WO1998023599A1 - Urea and thiourea derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists - Google Patents

Abstract

A novel series of substituted quinoxaline 2,3-diones useful as neuroprotective agents are taught. Novel intermediates, processes of preparation, and pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate antagonists and are useful in the treatment of stroke, cerebral ischemia, or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, seizure disorders, pain, Alzheimer's, Parkinson's, and Huntington's Diseases.

Description

UREA AND THIOUREA DERIVATIVES OF SUBSTITUTED

QUINOXALINE 2,3-DIONES AS GLUTAMATE

RECEPTOR ANTAGONISTS

FIELD OF THE INVENTION

The present invention concerns novel urea and thiourea derivatives of substituted quinoxaline 2,3-diones having utility as glutamate receptor antagonists. The fused ring quinoxaline 2,3-dione system is substituted at the a- or b-position by urea or thiourea derivatives. The compounds are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl-D-aspartate (NMD A) receptors and non-NMDA receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMP A) receptor and the kainate receptor. The invention also relates, therefore, to the use of those quinoxaline-2,3-diones as neuroprotective agents for treating conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as to treat chronic neurodegenerative disorders such as Alzheimer's Disease, Parkinsonism, and Huntington's Disease, and seizure disorders and pain. The compounds of the present invention may 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 believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, the α-amino-3-hydroxy-5-methyl-

4-isoxazole propionic acid (AMP A) receptor, and the kainate receptor. AMPA/kainate receptors may be referred to jointly as non-NMDA receptors. This excitotoxic 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 thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (Bigge C.F. and Malone T.C., Curr. Opin. Ther. Pat, 1993:951; Rogawski M.A., JjPS, 1993;14:325). AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (Li H. and Buchan A.M., J. Cerebr. Blood Flow Metab.. 1993;13:933; Nellgard B. and Wieloch T., J. Cerebr. Blood Flow Metab.. 1992; 12:2) and focal cerebral ischemia (Bullock R., Graham D.I., Swanson S., and McCulloch J., J. Cerebr. Blood Flow Metab.. 1994; 14:466; Xue D., Huang Z.-G., Barnes K.,

Lesiuk H.J., Smith K.E., and Buchan A.M., J. Cerebr. Blood Flow Metab., 1994;14:251). AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-J., Hao J.-X, Seiger A., and Wiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther.. 1993;267:140), and epilepsy (Namba T., Morimoto K., Sato K., Yamada N., and Kuroda S., Brain Res.. 1994;638:36; Brown S.E. and

McCulloch J., Brain Res.. 1994;641 :10; Yamaguchi S.I., Donevan S.D., and Rogawski M.A., Epilepsy Res.. 1993;15:179; Smith S.E., Durmuller N., and Meldrum B.S., Eur. J. Pharmacol.. 1991;201 :179). AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism (Klockgether T., Turski L., Honore T., Zhang Z., Gash D.M.,

Kurlan R., and Greenamyre J.T., Ann. Neurol.. 1993;34(4):585-593).

Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain, and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's Disease (Klockgether T. and Turski L., Ann. NeuroL. 1993;34:585-593), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's Disease (Francis P.T., Sims N.R., Procter A.W., and Bowen D.M., J. Neurochem., 1993;60(5):1589-1604), and Huntington's Disease. (See Lipton S., TINS. 1993;16(12):527-532; Lipton S.A. and Rosenberg P.A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C.F.. Biochem. Pharmacol.. 1993;45:1547-1561 and references cited therein.) NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).

Copending United States Serial Number 08/443,507 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula:

wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl, or CH2CH2OH. This application does not disclose or suggest compounds having the instant ureas or thioureas as substituents, or the requisite methodology to prepare the same.

Copending application United States Serial Number 08/404,400 teaches glutamate receptor antagonists which are quinoxalinediones of 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, CONR4R5 SO2CF3, SO2R4, SONR4R5, alkyl, alkenyl,

(CH2)_zCONR4R₅, (CH2)_zCOOR₄, or NHCOR4, wherein R4 and R5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, or alkylaryl, and z is an integer from 0 to 4;

R2 is alkylCOOR3, alkylamine, alkylguanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR₃alkyl, CONR₃aryl, CONR3 alkylaryl, CSNR₃alkyl,

CSNR3 alkylaryl or a common amino acid moiety joined by an amide bond, wherein R3 is hydrogen, alkyl, or alkylaryl; and m and n are independently 0, 1, or 2 provided that m + n is >1.

This application does not disclose or suggest the compounds of the instant invention having ureas or thioureas as substituents at the a- or b-positions nor the methodology to prepare them.

JP06228112- A discloses glutamate receptor antagonists which are quinoxaline-2,3(lH,4H)-dione derivatives of formula

wherein R\ is H, NO2, or CF3;

Ring A is a nitrogen-containing saturated heterocyclic group which may contain sulfur or oxygen;

R2 is H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH2, or lower alkoxy carbonyl-amino.

This reference does not teach or suggest the instant compounds which must be attached to the quinoxaline dione fused ring system by an alkylene.

WO 93/08188 covers a tricyclic quinoxalinedione of formula

as useful or selective antagonists of glutamate receptors.

European Patent Application 0627434 covers tricyclic quinoxalinedione of Formula I below which are selective antagonists of glycine binding site of the NMDA receptor

wherein X represents hydrogen, alkyl, halogen, cyano, trifluoromethyl, or nitro;

R\ represents hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; G represents -CONR2- or -NR2CO-, wherein R2 represents hydrogen or alkyl;

J represents an acidic group or a group which is convertible thereto in vivo;

E represents a basic group or a group which is convertible thereto in vivo;

Y represents a single bond, alkylene, alkenylene, substituted alkylene, or Yl-Q-Y2, wherein Y\ represents a single bond or alkylene, Y2 represents alkylene, and Q represents a heteroatom selected from oxygen or sulfur; and

Z represents alkylene.

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 NOR2, wherein R2 is hydrogen, alkyl, or benzyl; Y is N-R4, wherein R4 is hydrogen, OH, or alkyl; n is 0 or 1 ;

R6 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 with the benzo ring at the positions marked a and b.

