PT99899A - METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING NEW DERIVATIVES 3,4-DIHYDRO-3-OXO-QUINOXALINE 2-ACYL-AMIDES - Google Patents

Description

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Description of the invention of the US Patent and Trademark Office, established at 201 Tabor Road, Morris Plains, New Jersey 07950, United States of America, (inventors: Sheryl Jeanne Hays, Thomas Charles Malone , Graham Johnson, Perry Michael Novak and Leonard Joseph Lescosky, United States of America), " PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS CONTAINING NEW DERIVATIVES 2-ACYL AMIDES PE 3,4-DIHYDRO-3- OXQ-QUXNO-XALINE ".

DESCRIPTION

BACKGROUND OF THE INVENTION The present invention relates to novel 3,4-dihydro-3-oxo-quinoxaline 2-acyl amides useful as pharmaceutical agents, processes for their production, pharmaceutical compositions and methods for their use.

The compounds of the present invention are active as mediators of excitatory amino acid receptors.

Such activity is useful for the treatment of dis

neurodegenerative disorders including cerebrovascular disorders as well as in the treatment of schizophrenia, Parkin's disease or epilepsy and as analgesic and anxiolytic. Excessive excitation by neurotransmitters can lead to the degeneration and death of neurons. This degeneracy is believed to be mediated by the exotoxic effects of glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral squamous or cerebral infarction known as at least part of a range of states such as trorabo-embolic or hemorrhagic shock, cerebral vasospasm, hypoglycemia, cardiac arrest, epileptic conditions, perinatal asphyxia, anoxia such as drowning, pulmonary surgery, and trauma There are no specific therapies for these neurodegenerative disorders, however, compounds that act specifically as antagonists of the NMDA receptor complex, competitively or noncompetitively, offer a novel hypothesis for these disorders: R. Schawrcz and B · Meldrum, The Lancet 140 (1985) B. Meldrum in " Neurotoxins & their Pharmacological Implications " Etidate by P. Jenner, Raven Press New York (1987); 0. W. Choi, Neuron 1: 623 (1988). Confirmation of the protective effects of uncompetitive NMDA antagonists in various pharmacological models of neurodegenerative disorders has appeared in the literature: J. W. McDonald, F. Silverstein, and. V. Johnston, Eur. J. Pharraacol. 140: 359 (1987); R. Gill, A · C * Foster, and G, N · Woodruff, J. Neurosci, 7: 3343 (1987); S.M.Rothman, J.B. Thurs-ton, R.E. Hauhart, G.D. Clarck, and J.S. Soloman, Neurosci. 21: 673 (1987); M.P. Goldbert, P-C · Pham, and D.W. Choi, Neurosci. Lett. 80:11 (1987); . F 'Copeland, P.A. Boxer, and F.W. Mar-coux, Soc. Neurosci. Óbstr. 14 (part 1): 420 (1988); J · A. Kemp A.C.Foster, R. Gill, and G.N.Woodruff, TIPS (: 414 (1987);

R. Gill, A. C. Foster, and G, N. Woodruff J. Neurosci. 25: 847 (1988); C. K. Park, D. G. Nehls, D. X. Graham, G. M. Teasdale, and J. M. McCilloch, Ann. Neurol. 24, 533 (1988): G.K. Stein-burg, C. P. George, R. DeLaPaz, D. K. Shibata, and Ϊ. Gross, Sfcroke 19: 1112 (1988); J.F., Church, S * Zeman, and Lodge, Anesthesiology, 69: 702 (1988), U.S. Patent No. 4,181,174 describes certain acids and esters of quinoxaline compounds useful for the treatment of asthma, eczema or urticaria in animals. U.S. Patents Nos. 4210647 and 4262600 and European Patent Publication No. 010426 more specifically describe substitutes for acids and ethers of quinoxalinone compounds which are useful as antiviral agents, especially against influenza virus. Another preparation of these compounds is as described in Japanese Application 1075-474-A described in Derwent Abstra-cts No. 89-132587 / 18. Quinoxide quaternary ammonium salts of quinoxalinone compounds are also described as antiviral agents in U.S. Patent No. 4,252,954. Quinoxalinone amide derivatives are substituents of alkyl arylsulfonylureas for use in hyploglicemia in the Belgian patent nQ 764988 and are also substituents for cephalosporins for use as antibacterial agents in European Application No. 304158. Each of these references differs from the present invention in the hydroxamate, amide, acyl, urea, acyl carba-mate, imide, acylsulfonamide, or hydrazine of quinoxalinone as described herein.

SUMMARY OF THE INVENTION The present invention provides compounds of formula

- 3 -

or their tautomers; or a pharmaceutically acceptable acid addition or base addition salt thereof wherein (1) Y represents oxygen or sulfur; (2) the radicals R 1, R 2, R 3 and R 12 independently represent hydrogen, lower alkyl, halogen, trifluoromethyl, cyano, nitro, methylthio, lower alkenyl, lower alkynyl, SO 2 NH 2, S (O) in The radical R 2 represents hydrogen or lower alkyl, or wherein two of the radii R 1, R 2, R 2 and R 2 may together form a bicyclic ring of 6 carbon atoms or may together forming a heterocyclic or heteroaryl ring wherein the heteroatom mo is an oxygen, sulfur or nitrogen atom and wherein the carbon atom in the carbocyclic ring is optionally substituted by one of the radicals R 1, R 2, or R 2; (3) X represents (a) NR6 SO2, R3, (b) NR1 R3 with the proviso that one of the radicals R8 and R4 must be other than hydrogen at the same time as one of R1, R2 and R12 has to be different of radicals R 2, R 2, R 2, hydrogen, (c) nror 3,

(d) NR CONR R with the proviso that one of the radicals R and R has to be other than hydrogen, (e) NR 6 COOR 5, (f) NR 6 COO R 3,

R, H, 6 |

Cg) K-N-CO2 R3,

R? H

(i) an amino acid radical representing phenylglycine, phenylalanine, alanine, leucine, isoleucine, proline or valine, (j) lower alkyl esters of the amino acid radical as 34 i) the radicals R 2 and R 3 are independently defined above wherein R 3 is hydrogen; 4 Ϋ f

2) alkyl having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms; 3) alkenyl of 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms; 4) alkynyl containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms; 5) aryl which is phenyl, indenyl or naphthyl wherein the phenyl radical is (aa) unsubstituted or

bb) substituted with 1 to 5 lower alkyl or halogen, or substituted by 1 to 3 of xxi) trifluoromethyl, xxii) nitro, xxiii) amino, xxiv) mono- or di (lower) alkyl-alkylamino, xxv) hydroxy, xx vi) lower alkoxy, xxvii) carboxy, or

xxxiii) NHCOR wherein R is independently as defined below, wherein Alk2 is lower alkyl, xxx) HHSO2 R wherein R3 is independently as defined herein, xxxi) CN, cg 56 xxxii) CONR R R 2 and R 3 are independently as defined herein, (xxxiii) S (O) q wherein R is independently defined herein, (II) (xxx) -CR 3, 6) aryl-lower alkyl; 7) aryl-lower alkenyl; 8) heterocycle; 3) heteroaryl: 5-

10) (EC-) R, wherein q represents an integer A q is from 1 to 4 and R is A) heterocycle, B) heteroaryl, S 8 C) SO 2 R wherein R represents hydrogen or lower alkyl and R as defined herein,

Wherein R 2 is as previously defined, wherein R 2 is as defined above, or wherein R 1 and R 2 are as defined above,

independently, hydrogen or alkyl or R10 together form a heteroaryl ring; or 11) an amino acid radical as defined above; Ii) R 1 is hydrogen; 2) lower alkyl; 3) lower alkenyl; 4) aryl; 5) aryl-lower alkyl; 6) aryl-lower alkenyl; 7) heteroaryl; or 8) heteroaryl-lower alkyl; iii) R 1 is hydrogen or 2) lower alkyl, preferably hydrogen.

Preferred compounds of the present invention include, but are not limited to, compounds of formula 1 wherein R2 and R3 represent chlorine, Y represents oxygen and X represents NHS (O) 2 CH3, NHS (O) 2phenyl or NHS (O) 2 (CH2) 4H.

The most preferred compounds of the present invention are 6,7-dichloro-3,4-dihydro-3-oxo-N- [phenylsulfonyl] -2-oxyalkylcarboxamide and 6,7-dichloro- 4-dihydro-1H- (methylsulfonyl) -3-oxo-2-quinoxaline carboxamide. The present invention also includes a non-

The invention relates to a pharmaceutical composition for use in the treatment of cerebrovascular disorders, treatment of disorders of response to blocking glutamic and aspartic acid receptors or treatment of brain ischemia, cerebral infarction, cerebral vasospasm, hypoglycemia, cardiac arrest, epileptic conditions, cerebral trauma , schizophrenia, epilepsy, neurodegenetive disorders, Parkinson's disease, Alzheimer's disease or Huntington's disease including a therapeutically effective amount of a compound of formula .1 together with a pharmaceutically acceptable carrier. The present invention also includes a method for the treatment of cerebrovascular disorders which comprises administering to a patient in need of the above pharmaceutical composition in unit dosage forms. & present invention also includes a method for the treatment of glutamic and aspartic acid receptor blocking response disorders which comprises administering to a patient in need of a therapeutically effective amount of the above composition in unit dosage forms.

This invention also includes a method for the treatment of cerebral ischemia, cerebral infarction, cerebral vasospasm, hypoglycemia, cardiac arrest, epileptic conditions, cerebral trauma, schizophrenia, epilepsy, neurodegenerative disorders, Parkinson's disease, Alzheimer's disease or Huntington's disease that consists of administering to an apatite in need of an effective amount of the above composition in unit dosage forms.

This invention also includes a method for the treatment of shock in patients in need which comprises administering to a patient in need thereof a therapeutically effective amount of the above composition in unit dosage forms. This invention also includes the use of an anesthetic or use in conjunction with a nasal anesthetic,

composition in surgical operations where there is a risk of cerebrovascular damage.

This invention further includes processes for the preparation of compounds of formula I in which one of the novel intermediates of formula II wherein the radical R 6 is hydrogen are treated to obtain the corresponding selected compounds of formula 1. In addition, the compounds of formula IV are treated to provide the compounds of formula I.

This invention also includes novel intermediates useful in the process. The novel intermediate of the present invention is a pure compound of formula (II ')

Wherein the radicals R 1 and R 2 have the meanings given in relation to j. The compounds of the present invention may be prepared by reacting a compound of formula (I) with the proviso that R 1 and R 2 independently represent a hydrogen or halogen atom, wherein at least one of R 1 and R 2 is H and the radical R has the meaning given herein.

A novel intermediate of the present invention is also a compound of formula V

O

wherein R3 represents lower alkyl, "

A further additional intermediate of the present invention is a compound of formula IV

C02Alk1_g

In which R 1, R 2, R 2, R 2 and Alk 2 are as defined above.

Further, the present invention relates to a process for the preparation of a compound of the formula (L)

Wherein R1, R2, R3 and R4 are as defined above. The present invention relates to a process consisting of:

1) treatment of a compound of formula VI

with sodium nitrite to give a compound of the formula V 9 -

ϊ ^ Ύ ° 'VV' ΝΟΗ C02Alkl-4

V

no 2 later

2) treating the compound of formula V from step 1) with hydrogen on Raney nickel and then with TiCl2 to give a compound of formula IV

3) treating the compound of formula IV of step 2) with n-bromosuccinimide, bromine, NaOCl or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DOQ) in an inert solvent to give a compound of the formula (II *)

(4) hydrolysing the compound of the formula II with a hydroxide such as sodium or potassium hydroxide to give the compound of the formula (II)

wherein R 1, R 2, R 2 and R 3 have the meanings given above and Alk% is lower alkyl.

