MXPA97008431A - Derivatives of quinoxaline alkylamines 2,3-diages substituted as antagonists of the glutam receptor - Google Patents

Abstract

The present invention relates to: A new series of 2,3-substituted substitution quinoxalines as neuroprotective agents is taught. The new intermediates, the preparation processes and the pharmaceutical compositions containing the compounds also. The compounds are antagonists of glutamate and are useful in the treatment of attack, ischemia or cerebral infarction resulting from an attack by thromboembolism or hemorrhagic attack, cerebral vasospasms, hypoglycemia, cardiac arrest, epileptic state, asphyxia, anoxia, Alzheimer's, Parkinson's and Huntingt's diseases.

Description

DERIVATIVES OF ALKYL-AMINAS OF QUINOXALINA 2, 3 - DIONES SUBSTITUTED AS ANTAGONISTS OF THE GLUTAMATE RECEPTOR.

BACKGROUND OF THE INVENTION This invention is for new glutamate receptor antagonists which are novel compounds of the quinoxaline type 5, 6, 7, 8-substituted 2, 3-dione. The ring system fused in position a- or b- by amino acid derivatives. The compounds are active when the excitatory amino acid receptor antagonist acts on glutamate receptors, including one or both N-methyl-D-aspartate (NMDA) receptors and the kainate receptor. The invention also relates to the use of quinoxaline 2, 3 -diones as neuroprotective agents to treat conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thrombosis or hemorrhagic attack, cerebral vasospasms, hypoglycaemia, cardiac arrest, epileptic, perinatal asphyxia, anoxia, as drowning, lung surgery and brain trauma, as well as treating chronic neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, as well as anticonvulsants. The compounds of the present invention can also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain and drug addiction. Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is thought that this degeneration is partly mediated by the exotoxic actions of the exitable amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, the a-amino-3-hydroxy acid receptor 5-methyl 4-isoxazole propionic (AMP A) and the kainate receptor. The AMPA / kainate receptors can be referred to together as non-NMDA receptors. This exitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as attack by thrombosis or hemorrhagic attack, cerebral vasospasms, hypoglycaemia, cardiac arrest, epileptic status, perinatal asphyxia , anoxia, such as drowning, lung surgery and brain trauma, as well as treating chronic neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases.

Various classes of quinoxalinediones derivatives have been disclosed as glutamate receptor antagonists (EAA). For example, among the excitatory amino acid antagonists recognized for use in the treatment of disorders, are those that block AMPA receptors (Bigge CF and Malone T. C, Curr Opin, Ther.Pat, 1993; 951; Rogawski, MA., TiPS, 1993; 14: 325). AMPA receptor antagonists have prevented neuronal damage in several models of global cerebral ischemia (Li H. and Buchan AMJ Cerebr, Blood Flow Metab., 1933; 13: 933; Nellgard B. and Wieloch T., J. Cerebr. Metab., 1992; 12: 2) and focal cerebral ischemia (Bullock R, Graham D I., Swanson S., McCulloch J., J. Brain, Blood Flow Metab., 1994; 14: 446); Xue D., Huang Z. - G., Barnes K., Lasiuk H. J., Smith K. E., Buchan A.M., J. Cerebr. Blood Flow Metab., 1994; 14: 251 AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-I, Hao J.-X, Seiger A, Wiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther., 1993; 267: 140) and epilepsy (Namba T., Morimoto K., Sato K., Yamada N. Kuroda S., Brain Res., 1994; 638: 36; Brown SE, McCulloch J., Brain Res., 1994; 641: 10; Yamaguchi SI , Donevan SD, Rogawski MA, Epilepsy Res., 1993; 15: 179; Smith SE, Durmuller N., Meldrum BS, Eur. J. Pharmacol., 1991; 201: 179). AMPA receptor antagonists have also shown promise in chronic neurodegenerative disorders such as Parkinsonism (Klockgeter T., Turski L. Honoré T., Zhang Z., Gash D.M., Kurlan R, Greenamyre J. T., Ann. Neurol., 1993; 34 (4): 585-593).

Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for their utility in the treatment of disorders. Disorders that are known to be responsible for blocking the NMDA receptor, includes acute cerebral ischemia (attack or brain trauma, for example), muscle spasm, seizure disorders, neuropathic pain and anxiety and may be a significant causative factor in chronic neurodegenerative disorders such as Parkinson's disease (Klockgeter T., Turski L. , Ann. Neurol., 1993; 34: 585-593), human immunodeficiency virus (HIV) related to neuronal damage, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (Francis PT, Si s NR Procter AW, Bowen DM, J. Neurochem., 1993; (5): 1589-1604) and Huntington's disease. (See Lipton S., TINS, 1993; 16 (12): 527-532; Lipton SA, Rosemberg PA, New Biochem Pharmacol, 1994; 330: (9): 613-622; and Bigge CF, Biochem Pharmacol., 1993; 45: 1547-1561 and references cited therein). NMDA receptor antagonists can also be used to prevent tolerance to opiate analgesis or to the withdrawal symptoms of addictive drug help (Requests by Pat.Europe 488,959A).

The co-pending US serial number 08/124, 770 discloses the glutamate receptor antagonist derived from quinoxalinedione represented by the formula: where A is a ring containing from 5 to 7 atoms having a nitrogen that can be replaced by hydrogen, alkyl or CH2CH2OH. This application does not disclose or suggest compounds that have the instant amino as a substituent or the methodology necessary to prepare it.

The co-pending US application serial number 08 / 404,400 teaches that glutamate receptor antagonists are quinoxalinediones of the formula: or a pharmaceutically acceptable salt thereof wherein: R. is hydrogen, an alkyl or an alkylaryl; X and Y are independently hydrogen, halogen nitro, cyano, trifluoromethyl, COOH, CONRtRs, SO2CF3, SO2 », SONRtRj, alkyl, alkenyl, (CH2) Z CONRtRj, (CH2) zCOOR? or NHCORt, where R, and R5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, COalkyl, COalkyloaryl, CONR3 alkyl, CONR3 aryl, CONR3alkylaryl, CSNR3alkyl, CSNR3alkylaryl or a common amino acid moiety attached by an amide bond, wherein R3 is hydrogen, alkyl or alkylaryl; and m and n are independently 0, 1, or 2 provided such that m + n is > 1.

This application does not disclose or suggest the compounds of the present invention having amines as substituents at the a- or b-positions or the methodology for preparing them.

JP06228112-A, discloses glutamate receptor antagonists, which are derivatives of quinoxaline-2, 3 (1H, 4H) -dione of the formula: where Ri is H, NO2, or CF3; Ring A is a saturated heterocyclic group containing nitrogen which may contain sulfur or oxygen; R2 in H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH2 or lower alkoxy carbonyl amino. This reference does not teach or suggest the present compounds to be added to the quinoxaline dione fused to the ring system by an alkynene.

WO 93/08188 covers a tricyclic quinoxalinedione of the formula: as useful or selective antagonists of glutamate receptors.

European Patent Application 0627434 covers the tricyclic quinoxalinedione of Formula I below which are selective antagonists of the glycine binding site of the NMDA receptor: wherein X represents hydrogen, alkyl, halogen, cyano, trifluoromethyl or nitro; Ri represents hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; G represents - CONR2 - or - NR2CO -, where R2 represents hydrogen or alkyl; J represents an acidic group or a group which is converted thereinto in vivo; E represents a basic group or a group that converts to it live; Y represents a single bond, alkylene, alkenylene, substituted alkyne or Yi-Q- - Y2 where Yi represents a single bond or alkylene, Y2 represents alkyne and Q represents a heteroatom selected from oxygen or sulfide; and Z represents alkynene.