WO 97/08155 teaches compounds of formula

for the treatment of pathological conditions that are responsive to blocking of AMPA, kainate, and/or glycine binding sites of the NMDA receptor.

The process for the synthesis of these urea and thiourea derivatives is unique due to the excellent regioselectivity observed in the bromination reaction. Bromination takes place selectively at one of the methyl groups, which is used to synthesize the important convergent aminomethyl intermediate. Selectivity of bromination is particularly important as the other methyl group is important for rendering the aminomethyl group a semi-constrained conformation and noncoplanar with the quinoxaline 2,3-dione nucleus. This noncoplanarity is important to provide greater aqueous solubility for compounds having quinoxaline 2,3-dione nucleus. Increased aqueous solubility is an important attribute in pharmaceuticals.

An object of this invention is to provide novel quinoxalinediones with ureas or thioureas at the a- or b-positions which function as antagonists.

SUMMARY OF THE INVENTION

The present invention pertains to compounds represented by Formula I:

or a pharmaceutically acceptable salt thereof wherein R, Ri , R2, R3, R4, R5, and n are as described below.

The present invention also pertains to a pharmaceutical composition containing the compound defined by Formula I in an amount effective to treat cerebrovascular disorders responsive to the blockade of glutamate receptors (such as the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor), and a pharmaceutically acceptable carrier. Exemplary disorders responsive to such treatment include cerebral ischemia caused by cerebral trauma, stroke, hypoglycemia, 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 may also be employed as an analgesic or the treatment of epilepsy.

The invention further relates to a method of treating cerebrovascular disorders responsive to the antagonism of glutamate or aspartate receptors in a human by administering a pharmaceutically effective amount of the 2,3-quinoxalinediones of this invention and further to administering said compound in a unit dosage form.

The invention further relates to novel methods of preparing the 2,3-quinoxalinediones and to novel intermediates useful in their preparation.

DETAILED DESCRIPTION OF THE INVENTION

The substituted quinoxaline-2,3-diones of the instant invention are those of Formula I

or a pharmaceutically acceptable salt thereof wherein R is a urea or thiourea; n is an integer of from 1 to 4; R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;

R2 is hydrogen, hydroxy, or amino;

R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, halogen, haloalkyl, nitro, cyano, SO2CF3, CH2SO2R6, (CH₂)_mCO₂R₆, (CH₂)mCONR₇R₈, (CH₂)_mSO2NR₇R₈, or NHCOR₆ wherein m is an integer of from 0 to 4, and R , R7, and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl;

R5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, SO2CF3, (CH2)_mCO2R9, (CH₂)_mCONR₉R₁₀, SONR₉R! ₀, or NHCOR9; m is an integer of from 0 to 4;

R9 and RJO are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; and

R5 may be at the a-position and R-(CH2)_n- at the b-position on the ring. Preferred compounds are those of Formula I wherein R is

R X

11- R

\ II / 12

N— C-N

R 13 wherein X is O or S;

R\ i is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, hydroxyl, hydroxyalkyl, alkoxyalkyl;

Rj2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, hydroxyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, -SO2R14, -SO2NRi₅R₁₆, -(CH2)_nSO2Ri4, -(CH₂)_nSθ2NR₁₅R₁₆, -(CH₂)_nCO₂Ri7, -(CH₂)_nCONR₁₈R₁₉, or is a natural or unnatural amino acid (α-, β-, or γ-) backbone such as -CH(R2θ)C(O)ORι 7 or -CH(R2θ)C(O)NRι gRi 9; wherein R\A is hydroxy, alkoxy, or -NRi 5R15; R15, R\ g, R\ g, and R\ 9 are independently selected from hydrogen alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl; R17 is hydrogen, alkyl, aralkyl, cycloalkyl, heterocycloalkyl; R20 is hydrogen or a side chain of a natural or unnatural amino acid; n is an integer of from 1 to 4;

Ri 3 is hydrogen or joined together with R\ to form a mono- or bicyclic ring, unsubstituted or substituted by from 1 to 4 substituents, and is

of from 5 to 7 atoms or

1 of from 10 to 12 atoms

wherein

Y and Z are each independently carbon which is substituted by hydrogen, halogen, haloalkyl, alkyl, alkoxyl, alkoxyalkyl, -NR15R16, aminoalkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl, cycloalkyl, -SO₂Ri₄, -SO₂NR₁₅R₁₆, -(CH₂)nSO2NR₁₅Ri₆, -(CH₂)nSO₂Ri4, or is -O- or -S-;

R21 is absent or is hydrogen, alkyl, alkoxy, alkoxyalkyl, -NR13R14, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxyl, or hydroxyalkyl, or may represent a gem-dialkyl of two idependently selected alkyl groups and when Y is carbon an integral double bond may be optionally located between C3 and C4 of the 5- to 7-membered ring.

Bicyclic structures encompassed in this invention include spiro ring structures, wherein both ends of a second ring are attached to the same carbon unit on the parent ring.

For monocyclic and bicyclic structures wherein Y or Z represent a carbon atom, the structure may also include an integral double bond.

More preferred compounds of Formula I wherein R is

X ^lll- \ II / ^{^}12

N— C-N

R 13

are those wherein X is O or S;

R\ 1 is hydrogen, alkyl, cycloalkyl, aralkyl, heteroaralkyl, hydroxyl, alkoxyl, aralkoxyl;

Ri 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, -SO₂Ri₄, -SO₂NR₁₅R₁₆, -(CH₂)_nSO₂Ri4, -(CH₂)nSO2NR₁₅R₁₆;

Rj3 is hydrogen or joined together with Rj \ to form a monocyclic ring, unsubstituted or substituted by from 1 to 4 substituents and is

of from 5 to 7 atoms

wherein R21 is absent or is hydrogen or alkyl;

Y is carbon which is substituted by hydrogen, alkyl, alkoxyl, or aminoalkyl.

Still more preferred are those of Formula I wherein R is

R 11 ^x 1

^■\ II / ^l12

N — C-N / \ R 13

wherein X is O or S;

R\ 1 is hydrogen, alkyl, cycloalkyl, aralkyl, heteroaralkyl, hydroxyl, alkoxyl;

R]2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, -SO2R14, -SO2NR15R16; wherein R14 is hydroxyl, alkoxyl, -NRj 5R16, or haloalkyl and R\ζ and R\ are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl; and R13 is hydrogen.