This process is presented in scheme E below.

Detailed description

Lower alkyl means a straight or branched chain having 1 to 4 carbon atoms including, but not limited to, methyl, ethyl, propyl, butyl.

Lower alkenyl means a group having 2 to 4 carbon atoms, for example, but not limited to, ethyl, 1,2- or 2,3-propylene, 1,2,3,3-, or 3,4- butylene.

Lower alkynyl means a group having 2 to 4 carbon atoms, for example, but not limited to, ethyl, 2,3-propynyl, 2,3- or 3,4-butynyl; propynyl is the preferred group.

Lower cycloalkyl means cycloalkyl of 3 to 6 carbon atoms and lower alkyl as above, means for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl; cyclopropylmethyl and the preferred group.

Lower alkoxy means a group having 1 to 4 carbon atoms, for example, but not limited to, methoxy, ethoxy, propoxy] methoxy is the preferred group,

Halogen represents a fluorine, chlorine atom. - 11 -

bromine or iodine; fluorine, chlorine and bromine are preferred groups.

Aryl-lower alkyl means aryl as defined above and alkyl as defined above, for example benzyl, 2-phenylethyl, 3-phenylpropyl; preferred groups are benzyl and benzyl or phenyl is substituted as above.

Aryl-lower alkenyl means aryl as defined above and alkenyl as defined above, for example 2-phenylethenylenyl, 3-phenylpropenylenyl, preferred groups are 2-phenylethenylenyl and phenyl is as previously substituted.

Mono- (lower) alkylamino means a group containing from 1 to 4 carbon atoms, for example, but not limited to, methylamino, ethylamino, n- or i- (propylamino or butyl-araino).

(Lower) alkylamino means a group containing from 1 to 4 carbon atoms in each lower alkyl group, for example, but not limited to, represents dimethylamino, diethylamino, di- (n-propyl) - amino, di- (n-butyl) amino or may represent a linked ring, for example, piperidine.

Heteroaryl means a 5 or 6-membered monocyclic, bicyclic or bicyclic linked heteroaryl. The attached monocyclic or bicyclic aromatic ring contains at least 1 to 4 heteroatoms in at least one ring, such as nitrogen, oxygen or sulfur or a combination thereof. Such a heteroaryl group includes, for example, thienyl, benzothienyl, furanyl, benzofuranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazinyl, pyrazolyl, isothiazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolinyl or heteroalyl M-oxides containing one nitrogen atom.

More specifically, a heteroalyl may be -

a 2- or 3-thienyl which may be further substituted by, for example, a 2- or 3-furanyl ring; 2-, or 3-, or 4-pyridyl or 2-, 4-, or 5-pyrimidinyl N-oxide; 3- or 4-pyridazinyl; 2-pyrazinyl; 2-pyrazinyl N-oxide; 2- or 3-pyrrolyl; 3-, 4-, or 5-pyrazolyl; 2-, 4-, 5-oxazolyl; 2-, 4-, or 5-thiazolyloj 3-, 4-, or 5-isoxazolyl-3-4-, or 5-isothiazolyl; 5-tetrazolyl; 3- or 5- (1,2,4) triazolyl; 4-, 5- (1,2,3-triazolyl) 2-, 4-, or 5-imidazolyl 2-, 3-, 4-, 5-, 6-, or 7-indolyl 2-, 3- 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 5-, 6-, or 7-benzothiazolyl, 2-, 3-, 4-, 5-, 6- or 7-aryl, 7-benzothienyl, 1,2-benzoisoxazol-

Heterocycle means piperidine, piperazine, tetrahydropyridine, tetrahydropyranylpyrrolidinyl, pyrazolidinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydrothienyl and the like. Partially inclusive are N-piperidine and N-piperazine which may be further substituted by phenyl.

Well known protecting groups and their introduction and removal may be used according to the skilled person and are described, for example, in JFW McOmie, Pro-tective Groups of the Organic Chemistry, Plenum Press, London, New York (1973) and T, W. Greene, Froteetive Groups in Organic Synthesis. Wiley, New York (1981)

The compounds of the present invention contain asymmetric carbon atoms. The present invention includes diastereomers and individual enantiomers that can be prepared or isolated by methods known to those skilled in the art.

The selected compounds of the present invention may also exist as syn and anti forms and also belong to the present invention.

Any resulting racemate can be resolved at the optic antipodes by known methods, for example,

by separating its diastereomeric salts with an optically active acid and releasing the optically active amine compound by treatment with a base. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example by fractional crystallization of salts d-or 1- (tartrates, mandelates, or conforulfonate). The compounds of the present invention may also be resolved by the formation of diastereoisomeric amides or amides by reaction of the compounds of the present invention with an activated active carboxylic acid such as the (+) or (-) phenylalanine derivative, (+) or -) phenylglycine, (+) or (-) - camphonic acid or by formation of diastereoisomeric carbamates by reacting the compounds of the present invention with an optically active chloroform or the like.

Additional methods may be used for the solution of optical isomers known to those skilled in the art, for example, those discussed by J. Jacques, A. Collet, and S. Wilen in Enantiomersr Racemates and Resolutions, John Wiley and Sons, New York (1981 ).

Salts of the compounds of this invention are preferred for pharmaceutically acceptable salts. The compounds of this invention are basic amines from which pharmaceutically acceptable inorganic or organic acid addition salts such as strong mineral acids, for example hydrogen halides, for example, hydrochloric or hydrobromic acid, sulfuric acid, phosphoric or nitric; aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, propionic, succinic, glycolic, lactic, lactic, lactic, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acids *

The selected compounds of this invention are. also acids from which base salts can be prepared. 14 -

Likewise, hydrates of the compounds of this invention for which hydrates may exist also form part of the present invention.

The compounds of the present invention exhibit important pharmacological properties by the selective blocking of N-methyl-D-aspartara sensitive excitatory amino acid receptors in mammals. The compounds are thus useful for the treatment of disorders in the response to the blocking of excitatory amino acids in mammals. Such disorders include, but are not limited to, cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic shock, cerebral vasospasm, hypoglycemia, cardiac arrest, epileptic conditions, perinatal asphyxia, anoxia such as drowning, lung surgery and brain trauma. Other treatments are for schizophrenia, epilepsy, spasticity, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease or Huntington's disease, Olivo-pectoral atrophy, spinal cord damage, and poisoning by exogenous NMDA poisons (eg some forms of latirism). Other uses are as analgesics and anesthetics, particularly for use in surgical and anesthetic procedures, particularly for use in surgical procedures where there is a risk of cerebrovascular damage.

The effects are demonstrable in in vitro assays or in vivo animal tests using mammals or tissues or their enzyme preparations, for example rats, mice or monkeys. The compounds are administered to patients in tetanus or parenterally, for example, orally, transdermal, subcutaneous, intravenous or intraperitoneal. The forms include, but are not limited to, gelatin capsules or suspensions or aqueous solutions. The dose applied in vivo may range from about 0.01 to 100 mg / kg, preferably from 0.01 to 100 mg / kg, preferably from 0.05 to 50 mg / kg, more preferably from 0.1 and 10 mg / kg.

The processes of synthesis of the compounds of the pre-

The preparation of compounds of the formula I wherein X is NR SO2 R2, nr6r3, nr6rr3, nr6cor5, NR6KHSG2R3, R6HHC02R3 or HR6NHC02R3 and R11, R2 and R2 are as defined in Schemes A, and are as defined above are shown in Schemes A and B.

Scheme A

COX

R 1 R 11 Ϊ H · N 11 I R 12 II

1) Δ / carbonyl-di-iiiddazole - (a) wherein R = tietoaryl - XXXOψλ OR (d) Ν ^ ΗδΟ ^ -

(e) NROTSO (R f)

In addition the preparation of compounds of formula I and wherein X represents NHCONR3 R3 and R3 is H and R1, R2, R3, R12 and R4 are as previously defined is shown in Scheme B.

Scheme B

* The preferred process for the manufacture of compounds of formula I " is shown in scheme C. -

Scheme C

IVa D2) CH2 Cl2

Z represents KHR 4, R 4, R 4

- 17 -

Scheme D consists of treating compounds of formula 1 with chloroethyl malonate, chloromethyl malonate or the like in a solvent such as benzene or toluene or analogues to provide the compounds of formula B. The compounds of formula B are then treated with sodium ethoxide in ethanol or sodium methoxide in methanol to afford the compounds of formula C. The compounds of formula C further react with phosphorus trichloride or phosphorus tribromide in a solvent such as tetrahydrofuran, dioxane or the like to afford the compounds of formula formula D.

Scheme D

18 -

Scheme E and shows a preparation for compounds of Formula 1 which consists of treating compounds of Formula VI with sodium nitrite, potassium nitrite or the like in a solvent mixture of acetic acid / tetrahydrofuran / water to provide the compounds of formula V, compounds of formula V are then hydrogenated on Kaney nickel in a solvent such as tetrahydrofuran or dioxane or the like, followed by treatment with aqueous titanium trichloride to provide compounds of formula IV. The compounds of formula IV are further reacted with bromine, n-bromosuccinimide, NaOCl or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to provide the compounds of formula II ' . The compounds of formula IIa are saponified using KOH in water / iPrOH or analogues to provide the compounds of formula II * 2

- 19 -

Scheme E

toluene, Δ 0 0 C1AJU OAlk1_6

NaK02, AeOH, H2O

IV 0 0

Br2, THF or

NaOCl, THF or DDQ, THF

COOAlk 1-6

co2h - 20

The preparation of Scheme E provides the preferred process of preparation for the compounds IX * 2 defined above.

In general, the compounds of formula I above wherein X represents NHSO3 R4, NR6 CONR3 R4, NR6 COR5, NR6 CO, R3, NR6 NHSO2 R3, NR6 NHC02 R3 R where R2, R3, R12, R3, R4, R4 and R6 have the as given above, are prepared by the method of schemes A and E above. Scheme A consists of treating a carboxylic acid of general structure (XI) with a coupling reagent in an inert solvent to produce an activated carboxylic acid derivative. The resulting activated carboxylic acid derivative is reacted with a variety of azo-2-nucleophiles to produce amides of general structure I *, wherein X, R, R, R, R, R, R have the meanings given above. Suitable coupling agents for this purpose include, for example, reagents such as thionyl chloride, acetic anhydride, oxalyl chloride / DMF, carbonyldiimidazole, DCC and di-phenylphosphorylazide, preferably carbonyldiimidazole. &Quot; by activating carboxylic acid " it is meant an acid derivative which is susceptible to acylation of an azoin. Such acid derivatives include, for example, acid chlorides, acidic bromides, anhydrides and mixed anhydrides. &Quot; Inert solvent " is meant a non-aprotic solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran and dimethylformamide.

The compounds of formula IXa in scheme C may further be reacted to protect the carbonyl of the quinoxaline ring with a methoxy or allyloxy functionality to provide a compound of formula IVa. The acid IVa and the acid chloride are converted and then treated with ammonia to produce the amide Va. The compounds of the formula Va are further worked up by treatment with an isocyanate, symmetrical anhydride or a symmetrical pyrocarbonate to generate derivatives of structural formula Via. A for 21-

Route VIII is deprotected with trimethylsilyl iodide or a combination of trimethylsilyl chloride and sodium iodide if the protective ether is a methoxy group. The allyloxy group is removed using the Hilkinson catalyst to provide compounds of the formula VIIa.

All compounds prepared in Schemes A to E may optionally further be treated by conventional procedures to provide compounds of formula I wherein Y represents S *

Pharmaceutically acceptable salts of the compounds of formula I are also included as a part of the present invention.

