ethanol, 50 ml of 2M soda solution, 0.9 g of palladium tetrakistriphenylphosphine and 3.7 g of styrylboronic acid and heated under argon for 7 hours to a bath temperature of 110 0 C. After concentration by evaporation, it is dispersed into ethyl acetate and water, and the ethyl acetate phase is dried, filtered and concentrated by evaporation. The residue is chromatographed twice on silica gel, first with the mobile solvent toluene:ethyl acetate 1:1 and then the correspondingly combined fractions first with cyclohexane to separate triphenylphosphine and later with ethyl acetate. 5.8 g (58% of theory) of N-(4-nitro-2-trifluoromethyl-5-styryl)-phenylaminomethanephosphonic acid diethyl ester is obtained.

1 g of N-[(2-nitro-4-trifluoromethyl-5-styryl)-phenyl]aminomethanephosphonic acid diethyl ester is dissolved in 100 ml of ethanol and hydrogenated with 2 g of Raney nickel at room temperature and normal pressure. After the catalyst is drawn off on diatomaceous earth and the filtrate is concentrated by evaporation, 885 mg of N-(2-amino-4-trifluoromethyl-5-phenethyl)phenylaminomethanephosphonic acid diethyl ester, which is used without further purification in the next stage, is obtained.

Analogously produced are: N-(2-Amino-4-trifluoromethyl-5-(4-chlorophenylethyl)phenyl)-aminomethanephosphonic acid diethyl ester.

N-(2-Amino-4-trifluoromethyl-5-(4-methoxyphenylethyl)phenyl)-aminomethanephosphonic acid diethyl ester.

N-(2-Amino-4-trifluoromethyl-5-(4-fluorophenylethyl)phenyl)-aminomethanephosphonic acid diethyl ester.

N-(2-Amino-4-trifluoromethyl-5-(pyrid-2-ylethyl)-phenyl)aminomethanephosphonic acid diethyl ester.

2.96 g of N-(2-nitro-4-trifluoromethyl-5-styryl)-phenylaminomethanephosphonic acid diethyl ester is dissolved in 140 ml of methanol and 140 ml of methylene chloride and cooled to -78 0

C.

Ozone is then directed into the solution for 15 minutes. Since, as indicated by TLC monitoring, the starting material has disappeared, 2.8 g of triphenylphosphine is added. It is allowed to reach room temperature and concentrated by evaporation. The residue is chromatographed on silica gel with acetone:hexane 1:1. 1.8 g of N-(2-nitro-4-trifluoromethyl-5-formyl)-phenylaminomethanephosphonic acid diethyl ester is obtained.

2.56 g of N-(2-nitro-4-trifluoromethyl-5-formyl)-phenyl)aminomethanephosphonic acid diethyl ester is dissolved in 130 ml of methanol and mixed slowly in portions with 260 mg of sodium boranate. After the addition has been completed, it is stirred for 2 hours at room temperature. Then, it is concentrated by evaporation and dispersed into ethyl acetate and 1N hydrochloric acid. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with acetone:hexane 1:1. 2.2 g of N-(2-nitro-4-trifluoromethyl-5-hydroxymethyl)phenylaminomethanephosphonic acid-diethyl ester is obtained.

0.76 g of N-(2-nitro-4-trifluoromethyl-5-hydroxymethyl)phenyl-aminomethanephosphonic acid-diethyl ester is hydrogenated in 75 ml of ethanol with 0.24 g of palladium/carbon under normal hydrogen pressure at room temperature. After the catalyst is drawn off on diatomaceous earth, the filtrate is concentrated by evaporation. The residue of 0.73 g of N-(2-amino-4acid diethyl ester is used without further purification in the next stage.

Analogously produced are: N-(2-Amino-4-trifluoromethyl-5-N-morpholinomethyl)-phenylaminomethanephosphonic acid-diethyl ester.

N-(2-Amino-4-trifluoromethyl-5-(2-carbethoxyeth-1-yl)phenyl-aminomethanephosphonic acid-diethyl ester (from N-(2nitro-4-trifluoromethyl-5-(2-carbethoxyethen-1-yl)-phenylaminomethane-phosphonic acid diethyl ester).

1.75 g of N-(2-nitro-4-trifluoromethyl-5-hydroxymethyl)phenyl-aminomethanephosphonic acid-diethyl ester is dissolved in ml of methylene chloride and mixed in succession with 634 mg of dimethylaminopyridine and 980 mg of tosyl chloride. It is stirred overnight at room temperature. Then, 266 mg of dimethylaminopyridine and 400 mg of tosyl chloride are added again and stirred for another 7 hours at room temperature. It is diluted with methylene chloride, and washed once each with IN hydrochloric acid and with saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation.

