WO1999000384A1

WO1999000384A1 - New quinoxaline dione derivatives, the production thereof and use of the same in medicaments

Info

Publication number: WO1999000384A1
Application number: PCT/DE1998/001821
Authority: WO
Inventors: Andreas Huth; Eckhard Ottow; Ingrid Schumann; Martin Krüger
Original assignee: Schering Aktiengesellschaft
Priority date: 1997-06-27
Filing date: 1998-06-26
Publication date: 1999-01-07
Also published as: JP2002506450A; AU9061498A; EP0993461A1; DE19728326A1

Abstract

The invention relates to compounds of formula (I), the production thereof and the use of the same in medicaments.

Description

CHINOXALINDION DERIVATIVES AS AMPA RECEPTOR ANTAGONISTS

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

It is known from numerous publications, for example from WO94 / 25469, that quinoxaline derivatives have affinity for the quisqualate receptors and, because of the affinity, are suitable as medicaments for the treatment of diseases of the central nervous system. Furthermore, 1-carboxylic acid quinoxaline derivatives are known to be very sparingly soluble and, because of their poor dissolving behavior, cannot be used as medicaments.

It was therefore the task of synthesizing new compounds which are both very soluble and specifically act antagonistically on the AM PA receptor, as a result of which they are suitable as medicaments for the treatment of diseases which are mediated by the hyperactivity of the excitatory amino acids.

Surprisingly, it has now been found that the compounds according to the invention not only have excellent affinity for the AMPA receptor, but are also distinguished by very good solubility in water.

The compounds according to the invention have the formula I.

wherein

R ¹ - (CH ₂ ) _n -CR ² H- (CH2) mZ and R5 and R6 are the same or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C 1-8 alkyl,

R ⁷ - (CH ₂ ) _p -NR8R9

R ^{2 is} hydrogen or - (CH2> _q -R ³

R ^{3 is} hydrogen, hydroxy, C- | _6-alkoxy or NR ^{1 0} R ^{1 1} ,

n, m and q each 0, 1, 2 or 3

p 0, 1, 2, 3 or 4,

Z COR ^{1 6} ,

R ³ and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C- | _4-alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen,

R ^{1 6} OH, C-μe alkoxy or NR ^{1 2} R ^{1 3}

R10 _unc | R 1 1, R 1 2 _unc j R 1 3 are the same or different and form hydrogen, C 1-4 alkyl, phenyl or together with the nitrogen atom a 5-7 membered saturated heterocycle, which is another oxygen, sulfur or nitrogen atom can contain and be substituted

as well as their isomers or salts.

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

The substituents R ^, R6 _and R ⁷ can be in any position, preferably in the 6- and 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, tert. Butyl, pentyl, isopentyl, hexyl, with C-1.4 alkyl radicals being preferred.

If the alkyl radical is halogenated, it can be present one to more times or perhalogenated and in particular means CF3.

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

If R ^" O and R ^ 'R ^ ² and R ^ ^{3 form} a saturated heterocycle together with the nitrogen atom, this means, for example, pyrrolidine, morpholine, thiomorpholine, piperidine, hexahydroazepine or piperazine. Like the heterocycle NR8R9 1 -3, the heterocycles can -substituted with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical which is optionally substituted with halogen, for example N-methylpiperazine, 2,6-dimethylmorpholine or phenylpiperazine.

Compounds in which R ^ CF3 and R ^{7 are} morpholine, thiomorpholine are to be regarded as preferred. Compounds with Z = COOH are particularly preferred.

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 the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6- Hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylamino-methane, aminopropanediol, sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is included, the physiologically compatible salts of organic and inorganic acids such as HCI, H2SO4, phosphoric acid, citric acid, tartaric acid and others are suitable.

The compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AM PA receptors. Because of their activity profile, the compounds according to the invention are suitable for the treatment of diseases caused by hyperactivity excitatory amino acids such as 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 using the radiolabelled specific agonist (RS) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from to displace 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 AM PA 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. The 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, stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms associated with HIV infections, multi-infarct dementia as well as epilepsy and muscle spasticity become. 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.