WO 94/26747 discloses compounds of Formula I below as useful in the treatment of cerebrovascular disorder: wherein Ri is hydrogen, alkyl or benzyl; X is O or NO2, where R2 is hydrogen, alkyl or benzyl; Y is N - R », where R is hydrogen, OH or alkyl; n is 0 or 1; R $ is phenyl naphthyl, thienyl, pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen; CF3, NO2, amino, alkyl, alkoxy and phenyl; and A is a ring of 5 to 7 atoms fused to the benzo ring at the positions marked a and b.

The compounds of the present invention differ from the technique in that they provide non-coplanar compounds with greater solubility and therefore, better ability to penetrate the blood barrier of the brain. These are important attributes in the pharmaceutical area.

An object of this invention is to provide novel quinoxalinediones with amines in position a or b which function as antagonists.

SUMMARY OF THE INVENTION The present invention is directed to compounds represented by Formula I: or a pharmaceutically acceptable salt thereof wherein R, Ri, R2, R3, Rt, R5, Rp, R12 and n are as described below.

The present invention also relates to a pharmaceutical composition containing the compound defined by formula I in an amount effective to treat cerebrovascular disorders responsible for blocking glutamate receptors (such as the a-amino-3-hydroxy acid receptor). - methyl-4-isoxazole propionic (AMPA) and the kainate receptor) and a pharmaceutically acceptable carrier. Examples of disorders that respond to such treatments include cerebral ischaemia caused by brain trauma, stroke, hypoglycaemia, heart attack and surgery; anxiety and schizophrenia; and chronic neurodegenerative disorders such as Huntington's disease, ALS, Parkinsonism and Alzheimer's disease. The pharmaceutical composition of this invention can also be used as an analgesic or for the treatment of epilepsy.

The invention further relates to a method for treating cerebrovascular disorders that respond to antagonism of NMDA glutamate receptors by administering a compound of formula I defined above in unit dose form.

Another objective of this invention is to provide a method for treating disorders in response to antagonism of glutamate or aspartate receptors in a human by administering a therapeutically effective amount of the 2,3-quinoxalinediones of this invention.

Another objective of this invention is to provide new methods of preparing the 2, 3 - Quinoxalinediones.

A further objective of this invention is directed to novel intermediates useful in the preparation of the 2, 3-quinoxalinediones of this invention.

DETAILED DESCRIPTION OF THE INVENTION. The quinoxaline substituted 2, 3-diones of the present invention are those of the formula I: or a pharmaceutically acceptable salt thereof wherein R is a secondary or tertiary amine; Ri is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphorusalkyl, or phosphonoalkyl; R is hydrogen, hydroxy or amino; R3 and Rt are each independently hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, nitro, cyano, C (O) R *, (CH2) mC? 2R9 where R9 is hydrogen, alkyl, aralkyl or cycloalkyl, (CH2) mCONR7R8, NHCORβ where m is an integer from 0 to 4, R < It is hydroxy, alkoxy, R, alkyl, haloalkyl, aryl, aralkyl and R7 and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl or aryl; R5 is hydrogen, I rent, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aril, aralkyl, heteroaryl, nitro, cyano, - SO2CF3 C (O) R «, (CH2) mCONR7R «, NHCO-R-6 where m, R7 and R8 are as defined above; R5 can be in the position a - and ^ N- (CH) in 'a position b - in the ring; and R1, 2 ^ Rp and R12 are each independently: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, "13 or II - (C) q - C - R15 R14 where q is an integer from 0 to 3 and R? 3 and R? Are each independently selected from hydrogen, alkyl, aralkyl, cycloalkyl and heteroalkyl and Ru is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heteroaryl, and NR? 6Rp where R16 and R are each independently selected from hydrogen, alkyl and aryl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, , where p and p 'are each independently an integer selected from 0 to 1 and where 1 or 2 carbon atoms in the second ring can be replaced by 1 or 2 selected heteroatoms of N, O or S. "1 1 -N In v. R the Rn and the R12 are not joined and are not amino acids. is a secondary or tertiary amine having substituted alkyl groups. These include hydrogen, alkyl, for example, the group can be: alkenylalkyl, alkylalkenylalkyl, alkynylalkyl, alkylalkynylalkyl, cycloalkyl, non-aromatic heterocycloalkyl, hydroxyalkyl, alkylhydroxyalkyl, • OH • N \ (CHJ R 'and "^" «- -OR N (CH n 1 R *" n aminoalkyl, Alkylaminoalkyl, _ (c «2 'n ^^ - OH alkylthioalkyl ^ ^ -S-R '-N. (CHJ The preferred compounds are those of Formula I where: ^ D where Rn and R? 2 are each independently: hydrogen, I rent, cycloalkyl, non-aromatic heterocycloalkyl, and RH = independently hydrogen, alkyl, aralkyl, cycloalkyl, heteroaralkyl, R13 O - < C) q- C-R15 R14 where q is an integer from 0 to 3 and R15 is: hydrogen, alkyl, aralkyl, aryl, heteroaryl, NR16R1 where R1 and Rp are each independently selected from: hydrogen, alkyl and aryl. The most preferred compounds are those of the formula I wherein: R ji and R 12 are each independently: hydrogen, methyl, ethyl, propyl, butyl, cycloalkyl, heterocycloalkyl, alkylaminoalkyl, aminoalkyl, hydroxyalkyl, and alkoxyalkyl.