Most preferred compounds of Formula I are selected from: 1 -Methyl- 1 -(6-methyl-7-nitro-2,3 -dioxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-5- ylmethyl)-3-phenyl-urea,

3 -(4-Methoxy-phenyl)- 1 -methyl- 1 -(6-methyl-7-nitro-2,3-dioxo- 1 ,2,3 ,4- tetrahydro-quinoxalin-5-ylmethyl)-urea,

3 -(4-Methoxy-phenyl)- 1 -methyl- 1 -(6-methyl-7-nitro-2,3 -dioxo- 1 ,2,3 ,4- tetrahydro-quinoxalin-5-ylmethyl)-thiourea,

3 -(2,4-Dimethyl-phenyl)- 1 -methyl- 1 -(6-methyl-7-nitro-2,3-dioxo- 1 ,2,3 ,4- tetrahydro-quinoxalin-5-ylmethyl)-urea,

3-(2,5-Dimethoxy-phenyl)-l-methyl-l-(6-methyl-7-nitro-2,3-dioxo- l,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-urea, 1 -Methyl- 1 -(6-methyl-7-nitro-2,3 -dioxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-5- ylmethyl)-3 -(2-trifluoromethyl-phenyl)-urea, and 4-(3-Methyl-3-(6-methyl-7-nitro-2,3-dioxo-l,2,3,4-tetrahydro-quinoxalin- 5-ylmethyl)ureido)-benzoic acid ethyl ester.

Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. These forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, isethionate, and the like. Also contemplated are salts of amino acids 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 may 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.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

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

Certain of the compounds of the present invention may exist as a mixture of cis and trans isomers or as the individual cis and trans isomers or R and S stereoisomers. The mixture of 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 a straight 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 attached to a carboxy group.

The term "phosphoroalkyl" means alkyl as above and attached to a phosphoro group.

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

The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 3 to 6 carbon atoms and includes, for example, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like. Alkynyl means a straight or branched unsaturated hydrocarbon radical of from 2 to 6 carbon atoms and includes but is not limited to ethynyl, 2,3-propynyl, 1,2-propynyl, and 3,4-butynyl.

"Alkoxy" is O-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl". The term "aryl" means an aromatic radical which is a phenyl group, a phenyl 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 l,3-benzodioxol-5-yl.

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

The term "heteroaryl" means a heteroaromatic radical which is 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, isoquinolines, quinolines, imidazolines, pyrroles, indoles, and thiazoles.

"Halogen" is fluorine, chlorine, bromine, or iodine. The term "haloalkyl" means halogen and alkyl as defined above, for example, but not limited to, trifluoromethyl and trichloromethyl.

"Alkylaryl" means aryl as defined above and alkyl as defined above, for example, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; a preferred group is benzyl. The term "heterocycloalkyl" means a nonaromatic ring with from 4 to

7 members, with up to 4 heteroatoms for example, N, O, and S.

Common amino acid moiety means the naturally occurring α-amino acids, unnatural amino acids, substituted β, γ, δ amino acids and their enantiomers. Common amino acids are: Alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

Modified and unusual amino acids are as would occur to a skilled chemist and are, for example, but not limited to: 10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)glycine or α-Amino-10,1 l-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (Para- phenyl)phenylalanine,

3 ,3 -Diphenylalanine, 3-Hydroxyproline, 4-Hydroxyproline,

N-Methylphenylalanine, N-Methylaspartic acid, N-Methylisoleucine, N-Methylvaline, Norvaline, Norleucine,

Ornithine,

2-Aminobutyric acid, 2-Amino-4-pentanoic acid (Allylglycine),

NC-Nitroarginine, 2- Amino-3 -(2-amino-5 -thiazole)propanoic acid,

2-Amino-3-cyclopropanepropanoic acid (Cyclopropylalanine), Cyclohexylalanine (Hexahydrophenylalanine), N-Methylcyclohexylalanine (N-Methylhexahydro-phenylalanine), 2-Amino-4,4(RS)-epoxy-4-pentanoic acid, N^im-2,4-Dinitrophenylhistidine,

2-Aminoadipic acid,

2-Amino-5-phenylpentanoic acid (Homophenyl-alanine),

Methionine sulfoxide,

Methionine sulfone, 3-(l'-Naphthyl)alanine,

3 -(2'-Naphthyl)alanine,

2-Amino-3-cyanopropanoic acid (Cyanoalanine),

Phenylglycine,

2-Aminopentanoic acid (Propylglycine), 2-Amino-6-( 1 -pyrrollo)-hexanoic acid,

2-Amino-3-(3-pyridyl)-propanoic acid (3-Pyridylalanine),

1 ,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid,

2- Amino-3 -(4-thiazolyl)-propanoic acid,

O-Tertiary butyl-tyrosine, O-Methyl-tyrosine,

O-Ethyl-tyrosine, N^ιn-Formyl-tryptophan,

5H-Dibenzo[a,d]cycloheptene glycine,

9H-Thioxanthene glycine, and

9H-Xanthene glycine. Spiro rings include but are not limited to 5- to 7-membered carbocyclic or heterocyclic ring with up to 4 heteroatoms.

The compounds of the invention exhibit valuable biological properties because of their strong excitatory amino acid (EAA) antagonizing properties at one of several binding sites on glutamate receptors: the AMPA ((RS)-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (or kainic acid) binding site on

AMPA (non-NMDA) receptors or the glycine site of NMDA receptors.

The compounds of the present invention exhibit binding affinity for the AMPA receptors measured as described in Honore T., et al., Neuroscience Letters, 1985;54:27-32. Preferred compounds demonstrate IC50 values <100 μM in this assay. The compounds of the present invention exhibit binding affinity for the kainate site (non-NMDA receptor) measured 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 of the NMDA receptor measured as described in Jones S.M., et al., Pharmacol. Methods. 1989;21:161. To measure functional AMPA antagonist activity, the effects of the agent on AMPA-induced neuronal damage in primary cortical neuronal cultures was examined using techniques similar to those outlined by Koh J.-Y., et al., J. Neurosci., 1990; 10:693. In addition, the neuronal damage produced by long-term exposure to 100 μM AMPA may be measured by the release of the cytosolic enzyme lactate dehydrogenase (LDH).

