EP0828746A1

EP0828746A1 - Novel quinoxaline dione derivatives, their production and their use in medicaments

Info

Publication number: EP0828746A1
Application number: EP96919613A
Authority: EP
Inventors: Andreas Huth; Martin Krüger; Eckhard Ottow; Dieter Seidelmann; Roland Neuhaus; Herbert Schneider; Lechoslaw Turski
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1995-05-24
Filing date: 1996-05-23
Publication date: 1998-03-18
Also published as: WO1996037500A1; IL118365A0; AU5811196A; CA2221695A1; ZA964208B; US6136805A; DE19519979A1; AU701904B2; JPH11505809A

Abstract

The description relates to quinoxaline dione derivatives of the formula (I) and their use in medicaments.

Description

New quinoxalinedione derivatives, their production and use in pharmaceuticals

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

It is known that quinoxaline derivatives have affinity for the quisqualate receptors and, because of their affinity, are suitable as medicaments for the treatment of diseases of the central nervous system.

The compounds according to the invention have the formula I.

wherein

Rl - (CH ₂ ) _n -CR2H- (CH ₂ ) _m -Z and

R5, R6 _} R7 _unc i R8 are identical or different and are hydrogen, C _1-6 alkyl, in which one or more hydrogen atoms are optionally replaced by halogen atoms,

Nitro, halogen, NR ⁹ R ¹⁰ , cyano, SOpR ^Ü , SO ₂ NR ¹² R ¹³ , SO ₃ H, or

OR ¹⁴ mean, where

R ^{2 is} hydrogen or - (CH2) _q -R ³ ,

R ^{3 is} hydrogen, hydroxy, Cι_6-alkoxy or NR ¹⁵ R ¹⁶ , n, m and q each 0, 1, 2 or 3

Z POXY, OPOXY, SO ₂ R ¹⁷ , COR ¹⁸ , halogen, cyano or tetrazole,

R ¹¹ H, Ci.ö-alkyl, phenyl, p 0, 1 or 2

Rl2 and Rl independently of one another are hydrogen or Cι_4-alkyl,

R 4 A-Rl9 _> or a C6_ι aryl or hetaryl radical which is halogen, C ._-

Alkoxy, hydroxy, cyano, NR ² 0R21 _> optionally substituted with halogen C. (, -

Alkyl and / or COR ²² can be substituted and A straight-chain or branched, saturated or unsaturated alkylene with CI. Q-

Carbon atoms in which one or more carbon atoms is represented by O, S and / or

NR ² ^ can be replaced and which can be substituted one or more times with halogen, and

Rl9 hydrogen, NR ⁴ R 5 ₅ halogen, Ci.g-alkyl, which may be repeated several times

Halogen is substituted, C ^ .ö-alkoxy, COR ²³ , CN or a C6-i-aryl or

Hetaryl means with halogen, C ^ .ö-alkoxy, hydroxy, cyano, NR ² ^ R ² 1, C \ _ £ -

Alkyl which can be substituted by halogen and / or COR ²² can be substituted and means

R ^{18 is} hydrogen, C ^ -alkyl, hydroxy, C ^ -alkoxy or NR ²⁷ R ²⁸ ,

_R 17, _R 22 _{and R} 23 hydroxy, or NR ²⁹ R ³⁰ ,

R ^{26 is} hydrogen, Cχ.6 alkyl, C ^ öalkanoyl

X and Y are the same or different and are hydroxy, Cι_6-alkoxy, Cι_4-alkyl or

NR ²⁷ R ²⁸ mean

^R9 and RIO, R20 _unf j _R 21 _an d _or Jer R ^ ² and R ²⁴ are identical or different and

Hydrogen, CO-Cι_6-alkyl, phenyl or C _j .ö-alkyl, optionally with C \ ._ -

Alkoxy or one optionally mono- or di-substituted with Cι_4-alkyl

Amino group may be substituted, or together with the nitrogen atom form a 5-7-membered saturated heterocycle which may contain and be substituted by another N, S or O atom or form an unsaturated 5-membered heterocycle which

Contain 1-3 N atoms and can be substituted,

RL5 _unr j rioe ^ _R 27 _unf j _{R28? R} 29 _UΏ _ _R 30 are the same or different and are hydrogen,

Cj_4-alkyl, phenyl or together with the nitrogen atom form a 5-7-membered saturated heterocycle which is another oxygen, sulfur or

Contain nitrogen atom and can be substituted or an unsaturated 5-membered

Form a heterocycle which can contain 1-3 N atoms and can be substituted,

where one of the radicals R ^ - R ^{8 is} always OR * ⁴ , and R ^ ^{4 is} not H or, if appropriate, 1-3 times substituted with halogens means.