Still the most preferred compounds are those of Formula I where: Rn and R12 are each independently: hydrogen, methyl, ethyl, propyl, butyl, or cyclohexyl; Ri is hydrogen; R2 is hydrogen; R3 and R-j are each independently hydrogen or nitro and Rs is methyl.

The most preferred compounds are selected from: 5-Diethylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5-Dipropylaminoethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5-Dibutylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5-Cycloexilaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5 - [(Cyclohexyl-methyl-amino) -methyl] -6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; Y . 5-Dimethylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione.

The compounds of Formula I are capable of forming pharmaceutically acceptable acid addition salts.

The pharmaceutically acceptable acid addition salts of the compounds of the Formula I include salts derivatives of non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, iodide, phosphorous and the like, as well as the derivatives of non-toxic organic acid salts, such as mono- and dicarboxylic aliphatic acids, acids phenyl substituted alkanols, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and sulfonic aromatic acids, etc. Said salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate ptalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are amino acid salts such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977; 66: 1-19).

The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise, the salts are equivalent to their respective free base for purposes of the present invention.

Certain compounds of the present invention can exist in undissolved forms, as well as in dissolved forms, including hydrated forms. In general, the dissolved forms, including the hydrated forms, are equivalent to the undissolved forms and are intended to be encompassed within the scope of the present invention.

Certain compounds of the present invention may exist as a mixture of the cis or trans isomers or the R- or S- isomers, or as the individual cis or trans isomers or the R- and S- isomers. The mixture of the isomers, as well as the individual isomers, are intended to be encompassed within the scope of the present invention.

In the compounds of Formula I, the term "alkyl" means an in-line or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "carboxyalkyl" means alkyl as above and is attached to a carboxy group. The term "phosphorus alkyl" means alkyl as above and is attached to a phosphorus group.

The term "phosphonoalkyl" means alkyl as above and is attached to a phosphonyl group.

The term "alkenyl" means a linear or branched unsaturated hydrocarbon radical having from 3 to 6 carbon atoms and includes, for example, 2-propenyl, 1-butenyl, 2-bute? Il, 1-pentenyl, 2-pentenyl, 3-methyl, 3-cutenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and the like.

The term "alkynyl" means a linear or branched unsaturated hydrocarbon radical having from 2 to 6 carbon atoms and includes, but is not limited to, ethinyl, 2,3-propynyl, 2,3- or 3,4-butynyl.

The term "aryl" means an aromatic radical which is a phenyl group, a feml group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl , amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl or 1,3-benzodioxol-5-yl.

The term "aralkyl" means aryl and alkyl as defined above and includes, but is not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; a favorite group is benzil.

The term "heteroaryl" means a heteroaromatic radical which is, 2 -, 3 -, or 4-pyridinyl, 2 -, 4 -, or 5-pyrimidinyl, or 2 -, 3-thienyl.