Selected compounds of the present invention were tested by one or more of the above-described assays. The data obtained in the assays is set forth in Table 1 below. The IC50 values are a measure of the concentration (μM) of the test substance which inhibits 50% of an induced release from the tested receptors. TABLE 1. Quinoxaline 2,3-diones Compound IC50 (μM)

AMPA KA GLY

1. l-Methyl-l-(6-methyl-7-nitro-2,3-dioxo- 0.13 0.82 0.008 1 ,2,3 ,4-tetrahydro-quinoxalin-5 -ylmethyl)-3 - phenyl-urea

2. 3-(4-Methoxy-phenyl)-l-methyl-l-(6-methyl- 0.17 1.12 0.005 7-nitro-2,3-dioxo-l,2,3,4-tetrahydro- quinoxalin-5-ylmethyl)-urea

3. 3-(4-Methoxy-phenyl)-l-methyl-l-(6-methyl- 0.23 2.54 0.04 7-nitro-2,3 -dioxo- 1 ,2,3 ,4-tetrahydro- quinoxalin-5-ylmethyl)-thiourea

4. 3-(2,4-Dimethyl-phenyl)-l-methyl-l-(6- 3.6 6.7 0.02 methyl-7-nitro-2,3 -dioxo- 1 ,2,3 ,4-tetrahydro- quinoxalin-5-ylmethyl)-urea

5. 3-(2,5-Dimethoxy-phenyl)-l -methyl- 1 -(6- 3.0 9.54 0.01 methyl-7-nitro-2,3 -dioxo- 1 ,2,3 ,4-tetrahydro- quinoxalin-5 -ylmethyl)-urea

6. l-Methyl-l-(6-methyl-7-nitro-2,3-dioxo- 2.85 7.50 0.01 l,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-3- (2-trifluoromethyl-phenyl)-urea

7. 4-(3-Methyl-3-(6-methyl-7-nitro-2,3-dioxo- 4.11 18.4 0.01 1 ,2,3,4-tetrahydro-quinoxalin-5- ylmethyl)ureido)-benzoic acid ethyl ester

Additionally, as a preliminary indicator of in vivo CNS activity related to anticonvulsant activity and potential neuroprotection, a maximal electroshock assay in CF-1 strain mice (20-25 g) was performed with corneal electrodes by conventional methods as described previously (Krall, et al., Epilepsia, 1988;19:409-428). The compounds of this invention generally demonstrated ED50 values of <50 mg/kg.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 10 mg of active ingredients or, more broadly, 0.1 to 100 mg per tablet, and accordingly suitable representative unit dosage forms.

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

The compounds of this invention are extremely useful in the treatment of central nervous system disorders related to their biological activity. The compounds of this invention may accordingly be 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 includes especially excitatory amino-acid-dependent psychosis, excitatory amino-acid- dependent anoxia, excitatory amino-acid-dependent ischemia, excitatory amino- acid-dependent Parkinsonism, excitatory amino-acid-dependent convulsions, and excitatory amino-acid-dependent migraine. Suitable dosage ranges are 0.1 to 1000 mg daily, 10 to 50 mg daily, and especially 30 to 100 mg daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved, and the body weight of the subject involved, and further, the preference and experience of the physician or veterinarian in charge. The schemes and examples which follow are intended as an illustration of certain preferred embodiments of the invention, and no limitation of the invention is implied.

General Scheme I

( 1 ) ( 2 )

(d).

General Scheme I (continued)

( : ( 8 )

( 9 ) ( io ;

Step (a) of Scheme I above involves formation of a cyclic carbamate derivative of Formula (2) by reacting aminobenzyl alcohol derivative of Formula (1) with a reactive acylating agent, preferably phosgene in the presence of a tertiary organic base like triethylamine in a ethereal solvent, preferably THF at temperatures ranging from -10°C to room temperature. Alternatively, aqueous inorganic bases such as sodium carbonate, sodium bicarbonate, or potassium carbonate, preferably aqueous sodium carbonate. The reaction mixture is stirred for 2 to 16 hours and diluted with water. Product is extracted with water insoluble solvent like ethyl acetate. The extracts washed with water and brine and dried over MgSO4. The product was crystallized from solvent mixture, preferably EtOAc and pet. ether.

Step (b) involves bromination of the cyclic carbamate derivative of Formula (2) with a brominating agent like bromine in an acidic solvent mixture like AcOH and TFA. The reaction is done at temperatures between 10°C to room temperatures. Reaction mixture is stirred for around 2 hours and poured over ice water. The precipitate is filtered and dried at elevated temperatures, preferably at 120°C. Step (c) involves the nitration of the bromo cyclic carbamate derivative as shown in Formula (3) with a nitrating agent like nitronium fluoroborate nitric acid or potassium nitrate, preferably potassium nitrate in an acidic solvent like sulfuric acid at temperatures between 0°C to room temperature. Reaction carried out for 4 to 16 hours, preferably around 14 hours and poured over ice. The precipitate was filtered and air dried to give the desired product.

Step (d) involves the reaction of the nitro cyclic carbamate derivative as shown in Formula (4) with a secondary amine, preferably N-methyl-benzylamine. Reaction is carried out at elevated temperatures between 100°C to 180°C with or without a solvent like N-methyl-formamide, preferably without a solvent for about 18 hours. Volatile materials were evaporated under reduced pressure and the product isolated from the crude via column chromatography using pet. etheπEtOAc as the solvent mixture to give the desired benzylamine derivative. Step (e) involves the hydrogenation (H2, around 50 psi) of the benzylamine derivative as shown in Formula (5) in the presence of a catalyst like Ra Ni and a base, preferably KOH in a hydroxylated solvent like methanol. The catalyst is filtered off, and the filtrate is evaporated to give the o-phenylene derivative, which is used in the next step without additional purification. Step (f) involves cyclization reaction from quinoxaline 2,3-dione derivative by reacting the o-phenylene diamine derivative as shown in Formula (6) with an oxalic acid derivative like dimethyl oxalate in a hydroxylated or ethereal solvent, preferably THF at reflux temperature. Reaction carried out for about 12 to

24 hours, preferably 16 hours and partially evaporated to give a crude product which is purified by crystallization.