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

The substituents are preferably in the 6- and / or 7-position. Alkyl is to be understood in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl.

Halogen is to be understood as fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.

Examples of aryl radicals R and R ⁹ include naphthyl, biphenylyl and in particular phenyl.

The hetaryl radical R ¹⁴ and R ¹⁹ is 5-membered and can contain 1 - 3 heteroatoms such as N, O and / or S atoms such as thiophene, furan, pyrrole, imidazole, oxazole, thiazole, triazole, pyridine, pyrazine, pyrimidine and Pyridazine.

If A is a straight-chain or branched alkylene group, this contains in particular 1-8 carbon atoms, it being possible for 1-3 carbon atoms to be replaced by O, S and / or N ² ^, for example: methylene, ethylene, propylene, isopropylene , Butylene, isobutylene, 3-oxapropylene, 3-thiapentylene, 3-oxapentylene, 3- (N-methyl) -azapentylene, 4-oxapentylene, 4-oxa-hept-6-en-yl, 2-methyl-3-oxapentylene , 3,6-dioxaheptylene, 3-oxa-6-thiaoctylene, 3,6-dioxaoctylene.

Do R ⁹ and R * 0 _> R15 _{and R} 16 _{} R} 27 _{and R} 28 form _R 24 _{and R} 25 _{? R} 20 _{and R} 21, _R 29 _and R ³ 0 together with the nitrogen atom form a saturated heterocycle, for example piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine. The heterocycle can be substituted 1-3 times with C4 alkyl or an optionally substituted with halogen phenyl, benzyl or benzoyl. Examples include N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine or 4 (4-fluorobenzoyl) piperidine.

Suitable unsaturated alkenylene group A are alkenyl and alkynyls, for example 2-propenylene, 2-butenylene, 2-propynylene.

If R ⁹ and R ¹⁰ > R ¹⁵ and R ¹⁶ , R ²⁷ and R ²⁸ , R ²⁴ and R ²⁵ , R ²⁰ and R ² 1> R ²⁹ and R ³ 0 together with the nitrogen atom form an unsaturated heterocycle, for example imidazole Called pyrazole, pyrrole and triazole, which can be mono- to disubstituted by cyano, C _] _.4-alkyl, phenyl or CO Cι_6-alkyl. A preferred embodiment may be mentioned: R ^, R ^, 7 and R ⁸ , which may be the same or different, mean hydrogen, C ^ .ö-alkyl, in which one or more hydrogen atoms are optionally replaced by halogen atoms, nitro, cyano or OR ¹⁴ , R ³ means hydrogen and Z means POXY or COR ¹⁸ .

If an acidic function is present, the physiologically compatible salts of organic and inorganic bases are suitable as salts, for example the readily soluble alkali and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, sovak base, l-amino-2,3,4-butanetriol. If a basic function is included, the physiologically compatible salts of organic and inorganic acids such as HC1, H ₂ SÜ4, phosphoric acid, citric acid, tartaric acid and others are suitable

Phosphonic acid and carboxylic acid derivatives, which can be mono- or disubstituted, are preferred.

The compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AMPA receptors. On the basis of their activity profile, the compounds according to the invention are suitable for the treatment of diseases which 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 by the radioactively labeled specific agonist (RS) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA ) from the AMPA receptors, they are particularly suitable for the treatment of diseases which are influenced by the receptors of excitatory amino acids, in particular the AMPA receptor.

According to the invention, the compounds can be used for the treatment of neurological and psychiatric disorders which are triggered by overstimulation of the AMPA receptor. Neurological diseases that can be treated functionally and preventively include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar degeneration. According to the invention, the compounds can be used for the prevention of post-ischemic cell death, cell death after brain trauma, for stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile de- Menz, AIDS dementia, neurological symptoms related to HIV infection, multi-infarct dementia as well as epilepsy and muscle spasticity are used. Psychiatric disorders include anxiety, schizophrenia, migraines, pain, as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as alcohol, cocaine, benzodiazepine or opiate withdrawal. The compounds can also find use in the prevention of tolerance development during long-term treatment with sedative drugs such as benzodiazepines, barbiturates and morphine. In addition, the compounds can be used as anesthetics (anesthetic), anti-pain medication or antiemetics.