"Halogen is fluoro, chlorine, bromine or iodine.

The term "haloalkyl" means halogen and alkyl as defined above as, but not limited to, trifluoromethyl and trichloromethyl.

"Alkyloaryl" means aryl as defined above and alkyl as defined above, for example, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; a favorite group is benzil.

The term "heterocycloalkyl" means an alicyclic ring with one or more atoms substituted by a heteroatom, for example, N, O and S.

Spiro rings include, but are not limited to rings with 5 - or 5 - elements that are replaced by a heteroatom that is selected from N, O, and S.

The second ring can also be a gem-dialkyl group instead of a ring.

The compounds of the invention exhibit valuable biological properties due to their strong exatory amino acid antagonist (EAA) properties at one of the several binding sites on glutamate receptors: at the AMPA acid binding site ((RS) -amino- 3-hydroxy-5-methyl-4-isoxazole propionic (or cainic acid) on the AMPA (non-NMDA) receptors or the glycine receptors of the NMDA site.

The compounds of the present invention exhibit binding affinity for AMPA receptors measured as described in Honoré T., et al., Neuroscience Letters, 1985; 54: 27-32. Preferred compounds show that the IC5o < lOOμM in this trial. The compounds of the present invention exhibit binding affinity for the site of kainate (non-NMDA receptor) as described in London E. D. and Coyle J., Mol.

Pharmacol., 1979; 15: 492. The compounds of the present invention exhibit binding affinity for the glycine site at NMDA receptors as described in Jones S.M. et al., Pharmacol Methods, 1989; 21: 161. To measure the functional antagonist activity of AMPA, the effects of the agent on AMPA-induced neuronal damage in primary cortical neuronal cultures are examined using techniques similar to those reported by Koh J.-Y., et al., J. Neurosci, 1990; 10: 693. In addition, the neuronal damage produced by long-term exposure to 100 μM of AMPA can be measured by the release of the cytosolic enzyme dehydrogenase lactate (LDH).

The selected compounds of the present invention are tested by one or more of the above-described assays. The data obtained in these tests are set forth in Table 1 below. The IC 50 values set forth in Table 1 are a measure of the concentration (μM) of the test substance which inhibits 50% of the induced release of the tested receptors.

TABLE 1 Quinoxalinediones Additionally, a preliminary indicator of CNS activity in vivo related to anticonvulsant activity and potential neuroprotection, is a maximal electro shock test (MES) in stressed CF-1 mice (20-25 g) performed with corneal electrodes by conventional methods. as previously described (Krall, et al., Epilepsy, 1988; 19: 409-428). The compounds of this invention generally demonstrate DE50 values of < 50 mg / kg.

MONTH (IV) Data for compound 1 of Table 1 TABLE 2. Compound 1; MES information The compounds of the invention, together with a conventional adjuvant, transporter or diluent, can be put in the form of pharmaceutical compositions and unit doses thereof and in that form can be used as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, all for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral use (including the subcutaneous form). Said pharmaceutical compositions and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, and said unit dosage forms may contain any appropriate effective amount of the active ingredient commensurate with the daily dose ratio. intended to be used. Tablets containing 10 mg of the active ingredient or, more regularly from 0.1 to 100 mg per tablet and according to appropriate representative dosage unit forms.

Solid forms of the pharmaceutical compositions for PO administration and injectable solutions are preferred.

The compounds of this invention are extremely useful in the treatment of diseases of the central nervous system related to their biological activity. The compounds of this invention can be suitably administered to a subject, including a human in need of treatment, alleviation, or elimination of an indication associated with the biological activity of the compounds. This especially includes psychosis that depends on excitatory amino acids, Parkinsonism that depends on excitatory amino acids, seizures that depend on excitatory amino acids and migraine-dependent excitatory amino acids. The appropriate dose ranges are from 0.1 to lOOOmg daily, from 10 to 50 mg daily and especially from 30 to 100 mg daily, depending as is usual on the exact mode of administration, how it is administered, the indication to which the administration is directed, the subject involved and the body weight of the subject involved and also, the experience and preference of the doctor or veterinarian in charge.