Step (g) involves hydrogenation (H2, 50 psi) of the benzylamine quinoxaline 2,3-dione intermediate as shown in Formula (7) using Pd/C (5-20%), preferably Pd/C (20%) as a catalyst in a polar solvent like DMF. The suspension was filtered, and the filtrate was evaporated to give a solid, which was crystallized from a hydroxylated solvent like methanol.

Step (h) involves nitration of the quinoxaline 2,3-dione derivative shown in Formula (8) using potassium nitrate or nitric acid, preferably potassium nitrate as the nitrating agent. The reaction is carried out in an acidic solvent like sulfuric acid from temperatures ranging from 0°C to room temperature. Reaction mixture is poured in ice, and the precipitate obtained is filtered and air dried.

Step (i) involves reaction of the N-methyl- benzylamine moiety of quinoxaline-2,3-dione shown in Formula (9) with various isocyanates or isothiocyanates to give the corresponding ureas or thioureas. Thus, a solution of

Compound 9 in a polar solvent like DMF is treated with 0.95 to 1.5 equivalents of isocyanate or isothiocyanate at temperatures ranging from 0°C to room temperatures preferably room temperature. The reaction is carried out from 2 to 18 hours depending on the electrophile preferably around 16 hours. Reaction mixture is evaporated to dryness, and the residue is treated with water for 0.5 hour and filtered. The desired urea was purified by crystallization (CHCI3 and CH3OH mixture) or chromatography (Siθ2) using CHCl3:MeOH mixture as the eluent.

An alternative method for Step (i) uses parallel solution-phase synthesis. Thus, a solution of Compound 9 in a solvent like dioxane containing a organic base such as triethylamine is treated with 0.95 to 1.5 equivalents of the appropriate isocyanate or isothiocyanate and shaken for approximately 14 hours at ambient temperatures, preferably room temperature. A slight molar excess of sarcosine potassium salt followed by water are added, and the mixture is shaken for an additional 30 minutes. After filtration, the precipitated urea or thiourea is washed with CHCI3 and air dried.

These general experimental schemes cover most of the final products of the invention. Others are made by known experimental procedures.

The above methodology can be used to synthesize ureas or thioureas of the invention as follows: Scheme 1

5-Methyl- 1 ,4-dihydro-benzo[d1 \ 1 ,31-oxazin-2-one

To a solution of (2-amino-6-methyl-phenyl)-methanol (2.74 g, 20 mmol) and triethylamine (4.04 g, 40 mmol) in THF (150 mL), phosgene (12.5% solution in toluene, 17.42 g, 22 mmol) was added dropwise at 0°C. Reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Water (150 mL) was added under stirring, followed by EtOAc (2 x 100 mL). EtOAc extracts were washed with water and brine and dried over MgSO4. The product (buff solid) was crystallized from EtOAc:pet. ether mixture. (Yield: 2.37 = 73%); mp 222-226°C; MS (CI): M+l = 163.

6-Bromo-5-methyl-l,4-dihvdro-benzo[^"d][T.31oxazine-2-one

To a solution of 5-methyl-l,4-dihydro-benzo[d][l,3]oxazin-2-one (0.695 g, 4.3 mmol) in acetic acid (5 mL), Br2 (0.805 g = 5 mmol) solution in TFA

(5 mL) + acetic acid (5 mL) was added at 10°C. Reaction mixture was stirred for 2 hours and poured over ice water. Yellow precipitate was filtered and dried at 120°C.

(Yield: 0.941 g = 90%); MS (CI): M+l = 243; M+2 = 244.

6-Bromo-5-methyl-8-nitro-1.4-dihvdro-benzo d] l,31oxazin-2-one

To a solution of 6-bromo-5 -methyl- l,4-dihydro-benzo[d] [1,3] oxazin-2-one (0.726 g, 3 mmol) in concentrate H2SO4 (4 mL), KNO3 (0.303 g, 3 mmol) was added at 0°C. Reaction mixture stirred 14 hours and poured over crushed ice. Yellow precipitate was obtained, which was filtered and dried. (Yield: 0.782 = 91%); MS (CI): M+l = 288; M+2 = 289.

2-r(Benzyl-methyl-amino)-methyll-4-bromo-3-methyl-6-nitro-phenylamine

6-Bromo-5-methyl-8-nitro- 1 ,4-dihydro-benzo[d] [ 1 ,3]oxazine-2-one (11.48 g, 40 mmol) was heated to 140°C for 18 hours. TLC (Siθ2, pet ether:EtOAc, 1:1) indicated completion. Volatile material concentrated on rotavap and the dark oil extracted with ethyl acetate (2 x 250 mL). Solvent evaporated to give viscous oil, which on trituration with ethyl acetate (150 mL) gave yellow crystalline product. Yield in two crops: 10.17 g = 70%; MS (CI): M+l = 364; Elemental analysis calculated for Ci6Hj BrN3θ2:

C, 52.76; H, 4.98; N, 11.54. Found: C, 52.22; H, 4.87; N, 11.11.

3-r(Benzyl-methyl-amino)-methyl1-4-methyl-benzene-1.2-diamine

2-[(Benzyl-methyl-amino)-methyl]-4-bromo-3-methyl-6-nitro- phenylamine (6 g, 16.5 mmol) was hydrogenated (RaNi, 3 g) in the presence of KOH (0.498N). Reaction mixture filtered and extracted in CHCI3 (200 mL) and washed with water and dried (MgSO4). Solvent evaporated to give a dark oil

4.19 g = 99%.

H-NMR: 1.96 (s, 3H), 2.08 (s, 3H), 3.36-3.39 (m, 4H), 4.23 (s, 2H), 4.73 (s, 2H),

6.18 (d, 1H, J = 7.3 Hz), 6.33 (d, 1H, J = 7.3 Hz), 7.21-7.26 (m, 5H).