The pharmacological activity of the compounds of the formula I was determined using the tests described below:

Male NMRI mice weighing 1 8-22 g were kept under controlled conditions (6 ^{0 0} -1 8 ^{0 0} o'clock light / dark rhythm, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5 - 1 6 animals. The animals were observed between 8 ° and 13 °.

AMPA was injected into the left ventricle by freely moving mice. The applicator consisted of a cannula with a stainless steel device that limits the depth of the 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 for up to 180 seconds until clonic or tonic cramps occurred. The clonic movements that lasted longer than 5 seconds were counted as convulsions. The beginning of the clonic cramps was used as the end point for the determination of the cramp threshold. The dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments. The THRD50 and confidence limits were determined in a regression analysis.

The results of these experiments show that the compound of the formula I and its acid addition salts influence functional disorders of the AM PA receptor. They are therefore suitable for the manufacture of pharmaceuticals for the symptomatic and preventive treatment of diseases which are triggered by changes in the function of the AMPA-receptor complex.

Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.

The indications can be shown by conventional pharmacological tests.

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 administration, 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. contains. The pharmaceutical preparations can be in solid form, for example as tablets, dragées, 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 and liposomes or their components can also be used as carrier systems.

Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for 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 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, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.

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

a) a compound of formula II (CH ₂ ) _n -CR'H- (CH ₂ ) _m -Z '

(H)

wherein R ² 'R ⁵ , R * \ R ⁷ , n and m have the above meaning and Z' has the meaning of Z or -C≡N, cyclized with oxalic acid or reactive oxalic acid derivatives or

b) a compound of formula III

where R ² , R ^, R6, ^ _{n unc} | _m, - _(e j have the above significance, if desired, hydrolyzed and then esterified carboxyl or amidated or the isomers are separated or forms, the salts.

Compounds of the formula II and III are obtained, for example, by reacting in a compound of the formula IV

wherein R ¹ 'R ¹ or (CH2) n-CR ² - ( ^CH 2) rrf ^CsN and R ⁵ ', R ⁶ 'and R ⁷ ' represent a leaving group or R§, R6 or R ⁷ , substituted a leaving group and the nitro group is reduced and cyclized analogously to process variant a) with oxalic acid or reactive oxalic acid derivatives. 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 in which the diamine is present in the presence of an oxalic acid derivative such as oxal ester half-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 in water according to Schotten Baumann, is to be regarded as preferred a base such as organic amines, for example triethylamine, pyridine, Hünig base or dimethylaminopyridine or also soda or sodium hydroxide solution. The subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and solubilizers such as alcohol or acetonitrile can be added to the reaction mixture.

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

Halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, O-tosylate, O-triflate or O-nonaflate are suitable as escape groups of the compounds of the formula III.

The nucleophilic substitution with amines is carried out at the lowest possible temperature, preferably at room temperature. An excess of amine is not a disadvantage. The amine can also be used as a solvent. Suitable solvents are ethers such as tetrahydrofuran or hydrocarbons such as toluene or halogenated hydrocarbons such as methylene chloride.

The substitution by alkenyl compounds takes place with the catalysis of transition metal complexes such as Pd (0), e.g.

Palladium tetrakistriphenylphosphine or Pd < ^{2 +} ), such as palladium-bis-tri-o-tolylphosphine dichloride or nickel (O) according to methods known from the literature, if appropriate in the presence of a base and is preferably activated by an activating electron-withdrawing group such as nitro, cyano, trifluoromethyl Favored position. The corresponding boronic acids are, for example, nucleophiles. or - boranes or organotin compounds, organozinc compounds, Grignard compounds or the alkenyls as such are suitable. The reaction can be carried out in polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether. Suitable bases are inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or acetates or organic bases such as cyclic, alicyclic and aromatic amines such as pyridine, triethylamine, DBU, Hunig base, optionally with the addition of water.

Any subsequent oxidative cleavage of the alkenyl compounds to the aldehyde can be carried out using methods known from the literature. Ozonation in solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature. The ozonide which forms is reductively cleaved to form the aldehyde by trapping with thiourea, trialkylphosphites or, preferably, with triarylphosphines.