The residue is chromatographed on silica gel with ethyl acetate as a mobile solvent. 1.4 g of N-(2-nitro-4-trifluoromethyl-5chloromethyl)-phenyl-aminomethanephosphonic acid diethyl ester is obtained.

550 mg of N-(2-nitro-4-trifluoromethyl-5-chloromethyl)phenyl-aminomethanephosphonic acid-diethyl ester is mixed in ml of ethanol under argon first with 317 mg of potassium carbonate and then drop by drop with 0.12 ml of ethyl mercaptan.

It is stirred for 1.5 hours at room temperature. It is diluted with water, neutralized with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate as a mobile solvent. 460 mg of N-(2-nitro-4- -phenyl-aminomethanephosphonic acid diethyl ester is obtained.

356 mg of N-(2-nitro-4-trifluoromethyl-5-ethylthiomethyl)phenyl-aminomethanephosphonic acid diethyl ester is dissolved in 14 ml of methanol and added in drops to a solution of 212 mg of ammonium chloride in 14 ml of water, which was mixed with 140 mg of iron powder. After the addition has been completed, it is heated for 1 hour to 80 0 C. After suctioning-off on diatomaceous earth, the filtrate is concentrated by evaporation. The residue is used without further purification in the next stage.

Analogously produced is: N-(2-Amino-4-trifluoromethyl-5-phenylthio)-phenylaminomethanephosphonic acid diethyl ester.

0.5 ml of phosphonacetic acid triethyl ester in 1 ml of dimethoxyethane is added in drops to a suspension of 60 mg of sodium hydride (80% in oil) in 1 ml of dimethoxyethane. After 1 hour of stirring at room temperature, 384 mg of N-(2-amino-4acid diethyl ester in 8 ml of dimethoxyethane is added in drops to the batch, and after the addition has been completed, it is heated for 4 hours to a bath temperature of 80 0 C. Then, it is added to ice, dimethoxyethane is distilled off and extracted with ethyl acetate. The organic phase is dried, filtered and concentrated by evaporation, and the residue is separated on silica gel with acetone:hexane 1:1 as an eluant. 350 mg of N-(2-amino-4trifluoromethyl-5-(2-carbethoxyethen-l-yl)-phenylaminomethanephosphonic acid diethyl ester is obtained.

1.6 g of N-(2-nitro-4-trifluoromethyl-5-fluorophenyl)aminomethanephosphonic acid is dissolved in 20 ml of water and mixed with 1.6 g of sodium carbonate. It is then mixed with 660 mg of thiophenol and heated for 1.25 hours to a bath temperature of 120°C. After cooling, it is first extracted with ethyl acetate. This extract is discarded. The aqueous phase is made acidic with 4N hydrochloric acid and extracted three times with ethyl acetate. This collected ethyl acetate phase is dried, filtered and concentrated by evaporation and used without further purification in esterification 1.1 g of N-(2-nitro-4-trifluoromethyl-5-chloromethyl)phenylaminomethanephosphonic acid ethyl ester is heated in 25 ml of morpholine for 2 hours to 60 0 C. It is concentrated by evaporation, the residue is taken up in ethyl acetate and extracted with IN sodium hydroxide solution. The ethyl acetate is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with acetone:hexane 1:1 as an eluant. 600 mg of N-(2-nitro-4aminomethanephosphonic acid diethyl ester is obtained.

1.58 of N-(2-nitro-4-trifluoromethyl-5-formyl)phenyaminomethanephosphonic acid diethyl ester is introduced into 160 ml of absolute toluene under argon and mixed with 4.65 g of a mixture of 2-picolyltriphenylphosphonium chloride and sodium amide. The batch is stirred for 2 hours at room temperature.

After dilution with ethyl acetate, it is extracted twice from water. The ethyl acetate phase is concentrated by evaporation.

The residue is chromatographed on silica gel with acetone:hexane 1: as an eluant. 915 mg of N-(2-nitro-4-trifluoromethyl-5- (pyrid-2-yl-vinyl)-phenyl)-aminomethanephosphonic acid diethyl ester is obtained.

500 mg of N-(2-nitro-4-trifluoromethyl-5-formyl)phenylaminomethanephosphonic acid diethyl ester is introduced into 50 ml of absolute toluene, mixed with 1.36 g of 4methoxybenzyltriphenylphosphonium chloride, cooled to 0 0 C and mixed with 370 mg of potassium tert-butylate. Then, it is stirred for 3 hours at room temperature. It is mixed with water and extracted. The combined organic phases are washed with saturated common salt solution, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with acetone:hexane 1:1 as an eluant. 370 mg of N-(2-nitro-4trifluoromethyl-5-(4-methoxy(styryl)phenyl)aminomethanephosphonic acid diethyl ester is obtained.