The base salts may be formed from compounds of formula 1 by reaction thereof with one equivalent of a suitable non-toxic, pharmaceutically acceptable base followed by evaporation of the solvent used for the reaction and recrystallization from the salt if necessary. The compounds of formula I may be recovered from the base salt by reacting the salt with an aqueous solution of a suitable acid such as hydrobromic, hydrochloric or acetic acid.

Bases suitable for the formation of base salts of the compounds of this invention include amine such as triethylamine or diburylamine or alkali metal bases and alkaline earth metal bases. The alkali metal hydroxides and alkaline earth metal hydroxides preferred as salt formers are the lithium, sodium, potassium, magnesium or calcium hydroxides. The class of bases suitable for the formation of non-toxic pharmaceutically acceptable salts is well known to those skilled in the pharmaceutical formulation. See, for example, Stephen N. Berge, et al., J. Phatm. Know. 1977; 66: 1-19.

Suitable acids for the formation of acid salts. of the compounds of this invention containing a basic group include, but are not necessarily limited to, acetic,

tartaric, hydrobromic, hydrochloric, citric, fumaric, glucononic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric and tartaric acids. The acid addition salts are formed by procedures well known in the art.

In addition, the compounds of this invention may exist in unsolvated as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of this invention.

The starting materials for the processes described above are known or can be prepared by known methods.

The reaction products described herein are isolated by conventional means such as extraction, crystallization, distillation, chromatography and the like.

Pharmaceutical Compositions

The compounds of the present invention may be administered in a wide variety of oral and parenteral dosages. It is apparent to those skilled in the art that the following dosage forms may include as the active component a compound of formula 1 or a corresponding pharmaceutically acceptable salt of a compound of formula I.

For the preparation of pharmaceutical compositions from the compounds of the present invention the pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, lozenges, pills, capsules, suppositories and dispersible granules. A solid carrier may be one or more substances which may also function as a diluent, flavoring agent,

stabilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or an encapsulating material.

In the form of a powder, the carrier is a finely divided solid which is in a blend with the finely divided active component.

In pellets, the active component is incorporated with a carrier having the necessary binding properties in suitable proportions and compacted in the form and size of beads.

The powders and tablets preferably contain from 5 or 10 to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, alcantira, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term " preparation " is understood to include the formulation of the acetic compound with enepsulating material as a carrier providing a capsule in which the active component, with or without carrier, is encased by a carrier which is thus in association therewith . In the same way, tablets and lozenges are included. The tablets, powders, capsules, pills, tablets and lozenges may be used as solid dosage forms suitable for oral administration.

For the preparation of suppositories a low melting point wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and thus solidify. . The liquid form preparations include solutions, suspensions and emulsions, for example water or propane solutions.

pylene glycol in water. For example, liquid preparations for parenteral injections may be formulated in aqueous solution of polyethylene glycol.

Aqueous solutions suitable for oral use may be prepared by dissolving the active component in water and adding suitable colorants, flavorings, stabilizing agents and thickeners as desired.

Aqueous suspensions suitable for oral use may be obtained by dispersion of the active component finely divided in water with a viscous material such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethyl cellulose and other agents suspension systems.

Also included are the solid form preparations which are intended to be converted immediately prior to use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffering agents, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate amounts of the active compound. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules and packaged in vials or ampoules. The unit dosage form may also be a capsule, tablet, tablet or lozenge or may be an appropriate number of any of these forms and packages.

The amount of active component in a

The dosage unit dose rate may vary from 1 mg to 1000 mg, preferably from 10 mg to 100 mg according to the present invention.

the power of the active component. The composition may, if desired, also contain other compatible therapeutic agents. Method of treatment

The compounds of this invention are extremely useful in the treatment of disorders of the central nervous system related to their biological activity. The compounds of this invention may thus be administered to a subject, including man, in need of treatment, alleviation or elimination of a condition associated with the biological activity of the compounds. These especially include exciting amino acid dependent psychoses, exciting amino acid dependent anorexia, exciting amino acid dependent ischia, exciting amino acid dependent seizures and exciting amino acid dependent headaches. The suitable dosage ranges from 0.1 to 1000 mg per day, 10 to 40 mg per day and especially from 30 to 100 mg per day depending, as usual, on the exact mode of administration, in which form it is administered, the indication for which administration is directed, the subject involved and the weight of the individual's color and the preference and experience of the physician or veterinarian.

The following non-limiting examples illustrate the present invention.

General Preparation 1

Preparation of selected acyl sulfonamides

Solution A: 14.1 g; 0.087 mol of carbonyl-dihydrazide in 250 ml of dry DMF. To this solution was added 0.029 moles of a suitably substituted 2-oxo-quinoxoline-3-carboxylate. This 26-

solution at 80 ° C for 2 hours under a nitrogen atmosphere and then dry DMF was added until the solution was adjusted to 300 ml and the solution was cooled to 25 ° C.

Solution B: To a suspension of 0.38 g; 0.0116 moles of sodium hydride in 30 ml of dry DMF was added a 0.0116 mole portion of the selected sulfonamide. This solution was stirred at 25 ° C for 2 hours. To the solution B was added 60 ml of solution A at once. A solid formed at this point.

In cases where the solid forms rapidly in the solution, the reaction is stirred at 25 ° C for 1 to 5 days. When solid remains after mixing the solutions, the reaction is refluxed for 1 to 8 hours until complete.

In either case, the reaction is carried out in a mixture of 300 g of ice and 300 g of concentrated HCl. The solid precipitate was washed with water. The crude product was dissolved in hot DMF and precipitated with water. After cooling the solid was filtered, washed with cold DMF, water, heptane and then dried for 24 hours at 140 ° C under vacuum to provide the product with a yellow powder. In some cases, acetonitrile, diethyl ether or methanol replaces DMF as the washing solvent.

General Preparation 2

Preparation of 3,4-dihydro-1-alkoxy-3-oxo-2-quinoxaline carboxamide

Solution B: To a suspension of 0.38 g, 0.0116 mol of sodium hydride in 30 ml of anhydrous DMF was added in one portion 0.0116 moles of O-alkyl hydroxylamine hydrochloride or O hydrochloride -alkyl-aryl-hydroxylamine selected. This solution was stirred at 25 ° C for 1 hour. To solution B was added 60 ml of sodium sulfate,

as described for method A. The reaction was stirred at 25 ° C for 1 to 5 days. The reaction was poured into a mixture of 300 g of ice and 300 g of 3N HCl. The solid was washed with 50 ml of 5% NaHCO 3, 50 ml of water, 50 ml of acetonitrile and 50 ml of diethyl ether. The product was dried at 140 ° C in vacuo. In some cases the product was recrystallized from DMF / water or triturated by washing with hot acetonitrile or ethanol.

General Preparation 3

Preparation of 3,4-dihydro-N-alkyl-3-oxo-2-quinoxaline carbaamides

Solution B: To a suspension of 0.38 g; 0.0116 moles of sodium hydride in 20 ml of anhydrous DMF was added in one portion 0.116 mol of the selected amine hydrochloride or alternatively the free base of the amine directly used without the use of sodium hydride. To solution B was added 60 ml of solution A as described for Method A. The reaction was stirred at 25 ° C for 1 to 5 days or stirred at 25 ° C for 18 hours and then heated at 80 ° C for 1 to 4 hours. The reaction was poured into a mixture of 300 g of ice and 300 g of 3N SCI. The solid was washed with 50 ml of 5% NaHCO3, 50 ml of water, 50 ml of acetonitrile and 50 ml of diethyl ether. The product was dried at 140 ° C under vacuum. In some cases the product was recrystallized from DMF / water obtained by washing with acetonitrile or hot ethanol *

General Preparation 4

Preparation of 3,4-dihydro-3-oxo-N - ((1-amino) aminol-carbonyl] -2-thi ynoxalinecarboxamide To 60 ml of solution A in Method A,

1.49 g; 0.023 moles of sodium cyanate. The reaction was stirred at 25 ° C for 18 hours. The solvent was removed by vacuum at 60 ° C. Chloroform was added and the beige color pure solid was filtered. The solid was slurried in 140 ml of DMFani and at least 0.046 moles of an alkyl or alkylaryl amine was added and the reaction was heated at 60 ° C for 18 hours. The reaction was poured into a mixture of 300 g of ice and 300 g of 3N HCl. The solid was washed with 50 ml of 5% NaHCO 3, 50 ml of water, 50 ml of acetonitrile and 50 ml of diethyl ether. The product was purified on a silica gel column eluted initially with methylene chloride and then with methanol / dexethylene chloride to 30% methanol. The chromatographed product was washed with hot acetonitrile and filtered. The product was dried at 140 ° C under vacuum.

General Preparation 5

Preparation of 3,4-dihydro-3- (alkoxy) carbonyl-2-quinoxalinecarboxamides To 60 ml of solution A described in the method was added 1.49 g; 0.023 moles of sodium cyanate. The reaction was stirred at 25 ° C for 18 hours. The solvent was removed by vacuum at 60 ° C. Chloroform was added and the crude beige solid was filtered. The solid was slurried in 140 ml of anhydrous DMF and at least 0.46 mol of an alcohol was added and the reaction was heated at 60 ° C for 18 hours. The reaction was poured into a mixture of 300 g of ice and 300 g of 3N HCl. The solid was washed with 50 ml of 5% NaHCO 3, 50 ml of water, 50 ml of acetonitrile and 50 ml of diethyl ether. The product was purified on a silica gel column and initially extracted with methylene chloride and then with methanol / methylene chloride to 30% methanol. The chromatographed product was washed with hot acetonitrile and filtered. The product was dried at 140 ° C under vacuum.

Example 1 * 6,7-Dicyclo-3,4-dihydro-3-oxo-N - [(phenyl) sulfonyl] -2-guinoxali-. carboxamide.

A solution containing benzenesulphonamide (0.91 g, 5.8 mmol) and sodium hydride (0.24 g, 5.79 mmol) in dry DMF (10 mL) was heated at 60 ° C for 2 hours and cooled. A solution containing 3.9 mmol of the reagent prepared as described in General Preparation 1, solution Ar to the benzenesulfonamide mixture was added. The reaction was stirred at 25 ° C for 18 hours, poured into ice / HCl and the precipitate was collected and dried to afford the amide as a yellow solid (0.7 g, 90% yield). mp 325-330 ° C.

Elemental analysis calculated for C 13 H 14 Cl, 45.24; H, 2.28; N, 10.55; Found: C, 44.90; H, 1.94; N, 10.46; Anal. Calc'd. Cl, 17.90; S, 8.05. S, 8.24.

Example 2 6,7-Dichloro-N- [2- (dimethylamino) ethyl] -3,4-dihydro-3-oxo-quinoline-carboxamide The solution containing Κ, Ν'-dimethyl- (10.2 g, 11.6 mol) in dry DMF (20 ml) was added a solution containing 5.8 mmol of the reagent prepared as described in General Preparation I, solution A. A yellow precipitate of 5 minutes and the reaction was stirred for an additional 16 hours at 25 ° C. The reaction was poured onto ice and the precipitate collected to give the amide as a yellow solid (1.38 g, 72% yield); m.p. 272-274 ° C.

Elemental analysis calculated for C 19 H 19 N 4 O 5 • 13, 17.10 N, 17.02. C, 47.41; H, 4.20;

Found: C, 47.43; H, 4.29;

Example 3 6,7-dichloro-3,4-dihydro-3-oxo-N- (phenylmethoxy) -2-cruinoxaline-carboxamide

Sodium hydride (2.49 g;

15.6 mmol) in anhydrous DMF (20 mL) and 0-benzylhydroxy amine hydrochloride (2.49 g, 15.6 mmol) was added in one portion. The reaction was stirred for 1 hour and a solution containing 7.7 mmol of the reagent prepared as described in Preparation 1, solution A was added. The reaction was stirred at 25 ° C for 4 days. The reaction was poured onto ice containing 6N HCl and a yellow solid precipitated. The solid was filtered, washed with water and then with hot acetonitrile to provide the hydroxamate (2.23 g, 79% yield). m.p. 279-280 ° C.