To use the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral application, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose , Starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.

Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof as well as Lipo some or their components can also be used as carrier systems.

For oral use, tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable. It can also be used in liquid form, for example as juice, to which a sweetener may be added.

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

The compound according to the invention is prepared by methods known per se. For example, compounds of the formula I are obtained by

a) a compound of formula 33

(II):

wherein Rl to R ^{8 have} the above meaning, cyclized with oxalic acid or reactive oxalic acid derivatives or

b) a compound of formula III

(HD-

wherein R to R ^{8 have} the above meaning, reacted with oxalic acid or reactive oxa acid derivatives and cyclized after reduction of the nitro group or

c) a compound of formula IV

wherein R has the above meaning and one of the substituents R ^ ', R6', R7 ' _{or R} 8' _e i _ne leaving group, nucleophilically substituted and, if desired, then saponified the ester group or esterified or amidated the acid group or etherified or a hydroxy group Nitrile is converted into the tetrazole or the isomers are separated or the salts are formed.

The cyclization to compounds of formula I is carried out in a known manner with oxalic acid in a single stage in an acidic medium or with a reactive oxalic acid derivative in one or two stages. The two-stage process is to be regarded as preferred, in which the diamine with an oxalic acid derivative such as oxal ester half-chloride or other reactive oxalic acid derivatives such as mixed anhydride, activated esters, imidazolides 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 is reacted. Suitable bases for the two-stage process are also hydroxides such as solid sodium or potassium hydroxide or carbonates such as sodium carbonate in polar solvents such as tetrahydrofuran, or alkali metal hydrides such as NaH, which are used in inert solvents such as hydrocarbons or ethers.

The subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acid medium, it being possible for alcohol to be added to the reaction mixture as a solubilizer.

In process variant b), after the acylation with oxalic acid or the reactive oxalic acid derivative, the nitro group is reduced catalytically or by reduction with iron powder in acetic acid at elevated temperature or else with sodium sulfide and ammonium hydroxide in alcohol and cyclized as described above.

Halogens such as fluorine, chlorine, bromine, iodine or O-derivatives such as O-mesylate, O-tosylate, O-triflate or O-nonaflate are suitable as escape groups in process variant c) and in the preparation of the starting compounds of the formula II. The nucleophile Substitution is carried out according to methods known from the literature in the presence of a base and is favored by one or more activating electron-withdrawing groups such as nitro, cyano, trifluoromethyl, preferably in the o- or p-position.

Suitable nucleophiles are, for example, alcoholates, thiols or primary as well as secondary amines or water. The reaction can be carried out in polar solvents such as alcohols, halogenated hydrocarbons, dimethylacetamide, acetonitrile or water or without a solvent. Suitable 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, it being possible, if appropriate, to work without a further solvent. If the boiling point of the amine is too low, pressure can optionally be applied in the autoclave.

The optionally subsequent saponification of an ester group can be carried out in a basic or, preferably, acidic manner by hydrolyzing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid, if appropriate in solvents such as trifluoroacetic acid or alcohols. Phosphonic acid esters are preferred by heating in highly concentrated aqueous acids such as, for example, concentrated hydrochloric acid, optionally with the addition of an alcohol, or by treatment with trimethylsilyl halide in inert solvents such as e.g. Acetonitrile and subsequent treatment with water hydrolyzed.

The esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se with the corresponding alcohol, if appropriate with acid catalysis or by using the activated acid derivative. Examples of suitable acid derivatives are acid chloride, imidazolide or anhydride. For all acids, but especially the phosphonic acids, the esterification can be achieved by reaction with orthoesters, optionally with the addition of catalysts such as p-toluenesulfonic acid.

The amidation takes place 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 nitro group is reduced to the amino group catalytically in polar solvents at room temperature or elevated temperature. Metals are like catalysts Raney nickel or noble metal catalysts such as palladium or platinum, if appropriate, are suitable on supports. Instead of hydrogen, ammonium formate can also be used in a known manner. Reducing agents such as tin (II) chloride or titanium (III) chloride can be used, as can complex metal hydrides, possibly in the presence of heavy metal salts. Iron can also be used as a reducing agent. The reaction is then carried out in the presence of an acid such as acetic acid or ammonium chloride, optionally with the addition of a solvent such as water. It may be advantageous to introduce the ester group before the reduction. If there are several nitro groups in the molecule, the desired ortho-standing nitro group can also be selectively reduced in a conventional manner with Na ₂ S.