5-r(Benzyl-methyl-amino -methyll-6-methyl-l,4-dihydro-quinoxaline-2,3-dione To a solution of diamine (4.19 g) in THF, dimethyl oxalate (2.36 g,

20 mmol) was added. Reaction mixture stirred at reflux for 16 hours and cooled. Buff ppt was filtered (2.93 g). Mother liquor gave two additional crops. Total yield: 3.945 g = 77.4%; mp 205-206°C; MS (CI): M+l = 310.

6-Methyl-5-methylaminomethyl-1.4-dihydro-quinoxaline-2.3-dione

A solution of 5-[(benzyl-methyl-amino)-methyl]-6-methyl-l,4-dihydro- quinoxaline-2,3-dione (3.23 g, 10.45 mmol) in DMF (100 mL) was hydrogenated (Pd/C, 20%, 0.5 g) in DMF (100 mL). The suspension was filtered, and the filtrate was evaporated to give a solid, which was crystallized from methanol. Yield: 1.276 g = 56%. MS (CI): M+l = 220.

6-Methyl-5-methylaminomethyl-7-nitro-l,4-dihydro-quinoxaline-2.3-dione To a cooled (10°C) solution of 6-methyl-5-methylaminomethyl-l,4- dihydro-quinoxaline-2,3-dione (10°C) of (1.23 g, 5.6 mmol) in concentrate H2SO4 (5 mL), KNO3 (0.606 g, 6 mmol) was added. Reaction mixture stirred overnight and quenched with ice. Green ppt filtered and washed with ice-cold water and dried (0.77 g, 42%); mp 260-261 °C. MS (CI): M+l = 265. General method for the synthesis of N-methyl ureas and thioureas

To a solution of 6-methyl-5-methylaminomethyl-7-nitro-l,4-dihydro- quinoxaline-2,3-dione (0.1 mmol) in DMF (2 mL), appropriate isocyanate or isothiocyanate (0.11 mmol) was added. Reaction mixture was stirred for 16 hours and evaporated. The residue was treated with water for 0.5 hour and filtered. The product was further washed with water (3 x 5 mL) and dried. The final product was purified by column chromatography (Siθ2, CHCl3:CH3OH, 100% to 95:5) or crystallization (CHCI3/CH3OH) mixture.

Parallel solution-phase synthesis of N-methyl ureas and thioureas

To a solution of 6-methyl-5-methylaminomethyl-7-nitro-l,4-dihydro- quinoxaline-2,3-dione (0.055 g, 0.2 mmol) in dioxane (0.5 mL), triethylamine (0.032 g, 0.3 mmol) was added. Appropriate isocyanate (1.5 equivalent) was then added, and the reaction was shaken on a shaker for approximately 14 hours. Sarcosine potassium salt (0.038 g, 0.3 mmol) was then added and followed by water (1 mL). Reaction mixture was shaken for additional 0.5 hour and filtered. The precipitate (desired urea) was washed with CHCI3 (2 mL) and air dried. Scheme 2

Alternate method to synthesize 6-methyl-5-methylaminomethyl-7-nitro- l,2,3,4-tetrahydro-2,3-dioxo-quinoxaline starting from 2,3-dimethyl-6- nitroaniline.

3.4-Dimethyl-benzene-l .2-diamine

A solution of 2,3-dimethyl-6-nitroaniline (83 g, 500 mmol) in methanol (1000 mL) was hydrogenated (H2, 50 psi) over Raney Nickel (5 g). On completion, the reaction mixture was filtered, and the mother liquor was evaporated to dryness to give a dark solid as the product. Yield: 67.8 g = 99%. MS (CI) m/z l37 (M+l).

5.6-Dimethyl- 1.4-dihydro-quinoxaline-2.3-dione

To a solution of 3,4-dimethyl-benzene-l, 2-diamine (67.5 g, 496 mmol) in 5N HCl (250 mL) was added oxalic acid dihydrate (69.3 g, 550 mmol). The reaction mixture was heated to 100°C under stirring. The reaction mixture was stirred for 8 hours and cooled to room temperature. The dark precipitate was filtered, washed, and dried.

Yield: 94.13 g = 99%. MS (CI) m/z 191 (M+l).

5,6-Dimethyl-7-nitro-1.4-dihvdro-quinoxaline-2.3-dione

To a solution of 5,6-dimethyl-l,4-dihydro-quinoxaline-2,3-dione (28.5 g, 150 mmol) in concentrated H2SO4 (50 mL) was added KNO3 (15.15 g,

150 mmol) portionwise keeping temperature below 5°C. Reaction mixture was stirred for 2 hours and poured over ice. Yellow precipitate was filtered, washed, and air dried.

Yield: 33.11 g = 94%.

MS (CI) m/z 236 (M+l).

2,3-Dichloro-5,6-dimethyl-7-nitro-quinoxaline

To a solution of 5,6-dimethyl-7-nitro-l,4-dihydro-quinoxaline-2,3-dione (33.11 g, 141 mmol) POCI3 (250 mL) was added PCI5 (60.3 g, 290 mmol). The reaction mixture was heated to reflux for 16 hours. Reaction mixture was poured over ice under vigorous stirring. Brown precipitate was filtered, washed with aqueous NaHCO3, water, and air dried. The solid was dissolved in EtOAc (2 x

200 mL) and filtered. Solvent was evaporated to give the product. Yield: 31.32 g = 81.6%. MS (CI) m/z 273.

2.3-Dimethoxy-5.6-dimethyl-7-nitro-quinoxaline

To a freshly prepared solution of NaOMe (Na, 3.68 g, 160 mmol; MeOH 200 mL) was added 2,3-dichloro-5,6-dimethyl-7-nitro-quinoxaline (17.02 g, 64 mmol) 7-nitro-5,6-dimethyl-2,3-dichloro-quinoxaline portionwise under vigorous stirring. Reaction mixture was refiuxed for 16 hours and poured in water (1 L). Yellow-brown precipitate was filtered and suspended in EtOAc (500 mL). The suspension was filtered, and the filtrate was evaporated to give an off-white precipitate. Yield: 12 g = 71.3%. MS (CI) m/z 264 (M+l).