Elemental analysis calculated for: C, 52.77; H, 3.04; N, 11.54. Found: C, 52.51; H, 2.97; H, 11.73.

Example 4 N- (aminocarbonyl) -6,7-dichloro-3,4-dihydro-3-oxo-guinoxaline-carboxamide

4,5-Dichloro-1,2-enylenediamine (8.0 g, 45.2 mmol) was dissolved in ethanol (300 ml) and water (30 ml). Alloxane monohydrate (7.24 g, 45.2 mmol) was dissolved in ethanol / water (30 ml: 70 ml) and added dropwise to the diamine solution. The reaction was stirred for 20 hours and the precipitate was collected by filtration. A slurry of this crude product was made into hot DMF (steam bath) and filtered. The solid was washed with water, acetonitrile and diethyl ether to give the title compound as a yellow solid (10.5 g, 77% yield); mp < 300 ° C.

Elemental analysis calculated for C, 39.89; H, 2.01; N, 18.61; Cl, 23.55 Found: C, 39.75; H, 1.87; N, 18.52; Cl, 23.64.

Example 5 * 6,7-dichloro-3,4-dihydro-3-oxo-E - [[phenylmethyl) amino] carbonyl] carboxamide

Sodium cyanate (1.0 g, 15.3 mmol) was added to a solution containing 3.35 mmol of the reagent prepared as described in General Preparation 1, solution A. The reaction was stirred at 25 ° C for 18 hours. The solvent was removed by vacuum at 60 ° C and the slurry was slurried in chloroform and filtered to give an impure preparation containing the acyl isocyanate. The solid was dried in air overnight, suspended in dry DMF, and benzylamine (2.06 mL, 18.9 mmol) was added. The reaction was stirred at 65 ° C for 18 hours, then poured into water and the pad was adjusted to pH 7. The crude product was filtered to give a crude product (0.71 g) containing the benzylamide as the main component. The mother liquor pH 2 was further acidified and the yellow solid filtered to give a crude product (0.70 g) containing the title compound as the major component. This second solid was crystallized from DMF / water to afford the product as an off-white solid (0.67 g, 44% yield); mp 292-295 ° C. , 1224-243, 1432; Cl, 18.32 14.14; Cl, 18.03

Elemental analysis calculated for C₂ 52H₂ 52O,: C, 52.19; H, 3.09; N, Found: C, 52.12; H, 3.27; N,

Example 6 6,7-dichloro-3,4-dihydro-3-oxo-N - [(phenylamino) carbonyl] -2-quinolinecarboxamide

Step 1 Ethyl 3,6,7-trichloro-2-quinoxalyl carboxalit

Ethyl 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalylcarboxylate (36.0 g, 0.125 mmol) was suspended in toluene (50 ml) was added DMF (12.5 ml) and thionyl chloride (12.5 ml, 0.17 mol). The reaction was refluxed for 2 hours and the solution turned dark purple. The reaction was quenched and the toluene was removed under reduced pressure. - 32 -

The crude material was subjected to silica gel chromatography eluted with methylene chloride. The title compound was isolated as a pink solid (35.5 g, 93% yield). An analytical sample was prepared by recrystallization from hexane; p. 102-104 ° C.

Elemental analysis calculated for CH 2 Cl 3 N 2 O 2: C, 43.24; H, 2.31; N, 9.17. Found: C, 43.23; H, 2.23; N, 8.89.

Step 2

6,7-Dichloro-3-methoxy-2-quinoxaline carboxylate

Sodium metal was added in small units to anhydrous MeOH (1500 mL) and the resulting sodium methoxide solution was cooled to 25 ° C. Ethyl-3,6,7-trichloro-2-quinoxaline carboxylate (36.4 g, 0.119 mol) was added and the reaction was stirred for 18 hours. Water (50 ml) was added and the reaction was stirred for 3 hours at 25 ° C. The solvent was concentrated under reduced pressure to one third of its original volume and the slurry was added to pH 2 with hydrochloric acid at 25 ° C. The mixture was stirred for 30 minutes and the solid filtered to give the acid as a gray solid (30.8 g, 95% yield); mp 181-182 ° C. 10H 6 Cl 2 H 2 O 3, 10.26. , 10.24.

Elemental analysis calculated for C

C, 43.98; H, 2.21; N Found: C, 43.92; H, 2.02; N

Step 3 6,7-dichloro-3-methoxy-2-quinoxaline-carboxamide

A suspension of 6,7-dichloro-3-methoxy-2-quinoxaline carboxylate (16.38 g, 0.06 mol) in methylene chloride was added and oxalyl chloride (6.24 ml , 0.072 mol) and DI-1F (2 drops). The reaction was stirred for 18 hours and the methylene chloride was removed under reduced pressure. Dissol.

the crude acid chloride was purged with anhydrous TMF (500 ml) and gaseous ammonia was bubbled through the reaction for 1 hour. The reaction was then stirred for 18 hours at 25 ° C. The reaction was poured into water and the precipitate was collected by filtration to afford the amide as an off-white solid (14.41 g, 88% yield); 236-241 ° C.

Elemental analysis calculated for: C, 44.14; H, 2.59; N, 15.44.

Found: C, 44.07; H 2.60; N, 15.33.

Step 4 6,7-dichloro-3-methoxy-N- (phenylamino) carbonyl] -2-quinoxaline carboxamide

6,7-Dichloro-3-methoxy-2-quinoxalinecarboxamide (1.75 g, 0.0064 mol) in toluene (500 ml) was dissolved and phenyl isocyanate (1.19 g 0.01 mol). The reaction was refluxed for 24 hours and the toluene layer was extracted with water, dried (MgSO4), filtered and concentrated. The crude product was chromatographed on silica gel eluting with CH 2 Cl 2 / MeOH (95.5) to give the acyl urea (1.44 g, 58% yield). A sample was recrystallized from CH 2 Cl 2 / TMF to provide an analytical sample. 17H 12 Cl 2 N 4 O 3 S, 14.32. , 14.16.

Elemental analysis calculated for C₂ 52H₂ 52O,: C, 52.19; H, 3.09; N Found: C, 52.10; H, 2.79; N

Step 5 6,7-dichloro-3,4-dihydro-3-oxo-N- (phenylamino) carbonyl] -2-pyrazoxalinecarboxamide

6,7-Dichloro-3-methoxy-N- (phenylamino) carbonyl] -2-quinoxalinecarboxamide (1.25 g, 0.0032 mol) was dissolved in methylene chloride (200 ml) was triethylsilyl iodide. The reaction was stirred at 25 ° C for 18 hours. Verteu-! The reaction mixture was partitioned between 5% sodium bisulfite and

for 10 minutes. The two layers were filtered to produce a crude solid. The solid was dissolved in a minimum of DMF, stirred on charcoal and filtered through a pad of Celite. The bright yellow solution was diluted with EtOH so that the solution composition was approximately EtOH / DMF (2: 1). Water was added to the turbidity, the solution cooled to 5øC and filtered to give the title compound as a yellow solid (0.21 g, 17% yield), m.p. 300 ° C.

Elemental analysis calculated for C ηH01ΝNΝO:: H, 14.85. N, 14.83. C, 50.95; H, 2.67;

Found: C, 50.73; H, 2.56;

Example 7 N-acetyl-6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide

Step 1

6,7-Dichloro-3- (2-propenyloxy) -2-chloro-2-carboxylic acid

Sodium metal (2.28 g, 0.122 mol) was added in small units in allylic alcohol (150 ml) over a period of 20 minutes. The allyloxy solution was cooled to 25 ° C and ethyl 3,6,7-trichloro-2-quinoxaline carboxylate was added in one portion. The solid was dissolved in the solution rapidly, and then a precipitate formed. The reaction was stirred at 25 ° C for 18 hours and water (60 ml) was added and the reaction stirred for another four hours. The allylic alcohol was removed under reduced pressure and water (100 ml) was added. The reaction was acidified to pH 2 with 6N hydrochloric acid. A precipitate formed which was filtered and washed with water to provide the title compound as a pale purple solid (6.58 g, 85% yield); m.p. 160-161 ° C.

Calc'd for C 12 H 12 Cl 2 N 2 O 3 · 0.15H 2 O: C, 47.76; H, 2.77; N, 2.98.

Found: C, 45.57; H, 2.77; N, 9.11. - 35 -

Step 2 6,7-dichloro-3- (2-propenyloxy) -2-quinoxaline-carboxamide

A suspension of 6,7-dichloro-3 - [(1-propyl-2-ene) oxy] -2-quinoxaline carboxylate (5.0 g, 0.0167 mol) in methylene chloride was added, was added oxalyl chloride (1.75 ml, 0.02 mol) and DMF (2 drops). The reaction was stirred for 4 hours and the methylene chloride was removed under reduced pressure. The crude acid chloride was dissolved in anhydrous TMF (150 ml) and gaseous ammonia was bubbled through the reaction for 30 minutes. The reaction was then stirred for 18 to 25 ° C. The reaction was poured into water and the precipitate collected by filtration to give the amide as an off-white solid (4.57 g, 95% yield): mp 185-186 ° C.

Calc'd for C 12 H 14 ClN 4 O 4: C, 52.96; H, 4.44) N, 12.35.

Found: C, 51.53; H, 4.26; N, 12.04 *

Step 3: Ethyl [16,7-dichloro-3- (2-propenyloxy) -2-quinoxalinyl] carbonylcarbamate

Dichloro-3- (2-propenyloxy) -2-quinoxalinecarboxamide (0.5 g, 1.68 mmol) and diethyl pyrocarbonate (20 mL) were heated at 140 ° C for 18 hours. The carbonate was removed under reduced pressure and the crude product was subjected to silica gel column chromatography eluted with methylene chloride. The product eluted as a clear oil solidified on standing (0.32 g, 51% yield).

Step 4 Ethyl [[6,7-dichloro-3,4-dihydro-3-oxo-2-cpiinoxalinyl] carbonyl] carbamate

6,7-Dichloro-3 - [(1-propyl-2-ene) oxy] -N-

- (ethoxycarbonyl) -2-quinoxaline carboxamide (0.32 g, 0.97 mmol) in THF (18 mL) and water (2 mL) and tris (triphenylphosphine) . The reaction was refluxed for 30 minutes, cooled and filtered through the celite pad. The THF was removed under reduced pressure and the crude product recrystallized from ethyl acetate to give the title compound as a yellow solid (80 mg).

Example 8 N-Acetyl-6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide

Step 1: N-Acetyl-6,7-dichloro-3- (2-propenyloxy) -2-quinoxalyl carboxamide

6,7-Dichloro-3- (2-propenyl-xy) -2-quinoxalia-carbaxamide (1.2 g, 0.004 mol) was suspended in acetic anhydride and heated to reflux for 18 hours. The reaction was cooled and acetic anhydride was removed under reduced pressure at 60 ° C. The crude solid was recrystallized from toluene to give the imide as a beige-colored solid (0.58 g, 43% yield),

Elemental analysis calculated for C 14 H 10 Cl 2 N 3 O 3: C, 49.58; H, 2.97; N, 12.39.

I find; C, 49.32; H, 3.19; N, 12.29.