The phenolic function can be, for example, by reaction with an alkyl halide, tosylate, triflate or the like in the presence of bases such as e.g. Alkaline earth or alkali hydroxides or carbonates in polar solvents such as DMF, THF or methylene chloride or according to the Mitsonubo variant by reaction with an alcohol in the presence of a phosphine such as e.g. Triphenylphosphine and azodicarboxylic acid ester or amide are etherified.

The introduction of a NO ₂ group succeeds through a number of known nitration methods. For example, nitration can be carried out with nitronium tetrafluoroborate in inert solvents such as halogenated hydrocarbons or in sulfolane, glacial acetic acid or acetonitrile. It is also possible, for example, to introduce nitrating acid in conc. Sulfuric acid or nitrates such as KNO3 in trifluoroacetic acid as a solvent at temperatures between 0 C and 30 C.

Halogen can be introduced using known halogenation methods such as e.g. by electrophilic aromatic substitution.

For example, according to a method using iodine and iodic acid by Wirth et al. [Liebigs Ann. Chem. 634, 84 (i960)] or with i-iodosuccinimide in solvents such as tetrahydrofuran, dimethylformamide or trifluoromethanesulfonic acid.

The tetrazole can be introduced by reacting the corresponding nitrile with an azide such as trimethylsilyl azide, hydrochloric acid or sodium azide, optionally with the addition of a proton source such as ammonium chloride or triethylammonium chloride in polar solvents such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone at temperatures to the boiling point of the solvent. The isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.

The salts are prepared in the customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and separating off the precipitate or working up the solution in the customary manner .

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds, for example according to WO93 / 08173 or the processes described here.

The following examples are intended to explain the process according to the invention:

Preparation of the starting compounds

i-)

3.2 g of N- (2-nitro-4-trifluoromethyl-5-fluorophenyl) aminomethanephosphonic acid are stirred in 40 ml of 2-N potassium hydroxide solution for 36 hours at room temperature. The source material has practically disappeared. The mixture is acidified to pH 1 with 4N hydrochloric acid and shaken three times with 80 ml of ethyl acetate. The ethyl acetate phase is washed with 80 ml of concentrated sodium chloride solution, dried, filtered and concentrated. After stirring the residue with ethyl acetate, 2.29 g of N- (2-nitro-4-trifluoromethyl-5-hydroxy-phenyl) -aminomethanephosphonic acid are obtained.

2

2.29 g of N- (2-nitro-4-trifluoromethyl-5-hydroxyphenyl) aminomethanephosphonic acid are in

28ml triethyl orthoformate under argon and moisture exclusion lh am

Water separator heated to 120 ° C. The mixture is then concentrated and chromatographed on silica gel with methylene chloride: ethanol = 95: 5. 1.9 g of diethyl N- (2-nitro-4-trifluoromethyl-5-hydroxy-phenyl) -aminomethanephosphonate are obtained.

³³

930 mg of diethyl N- (2-nitro-4-trifluoromethyl-5-hydroxyphenyl) aminomethanephosphonate are dissolved with 860 mg of 2- (4-chlorophenoxy) ethanol and 1.31 g of triphenylphosphine in 25 ml of tetrahydrofuran, mixed with 870 mg (0.8 ml of diethyl azodicarboxylic acid) and 0 , 25h to 80 ° C. in a preheated oil bath After concentration in vacuo, the residue is chromatographed on silica gel with methylene chloride: ethanol = 95: 5. The fractions correspondingly combined contain N- [2-nitro-4 contaminated with triphenylphosphine oxide -trifluoromethyl-5- (2 (-4-chlorooxy) ethoxy) phenyl] aminomethanephosphonic acid diethyl ester and are used in the next step without further purification.

The following are produced in an analogous manner:

N- [2-Nitro-4-trifluoromethyl-5- (N- [4 (-4-fluorobenzoyl) piperidin-l-yl)] propyloxyphenyl] - diethyl aminomethanephosphonate

N- [2-nitro-4-trifluoromethyl-5- (2-diethylaminoethoxy) phenyl] aminomethanephosphonic acid diethyl ester ^4th

3.18 g of N- (2-nitro-4-trifluoromethyl-5-fluorophene) -aminomethanephosphonic acid are stirred together with 3.18 g of sodium carbonate and 2.82 g of phenol in 40 ml of water for 4 hours at a bath temperature of 120 ° C. After acidification with 4N hydrochloric acid, the product which has precipitated is filtered off with suction. 2.69 g of N- (2-nitro-4-trifluoromethyl-5-phenoxyphenyl) aminomethanephosphonic acid are obtained.