5-Bromomethyl- 1 -2.3-dimethoxy-6-methyl-7-nitro-quinoxaline

To a solution of 2,3-dimethoxy-5,6-dimethyl-7-nitro-quinoxaline (2.63 g, 10 mmol) in CCI4 (50 mL) was added azo-isobutyronitrile (AIBN) (0.05 g) and

N-bromosuccinimide (1.95 g, 11 mmol). Reaction mixture was heated to 75 °C for about 16 hours and cooled. The filtrate was evaporated to dryness and product purified by column chromatography (Siθ2) using CHCI3 as the eluent. Off-white solid was obtained.

Yield: 3.29 g = 96%.

MS (APCI) m/z 341.8, 342.8

6-Methyl-5-methylaminomethyl-7-nitro-2,3-dimehoxy quinoxaline

To a solution of 5-bromomethyl-2,3-dimethoxy-6-methyl-7-nitro- quinoxaline (0.238 g, 0.76 mmol) in THF (5 mL) was added a saturated methylamine solution in THF (2 mL) at 5°C. Reaction mixture was allowed to warm to room temperature and stirred for 14 hours and evaporated to dryness. Water (5 mL) was added and the product extracted in EtOAc (2 x 25 mL). EtOAc extracts were dried (MgSO4), filtered, and evaporated to dryness. The product was purified by chromatography (Siθ2) using CHC^/MeOH (100% to 9:1) as the eluent.

Yield: 0.88 g = 40%.

MS (CI) m z 293 (M+l).

6-Methyl-5-methylaminomethyl-7-nitro-l,2.3.4-tetrahydro-2,3-dioxo-quinoxaline hydrochloride

To a solution of 6-methyl-5-methylaminomethyl-7-nitro-2,3-dimethoxy- quinoxaline (0.028 g, 0.095 mmol) in dioxane (1 mL) was added aqueous HCl (1 mL). The reaction was heated to reflux for 4 hours, cooled, and filtered. The pale yellow solid was filtered and washed with methanol. Yield: 0.017 g = 61%. MS (CI) m/z 265 (M+l).

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione

Compound Structure Yield 1 H-NMR (DMSO)δ

%

1 -Methyl- 1 -(6-methyl-7-nitro- 2,3 -dioxo- 1 ,2,3,4-tetrahydro- quinoxalin-5 -ylmethyl)-3 - phenyl-urea

(s, lH, 12.14 (s, lH)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione (cont'd)

Compound Structure Yield 1 H-NMR (DMSO)δ

%

3 -(4-Methoxy-phenyl)- 1 - methyl- 1 -(6-methyl-7-nitro- 2,3-dioxo-l ,2,3,4-tetrahydro- quinoxalin-5-ylmethyl)-urea

1H), 12.08 (s, 1H)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione (cont'd)

Compound Structure Yield 1 H-NMR (DMSO)δ

%

3 -(4-Methoxy-phenyl)- 1 - methyl- 1 -(6-methyl-7-nitro- 2,3-dioxo- 1 ,2,3,4-tetrahydro- quinoxalin-5 -ylmethyl)- thiourea

1H), 12.05 (s, 1H), 12.21 (s, 1H)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione (cont'd)

Compound Structure Yield 1 H-NMR (DMSO)δ

%

3 -(2,4-Dimethyl-phenyl)- 1- methyl- 1 -(6-methyl-7-nitro- 2,3 -dioxo- 1 ,2,3, 4-tetrahydro- quinoxalin-5 -ylmethyl)-urea

7.59 (d, 1H, J = 8.5 Hz), 8.05 (s, 1H)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione

Compound Structure Yield 1 H-NMR (DMSO)δ

%

3-(2,5-Dimethoxy-phenyl)- 1 - methyl- 1 -(6-methyl-7-nitro- 2,3 -dioxo- 1 ,2,3, 4-tetrahydro- quinoxalin-5-ylmethyl)-urea

1H, J = 8.8 Hz), 7.56 (s, lH), 7.79 (d, 1H, J = 2.9 Hz), 8.93 (s, 1H)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione (cont'd)

Compound Structure Yield 1 H-NMR (DMSO)δ

%

6. 1 -Methyl- 1 -(6-methyl-7-nitro- 2,3 -dioxo- 1,2,3, 4-tetrahydro- quinoxalin-5 -ylmethyl)-3 -(2- trifluoromethyl-phenyl)-urea

J = 7.5 Hz), 7.64 (d, lH, J = 7.8 Hz), 7.76 (d, lH, J = 8.3 Hz), 8.67 (s, 1H)

TABLE 2. N-Methyl Urea and Thiourea Derivatives of Quinoxaline 2,3-dione (cont'd)

Compound Structure Yield 1 H-NMR (DMSO)δ

%

4-(3-Methyl-3-(6-methyl-7- nitro-2,3 -dioxo- 1 ,2,3 ,4- tetrahydro-quinoxalin-5- ylmethyl)ureido)-benzoic acid ethyl ester

(d, 1H, J = 8.5 Hz),

9.2 (s, 1 Hz)

Claims

We claim:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein R is a urea or thiourea; n is an integer of from 1 to 4; R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;

R2 is hydrogen, hydroxy, or amino;

R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, halogen, haloalkyl, nitro, cyano, SO2CF3,

CH₂SO₂R₆, (CH₂)_mCO₂R6, (CH₂)_mCONR₇R , (CH₂)mSO₂NR7R₈, or

NHCORg wherein m is an integer of from 0 to 4, and R5, R7, and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl;

R5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, SO2CF3, (CH2)_mCO2R9,

(CH2)_mCONR₉R₁₀, SONR₉R₁₀, or NHCOR₉; m is an integer of from 0 to 4;

R9 and Rio are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; and R5 may be at the b-position and R-(CH2)_n- at the a-position on the ring.