Step 2: N-Acetyl-6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide

N-Acetyl-6,7-dichloro-3- (2-propenyloxy) -2-quinoxalylcarboxamide (0.50 g, 1.47 mmol) was dissolved in EtOH (18 mL) and water (2 mL) and tris (triphenylphosphine) rhodium chloride (50 mg). The reaction was refluxed for 30 minutes and a yellow solid was precipitated which was filtered from the reaction,

heating. The solid was crystallized from DMF / water to give the title compound as a bright yellow solid (0.22 g, 39% yield); mp 297-300 ° C. Calc'd for C 20 H 13 N 4 O 3: C, 44.03; H, 2.35; N, 14.00.

Found: C, 43/76; H, 2.32; M, 13.85.

Example 9

6,7-Dichloro-3,4-dihydro-3-oxo-2- (methoxycarbonyl) hydrazide-2-quinoxalinecarboxylic acid is added to a solution of methylcarbazate (3.5 g, 38/6 mmol) in dry DMF (50 ml) was added a solution containing 7.72 mol of the reagent prepared as described in Preparation 1, solution A. The reaction was stirred at 25 ° C for 4 days and poured into water ( 50 ml). The acid solution was made up with 6N HCl at pH 2. The precipitate was collected and hot DMF was absorbed. The DMF solution was treated with charcoal and filtered. The solution was cooled and diluted with an equal volume of water. The yellow solid was collected by filtration and washed with acetonitrile followed by diethyl ether to give the title compound (2.56 g, 100% yield); m.p. 333-340 ° C (decomposes).

Elemental analysis calculated for C 19 H 28 K 4 O 4 Cl 2: C, 39.9; H, 2.44; N, 16.92; Cl, 21.41.

Found: C, 39.52; H, 2.29; H, 16.86; Cl, 21.94.

Example 10

6,7-Dichloro-3,4-dihydro-3-oxo-2- (phenylsulfonyl) hydrazide-2-guinoxaline carboxylic acid

Solution B: To a suspension of sodium hydride (1.5 g, 38.6 mmol) (60% dispersion in mineral oil) in dry DMF (20 ml) was added benzenesulphonylhydrazide (6.65 g, 38.6 mmol). The reaction was stirred at 25 ° C for 24 hours.

1 hour and a solution containing 7.72 mmol of the reaction prepared as described in General Preparation 1, solution & To solution B, this solution was stirred at 90 ° C for 24 hours and then poured into water (500 ml). The solution was made acidic to pH 2 with 6N HCl. The solid was collected and recrystallized twice from hot DMF / water, washed with acetonitrile and then with diethyl ether and then dried at 137 ° C under vacuum to provide the title compound (1 , 44 g, 45% yield) as a yellow solid; m.p. 283 ° C.

Elemental analysis calculated for C14 H14 N4 O4. = .C1-S: 15 10 4 4 2 C, 43.6; H, 2.44; N, 13.56; Cl, 17.16.

Found: C, 43.23; B, 2.26; N, 13.80; Cl, 17.69.

Example 11 N-benzoyl-6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide

To a suspension of sodium hydride (0.93 g, 23.2 mmol) (60% dispersion in mineral oil) in dry DMF (20 mL) was added benzamide (2.81 g, 23.2 mmol) irrnio-les). The solution was stirred at 25 ° C for 1 hour. A solution containing 7.72 mmol of the reaction prepared as described in General Preparation 1, solution A was added to solution B. The reaction was stirred at 25 ° C for 24 hours and the solution was poured into water ( 500 ml). The acid solution was made pH 2 with 6N HCl. The solid was collected and absorbed in hot DMF. The DMF solution was treated with charcoal and filtered. The solution was cooled and diluted with an equal volume of water. The yellow solid was collected, washed with acetonitrile and then with diethyl ether to provide the title compound (1.09 g, 39% yield) as a yellow solid: m.p. 302 ° C (decomposes). . Elemental analysis calculated for C 19 H 28 Cl 3 Cl 2; - 39 -

C, 53.06; Η, 2.5; N, 11.6; Cl, 19.58. Found: C, 52.65; H, 2.28; N, 11.79; Cl, 19.78.

Example 12 6,7-dichloro-3-hydroxy-N- (1-piperidinylcarbonyl) -2-guinoxyalkyl) carboxamide

Solution B: To a suspension of sodium hydride (0.39 g, 23.2 mmol) (60% dispersion was mineral oil) in dry DMF (20 mL) was added 1-piperidine carboxamide (2.97 g, g; 23.2 mmol). The solution was stirred at 60 ° C for 0.5 hour. A solution containing 0.00772 moles of the reagent prepared as described in General Preparation 1, solution A, was added to solution B. This was stirred at 60 ° C for 3 days. The solution was water (500æl-1) and the acid solution was made with 6N HCl at pH 2 .. The solid was collected and absorbed in hot DMF. The DMF solution was treated with charcoal and filtered. The solution was cooled and diluted with an equal volume of water. The yellow solid was collected, washed with acetonitrile and then with diethyl ether to provide the title compound (0.95 g, 33% yield) as a yellow solid; mp 277-278 ° C.

Calc'd for C 15 H 14 N 4 O • Cl 2: C, 48.80; H, 3.82; W, 15.17; Found: C, 48.59; H, 3.76; M, 14.92; Cl, 19.4.

Example 13 6,7-dichloro-N- (dimethylamino) catbonyl-3-hydroxy-2-quinoxalinecarboxamide

Solution B: To a suspension of sodium hydride (0.93 g, 23.2 mmol) (60% dispersion in mineral oil) in DMF,

20 ml) was added 1,1-dimethylurea (2.04 g, 23.2 mmol). The solution was stirred at 50 ° C for 0.5 hour. A solution containing 7.72 mmol of the prepared reagent was added as described in General Preparation 1, solution A to solution B. This was stirred at 60 ° C for 3 days. The solution was poured into water (500 ml). The acid solution was acidified to pH 2 with 6N HCl. The solid was collected and absorbed in hot DMF. The DMF solution was treated with charcoal and filtered. The solution was cooled and diluted with an equal volume of water. The yellow solid was collected, washed with acetonitrile and then with diethyl ether to provide the title compound (1.5 g, 50.8% yield) as a yellow solid; m.p. 289-290 ° C.

Calc'd for C 12 H 10 N 4 O 3 Cl 2, C, 43.79; H, 3.06; N, 17.02; Cl Found; C, 43.76; H, 3.03; N, 16.95; Cl, 21.54. 21.60.

In the same manner and in an analogous manner to the procedures of General Preparations 1 to 3, but using the appropriate corresponding starting materials, the following compounds were prepared.

Example 14

[E (6,7-dichloro-3,4-dihydro-3-oxo-2-guinoxalinyl) carbonyl] amino] benzeneacetic acid: yield 9.8%, mp 244 ° -252 ° C (dec.).

Calculated; C, 52.06; H, 2.83; K, 10.71.

Found: C, 51.98; H, 2.89; N, 10.85.

Example 15 6,7-dichloro-3,4-dihydro-N- (methylsulfonyl) -3-oxo-2-cruinoxaline carboxamide; 32% yield; mp > 355 ° C.

Calculated: C, 35.73; H, 2.10; N, 12.50. * Found; C, 35.74; E, 2.02; SJ, 12.27. - 41

Example 16 6,7-dichloro-3,4 " -hydroxy "3-oxo-2-cyanooxalyl-carboxamide; 44% yield; m.p. 30 ° C.

Calculated: C, 39.44; XI, 1.84; 33, 15.33.

Found: C, 39.22; H, 1.59; 8, 14.95.

Example 17 N- (Butylsulfonyl) -G, 7-dieloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide; mp > 295 ° C.

Calculated: C, 41.28; H, 3.45; N, 11.11.

Found: C, 41.22; H, 3.22; 8, 11.22 *

Example 18 6,7-dichloro-3,4-dihydro-3? -Methyl-3'-oxo-2-quinaxaline-carboxamide; 95% yield; mp.> 308 ° C.

Calculated: C, 44.14; H, 2.59; N, 14.44.

Found; C, 43.83; Η, 2, δ7; N, 15.10.

Example 19 6,7-Aichloro-3,4-dihydro-N-methoxy-3-oxo-2-quinoxaline carbaxamide; 67% yield; m.p. 298-300 ° C.

Calculated: C, 41.69; H, 2.45; 8, 14.59.

Found: C, 41.66; H, 2.37; H, 14.22.

Example 20 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline carboxaride; 94% yield; mp > 320 ° C.

Calculated; C, 41.89; H, 1.95; 8, 16.28. . Found; C, 41.62; H, 1.63; 8, 16.06. - 42 -

Example 21 6,7-dichloro-3,4-dihydro-3-oxo-N- (phenylmethyl) -2-quinoxalinecarboxamide, 86% yield; Found: C, 54.97; H, 3.18; N, 11.96. Found: C, 54.97;

Example 22

1 - [(6,7-dichloro-3,4-dihydro-3-oxa-2-quinoxynyl) carbonyl] -4- (phenylmethyl-piperazine monohydrochloride, 296 ° C (dec.).

Calc'd C, 52.94; H, 4.22; N, 12.35 *

Found: C, 52.59; H, 4.40; IS, 12.45.

Example 23

[[(6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) " carbonylamino-acetic acid, 1,1-dimethyl ester; 74% yield; P. f. > 300 ° C.

Calc'd (with 0.25 H2 O): C, 47.83; E, 4.15; N, 11.16; Cl, 18.82.

Found: C, 47.65; H, 4.05; Έ, 11.18; Cl, 18.04,

Example 24 N- (6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl] glycine; 98% yield? p. 285-306 ° C (dec.).

Calc'd C, 41.80; E, 2.23? IS, 13.29.

Found; C, 41.52; E, 2.04; IS, 13.14.

Example 25

[[6,7-Dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl] amino] acetic acid; 62% yield? p. 248-268 ° C (dec.). Calc'd C, 39.78; H, 2.12; N, 12.65. ] Found: C, 39.71; H, 2.17; N, 13.09. - 43

Example 26 6,7-dichloro-3,4-dihydro-N - [(4-methylphenyl) sulfonyl] -3-oxo-2-quinoxalylcarboxamide; 43% yield, m.p. 320 ° C.

Calc'd C, 46.62; H, 2.69; N, 10.19; Cl, 17.20; S, 7.78

Found: C, 46.47; H, 2.61; N, 10.08; Cl, 17.33; S, 7.66.

Example 27 6,7-dichloro-3,4-dihydro-N - [(2-chloro-5-nitrophenyl) sulfonyl] -3-oxo-2-quinoxaline-carboxamide; 81% yield; mp 340 ° C.

Calculated; C, 37.72; H, 1.48; B, 11.73; Cl, 22.27; S, 6.71.

Found: C, 38.10; H, 1.52; H, 11.66; Cl, 22.01; S, 7.01.

Example 28 6,7-dichloro-N - [(4-chloro-2-nitrophenyl) sulfonyl] -3,4-dihydro-3-oxo-2-quinoxaline-carboxamide; 93% yield; mp 330 ° C.

Calc'd C, 37.72; H, 1.48; N, 11.73; Cl, 22.27; S, 6.71.

Found: C, 37.61; H, 1.28; N, 11.53; Cl, 22.27; S, 7.19.

Preparation 1 3,4-Dihydro-3-oxo-2-quinoxalinecarboxylic acid

3-Hydroxy-2-quinoxalinecarboxylic acid (10.0 g, 52.6 mmol) was dissolved in concentrated N2 SO4 (150 mL) and cooled in an ice bath. Potassium nitrate powder (16.0 g, 178 mmol) was added portionwise with stirring and the reaction was allowed to warm overnight. In the morning the reaction was poured into 600 g of ice and after the ice melted the precipitate was filtered off. The solid was dissolved in boiling water (1600 ml), filtered hot and then cooled and the precipitate filtered to provide (7.5 g, 64%) of the title compound. Recrystallization from ethanol / water provided 3,4-dihydro-7-nitro-3-oxo-2-quinoxaline-carbo-

as a yellow solid.