The following are produced in an analogous manner:

N- (2-Nitro-4-trifluoromethyl-5- (4-methoxyphenoxy) phenyl) aminomethanephosphonic acid

N- (2-Nitro-4-trifluoromethyl-5- (4-chlθφhenoxy) phenyl) aminomethanephosphonic acid

N- (2-nitro-4-trifluoromethyl-5- (3-trifluoromethylphenoxy) phenyl) aminomethanephosphonic acid

N- (2-nitro-4-trifluoromethyl-5- (4-hydroxycarbonylphenoxy) phenyl) aminomethanephosphonic acid (from 4-trifluoromethylphenol)

N- (2-Nitro-4-trifluoromethyl-5- (hexafluoroisopropoxyphenyl) aminomethanephosphonic acid

N- (2-Nitro-4-trifluoromethyl-5- (pentafluoropropoxyphenyl) aminomethanephosphonic acid

N- (2-Nitro-4-trifluoromethyl-5- (heptafluorobutoxyphenyl) aminomethanephosphonic acid

N- (2-Nitro-4-trifluoromethyl-5- (butoxycarbonylmethyloxyphenyl) aminomethanephosphonic acid

5.)

An ethyl acetate solution of 3.18 g of N- (2-nitro-4-trifluoromethyl-5-fluorophenyl) aminomethanephosphonic acid is mixed with 30 ml of benzyl alcohol and the ethyl acetate is distilled off. 60 ml of 1N sodium hydroxide solution are added and the mixture is stirred for 1.25 hours at a bath temperature of 120 ° C. Then another 30 ml of 1N sodium hydroxide solution is added and the mixture is stirred for a further 0.75 h at 120 ° C. After cooling, it is extracted twice with 100 ml of ethyl acetate. The vinegar phase is discarded. The aqueous phase is acidified to pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate. This collected Essigesteφhase is washed once with water, dried, filtered and concentrated. The residue contains N- [2-nitro-4-trifluoromethyl-5-benzyloxyphenyl] aminomethanephosphonic acid and is reacted further without further purification.

The following is produced in an analogous manner:

N- [2-Nitro-4-trifluoromethyl-5 - ((- 3,6-dioxahept-l-yl) oxy) phenyl] - aminomethanephosphonic acid 6.)

2.5 g of N- (2-nitro-4-trifluoromethyl-5-phenoxyphenyl) aminomethanephosphonic acid are heated in inl9 ml of triethyl orthoformate with 184 mg of p-toluenesulfonic acid at 3.75 h at 120 ° C. on a water separator. After concentration in vacuo, the residue is chromatographed on silica gel with methylene chloride: ethanol = 10: 2. 2.71 g of diethyl N- (2-nitro-4-trifluoromethyl-5-phenoxyphenyl) aminomethanephosphonate are obtained and are used in the next step without further purification.

The following are produced in an analogous manner:

N- (2-nitro-4-trifluoromethyl-5- (4-methoxyphenoxy) phenyl) aminomethanephosphonic acid diethyl ester

N- (2-nitro-4-trifluoromethyl-5- (4-chlθφhenoxy) phenyl) - aminomethanephosphonic acid diethyl ester

N- (2-nitro-4-trifluoromethyl-5- (3-trifluoromethylphenoxy) phenyl) aminomethanephosphonic acid diethyl ester

N- (2-nitro-4-trifluoromethyl-5- (4-ethoxycarbonylphenoxy) phenyl) aminomethanephosphonic acid diethyl ester

N- (2-nitro-4-trifluoromethyl-5- (hexafluoroisopropoxyphenyl) diethyl aminomethanephosphonate

N- (2-Nitro-4-trifluoromethyl-5- (pentafluoφropoxyphenyl) - aminomethanephosphonic acid diethyl ester

N- (2-nitro-4-trifluoromethyl-5- (heptafluorobutoxyphenyl) aminomethanephosphonic acid diethyl ester

Diethyl N- [2-nitro-4-trifluoromethyl-5-benzyloxyphenyl] aminomethanephosphonate

Diethyl N- [2-nitro-4-trifluoromethyl-5 - ((- 3,6-dioxahept-l-yl) oxy) phenyl] aminomethanephosphonate

Diethyl N- [2-nitro-4-trifluoromethyl-5- (butoxycarbonylmethyloxy) phenyl] aminomethanephosphonate

7.)