The schemes and examples below are intended to be an illustration of certain preferred specimens of the invention and involve the non-limitation of the invention.

General Schemes I and II illustrate the preparation of the compounds when R-? it's nitro; however, the nitration step can be replaced by other electrophiles by electrophilic aromatic substitution.

GENERAL SCHEME I (1; 3) ( 4 ) (6) Step (a) of Scheme I above involves reacting the nitroaniline derivatives of Formula (1) with amine as represented in Formula (2) in the presence of triarylphosphine, preferably trifemlfosphine and diester. diazodicarboxylate, preferably diethyldiazodicarboxylate in a solution of a hydrocarbon solvent such as benzene or another solvent, such as THF, preferably benzene at temperatures of about 5 ° C.

The reaction mixture is stirred for 2 to 16 hours and monitored by TLC (SiO2, pet ether: EtOAc, 1: 1). The solvent is evaporated under pressure and the product is isolated by column chromatography (SIO2, pet ether: EtOAc, 95: 5 to 75:25).

Step (b) involves the selective reduction of the nitroaniline derivative of the formula (3) via hydrogenolysis (hydrogen gas about 50 psi) in the presence of a catalyst such as Ra Ni or Pd / C, preferably Ra Ni in a hydroxylated solvent like methanol. The catalyst is filtered and the filtrate is evaporated to give the o-phenylenediamine derivative, which is used in the next step without further purification.

Step (c) involves reacting the o-phenylenediamine derivative represented in formula (4) with the oxalic acid derivative such as dimethyl oxalate in a hydroxylated solvent such as methanol at reflux temperatures of 12 to 24 hours. The reaction mixture is partially evaporated to give the crude product, which is purified by crystallization.

Step (d) involves reacting the derivative of the quinoxaline-2,3-dione shown in Formula (5) with a nitrating mixture, preferably KNO3 and sulfuric acid or TFA at temperatures ranging from 0 ° C. the temperature of the room. The reaction mixture is poured onto ice and the resulting solid is purified by crystallization or column chromatography (SiO2, pet ether mixture: EtOAc).

Scheme II Step (a) in Scheme II above involves bromination of the nitroaniline derivative shown in Formula (1) with brominating agents such as CBr-j / PPh3 or PBr3 in a solvent such as ether. The volatile materials are evaporated under reduced pressure and the crude product is used directly in step (b) or purified by column chromatography (SiO2, pet ether mixture: EtOAc).

Step (b) involves reacting the benzyl bromide derivative shown in Formula (2) with the appropriate amino compound shown in structure (3) in the presence of a base such as triethylamine and an ether solvent such as THF a temperatures that go from 10-60 ° C. The reaction mixture is evaporated under reduced pressure and quenched with water. The product is extracted with a solvent such as EtOAc. The final product is purified by column chromatography (SIO2, pet ether: EtOAc).

Formula (3) in Scheme II can not be derived more for 4, 5, and 6 in Scheme I.

These General Experimental Schemes cover most of the final products of the invention. Others are made by known experimental procedures. SCHEME I Japan, 1977; 50: 3276-3280. 1. K0H / H20: Me0H 2. R.- PPhj, DEAD or PBr3 / NRj 2 / TEA Scheme 1 (2-amino-6-methyl-phenyl) -methanol 2-Amino-6-methyl-benzoic acid (45 g, 300 mol) is suspended in ether and LAH (13.26 g, 350 mol) is added in portions. The reaction mixture is stirred at room temperature for 4 hours and quenched with aqueous NHtCl. The reaction mixture is filtered and the filtrate extracted with ether (3 x 200 mL). The wet cake is also washed with ether (200 mL) and the ether solutions are combined and washed with water (200 mL) and dried over MgSO. The solvent is evaporated to give a crystalline product (19.04 g, 46%), with a melting point of 78-81 ° C; MS (Cl): M + l = 138.