Analogously produced are: N-(2-Nitro-4-trifluoromethyl-5-(4-fluoro(styryl)phenyl)aminomethanephosphonic acid diethyl ester N-(2-nitro-4-trifluoromethyl-5-(4-chloro(styryl)phenyl)aminomethanephosphonic acid diethyl ester Example 1 870 mg of N-[(2-amino-4-trifluoromethyl-5-phenethyl)phenyl]-aminomethanephosphonic acid diethyl ester is dissolved in ml of absolute tetrahydrofuran and mixed with 0.57 g of triethylamine. A solution of 0.6 g of oxalic acid ethyl ester chloride in 12 ml of absolute tetrahydrofuran is added in drops to this solution at room temperature. After the addition has been completed, stirring is continued for 4 hours at room temperature. Precipitate is then drawn off, and the filtrate is concentrated by evaporation. The residue is taken up in 50 ml of 1N hydrochloric acid and 50 ml of ethanol, and it is stirred for 3 hours at a bath temperature of 120 0 C. The precipitate is suctioned off, and the filtrate is discarded. After recrystallization from ethanol, 230 mg (60% of theory) of trifluoromethyl-7-phenylethyl-1,2,3,4-tetrahydroquinoxaline-2,3dion)-lyl]-methanephosphonic acid diethyl ester is obtained.

Analogously produced are: [(6-Trifluoromethyl-7-(4-(chlorophenylethyl)-1,2,3,4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester.

[(6-Trifluoromethyl-7-(4-fluorophenylethyl)-1,2,3,4tetrahydroquinoxaline-2,3-dion) -lyl] -methanephosphonic acid diethyl ester.

[(6-trifluoromethyl-7-(4-methoxyphenylethyl)-1,2,3,4 tetrahydroquinoxaline-2,3-dion)-lyl] -methanephosphonic acid diethyl ester.

[(6-Trifluoromethyl-7-hydroxymethyl-1,2,3,4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester.

[(6-trifluoromethyl-7-ethylthiomethyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid diethyl ester.

[(6-trifluoromethyl-7-phenylthio-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl]J-methanephosphonic acid diethyl ester.

[(6-Trifluoromethyl-7-(N-morpholinomethyl-l, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid diethyl ester.

[(6-Trifluuromethyl-7-(2-hydroxycarbonyleth-l-yl) -1,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl]J-methanephosphonic acid diethyl ester. (The carboxylic acid ester that was originally present is saponified under the reaction conditions.) [(6-Trifluoromethyl-7-(2-pyridylethyl) 3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid diethyl ester.

Example 2 150 mg of [(6-trifluoromethyl-7-phenylthio-l,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid diethyl ester is dissolved in 10 ml of methanol and mixed with a solution of 110 mg of sodium periodate in 3 ml of water and stirred for 10 hours at room temperature. It is then diluted with water and shaken out three times with ethyl acetate. The organic phase is concentrated by evaporation and chromatographed twice on silica gel first with the eluant toluene:glacial acetic acid:water 10:10:1 and for a second time with methylene chloride:ethanol 10:1. 121 mg of 6-trifluoromethyl-7sulfoxyphenyl-1,2,3,4-tetrahydroquinoxaline-2,3-dion)-lyl]methanephosphonic acid diethyl ester is obtained.

Analogously produced is: 6-Trifluoromethyl-7-(ethylsulfonoxymethyl)-1,2,3,4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester Example 3 122 mg of 6-trifluoromethyl-7-phenylthio-1,2,3,4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester is dissolved in 2 ml of acetonitrile and mixed in succession with 2 ml of carbon tetrachloride, 4 ml of water, 160 mg of sodium periodate and a spatula-tip full of ruthenium trichloride. After 8 hours of stirring at room temperature, it is diluted with 30 ml of water and shaken out three times with ml of ethyl acetate each. The collected organic phase is filtered on diatomaceous earth, concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride:ethanol 10:1, whereby it is still necessary to wash the remainder of the compound from the column with methanol. 98 mg of 6-trifluoromethyl-7-phenylsulfonyl-1,2,3,4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester is obtained.