2.5 g of unpurified N- [2-nitro-4-trifluoromethyl-5- (2 (-4-chloro-phenoxy) ethoxy) .phenyl] aminomethanephosphonic acid diethyl ester are dissolved in 27 ml of methanol and rapidly mixed under nitrogen to a mixture of 658 mg of ammonium chloride and 419 mg of iron powder placed in 13ml of water. The mixture is then heated to 80 ° C. for 0.5 hours. After suction filtration over diatomaceous earth and washing with warm methanol, the filtrate is diluted to 75 ml with water and extracted three times with 50 ml of ethyl acetate each time. The vinegar phase is included Washed water, dried, filtered and concentrated. 2.5 g of N- [2-amino-4-trifluoromethyl-5- (2 (-4-chlθφhenoxy) ethoxy) phenyl] aminomethanephosphonic acid diethyl ester, which is still contaminated with triphenylphosphine, is obtained and is reacted further without further purification.

The following are produced in an analogous manner:

N- [2-Amino-4-trifluoromethyl-5 - ((- 3,6-dioxahept-l-yl) oxy) phenyl] - aminomethanephosphonic acid diethyl ester

N- [2-A ino-4-trifluoromethyl-5-benzyloxyphenyl] aminomethanephosphonic acid diethyl ester

N- [2-Amino-4-trifluoromethyl-5 - ((N-4 (-4-fluorobenzoyl) piperidin-l-yl)) propyloxyphenyl] - diethyl aminomethanephosphonate

8th.)

In 100 ml of ethanol, 1 g of palladium on carbon (10%) is added to N- (2-nitro-4-trifluoromethyl-5-phenoxyphenyl) aminomethanephosphonic acid and hydrogenated under a hydrogen atmosphere at room temperature and normal pressure for 2 hours. After suctioning off the catalyst over diatomaceous earth and concentrating in vacuo, 2.6 g of diethyl N- (2-amino-4-trifluoromethyl-5-phenoxyphenyl) aminomethanephosphonate are obtained, which are used in the next step without further purification.

The following are produced in an analogous manner:

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

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

N- (2-Amino-4-trifluoromethyl-5- (3-trifluoromethylphenoxy) phenyl) aminomethanephosphonic acid diethyl ester

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

N- (2-Amino-4-trifluoromethyl-5- (hexafluoroisopropoxyphenyl) aminomethanephosphonic acid diethyl ester

N- (2-Amino-4-trifluoromethyl-5- (pentafluoropropoxyphenyl) aminomethanephosphonic acid diethyl ester

N- (2-Amino-4-trifluoromethyl-5- (heptafluorobutoxyphenyl) aminomethanephosphonic acid diethyl ester

N- [2-Amino-4-trifluoromethyl-5- (2-diethylaminoethoxy) phenyl] aminomethanephosphonic acid diethyl ester N- [2-Amino-4-trifluoromethyl-5- (butoxycarbonylmethyloxy) phenyl] aminomethanephosphonic acid diethyl ester

Example 1:

2.5 g of N- [2-amino-4-trifluoromethyl-5- (2 (-4-chlθφhenoxy) ethoxy) phenyl] aminomethane-phosphonic acid diethyl ester are placed in 60 ml of tetrahydrofuran with 733 mg of triethylamine and at room temperature with a solution of 719 mg (0.59ml) oxalic acid ethyl chloride in 15ml tetrahydrofuran added dropwise. The mixture is then stirred at room temperature for 2 hours. After the triethylammonium hydrochloride has been suctioned off, the filtrate is concentrated. The residue is taken up in 25 ml of ethanol and 25 ml of 1N hydrochloric acid and heated to a bath temperature of 120 ° C. for 2 hours. After the ethanol has been distilled off, the mixture is diluted to 50 ml with water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate phase is washed with water, dried, filtered and concentrated. The residue is chromatographed on silica gel with methylene chloride: ethanol = 10: 1. 810 mg of [(6 trifluoromethyl-7- (2 (-4-chlθφhenoxy) ethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline-1-yl-methanephosphonic acid diethyl ester are obtained.