Elemental analysis calculated for 2 moles of H2 O: C, 39.89; H, 3.34; N, 15.51.

Found: C, 39.89; H, 3.37; N, 15.30.

Preparations 2 and 3 are analogous to U.S. Patent 4,266,400 beginning with the corresponding appropriate starting materials.

Preparation 2 Ethyl 6-nitro-3,4-dihydro-3-oxo-quinoxaline-2-carboxylate 52% yield; p. 229 ° C.

Calc'd C, 50.16; H, 3.48; N, 15.78.

Found: C, 50.20; H, 3.45; N, 15.96.

Preparation 3

6-Nitro-4-dihydro-3-oxo-quinoxaline-2-carboxylic acid; 75% yield; mp 270 ° C.

Calc'd C, 45.97; H, 2.14; N, 17.87.

Found: C, 45.82; H, 2.10; N, 17.75.

Example 29 6,7-dichloro-3,4-dihydro-N- (2-thionylsulfonyl) -3-oxo-2-quinoxalinecarboxamide; 22% yield; mp 320 ° C.

Calc'd C, 38.63; H, 1.25; N, 10.39; Cl, 17.54.

Found: C, 38.75; H, 1.58; N, 10.29; Cl, 1771.

Example 30 6,7-dichloro-3,4-dihydro-N- (4-methoxyphenyl) sulfonyl] -3-oxo-2-quinoxaline-carboxamide; 45% yield; p. 313 ° C. Calculated: C, 44.37; H, 2.59; N, 9.81; Cl, 16.56; S, 7.49. . Found: C, 44.75; H, 2.65; N, 9.74; Cl, 16.46; S, 7.72. - 45 -

Example 31

6.7-aza-3,4-dihydro-N- (4-bromophenyl) sulfonyl] -3-ozo-2-Cι-noxalinecarboxamide; 25% yield; m.p. 330Â ° C

Calc'd C, 37.76; E, 1.69; E, 8.81; Cl, 14.86; Br, 16.75. Found: C, 38.93; E, 1.90; E, 8.42; Cl, 14.76; N, 17.03.

Example 32

6,7-dichloro-3,4-dihydro-2H- (2-methylphenyl) sulfonyl] -3-oxo-2-oxo-noxalinecarboxamide; 21% yield; mp 322 ° C.

Calc'd C, 46.62; E, 2.69; 11, 10.19; Cl, 17.20; S, 7.78. Found: C, 46.66; E, 2.63; N, 10.12; Cl, 17.28; S, 7.72.

Example 33 6,7-dichloro-3,4-dihydro-E - [(4-chlorophenyl) sulfonyl] -3-oxo-2-quinolinecarboxamide; 12% yield; Federal Police. 335 ° C.

Calculated: C, 41.64; H, 1.86; H, 9.71. Found: C, 41.41; H, 1.96; N, 9.62,

Example 34 6,7-dichloro-3,4-dihydro-3-oxo-1H- [5- (2-pyridinyl) -2-thienyl] sulfonyl-2-quinoxaline-carboxamide; 52% yield; m.p. 325Â ° C.

Calc'd C, 44.92; H, 2.09; B, 11.64.

Found: C, 45.49; H, 2.03; N, 11.21.

Example 35 6,7 "dichloro-3,4-dihydro-3-oxo-N - [[3- (trifluoromethyl) -phenyl] sulfonyl] -2-quinoxaline-carboxamide; 25% yield; mp 31-31 ° C. «··

Calculated: C, 41.22; H, 1.73; B, 9.01; Cl, 15.21; F, 12.22 S, 6.89. - 46

Cl, 15.55; F, 18.82;

Found: C, 41.10; H, 1.43; N, 9.12; S, 6.55.

Example 36 6,7-dichloro-3,4-dihydro-3-oxo-N- (4-fluorophenyl) sulfonyl] -2-quinoxaline-carboxamide; 33% yield? m.p. 313-315 ° C.

Calculated: C, 43.29; H, 1.94; H, 10.10; Cl, 17.04; F, 4.56; S, 7.70, Found: C, 43.07; H, 2.01; N, 3/97. Cl, 17.02; F, 7.40; S, 7.70.

Example 37 6,7-dichloro-N - [(2,3-dihydro- (H-inden-5-yl) sulfonyl] -3,4-dihydro-3-oxo-2-quinoxaline- carboxamide, 22% yield, mp 320-322 ° C.

Calculated: C, 49.33; H, 2.99; N, 9.59; Cl, 16.18; S, 7.32. Found: C, 49.46; H, 2.94; N, 9.68; Cl, 16.95; S, 7.31.

Example 38 6,7-dichloro-3,4-dihydro-N-1 (3-chlorophenyl) sulfonyl] -3-oxo-2-quinolinecarboxamide; 64% yield? mp 320 ° C.

Calculated: C, 41.64; H, 1.86; N, 9.71; Cl, 24.58; S, 7.41. Found: C, 41.58; H, 1.87; N, 9.60; Cl, 24.90; S, 6.99.

Example 39 6,7-dichloro-3,4-dihydro-N - [(2-chlorophenyl) sulfonyl] -3-oxo-2-quinoxaline-carboxamide; 22% yield? P. f. 317-318 ° C. Calculated: C, 41.64; H, 1.86; H, 9.71; Cl, 24.58; s, 7.41. Found: C, 41.63; H, 1.17; N, 9.82; Cl, 24.29; s, 7.91.

Example 40

H, 2.47; N, 9.37; H, 2.11; N, 9.39 Cl, 15.82; S, 7.15. Cl, 15.86; S, 7.10.

Calc'd C, 50.91; Found; C, 51.03;

Example 41 6,7-dichloro-3,4-dihydro-3-oxo-H - [(3-nitrophenyl) sulfonyl] -2-quinoxaline carboxamide; 55% yield; mp 325-327 ° C.

Calculated: C, 40.65; H, 1.82; N, 12.64; Cl, 16.00; S, 7.23. Found: C, 40.42; H, 1.46; N, 12.55; Cl, 16.04; S, 7.56.

Example 42 6,7-dichloro-3,4-dihydro-3-oxo-N- (4-nitrophenyl) sulfonyl] -2-quinoxalinecarboxamide; 55% yield; m.p. 316-319 ° C.

Calculated; C, 40.65; H, 1.82; N, 12.64; Cl, 16.00; S, 7.23. Found: C, 40.55; H, 1.66; N, 12.58; Cl, 16.40; S, 7.10.

Example 43 6,7-dichloro-3,4-dihydro-3-oxo-N - [(2-nitrophenyl) sulfonyl] -2-quinoxaline-carboxamide; 77% yield; m.p. 313-317 ° C.

Calc'd C, 40.65; H, 1.82; 3, 12.64; Cl, 16.00; S, 7.23 Found: C, 40.74; H, 1.85; N, 12.40; Cl, 16.64; S, 6.81.

Example 44 6,7-Dichloro-3,4-dihydro-3-oxo-N - [(2,4,6-tris (1-methylethyl) ethyl] sulfonyl] -2- quinoline: hexane-carboxamide, 12% yield, mp 289 ° C.

Calculated: C, 54.96; H, 5.19; H, 8.01; Cl, 13.52; S, 6.11. Found: C, 54.71; α, 5.04; N, 8.00; Cl, 13.21; S, 5.99.

Example 45 O-7-dichloro-3,4-dihydro-3-oxo-M - [(2-fluorophenyl) sulfonyl) -2-eminoxaline carhoxamide; 30% yield; Federal Police. 312-314 ° C. - 43 -

Calculated: C, s, 43.29; 7.70. H, 1.94; N, 10.10; Cl, 17.04; 4.56 Found: C, H, O, 43.09; 7; 53. n, 1.63; IS, 10.04; Cl, 17.38; F, 4.90

Example 46 6,7-dichloro-3,4-dihydro-3-oxo-N - [(pentamethylphenyl) sulfonyl] -2-quinoxaline carboxamide; 36% yield; m.p. 270Â ° C.

Calculated: C, 51.29; H, 4.09; K, 8.97; S, 6.85.

Found: C, 51.11; H, 3.81; N, 8.94; S, 6.95.

Example 47 Nt (1,2 > benzisoxazol-3-ylmethyl) sulfonyl] -6,7-dichloro-3,4-dihydro-3,4-dihydro-3-oxa-2-quinoxaline carboxamide ; 56% yield; mp. 233-285 ° C. Calculated: C, 45.05; H, 2.22; N, 12.36; Cl, 15.54; Found: C, 44.77; H, 2.25; K, 12.27; Cl, 16.04; S, 6.92.

The following pre-preparations of the compounds are within the procedures set forth in the Sorte America-ca n & 426,400.

Preparation 4 Ethyl 3,4-dihydro-3-oxo-2-quinoxaline carboxylate-6,7-dimethyl.

Preparation 5 6,7-Dimethyl 3,4-dihydro-3-oxo-2-quinoxalinecarboxylate; 97% yield; P. f. 304-308Â ° C.

Analysis for 2 moles of B20:

Calculated: C, 59.22; E, 76; N, 12.56. Found: C, 59.22; H, 4.41; N, 12.62. • 3 - 49 -

Preparation 6 Ethyl 3,4'-dihydro-3-oxo-benzo (q) -quinoxaline-2-carboxylate; 79% yield? mp 205 ° C.

Calculated: C, 67.16; H, 4.51; N, 10.44.

Found: C, 67.35; H, 4.51; N, 10.68.

Preparation 7 Ethyl 5,8-dibrorcc-3,4-dihydro-3-osro-quinoxaline-2-carboxylate 89% yield? mp 205 ° C.

Calculated: C, 35.14; H, 2.14; N, 7.45.

Found: C, 35.05; H, 1.94; N, 6.99.

Preparation 8

5,8-Dibromo-3,4 " dihydro-3β, O-quinoxaline-2-carboxylic acid; 74% yield? mp 280-283 ° C.

Calculated: C, 31.07; H, 1.16; H, 8.05; Br, 45.93.

Found: C, 30.97; H, 1.15; 8.10; Br, 48.30.

Preparation 9 Ethyl 6,7-dibromo-3,4-dihydro-3-oxo-quinoline-2-carboxylate 78% yield? mp 238 ° C.

Calculated: C, 35.14; H, 2.14; H, 7.45; Br, 42.50.

Found: C, 35.22; E, 2.09; 6.92; Br, 42.76.

Preparation 10 6,7-Dibromo-3,4-dihydro-3-o-O-quinoxaline-2-carboxylic acid 82% yield? mp 300 ° C.

Calculated: C, 31.07; H, 1.16; N, 8.05. . Found: C, 31.18; H, 1.32; H, 8.32. - 50 -

Preparation 11 Ethyl 6,7-dinitro-3-dihydro-3-oxo-quinoxaline-2-carboxylate 36% yield? mp 220 ° C.

Calculated: C, 42.87; H, 2.62; N, 18.18. Found: C, 42.54; H, 2.52; N, 17.78.

Preparing the

Q

3 - [(2,4-dichloro-6-nitrophenyl) amino] -3-oxo-propanoate

A solution of 4,6-dichloro-2-nitroaniline (310.0 g, 0.15 mol) and chloro malonate (25.0 g, 0.17 mol) in toluene (500 ml) was heated to The reaction mixture was cooled and concentrated. The residue was dissolved in hot ethanol, decoloured with charcoal and filtered. Sodium, which had formed by cooling, was collected by suction filtration and dried to afford the title compound as a yellow solid (13.6 g, 28%).