Acetic acid 2-acetylamino-6-methyl-benzyl ester. A solution of 2-amino-6-methyl-phenyl) -methanol (19.04 g, 138.9 mol) in acetic anhydride (100 mL) is heated to 50 ° C. for 2 hours. The excess acetic anhydride was removed under vacuum to give a pale brown solid, crystallized from CC14 (29.8 g, 97%), with a melting point of 118-119 ° C. (Rep. 118-118.5 ° C); MS (Cl): M + l = 222.

Acetic acid 2-acetylamino-6-methyl-3-nitro-benzyl ester. To a solution of acetic acid 2-acetylamino-6-methyl-benzyl ester in acetic acid (400 mL), nitric acid (60%, 16 mL) is added dropwise maintaining the temperature below 5 ° C. while stirring. The reaction mixture is stirred for an additional 2 hours at room temperature and poured into ice water and stirred for 0.5 hours. A brown oil is separated which under a treatment with ethyl acetate (50 mL) gives fluffy needles, (7.65 g, 18.5%), with a melting point of 148-149 ° C. (Rep. 147-148 ° C); MS (Cl): M + l = 267. (2-amino-6-methyl-3-nitro-phenyl-methanol) Acetic acid 2-acetylamino-6-methyl-3-nitro-benzyl ester (7g, 26.2 moles) is dissolved in methanolic KOH (0.5N). The solution is evaporated after 1 hour of stirring at room temperature.The product is extracted into EtOAc (150 mL), washed with water and saline and dried with MgSO.The evaporation of the solvent gives orange needles (4.45 g, 93.4%), with a melting point of 134-136 ° C. (rep 135-136 ° C).

General Method for the Preparation of 2- (disubstituted aminomethyl-3-methyl-6-nitro-phenylamine) To a suspension of (2-amino-6-methyl-3-nitro-phenyl) -methanol (1 eq) and PPh3 (1.5 eq.) In benzene (10 mL), diethyl azodicarboxylate (DEAD) (1.5 eq) is added under nitrogen at 5 ° C. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The dark reaction mixture is concentrated in vacuo and the residue is chromatographed on silica gel (hexanes: ethyl acetate, 95: 5 to 75:25) to give the desired product. Several synthesized derivatives are mentioned in Table 1 below: TABLE 1 General Method for the preparation of 3-dialkylamino-methyl-4-methyl-benzene-1, 2-diamine A solution of 2 - (disubstituted aminomethyl-3-methyl-6-nitro-phenylamine (1 eq., Approximately 5 moles) ) in methanol (75 mL) is hydrogenated (CH2, 50 psi) in a Parr apparatus The reaction is monitored by TLC (SIO2, pet ether: EtOAc, 1: 1) and filtered to completion. and the product obtained is used in addition without further purification.

General Method for the preparation of 5-dialkylamino-methyl-6-methyl-1,4-dihydro-quinoxaline-2,3-dione.

A solution of 3-dialkylaminomethyl-4-methyl-benzene-1,2-diamine (1 eq) and dimethyl oxalate (1.5 eq) in methanol (35 mL) is heated at reflux for 16 hours. The reaction mixture is partially evaporated to give the product as a solid, which is further used without further purification. The synthesized compounds are mentioned in Table 2 below: TABLE 2 General Method for the preparation of 5-dialkylamino-methyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione To a solution of 5-dialkylamino-ethyl-6-methyl-1,4- dihydro-quinoxaline-2, 3-dione (1 eq., ca. 2-5 moles) in concentrated H2SO4 (5 mL) or TFA (5 mL). KN03 is added at 0 ° C: while stirring. In case of having H2SO4 as a solvent, the reaction mixture is poured onto ice and the resulting solid is crystallized or passed through a column (SiO2, CHC13 and CHCl3: MeOH 95: 5) to give the product pure. With TFA as a solvent, the excess TFA is evaporated (<35 ° C.) and the resulting solid is purified as mentioned above after neutralization with NH3.

The synthesized compounds are mentioned in Table 3 below: TABLE 3

Claims (14)

CLAIMS.