Analogously produced is: 6-Trifluoromethyl-7- (ethylsulfoflylmethyl) -1,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid diethyl ester Example 4 220 mg of [(6-trifluoromethyl-7-phenylethyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid diethyl ester is heated in 20 ml of concentrated hydrochloric acid f or 3 hours to a bath temperature of 120 0 C. it is concentrated by evaporation, and 200 mg of [(6-trifluoromethyl-7phenylethyl-1, 2,3, 4-tetrahydroquinoxaline-2, 3-dion) -lyl] methanephosphonic acid with a melting point of 260 0 C is obtained.

Analogously produced are: [(6-Trifluoromethyl-7-hydroxycarboflylethyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid.

[(6-Trifluoromethyl-7-phensulfonyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid.

((6-Trifluoromethyl-7-phenylthio-l, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid.

(6-Trifluoromethyl-7-fornyl-l, 2,3, 4-tetrahydroquinoxaline- 2,3-dion) -lyl)-methanephosphonic acid.

[(6-Trifluoromethyl-7-(4-chlorphenyl)-ethyl-1,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl J-methanephosphonic acid.

[(6-Trifluoromethyl-7- (4-f luorophenyl) -ethyl-i, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid.

Example 200 mg of [(6-trifluoromethyl-7-hydroxymethYl-l,2,3, 4 tetrahydroquinoxaline-2, 3-dion) -lyl]3-methanephosphonic acid diethyl ester is introduced into 9 ml of acetonitrile and mixed with 0.44 ml of trimethyibromosilane. It is stirred for 8 hours at room temperature, then mixed with water and concentrated by evaporation. The residue is absorptively precipitated with-water and suctioned of f. 80 mg of [(6-trifluoromethyl-7-hydroxymethYl- 1,2,3, 4-tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid is obtained.

Analogously produced are: [(6-Trifluoromethyl-7-ethylthiomethyl-l, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid.

[(6-Trifluoromethyl-7-ethylsulfonylmethyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl 3-methanephosphonic acid.

[(6-Trifluoromethyl-7-morpholinomethyl-1, 2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl)3-methanephosphonic acid.

((6-Trifluoromethyl-7-(2-pyridylethyl) -1,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid.

[(6-Trifluoromethyl-7-(4-methoxyphenyl) -ethyl-1,2,3,4tetrahydroquinoxaline-2, 3-dion) -lyl) -methanephosphonic acid.

Example 6 650 mg of [(6-trifluoromethy1-7-hydroxymfethyl-l,2,3,4tetrahydroquinoxaline-2, 3-dio-n) -lyl) -methanephosphonic acid diethyl ester is introduced into 10 ml of acetone and stirred with 1.2 ml of Jones reagent (produced from 26.7 g of chromium trioxide, 23 ml of concentrated sulfuric acid made up to 100 ml with water) for 4 hours at room temperature. Then, it is mixed with 3 ml of isopropanol and stirred for 10 more minutes. It is then concentrated by evaporation and dispersed into ethyl acetate:water. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with toluene:glacial acetic acid:water 10:10:1. 160 mg of [(6-trifluoromethyl-7-formyl-1,2,3,4-tetrahydroquinoxaline- 2,3-dion)-lyl]-methanephosphonic acid diethyl ester is obtained in addition to the recovery of 375 mg of starting material.

Example 7 215 mg of [(6-trifluoromethyl-7-formyl-l, 2 4tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester is introduced into 10 ml of benzene and mixed in succession with 0.1 ml of triethylamine as well as 63 mg of Nisopropylhydroxylaminehydrochloride. It is stirred for 8 hours at room temperature. Solid is then drawn off. The solid is chromatographed on silica gel with toluene:glacial acetic acid:water 10:10:1. 120 mg of [6-trifluoromethyl-7-[N-oxy-(Nisopropylformylimino))-1,2,3,4-tetrahydroquinoxaline 2 ,3-dion)lyl]-methanephosphonic acid diethyl ester is obtained.

Analogously produced is: [(6-Trifluoromethyl-7-[N-oxy-(N-isopropylformylimino)- 1,2,3,4-tetrahydroquinoxaline2,3-dion) -lyl -methanephosphonic acid.