The aldehyde can be chain extended by e.g. by Petersonolefinierung, or by Wittig or Wittig-Homer reaction initially produces an appropriate enol ether. For this purpose, the aldehyde with the previously generated anion e.g. an appropriately substituted phosphonium salt or phosphonic acid ester in solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane. As bases are e.g. Alkali hydrides, alkali amides, alkali alcoholates such as potassium tert-butoxide, alkali or alkaline earth carbonates or hydroxides, optionally in the presence of phase transfer catalysts such as e.g. Crown ethers or organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane, if appropriate in the presence of salts such as lithium bromide, are suitable. The corresponding enol ether can then be cleaved by acid.

The aldehydes can be reduced to the corresponding alcohols by methods known from the literature. The reduction is preferably carried out with complex metal hydrides such as sodium boranate in solvents such as alcohol. The hydroxyl group can be converted into escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate by methods known from the literature and by various processes. It is preferably converted into the chloride or tosylate with tosyl chloride in the presence of bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.

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

Dimethylaminopyridine.

The nitro group is reduced in the customary manner catalytically or by reduction with iron powder in acetic acid at elevated temperature or else with sodium sulfide and ammonium hydroxide in alcohol. The reduction of the alkenyl group takes place in the usual way catalytically and then usually takes place together with the reduction of the nitro group.

The optionally subsequent saponification of an ester group or the saponification of a nitrile group can be carried out in a basic or, preferably, acidic manner by hydrolysing at elevated 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.

The esterification of the carboxylic acid takes place in a manner known per se with the corresponding alcohol with acid catalysis or in the presence of an activated acid derivative. Examples of suitable acid derivatives are acid chloride, imidazolide or anhydride.

The amidation takes place on the free acids or on their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature. The amidation can also be carried out directly from the ester by reaction with an amine in the presence of trimethyl aluminum. 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 removing 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 WO94 / 25469, PCT / DE96 / 0227 or the processes described here.

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

The starting materials are produced by processes known from the literature.

example 1

A.) 2.3 g of 2,4-difluoro-5-trifluoromethyl-nitrobenzene are dissolved in 10 ml of toluene, mixed with 0.84 g of sodium hydrogen carbonate and mixed with a two-phase mixture of 0.95 g of aminoacetonitrile in 5 ml of toluene. It is then heated to a bath temperature of 120 ° C. for 3.75 hours. After cooling, 50 ml of water are added and the mixture is extracted three times with 50 ml of ethyl acetate each time. The organic phase is washed successively with water, dried, filtered and concentrated. 2.6 g of 2-cyanomethylamino-4-fluoro-5-trifluoromethyl-nitrobenzene are obtained.

The following is produced in an analogous manner:

2- (2-cyanoethylamino) -4-fluoro-5-trifluoromethyl-nitrobenzene B.) 3.5 g of 2-cyanomethylamino-4-fluoro-5-trifluoromethylbenzene are stirred in 1 5 ml of morpholine for 6.5 hours at room temperature. After standing overnight, water is added and suction filtered. 3.97 g of 2-cyanomethylamino-4-morpholino-5-trifluoromethyl-nitrobenzene are obtained.

The following is produced in an analogous manner:

2-cyanomethylamino-4- (thiomorpholin-1-yl) -5-trifluoromethyl-nitrobenzene 2-cyanomethylamino-4- (2,6-dimethylmorpholin-1-yl) -5-trifluoromethyl-nitrobenzene

2- (2-cyanoethylamino) -4-morpholino-5-trifluoromethyl-nitrobenzene

C.) 2.95 g of ammonium chloride are dissolved in 60 ml of water and mixed with 1.88 g of iron powder. A slurry of 3.7 g of 2-cyanomethylamino-4-morpholino-5-trifluoromethyl-nitrobenzene in 1 20 ml of methanol is added dropwise to this batch. During the dropwise addition, the batch is brought to a bath temperature of 80 ° C. and, after the dropwise addition has ended, heated to this temperature for 1.5 hours. After suction filtration over diatomaceous earth and washing with hot methanol, the filtrate is evaporated down to the water and the precipitated product is filtered off with suction. 3.09 g of 3-amino-4-cyanomethylamino-6-morpholino-trifluoromethylbenzene are obtained.