1. A compound of Formula I or a pharmaceutically acceptable salt thereof where: R is a secondary or tertiary amine; Ri is hydrogen, alkyl, aralkyl, carboxy alkyl, phosphoalkyl, or phosphonoalkyl; R2 is hydrogen, hydroxy or amino; R3 and R-i are each independently: hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, nitro. cyano, SO2CF3, C (O) Re, (CH2) mCO2R9 where R9 is hydrogen, alkyl, aralkyl or cycloalkyl, (CH2) raCONR7R8, (CH2) mS02NR7R8, or NHCORi where m is an integer from 0 to 4, R? is hydroxy, alkoxy, ', alkyl, haloalkyl, aryl, aralkyl and R7 and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl or aryl; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano, - S02CF3 C (O) R ", (CH2) mCONR7R8, SONR7R «, or NHCOR« where m, R7 and Rg are as defined above; in position b - in the ring; and Rn and R12 are each independently: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, where q is an integer from 0 to 3 and Ri3 and R1 are each independently selected from hydrogen, alkyl, aralkyl, cycloalkyl and heteroalkyl and R15 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and NRißRp where R and Rp are each independently selected from hydrogen, alkyl and aryl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, where p and p 'are each independently an integer selected from 0 to 1 and where 1 or 2 carbon atoms in the second ring can be replaced by 1 or 2 heteroatoms selected from N, O or S.

2. A compound according to claim 1 wherein: ~~ NX ^ p where Rp and R12 are each independently: hydrogen, alkyl, cycloalkyl, non-aromatic heterocycloalkyl, R13 and R14 = independently hydrogen, alkyl, aralkyl, cycloalkyl, heteroaralkyl, where q is an integer from 0 to 3 and R] 5 is: hydrogen, alkyl, aralkyl, aryl, heteroaryl, NRißRp wherein R 6 and Rp are each independently selected from: hydrogen, alkyl and aryl.

3. A compound according to Claim 2 wherein: Rn and R12 are each independently: hydrogen, methyl, ethyl, propyl, butyl, or cycloalkyl, heterocycloalkyl, alkylaminoalkyl, aminoalkyl, hydroxyalkyl, and alkoxyalkyl.

4. A compound according to Claim 2 where: Rp and R12 are each independently: hydrogen, methyl, ethyl, propyl, butyl, or cyclohexyl; Ri is hydrogen; R2 is hydrogen; R- and R. are each independently hydrogen or nitro and R5 is methyl.

5. A compound according to Claim 2, selected from: 5-Diethylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5 - . 5 - . 5-Dipropylaminoethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5-Dibutylaminomethyl-6-methyl-7-mtro-1,4-dihydro-quinoxaline-2,3-dione; 5-Cycloexilaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione; 5 - [(Cyclohexyl-methyl-amino) -methyl] -6-methyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione.

6. A compound according to Claim 2 called 5 Dimethylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 together with a pharmaceutically acceptable carrier in unit dosage form.

8. A method for treating disorders in response to blockage of glutamate receptors in a patient suffering from that and which comprises the administration of a composition according to Claim 1.

9. A method for treating attacks which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of such treatment.

10. A method for treating hypoxia / cerebral ischemia which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of such treatment.

11. A method for treating Alzheimer's disease, which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of such treatment.

12. A method for treating Parkinsonism, which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of such treatment.

13. A method for treating Huntington's disease, which comprises administering a therapeutically effective amount of a compound according to the Claim 1 to a patient in need of said treatment.

14. A method for treating disorders in response to anticonvulsants, which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of such treatment. EXTRACT OF THE INVENTION A new series of substituted 2, 3-dione quinoxalines useful as neuroprotective agents is taught. The novel intermediates, the preparation processes and the pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate antagonists and are useful in the treatment of attacks, ischemia or cerebral infarction resulting from an attack by thromboembolism or hemorrhagic attack, cerebral vasospasms, hypoglycemia, cardiac arrest, epileptic status, perinatal asphyxia, anoxia, Alzheimer's diseases, Parkinson's. and Huntington.