Preparation 2

3 - [(2,4-dibasio-6-nitrophenyl) amino] -3- [5-chloropropanoate. A solution of 4, S-dibromo-2-nitroaniline (44.3 g, 0.15 mol) and chloroethyl malonate were heated at reflux

In a manner similar to that described in Preparation 3a, the product of Preparation 2a (30.0 g) was converted to the title compound as a yellow solid (13.3 g, 46%).

Preparation 5a

Ethyl 5,7-dichloro-3,4-dihydro-3-oss-o-2-phyloxaline carboxylate

A solution of the product of preparation 3a (5.00 g, 17.3 mmol) and phosphorus trichloride (30 ml) in tetrahydrofuran (200 ml) was refluxed for 24 hours. The reaction was cooled and poured onto ice. The resulting suspension was extracted with CH2 Cl2. The organic phase was washed with water, dried (Na2SO4) and concentrated. The residue was suspended in EtOH, collected by suction filtration and dried to afford the title compound as a yellow solid (1.77 g, 34%).

Preparation 6a

Ethyl 5,7-dibromo-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate

In a manner similar to that described in preparation 5a, the product of Preparation 4a (813.4 g, 34.2 53 -

mmoles) in the title compound as a yellow solid (3.64 g, 28%).

Preparation 7a

5,7-Achoro-3,4-dihydro-3-oxo-2-quinaxaline-carboxylic acid

A solution of the product of Preparation 5a (2.14 g, 8.26 mmol) and potassium hydroxyde (2.08 g, 37.1 mmol) in 3: 1 water / iPrOH (100 ml). The reaction mixture was cooled to room temperature and acidified to pH 1 with concentrated HCl. The solid which formed was collected by suction filtration and dried to afford the title compound as a yellow solid (1.89 g, 37%), m.p. 196-198Â ° C.

Elemental analysis calculated for CHHHllClN₂O: C, 41.73; H, 1.56; N, 10.81. Found; C, 41.43; H, 1.33; ιί, 10.77.

Preparation 8a

5,7-Dibromo-3,4-dihydro-3-oxo-2-quinoxalyl carboxylic acid

In a manner similar to that described in preparation 7a, the product of preparation 6a (2.41 g, 6.41 mmol) was converted to the title compound as a yellow solid (2.41 g, 34%), mp 202-206 ° C. - 54 9

Elemental analysis calculated for C 31.07; H, 1.06; N, 8.05. Found: C, 31.26; H, 1.01; N, 8.20.

Preparation 9a

Cl | HCl. Compound No. 5,7-Dichloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-quinolylcarboxamide

In a manner similar to that described in Preparation 10a, the product of Preparation 7a (0.50 g, 1.93 mmol) was converted to the title compound as a yellow solid (0.55 g, 71%), mp 286-290 E.

Calc'd for C 19 H 13 F 3 N 3 O 4 S: C, 45.24; H, 2.28; N, 10.55; S, 8.05.

Found: C, 44.90; H, 2.16; N, 10.31; B, 7.74.

Preparation 10a

5,7-dibromo-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-quinoxalinecarboxamide

A solution of the preparation product 8a (0.50 g, 1.44 mmol) in DMF (12 ml) was treated with carbonyl-di imide-zol (0.70 g) and the resulting solution was heated at 60 ° C for 4 hours. At the same time a suspension of benzenesulfonamide (0.67 g, 4.26 mmol) and NaH (0.17 g, 4.57 mmol)

in DMF (10 ml) for 4 hours at room temperature. The two reaction mixtures were combined and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into ice and 1N HCl. The solids collected were collected by suction filtration, washed with water and dried under vacuum (P2 O5) to provide the title compound as a yellow solid (0.44 g, 63%), mp = f. 290-293 ° C.

Calc'd for C 15 H 19 Br 2 N 3 O 4 S: C, 36.98; H, 1.71; N, 8.43; S, 6.58.

Found; C, 36.80; H, 1.71; N, 8.43; S, 6.57.

Preparation 11a

O

3 - [(3,5-dichloro-2-nithoxyphenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation was converted 3,5-dichloro-2-nitroaniline (47.5 g, 0.229 mmol) into the title compound as a yellow solid (51.7 g, 70%).

Preparation 12a A → C02Et

Cl Cl

N

Cl

Y 2 N02 Ethyl 3 - ((2,3-dichloro-6-nitrophenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation there was converted 5,6-dichloro-2-nitroaniline with the title compound

3 - [(3 * 4-dichloro-2-nitrophenyl) amino] " -3-oxopropanoate

A similar form as described in the preparation was converted to 3,4-dichloro-2-nitroaniline in the title compound

Preparation 14a

3 - [(5-chloro-2-nitrophenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation, 5-chloro-2-nitroaniline (26.0 g, 0.15 mmol) was converted to the title compound as a yellow solid (34.5 g, 80%).

Preparation 15a 0

Ethyl 3 - [(4-chloro-2-nitrophenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation, 4-chloro-2-nitroaniline (26.0 g, 0.15 mmol) was converted. in the title compound as a yellow solid (33.8 g, 78%). - 57 -

Ethyl 3 - [(4,5-difluoro-2-nitrophenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation, 4,5-difluoro-2-nitroaniline (20.0 g, 0.115 mmol) was converted to the title compound as a yellow solid.

Preparation 17a

3 - [(4-fluoro-2-nitrophenyl) amino] -3-oxopropanoate

In a manner similar to that described in the preparation, 4-fluoro-2-nitroaniline (21.6 g, 0.138 mmol) was converted to the title compound as a yellow solid (19.4 g, 52%).

Preparation 18a

Ethyl 3- [2-nitro-4- (trifluoromethyl) phenyl] amino] -3-oxopropanoate

In a manner similar to that described in the preparation was converted 4-amino-3-nitrobenzenetrifluoride (31.1 g;

0.151 mol) in the title compound as a yellow solid (31.9 g, 66%).

Preparation 19a

3 - [(3,5-dichloro-2-nitrophenyl) amino] -2- (hydroxyimino) -3-axopropanoate

A solution of the preparation product 11a (7.00 g, 23.9 mmol) in 4: 2: 1 ACQH / THF / E20 (210 ml) was treated with NaOH (1.81 g, 26.3 mmol) in one portion, and It was stirred at room temperature for 4 hours. Additional NaNO 2 (1.81 g, 26.3 mmol) was added and stirring was continued overnight. The reaction was extracted into CH 2 Cl 2, dried (MgSO 4), filtered and concentrated to provide the title compound as a yellow solid (4.33 g, 76%).

Preparation 20a

3 - [(2,3-dichloro-2-nitrophenyl) amino] -2- (hydroxyimino) -3-oxopropanoate

In a manner similar to that described in preparation 9a the product of example 12a was converted into the title compound. Preparation 21a - 59

Ethyl 3 - [(3,4-dichloro-2-nitrophenyl) amino] -2- (hydroxyimino) -3-oxopropanoate In a similar manner to that described in Preparation 19a, the product of Preparation 13a was converted into compound in the title.

Preparation 22a 0 o

3 - [(5-chloro-2-nitrophenyl) amino] -2- (hydroxyimino) -3-oxopropanoate

In a manner similar to that described in Preparation 19a, the product of Preparation 14a (10.0 g, 36.7 mmol) was converted to the title compound as a yellow solid (9.24 g, 80%).

Preparation 23a

60

i

Ethyl 2- [hydroxyimino] -3 - [[2-nitro-4- (trifluoromethyl) phenyl] aminol-3-oxopropanoate

In a similar manner to that described in Preparation 19a, the product of Preparation 18a (10.0 g, 31.2 mmol) was converted to the title compound as a yellow solid (9.49 g, 87%).

Preparation 27a

H

Ethyl 6,8-dichloro-1,2,3,4-tetrahydro-3-oxo-2-quinoxalinecarboxylate

A solution of the product from preparation 19a (80.00 g, 22.8 mmol) in THF (200 ml) was hydrogenated over NiRa (1.00 g) for 3 hours. The reaction was filtered and concentrated, and the residue was dissolved in dioxane (300 ml) and treated with TiClâ,, (53 ml of a 1.33â in solution in water). The resulting purple solution was stirred at room temperature until color disappeared. The reaction mixture was cooled with saturated CH 2 Cl 2 solution. The resulting suspension was extracted with 1: 1 EtOAc / THF and concentrated. The residue was quenched with EtOH and collected to give the title compound. as a brown solid (3.50 g, 53%) m.p. 244-250 ° C. - 62 -

Elemental analysis calculated for C 11 H 11 Cl 2 N 2 O 3! C, 45.70; H, 3.49; Eph, 9.69. Found: C, 45.67; H, 3.20; N, 9.53.

Preparation 28a

Ethyl 5,6-dichloro-1,2,3,4-tetrahydro-3-oxa-2-cruinoxaline carboxylate

In a similar manner as described in Preparation 27a, the product of Preparation 20a was converted into the title compound.

Preparation 29a 0

Ethyl 7,8-dichloro-1,2,3,4-tetrahydro-3-oxo-2-methoxyoxymethyl carbosylate

In a manner similar to that described in preparation 27a the product of preparation 20a was converted into the title compound.

Preparation 30a:

6-chloro-1,2,3,4-tetrahydro-3-oxo-2-quinoxaline carboxylate.

In a manner similar to that described in preparation 27a, the product of preparation 22a was converted into the title compound.

Preparation 31a 0

Ethyl 7-chloro-1,2,3,4-tetrahydro-3-oxo-2-guanine: allyl carboxylate.

In a manner similar to that described in preparation 27a the product from preparation 23a (8.00 g, 25.3 mmol) was converted to the title compound as a yellow solid (2.11 g, 33%); mp 196-198 ° e.

Elemental analysis calculated for C 11 H 11 ClN 2 O 3: c, 51.88; H, 4.35; 25, 11.00; Cl Found: C, 52.05; H, 3.76; N, 10.81; Cl, 13.92. 14.24.

Preparation 32a - 64 -

6,7-difluoro-1,2,3,4-tetrahydro-3-oxo-2-quinoxalinecarboxylate

In a similar manner to that described in preparation 27a, the product from preparation 24a was converted to the title compound.

Preparation 33a

Ethyl 7-fluoro-1,2,3,4-tetrahydro-3-oxo-2-quinoxaline carboxylate

In a manner similar to that described in preparation 27a, the product of preparation 25a was converted into the title compound.

Preparation 34a 0

65

1,2,3,4-tetrahydro-3-oxo-7- (trifluoromethyl) -2-quinoxalinecarboxylate

In a manner similar to that described in preparation 27a, the preparation product 26a (8.00 g, 22.9 mmol) was converted into the title compound as a yellow solid (3.39g, 52%); m.p. 178-180 ° C.

Elemental analysis calculated for C 12 H 13 F 3 N 2 O 3: C, 50.01; H, 3.85; N, 9.72. Found; C, 50.29; H, 3.52; N, 9.35.

Preparation 35a

6,8-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate

A solution of the product from preparation 27a (1.00 g, 3.46 mmol) in THF (150 mL) was treated with bromine (3.5 mL of a 1M solution in CH 2 Cl 2). The reaction mixture was stirred for 30 minutes and concentrated to provide the title compound as a yellow solid (0.98 g, 98%).

Preparation 36a

H

. Ethyl-5'-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate

In a similar manner to that described in Preparation 39a, the product of Preparation 28a was converted to the title compound.

Preparation 37a

Ethyl 7,8-dichloro-3,4-dihydro-3-oxo-2-quinoxaline carboxylate

In a manner similar to that described in preparation 39a, the product of preparation 29a was converted into the title compound.