The following is produced in an analogous manner:

3-amino-4-cyanomethylamino-6- (thiomorpholin-1-yl) trifluoromethylbenzene 3-amino-4-cyanomethylamino-6- (2,6-dimethylmorpholin-1-yl) trifluoromethylbenzene 3-amino-4- (2nd -cyanoethylamino) -6- (morpholin-1-yl) trifluoromethylbenzene

D.) 3.09 g of 3-amino-4-cyanomethylamino-6-morpholino-trifluoromethylbenzene are dissolved in 250 ml of tetrahydrofuran and mixed with 2.35 g of triethylamine. A solution of 3.16 g of oxalic acid ester chloride in 50 ml of tetrahydrofuran is added dropwise to this solution while cooling with ice. After the addition has ended, the mixture is stirred at room temperature for 3.5 hours. The batch is suctioned off from the triethylamine hydrochloride and the mother liquor is concentrated. The residue is taken up in 100 ml of ethanol, mixed with 100 ml of 1N hydrochloric acid and heated to a bath temperature of 110 ° C. for 2 h. The ethanol is then drawn off and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried, filtered and concentrated. The residue is covered with silica gel

Methylene chloride: ethanol = 10: chromatographed as eluent. 1.67 g of 1-cyanomethyl-6-trifluoromethyl-7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline with a melting point of 279 ° C. are obtained.

The following is produced in an analogous manner:

1-cyanomethyl-6-trifluoromethyl-7- (thiomorpholin-1-yl) -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline

1-cyanomethyl-6-trifluoromethyl-7- (2,6-dimethylmorpholin-1-yl) -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline

1-cyanoeth-2-yl- (6-trifluoromethyl) -7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline

E.) 300 mg of 1-cyanomethyl-6-trifluoromethyl-7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxoquinoxaline are heated with 1 5 ml of concentrated hydrochloric acid for 3 hours at a bath temperature of 20 ° C. After concentration, the mixture is stirred in water in crystalline form and filtered off with suction. 300 mg of 1 - (6-trifluoromethyl-7-

[morpholinl -yl] -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-y-acetic acid with a melting point> 300 ° C.

The following are prepared in an analogous manner: 1 - (6-trifluoromethyl-7- [thiomorpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid

1 - (6-Trifluoromethyl-7- [2,6-dimethylmorpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-y-acetic acid

2- (6-trifluoromethyl-7- [morpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) propionic acid

Claims

claims

1.) Compounds of the formula I.

wherein

R ¹ - (CH ₂ ) n -CR ² H- (CH ₂ ) mZ and

R5 and R6 are identical or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C -] _6-alkyl,

R ⁷ - (CH ₂ ) _p -NR ⁸ R ⁹

R ^{2 is} hydrogen or - (CH2> _q -R ³

R ^{3 is} hydrogen, hydroxy, C-μe alkoxy or NR ^{1 0} R ¹ 1,

n, m and q each 0, 1, 2 or 3

p 0, 1, 2, 3 or 4,

Z COR ^{1 6} ,

R8 and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C- | _4-alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen,

R ^{1 6} OH, C- | _6-alkoxy or NR1 ² R ^{1 3} RI O and R1 1 'R ^ ² and R ^ ^{3 are the} same or different and are hydrogen, C- | _4-alkyl, phenyl or together with the nitrogen atom form a 5-7-membered saturated heterocycle which may contain and be substituted by another oxygen, sulfur or nitrogen atom

as well as their isomers or salts.

2.) 1 - (6-Trifluoromethyl-7- [morpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid 1 - (6-trifluoromethyl-7- [thiomorpholine1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid

2- (6-trifluoromethyl-7- [morpholin 1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 -yl) propionic acid according to claim 1.

3.) Medicament containing a compound according to claim 1 or 2 and one or more conventional pharmaceutical carriers.

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

a) a compound of formula II

PS

wherein R ² 'R ^, R6, R7, n and m have the above meaning and Z' has the meaning of Z or -C≡N, cyciisiert with oxalic acid or reactive oxalic acid derivatives or

b) a compound of formula III

in which R ² , R5, R6, R ⁷ , _n and m have the above meaning, hydrolyze and, if desired, then esterify or amidate the carboxyl group or separate the isomers or form the salts.