Claims

1. Compounds of formula I R R N 0 6 SN 1 R H (I) in which R1 means -(CH 2 -CR 2 H-(CH 2 -Z and RlI means alkyl substituted with halogen, -OR, NR 9 R'O, SOo-R", COR", optionally substituted aryl or optionally substituted hetaryl; C 2 6 alkenyl, which S can be substituted with halogen, -OR, -NR 9 R'O, COR' 2 optionally substituted aryl or optionally substituted hetaryl; or -CH=R 15 R 6 and RT are the same or different and mean hydrogen, 0 halogen, N0 2 -cyano, NRR 7 -COR", OR 8 optionally substituted S: aryl, optionally substituted hetaryl, C 1 6 alkyl, which can be -1- substituted with halogen, NR 9 R'O, SO-R", SO-Ru', COR' 2 optionally substituted aryl S or optionally substituted hetaryl, C 2 6 alkenyl, which can be substituted with halogen, -OR 8 -NR 9 Ro 0 COR 1 optionally substituted aryl, SO,-_R or -CH=R R 2 means hydrogen or (CH) q-R' R means hydrogen, hydroxy, C, 1 _6 alkoxy or NR'9R20 n, m and q each mean 0, 1, 2 or 3, Z means POXY, OPOXY, S0 2 R 2 1 C0 2 R1 2 cyano or tetrazole, R 8 and R 18 mean hydrogen, C-6 alkyl optionally substituted with halogen, o and p in each case mean 0, 1 or 2, R" and R 13 mean hydrogen, C- 6 alkyl or aryl, means substituted aryl, R 12 1 4 R 21 and R 22 mean OH, C.-6 alkoxy or NR23R 24 R11 means oxygen, =NOH or C 1 6 -Alkyl 0 0 ee X and Y are the same or different and mean hydroxy, C 1 6 Se alkoxy, C 1 4 alkyl or N00R 2 6 R! and RI, R 16 and R 1 7 R 1 and R2, Ra and Ri, R 2 s and R 26 are the same or different and mean hydrogen, C,_4 alkyl, aryl or S together with the nitrogen atom form a 5-7-membered saturated se. e heterocycle that can contain another oxygen, sulfur or nitrogen atom and can be substituted or form an unsaturated heterocycle that can contain 1-3 N atoms and can be substituted, **C as well as their isomers or salts, whereby RS does not mean CF 3 or CH 3 and when RS means C 1 alkyl substituted with halogen, -NR 9 R'Io or SOR"' one of R9 and R 7 does not mean C 1 -C 6 alkyl substituted with halogen, -NRRo or SOR"

2. N-([(6-Trifluoromethyl-7-phenylethyl-1,2,3,4- tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester. [(6-Trifluoromethyl-7-phenylthio-1, 2,3,4- tetrahydroquinoxaline-2,3-dion)-lyl]-methanephosphonic acid diethyl ester. ((6-Trifluoromethyl-7-(2-pyridylethyl)- 1,2,3,4- tetrahydroquinoxaline-2,3-dion) -lyl] -methanephosphonic acid diethyl ester. [(6-Trifluoromethyl-7-phenylethyl-I 2,3,4- tetrahydroquinoxaline-2,3-dion) -lyl-methanephosphonic acid. ((6-Trifluoromethyl-7-ethylthiomethyl-1,2,3,4- tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid. ((6-Trifluoromethyl-7-morpholinomethyl-1, 2,3,4- tetrahydroquinoxaline-2, 3-dion) -lyl] -methanephosphonic acid.

3. Pharmaceutical agents that contain a compound of formula I according to claim 1.

4. Process for the production of the compounds of formula I according to claim 1, characterized in that a compound of formula II 9**9 R S NH-R' 66 7 NH. R 2 in which RI, RiR and R'havre the above-mentioned meaning, is cyclized with oxalic acid or reactive oxalic acid derivatives and then optionally the ester group is saponified or the -acid group is esterified or amidated or a tetrazole group is introduced or alcohols are oxidized to aldehydes or thioethers to sulfoxides or sulfones or sulfoxides to sulfones, or aldehydes are converted into oximes or nitrons or the isomers are separated or the salts are formed.

A method for the prevention or treatment of neurological and psychiatric disorders that are triggered by the overstimulation of the AHPA receptor which comprises administering to a subject in need of such prevention or treatment one or more compounds of the formula according to claim 1 or isomers or salts thereof optionally in combination with one or more pharmaceutically acceptable vehicles.

6. A composition comprising one or more compounds of the formula in combination with one or more pharmaceutically acceptable vehicles. 20

7. Use of a compound of the formula for the preparation of a medicament for the 0** to treatment of neurological and psychiatric disorders that are triggered by the overstimulation of the AHPA receptor. S* i

8. Compounds of the formula according to claim 1, processes for their preparation or pharmaceutical compositions or methods of treatment involving/containing them, .**Esubstantially as hereinbefore described with reference to the Examples. S: SCHERING AKTIENGESELLSCHAFT By its Patent Attorneys DAVIES COLLISON CAVE DAVIES COLLISON CAVE