2. A compound according to Claim 1 wherein R is

X R

"11« \ II / 12

N — C-N / \ R 13

and wherein X is O or S;

R\ 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, hydroxyl, hydroxyalkyl, alkoxyalkyl; Rj2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, hydroxyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, -SO2R14,

-SO₂NR₁₅R₁₆, -(CH₂)_nSO₂R₁₄, -(CH₂)nSO₂NR₁₅R₁₆, -(CH2)_nCO2Ri7, -(CH2)_nCONRι Ri9, or is a natural or unnatural amino acid (α-, β-, or γ-) backbone such as -CH(R2θ)C(O)ORj7 or -CH(R2θ)C(O)NRj Ri9; wherein R14 is hydroxy, alkoxy, or -NR15R16; Rj 5, Ri 5, Rj g, and R\ 9 are independently selected from hydrogen alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl; R17 is hydrogen, alkyl, aralkyl, cycloalkyl, heterocycloalkyl; R20 is hydrogen or a side chain of a natural or unnatural amino acid; n is an integer of from 1 to 4;

R\ is hydrogen or joined together with R\ \ to form a mono- or bicyclic ring, unsubstituted or substituted by from 1 to 4 substituents, and is

/ of from 5 to 7 atoms or __γ

of from 10 to 12 atoms

wherein

Y and Z are each independently carbon which is substituted by hydrogen, halogen, haloalkyl, alkyl, alkoxyl, alkoxyalkyl, -NR^R^g, aminoalkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl, cycloalkyl, -SO₂Ri4, -SO2NR15R1 , -(CH₂)nSO2NR₁₅Ri₆, -(CH₂)nSO₂Ri4, or is -O- or -S-;

R21 is absent or is hydrogen, alkyl, alkoxy, alkoxyalkyl,

-NR13R14, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxyl, or hydroxyalkyl, or may represent a gem- dialkyl of two idependently selected alkyl groups and when Y is carbon an integral double bond may be optionally located between C3 and C4 of the

5- to 7-membered ring.

3. A compound according to Claim 1 wherein R is

and wherein X is O or S;

R\ 1 is hydrogen, alkyl, cycloalkyl, aralkyl, heteroaralkyl, hydroxyl, alkoxyl, aralkoxyl;

Rl2 is hydrogen, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, -SO2R14, -SO2NR15R16,

-(CH₂)_nSθ2Rl4, -(CH2)_nSθ2NR₁₅Rι₆; Ri 3 is hydrogen or joined together with R\ \ to form a monocyclic ring, unsubstituted or substituted by from 1 to 4 substituents and is

of from 5 to 7 atoms

wherein R2 is absent or is hydrogen or alkyl;

Y is carbon which is substituted by hydrogen, alkyl, alkoxyl, or aminoalkyl.

A compound according to Claim 1 wherein R is

and wherein X is O or S; Rj j is hydrogen, alkyl, cycloalkyl, aralkyl, heteroaralkyl, hydroxyl, alkoxyl;

Rl2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, -SO2 14, -SO2NR15R15; wherein R\ is hydroxyl, alkoxyl, -NR15R16, or haloalkyl and R15 and R\ are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl.

5. A compound according to Claim 1 selected from the group consisting of:

1 -Methyl- 1 -(6-methyl-7-nitro-2,3-dioxo- 1 ,2,3 ,4-tetrahydro- quinoxalin-5-ylmethyl)-3-phenyl-urea, 3-(4-Methoxy-phenyl)-l-methyl-l-(6-methyl-7-nitro-2,3-dioxo-

1 ,2,3 ,4-tetrahydro-quinoxalin-5-ylmethyl)-urea, 3-(4-Methoxy-phenyl)-l-methyl-l-(6-methyl-7-nitro-2,3-dioxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-5-ylmethyl)-thiourea,

3-(2,4-Dimethyl-phenyl)- 1 -methyl- 1 -(6-methyl-7-nitro-2,3-dioxo- l,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-urea, 3-(2,5-Dimethoxy-phenyl)-l-methyl-l-(6-methyl-7-nitro-2,3- dioxo- 1 ,2,3 ,4-tetrahydro-quinoxalin-5-ylmethyl)-urea, l-Methyl-l-(6-methyl-7-nitro-2,3-dioxo-l,2,3,4-tetrahydro- quinoxalin-5-ylmethyl)-3-(2-trifluoromethyl-phenyl)-urea, and

4-(3-Methyl-3-(6-methyl-7-nitro-2,3-dioxo-l,2,3,4-tetrahydro- quinoxalin-5-ylmethyl)ureido)-benzoic acid ethyl ester.

6. 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.

7. A method for treating disorders responsive to the blockade of glutamate receptors in a patient suffering therefrom which comprises administering a composition according to Claim 1.

8. A method for treating stroke which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of said treatment.

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

10. 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 said treatment.

11. 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 said treatment.

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

13. A method for treating disorders responsive to anticonvulsants which comprises administering a therapeutically effective amount of a compound according to Claim 1 to a patient in need of said treatment.

14. A process for the preparation of a compound of Formula I above comprising:

(a) reacting 7-nitro-5,6-dimethyl-2,3-dimethoxy-quinoxaline in solvent with AIBN and N-bromosuccinimide and heating to 70°C to 80°C for 14 to 18 hours to produce 5-bromomethyl-2,3-dimethoxy-6-methyl- 7-nitro-quinoxaline

(b) adding a saturated methylamine solution to the product of Step (a) above and warming the mixture to room temperature to produce 6-methyl-5-methylamino-methyl-7-nitro-2,3-dimethoxy-quinoxaline, which on treatment with aqueous HCl gave the corresponding quinoxaline 2,3-dione derivative.

15. A process for the preparation of a compound of Formula I comprising: (a) adding an appropriate isocyanate or isothiocyanate, RNCO, to a solution of 6-methyl-5-methylaminomethyl-7-nitro-l ,4- dihydroquinoxaline-2,3-dione, (b) stirring the mixture from Step (a) above to produce a compound of formula

wherein R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryle,-SO₂ R14,

-SO₂NR₁₅R₁₆ (CH₂)_n SO₂R₁₄,

-(CH₂)n SO2 R 5R16 wherein R14 is hydroxyl, alkoxyl, -NR15R16 or haloalkyl and R15 and Ri g are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, and aryl.

16. A process according to Claim 15 wherein R is hydrogen, alkyl, cycloalkyl, cycloalkyalkyl, heterocycloalkyl, -SO2NR14, -SO2NR15R16; wherein

R14 is hydroxyl, alkoxyl, NR15R16, or haloalkyl