The following are produced in an analogous manner:

[(6-Trifluoromethyl-7 - (- 3,6-dioxahept-l-yl) oxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7- (4-methoxyphenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - diethyl methanephosphonate

[(6-Trifluoromethyl-7-benzyloxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7-phenoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7- (4-chloro-phenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester of melting point

[(6-Trifluoromethyl-7- (3-trifluoromethylphenoxy) -l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7-hexafluoroisopropoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - diethyl methanephosphonate

[(6-Trifluoromethyl-7-pentafluoropropoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7-heptafluorobutoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - diethyl methanephosphonate [(6-Trifluoromethyl-7- (4-ethoxycarbonylphenoxy) -1, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -1-yl] -methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7- (2-diethylaminoethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7- (N-4 (-4-fluorobenzoyl) piperidin-l-yl)) propyloxy) -l, 2,3,4-tetrahydro -

2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid diethyl ester

[(6-Trifluoromethyl-7- (hydroxycarbonylmethyloxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) lyl] methanephosphonic acid diethyl ester

Example 2

750mg [(6-trifluoromethyl-7- (2 (-4-chlθφhenoxy) ethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid diethyl ester are dissolved in 36ml acetonitrile with 1, 73 g (1.46 ml) of trimethylbromosilane are added and the mixture is stirred for 1.5 hours at room temperature and then at 80 ° C., then a little water is added and the mixture is stirred at room temperature for 15 minutes. The mixture is then concentrated in vacuo and the residue is stirred with water and suction filtered. This gives 650 mg of [(6-trifluoromethyl-7- (2 (-4-chlθφhenoxy) ethoxy) -l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid with a melting point of 250 ° C. .

The following are produced in an analogous manner:

[(6-Trifluoromethyl-7 - (- 3,6-dioxahept-l-yl) oxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid, (thereby as a by-product [(6-trifluoromethyl-7 - (- 3,6-dioxahex-l-yl) oxy) -l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid [( 6-trifluoromethyl-7- (4-methoxyphenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid with a melting point> 300 ° C

[(6-Trifluoromethyl-7-benzyloxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid with a melting point> 300 ° C

[(6-Trifluoromethyl-7- (N-4 (-4-fluorobenzoyl) piperidin-l-yl)) propyloxy) -l, 2,3,4-tetrahydro - 2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid, melting point 233.5 ° C [(6-trifluoromethyl-7- (hydroxycarbonylmethyloxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

Example 3:

256 mg [(6-trifluoromethyl-7-phenoxy-l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid diethyl ester are heated in 4 ml of concentrated hydrochloric acid at 120 ° C. for 2 hours. The batch is diluted with water and the precipitated product is aspirated. 207 mg [(6-trifluoromethyl-7-phenoxy-l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid with a melting point> 300 ° C. are obtained.

Are produced in an analogous manner

[(6-Trifluoromethyl-7- (4-chloro-phenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid with a melting point> 300 ° C

[(6-Trifluoromethyl-7- (3-trifluoromethylphenoxy) -l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid, melting point 222 ° C

[(6-Trifluoromethyl-7-hexafluoroisopropoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid, melting point 280 ° C

[(6-Trifluoromethyl-7-pentafluoropropoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid, melting point 239.2 ° C

[(6-Trifluoromethyl-7-heptafluorobutoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid, melting point 161.9 ° C

[(6-Trifluoromethyl-7- (4-hydroxycarbonylphenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] -methanephosphonic acid, melting point> 300 ° C

[(6-Trifluoromethyl-7- (2-diethylaminoethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid with a melting point> 300 ° C

Claims

claims

1.) Compounds of formula I.

wherein

R ¹ - (CH ₂ ) _n -CR ² H- (CH ₂ ) _m -Z and

R ^, R6 ₅ R7 _{and R} 8 are the same or different and hydrogen, Cι_ alkyl, in which one or more hydrogen atoms are optionally replaced by halogen atoms,

Nitro, halogen, NR ⁹ R ¹⁰ , cyano, SO _p RH, SO ₂ NR ¹² Rl ³ , SO ₃ H, SO ₃ Cι_6-alkyl or

OR ¹⁴ mean, where

R ^{2 is} hydrogen or - (CH) _q -R ³ ,

R ^{3 is} hydrogen, hydroxy, C 1-4 alkoxy or NR ¹⁵ R ¹⁶ , n, m and q are each 0, 1, 2 or 3