Preparation 38a

Ethyl 6-chloro-3,4-dihydro-3-oxo-2-chiraloxalino-carboxylate

In a manner similar to that described in Preparation 39a the product of Preparation 39a was converted to the title compound.

Preparation 39a

C02Et Μ

Ethyl 7-chloro-3,4-dihydro-3-oxo-2-cfuinoxalinecarboxylate

A solution of the product of preparation 31a (0.50 g, 1.90 mmol) in dioxane (15 mL) was treated with DDQ (0.47 g, 2.06 mmol). The reaction was stirred at room temperature for 15 minutes and filtered. The filtrate was concentrated and crystallized from hot EtOH. The solid, which formed by cooling, was collected by suction filtration to provide the title compound as a yellow solid (0.43 g - 87%).

Preparation 40a

Ethyl 6,7-difluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate

In a manner similar to that described in preparation 39a, the product from preparation 32a was converted into the title compound.

Preparation 41a

Ethyl 7-fluoro-3,4-dihydro-3-oxo-2-cfuinoxalinecarboxylate

In a manner similar to that described in preparation 39a, the product of preparation 33a was converted to the title compound. title. - 68 -

Preparation 42a

Ethyl 3,4-dihydro-3-oxo-7- (trifluoromethyl) -2-quinoxaline carboxylate

In a manner similar to that described in example 39a, the product from preparation 34a (0.50 g, 1.73 mmol) was converted to the title compound as a brown solid (0.32 g; 65%).

6,8-Dichloro-3,4-dihydro-3-oxo-2-quinoxaline-carboxylic acid

In a manner similar to that described in preparation 7a, the product of preparation 35a was converted into the title compound.

5,6-Chloro-3,4-dihydro-3-oxo-2-aminoquinoline-1-carboxylic acid

In a manner similar to that described in preparation 7a, the product of preparation 36a was converted to compound 69

title.

Preparation 45a

7,8-Dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid

In a similar manner as described in preparation 7a, the product of Preparation 37a was converted into the title compound.

Preparation 46a

6-Chloro-3,4-dihydro-3-oxo-2-quinolinecarboxylic acid

In a manner similar to that described in Preparation 7a, the product of Preparation 38a was converted to the title compound.

Preparation 47a

7-Chloro-3,4-dihydro-3-oxo-2-CToxynyloxycarbonyloxy-

In a similar manner to that described in Preparation 7a, the product of Preparation 42a was converted into the title compound.

Example 48

6,8-dichloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-cruinoxaline carhoxamide

In a manner similar to that described in Preparation 10a, the product of Preparation 10a was converted to the previous compound.

Example 49

5,6-dichloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-oxynaline carboxamide

In a similar manner to that described in Preparation 10a, the product of Preparation 44a was converted to the previous compound.

Example 50

7,8-dichloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-guinoxaline-carboxamide

From a stream similar to that described in Preparation 10a, the product of Preparation 45a was converted into the title compound.

Example 51 6-chloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-quinoxaline-carboxamide hydrochloride

In a manner similar to that described in preparation 10a, the product of preparation 46a was converted into the title compound

Example 52

7-chloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-quinoxaline-carboxamide

In a manner similar to that described in Preparation 10a, the product of Preparation 47a was converted into the title compound.

Example 53 - 73

In a manner similar to that described in Preparation 10a, the product of Preparation 50a was converted into the title compound.

Biological assays

Specifically the compounds of this invention possess activity as antagonists at the non-sensitive ES-triquinine glycine receptors that are located in the NMDA receptor complex. As such, the compounds of the present invention are NMDA receptor antagonists. Thus the compounds of the present invention possess α and β receptor antagonist activity.

For example, the compounds of this invention exhibit important biological properties as these properties antagonize the exciting amino acids. The glycine binding assay is performed as described by W. Frost WHite, et al, Journal of Neurochemistry, 1989, 53 (2) -503-12.

Selected compounds having formula I of the present invention were tested in the glycine binding assay and provided the following data expressed as percent inhibition at the expressed dose as the molar concentration.

TABLE I

Example No. Cone. molar% of Inhibition 1 1.00E-4 89 2 5.Q0E-5 23 3 1-GQE-4 38 4 1.00E-4 71 6 1.00E-4 55 9 1.OQE-4 73 - 75 -

Example No. 10 11 12 13 14 16 17 18 19 21 22 23 24 25 26 27 28 29 31 32 33 34 35 36 37 38 40 41 42 43 44 45 46 TABLE I (continued from previous page)

Cone. 1.0E-4 1.00E-4 1.00E-4 5.00E-5 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1 1.00E-4 1.00E-4 1.00E-4 1.00E-4 5.00E-5 1.00E-4 1.G0E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 1.00E-4 5.00E- 4 5.00E-4 1.00E-4 5.0GE-5 1.00E-4 1.00E-4 1.00E-4 Ι, ΟΟΕ-4 5.0GE-5 5.00E-4

% Inhibition 40 85 53 55 64 91 92 18 94 29 25 36 68 90 75 42 72 88 100 76 76 81 83 100 100 83 90 34 86 36 82 100 100 76

In addition, the selective intermediates of the present invention also provide inhibition in the glycine binding assay as follows.

TABLE II

Preparation NQ Cone. molar% inhibition 1 1.11E-4 30 2 1.00E-4 6 3 1.008-4 97 5 1.00E-4 88 6 1.00B-4 10 7 1.00E-4 13 8 1.00E-4 0 9 1.00E-4 The AMPA binding assay may also be performed to provide an activity profile for the compounds of the present invention. The kainate binding assay is performed as described by T * Honore et al, Neuroscience Letters 1986? 65: 47-52.

Thus, compounds of formula I and their pharmacologically acceptable acid addition salts are effective agents in the prophylaxis and / or therapeutic treatment of disorders responsive to NMDA receptor blocking agents thus forming a further aspect of the present invention.

- 77 -

Claims (1)

1. A process for the preparation of pharmaceutical compositions for the treatment of neurodegenerative diseases characterized in that the compounds of general formula I or a salt thereof by the addition of pharmaceutically acceptable acids or bases, wherein (1) Y is oxygen or sulfur; (2) the radicals R 1, R 2, R 1, L and R 12 is independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, nitro, methylthio, lower alkenyl, lower alkynyl, SO 2 NH 2, R 2 represents a hydrogen atom or a lower alkyl group, OCF 3, or two of the radicals R 2, R 2, R 2 and R 2 may be taken together to form a carbocyclic ring having 6 atoms or may be taken together to form a heterocyclic ring or a heteroaryl ring wherein the heteroatom is an oxygen, sulfur or azide atom, and wherein the carbon atom in the carbocyclic ring is optionally substituted by one of the substituents R R 2, R 1, or R 12 * (3) X is (a) NR 6 SO 2 R 3, (b) NRR with the proviso that one of the radicals R and R is different from the hydrogen atom and simultaneously one of the radicals R 1, R 2, R 11 and R 12 is different from the (c) NR6 OR3, (d) NR6 CONR3 R4 with the proviso that one of the radicals R3 and R4 is other than hydrogen, (e) NR6 COR5, (f) NR6 COO R3, (I) an amino acid residue selected from phenyl glycine, phenylalanine, alanine, leucine, isoleucine, proline, or valine, (j) lower alkyl esters of the above defined amino acid residue; wherein: i) the radicals R and R are independently 1) the hydrogen atom; 2) an alkyl group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms; 3) an alkenyl group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms; 4) an alkynyl group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms; 5) an aryl group selected from phenyl, indene, or naphthyl wherein the phenyl group is aa) unsubstituted or bb) substituted by one to five lower alkyl groups or by halogen atoms, (c) is substituted by one to three groups selected from xxi) trifluoromethyl, xxii) nitro, xxiii) amino, xxiv) mono- or di (lower alkyl) amino, xxv) hydroxy, xxvi) lower alkoxy, xxvii) carboxy, or (5) (xxviii) NHCQR wherein the radical R independently has the further defined meanings, wherein R representa is a lower alkyl group, and wherein R possui has independently the further defined meanings, (xxxi) CN, wherein the radicals R and R are independently defined as defined above, (a) and (c) R4 is independently defined as defined below, (xxxiv) -CR; 6) an aryl-lower alkyl group; 7) a lower aryl-alkenyl group; 8) a heterocycle group; 9) a heteroaryl group (10) (CEL) R wherein q is an integer from 1 to 4 and the radical R represents (A) a heterocycle group, (B) a heteroaryl group, Wherein the radical R represents a hydrogen atom or an lower alkyl group and the radical R independently has the above defined meanings, wherein the radical R 8 is as defined above, wherein the radical R is as previously defined, or R 9 is independently a hydrogen atom or an alkyl group or the radicals R 2 and R 3 taken together form a heteroaryl ring; or 11) an amino acid residue as defined above; ii) the radical R represents a hydrogen atom or a lower alkyl, lower alkenyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl or heteroaryl-lower alkyl group; iii) the radical represents a hydrogen atom or a lower alkyl group, preferably the hydrogen atom, in an amount in a unit dose of from 1 mg to 1000 mg. 2. A process as claimed in claim 1, wherein the radicals R 2 and R 2 are the hydrogen atom and the radicals R 2 and R 2 represents the chlorine atom. 3. A process as claimed in claim 1, wherein X is NR2 SO2 -R4. 4. A process as claimed in claim 1, wherein X is NR 1 R 2. A process according to claim 1, wherein X is NR ORR ORR ^. - 63 A process as claimed in claim 1, wherein X is NR3 CONR4 R4. A process according to claim 1, wherein X is NR3 COR5. Method according to claim 1, characterized in that X represents a group of the formula: A compound according to claim 1, wherein X is a group of the general formula NH2 CH3 R3. A process according to claim 1, wherein X is NH 3 COO 2 R 3. The process according to claim 4, wherein the active ingredient is 6 - [[6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl] carbonyl] A process as claimed in claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro- -N- (methylsulfonyl) -3-oxo-2-quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-3-oxo-N- (phenylsulfonyl) -2-quinoxaline carboxamido. A process according to claim 3, wherein the active ingredient is N- (butylsulfonyl) -6,7-dichloro-3,4-dihydro-3-oxo-2- quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-N - [(4-methylphenyl) sulfonyl] -3- oxo-quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-N - [(2-chloro-5-nitro-phenyl) sulfonyl] -3-oxo-quinoxalinecarboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-N - [(4-chloro-2-nitro-phenyl) sulfonyl} -3,4- dihydro-3-oxo-2-quinolinecarboxamide. The process of claim 3, wherein the active ingredient is 6,7-dichloro-3,4-hydro (2-thionylsulfonyl) -3-oxo-2-quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-NE (4-methoxy-phenyl) sulfonyl} -3- oxo-2-quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-3-oxo-N - {[5- (2-pyridinyl) -2-thienyl] sulfonyl} -2-quinoxalinecarboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-N - [(3-chloro-phenyl) sulfonyl} -3- oxo-2-quinoxaline carboxamide. A process according to claim 3, wherein the active ingredient is 6,7-dichloro-3,4-dihydro-3-oxo-N- [ (3-nitro-phenyl) sulfonyl] -2-quinoxaline-carboxamide. - 23e - A process according to claim 3, wherein the active ingredient is 6,8-dichloro-3,4-dihydro-N- (methylsulfonyl) -3-oxa-2-quinaxalin- carboxamide-243 A process according to claim 3, wherein the active ingredient is 6,8-dichloro-3,4-dihydro-3-oxo-6-phenylsulfonyl) -2-quinoxaline carboxamide. The applicant claims the priority of the United States patent application filed on December 20, 1990, under serial number 631,139, Lisbon, December 20, 1991 86