Z POXY, OPOXY, SO ₂ R ¹⁷ , COR ¹⁸ , halogen, cyano or tetrazole,

R ¹¹ H, Cι_6-alkyl, phenyl, p 0, 1 or 2

Rl ² and RI ³ independently of one another are hydrogen or Cι_4-alkyl,

R ⁴ A-Rl ⁹ , or a C6_ ^ ₂ aryl or hetaryl radical which is halogen, Cj.g-

Alkoxy, hydroxy, cyano, NR ² ^ R ² 1, optionally substituted with halogen Cj.g-

Alkyl and / or COR ²² can be substituted and

A straight-chain or branched saturated or unsaturated alkylene with CI_ ₂ Q-

Carbon atoms in which one or more carbon atoms is represented by O, S and / or

R ^ hydrogen, NR ²⁴ R ² ^, halogen, Cj.ö-alkyl, which may be repeated several times

Halogen is substituted, Cj.ö-alkoxy, COR ²³ , CN or a C6-i-aryl or

Hetaryl radical means that with halogen, C _j .g-alkoxy, hydroxy, cyano, NR ² ^ R ² 1, C _j .g- Alkyl, which can be substituted by halogen and / or can be substituted by COR ²² , means and

R ^{18 is} hydrogen, C 1-4 -alkyl, hydroxy, Ci.g-alkoxy or NR ²⁷ R ²⁸ ,

_R 17, _R 22 _{and R} 23 hydroxy, C _j ^ alkoxy or NR ²⁹ R ³⁰ ,

R ^{26 is} hydrogen, C 1-4 alkyl, C 1-6 alkanoyl

X and Y are the same or different and are hydroxy, Cι_6-alkoxy, Cι_4-alkyl or R27 _R 28,

R ⁹ and RIO, 20 _{and R} 21 _and / _{o er R} 25 _and 24 _? are the same or different and

Hydrogen, CO-Ci.g-alkyl, phenyl or Ci.g-alkyl, optionally with C ._ -

Alkoxy or one optionally mono- or di-substituted with Cι_4-alkyl

Contain 1-3 N atoms and can be substituted,

Rl and Rl6, R27 _{and R} 28 _{} R} 29 _{and R} 30 are the same or different and are hydrogen,

Cι_4-alkyl, phenyl or together with the nitrogen atom form a 5-7-membered saturated heterocycle, which is another oxygen, sulfur or

Contain nitrogen atom and can be substituted or an unsaturated 5-membered

Form a heterocycle which can contain 1-3 N atoms and can be substituted,

where one of the radicals R ^ - R ⁸ always means OR * ⁴ , and R * ⁴ does not mean H or, if appropriate, C 1-4 alkyl which is substituted 1-3 times with halogens.

2.)

[(6-Trifluoromethyl-7- (2- (4-chlθφhenoxy (ethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

[(6-Trifluoromethyl-7-phenoxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] -methane-phosphonic acid

[(6-Trifluoromethyl-7 - (- 3,6-dioxahept-l-yl) oxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

[(6-Trifluoromethyl-7- (4-methoxyphenoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid [(6-Trifluoromethyl-7-benzyloxy-l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

[(6-Trifluoromethyl-7- (N-4 (-4-fluorobenzoyl) piperidin-l-yl)) propyloxy) -l, 2,3,4-tetrahydro - 2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid

[(6-Trifluoromethyl-7- (hydroxycarbonylmethyloxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

[(6-Trifluoromethyl-7- (4-chlθφhenoxy) -l, 2,3 ₎ 4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] - methanephosphonic acid

[(6-Trifluoromethyl-7- (3-trifluoromethylphenoxy) -l, 2,3,4-tetrahydro -2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

[(6-Trifluoromethyl-7- (4-hydroxycarbonylphenoxy) -1, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -1-yl] methanephosphonic acid

[(6-Trifluoromethyl-7- (2-diethylaminoethoxy) -l, 2,3,4-tetrahydro-2,3-dioxoquinoxaline) -l-yl] methanephosphonic acid

3.) Use of the compounds according to claim 1 or 2 for the manufacture of medicaments.

4.) Process for the preparation of the compounds of formula I in that

a) a compound of formula II

R ⁸

R ⁵

(II). wherein R to R ⁸ are as defined above, cyclized with oxalic acid or reactive oxalic acid derivatives or

b) a compound of formula T.

010.

wherein R to R ⁸ d have the above meaning, reacted with oxalic acid or reactive oxalic acid derivatives and cyclized after reduction of the nitro group or

c) a compound of formula IV

wherein Rl has the meaning given above and one of the substituents R ^ ', R6', R7 ' _{or he} 8' _e i _ne leaving group, nucleophilically substituted and, if desired, then saponified the ester group or esterified or amidated the acid group or etherified a hydroxy group or a nitrile converted into the tetrazole or separates the isomers or forms the salts.